Редактирование: Публикации о генах и старении (freqs)

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==CD4==

{{medline-entry
|title=Identification of Key Genes and Potential New Biomarkers for Ovarian Aging: A Study Based on RNA-Sequencing Data.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33304387
|abstract=Ovarian aging leads to reproductive and endocrine dysfunction, causing the disorder of multiple organs in the body and even declined quality of offspring's health. However, few studies have investigated the changes in gene expression profile in the ovarian aging process. Here, we applied integrated bioinformatics to screen, identify, and validate the critical pathogenic genes involved in ovarian aging and uncover potential molecular mechanisms. The expression profiles of GSE84078 were downloaded from the Gene Expression Omnibus (GEO) database, which included the data from ovarian samples of 10 normal C57BL/6 mice, including old (21-22 months old, ovarian failure period) and young (5-6 months old, reproductive bloom period) ovaries. First, we filtered 931 differentially expressed genes (DEGs), including 876 upregulated and 55 downregulated genes through comparison between ovarian expression data from old and young mice. Functional enrichment analysis showed that biological functions of DEGs were primarily immune response regulation, cell-cell adhesion, and phagosome pathway. The most closely related genes among DEGs ([i]Tyrobp[/i], [i]Rac2[/i], [i]Cd14[/i], [i]Zap70[/i], [i]Lcp2[/i], [i]Itgb2[/i], [i]H2-Ab1[/i], and [i]Fcer1g[/i]) were identified by constructing a protein-protein interaction (PPI) network and consequently verified using mRNA and protein quantitative detection. Finally, the immune cell infiltration in the ovarian aging process was also evaluated by applying CIBERSORT, and a correlation analysis between hub genes and immune cell type was also performed. The results suggested that plasma cells and naïve [[CD4]]  T cells may participate in ovarian aging. The hub genes were positively correlated with memory B cells, plasma cells, M1 macrophages, Th17 cells, and immature dendritic cells. In conclusion, this study indicates that screening for DEGs and pathways in ovarian aging using bioinformatic analysis could provide potential clues for researchers to unveil the molecular mechanism underlying ovarian aging. These results could be of clinical significance and provide effective molecular targets for the treatment of ovarian aging.

|keywords=* GEO database
* bioinformatics
* biomarker
* immune cell infiltration
* ovarian aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701310
}}
{{medline-entry
|title=Distinct Age-Related Epigenetic Signatures in [[CD4]] and CD8 T Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33262764
|abstract=Healthy immune aging is in part determined by how well the sizes of naïve T cell compartments are being maintained with advancing age. Throughout adult life, replenishment largely derives from homeostatic proliferation of existing naïve and memory T cell populations. However, while the subpopulation composition of [[CD4]] T cells is relatively stable, the CD8 T cell compartment undergoes more drastic changes with loss of naïve CD8 T cells and accumulation of effector T cells, suggesting that [[CD4]] T cells are more resilient to resist age-associated changes. To determine the epigenetic basis for these differences in behaviors, we compared chromatin accessibility maps of [[CD4]] and CD8 T cell subsets from young and old individuals and related the results to the expressed transcriptome. The dominant age-associated signatures resembled hallmarks of differentiation, which were more pronounced for CD8 naïve and memory than the corresponding [[CD4]] T cell subsets, indicating that CD8 T cells are less able to keep cellular quiescence upon homeostatic proliferation. In parallel, CD8 T cells from old adults, irrespective of their differentiation state, displayed greater reduced accessibility to genes of basic cell biological function, including genes encoding ribosomal proteins. One possible mechanism is the reduced expression of the transcription factors YY1 and NRF1. Our data suggest that chromatin accessibility signatures can be identified that distinguish [[CD4]] and CD8 T cells from old adults and that may confer the higher resilience of [[CD4]] T cells to aging.

|keywords=* T-cell
* T-cell homeostasis
* aging
* chromatin accessibility
* epigenetics
* ribosomal proteins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686576
}}
{{medline-entry
|title=IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A Foxp3  Cells During Mucosal Infection and Is Dysregulated With Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33240286
|abstract=[[CD4]] Foxp3 T  maintain immune homeostasis, but distinct mechanisms underlying their functional heterogeneity during infections are driven by specific cytokine milieu. Here we show that MyD88 deletion in Foxp3  cells altered their function and resulted in increased fungal burden and immunopathology during oral [i]Candida albicans[/i] (CA) challenge. Excessive inflammation due to the absence of MyD88 in T  coincided with a reduction of the unique population of IL-17A expressing Foxp3  cells (T 17) and an increase in dysfunctional IFN-γ /Foxp3  cells (T IFN-γ) in infected mice. Failure of MyD88  T  to regulate effector [[CD4]]  T cell functions correlated with heightened levels of IFN-γ in [[CD4]]  T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa [i]in vivo[/i]. Mechanistically, IL-1β/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of T 17 cells. In the absence of IL-1 receptor signaling, T 17 cells were reduced, but IL-6-driven expansion of T IFN-γ cells was increased. This mechanism was physiologically relevant during [i]Candida[/i] infection in aged mice, as they exhibited IL-1 receptor/MyD88 defect in Foxp3  cells, loss of p-mTOR T 17 cells and reduced levels of IL-1β in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with T  dysfunction, aging was associated with increased [[CD4]]  T cell hyperactivation and heightened levels of IL-6 in mice and humans in oral mucosa [i]in vivo[/i]. Taken together, our data identify IL-1β/MyD88/T  axis as a new component that modulates inflammatory responses in oral mucosa. Also, dysregulation of this axis in an aging immune system may skew host defense towards an immunopathological response in mucosal compartments.

|keywords=* Candida
* Foxp3
* IL-1β
* Treg
* Treg17
* aging
* fungal infection
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677307
}}
{{medline-entry
|title=Thymus involution sets the clock of declined immunity and repair with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33248315
|abstract=Aging is generally characterized as a gradual increase in tissue damage, which is associated with senescence and chronic systemic inflammation and is evident in a variety of age-related diseases. The extent to which such tissue damage is a result of a gradual decline in immune regulation, which consequently compromises the capacity of the body to repair damages, has not been fully explored. Whereas [[CD4]] T lymphocytes play a critical role in the orchestration of immunity, thymus involution initiates gradual changes in the [[CD4]] T-cell landscape, which may significantly compromise tissue repair. In this review, we describe the lifespan accumulation of specific dysregulated [[CD4]] T-cell subsets and their coevolution with systemic inflammation in the process of declined immunity and tissue repair capacity with age. Then, we discuss the process of thymus involution-which appears to be most pronounced around puberty-as a possible driver of the aging T-cell landscape. Finally, we identify individualized T cell-based early diagnostic biomarkers and therapeutic strategies for age-related diseases.

|keywords=* Aging
* Chronic systemic inflammation
* Dysregulated CD4 T cells
* Immune-mediated repair
* Thymus
|full-text-url=https://sci-hub.do/10.1016/j.arr.2020.101231
}}
{{medline-entry
|title=Food insecurity and T-cell dysregulation in women living with HIV on antiretroviral therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33247896
|abstract=Food insecurity is associated with increased morbidity and mortality in people living with HIV on antiretroviral therapy, but its relationship with immune dysregulation, a hallmark of HIV infection and comorbidity, is unknown. In 241 women participating in the Women's Interagency HIV Study, peripheral blood mononuclear cells were characterized by flow cytometry to identify cell subsets, comprising surface markers of activation (%CD38+HLADR+), senescence (%CD57+CD28-), exhaustion (%PD-1+), and co-stimulation (%CD57- CD28+) on [[CD4]]+ and CD8+ T-cells. Mixed-effects linear regression models were used to assess the relationships of food insecurity with immune outcomes, accounting for repeated measures at up to three study visits and adjusting for sociodemographic and clinical factors. At the baseline study visit, 71% of participants identified as non-Hispanic Black, 75% were virally suppressed, and 43% experienced food insecurity. Food insecurity was associated with increased activation of [[CD4]]+ and CD8+ T-cells, increased senescence of CD8+ T-cells, and decreased co-stimulation of [[CD4]]+ and CD8+ T-cells (all p<0.05), adjusting for age, race/ethnicity, income, education, substance use, smoking, HIV viral load, and [[CD4]] cell count. In stratified analyses, the association of food insecurity with [[CD4]]+ T-cell activation was more pronounced in women with uncontrolled HIV (viral load >40 copies/mL and [[CD4]] <500 cells/mm 3), but remained statistically significant in those with controlled HIV. Food insecurity may contribute to the persistent immune activation and senescence in women living with HIV on antiretroviral therapy, independently of HIV control. Reducing food insecurity may be important for decreasing non-AIDS-related disease risk in this population.

|keywords=* HIV
* exhaustion
* food insecurity
* immune activation
* senescence
|full-text-url=https://sci-hub.do/10.1093/cid/ciaa1771
}}
{{medline-entry
|title=Rapamycin Eyedrops Increased [[CD4]] Foxp3  Cells and Prevented Goblet Cell Loss in the Aged Ocular Surface.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33255287
|abstract=Dry eye disease (DED), one of the most prevalent conditions among the elderly, is a chronic inflammatory disorder that disrupts tear film stability and causes ocular surface damage. Aged C57BL/6J mice spontaneously develop DED. Rapamycin is a potent immunosuppressant that prolongs the lifespan of several species. Here, we compared the effects of daily instillation of eyedrops containing rapamycin or empty micelles for three months on the aged mice. Tear cytokine/chemokine profile showed a pronounced increase in vascular endothelial cell growth factor-A (VEGF-A) and a trend towards decreased concentration of Interferon gamma (IFN)-γ in rapamycin-treated groups. A significant decrease in inflammatory markers in the lacrimal gland was also evident ([i]IFN-γ[/i], [i]IL-12[/i], [i]CIITA[/i] and [i]Ctss[/i]); this was accompanied by slightly diminished [i]Unc-51 Like Autophagy Activating Kinase 1[/i] ([i]ULK1[/i]) transcripts. In the lacrimal gland and draining lymph nodes, we also observed a significant increase in the [[CD4]]5 [[CD4]] Foxp3  cells in the rapamycin-treated mice. More importantly, rapamycin eyedrops increased conjunctival goblet cell density and area compared to the empty micelles. Taken together, evidence from these studies indicates that topical rapamycin has therapeutic efficacy for age-associated ocular surface inflammation and goblet cell loss and opens the venue for new investigations on its role in the aging process of the eye.

|keywords=* aging
* dry eye
* goblet cell
* inflammation
* lacrimal gland
* ocular surface
* rapamycin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727717
}}
{{medline-entry
|title=Antioxidants N-Acetylcysteine and Vitamin C Improve T Cell Commitment to Memory and Long-Term Maintenance of Immunological Memory in Old Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33228213
|abstract=Aging is characterized by reduced immune responses, a process known as immunosenescence. Shortly after their generation, antigen-experienced adaptive immune cells, such as CD8  and [[CD4]]  T cells, migrate into the bone marrow (BM), in which they can be maintained for long periods of time within survival niches. Interestingly, we recently observed how oxidative stress may negatively support the maintenance of immunological memory in the BM in old age. To assess whether the generation and maintenance of immunological memory could be improved by scavenging oxygen radicals, we vaccinated 18-months (old) and 3-weeks (young) mice with alum-OVA, in the presence/absence of antioxidants vitamin C (Vc) and/or N-acetylcysteine (NAC). To monitor the phenotype of the immune cell population, blood was withdrawn at several time-points, and BM and spleen were harvested 91 days after the first alum-OVA dose. Only in old mice, memory T cell commitment was boosted with some antioxidant treatments. In addition, oxidative stress and the expression of pro-inflammatory molecules decreased in old mice. Finally, changes in the phenotype of dendritic cells, important regulators of T cell activation, were additionally observed. Taken together, our data show that the generation and maintenance of memory T cells in old age may be improved by targeting oxidative stress.

|keywords=* NAC
* T cells
* aging
* antioxidants
* immunosenescence
* vaccination
* vitamin C
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699597
}}
{{medline-entry
|title=Evolution of comorbidities in people living with HIV between 2004 and 2014: cross-sectional analyses from ANRS CO3 Aquitaine cohort.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33198667
|abstract=The objective of the study was to describe the evolution of chronic non-AIDS related diseases and their risk factors, in patients living with HIV (PLHIV) in the French ANRS CO3 Aquitaine prospective cohort, observed both in 2004 and in 2014 in order to improve long-term healthcare management. The ANRS CO3 Aquitaine cohort prospectively collects epidemiological, clinical, biological and therapeutic data on PLHIV in the French Aquitaine region. Two cross sectional analyses were performed in 2004 and 2014, to investigate the patient characteristics, HIV RNA, [[CD4]] counts and prevalence of some common comorbidities and treatment. 2138 PLHIV (71% male, median age 52.2 years in 2014) were identified for inclusion in the study, including participants who were registered in the cohort with at least one hospital visit recorded in both 2004 and 2014. Significant increases in the prevalence of diagnosed chronic kidney disease (CKD), bone fractures, cardiovascular events (CVE), hypertension, diabetes and dyslipidaemia, as well as an increase in treatment or prevention for these conditions (statins, clopidogrel, aspirin) were observed. It was also reflected in the increase in the proportion of patients in the "high" or "very high" risk groups of the disease risk scores for CKD, CVE and bone fracture score. Between 2004 and 2014, the aging PLHIV population identified in the French ANRS CO3 Aquitaine prospective cohort experienced an overall higher prevalence of non-HIV related comorbidities, including CKD and CVD. Long-term healthcare management and long-term health outcomes could be improved for PLHIV by: careful HIV management according to current recommendations with optimal selection of antiretrovirals, and early management of comorbidities through recommended lifestyle improvements and preventative measures.

|keywords=* Aging
* Cardiovascular events
* Chronic kidney disease
* Comorbidities
* HIV
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670698
}}
{{medline-entry
|title=Impact of age on [[CD4]] recovery and viral suppression over time among adults living with HIV who initiated antiretroviral therapy in the African Cohort Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33183355
|abstract=With increased use of antiretroviral therapy (ART), HIV mortality rates are declining and people living with HIV (PLWH) are surviving longer. We characterized [[CD4]] recovery and viral suppression among adults aged < 50 and ≥ 50 years living with HIV who initiated ART in the African Cohort Study (AFRICOS). Beginning in January 2013, PLWH at twelve clinics in Kenya, Uganda, Tanzania and Nigeria underwent medical history review, [[CD4]] and viral load testing as part of the ongoing African Cohort Study (AFRICOS). ART-naïve PLWH who initiated ART within 30 days of enrollment and had at least one year of follow-up were included in these analyses. To compare ART response in participants < 50 years and ≥ 50 years old, changes in [[CD4]] count and viral load suppression after ART initiation were examined at different time points using linear and binomial regression with generalized estimating equations. Variables for time since ART initiation and the interaction between age group and time on ART were included in the model to evaluate longitudinal changes in [[CD4]] recovery and viral suppression by age. Between January 2013 and September 2019, 2918 PLHV were enrolled in the cohort. Of these, 443 were ART naïve and initiated on ART within 30 days of enrollment, with 90% (n = 399) aged < 50 years old at ART initiation. At ART initiation, participants aged 50 and older had a higher median [[CD4]] count compared to participants younger than 50 years of age although it did not reach statistical significance (306 cells/mm , IQR:130-547 vs. 277cells/mm , IQR: 132-437). In adjusted models examining [[CD4]] recovery and viral suppression there were no significant differences by age group over time. By the end of follow-up viral suppression was high among both groups of adults (96% of adults ≥ 50 years old and 92% of adults < 50 years old). This study found no difference in long-term [[CD4]] recovery or viral suppression by age at ART initiation. We found that particularly among younger adults participants had lower median [[CD4]] counts at ART initiation, suggesting the importance of identifying and putting this population on treatment earlier in the disease course.

|keywords=* Elders on antiretroviral drugs
* HIV and aging
* HIV treatment outcomes
* Sub-saharan Africa
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664082
}}
{{medline-entry
|title=hPMSCs protects against D-galactose-induced oxidative damage of [[CD4]]  T cells through activating Akt-mediated Nrf2 antioxidant signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33148324
|abstract=Mesenchymal stem cells (MSCs) were considered a regenerative therapeutic approach in both acute and chronic diseases. However, whether MSCs regulate the antioxidant metabolism of [[CD4]]  T cells and weaken immunosenescence remains unclear. Here, we reported the protective effects of hPMSCs in aging-related [[CD4]]  T cell senescence and identified the underlying mechanisms using a D-gal-induced mouse aging model. In vivo study, 40 male C57BL/6 mice (8 weeks) were randomly divided into four groups: control group, D-gal group, hPMSC group, and PBS group. In in vitro experiment, human naive [[CD4]]  T ([[CD4]][[CD4]]5RA) cells were prepared using a naive [[CD4]]  T cell isolation kit II and pretreated with the Akt inhibitor LY294002 and Nrf2 inhibitor ML385. Then, isolated naive [[CD4]]  T cell were co-cultured with hPMSCs for 72 h in the absence or presence of anti-CD3/CD28 Dynabeads and IL-2 as a mitogenic stimulus. Intracellular ROS changes were detected by flow cytometry. The activities of the antioxidant enzymes superoxide dismutase, glutathione peroxidase, and catalase were measured by colorimetric analysis. The senescent T cells were detected SA-β-gal stain. The expression of aging-related proteins was detected by Western blotting, RT-PCR, and confocal microscopy. We found that hPMSC treatment markedly decreased the ROS level, SA-β-gal-positive cells number, senescence-associated secretory phenotype (IL-6 and OPN) expression, and aging-related protein (P16 and P21) expression in senescent [[CD4]]  T cells. Furthermore, hPMSC treatment effectively upregulated Nrf2 nuclear translocation and the expression of downstream target genes (HO-1, CAT, GCLC, and NQO1) in senescent [[CD4]]  T cells. Moreover, in vitro studies revealed that hPMSCs attenuated [[CD4]]  T cell senescence by upregulating the Akt/GSK-3β/Fyn pathway to activate Nrf2 functions. Conversely, the antioxidant effects of hPMSCs were blocked by the Akt inhibitor LY294002 and Nrf2 inhibitor ML385 in senescent [[CD4]]  T cells. Our results indicate that hPMSCs attenuate D-gal-induced [[CD4]]  T cell senescence by activating Nrf2-mediated antioxidant defenses and that upregulation of Nrf2 by hPMSCs is regulated via the Akt/GSK-3β/Fyn pathway.

|keywords=* Aging
* CD4+ T cells
* Nrf2
* Oxidative stress
* Senescence-associated secretoryphenotype
* hPMSC
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641865
}}
{{medline-entry
|title=Substantial gap in primary care: older adults with HIV presenting late to care.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33129258
|abstract=Late diagnosis of human immunodeficiency virus (HIV) is associated with increased morbidity and mortality, and represents a serious public health concern. A retrospective medical record review was conducted on 188 patients with newly diagnosed HIV at a large academic center's HIV clinic from 1/2010 to 12/2019. Patient demographic data, HIV staging, and response to combination antiretroviral therapy (cART) as measured by HIV viral suppression at 12 weeks (HIV RNA < 50 copies) were collected. Bivariate analyses were applied to compare patients ≥50 years old to those < 50 years old. Over two-thirds of the older patients with a new diagnosis of HIV presented with a [[CD4]] count < 200, or an AIDS-defining illness. Though not statistically significant, this same group also had a delay to viral suppression with only 59% achieving viral suppression after 12-weeks of cART initiation. This study suggests that older patients are presenting to care with advanced stages of HIV, and may also have a delay in achieving viral suppression after cART initiation. Future studies should aim to target HIV testing and treatment strategies for this at-risk older adult group.

|keywords=* Aging population
* HIV
* Older adults
* Risk
* Stigma
* Testing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603686
}}
{{medline-entry
|title=Quantitative Digitography Measures Fine Motor Disturbances in Chronically Treated HIV Similar to Parkinson's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33132893
|abstract=: Motor and cognitive deficits were compared in aging, chronically treated human immunodeficiency virus (HIV) people, people with mild-to-moderate stage Parkinson's disease (PD), and healthy controls.  : Groups consisted of 36 people with PD, 28 with HIV infection, and 28 healthy controls. Motor function was assessed with the Unified Parkinson's Disease Rating Scale (MDS-UPDRS-III) and a rapid alternating finger tapping (RAFT) task on an engineered keyboard known as Quantitative Digitography (QDG). Executive function, verbal memory, and visuospatial processing were assessed using standard neuropsychological tests.  : HIV demonstrated RAFT deficits similar to PD such as reduced amplitude ([i]P[/i] = 0.023) and greater amplitude variability ([i]P[/i] = 0.019) in the index finger when compared to controls. This fine motor disturbance correlated with HIV's immune health, measured by their [[CD4]]  T cell count ([i]P[/i] < 0.01). The UPDRS did not yield motor differences between HIV and controls. Executive function and verbal memory were impaired in HIV ([i]P[/i] = 0.006, [i]P[/i] = 0.016, respectively), but not in PD; visuospatial processing was similarly impaired in HIV and PD ([i]P[/i] < 0.05) although motor deficits predominated in PD.  : Fine motor bradykinesia measured quantitatively by QDG RAFT holds promise as a marker of motor decline related to current immune health in aging HIV patients and may be useful in longitudinal studies regarding mechanisms of immunosenescence vs. potential toxicity of combination antiretroviral therapy (cART) in this population. Additionally, motor and cognitive networks in HIV may be affected differently as the disease progresses as observed in the differential patterns of impairment between HIV and PD, providing insight into the mechanisms of brain deterioration in HIV.

|keywords=* HIV—human immunodeficiency virus
* Parkinson’s disease
* aging
* fine motor activities
* motor control
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575770
}}
{{medline-entry
|title=Monocyte and T Cell Immune Phenotypic Profiles Associated With Age Advancement Differ Between People With HIV, Lifestyle-Comparable Controls and Blood Donors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33123168
|abstract=People with HIV on successful antiretroviral therapy show signs of premature aging and are reported to have higher rates of age-associated comorbidities. HIV-associated immune dysfunction and inflammation have been suggested to contribute to this age advancement and increased risk of comorbidities. Partial least squares regression (PLSR) was used to explore associations between biological age advancement and immunological changes in the T cell and monocyte compartment in people with HIV (n=40), comparable HIV-negative individuals (n=40) participating in the Comorbidity in Relation to AIDS (COBRA) cohort, and blood donors (n=35). We observed that age advancement in all three groups combined was associated with a monocyte immune phenotypic profile related to inflammation and a T cell immune phenotypic associated with immune senescence and chronic antigen exposure. Interestingly, a unique monocyte and T cell immune phenotypic profile predictive for age advancement was found within each group. An inflammatory monocyte immune phenotypic profile associated with age advancement in HIV-negative individuals, while the monocyte profile in blood donors and people with HIV was more reflective of loss of function. The T cell immune phenotypic profile in blood donors was related to loss of T cell function, whereas the same set of markers were related to chronic antigen stimulation and immune senescence in HIV-negative individuals. In people with HIV, age advancement was related to changes in the [[CD4]]  T cell compartment and more reflective of immune recovery after cART treatment. The identified monocyte and T cell immune phenotypic profiles that were associated with age advancement, were strongly related to inflammation, chronic antigen exposure and immune senescence. While the monocyte and T cell immune phenotypic profile within the HIV-negative individuals reflected those observed in the combined three groups, a distinct profile related to immune dysfunction, was observed within blood donors and people with HIV. These data suggest that varying exposures to lifestyle and infection-related factors may be associated with specific changes in the innate and adaptive immune system, that all contribute to age advancement.

|keywords=* HIV
* T cell
* aging
* immune activation
* immune dysfunction
* inflammation
* monocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573236
}}
{{medline-entry
|title=HIV and three dimensions of Wisdom: Association with cognitive function and physical and mental well-being: For: Psychiatry Research.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33096437
|abstract=Wisdom is a unique human personality trait with cognitive, affective or compassionate, and reflective dimensions. We evaluated relationships of three specific dimensions of wisdom with cognitive function and physical and mental well-being in people with HIV (PWH) and HIV-negative (HIV-) participants. Subjects included 138 adults (61 PWH, 77 HIV-) from the San Diego community. Validated measures were used to assess wisdom and well-being. Cognitive function was assessed via the Montreal Cognitive Assessment. We conducted multivariate linear regressions to evaluate the associations of wisdom dimensions with cognitive function and physical and mental well-being. Compared to the HIV- group, PWH had lower mean scores on cognitive function, and physical and mental well-being, and cognitive and reflective dimensions of wisdom, but similar scores on affective or compassionate wisdom. Among PWH, higher total wisdom scores were associated with older age, lower likelihood of substance dependence, greater mental well-being, better cognitive function, higher resilience, social support, and optimism scores, as well as lower levels of perceived stress and nadir [[CD4]] count. Our findings of an association of different dimensions of wisdom with physical and/or mental well-being in PWH would point to a possibility that enhancing these dimensions of wisdom might improve health outcomes in PWH.

|keywords=* Affective
* Aging
* Aids
* Compassion
* Reflective
|full-text-url=https://sci-hub.do/10.1016/j.psychres.2020.113510
}}
{{medline-entry
|title=CD8  T cells are present at low levels in the white matter with physiological and pathological aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33049712
|abstract=The presence and functional role of T cell infiltration in human brain parenchyma with normal aging and neurodegeneration is still under intense debate. Recently, CD8  cells have been shown to infiltrate the subventricular zone in humans and mice with a deleterious effect on neural stem cells. However, to which extent T cell infiltration in humans also occurs in other regions such as cortical areas and, especially, white matter (WM) has not yet been addressed. In this work, we report a low-grade infiltration of T cells (CD3 , [[CD4]]  and CD8 ) in the WM of aged individuals that is also observed at similar levels in patients with neurodegenerative disorders (Alzheimer´s disease). In particular, CD3  and CD8  cells were increased in perivascular and parenchymal WM and cortical regions (enthorinal cortex). These results reveal that T cell infiltration in brain parenchyma occurs with physiological and pathological aging in several regions, but it seems to be lower than in the subventricular zone neurogenic niche.

|keywords=* aging
* neuroscience
* pathology
|full-text-url=https://sci-hub.do/10.18632/aging.104043
}}
{{medline-entry
|title=Immunotherapy in older patients with cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33041248
|abstract=Ageing implicates a remodeling of our immune system, which is a consequence of the physiological senescence of our cells and tissues coupled with environmental factors and chronic antigen exposure. An immune system that senesces includes more differentiated cells with accumulation of highly differentiated [[CD4]] and CD8 T cells. The pool of naive T cells decreases with the exponential thymic involution induced by age. Differentiated T cells have similar, if not higher, functional capacities but scarce studies are looking at the impact of senescence among specific T cells. After a stimulation, other immune cells (monocytes, dendritic cells and NK) are functionally altered during ageing. It is as if the immune system was more efficient at the basal level, but less efficient after a stimulation in the old compared to young people, likely due to less reserve. Concerning the clinical impact, older people are more prone to certain pathogens and their clinical manifestations differ from the younger people. Severe flu and VZV reactivation are more frequent with an altered cellular response to vaccination. Vaccination failure can have detrimental consequences in people presenting frailty criteria. Old people frailty is majored by their comorbidities and diseases like cancer. Thus, chemotherapies are employed with circumspection in older patients. The use of anti-PD-1/PD-L1 immunotherapies is therefore attractive, because of less side effects with a better response compared to chemotherapy. Old persons inclusion is lacking in current studies and clinical trials. Some subgroups or pooled analyses confirm the gain in response without increased toxicities in older patients but their inclusion criteria differ from the real-life practice. Specific studies focusing on this population are needed because of the increasing cancer incidence with age and the overall ageing of the population.

|keywords=* Ageing
* Cancer
* Elderly
* Immunosenescence
* Immunotherapy
* Old people
* Oncogeriatry
|full-text-url=https://sci-hub.do/10.1016/j.bj.2020.07.009
}}
{{medline-entry
|title=Multiple genetic programs contribute to [[CD4]] T cell memory differentiation and longevity by maintaining T cell quiescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32987276
|abstract=While memory T-cells represent a hallmark of adaptive immunity, little is known about the genetic mechanisms regulating the longevity of memory [[CD4]] T cells. Here, we studied the dynamics of gene expression in antigen specific [[CD4]] T cells during infection, memory differentiation, and long-term survival up to nearly a year in mice. We observed that differentiation into long lived memory cells is associated with increased expression of genes inhibiting cell proliferation and apoptosis as well as genes promoting DNA repair response, lipid metabolism, and insulin resistance. We identified several transmembrane proteins in long-lived murine memory [[CD4]] T cells, which co-localized exclusively within the responding antigen-specific memory [[CD4]] T cells in human. The unique gene signatures of long-lived memory [[CD4]] T cells, along with the new markers that we have defined, will enable a deeper understanding of memory [[CD4]] T cell biology and allow for designing novel vaccines and therapeutics.

|keywords=* CD4 T cell
* Cell longevity
* Gene
* Genetic programs
* Memory T cell
* Memory cell markers
|full-text-url=https://sci-hub.do/10.1016/j.cellimm.2020.104210
}}
{{medline-entry
|title=Conventional Treatment for Multiple Myeloma Drives Premature Aging Phenotypes and Metabolic Dysfunction in T Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33013907
|abstract=New diagnoses of multiple myeloma (MM) tend to occur after the age of 60, by which time thymic output is severely reduced. As a consequence, lymphocyte recovery after lymphopenia-inducing anti-MM therapies relies on homeostatic proliferation of peripheral T cells rather than replenishment by new thymic emigrants. To assess lymphocyte recovery and phenotype in patients with newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM), we tracked [[CD4]]  and CD8  T cell populations at serial time points throughout treatment and compared them to age-matched healthy donors (HD). Anti-MM therapies and autologous stem cell transplant (ASCT) caused a permanent reduction in the [[CD4]]:8 ratio, a decrease in naïve [[CD4]]  T cells, and an increase in effector memory T cells and PD1-expressing [[CD4]]  T cells. Transcriptional profiling highlighted that genes associated with fatty acid β-oxidation were upregulated in T cells in RRMM, suggesting increased reliance on mitochondrial respiration. High mitochondrial mass was seen in all T cell subsets in RRMM but with relatively suppressed reactive oxygen species and mitochondrial membrane potential, indicating mitochondrial dysfunction. These findings highlight that anti-MM and ASCT therapies perturb the composition of the T cell compartment and drive substantial metabolic remodeling, which may affect the fitness of T cells for immunotherapies. This is particularly pertinent to chimeric antigen receptor (CAR)-T therapy, which might be more efficacious if T cells were stored prior to ASCT rather than at relapse.

|keywords=* T cell
* aging
* autologous stem cell transplant
* metabolism
* myeloma
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7494758
}}
{{medline-entry
|title=Immunosenescence: the role of age in multiple sclerosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32962809
|abstract=The number of elderly people with multiple sclerosis (MS) has increased in line with population ageing. As the immune system presents profound changes over an individual's lifetime, it is important to understand the differences between these patients and younger patients. Immunosenescence, defined as age-related alterations naturally occurring in the immune system, particularly influences tolerance, response, and adverse effects of disease-modifying treatments for MS. Thymic involution is the most noteworthy characteristic of this phenomenon. This process leads to a reduction in the number of virgin T cells. Other effects include an inverted [[CD4]] + /CD8 + cell ratio, severe alterations in NK cell functioning, and reduced tissue repair capacity in the brain. The number of older people with MS is increasing due to population ageing, advances in disease-modifying treatments, and improved health and social care of these patients. Ageing of the immune system increases the risk of infections, tumours, and autoimmune diseases in elderly individuals. Furthermore, neurodegeneration is accelerated in patients with MS due to the nervous system's loss of remyelination capacity. Understanding of the changes affecting the immune system in the elderly population is essential to improving the care provided to this ever-growing patient group.

|keywords=* Ageing
* Envejecimiento
* Esclerosis múltiple
* Esclerosis múltiple de comienzo tardío
* Immunosenescence
* Inmunosenescencia
* Late-onset multiple sclerosis
* Multiple sclerosis
|full-text-url=https://sci-hub.do/10.1016/j.nrl.2020.05.016
}}
{{medline-entry
|title=Umbilical cord mesenchymal stem cells protect thymus structure and function in aged C57 mice by downregulating aging-related genes and upregulating autophagy- and anti-oxidative stress-related genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32924972
|abstract=To study the effect of allogeneic umbilical cord mesenchymal stem cell transplantation on the structure and function of the thymus in aged C57 mice and provide a new method for the treatment of senile thymic atrophy. The changes in the thymus cortex and medulla volume and the lymphocyte ratio were analyzed by immunofluorescence. For thymus tissue sections, immunohistochemical staining was performed to detect p16, p53, SOD, becline1, LC3b, p62, sirt1, and sirt3. Changes in CK5, CK8, [[CD4]] and CD8 expression were observed. Treatment with mUCMSCs could promote hair regeneration in aging mice and regenerate the thymus structure. mUCMSCs inhibited senescence of the thymus and promoted structural and functional thymus regeneration by downregulating the senescence genes p53 and p16 and upregulating the SOD, Sirt1 and Sirt3 genes, but the mechanism requires further research. C57 mice were obtained and met the requirements of thymic aging. mUCMSCs were infused via the tail vein at a dose of 1×10  cells/kg twice per week for 3 weeks. Six weeks after the last transplantation, the thymus was weighed, and the thymus-to-body weight ratio was calculated. The thymus tissue was stained with HE.

|keywords=* aged
* senescence
* thymus
* transplantation
* umbilical cord mesenchymal stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521525
}}
{{medline-entry
|title=Impaired Cytotoxic CD8  T Cell Response in Elderly COVID-19 Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32948688
|abstract=Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a T cell response that most likely contributes to virus control in COVID-19 patients but may also induce immunopathology. Until now, the cytotoxic T cell response has not been very well characterized in COVID-19 patients. Here, we analyzed the differentiation and cytotoxic profile of T cells in 30 cases of mild COVID-19 during acute infection. SARS-CoV-2 infection induced a cytotoxic response of CD8  T cells, but not [[CD4]]  T cells, characterized by the simultaneous production of granzyme A and B as well as perforin within different effector CD8  T cell subsets. PD-1-expressing CD8  T cells also produced cytotoxic molecules during acute infection, indicating that they were not functionally exhausted. However, in COVID-19 patients over the age of 80 years, the cytotoxic T cell potential was diminished, especially in effector memory and terminally differentiated effector CD8  cells, showing that elderly patients have impaired cellular immunity against SARS-CoV-2. Our data provide valuable information about T cell responses in COVID-19 patients that may also have important implications for vaccine development.  Cytotoxic T cells are responsible for the elimination of infected cells and are key players in the control of viruses. CD8  T cells with an effector phenotype express cytotoxic molecules and are able to perform target cell killing. COVID-19 patients with a mild disease course were analyzed for the differentiation status and cytotoxic profile of CD8  T cells. SARS-CoV-2 infection induced a vigorous cytotoxic CD8  T cell response. However, this cytotoxic profile of T cells was not detected in COVID-19 patients over the age of 80 years. Thus, the absence of a cytotoxic response in elderly patients might be a possible reason for the more frequent severity of COVID-19 in this age group than in younger patients.
|mesh-terms=* Aged, 80 and over
* Antigens, CD
* Betacoronavirus
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* COVID-19
* Coronavirus Infections
* Cytotoxins
* Female
* Humans
* Immunity, Cellular
* Male
* Middle Aged
* Pandemics
* Pneumonia, Viral
* SARS-CoV-2
* T-Lymphocyte Subsets
* T-Lymphocytes, Cytotoxic
|keywords=* CD4+

* CD8+

* COVID-19
* PD-1
* SARS-CoV-2
* aging
* cytotoxic T cells
* granzyme
* perforin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502863
}}
{{medline-entry
|title=What are the roles of antibodies versus a durable, high quality T-cell response in protective immunity against SARS-CoV-2?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32875286
|abstract=The first SARS-CoV-2 vaccine(s) will likely be licensed based on neutralizing antibodies in Phase 2 trials, but there are significant concerns about using antibody response in coronavirus infections as a sole metric of protective immunity. Antibody response is often a poor marker of prior coronavirus infection, particularly in mild infections, and is shorter-lived than virus-reactive T-cells; strong antibody response correlates with more severe clinical disease while T-cell response is correlated with less severe disease; and antibody-dependent enhancement of pathology and clinical severity has been described. Indeed, it is unclear whether antibody production is protective or pathogenic in coronavirus infections. Early data with SARS-CoV-2 support these findings. Data from coronavirus infections in animals and humans emphasize the generation of a high-quality T cell response in protective immunity. Yellow Fever and smallpox vaccines are excellent benchmarks for primary immune response to viral vaccination and induce long-lived virus-reactive CD8 T-cells, which are present and measurable within 1-4 months of vaccination. Progress in laboratory markers for SARS-CoV2 has been made with identification of epitopes on [[CD4]] and CD8 T-cells in convalescent blood. These are much less dominated by spike protein than in previous coronavirus infections. Although most vaccine candidates are focusing on spike protein as antigen, natural infection by SARS-CoV-2 induces broad epitope coverage, cross-reactive with other betacoronviruses. It will be important to understand the relation between breadth, functionality and durability of T-cell responses and resulting protective immunity. It would be a public health and general trust-in-medicine nightmare - including a boost to anti-vaccine forces - if immune protection wears off or new disease patterns develop among the immunized. Data correlating clinical outcomes with laboratory markers of cell-mediated immunity, not only with antibody response, after SARS-CoV-2 natural infection and vaccines may prove critically valuable if protective immunity fades or if new patterns of disease emerge.

|keywords=* Antibodies
* Antibody-dependent enhancement
* CD8 T-cells
* COVID-19
* Durable immunity
* Protective immunity
* SARS
* SARS-CoV-2
* T cell lifespan
* T-cell epitopes
* T-cells
* Vaccines
* Yellow Fever Vaccine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452821
}}
{{medline-entry
|title=Per2 Upregulation in Circulating Hematopoietic Progenitor Cells During Chronic HIV Infection.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32850472
|abstract=Chronic HIV infection accelerates immune aging and is associated with abnormal hemato-lymphopoiesis, but the relationship between HIV-induced aging and Hematopoietic Progenitor Cells (HPC) function is not well-defined. In the context of aging, it has been demonstrated using a murine model that Per2 (Period circadian clock 2) is a negative regulator of HPC survival and lineage potential. A possible involvement of Per2 modulation on hematopoietic failure during HIV infection has not yet been investigated. The aim of this study was to analyze whether Per2 is differently expressed and regulated on HPC during HIV infection, possibly providing a therapeutic target to restore lymphoid potential in the HPC compartment. To this purpose, Per2 expression in circulating HPC was compared in 69 chronic HIV infected patients under successful ART and in matched 30 uninfected healthy donors (HD). HPC aging was assessed by measuring relative telomere length (RTL), and HPC functionality was evaluated by Colony Forming Cell (CFC) assay from both [i]ex vivo[/i] HIV+ patients and [i]in vitro[/i] Per2 overexpressing donors. Our results showed a lower RTL in HPC and a decrease of white progenitor colonies from HIV+ patients with lower [[CD4]] respect to those with higher [[CD4]] T cell count (<500 respect to >500 [[CD4]] T cell/mmc). Interestingly, we found that the frequency of Per2-expressing HPC is higher in HIV+ patients than in HD and correlated to RTL of CFC derived cells, highlighting a relationship between low proliferative rate and Per2 expression. Indeed, the [i]in vitro[/i] overexpression of Per2 resulted in a significant decrease of white progenitor colonies respect to control cells. Finally, we showed that the deacetylase Sirtuin 1, a negative regulator of Per2, was downregulated in HPC from HIV+ patients, and the peripheral blood treatment with resveratrol (Sirtuin 1 inducer) determined a decrease of Per2 expressing HPC. Altogether, these results suggest that during HIV infection, Per2 is involved in the regulation of HPC expansion and differentiation and its overexpression may impair the immune reconstitution. These data support the rationale to explore the role of this regulatory mechanism during aged-associated hemato-lymphopoiesis impairment in HIV infection.

|keywords=* HIV
* Sirtuin 1
* hematopoietic progenitor cells
* period circadian clock 2
* senescence
* telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396677
}}
{{medline-entry
|title=COVID-19: age, Interleukin-6, C-reactive protein, and lymphocytes as key clues from a multicentre retrospective study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32802142
|abstract=The SARS-CoV-2 infection has widely spread to become the greatest public health challenge to date, the COVID-19 pandemic. Different fatality rates among countries are probably due to non-standardized records being carried out by local health authorities. The Spanish case-fatality rate is 11.22%, far higher than those reported in Asia or by other European countries. A multicentre retrospective study of demographic, clinical, laboratory and immunological features of 584 Spanish COVID-19 hospitalized patients and their outcomes was performed. The use of renin-angiotensin system blockers was also analysed as a risk factor. In this study, 27.4% of cases presented a mild course, 42.1% a moderate one and for 30.5% of cases, the course was severe. Ages ranged from 18 to 98 (average 63). Almost 60 % (59.8%) of patients were male. Interleukin 6 was higher as severity increased. On the other hand, CD8 lymphocyte count was significantly lower as severity grew and subpopulations [[CD4]], CD8, CD19, and NK showed concordant lowering trends. Severity-related natural killer percent descents were evidenced just within aged cases. A significant severity-related decrease of [[CD4]] lymphocytes was found in males. The use of angiotensin-converting enzyme inhibitors was associated with a better prognosis. The angiotensin II receptor blocker use was associated with a more severe course. Age and age-related comorbidities, such as dyslipidaemia, hypertension or diabetes, determined more frequent severe forms of the disease in this study than in previous literature cohorts. Our cases are older than those so far reported and the clinical course of the disease is found to be impaired by age. Immunosenescence might be therefore a suitable explanation for the hampering of immune system effectors. The adaptive immunity would become exhausted and a strong but ineffective and almost deleterious innate response would account for COVID-19 severity. Angiotensin-converting enzyme inhibitors used by hypertensive patients have a protective effect in regards to COVID-19 severity in our series. Conversely, patients on angiotensin II receptor blockers showed a severer disease.

|keywords=* ACE2
* C-reactive protein
* COVID-19
* Immunity
* Immunosenescence
* Interleukin-6
* Lymphocytes
* Renin-angiotensin system
* Severe acute respiratory syndrome coronavirus 2
* Spain
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426672
}}
{{medline-entry
|title=Immunosenescence profiles are not associated with muscle strength, physical performance and sarcopenia risk in very old adults: The Newcastle 85+ Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32735896
|abstract=Decline in immune system function (immunosenescence) has been implicated in several age-related disorders. However, little is known about whether alteration in T-cell senescence, a process underlying immunological ageing, is related to muscle health in very old adults (aged ≥85 years). Utilising data from the Newcastle 85+ Study, we aimed to (a) derive and characterise immunosenescence profiles by clustering 13 baseline immunosenescence-related biomarkers of lymphocyte compartments in 657 participants; (b) explore the association between the profiles and 5-year change in muscle strength (grip strength) and physical performance (Timed Up-and-Go test), and (c) determine whether immunosenescence profiles predict 3-year incident sarcopenia. Two distinct clusters were identified; Cluster 1 ('Senescent-like phenotype', n = 421), and Cluster 2 ('Less senescent-like phenotype', n = 236) in individuals with complete biomarker data. Although Cluster 1 was characterised by T-cell senescence (e.g., higher frequency of [[CD4]] and CD8 senescence-like effector memory cells), and elements of the immune risk profile (lower [[CD4]]/CD8 ratio, CMV+), it was not associated with change in muscle function over time, or with prevalent or incident sarcopenia. Future studies will determine whether more in-depth characterisation or change in T-cell phenotypes predict the decline in muscle health in late adulthood.

|keywords=* immunosenescence
* lymphocyte compartments
* physical performance
* sarcopenia
* very old adults
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111321
}}
{{medline-entry
|title=Homeostasis and the functional roles of [[CD4]]  Treg cells in aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32717201
|abstract=An upward trend in life expectancy has been observed in a majority of developed countries and leading to increasing in aging-related diseases. Aging is a risk factor for the development of widespread clinical conditions such as cardiovascular and autoimmune diseases, cancer, infections. Although studies have been very active, the problem of aging still remains one of the most obscure aspects of human biology. Regulatory T (Treg) cells with immunosuppressive properties have a pivotal role in the maintenance of immune homeostasis. Alterations in Treg cell functionality appear to be of great importance in the development of immune senescence and contribute to increased susceptibility to immune-mediated diseases with age. This review highlights recent findings regarding the age-related changes in the numbers and functional activity of human Tregs. Some of the mechanisms that maintain the balance of Tregs during human aging are discussed. The possible roles of Tregs in the pathogenesis of diseases associated with advanced age are also considered. Age-related systemic changes, such as thymic involution, hormonal status, and epigenetic modifications, may affect the state of the Treg population and trigger various diseases. These changes involve decline or amplification in the functional activity of Tregs, an increase in the memory Treg subset and shifting of a Th17/Treg balance. Taken together, the reviewed data suggest equal or even increased Treg functionality with age. Thus, age-mediated Treg expansion and higher Treg activity may contribute to elevated immune suppression and increased risk of infections and cancer.

|keywords=* Aging
* Autoimmunity
* Cancer
* FOXP3
* Immune senescence
* Immune suppression
* Inflammaging
* Regulatory T cells
* T helper 17
* Treg
|full-text-url=https://sci-hub.do/10.1016/j.imlet.2020.07.004
}}
{{medline-entry
|title=A Comprehensive Evaluation of the Impact of Bovine Milk Containing Different Beta-Casein Profiles on Gut Health of Ageing Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32707687
|abstract=Ageing is often characterised by nutritional deficiencies and functional alterations of the digestive and immune system. The aim of the present study was to analyse the impact of consumption of conventional milk with A1/A2 beta-casein, compared to milk containing only the A2 beta-casein variant, characterised by a protein profile favouring gut health. Twenty-four ageing Balb-c mice (20 months old) were fed for 4 weeks, with either a control diet (CTRL), a diet supplemented with bovine milk containing A1/A2 beta-casein (A1A2) or a diet containing A2/A2 beta-casein (A2A2). Lymphocyte subpopulations, enzymatic activities, cytokine secretion, gut morphology and histopathological alterations were measured in different gut segments, while short-chain fatty acids (SCFAs) content and microbiota composition were evaluated in faecal samples. The A2A2 group showed higher content of faecal SCFAs (in particular, isobutyrate) of intestinal [[CD4]]  and CD19  lymphocytes in the intraepithelial compartment and improved villi tropism. The A1A2 group showed higher percentages of intestinal TCRγδ  lymphocytes. Faecal microbiota identified [i]Deferribacteriaceae[/i] and [i]Desulfovibrionaceae[/i] as the most discriminant families for the A2A2 group, while [i]Ruminococcaceae[/i] were associated to the A1A2 group. Taken together, these results suggest a positive role of milk, in particular when containing exclusively A2 beta-casein, on gut immunology and morphology of an ageing mice model.

|keywords=* A2 beta-casein
* SCFAs
* elderly
* gut inflammation
* gut microbiota
* gut morphology
* immunosenescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400800
}}
{{medline-entry
|title=Premature aging of circulating T cells predicts all-cause mortality in hemodialysis patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32660510
|abstract=Patients with end-stage renal disease (ESRD) exhibit a premature aging phenotype of immune system, which is recently concerned as a significant factor for increased risk of various morbidities. Nevertheless, there are few dates explicating the relevancy of T cell senescence to mortality. In this study, we prospectively studied the predictive value of T cell senescence for mortality in hemodialysis patients. Patients who had been on hemodialysis treatment for at least 6 months were enrolled. T cell senescence determined by differentiation status was evaluated by flow cytometry. Survival outcomes were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed to evaluate the prognostic impact of T cell premature aging and other clinical factors on all-cause mortality. A total of 466 patients (277 man and 169 women) were enrolled in this study. Decreased number of naïve T cell, as the most prominent feature of T cell senescence, did not change in parallel with age in these patients. Decreased absolute count of T cell, naïve T cell, [[CD4]]  naïve T cell were independently associated with all-cause mortality. Decreased percentage of T cell and increased percentage of CD8 central-memory T cell were also independently associated with all-cause mortality. After including all the T cell parameters in one regression model, only decreased count of naïve T cell was significantly associated with increased mortality in these patients. Aging-associated T cell changes are aggravated in ESRD patients. For the first time, our study demonstrates that naïve T cell depletion is a strong predictor of all-cause mortality in HD patients.

|keywords=* Hemodialysis
* Inflammation
* Mortality
* T cell aging
* naïve T cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359274
}}
{{medline-entry
|title=In-depth immune cellular profiling reveals sex-specific associations with frailty.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32582361
|abstract=With advancing age, the composition of leukocyte subpopulations in peripheral blood is known to change, but how this change differs between men and women and how it relates to frailty is poorly understood. Our aim in this exploratory study was to investigate whether frailty is associated with changes in immune cell subpopulations and whether this differs between men and women. Therefore, we performed in-depth immune cellular profiling by enumerating a total of 37 subpopulations of T cells, B cells, NK cells, monocytes, and neutrophils in peripheral blood of 289 elderly people between 60-87 years of age. Associations between frailty and each immune cell subpopulation were tested separately in men and women and were adjusted for age and CMV serostatus. In addition, a random forest algorithm was used to predict a participant's frailty score based on enumeration of immune cell subpopulations. In the association study, frailty was found to be associated with increased numbers of neutrophils in both men and in women. Frailer women, but not men, showed higher numbers of total and CD16  monocytes, and lower numbers of both CD56  T cells and late differentiated [[CD4]]  TemRA cells. The random forest algorithm confirmed all the findings of the association studies in men and women. In men, the predictive accuracy of the algorithm was too low (5.5%) to warrant additional conclusions on top of the ones derived from the association study. In women however, the predictive accuracy was higher (23.1%), additionally revealing that total T cell numbers and total lymphocyte numbers also contribute in predicting frailty. In-depth immune cellular profiling revealed consistent associations of frailty with elevated numbers of myeloid cell subpopulations in both men and women. Furthermore, additional associations were found between frailty and lower numbers of some T cell subpopulations, in women only. Thus, our study indicates sex-specific associations of immune subpopulations with frailty. We hope that our study will prompt further investigation into the sex-specific immune mechanisms associated with the development of frailty.

|keywords=* Frailty
* Healthy aging
* Immune cellular profiling
* Immune homeostasis
* Immunosenescence
* Sex-specific immune profile
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310472
}}
{{medline-entry
|title=CD70 contributes to age-associated T cell defects and overwhelming inflammatory responses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32559178
|abstract=Aging is associated with immune dysregulation, especially T cell disorders, which result in increased susceptibility to various diseases. Previous studies have shown that loss of co-stimulatory receptors or accumulation of co-inhibitory molecules play important roles in T cell aging. In the present study, CD70, which was generally regarded as a costimulatory molecule, was found to be upregulated on [[CD4]]  and CD8  T cells of elderly individuals. Aged CD70  T cells displayed a phenotype of over-activation, and expressed enhanced levels of numerous inhibitory receptors including PD-1, 2B4 and LAG-3. CD70  T cells from elderly individuals exhibited increased susceptibility to apoptosis and high levels of inflammatory cytokines. Importantly, the functional dysregulation of CD70  T cells associated with aging was reversed by blocking CD70. Collectively, this study demonstrated CD70 as a prominent regulator involved in immunosenescence, which led to defects and overwhelming inflammatory responses of T cells during aging. These findings provide a strong rationale for targeting CD70 to prevent dysregulation related to immunosenescence.

|keywords=* CD70
* T cell aging
* co-inhibitory molecules
* immunosenescence
* overwhelming inflammatory responses
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343466
}}
{{medline-entry
|title=Comparison of Overall and Comorbidity-Free Life Expectancy Between Insured Adults With and Without HIV Infection, 2000-2016.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32539152
|abstract=Antiretroviral therapy (ART) has improved life expectancy for individuals with HIV infection, but recent data comparing life span and comorbidity-free years by HIV status are lacking. To quantify the gap in life span and comorbidity-free years by HIV status among adults with access to care. This matched cohort study used data from insured adults with and without HIV infection (aged ≥21 years) matched 1:10 at medical centers of Kaiser Permanente in northern and southern California and the mid-Atlantic states of Washington DC, Maryland, and Virginia from January 1, 2000, through December 31, 2016. Data were analyzed from September 1, 2019, through March 31, 2020. HIV status and, for individuals with HIV infection, ART initiation at a [[CD4]] cell count of 500/μL or greater. Overall life expectancy and expected years free of major chronic comorbidities, including chronic liver disease, chronic kidney disease, chronic lung disease, diabetes, cancer, and cardiovascular disease. Of 39 000 individuals with HIV infection and 387 785 matched uninfected adults, 374 421 (87.7%) were male, with a mean (SD) age of 41.4 (10.8) years. Among 359 244 individuals with known race/ethnicity, 90 177 (25.1%) were non-Hispanic black and 87 191 (24.3%) were Hispanic. From 2000 to 2003, overall life expectancy at age 21 years of age was 37.6 years among individuals with HIV infection and 59.7 years among uninfected adults, (difference, 22.1 years; 95% CI, 20.2-24.0 years). From 2014 to 2016, overall life expectancy at 21 years of age among individuals with HIV infection increased to 56.0 years compared with 65.1 years among uninfected adults (difference, 9.1 years; 95% CI, 7.9-10.2 years). During 2011 to 2016, individuals with HIV infection who initiated ART with a [[CD4]] cell count of 500/μL or greater had a life expectancy at 21 years of age of 57.4 years compared with 64.2 years among uninfected adults (difference, 6.8 years; 95% CI, 5.0-8.5 years). From 2000 to 2003, the expected number of comorbidity-free years remaining at 21 years of age was 11.3 for individuals with HIV infection and 26.6 years for uninfected adults (difference, 15.3 years; 95% CI, 13.9-16.6 years). This difference in comorbidity-free years persisted over time but decreased to 9.5 years (95% CI, 7.7-11.2 years) for individuals with HIV infection who initiated ART at a [[CD4]] cell count of 500/μL or greater. The results suggest that life expectancy of adults with HIV infection may be near that of life expectancy of individuals without HIV infection, but greater attention is needed to prevention of comorbidities among individuals with HIV infection.
|mesh-terms=* Adult
* Chronic Disease
* Cohort Studies
* Comorbidity
* Female
* HIV Infections
* Humans
* Insurance, Health
* Life Expectancy
* Male
* Middle Aged

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296391
}}
{{medline-entry
|title=Comparative Analysis of Age-Related Changes in Lacrimal Glands and Meibomian Glands of a C57BL/6 Male Mouse Model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32545199
|abstract=It is not known how biological changes in the lacrimal (LGs) and meibomian (MGs) glands contribute to dry eye disease (DED) in a time-dependent manner. In this study, we investigated time-sequenced changes in the inflammation, oxidative stress, and senescence of stem cells in both glands of an aging-related DED mouse model. Eight-week (8W)-, one-year (1Y)-, and two-year (2Y)-old C57BL/6 male mice were used. MG areas of the upper and lower eyelids were analyzed by transillumination meibography imaging. The number of [[CD4]]5 , 8-OHdG , Ki-67 , and BrdU  cells was compared in both glands. Increased corneal staining and decreased tear secretion were observed in aged mice. The MG dropout area increased with aging, and the age-adjusted MG area in lower lids was negatively correlated with the National Eye Institute (NEI) score. Increased [[CD4]]  interferon (IFN)-γ  cells in LGs were found in both aged mice. An increase in 8-OHdG  cells in both glands was evident in 2Y-old mice. Reduced Ki-67  cells, but no change in [[CD4]]5  cells, was observed in the MGs of 1Y-old mice. Increased BrdU  cells were observed in the LGs of aged mice. This suggests that age-dependent DED in C57BL/6 mice is related to inflammation of the LGs, the development of MG atrophy, and oxidative stress in both glands.

|keywords=* aging
* dry eye
* inflammation
* lacrimal glands
* meibomian glands
* oxidative stress
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313015
}}
{{medline-entry
|title=Thymus aging in mice deficient in either EphB2 or EphB3, two master regulators of thymic epithelium development.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32506584
|abstract=The epithelial microenvironment is involved in thymus aging, but the possible role of EphB receptors that govern the thymic epithelium development has not been investigated. Herein, we study the changes undergone by the thymus of EphB-deficient mice throughout their life. Immune alterations occurring throughout life were more severe in mutant than in wild-type (WT) mice. Mutant thymuses exhibit lower cellularity than WT ones, as well as lower proportions of early thymic progenitors cells and double-positive ([[CD4]]  CD8  ) thymocytes, but higher of double-negative ([[CD4]]  CD8  ) and single-positive ([[CD4]]  CD8  , [[CD4]]  CD8  ) cells. Throughout life, [[CD4]]  naïve cells decreased particularly in mutant mice. In correlation, memory T cells, largely CD8  cells, increased. Aged thymic epithelium undergoes changes including appearance of big epithelial free areas, decrease of K8  K5  areas, which, however, contain higher proportions of Ly51  UEA1  cortical epithelial cells, in correlation with reduced Aire  medullary epithelial cells. Also, aged thymuses particularly those derived from mutant mice exhibited increased collagen IV, fat-storing cells, and connective cells. The absence of EphB accelerates the alterations undergone throughout life by both thymic epithelium and thymocytes, and the proportions of peripheral naïve and memory T cells, all of which are hallmarks of immune aging.

|keywords=* senescence
* thymic epithelial cells
* thymocytes
|full-text-url=https://sci-hub.do/10.1002/dvdy.212
}}
{{medline-entry
|title=CD8  T-cell senescence and skewed lymphocyte subsets in young Dyskeratosis Congenita patients with PARN and DKC1 mutations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32452087
|abstract=Dyskeratosis congenita (DC) is a syndrome resulting from defective telomere maintenance. Immunodeficiency associated with DC can cause significant morbidity and lead to premature mortality, but the immunological characteristics and molecular hallmark of DC patients, especially young patients, have not been described in detail. We summarize the clinical data of two juvenile patients with DC. Gene mutations were identified by whole-exome and direct sequencing. Swiss-PdbViewer was used to predict the pathogenicity of identified mutations. The relative telomere length was determined by QPCR, and a comprehensive analysis of lymphocyte subsets and CD57 expression was performed by flow cytometry. Both patients showed typical features of DC without severe infection. In addition, patient 1 (P1) was diagnosed with Hoyeraal-Hreidarsson syndrome due to cerebellar hypoplasia. Gene sequencing showed P1 had a compound heterozygous mutation (c.204G > T and c.178-245del) in PARN and P2 had a novel hemizygous mutation in DKC1 (c.1051A > G). Lymphocyte subset analysis showed B and NK cytopenia, an inverted [[CD4]]:CD8 ratio, and decreased naïve [[CD4]] and CD8 cells. A significant increase in CD21  B cells and skewed numbers of helper T cells (Th), regulatory T cells (Treg), follicular regulatory T cells (Tfr), and follicular helper T cells (Tfh) were also detected. Short telomere lengths, increased CD57 expression, and an expansion of CD8 effector memory T cells re-expressing [[CD4]]5RA (TEMRA) were also found in both patients. Unique immunologic abnormalities, CD8 T-cell senescence, and shortened telomere together as a hallmark occur in young DC patients before progression to severe disease.

|keywords=* 
DKC1

* 
PARN

* Dyskeratosis Congenita
* primary immunodeficiency
* senescence
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521304
}}
{{medline-entry
|title=Short-Term Environmental Enrichment is a Stronger Modulator of Brain Glial Cells and Cervical Lymph Node T Cell Subtypes than Exercise or Combined Exercise and Enrichment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32451728
|abstract=Physical exercise (PE) and environmental enrichment (EE) can modulate immunity. However, the differential effects of short-term PE, EE, and PE + EE on neuroimmune mechanisms during normal aging has not been elucidated. Hence, a cohort of 3-, 8-, and 13-month-old immunologically unchallenged C57BL/6 wild-type mice were randomly assigned to either Control, PE, EE, or PE + EE groups and provided with either no treatment, a running wheel, a variety of plastic and wooden objects alone or in combination with a running wheel for seven weeks, respectively. Immunohistochemistry and 8-color flow cytometry were used to determine the numbers of dentate gyrus glial cells, and the proportions of [[CD4]]  and CD8  T cell numbers and their subsets from cervical lymph nodes, respectively. An increase in the number of IBA1  microglia in the dentate gyrus at 5 and 10 months was observed after EE, while PE and PE + EE increased it only at 10 months. No change in astroglia number in comparison to controls were observed in any of the treatment groups. Also, all treatments induced significant differences in the proportion of specific T cell subsets, i.e., [[CD4]]  and CD8  T naïve (T ), central memory (T ), and effector memory (T ) cells. Our results suggest that in the short-term, EE is a stronger modulator of microglial and peripheral T cell subset numbers than PE and PE + EE, and the combination of short-term PE and EE has no additive effects.

|keywords=* Aging
* Astrocytes
* Environmental enrichment
* Microglia
* Physical exercise
* T cells
|full-text-url=https://sci-hub.do/10.1007/s10571-020-00862-x
}}
{{medline-entry
|title=Viral and host factors related to the clinical outcome of COVID-19.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32434211
|abstract=In December 2019, coronavirus disease 2019 (COVID-19), which is caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified in Wuhan (Hubei province, China) ; it soon spread across the world. In this ongoing pandemic, public health concerns and the urgent need for effective therapeutic measures require a deep understanding of the epidemiology, transmissibility and pathogenesis of COVID-19. Here we analysed clinical, molecular and immunological data from 326 patients with confirmed SARS-CoV-2 infection in Shanghai. The genomic sequences of SARS-CoV-2, assembled from 112 high-quality samples together with sequences in the Global Initiative on Sharing All Influenza Data (GISAID) dataset, showed a stable evolution and suggested that there were two major lineages with differential exposure history during the early phase of the outbreak in Wuhan. Nevertheless, they exhibited similar virulence and clinical outcomes. Lymphocytopenia, especially reduced [[CD4]]  and CD8  T cell counts upon hospital admission, was predictive of disease progression. High levels of interleukin (IL)-6 and IL-8 during treatment were observed in patients with severe or critical disease and correlated with decreased lymphocyte count. The determinants of disease severity seemed to stem mostly from host factors such as age and lymphocytopenia (and its associated cytokine storm), whereas viral genetic variation did not significantly affect outcomes.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Animals
* Asymptomatic Infections
* Betacoronavirus
* COVID-19
* China
* Cohort Studies
* Coronavirus Infections
* Critical Illness
* Disease Progression
* Evolution, Molecular
* Female
* Genetic Variation
* Genome, Viral
* Hospitalization
* Host-Pathogen Interactions
* Humans
* Inflammation Mediators
* Interleukin-6
* Interleukin-8
* Lymphocyte Count
* Lymphopenia
* Male
* Middle Aged
* Pandemics
* Phylogeny
* Pneumonia, Viral
* Respiratory Distress Syndrome
* SARS-CoV-2
* T-Lymphocytes
* Time Factors
* Treatment Outcome
* Virulence
* Virus Shedding
* Young Adult
* Zoonoses

|full-text-url=https://sci-hub.do/10.1038/s41586-020-2355-0
}}
{{medline-entry
|title=Use of comedications and potential drug-drug interactions in people living with HIV in China.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32354599
|abstract=Because people living with HIV (PLWH) are ageing, they will inevitably develop non-communicable diseases (NCDs) and the number of non-HIV medications will increase. Drug-drug interactions(DDIs) will become an ever-increasing issue. However, little is known about this important issue in Chinese PLWH. This study aimed to investigate the prevalence and risk factors of DDIs among PLWH in China. Chinese PLWH aged ≥18 years were enrolled prospectively from October 2018 to April 2019 and after informed consent was obtained, they were ask to fill out a questionnaire about comorbidity and co-medications. Potential DDIs were identified using the University of Liverpool HIV Drug Interaction Checker. A total of 1804 questionnaires were included. Antiretroviral drugs (ARVs) that most frequently were prescribed were lamivudine (96.18%), efavirenz(64.64%) and tenofovir(60.62%). 16.96% of the participations reported current co-infection with HIV and14.69% reported NCDs. 263(14.57%) participations reported they had used co-medications in the past six months while 186(10.31%) reported they were taking co-medications. Age≥50 years (p < 0.001), living in developed areas(p < 0.001) and lower [[CD4]] cell count(p = 0.045) were independently associated with the use of co-medications. Potential DDIs were identified in 54 (19.15%) persons using co-medications. Age≥50 [OR = 2.272(1.241-4.158)], PLWH with NCDs[OR = 2.889(1.509-5.532)] and usage of protease inhibitors[OR = 2.538(1.250-5.156)] were independently associated with the potential DDIs. The prevalence of the use of co-medications and potential DDIs among Chinese PLWH are low. Older age, NCDs and use of PIs were risk factors for the potential of developing DDIs. With the aging of PLWH, co-medications and DDIs in China warrants more attention.

|keywords=* Aging
* China
* Co-medication
* Drug-drug interaction
* HIV
|full-text-url=https://sci-hub.do/10.1016/j.jiac.2020.04.003
}}
{{medline-entry
|title=[[CD4]]  T helper 17 cell response of aged mice promotes prostate cancer cell migration and invasion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32356608
|abstract=Aging is the most important risk factor for prostate cancer (PCa), but how age contributes to PCa is poorly understood. Aging is characterized by low-grade systemic inflammation (i.e., inflammaging) that is often attributed to the progressive activation of immune cells over time, which may play an important role in prostate carcinogenesis. Th17 response is elevated in aging humans and mice, but it remains unknown whether it is increased in prostate tissue or contributes to prostate carcinogenesis during aging. In this study, we aimed to determine the role of age-related Th17 response in PCa cell growth, migration, and invasion. C57BL/6J (B6) mouse was used as an aging animal model and the prostate histopathology during aging was analyzed. Splenic [[CD4]]  T cells were isolated from young (16-20 weeks old) and aged (96-104 weeks old) mice, and cultured in the presence of plate-bound anti-CD3/anti-CD28, with or without Th17 differentiation conditions. The cells were collected and used for subsequent flow cytometry or quantitative reverse transcription polymerase chain reaction. The supernatant was collected and used to treat PCa cell lines. The treated PCa cells were analyzed for cell viability, migration, invasion, and nuclear factor kappa B (NF-κB) signaling. Aged mice had enlarged prostate glands and increased morphological alterations, with not only increased inflammatory cell infiltration but also increased Th17 cytokines in prostate tissue, compared to young mice. Naïve [[CD4]]  T cells from aged mice differentiated increased interleukin (IL)-17-expressing cells. [[CD4]]  T cells from aged mice spleen had increased Th17 cells, Th17 cytokines and Th17/Treg ratio compared to young mice. Factors secreted from aged [[CD4]]  T cells, especially from ex vivo differentiated Th17 cells, not only promoted PCa cell viability, migration, and invasion but also activated the NF-κB signaling in PCa cells compared to young mice. These results indicate that age-related [[CD4]]  T cells, especially Th17 cells-secreted factors have the potential to contribute to prostate carcinogenesis. Our work could prompt further research using autochthonous PCa mouse models at different ages to elucidate the functional role of Th17 response in prostate carcinogenesis during aging.
|mesh-terms=* Aging
* Animals
* CD4-Positive T-Lymphocytes
* Cell Differentiation
* Cell Line, Tumor
* Cell Movement
* Humans
* Inflammation
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Models, Animal
* NF-kappa B
* Neoplasm Invasiveness
* PC-3 Cells
* Prostatic Neoplasms
* Th17 Cells
|keywords=* CD4+ T cell-secreted factors
* PCa cells
* Th17 cytokines
* aging
* inflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310589
}}
{{medline-entry
|title=The Rules of Human T Cell Fate [i]in vivo[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32322253
|abstract=The processes governing lymphocyte fate (division, differentiation, and death), are typically assumed to be independent of cell age. This assumption has been challenged by a series of elegant studies which clearly show that, for murine cells [i]in vitro[/i], lymphocyte fate is age-dependent and that younger cells (i.e., cells which have recently divided) are less likely to divide or die. Here we investigate whether the same rules determine human T cell fate [i]in vivo[/i]. We combined data from [i]in vivo[/i] stable isotope labeling in healthy humans with stochastic, agent-based mathematical modeling. We show firstly that the choice of model paradigm has a large impact on parameter estimates obtained using stable isotope labeling i.e., different models fitted to the same data can yield very different estimates of T cell lifespan. Secondly, we found no evidence in humans [i]in vivo[/i] to support the model in which younger T cells are less likely to divide or die. This age-dependent model never provided the best description of isotope labeling; this was true for naïve and memory, [[CD4]]  and CD8  T cells. Furthermore, this age-dependent model also failed to predict an independent data set in which the link between division and death was explored using Annexin V and deuterated glucose. In contrast, the age-independent model provided the best description of both naïve and memory T cell dynamics and was also able to predict the independent dataset.

|keywords=* decision
* fate
* half-life
* labeling
* lifespan
* lymphocyte
* mathematical model
* proliferation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156550
}}
{{medline-entry
|title=[[CD4]]/CD8 ratio, comorbidities, and aging in treated HIV infected individuals on viral suppression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32314818
|abstract=The progression of the human immunodeficiency virus (HIV) infection to acquired immunodeficiency syndrome (AIDS) can be efficiently interrupted by antiretroviral therapy (ART). However, even successfully treated HIV-infected individuals are prone to develop non-AIDS-related diseases that affect the metabolism and several organs and systems. Biomarkers that predict the occurrence of comorbidities may help develop preventive measures. Current research shows that [[CD4]]  T cell counts and viral load do not predict the development of non-AIDS-related diseases. The [[CD4]]/CD8 ratio has been indicated as a suitable marker of persistent immune dysfunction and the occurrence of non-AIDS-related events in treated HIV-positive patients. In this study, we explored the relationship between [[CD4]]/CD8 ratios, comorbidities, and aging in ART-treated HIV patients on viral suppression. We collected and evaluated data from 352 HIV-positive adults who were virologically suppressed (<40 copies/mL) on ART and with [[CD4]] counts above 350 cells/mm  . The median age for participants was 46 years, 218 individuals had at least one comorbidity, and 239 had inverted [[CD4]]/CD8 ratios (<1). Current [[CD4]]/CD8 ratios were predicted by baseline [[CD4]]/CD8 ratios and nadir [[CD4]] counts. Despite the high rates of inverted [[CD4]]/CD8 ratios and prevalence of comorbidities, no association between them was observed. The prevalence of comorbidities was significantly higher in older individuals, though aging alone did not explain the rate of all individual comorbidities. Low [[CD4]]/CD8 ratios were linked to neurocognitive disorders, suggesting that persistent T cell dysfunction contributes to neurocognitive decline.

|keywords=* CD4/CD8 ratio
* HIV
* aging
* comorbidities
|full-text-url=https://sci-hub.do/10.1002/jmv.25911
}}
{{medline-entry
|title=The effects of advanced maternal age on T-cell subsets at the maternal-fetal interface prior to term labor and in the offspring: a mouse study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32279324
|abstract=Women who conceive at 35 years of age or older, commonly known as advanced maternal age, have a higher risk of facing parturition complications and their children have an increased risk of developing diseases later in life. However, the immunological mechanisms underlying these pathological processes have yet to be established. To fill this gap in knowledge, using a murine model and immunophenotyping, we determined the effect of advanced maternal age on the main cellular branch of adaptive immunity, T cells, at the maternal-fetal interface and in the offspring. We report that advanced maternal age impaired the process of labor at term, inducing dystocia and delaying the timing of delivery. Advanced maternal age diminished the number of specific proinflammatory T-cell subsets [T helper type 1 (Th1): [[CD4]]  IFN-γ  , CD8  IFN-γ  and Th9: [[CD4]]  IL-9  ], as well as [[CD4]]  regulatory T cells ([[CD4]]  CD25  FoxP3  T cells), at the maternal-fetal interface prior to term labor. Advanced maternal age also altered fetal growth and survival of the offspring in early life. In addition, infants born to advanced-age mothers had alterations in the T-cell repertoire but not in CD71  erythroid cells (CD3  CD71  TER119  cells). This study provides insight into the immune alterations observed at the maternal-fetal interface of advanced-age mothers and their offspring.
|mesh-terms=* Adult
* Aging
* Animals
* Female
* Humans
* Live Birth
* Mice
* Mice, Transgenic
* Placenta
* Pregnancy
* T-Lymphocyte Subsets
|keywords=* birth weight
* neonate
* offspring
* pregnancy
* preterm labor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290081
}}
{{medline-entry
|title=Structural and Functional Changes in the Mesenteric Lymph Nodes in Humans during Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32248450
|abstract=Morphometric analysis of structural and functional changes in the human mesenteric lymph nodes during aging revealed the development of fibrous connective tissue, fragmentation of the lymphoid parenchyma, the absence of follicles with germinal centers, and a decrease in the level of lymphocyte proliferation, which was confirmed by the absence of Ki-67  cells. The paracortical zone lacked [[CD4]]  T helpers that regulate both cellular and humoral immunity. High content of plasma cells and eosinophilic granulocytes in the medullary cords and sinuses reflects the development of autoimmune processes associated with a decrease in the number of regulatory T lymphocytes. The development of fibrous connective tissue in the sinus system complicates lymph flow through the lymph node and impairs lymph filtration.

|keywords=* age-related involution
* aging
* immune system
* immunomorphology
* mesenteric lymph nodes
|full-text-url=https://sci-hub.do/10.1007/s10517-020-04782-0
}}
{{medline-entry
|title=Neurocognitive Functioning is Associated with Self-Reported and Performance-Based Treatment Management Abilities in People Living with HIV with Low Health Literacy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32090235
|abstract=People living with HIV (PLWH) are at higher risk for poorer neurocognitive functioning and health literacy than uninfected persons, which are associated with worse medical outcomes. Aging research suggests that the effect of neurocognitive functioning on health outcomes may be more pronounced in those with low health literacy. We aimed to determine whether low health literacy might amplify the adverse effects of neurocognitive functioning on treatment management outcomes in 171 PLWH aged 40+. In this cross-sectional, observational study, participants completed a well-validated battery of neurocognitive, health literacy, and treatment management measures. A binary health literacy variable (low vs. adequate) was determined via established cut points on the well-validated health literacy tests. Treatment management outcomes included biomarkers of HIV (i.e., [[CD4]] counts and viral load), self-management of HIV disease (i.e., self-reported medication adherence and self-efficacy for HIV disease management), and performance-based health-related decision-making. Forty-seven percent of the sample met the criteria for low health literacy. Multivariable regressions adjusting for clinicodemographic (e.g., race, socioeconomic status) covariates revealed significant interactions for self-efficacy for HIV disease management and health-related decision-making, such that neurocognitive functioning was associated with these outcomes among those with low, but not adequate health literacy. Findings suggest that low health literacy may increase the vulnerability of PLWH to the adverse effects of neurocognitive impairment on health outcomes, or conversely that adequate health literacy may provide a buffer against the health risks associated neurocognitive impairment. Interventions targeting health literacy in PLWH may mitigate the effects of neurocognitive impairment on health outcomes.
|mesh-terms=* Adult
* Cognition
* Cross-Sectional Studies
* HIV Infections
* Health Literacy
* Humans
* Neuropsychological Tests
* Self Report
|keywords=* Adherence
* Aging
* Cognitive impairment
* HIV/AIDS
* Health illiteracy
* Observational study
|full-text-url=https://sci-hub.do/10.1093/arclin/acaa005
}}
{{medline-entry
|title=Blockade of Stat3 oncogene addiction induces cellular senescence and reveals a cell-nonautonomous activity suitable for cancer immunotherapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32064174
|abstract=Stat3 is constitutively activated in several tumor types and plays an essential role in maintaining their malignant phenotype and immunosupression. To take advantage of the promising antitumor activity of Stat3 targeting, it is vital to understand the mechanism by which Stat3 regulates both cell autonomous and non-autonomous processes. Here, we demonstrated that turning off Stat3 constitutive activation in different cancer cell types induces senescence, thus revealing their Stat3 addiction. Taking advantage of the senescence-associated secretory phenotype (SASP) induced by Stat3 silencing (SASP-siStat3), we designed an immunotherapy. The administration of SASP-siStat3 immunotherapy induced a strong inhibition of triple-negative breast cancer and melanoma growth associated with activation of [[CD4]] + T and NK cells. Combining this immunotherapy with anti-PD-1 antibody resulted in survival improvement in mice bearing melanoma. The characterization of the SASP components revealed that type I IFN-related mediators, triggered by the activation of the cyclic GMP-AMP synthase DNA sensing pathway, are important for its immunosurveillance activity. Overall, our findings provided evidence that administration of SASP-siStat3 or low dose of Stat3-blocking agents would benefit patients with Stat3-addicted tumors to unleash an antitumor immune response and to improve the effectiveness of immune checkpoint inhibitors.

|keywords=* Stat3
* immune checkpoint blockade
* immunotherapy
* oncogene addiction
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996562
}}
{{medline-entry
|title=Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32082401
|abstract=The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers ([i]n[/i] = 48, 21-84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40-69 yrs.; blood: [i]n[/i] = 13; TIL: [i]n[/i] = 17) and elderly cancer patients (70-90 yrs.; blood: [i]n[/i] = 20; TIL: [i]n[/i] = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of [[CD4]]  and CD8  T cells as well as regulatory T cells (T ) were assessed by flow cytometry. We observed lower frequencies of CD8  cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients.

|keywords=* Aging
* Head and neck cancer
* Immune escape
* Immunosenescence
* T cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017629
}}
{{medline-entry
|title=Immunological history governs human stem cell memory [[CD4]] heterogeneity via the Wnt signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32041953
|abstract=The diversity of the naïve T cell repertoire drives the replenishment potential and capacity of memory T cells to respond to immune challenges. Attrition of the immune system is associated with an increased prevalence of pathologies in aged individuals, but whether stem cell memory T lymphocytes (T ) contribute to such attrition is still unclear. Using single cells RNA sequencing and high-dimensional flow cytometry, we demonstrate that T  heterogeneity results from differential engagement of Wnt signaling. In humans, aging is associated with the coupled loss of Wnt/β-catenin signature in [[CD4]] T  and systemic increase in the levels of Dickkopf-related protein 1, a natural inhibitor of the Wnt/β-catenin pathway. Functional assays support recent thymic emigrants as the precursors of [[CD4]] T . Our data thus hint that reversing T  defects by metabolic targeting of the Wnt/β-catenin pathway may be a viable approach to restore and preserve immune homeostasis in the context of immunological history.
|mesh-terms=* Aging
* Animals
* Antigens, CD
* CD4-Positive T-Lymphocytes
* Gene Expression Profiling
* HIV Infections
* Humans
* Immunologic Memory
* Intercellular Signaling Peptides and Proteins
* Mice
* Precursor Cells, T-Lymphoid
* Thymus Gland
* Wnt Signaling Pathway
* beta Catenin

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010798
}}
{{medline-entry
|title=Estimating HIV Management and Comorbidity Costs Among Aging HIV Patients in the United States: A Systematic Review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32011956
|abstract=As life expectancy of patients infected with human immunodeficiency virus (HIV) approaches that of the general population, the composition of HIV management costs is likely to change. To (a) review treatment and disease management costs in HIV, including costs of adverse events (AEs) related to antiretroviral therapy (ART) and long-term toxicities, and (b) explore the evolving cost drivers. A targeted literature review between January 2012 and November 2017 was conducted using PubMed and major conferences. Articles reporting U.S. costs of HIV management, acquired immunodeficiency syndrome (AIDS)-defining events, end of life care, and ART-associated comorbidities such as cardiovascular disease (CVD), chronic kidney disease (CKD), and osteoporosis were included. All costs were inflated to 2017 U.S. dollars. A Markov model-based analysis was conducted to estimate the effect of increased life expectancy on costs associated with HIV treatment and management. 22 studies describing HIV costs in the United States were identified, comprising 16 cost-effectiveness analysis studies, 5 retrospective analyses of health care utilization, and 1 cost analysis in a resource-limited setting. Management costs per patient per month, including routine care costs (on/off ART), non-HIV medication, opportunistic infection prophylaxis, inpatient utilization, outpatient utilization, and emergency department utilization were reported as [[CD4]]+ cell-based health state costs ranging from $1,192 for patients with [[CD4]] > 500 cells/mm  to $2,873 for patients with [[CD4]] < 50 cells/mm . Event costs for AEs ranged from $0 for headache, pain, vomiting, and lipodystrophy to $31,545 for myocardial infarction. The mean monthly per-patient costs for CVD management, CKD management, and osteoporosis were $5,898, $6,108, and $4,365, respectively. Improvements in life expectancy, approaching that of the general population in 2018, are projected to increase ART-related and AE costs by 35.4% and comorbidity costs by 175.8% compared with estimated costs with HIV life expectancy observed in 1996. This study identified and summarized holistic cost estimates appropriate for use within U.S. HIV cost-effectiveness analyses and demonstrates an increasing contribution of comorbidity outcomes, primarily associated with aging in addition to long-term treatment with ART, not typically evaluated in contemporary HIV cost-effectiveness analyses. This analysis was sponsored by ViiV Healthcare, which had no role in the analyses and interpretation of study results. Ward, Sugrue, Hayward, and McEwan are employees of HEOR Ltd, which received funding from ViiV Healthcare to conduct this study. Anderson is an employee of GlaxoSmithKline and holds shares in the company. Punekar and Oglesby are employees of ViiV Healthcare and hold shares in GlaxoSmithKline. Lopes was employed by ViiV Healthcare at the time of the study and holds shares in GlaxoSmithKline.
|mesh-terms=* Anti-HIV Agents
* CD4 Lymphocyte Count
* Comorbidity
* Cost-Benefit Analysis
* HIV Infections
* Health Care Costs
* Humans
* Life Expectancy
* United States

|full-text-url=https://sci-hub.do/10.18553/jmcp.2020.26.2.104
}}
{{medline-entry
|title=Sex Differences in People Aging With HIV.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32032279
|abstract=To evaluate differences between older women and men with HIV regarding HIV variables, comorbidity, physical function, and quality of life (QOL). The Modena HIV clinic. Prospective cohort study. Cross-sectional analysis. Patients >50 years were included, stratified by sex. We recorded sociodemographic data, comorbidities, variables related to HIV infection, frailty, data on body composition, physical function, physical activity, and QOL. We evaluated 1126 older adults with HIV, of which 284 (25.2%) were women. Median age was 55 (IQR 6) years. There were significant differences between women and men in the median current [[CD4]] T-cell and the mean [[CD4]]/CD8 ratio. There were differences regarding alcohol consumption, cardiovascular (CV) disease, hypertension, diabetes mellitus, and renal failure. Sarcopenia and slower gait speed were found more prevalent among men, but without significant differences. Significant differences were found regarding lower extremity strength measured by the chair stand test and in the short physical performance battery score. Short physical performance battery <9 was detected for 11.1% women vs. 5.6% men (P = 0.002). EQ5D5L score was 0.87 in women vs. 0.89 in men (P = 0.002). In our cohort, older women represented one in 4 of the total patients. Despite the fact that women have better immunological recovery measured by [[CD4]] T-cell count and [[CD4]]/CD8 ratio, and fewer CV disease and CV risk factors than men, their physical function and their QOL are worse. Therefore, older HIV-infected women have special characteristics, and the assessment of physical function in this group seems to be crucial.
|mesh-terms=* Aged
* Aging
* Alcohol Drinking
* Body Composition
* CD4 Lymphocyte Count
* CD4-CD8 Ratio
* CD4-Positive T-Lymphocytes
* Cohort Studies
* Cross-Sectional Studies
* Female
* Frailty
* HIV Infections
* Humans
* Male
* Middle Aged
* Muscle Strength
* Prospective Studies

|full-text-url=https://sci-hub.do/10.1097/QAI.0000000000002259
}}
{{medline-entry
|title=Identification of Differentially Expressed miRNAs in the Response of Spleen [[CD4]]  T Cells to Electroacupuncture in Senescence-Accelerated Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32026263
|abstract=Immunological aging impairs immune system protection in the body and is associated with high morbidity and mortality in aged people. Electroacupuncture (EA) has been proven to boost immunity. The purpose of this study was to identify the effect of EA on miRNA expression in the immune system of senescence-accelerated mouse P8 (SAMP8) mice. We utilized SAMP8 mice as an aging model and detected the altered expression of miRNAs in [[CD4]]  T cells after EA stimulation by deep sequencing. Differentially expressed miRNAs in different groups were identified using Venn diagrams and functional analysis was performed. The effect of EA on the expression of the identified miRNAs was investigated in natural-aged C57BL/6J mice and the biological functions of miR-301a-3p and miR-181a-1-3p in [[CD4]]  T cells were identified. Four upregulated and two downregulated miRNAs were identified in group I (EA-SAMP8 vs. shEA-SAMP8); 41 upregulated and nine downregulated miRNAs were identified in group II (EA-SAMP8 vs. SAMP8); 42 upregulated and eight downregulated miRNAs were identified in group III (shEA-SAMP8 vs. SAMP8). The three groups shared four overlapping differentially expressed miRNAs, and 10 miRNAs were only found in group II. Gene Ontology enrichment analysis of these 14 miRNAs revealed that their target genes were enriched in 229 "biological process" categories. Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the targets were significantly mapped in 76 pathways. Furthermore, five significant pathways were involved in T cell differentiation. MiRNA-gene-net showed that miR-582-5p, miR-17-5p, miR-144-3p, miR-451a, and miR-301a-3p regulated the most important target genes in these pathways. The expression of these miRNAs was also regulated by EA in aged C57BL/6J mice. In addition, miR-301a-3p was involved in regulating the expression of inflammatory factors by mediating the differentiation of [[CD4]]  T cells in C57BL/6J mice. Analysis of miRNAs indicated that EA contributes to maintaining the balance of [[CD4]]  T cell differentiation in the aging immune system. These results provide novel insights into the effect of EA in immunological aging.
|mesh-terms=* Aging
* Animals
* Antagomirs
* CD4-Positive T-Lymphocytes
* Cell Differentiation
* Cytokines
* Down-Regulation
* Electroacupuncture
* Female
* Gene Regulatory Networks
* High-Throughput Nucleotide Sequencing
* Male
* Mice
* Mice, Inbred C57BL
* MicroRNAs
* Sequence Analysis, RNA
* Spleen
* Up-Regulation
|keywords=* CD4+ T cell
* Deep sequencing
* Electroacupuncture
* Immunological aging
* miRNA
|full-text-url=https://sci-hub.do/10.1007/s12013-020-00900-x
}}
{{medline-entry
|title=Thymus Involution and Intravenous Drug Abuse.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32000220
|abstract=Thymus glands from 283 autopsy cases were sampled and evaluated with histochemical and immunohistochemical methods. A subpopulation of 41 intravenous drug addicts were compared with age-matched control cases.It was found that an accelerated involution of the thymus occurred in the 20- to 25-year interval and thereafter with a steady pace of 5% per year. Also the size of Hassall bodies declined successively.In drug addicts, an increased dystrophic calcification of the Hassall bodies and a significant difference in thymus size (atrophy) compared with controls were seen. Moreover, a difference was seen in the relative numbers of [[CD4]] and CD8 lymphocytes where [[CD4]]+ cells were reduced in drug addicts.It is hypothesized that signs of hepatitis C virus infection that was found in the majority of drug addicts and the reduced number of functionally intact Hassall corpuscles could explain the reduction of [[CD4]]+ lymphocytes and thymic hypotrophy in this population.
|mesh-terms=* Adolescent
* Adult
* Aging
* Atrophy
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Calcinosis
* Case-Control Studies
* Drug Users
* Female
* Forensic Pathology
* Hepatitis C, Chronic
* Humans
* Male
* Middle Aged
* Substance Abuse, Intravenous
* Thymus Gland
* Young Adult

|full-text-url=https://sci-hub.do/10.1097/PAF.0000000000000530
}}
{{medline-entry
|title=Depletion of [[CD4]] T cells provides therapeutic benefits in aged mice after ischemic stroke.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31954116
|abstract=T-lymphocytes have a multifaceted role in ischemic stroke, but the majority of studies have been conducted in young mice, which may limit the translational value of these findings. Previous studies have shown that aging results in T cell dysfunction, leading to enhanced production of pro-inflammatory cytokines and chemokines, including interferon gamma (IFN-γ) and interferon-gamma-inducible protein (IP-10). This study assessed the role of T cells and pro-inflammatory factors on histologic and functional outcomes in an aged mouse model. Levels of IP-10 were measured in the brain and serum of young and aged male mice following middle cerebral artery occlusion (MCAo) or sham surgery. Additionally, IP-10 levels were evaluated in stroke patients. To directly determine the role of brain-infiltrating T cells after stroke, a separate cohort of aged male and female animals received either an anti-[[CD4]] depletion antibody or IgG isotype control at 72 and 96 h following experimental stroke. Behavioral assessments were performed on day 7 post-MCAo. [[CD4]] T cell depletion resulted in improved behavioral outcomes, despite the lack of differences in infarct size between the isotype control and anti-[[CD4]] antibody treated stroke groups. Circulating IP-10 levels were increased in both humans and mice with age and stroke, and depletion of [[CD4]] T cells led to a reduction in IFN-γ and IP-10 levels in mice. Since anti-[[CD4]] treatment was administered three days after stroke onset, targeting this inflammatory pathway may be beneficial to aged stroke patients who present outside of the current time window for thrombolysis and thrombectomy.
|mesh-terms=* Aging
* Animals
* Behavior, Animal
* Brain Chemistry
* Brain Ischemia
* CD4-Positive T-Lymphocytes
* Chemokines
* Cytokines
* Female
* Infarction, Middle Cerebral Artery
* Inflammation
* Male
* Mice
* Mice, Inbred C57BL
* Stroke
* Treatment Outcome
|keywords=* Age
* CD4 T cells
* CXCL10
* Inflammation
* Stroke
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059209
}}
{{medline-entry
|title=Immunological and Virological Responses in Older HIV-Infected Adults Receiving Antiretroviral Therapy: An Evidence-Based Meta-Analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31913990
|abstract=Millions of people living with the HIV have received antiretroviral therapy (ART). Older adults make up a significant portion of these individuals; however, the immunological and virological responses to ART for older patients still need to be clarified. Meta-analysis. In this article, we systematically reviewed research articles published between 2001 and 2018 that reported immunological and virological responses and AIDS-related mortality among HIV- infected adults (including individuals aged 50 years and older) receiving ART, using meta-analysis. ART efficiency was measured using 3 outcomes: (1) immunological response, (2) virological response, and (3) mortality. We identified 4937 citations, and 40 studies were eventually selected to investigate ART efficiency in older HIV-infected patients, comprising more than 888,151 patients initiating ART. We report that older patients showed poor immunological responses, with [[CD4]] counts and the restoration of [[CD4]] counts after ART initiation being significantly lower than seen in younger patients. However, older patients exhibited better viral suppression rates (risk ratio: 1.04; 95% confidence intervals: 1.01 to 1.08) after 36 months following ART initiation. In addition, older adults had a higher risk of AIDS-related death (adjusted hazard ratio: 1.44, 95% confidence interval: 1.30 to 1.60). Older age after ART initiation was associated with a poorer immunological response and a higher risk of mortality, suggesting the need to increase early diagnosis and treatment among older HIV patients.
|mesh-terms=* Aged
* Aging
* Anti-HIV Agents
* HIV Infections
* Humans
* Middle Aged

|full-text-url=https://sci-hub.do/10.1097/QAI.0000000000002266
}}
{{medline-entry
|title=African Mitochondrial DNA Haplogroup L2 Is Associated With Slower Decline of β-cell Function and Lower Incidence of Diabetes Mellitus in Non-Hispanic, Black Women Living With Human Immunodeficiency Virus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31927570
|abstract=Susceptibility to metabolic diseases may be influenced by mitochondrial genetic variability among people living with human immunodeficiency virus (HIV; PLWH), but remains unexplored in populations with African ancestry. We investigated the association between mitochondrial DNA (mtDNA) haplogroups and the homeostatic model assessments of β-cell function (HOMA-B) and insulin resistance (HOMA-IR), as well as incident diabetes mellitus (DM), among Black women living with or at risk for HIV. Women without DM who had fasting glucose (FG) and insulin (FI) data for ≥2 visits were included. Haplogroups were inferred from genotyping data using HaploGrep. HOMA-B and HOMA-IR were calculated using FG and FI data. Incident DM was defined by a combination of FG ≥ 126 mg/dL, the use of DM medication, a DM diagnosis, or hemoglobin A1c ≥ 6.5%. We compared HOMA-B, HOMA-IR, and incident DM by haplogroups and assessed the associations between HOMA-B and HOMA-IR and DM by haplogroup. Of 1288 women (933 living with HIV and 355 living without HIV), PLWH had higher initial HOMA-B and HOMA-IR than people living without HIV. PLWH with haplogroup L2 had a slower decline in HOMA-B per year (Pinteraction = .02) and a lower risk of incident DM (hazard ratio [HR], 0.51; 95% confidence interval [CI], .32-.82) than PLWH with other haplogroups after adjustments for age, body mass index, combination antiretroviral therapy use, [[CD4]] cell counts, and HIV RNA. The impact of HOMA-IR on incident DM was less significant in those with haplogroup L2, compared to non-L2 (HR, 1.28 [95% CI, .70-2.38] vs 4.13 [95% CI, 3.28-5.22], respectively; Pinteraction < .01), among PLWH. Mitochondrial genetic variation is associated with β-cell functions and incident DM in non-Hispanic, Black women with HIV and alters the relationship between insulin resistance and DM.

|keywords=* HIV
* aging
* diabetes mellitus
* mitochondrial genetics
|full-text-url=https://sci-hub.do/10.1093/cid/ciaa026
}}
{{medline-entry
|title=DP1 Activation Reverses Age-Related Hypertension Via NEDD4L-Mediated T-Bet Degradation in T Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31893939
|abstract=Blood pressure often rises with aging, but exact mechanisms are still not completely understood. With aging, the level of proinflammatory cytokines increases in T lymphocytes. Prostaglandin D , a proresolution mediator, suppresses Type 1 T helper (Th1) cytokines through D-prostanoid receptor 1 (DP1). In this study, we aimed to investigate the role of the prostaglandin D /DP1 axis in T cells on age-related hypertension. To clarify the physiological and pathophysiological roles of DP1 in T cells with aging, peripheral blood samples were collected from young and older male participants, and [[CD4]]  T cells were sorted for gene expression, prostaglandin production, and Western blot assays. Mice blood pressure was quantified by invasive telemetric monitor. The prostaglandin D /DP1 axis was downregulated in [[CD4]]  T cells from older humans and aged mice. DP1 deletion in [[CD4]]  T cells augmented age-related hypertension in aged male mice by enhancing Th1 cytokine secretion, vascular remodeling, [[CD4]]  T cells infiltration, and superoxide production in vasculature and kidneys. Conversely, forced expression of exogenous DP1 in T cells retarded age-associated hypertension in mice by reducing Th1 cytokine secretion. Tumor necrosis factor α neutralization or interferon γ deletion ameliorated the age-related hypertension in DP1 deletion in [[CD4]]  T cells mice. Mechanistically, DP1 inhibited Th1 activity via the PKA (protein kinase A)/p-Sp1 (phosphorylated specificity protein 1)/neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) pathway-mediated T-box-expressed-in-T-cells (T-bet) ubiquitination. T-bet deletion or forced NEDD4L expression in [[CD4]]  T cells attenuated age-related hypertension in [[CD4]]  T cell-specific DP1-deficient mice. DP1 receptor activation by BW245C prevented age-associated blood pressure elevation and reduced vascular/renal superoxide production in male mice. The prostaglandin D /DP1 axis suppresses age-related Th1 activation and subsequent hypertensive response in male mice through increase of NEDD4L-mediated T-bet degradation by ubiquitination. Therefore, the T cell DP1 receptor may be an attractive therapeutic target for age-related hypertension.
|mesh-terms=* Aged
* Aging
* Animals
* Antihypertensive Agents
* CD4-Positive T-Lymphocytes
* Cyclic AMP-Dependent Protein Kinases
* Cytokines
* Humans
* Hypertension
* Mice
* Mice, Inbred C57BL
* Nedd4 Ubiquitin Protein Ligases
* Prostaglandin D2
* Receptors, Prostaglandin
* Signal Transduction
* Sp1 Transcription Factor
* Superoxides
* T-Box Domain Proteins
* Th1 Cells
* Ubiquitination
|keywords=* D-prostanoid receptor 1
* aging
* hypertension
* lymphocyte
* prostaglandin (PG) D2
|full-text-url=https://sci-hub.do/10.1161/CIRCULATIONAHA.119.042532
}}
{{medline-entry
|title=An Emerging Concern-High Rates of Frailty among Middle-aged and Older Individuals Living with HIV.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31885759
|abstract=The aim of the present study was to calculate a frailty index (FI) in older adults (≥50) living with HIV, search for cross-sectional associations with the FI, and investigate the association between the FI score and two-year mortality. Cross-sectional study with a short-term prospective component for the determination of two-year mortality was performed. The study took place in an HIV outpatient clinic in Calgary, Canada between November 1, 2016 and December 31, 2018. Over 700 patients 50 years of age or older took part. We calculated a FI for each patient, examined associations between FI and select patient characteristics, and evaluated the association between FI value and two-year mortality. The mean FI was 0.303 (± 0.128). Mean FI did not differ between males and females, nor was it associated with either nadir or current [[CD4]] cell count. It did increase with age, duration of ART, and duration of diagnosed HIV infection. Mean FI was higher among those who died compared to survivors (0.351 vs. 0.301; [i]p[/i]=.033). Frailty is highly prevalent in persons living with HIV and associated with a higher mortality rate. Health-care providers should be aware of the earlier occurrence of frailty in adults living with HIV.

|keywords=* accelerated aging
* anti-retroviral therapy
* frailty
* frailty index
* geriatric syndrome
* human immunodeficiency virus (HIV)
* multimorbidity
* vulnerability
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887139
}}
{{medline-entry
|title=Higher Acuity Resource Utilization With Older Age and Poorer HIV Control in Adolescents and Young Adults in the HIV Research Network.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31904706
|abstract=Adolescents and young adults (AYA) with HIV experience poorer health outcomes compared with adults. To improve care for AYA with HIV, information about patterns of costly health care resource utilization is needed. Among 13-30 year olds in the US HIV Research Network, we stratified outpatient visits, emergency department (ED) visits, and inpatient days/person-year (PY) by HIV acquisition model [perinatal (PHIVY) and nonperinatal (NPHIVY)], age (13-17, 18-23, and 24-30 years), [[CD4]] strata (<200, 200-499, and ≥500 cells/µL), and viral load (VL) suppression (<, ≥400 copies/mL [c/mL]) combined with antiretroviral (ARV) use. Among 4540 AYA (PHIVY: 15%; NPHIVY: 85%), mean follow-up was 2.8 years. Among PHIVY, most person-time (PT) was spent between ages 13 and 23 years (13-17 years: 43%; 18-23 years: 45%), [[CD4]] ≥500/µL (61%), and VL <400 c/mL (69%). Among NPHIVY, most PT was spent between ages 24 and 30 years (56%), with [[CD4]] ≥500/µL (54%), and with VL <400 c/mL (67%). PT spent while prescribed ARVs and with VL ≥400 c/mL was 29% (PHIVY) and 24% (NPHIVY). For PHIVY and NPHIVY, outpatient visit rates were higher at younger ages (13-17 years and 18-23 years), lower [[CD4]] (<200 and 200-499/µL), and among those prescribed ARVs. Rates of ED visits and inpatient days were higher during PT spent at older ages (18-23 years and 24-30 years), lower [[CD4]] (<200 and 200-499/µL), and VL ≥400 c/mL. Utilization was higher among PHIVY than NPHIVY (outpatient: 12.1 vs. 6.0/PY; ED: 0.4 vs. 0.3/PY; inpatient: 1.5 vs. 0.8/PY). More ED visits and inpatient days were observed during time spent at older ages, lower [[CD4]] count, and VL ≥400 c/mL. Interventions to improve virologic suppression and immune response may improve outcomes, and thus decrease costly resource utilization, for AYA with HIV.
|mesh-terms=* Adolescent
* Adult
* Aging
* Anti-Retroviral Agents
* CD4 Lymphocyte Count
* Drug Administration Schedule
* Female
* HIV Infections
* HIV-1
* Humans
* Male
* Medication Adherence
* Viral Load
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055514
}}
{{medline-entry
|title=Mitochondrial DNA Haplogroups and Frailty in Adults Living with HIV.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31822125
|abstract=Mitochondrial DNA (mtDNA) haplogroup has been associated with disease risk and longevity. Among persons with HIV (PWH), mtDNA haplogroup has been associated with AIDS progression, neuropathy, cognitive impairment, and gait speed decline. We sought to determine whether haplogroup is associated with frailty and its components among older PWH. A cross-sectional analysis was performed of AIDS Clinical Trials Group A5322 (HAILO) participants with available genome-wide genotype and frailty assessments. Multivariable logistic regression models adjusted for age, gender, education, smoking, hepatitis C, and prior use of didanosine/stavudine. Among 634 participants, 81% were male, 49% non-Hispanic white, 31% non-Hispanic black, and 20% Hispanic. Mean age was 51.0 (standard deviation 7.5) years and median nadir [[CD4]] count was 212 (interquartile range 72, 324) cells/μL; 6% were frail, 7% had slow gait, and 21% weak grip. H haplogroup participants were more likely to be frail/prefrail ([i]p[/i] = .064), have slow gait ([i]p[/i] = .09), or weak grip ([i]p[/i] = .017) compared with non-H haplogroup participants (not all comparisons reached statistical significance). In adjusted analyses, PWH with haplogroup H had a greater odds of being frail versus nonfrail [odds ratio (OR) 4.0 (95% confidence interval 1.0-15.4)] and having weak grip [OR 2.1 (1.1, 4.1)], but not slow gait [OR 1.6 (0.5, 5.0)] compared with non-H haplogroup. Among black and Hispanic participants, haplogroup was not significantly associated with frailty, grip, or gait. Among antiretroviral therapy (ART)-treated PWH, mtDNA haplogroup H was independently associated with weak grip and frailty. This association could represent a mechanism of weakness and frailty in the setting of HIV and ART.

|keywords=* HIV
* aging
* frailty
* haplotypes
* mitochondria
* sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133433
}}
{{medline-entry
|title=Gallic acid attenuates thymic involution in the d-galactose induced accelerated aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31822433
|abstract=Senescence is an inevitable and complicated phenomenon. Age-associated thymic involution increases the risk of infectious diseases, which results in the immunosenescence and leads to a poor immune function. d-galactose (d-gal) can cause damages that resemble accelerated aging in mice. Gallic acid (GA), as one of the natural phenolic compounds, has been demonstrated to act in antioxidant and anti-tumor effects. In this study, we explored the effects of GA in preventing the age-related thymic involution and the alterations of the forkhead box protein N1 (FoxN1) in d-gal induced accelerated aging mice. The accelerated aging mice model was established by intraperitoneal injection d-gal for eight weeks and given GA with 200, 250, 500 mg/kg body weight per day, respectively, for six weeks. It showed that the d-gal-treated mice developed structural changes in the thymi compared to normal control mice. With supplement of GA, the mice restored the normal thymic anatomy, including the thickening cortex compartment and clearer cortico-medullary junction. The d-gal-treated mice showed a severe reduction in the number of thymocytes, GA mice also displayed the increased numbers of [[CD4]] + T cells through flow cytometric analysis. GA treatment increased the proliferative cells by BrdU incorporation assay and reduced the numbers of apoptotic cells with FITC-12-dUTP labeling (TUNEL). The expression of FoxN1 was also found increased in GA treated mice by immunohistochemistry and quantitative reverse transcriptase PCR (qRT-PCR). Taken together, our results suggested that the administration of GA opposed the involution of thymus via stimulation of FoxN1 expression and proliferation of cells in a dose-dependent manner.

|keywords=* Aging
* FoxN1
* Gallic acid
* Thymus
* d-galactose
|full-text-url=https://sci-hub.do/10.1016/j.imbio.2019.11.005
}}
{{medline-entry
|title=Mitochondrial mass governs the extent of human T cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31788930
|abstract=The susceptibility of human [[CD4]]  and CD8  T cells to senesce differs, with CD8  T cells acquiring an immunosenescent phenotype faster than the [[CD4]]  T cell compartment. We show here that it is the inherent difference in mitochondrial content that drives this phenotype, with senescent human [[CD4]]  T cells displaying a higher mitochondrial mass. The loss of mitochondria in the senescent human CD8  T cells has knock-on consequences for nutrient usage, metabolism and function. Senescent [[CD4]]  T cells uptake more lipid and glucose than their CD8  counterparts, leading to a greater metabolic versatility engaging either an oxidative or a glycolytic metabolism. The enhanced metabolic advantage of senescent [[CD4]]  T cells allows for more proliferation and migration than observed in the senescent CD8  subset. Mitochondrial dysfunction has been linked to both cellular senescence and aging; however, it is still unclear whether mitochondria play a causal role in senescence. Our data show that reducing mitochondrial function in human [[CD4]]  T cells, through the addition of low-dose rotenone, causes the generation of a [[CD4]]  T cell with a CD8  -like phenotype. Therefore, we wish to propose that it is the inherent metabolic stability that governs the susceptibility to an immunosenescent phenotype.
|mesh-terms=* Adenosine Triphosphate
* Adult
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Cell Movement
* Cell Proliferation
* Cellular Senescence
* Glucose
* Glycolysis
* Humans
* Immunosenescence
* Leukocyte Common Antigens
* Microscopy, Electron, Transmission
* Middle Aged
* Mitochondria
* Rotenone
|keywords=* T cell
* aging
* metabolism
* mitochondria
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996952
}}
{{medline-entry
|title=T cells and immune functions of plasma extracellular vesicles are differentially modulated from adults to centenarians.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31785146
|abstract=Aging is a universal and complex process that affects all tissues and cells types, including immune cells, in a process known as immunosenescence. However, many aspects of immunosenescence are not completely understood, as the characteristics of the immune cells of nonagenarians and centenarians or the features and implications of extracellular vesicles (EVs). In this study, we analyzed blood samples from 51 individuals aged 20-49 and 70-104 years. We found that senescent CD8 cells accumulate with age, while there is a partial reduction of senescent [[CD4]] cells in nonagenarians and centenarians. Moreover, plasma EVs carry T cell specific markers, but no accumulation of "senescent-like EVs" was found within any of analyzed age groups. Our functional studies of cocultures of peripheral blood mononuclear cells and EVs showed that EVs enhance T cell viability and, under phytohemagglutinin stimulation, they influence cytokine secretion and cell activation in an age-dependent manner. These results underline the importance of EVs on the immune system functioning, and open new perspectives to further study their implication in human aging.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Extracellular Vesicles
* Female
* Humans
* Immunosenescence
* Lymphocyte Activation
* Male
* Middle Aged
* T-Lymphocytes
|keywords=* T cells
* aging
* centenarians
* extracellular vesicles (EVs)
* immunosenescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914389
}}
{{medline-entry
|title=Defects in Antiviral T Cell Responses Inflicted by Aging-Associated miR-181a Deficiency.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31747595
|abstract=Generation of protective immunity to infections and vaccinations declines with age. Studies in healthy individuals have implicated reduced miR-181a expression in T cells as contributing to this defect. To understand the impact of miR-181a expression on antiviral responses, we examined LCMV infection in mice with miR-181ab1-deficient T cells. We found that miR-181a deficiency delays viral clearance, thereby biasing the immune response in favor of [[CD4]] over CD8 T cells. Antigen-specific [[CD4]] T cells in mice with miR-181a-deficient T cells expand more and have a broader TCR repertoire with preferential expansion of high-affinity T cells than in wild-type mice. Importantly, generation of antigen-specific miR-181a-deficient CD8 effector T cells is particularly impaired, resulting in lower frequencies of CD8 T cells in the liver even at time points when the infection has been cleared. Consistent with the mouse model, [[CD4]] memory T cells in individuals infected with West Nile virus at older ages tend to be more frequent and of higher affinity.
|mesh-terms=* Aging
* Animals
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Disease Models, Animal
* Lymphocytic Choriomeningitis
* Lymphocytic choriomeningitis virus
* Mice
* MicroRNAs
|keywords=* CD8 effector T cell
* T cell repertoire
* antiviral response
* immune aging
* immunosenescence
* microRNA
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957231
}}
{{medline-entry
|title=Increased Prevalence of Neurocognitive Impairment in Aging People Living With Human Immunodeficiency Virus: The ANRS EP58 HAND 55-70 Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31755936
|abstract=There are limited data on the comparative prevalence of neurocognitive impairment (NCI) in aging people living with human immunodeficiency virus (PLHIV) and people not living with HIV. This was a cross-sectional study of PLHIV randomly matched by age (±4 years), gender, and education with 5 HIV-uninfected individuals from the CONSTANCES cohort. PLHIV were fluent in French and sequentially included during routine outpatient visits if aged 55-70 years, with HIV viral load <50 copies/mL, and lymphocyte T-[[CD4]] level ≥200 cells/µL in the past 24 and 12 months, respectively. The primary outcome was NCI as defined by the Frascati criteria. Multivariate normative comparison (MNC) and -1.5 standard deviations in ≥2 neurocognitive domains were secondary outcomes of NCI. Two hundred PLHIV were matched with 1000 controls. Median age was 62 years, and 85% were men. In PLHIV, the median T-[[CD4]] lymphocyte level was 650 cells/µL, and median nadir T-[[CD4]] lymphocyte level was 176 cells/µL. NCI was found in 71 (35.5%) PLHIV and in 242 (24.2%) controls (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.25, 2.41). After adjusting for confounders, HIV remained significantly associated with NCI (OR, 1.50; 95% CI, 1.04, 2.16). Adjusted results were similar with NCI defined by MNC (ORMNC, 2.95; 95% CI, 1.13, 3.50) or -1.5 SD (OR-1.5, 2.24; 95% CI, 1.39, 3.62). In this matched study of aging individuals, HIV was significantly associated with an increased risk of NCI after adjusting for major confounders. Results were confirmed with more stringent NCI classifications. NCT02592174.

|keywords=* Frascati criteria
* HAND
* HIV
* aging
* neurocognitive impairment
|full-text-url=https://sci-hub.do/10.1093/cid/ciz670
}}
{{medline-entry
|title=Age-associated changes in human [[CD4]]  T cells point to mitochondrial dysfunction consequent to impaired autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31707363
|abstract=To gain understanding on the mechanisms that drive immunosenescence in humans, we examined [[CD4]]  T cells obtained from younger (20-39 years-old) and older (70+ years-old) healthy participants of the Baltimore Longitudinal Study on Aging (BLSA). We found that mitochondrial proteins involved in the electron transport chain were overrepresented in cells from older participants, with prevalent dysregulation of oxidative phosphorylation and energy metabolism molecular pathways. Surprisingly, gene transcripts coding for mitochondrial proteins pertaining to oxidative phosphorylation and electron transport chain pathways were underrepresented in older individuals. Paralleling the observed decrease in gene expression, mitochondrial respiration was impaired in [[CD4]]  T cells from older subjects. Though mitochondrial number in both naïve and memory cells visualized with electron microcopy was similar in older versus younger participants, there were a significantly higher number of autophagosomes, many of them containing undegraded mitochondria, in older individuals. The presence of mitochondria inside the accumulated autophagic compartments in [[CD4]]  T cells from older individuals was confirmed by immunofluorescence. These findings suggest that older age is associated with persistence of dysfunctional mitochondria in [[CD4]]  T lymphocytes caused by defective mitochondrial turnover by autophagy, which may trigger chronic inflammation and contribute to the impairment of immune defense in older persons.
|mesh-terms=* Adult
* Aged
* CD4-Positive T-Lymphocytes
* Cell Respiration
* Humans
* Immunosenescence
* Longitudinal Studies
* Mitochondria
* Mitophagy
* Young Adult
|keywords=* CD4+ T cells
* aging
* autophagy
* mitochondria
* proteomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874450
}}
{{medline-entry
|title=Sex Differences in the Blood Transcriptome Identify Robust Changes in Immune Cell Proportions with Aging and Influenza Infection.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31722210
|abstract=Sex differences in autoimmunity and infection suggest that a better understanding of molecular sex differences will improve the diagnosis and treatment of immune-related disease. We identified 144 differentially expressed genes, referred to as immune sex expression signature (iSEXS), between human males and females using an integrated multi-cohort analysis of blood transcriptome profiles from six discovery cohorts from five continents with 458 healthy individuals. We validated iSEXS in 11 additional cohorts of 524 peripheral blood samples. When we separated iSEXS into genes located on sex chromosomes (XY-iSEXS) or autosomes (autosomal-iSEXS), both modules distinguished males and females. iSEXS reflects sex differences in immune cell proportions, with female-associated genes showing higher expression by [[CD4]]  T cells and male-associated genes showing higher expression by myeloid cells. Autosomal-iSEXS detected an increase in monocytes with age in females, reflected sex-differential immune cell dynamics during influenza infection, and predicted antibody response in males, but not females.
|mesh-terms=* Aging
* CD4-Positive T-Lymphocytes
* Female
* Humans
* Influenza, Human
* Male
* Monocytes
* Sex Characteristics
* Transcriptome
|keywords=* CD4(+) T cells
* aging
* immune system
* immunology
* influenza
* meta-analysis
* monocytes
* multi-cohort analysis
* sex differences
* transcriptome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856718
}}
{{medline-entry
|title=Going Beyond Giving Antiretroviral Therapy: Multimorbidity in Older People Aging with HIV in Nigeria.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31711310
|abstract="Graying of HIV epidemic" is observed globally, as people living with HIV (PLWH) are aging, due to effectiveness of antiretrovirals. The normal aging processes and HIV-induced immune dysfunction, are potential mechanisms, driving multimorbidity (MM) in PLWH. MM is the concurrent presence of two or more diseases in a single individual. Aging PLWH, are at increased risk of acute and chronic morbidities compared with counterpart without HIV. Despite increasing concern in Nigeria, research on correlates of MM in aging PLWH is lagging. This was a comparative study, of ≥60 years of age, age-matched (±5 years) HIV-positive and HIV-negative patients. Patients were recruited, from the Infectious Disease Institute and Geriatric clinics of the University College Hospital, Ibadan, Nigeria, between April and June 2018. MM was defined as the occurrence of more than two morbidities in an individual, and it was considered acute, when within 30 days and chronic, when above 3-months duration. Data analysis was done using SPSS 23. We studied 186 individuals (62 HIV-positive and 124 HIV-negative). The PLWH had lower mean age (63.9 vs. 68.1 years, [i]p[/i] = .00, [i]t[/i] = 5.68), more chronic MM (2.0 vs. 1.3, [i]p[/i] = .004, [i]t[/i] = 2.970), which occurred earlier (4.7 vs. 9.6 years, [i]p[/i] = .003, [i]t[/i] = 3.05), more overall MM (3.6 vs. 2.8, [i]p[/i] = .015, [i]t[/i] = 2.448), and lower quality of life (82.7 vs. 86.2, [i]p[/i] = .002, [i]t[/i] = 3.130). Risk estimates for "any" MM revealed the odds are in favor of the older PLWH [69.4% vs. 46.8%, [i]p[/i] = .004, odds ratio = 0.388 (95% confidence interval = 0.204-0.740)]. Logistic regression revealed, age >64 years, higher total body fat, lower nadir [[CD4]] counts, and longer duration of HIV infection, were significantly associated with MM in aging PLWH ([i]p[/i] = .019). Older individuals with HIV on antiretrovirals in Ibadan, had a significantly greater burden of MM compared with those without HIV. HIV treatment programs in Nigeria will need to adapt a comprehensive health care plan for aging PLWH.

|keywords=* ART
* PLWH
* aging
* multimorbidity
* quality of life
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071065
}}
{{medline-entry
|title=Alterations in composition of immune cells and impairment of anti-tumor immune response in aged oral cancer-bearing mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31683168
|abstract=Aging has been suggested to be associated with immune dysregulation. An understanding of alterations in the host immunity with advancing age is, therefore, important for designing immune therapy for elderly cancer patients. In this context, not much is known about age-associated alterations in the immune system in oral cancer. To evaluate age-associated alterations in the immune system, which might affect anti-tumor immune responses in oral cancer, we performed a comparative analysis of the proportion of different immune cells, the proliferative capacity of T cell compartment, and the response against immune therapies targeting immune check point molecules between young and aged oral cancer-bearing mice. The proportion of immune regulatory cells, such as regulatory T cells and myeloid derived suppressor cells, was significantly increased in aged mice compared to that in young mice. Moreover, the expression of PD-1 and CTLA-4 on both [[CD4]]  and CD8  T cells was elevated in aged mice compared to that in young mice, and the proliferative abilities of [[CD4]]  and CD8  T cells derived from aged mice were significantly reduced following stimulation of T-cell receptors. Moreover, tumor growth was significantly enhanced in aged mice compared to that in young mice. However, immunotherapies targeting PD-1, CTLA-4, and PD-L1 resulted in faster tumor regression in aged mice than in young mice. Together, our results indicate that age-associated alterations in the immune system are directly associated with the impairment of anti-tumor immunity in aged mice bearing oral cancer, and might facilitate the progression of the tumor.
|mesh-terms=* Aged
* Animals
* Cell Line, Tumor
* Cell Proliferation
* Female
* Humans
* Immunotherapy
* Mice
|keywords=* Aging
* Immune check-point molecules
* Immunosenescence
* Immunotherapy
* Myeloid derived suppressor cells
* Oral cancer
* Regulatory T cells
|full-text-url=https://sci-hub.do/10.1016/j.oraloncology.2019.104462
}}
{{medline-entry
|title=LTA1 is a safe, intranasal enterotoxin-based adjuvant that improves vaccine protection against influenza in young, old and B-cell-depleted (μMT) mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31641151
|abstract=Enterotoxin-based adjuvants including cholera toxin and heat-labile toxin (LT) are powerful manipulators of mucosal immunity; however, past clinical trials identified unacceptable neurological toxicity when LT or mutant AB  adjuvant proteins were added to intranasal vaccines. Here, we examined the isolated enzymatic A1 domain of LT (LTA1) for intranasal safety and efficacy in combination with influenza (flu) vaccination. LTA1-treated mice exhibited no neurotoxicity, as measured by olfactory system testing and H&E staining of nasal tissue in contrast with cholera toxin. In vaccination studies, intranasal LTA1 enhanced immune responses to inactivated virus antigen and subsequent protection against H1N1 flu challenge in mice (8-week or 24-months). In addition, lung H1N1 viral titers post-challenge correlated to serum antibody responses; however, enhanced protection was also observed in μMT mice lacking B-cells while activation and recruitment of [[CD4]] T-cells into the lung was apparent. Thus, we report that LTA1 protein is a novel, safe and effective enterotoxin adjuvant that improves protection of an intranasal flu vaccination by a mechanism that does not appear to require B-cells.
|mesh-terms=* Adjuvants, Immunologic
* Administration, Intranasal
* Aging
* Animals
* Antibodies
* Antibody Formation
* B-Lymphocytes
* CD4-Positive T-Lymphocytes
* Dose-Response Relationship, Immunologic
* Enterotoxins
* Female
* Immunity, Mucosal
* Immunization
* Inflammation
* Influenza A Virus, H1N1 Subtype
* Lung
* Lymphocyte Activation
* Lymphocyte Depletion
* Mast Cells
* Mice, Inbred C57BL
* Orthomyxoviridae Infections

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6805908
}}
{{medline-entry
|title=Thymus Imaging Detection and Size Is Inversely Associated With Metabolic Syndrome and Frailty in People With HIV.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31660382
|abstract=People with HIV (PWH) may experience accentuating aging in relation to immuno-activation. Little is known regarding thymus (THY) involution in this process. We sought to investigate the relationship between THY imaging detection/size and clinically relevant aging outcomes such as metabolic syndrome (MetS), multimorbidity (MM), and frailty in PWH. This was a cross-sectional observational study including 665 HIV patients (81% males; median age, 53 years) attending Modena HIV Metabolic Clinic from 2014 to 2017. They underwent thoracic computed tomography scan as part of the medical assessment for cardiovascular disease, in which THY detection and size were reported using a semiquantitative score. Outcome measures were MetS, MM, and frailty. THY was detected in 27.0% of subjects; 71.1% showed THY size of grade 1-2, and 28.9% exhibited grade ≥3. Covariates that inversely correlated with THY detection were age, male gender, body mass index (BMI), and HIV duration. Covariates that inversely correlated with MetS were age, HIV duration, BMI, and THY grade 1-2. Covariates that inversely correlated with MM were age, HIV duration, and [[CD4]] nadir. Covariates that inversely correlated with frailty were age, HIV duration, [[CD4]] nadir, BMI, and THY detection. THY is inversely associated with MetS and frailty in PWH.

|keywords=* HIV
* aging
* frailty
* metabolic syndrome
* thymus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6809752
}}
{{medline-entry
|title=Alterations in peripheral T cell and B cell subsets in patients with osteoarthritis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31624962
|abstract=Our study objective was to explore whether abnormalities in the subtypes of T cells and B cells were present in peripheral blood of patients with osteoarthritis (OA) and healthy controls (HCs). Demographic and clinical variables and blood were collected. OA severity was measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire. Flow cytometry was used to establish the frequencies of lineage subsets. Monoclonal antibodies against 21 surface markers were used to distinguish and evaluate T cells' and B cells' subpopulation. The proportion of each subset was compared and correlations between age, immune cells, and clinical data were analyzed. A total of 30 OA patients (male/female = 9/21) and 45 HCs (male/female = 14/31) were included. Median WOMAC pain was 3.0 (2.0). There was no difference in the proportion of T cells, CD8+ T cells, and B cells (p > 0.05). The proportion of [[CD4]]+ T cells was higher in OA groups, together with an increased [[CD4]] to CD8 ratio (p = 0.016). CD8+[[CD4]]5RA+ T cells were reduced after adjustment for age, while CD8+[[CD4]]5RA- T cells were elevated in OA (p < 0.05). [[CD4]]+[[CD4]]5RA-CCR7+ T cells and [[CD4]]+[[CD4]]5RA-CCR7- T cells were increased (p < 0.004). The proportion of T helper (Th) 17 and T follicular helper (Tfh) 2 cells was higher, but cytotoxic T (Tc) 17 cells were fewer in OA (p < 0.05). CD3-CD19+IgD-IgM-CD27+CD38+ B cells were decreased in OA (p ≤ 0.001). The WOMAC pain score correlated with CD3+[[CD4]]+CXCR5-PD-1+ T cells positively (B = 0.404, p = 0.027). CD3-CD19+CD27-IgD+ cells correlated negatively with erythrocyte sedimentation rate (ESR) (B = -0.550, p = 0.005). The T cell and B cell profiles were proved to have alteration suggesting that acquired immune system may play a substantial role in the pathogenesis of OA.Key Points• The T cell and B cell profiles were proved to have alteration suggesting that acquired immune system may play a substantial role in the pathogenesis of OA.• The WOMAC pain score correlated with CD3+[[CD4]]+CXCR5-PD-1+ T cells and T helper 17 cells positively.• Memory T cells were increased in OA patients, suggesting they could play an important role in OA.
|mesh-terms=* Aged
* Aging
* B-Lymphocyte Subsets
* Case-Control Studies
* Female
* Humans
* Male
* Middle Aged
* Osteoarthritis, Knee
* T-Lymphocyte Subsets
|keywords=* B cell
* Lymphocyte
* Osteoarthritis
* T cell
|full-text-url=https://sci-hub.do/10.1007/s10067-019-04768-y
}}
{{medline-entry
|title=Short Communication: Carotid Intima-Media Thickness Is Not Associated with Neurocognitive Impairment Among People Older than 50 Years With and Without HIV Infection from Thailand.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31588776
|abstract=Neurocognitive impairment (NCI) contributes to poor quality of life among HIV-positive individuals. Cardiovascular risk factors, including the predictor of subclinical atherosclerosis, carotid intima-media thickness (cIMT), are reported to be associated with NCI. Data on NCI and its association with cIMT among HIV positive are limited, especially in Asian populations. We aimed to determine the prevalence of NCI and its association with cIMT among HIV-positive and HIV-negative aging Thai individuals. Cognitive performance was evaluated by the Thai version of Montreal Cognitive Assessment (MoCA) with a cutoff of <25/30 for diagnosis of NCI. Depression was evaluated by PHQ-9 Patient Depression Questionnaire, with scores ≥5 indicating depression. cIMT measurement was performed by experienced neurologists, and abnormal cIMT was defined as cIMT ≥0.9 mm or presence of carotid plaques. Among 340 well suppressed and aging HIV-positive and 102 HIV-negative matched participants, the median age (interquartile range) was 55 (52-59) years and 61.5% were males. For HIV positive group, the median duration on antiretroviral therapy was 18.3 years with median [[CD4]] of 615.5 cells/mm , and 97.4% had current plasma HIV RNA <50 copies/mL. The most common antiretroviral agents used were tenofovir disoproxil fumarate (76.8%), lamivudine (70.3%), efavirenz (26.7%), and emtricitabine (23.8%). HIV-positive and HIV-negative participants performed comparably between each domain and had comparable prevalence of NCI (59.4% vs. 61.7%, [i]p[/i] = .69). However, the HIV-positive group had a high prevalence of depression (24.71% vs. 13.73%, [i]p[/i] = .019). HIV-positive status [adjusted odd ratio (aOR) 0.91; 95% confidence interval (CI) 0.57-1.47, [i]p[/i] = .71] and cIMT (aOR 1.17; 95% CI 0.77-1.79, [i]p[/i] = .47) were not significantly associated with NCI. Given the high prevalence of NCI and depression among aging HIV-positive individuals, routine screening for NCI and depression should be integrated into the HIV care services.
|mesh-terms=* Aging
* Anti-Retroviral Agents
* Cardiovascular Diseases
* Carotid Intima-Media Thickness
* Cross-Sectional Studies
* Depression
* Female
* HIV Infections
* Humans
* Male
* Middle Aged
* Neurocognitive Disorders
* Quality of Life
* Risk Factors
* Thailand
|keywords=* HIV
* aging
* carotid intima-media thickness
* neurocognitive
|full-text-url=https://sci-hub.do/10.1089/AID.2019.0139
}}
{{medline-entry
|title=Implications of Immune Checkpoint Expression During Aging in HIV-Infected People on Antiretroviral Therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31578868
|abstract=Immune checkpoint molecules (ICMs) regulate T cell responses. In chronic viral infections and cancer, where antigens can persistently stimulate the immune system, ICMs can serve as a barrier to effective immune responses. The role of ICMs in the setting of systemic low-grade inflammation as in aging and antiretroviral therapy (ART)-suppressed HIV infection is not known. In this study, we made use of stored samples from the FLORAH cohort of HIV-infected ART-suppressed adults (age range 19-77 years.) and age-matched HIV-uninfected controls. We measured the expression levels of ICMs: PD-1, LAG-3, TIGIT, TIM-3, and 2B4 on resting [[CD4]] and CD8 T cells and maturation subsets. To determine how expression of these molecules can affect T cell function, we stimulated peripheral blood mononuclear cell with HIV Gag or p09/H1N1 antigen and performed intracellular cytokine staining by multiparameter flow cytometry. ICMs were expressed at higher levels in CD8 compared with [[CD4]]. PD-1 was the only molecule that remained significantly higher in HIV-infected individuals compared with controls. LAG-3 expression increased with age in [[CD4]] and CD8 T cells. 2B4 expression on CD8 T cells was negatively associated with IL-2 production but showed no effect on [[CD4]] T cell function. TIM-3 expression was negatively associated with IL-21 production in [[CD4]] and CD8 T cells and also negatively correlated with flu vaccine responses in HIV-negative individuals. Taken altogether, this study demonstrates the marked variation in ICM expression in T cells among adults and sheds light on the biology of these molecules and their effects on antigen-specific T cell functions. Overall, our results point to TIM-3 as a potential biomarker for immune function in HIV  individuals on ART.
|mesh-terms=* Adult
* Aged
* Aging
* Anti-HIV Agents
* Antiretroviral Therapy, Highly Active
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Cytokines
* Female
* Flow Cytometry
* Gene Expression
* HIV Infections
* HIV-1
* Hepatitis A Virus Cellular Receptor 2
* Humans
* Leukocytes, Mononuclear
* Male
* Middle Aged
* Young Adult
* gag Gene Products, Human Immunodeficiency Virus
|keywords=* aging
* immune checkpoint molecules
* virus suppression
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862963
}}
{{medline-entry
|title=Age-related alterations in human gut [[CD4]] T cell phenotype, T helper cell frequencies, and functional responses to enteric bacteria.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31573727
|abstract=Intestinal lamina propria (LP) [[CD4]] T cells play critical roles in maintaining intestinal homeostasis and in immune responses to enteric microbes, yet little is known regarding whether they contribute to age-associated intestinal immune dysfunction. In this study, we evaluated the direct ex vivo frequency, activation/inhibitory phenotype, death profiles, and in vitro functional responses of human jejunum LP [[CD4]] T cells, including Th1, Th17, and Th22 subsets isolated from younger (<45 years) and older (>65years) persons. Expression of the co-inhibitory molecule CTLA-4 was significantly lower in older [[CD4]] T cells, whereas expression of HLA-DR, CD38, CD57, and PD-1 were not significantly different between groups. Total [[CD4]] T cell frequencies were similar between age groups, but lower frequencies and numbers of Th17 cells were observed directly ex vivo in older samples. Older Th17 and Th1 cells proliferated to a lesser degree following in vitro exposure to bacterial antigens vs. their younger counterparts. Levels of spontaneous cell death were increased in older [[CD4]] T cells; however, cellular death profiles following activation did not differ based on age. Thus, small intestinal [[CD4]] T cells from older persons have altered phenotypic and functional profiles including reduced expression of a co-inhibitory molecule, increased spontaneous cell death, and both reduced frequencies and altered functional responses of specific Th cell subsets. These changes may contribute to altered intestinal homeostasis and loss of protective gut immunity with aging.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* CD4-Positive T-Lymphocytes
* Female
* Gastrointestinal Microbiome
* Humans
* Interleukin-17
* Intestinal Mucosa
* Male
* Middle Aged
* Phenotype
* Th1 Cells
* Th17 Cells
* Young Adult
|keywords=* T helper cells
* aging
* gut
* human
|full-text-url=https://sci-hub.do/10.1002/JLB.5A0919-177RR
}}
{{medline-entry
|title=Determinants of blood telomere length in antiretroviral treatment-naïve HIV-positive participants enrolled in the NEAT 001/ANRS 143 clinical trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31532902
|abstract=Our aim was to investigate factors associated with baseline blood telomere length in participants enrolled in NEAT 001/ANRS 143, a randomized, open-label trial comparing ritonavir-boosted darunavir (DRV/r) plus raltegravir (RAL) with DRV/r plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) in antiretroviral therapy (ART)-naïve HIV-positive adults. A cross-sectional study of 201 randomly selected participants who had stored samples available was carried out. We measured telomere length (i.e. the relative telomere length, calculated as the telomere to single copy gene ratio) at baseline with monochrome quantitative multiplex polymerase chain reaction (PCR). We used multivariable predictive linear regression to calculate mean differences and 95% confidence intervals (CIs) for the association between baseline telomere length and baseline characteristics. The baseline characteristics of the 201 participants did not differ from those of the 805 participants in the parent trial population: 89% were male, the mean age was 39 years, 83.6% were Caucasian, 93% acquired HIV infection via sexual transmission, the mean estimated time since HIV diagnosis was 2.1 years, the mean HIV-1 RNA load was 4.7 log  HIV-1 RNA copies/mL, the mean nadir and baseline [[CD4]] counts were 301 and 324 cells/μL, respectively, and the mean [[CD4]]:CD8 ratio was 0.4. In the univariate analysis, shorter telomere length was associated with older age (per 10 years) (P < 0.001), HIV-1 RNA ≥ 100 000 copies/mL (P = 0.001), [[CD4]] count < 200 cells/μL (P = 0.037), lower [[CD4]]:CD8 ratio (P = 0.018), statin treatment (P = 0.004), and current alcohol consumption (P = 0.035). In the multivariable analysis, older age (P < 0.001) and HIV RNA ≥ 100 000 copies/mL (P = 0.054) were independently associated with shorter telomere length. Both age and HIV RNA viral load correlated with shorter blood telomere length in untreated persons living with HIV. These results suggest that HIV infection and age have synergistic and independent impacts upon immunosenescence.
|mesh-terms=* Adult
* Aged
* Anti-Retroviral Agents
* Cross-Sectional Studies
* Darunavir
* Emtricitabine
* Female
* HIV Infections
* Humans
* Logistic Models
* Male
* Middle Aged
* RNA, Viral
* Raltegravir Potassium
* Ritonavir
* Telomere
* Tenofovir
|keywords=* HIV infection
* aging
* immunosenescence
* telomere length
* viral load
|full-text-url=https://sci-hub.do/10.1111/hiv.12791
}}
{{medline-entry
|title=Human T Cell Differentiation Negatively Regulates Telomerase Expression Resulting in Reduced Activation-Induced Proliferation and Survival.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31497023
|abstract=Maintenance of telomeres is essential for preserving T cell proliferative responses yet the precise role of telomerase in human T cell differentiation, function, and aging is not fully understood. Here we analyzed human telomerase reverse transcriptase (hTERT) expression and telomerase activity in six T cell subsets from 111 human adults and found that levels of hTERT mRNA and telomerase activity had an ordered decrease from naïve (T ) to central memory (T ) to effector memory (T ) cells and were higher in [[CD4]]  than their corresponding CD8  subsets. This differentiation-related reduction of hTERT mRNA and telomerase activity was preserved after activation. Furthermore, the levels of hTERT mRNA and telomerase activity were positively correlated with the degree of activation-induced proliferation and survival of T cells [i]in vitro[/i]. Partial knockdown of hTERT by an anti-sense oligo in naïve [[CD4]]  cells led to a modest but significant reduction of cell proliferation. Finally, we found that activation-induced levels of telomerase activity in [[CD4]]  T  and T  cells were significantly lower in old than in young subjects. These findings reveal that hTERT/telomerase expression progressively declines during T cell differentiation and age-associated reduction of activation-induced expression of hTERT/telomerase mainly affects naïve [[CD4]]  T cells and suggest that enhancing telomerase activity could be a strategy to improve T cell function in the elderly.
|mesh-terms=* Adult
* Cell Differentiation
* Cell Proliferation
* Cell Survival
* Humans
* T-Lymphocytes
* Telomerase
|keywords=* T cell subsets
* T lymphocytes
* aging
* alternative splicing
* differentiation
* hTERT
* proliferation
* telomerase
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712505
}}
{{medline-entry
|title=Short Communication: Getting Older with HIV: Increasing Frequency of Comorbidities and Polypharmacy in Brazilian HIV Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31452382
|abstract=Life expectancy of HIV patients has increased over time. Older HIV patients have a higher frequency of noncommunicable diseases (NCD) than general population, and require multiple treatments. The main objective is to evaluate the changes in frequency of NCD and polypharmacy in HIV patients of three referral centers in Salvador and São Paulo. We compared the frequency of NCD and use of concomitant treatments in HIV patients, >50 years, in three Brazilian referral centers (São Paulo and Salvador). Data on sociodemographic characteristics, HIV therapy, [[CD4]] count and viral load measurements, and frequency of NCD at baseline and last medical visit were recorded. We evaluated 451 patients, 128 in Salvador and 323 in São Paulo. Mean age was 57.9 ± 6.9 years. Mean baseline [[CD4]] count was 199 ± 169. At baseline, dyslipidemia (4.0%) was the most frequent comorbidity, but at last visit we detected a high frequency of diabetes (14.9%), dyslipidemia (26.7%), osteoporosis (6.7%), stroke (4.4%), and malignancies (3.1%). Use of concomitant drugs for treatment of NCD increased significantly between first and last visit, especially antihypertensive, lipids lowering, and diabetes drugs. Aging in HIV patients in Brazil is characterized by an increasing incidence of NCD and polypharmacy.
|mesh-terms=* Aged
* Aging
* Brazil
* CD4 Lymphocyte Count
* Cardiovascular Diseases
* Comorbidity
* Diabetes Mellitus
* Female
* HIV Infections
* Humans
* Life Expectancy
* Male
* Middle Aged
* Neoplasms
* Polypharmacy
|keywords=* Brazil
* HIV
* aging
* noncommunicable diseases
|full-text-url=https://sci-hub.do/10.1089/AID.2019.0069
}}
{{medline-entry
|title=Gait Speed Decline Is Associated with Hemoglobin A1C, Neurocognitive Impairment, and Black Race in Persons with HIV.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31468979
|abstract=Gait speed declines at a faster rate in persons with HIV (PWH) than in the general population but the risk factors associated with this decline are not well understood. In the AIDS Clinical Trials Group (ACTG) A5322 (HAILO, HIV Infection, Aging, and Immune Function Long-term Observational Study), an observational cohort study of PWH ≥40 years of age, those who developed slow gait during the first 3 years of follow-up were compared with persons who maintained normal speed. Associations with demographic and clinical covariates were assessed using multivariable logistic regression. Of 929 participants, 81% were men, 31% Black, and 20% Hispanic. Median age was 51 years [interquartile range (IQR) = 46-56]. At study entry, 92% had plasma HIV RNA <50 copies/mL with median [[CD4]] count 631 cells/mm  (IQR = 458-840). At study entry, 7% of participants had slow gait, 16% had neurocognitive impairment (NCI), and 12% had diabetes. Over 3 years, 87% maintained normal gait speed, 3% maintained a slow gait, 6% developed a slow gait, and 4% improved from slow to normal gait speed. In multivariable models, hemoglobin A1C (HbA1C) percentage, per one unit increase [odds ratio (OR) = 1.36; 95% confidence interval (CI) = 1.03-1.81; [i]p[/i] = .033], NCI (OR = 3.47; 95% CI = 1.57-7.69 [i]p[/i] = .002), and black versus white race (OR = 2.45; 95% CI = 1.08-5.59; [i]p[/i] = .032) at entry were significantly associated with development of slow gait compared with those maintaining normal gait speed. The association between baseline HbA1C and development of slow gait speed highlights an intervenable target to prevent progression of physical function limitations.
|mesh-terms=* Adult
* African Americans
* Aging
* CD4 Lymphocyte Count
* Cohort Studies
* Female
* Glycated Hemoglobin A
* HIV Infections
* Humans
* Longitudinal Studies
* Male
* Middle Aged
* Neurocognitive Disorders
* Odds Ratio
* RNA, Viral
* Risk Factors
* Walking Speed
|keywords=* aging
* gait speed
* hemoglobin A1C
* neurocognitive impairment
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862955
}}
{{medline-entry
|title=Noncommunicable Diseases Burden and Risk Factors in a Cohort of HIV+ Elderly Patients in Malawi.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31468993
|abstract=HIV-infected patients have increased risk of noncommunicable diseases (NCDs). HIV+ patients in Africa are experiencing growing comorbidities due to increase in life expectancy and long-time antiretroviral therapy (ART). HIV prevalence in Malawi is one of highest in the world (10.8% in women and 6.4% in men); few data are available about NCDs epidemiology in HIV+ elderly patients in Malawi. A retrospective analysis of routine medical records in 14 health centers run by Disease Relief through Excellent and Advanced Means (DREAM) program in Malawi was carried out. All HIV+ patients aged >40 years in care in the period January 01, 2017-December 31, 2018 were included. Clinical and laboratory features were collected in the last visit of the study period. Files from 7,071 patients (62.1% women) in ART were analyzed, 362 (5.1%) were aged >65 years. Median time on ART was 98.9 (64.8-118.0) months; median body mass index, haemoglobin (HB), and [[CD4]] count were, respectively, 21.63 kg/m  (19.5-24.5), 13 mg/dL (12-14), and 457 cell/mm  (328-613). Elderly patients >65 years were more likely to be malnourished (odds ratio [OR] = 2.0, confidence interval [CI]: 1.54-2.59), diagnosed with arterial hypertension (OR = 2.5, CI: 1.94-3.43), affected with diabetes (OR = 2.7, CI: 1.25-6.22), have macrocytic anemia (OR = 2.5, CI: 2.00-3.35), and increased serum creatinine (OR = 1.5, CI: 1.03-2.43]). Other factors were associated with NCD burden, but age remained always independently related. Two concomitant chronic conditions in addition to HIV were present in 19.2% (66/343) of elderly people and 5.2% (338/6.454) of patients aged <65 years (OR = 4.3, CI: 3.22-5.76). Some associations were observed: nevirapine (NVP) was associated with kidney disease (OR = 1.5, CI: 1.22-2.06), NVP and protease inhibitor (PI) with hypertension (OR = 2.79, CI: 2.16-3.35 and OR = 2.15, CI: 1.52-3.02), azidothymidine (AZT) with macrocytic anemia (OR = 15.6, CI: 13.18-18.68). NVP, AZT, and duration of any ART >3 years were associated with the presence of two or more comorbidities (OR = 2.1 1.54-2.96, OR = 2.6 1.87-3.71, and OR = 1.7 1.12-2.84). Our data show the burden of NCDs in aging HIV+ patients in Malawi. The expansion of HIV treatment programs will require special attention to such comorbidities in elderly patients.
|mesh-terms=* Adult
* Age Factors
* Aged
* Anti-HIV Agents
* Anti-Retroviral Agents
* CD4 Lymphocyte Count
* Comorbidity
* Cost of Illness
* Cross-Sectional Studies
* Diabetes Mellitus
* Female
* HIV Infections
* Humans
* Hypertension
* Malawi
* Male
* Middle Aged
* Noncommunicable Diseases
* Odds Ratio
* Prevalence
* Retrospective Studies
* Risk Factors
|keywords=* HIV infection
* Malawi
* aging
* noncommunicable diseases
|full-text-url=https://sci-hub.do/10.1089/AID.2019.0125
}}
{{medline-entry
|title=Aging promotes reorganization of the [[CD4]] T cell landscape toward extreme regulatory and effector phenotypes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31457092
|abstract=Age-associated changes in [[CD4]] T-cell functionality have been linked to chronic inflammation and decreased immunity. However, a detailed characterization of [[CD4]] T cell phenotypes that could explain these dysregulated functional properties is lacking. We used single-cell RNA sequencing and multidimensional protein analyses to profile thousands of [[CD4]] T cells obtained from young and old mice. We found that the landscape of [[CD4]] T cell subsets differs markedly between young and old mice, such that three cell subsets-exhausted, cytotoxic, and activated regulatory T cells (aT )-appear rarely in young mice but gradually accumulate with age. Most unexpected were the extreme pro- and anti-inflammatory phenotypes of cytotoxic [[CD4]] T cells and aT , respectively. These findings provide a comprehensive view of the dynamic reorganization of the [[CD4]] T cell milieu with age and illuminate dominant subsets associated with chronic inflammation and immunity decline, suggesting new therapeutic avenues for age-related diseases.
|mesh-terms=* Aging
* Animals
* CD4-Positive T-Lymphocytes
* High-Throughput Nucleotide Sequencing
* Immunomodulation
* Mice
* Phenotype
* Sequence Analysis, RNA
* Single-Cell Analysis
* T-Lymphocyte Subsets

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703865
}}
{{medline-entry
|title=Prevalence of hypertension and cardiovascular risk factors among long-term AIDS survivors: A report from the field.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31448551
|abstract=HIV infection is associated with increased risk and progression of cardiovascular disease (CVD), yet little is known about the prevalence of CVD risk factors among long-term AIDS survivors in resource-limited settings. Using routinely collected data, we conducted a retrospective study to describe the prevalence of CVD risk factors among a cohort of HIV-infected patients followed for over 10 years in Port-au Prince, Haiti. This cohort includes 910 adults who initiated antiretroviral therapy (ART) between 2003 and 2004 and remained in care between 2014 and 2016 when routine screening for CVD risk factors was implemented at a large clinic in Haiti. A total of 397 remained in care ≥10 years and received screening. At ART initiation, 59% were female, median age was 38 years (IQR 33-44), and median [[CD4]] count was 117 cells/mm  (IQR 34-201). Median follow-up time from ART initiation was 12.1 years (IQR 11.7-12.7). At screening, median [[CD4]] count was 574 cells/mm  (IQR 378-771), and 84% (282 of 336 screened) had HIV-1 RNA < 1000 copies/mL. Seventy-four percent of patients had at least 1 risk factor including 58% (224/385) with hypertension, 8% (24/297) diabetes, 43% (119/275) hypercholesterolemia, 8% (20/248) active smoking, and 10% (25/245) obesity. Factors associated with hypertension were age (adjusted OR 1.06, P < .001) and weight at screening (adjusted OR 1.02, P = .019). Long-term AIDS survivors have a high prevalence of CVD risk factors, primarily hypertension. Integration of cardiovascular screening and management into routine HIV care is needed to maximize health outcomes among aging HIV patients in resource-limited settings.
|mesh-terms=* Acquired Immunodeficiency Syndrome
* Adult
* Anti-Retroviral Agents
* CD4 Lymphocyte Count
* Cardiovascular Diseases
* Diabetes Mellitus
* Diagnostic Screening Programs
* Female
* HIV Infections
* HIV-1
* Haiti
* Humans
* Hypercholesterolemia
* Hypertension
* Male
* Middle Aged
* Obesity
* Prevalence
* Retrospective Studies
* Risk Factors
* Smoking
* Survivors
|keywords=* HIV
* aging
* cardiovascular disease
* hypertension
* risk assessment
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896990
}}
==TNF==

{{medline-entry
|title=Naringenin alleviates nonalcoholic steatohepatitis in middle-aged Apoe mice: role of SIRT1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33234364
|abstract=Naringenin is naturally isolated from citrus fruits possessing many pharmacological activities. However, little is known about the effect of naringenin on nonalcoholic steatohepatitis (NASH) in the model of metabolic syndrome. The present study is aimed to investigate the effect of naringenin on NASH in 12-mo-old male ApoE  mice and its possible underlying mechanism. In vivo, 12-mo-old male ApoE  mice were administrated with naringenin by intragastric gavage for 12 weeks. At the end of experiment, the blood samples and liver tissues were collected. Metabolic parameters in serum, levels of triglyceride, cholesterol and hydroxyproline, activities of antioxidant enzymes, and content of inflammatory cytokines ([[TNF]]-α and IL-6) in liver were examined by corresponding assay kits. Pathological changes in liver were observed by hematoxylin-eosin, oil red O, masson's trichrome, picro-sirius red and senescence β-galactosidase staining. Dihydroethidium was used for detection of reactive oxygen species (ROS). In vitro, AML-12 cells were treated with oleic acid in the presence or absence of naringenin for 24 h. Transfection of SIRT1 siRNA was also conducted in vitro. Lipid accumulation, cellular ROS generation, malondialdehyde content, antioxidant enzyme activities and secretion levels of [[TNF]]-α and IL-6 were examined. Both in vivo and in vitro, gene expressions were detected by real-time PCR or western blot. Naringenin administration improved metabolic parameters, suppressed hepatic steatosis, regulated expression of genes involved in lipid metabolism (FASN, SCD1, PPARα and CPT1α), reduced hepatic fibrosis and cell senescence, inhibited hepatic inflammation as evidenced by the decreased macrophage recruitment and content of [[TNF]]-α and IL-6, and reduced hepatic oxidative stress by suppressing ROS generation and normalizing activities of antioxidant enzymes. Notably, naringenin administration increased hepatic SIRT1 protein expression and activity along with the increased deacetylation of liver kinase B1 (LKB1), PGC1α and NF-κB. In vitro study, the benefits of naringenin on lipid accumulation, oxidative stress and inflammation were diminished by SIRT1 siRNA transfection. These results indicate that naringenin administration may be a potential curative therapy for NASH treatment and the activation of hepatic SIRT1-mediated signaling cascades is involved in its beneficial effects.

|keywords=* AML-12 cells
* Aging
* ApoE(−/−) mice
* Naringenin
* Nonalcoholic steatohepatitis
* SIRT1
|full-text-url=https://sci-hub.do/10.1016/j.phymed.2020.153412
}}
{{medline-entry
|title=Protective role of microglial HO-1 blockade in aging: Implication of iron metabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33212416
|abstract=Heme oxygenase-1 (HO-1) is an inducible enzyme known for its anti-inflammatory, antioxidant and neuroprotective effects. However, increased expression of HO-1 during aging and age-related neurodegenerative diseases have been associated to neurotoxic ferric iron deposits. Being microglia responsible for the brain's innate immune response, the aim of this study was to understand the role of microglial HO-1 under inflammatory conditions in aged mice. For this purpose, aged wild type (WT) and LysMCreHmox1  (HMOX1 ) mice that lack HO-1 in microglial cells, were used. Aged WT mice showed higher basal expression levels of microglial HO-1 in the brain than adult mice. This increase was even higher when exposed to an inflammatory stimulus (LPS via i.p.) and was accompanied by alterations in different iron-related metabolism proteins, resulting in an increase of iron deposits, oxidative stress, ferroptosis and cognitive decline. Furthermore, microglia exhibited a primed phenotype and increased levels of inflammatory markers such as iNOS, p65, IL-1β, [[TNF]]-α, Caspase-1 and NLRP3. Interestingly, all these alterations were prevented in aged HMOX1  and WT mice treated with the HO-1 inhibitor ZnPPIX. In order to determine the effects of microglial HO-1-dependent iron overload, aged WT mice were treated with the iron chelator deferoxamine (DFX). DFX caused major improvements in iron, inflammatory and behavioral alterations found in aged mice exposed to LPS. In conclusion, this study highlights how microglial HO-1 overexpression contributes to neurotoxic iron accumulation providing deleterious effects in aged mice exposed to an inflammatory insult.

|keywords=* Aging
* Ferroptosis
* Heme oxygenase-1
* Iron metabolism
* Microglia
* Neuroinflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680814
}}
{{medline-entry
|title=Anti-aging effect of DL-β-hydroxybutyrate against hepatic cellular senescence induced by D-galactose or γ-irradiation via autophagic flux stimulation in male rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33147533
|abstract=The present study aims to shed new light on anti-aging effect of DL-β-hydroxybutyrate (βOHB) against hepatic cellular senescence induced by d-galactose or γ-irradiation. The rats divided into 6 groups. Group 1, control, group 2, exposed to γ-ray (5 GY), group 3, injected by d-galactose (150 mg/kg) daily for consecutive 6 weeks, which regarded to induce the aging, group 4, injected intraperitoneal by β-hydroxybutyrate (βOHB) (72.8 mg/kg) daily for consecutive 14 days, group 5, exposed to γ-ray then treated with βOHB daily for consecutive 14 days, group 6, injected daily with d-galactose for consecutive 6 weeks, then treated with βOHB daily at the last two weeks of d-galactose. Aspartate amino transferase (AST), alanine amino transferase (ALT), Insulin, interleukin-6 (IL-6) and tumor necrosis factor-α ([[TNF]]-α) were estimated in serum. Moreover, protein expression of Microtubule-associated proteins 1A/1B light chain 3B (LC3-II/LC3-I) ratio, mechanistic target of rapamycin (mTOR), pAMPK, mRNA gene expression of 5' AMP-activated protein kinase (AMPK), Nucleoporin p62 (p62), cyclin-dependent kinase inhibitor 1(P21 ), cyclin-dependent kinase inhibitor 2A (p16 ) and DNA fragmentation percentage were measured in liver tissue as a biomarker of cellular senescence. The results confirmed that βOHB modulated serum level of AST, ALT, insulin, IL-6 and [[TNF]]-α, protein expression of mTOR and LC3-II/LC3-I ratio, pAMPK and p62 in liver aging model induced by d-galactose or γ-irradiation. Histopathological examination results of liver tissue indicated coincidence with those recorded by molecular biochemical inspection. Taken together, these findings suggest that βOHB may be useful in combating hepatic cellular senescence induced by d-galactose or γ-irradiation via autophagy dependent mechanisms.

|keywords=* Autophagy
* D-galacose
* Ionizing radiation
* Senescence
* β-hydroxybutyric acid
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104288
}}
{{medline-entry
|title=Exploring the extensive crosstalk between the antagonistic cytokines- TGF-β and [[TNF]]-α in regulating cancer pathogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33153895
|abstract=A plethora of cytokines are produced in the tumor microenvironment (TME) those play a vital role in cancer prognosis. Though it is completely contextual, cytokines produced from an inflammatory micro-environment can either modulate cancer progression at early stages of tumor development or in later stages cytokine derived cues can in turn control tumor cell invasion and metastasis. Therefore, understanding the crosstalk between the key cytokines regulating cancer prognosis is critical for the development of an effective therapy. In this regard, the role of transforming growth factor-beta (TGF-β) in cancer is controversially discussed in general inhibition of TGF-β promotes de novo tumorigenesis whereas paradoxically, TGF-β can promote malignancy in already established tumors. Another important cytokine, [[TNF]]-α have intense crosstalk with TGF-β from the fact that in a non-cancer context, TGF-β promotes fibrosis whereas [[TNF]]-α has anti-fibrotic activity. We have recently reported that TGF-β-induced differentiation of epithelial cells to mesenchymal type is suppressed by [[TNF]]-α through regulation of cellular homeostatic machinery- autophagy. Moreover, there are also rare reports of synergy between these two cytokines as well. The crosstalk between TGF-β and [[TNF]]-α is not only limited to regulating cancer cell differentiation and proliferation but also includes involvement in cell death. In this review, we hence summarize the molecular mechanisms by which these two important cytokines, TGF-β and [[TNF]]-α control cancer prognosis.

|keywords=* Apoptosis
* Autophagy
* EMT
* Fibrogenesis
* Senescence
* TGF-β and TNF-α
|full-text-url=https://sci-hub.do/10.1016/j.cyto.2020.155348
}}
{{medline-entry
|title=Long non-coding RNA SNHG29 regulates cell senescence via p53/p21 signaling in spontaneous preterm birth.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33080448
|abstract=Spontaneous preterm birth affects>5-18% of pregnancies and causes infant morbidity and mortality. Long non-coding RNAs can regulate gene expression and have been associated with preterm birth. In this study, we investigated whether the long non-coding RNA SNHG29 was associated with spontaneous preterm birth. We collected the placentas from women who underwent preterm/full-term birth with/without labor. We determined the levels of expression of SNHG29 in the placental tissues using quantitative real-time polymerase chain reaction. We generated a senescence model by treating HTR8/SVneo cells with 200 μM H2O2 for 2 h. The degree of senescence induced in cells depleted of or overexpressing SNHG29 was determined by measuring senescence-associated gene expression and β-galactosidase activity. SNHG29 was overexpressed in the placentas of women who delivered preterm with labor and in HTR8/SVneo cells treated with H2O2 (p < 0.05). The levels of mRNA of p53 and p21, protein levels of p53, phospho-p53, p21and phospho-p21, and β-galactosidase activity was decreased in HTR8/SVneo cells depleted of SNHG29, while the opposite trend was observed in HTR8/SVneo cells overexpressing SNHG29 (p < 0.05). We observed an increase in the expression of IL-8 and [[TNF]]-α in senescent HTR8/SVneo cells (p < 0.05). SNHG29 was overexpressed in placentas from women who delivered preterm with labor compared to those in women who underwent preterm birth without labor and full-term birth with/without labor. High levels of SNHG29 enhanced senescence in vivo. The increase in pro-inflammatory cytokine expression and release by senescent cells may be pivotal to the pathophysiology of spontaneous preterm birth.

|keywords=* Cellular senescence
* Oxidative stress
* SASP
* SNHG29
* Spontaneous preterm birth
* p53/p21
|full-text-url=https://sci-hub.do/10.1016/j.placenta.2020.10.009
}}
{{medline-entry
|title=Cognition Is Associated With Peripheral Immune Molecules in Healthy Older Adults: A Cross-Sectional Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32983153
|abstract=Cognition in the elderly is heterogeneous. Senescence of the immune system is increasingly considered as a potential player in cognitive performance. We explored here the interplay between cognitive performance and peripheral immune molecules in healthy older individuals. A cross-sectional study of clinically well characterized senior healthy individuals (120; 51-87 years old) previously clustered as "Good" and "Poor" performers based on established tests that evaluate memory and executive function. A plasma concentration of 30 immune molecules was assessed by multiplex analysis and correlated with parameters of cognitive performance. Participants with worse cognitive performance ("Poor") exhibited increased concentrations of IL-1β, IL-8, IL-13, and tumor necrosis factor ([[TNF]]) when compared to individuals with a better cognitive performance ("Good"). The cognitive dimensions memory and executive function, when considered separately, displayed a negative association with several immune molecules (IL-1β, IL-1RA, IL-6, IL-13, IP-10, and [[TNF]] with memory and only IL-1β with executive function), even controlling for age, sex, years of formal education, mood, and use of anti-inflammatory drugs. Regression analysis showed that several of these molecules (IL-1β, IL-6, IL-8, and IL-13) contribute to predicting whether an individual belongs to the "Good" or "Poor" cognitive performance group. These results strengthen the hypothesis that increased concentrations of peripheral immune molecules, like IL-1β, are associated with worse cognitive performance in senior healthy individuals. It further highlights that some poorly studied immune molecules should be considered in the context of cognitive aging, such as IL-13, here revealed as a new player in such interaction.

|keywords=* chemokines
* cognition
* cytokines
* healthy aging
* immune molecules
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493640
}}
{{medline-entry
|title=Anti-aging effects of [i]Ribes meyeri[/i] anthocyanins on neural stem cells and aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32920547
|abstract=Aging is associated with neurological impairment and cognitive decline. Flavonoids are very promising in anti-aging research in mouse models. [i]Ribes meyeri[/i] anthocyanins are rich in abundant flavonoids, but their anti-aging biological activities remain unknown. In this study, we prepared an [i]R. meyeri[/i] anthocyanin extract and analyzed its effects on neural stem cell (NSC) senescence [i]in vivo[/i] and [i]in vitro[/i]. We isolated mouse NSCs and used cell counting kit-8 (CCK-8), cell cycle, reactive oxygen species (ROS), and immunofluorescence methods to analyze the anti-aging effects of [i]R. meyeri[/i] anthocyanins as well as naringenin (Nar), which metabolic analysis revealed as an important flavonoid in [i]R. meyeri[/i] anthocyanins. RNA-sequencing (RNA-seq) and enzyme-linked immuno sorbent assay (ELISA) methods were also used to investigate Nar-specific mechanisms of anti-aging. After [i]R. meyeri[/i] anthocyanin treatment, NSC proliferation accelerated, and NSCs had decreased senescence markers, and reduced P16  expression. [i]R. meyeri[/i] anthocyanin treatment also reversed age-dependent neuronal loss [i]in vivo[/i] and [i]in vitro[/i]. Nar blocked mNSC aging [i]in vitro[/i] and improved spatial memory and cognitive abilities in aging mice through downregulation of plasma [[TNF]]-α protein. These findings suggest that [i]R. meyeri[/i] anthocyanins increase NSC proliferation and improve neurogenesis with aging via Nar-induced reductions in [[TNF]]-α protein levels [i]in vivo[/i].

|keywords=* Ribes meyeri anthocyanin
* aging
* cognition
* naringenin
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521483
}}
{{medline-entry
|title=Effects of a four week detraining period on physical, metabolic, and inflammatory profiles of elderly women who regularly participate in a program of strength training.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32863968
|abstract=Human aging has innumerable health implications, including loss of muscle mass and increased circulating inflammatory markers. Resistance exercise in the elderly can prevent muscle mass loss and improve the inflammatory profile. Conversely, detraining can reverse this picture. Thus, there is a strong need for studies with the elderly population to clarify the real impacts of a training interruption. Therefore, the objective of this study was to analyze the inflammatory profile of resistance trained elderly women after 4 weeks of detraining. Seventeen elderly women with regular participation in an exercise program participated in the study. Body mass index (BMI), physical activity level assessments, total cholesterol and its fractions, triglycerides, glycemia and insulin blood levels, IL-1β, IL-4, IL-6, IL-10, IL-13, [[TNF]]-α, IFNγ, and MCP-1 were assessed before and after the detraining protocol. The 4 week detraining period decreased physical fitness without altering body mass and BMI  The short detraining period was able to induce some metabolic disturbances in elderly women who regularly participate in a program of strength training, such as increasing HOMA-IR (0.72 ± 0.14 to 0.81 ± 0.23; [i]p[/i] = 0.029), and increasing total blood cholesterol (178.21 ± 23.64 to 220.90 ± 64.98 mg/dL; [i]p[/i] = 0.008) and LDL fraction (111.79 ± 21.09 to 155.33 ± 60.95 mg/dL; [i]p[/i] = 0.048). No alteration in levels of inflammatory cytokines was observed, however, this detraining period significantly reduced IL-13 (44.84 ± 100.85 to 35.84 ± 78.89 pg/mL; [i]p[/i] = 0.031) a Th2 cytokine that induces M2 macrophage polarization. These data demonstrate that even a short period of detraining is harmful for elderly women who regularly participate in a program of strength training, since it impairs physical performance, insulin sensitivity and cholesterol metabolism.

|keywords=* Aging
* Inflammation
* Physical exercise
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450596
}}
{{medline-entry
|title=Contribution of Porphyromonas gingivalis lipopolysaccharide to experimental periodontitis in relation to aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32851571
|abstract=Aging is associated with increased prevalence and severity of pathogenic outcomes of periodontal disease, including soft tissue degeneration and bone loss around the teeth. Although lipopolysaccharide (LPS) derived from the key periodontal pathogen Porphyromonas gingivalis (Pg) plays an important role in the promotion of inflammation and osteoclastogenesis via toll-like receptor (TLR)4 signaling, its pathophysiological role in age-associated periodontitis remains unclear. This study investigated the possible effects of Pg-LPS on RANKL-primed osteoclastogenesis and ligature-induced periodontitis in relation to aging using young (2 months old) and aged (24 months old) mice. To the best of our knowledge, our results indicated that expression of TLR4 was significantly diminished on the surface of osteoclast precursors isolated from aged mice compared with that of young mice. Furthermore, our data demonstrated that the TLR4 antagonist (TAK242) dramatically decreased the numbers of tartrate-resistant acid phosphatase positive (TRAP+) osteoclasts differentiated from RANKL-primed young osteoclast precursors (OCPs) compared with those isolated from aged mice in response to Pg-LPS. In addition, using a ligature-induced periodontitis mouse model, we demonstrated that Pg-LPS elevated (1) secretion of senescence-associated secretory phenotype (SASP) markers, including the pro-inflammatory cytokines [[TNF]]-α, IL-6, and IL-1β, as well as osteoclastogenic RANKL, and (2) the number of OCPs and TRAP+ osteoclasts in the periodontal lesion induced in young mice. In contrast, Pg-LPS had little, or no, effect on the promotion of periodontitis inflammation induced in aged mice. Altogether, these results indicated that periodontal disease in older mice occurs in a manner independent of canonical signaling elicited by the Pg-LPS/TLR4 axis.

|keywords=* Aging
* Bone loss
* Osteoclastogenesis
* Periodontitis
* Porphyromonas gingivalis lipopolysaccharide
|full-text-url=https://sci-hub.do/10.1007/s11357-020-00258-1
}}
{{medline-entry
|title=New MoDC-Targeting [[TNF]] Fusion Proteins Enhance Cyclic Di-GMP Vaccine Adjuvanticity in Middle-Aged and Aged Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32849581
|abstract=Cyclic dinucleotides (CDNs) are promising vaccine adjuvants inducing balanced, potent humoral, and cellular immune responses. How aging influences CDN efficacy is unclear. We examined the vaccine efficacy of 3',5'-cyclic diguanylic acid (cyclic di-GMP, CDG), the founding member of CDNs, in 1-year-old (middle-aged) and 2-year-old (aged) C57BL/6J mice. We found that 1- and 2-year-old C57BL/6J mice are defective in CDG-induced memory T helper (Th)1 and Th17 responses and high-affinity serum immunoglobulin (Ig)G, mucosal IgA production. Next, we generated two novel tumor necrosis factor ([[TNF]]) fusion proteins that target soluble [[TNF]] (sol[[TNF]]) and transmembrane [[TNF]] (tm[[TNF]]) to monocyte-derived dendritic cells (moDCs) to enhance CDG vaccine efficacy in 1- and 2-year-old mice. The moDC-targeting [[TNF]] fusion proteins restored CDG-induced memory Th1, Th17, and high-affinity IgG, IgA responses in the 1- and 2-year-old mice. Together, the data suggested that aging negatively impacts CDG vaccine adjuvanticity. MoDC-targeting [[TNF]] fusion proteins enhanced CDG adjuvanticity in the aging mice.

|keywords=* 3′
* 5′-cyclic diguanylic acid (cyclic di-GMP)
* aging
* monocyte-derived dendritic cells (moDCs)
* tumor necrosis factor (TNF)
* vaccine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427090
}}
{{medline-entry
|title=Cognitive impairment in elderly patients with rheumatic disease and the effect of disease-modifying anti-rheumatic drugs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32862311
|abstract=Recent development of biologic disease-modifying anti-rheumatic drugs (DMARDs) has led to better control of disease activity among patients with chronic rheumatological diseases. Many patients with rheumatic disease are living longer, adding to the growing elderly population. Rheumatic diseases, most notably rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), are known to increase the risk of cognitive impairment. Systemic inflammation associated with chronic rheumatological diseases has been postulated to be key driver of cognitive decline. Recent development of classic and biologic DMARDs have led to better control of disease activity among patients with rheumatic conditions. It is proposed that strict control of systemic inflammation will significantly lower the risk of cognitive impairment among patients with rheumatic disease. The impact of classic DMARDs on cognitive function appears to be variable. On the other hand, biologic DMARDs, specifically antitumor necrosis factor ([[TNF]]) drugs (i.e., etanercept), have been shown to significantly lower the risk of dementia. Experimental studies on IL-1, IL-6, and B and T cell blockade are promising. However, clinical data is limited. Preclinical studies on targeted therapies, specifically JAK/STAT inhibitors, also show promising results. Additional studies are necessary to better understand the impact of these newer biologic agents on cognitive function in elderly patients with rheumatic disease. Key points • Patients with chronic rheumatic conditions are beginning to live longer, adding to the elderly population. • Patients with chronic rheumatologic disease are at increased risk of cognitive impairment compared to the general population. • Recent development of biologic (i.e., [[TNF]], IL-1, IL-6) and targeted drugs (i.e., Janus kinase inhibitors) have led to better control of disease activity. • Current evidence suggests that [[TNF]] inhibitors may have beneficial effects on cognitive function. However, evidence on newer biologic and targeted therapies is limited.

|keywords=* Aging
* Biologics
* Cognition
* Rheumatic diseases
|full-text-url=https://sci-hub.do/10.1007/s10067-020-05372-1
}}
{{medline-entry
|title=Cotinine ameliorates memory and learning impairment in senescent mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32818583
|abstract=This study aimed to assess the effects of cotinine on age-induced memory and learning impairment and related downstream pathways in mice. Thirty aged (18-month old) and 10 young mice (8-week old) were randomly divided into 4 groups (n = 10 each) and subjected to cotinine at 5 mg/kg dose and/or methyllycaconitine (MLA) at 1 mg/kg, i.p. dose (α  nAChRs antagonist) for 4 weeks. Morris water maze (MWM) and novel object recognition (NOR) tasks were used to assess spatial and recognition learning and memories of the mice, respectively. Levels of oxidative stress, apoptosis, neuroinflammation, and structural synaptic plasticity, and also neurotrophic factors and α  nAChRs were assessed in the hippocampus using either ELISA or Western blotting. Aging was associated with learning and memory disabilities and dysregulation of the assessed pathways in the hippocampus of mice. Chronic cotinine treatment improved learning and memory in aged animals, indicated by decreased latency time, and increased time spent in the target quadrant and discrimination index (DI) in the MWM and NOR tasks. Also, chronic cotinine injection increased total antioxidant capacity (TAC), SOD and GSH-px activity, PSD-95, GAP-43, SYN, brain-derived neurotrophic factor, and neural growth factor levels and decreased malondialdehyde, [[TNF]]-α, and IL-1β in the hippocampus of aged mice. Conversely, MLA treatment reversed most of the mentioned effects via the blockade of α  nAChRs. Cotinine improves age-induced memory and learning impairment via its modulatory effects on α  nAChRs and subsequent activation/deactivation of the mentioned pathways in the hippocampus of aged mice.

|keywords=* Aging
* Cognitive impairment
* Cotinine
* Improvement
* α(7)nAChRs
|full-text-url=https://sci-hub.do/10.1016/j.brainresbull.2020.08.010
}}
{{medline-entry
|title=Kynurenines link chronic inflammation to functional decline and physical frailty.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32814718
|abstract=Chronic inflammation is associated with physical frailty and functional decline in older adults; however, the molecular mechanisms of this linkage are not understood. A mouse model of chronic inflammation showed reduced motor function and partial denervation at the neuromuscular junction. Metabolomic profiling of these mice and further validation in frail human subjects showed significant dysregulation in the tryptophan degradation pathway, including decreased tryptophan and serotonin, and increased levels of some neurotoxic kynurenines. In humans, kynurenine strongly correlated with age, frailty status, [[TNF]]-αR1 and IL-6, weaker grip strength, and slower walking speed. To study the effects of elevated neurotoxic kynurenines on motor neuronal cell viability and axonal degeneration, we used motor neuronal cells treated with 3-hydroxykynurenine and quinolinic acid and observed neurite degeneration in a dose-dependent manner and potentiation of toxicity between 3-hydroxykynurenine and quinolinic acid. These results suggest that kynurenines mediate neuromuscular dysfunction associated with chronic inflammation and aging.

|keywords=* Aging
* Cytokines
* Inflammation
* Neurodegeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455140
}}
{{medline-entry
|title=Voluntary exercise training attenuated the middle-aged maturity-induced cardiac apoptosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32781061
|abstract=Voluntary exercise training has cardioprotective effects in humans, but the underlying mechanism is unknown. This research was done to estimate the effect of voluntary exercise training to attenuate middle-aged maturity-induced cardiac apoptosis. The study was designed to divide 64 male mice randomly into four groups, consisting of a 9-month sedentary pre-middle-aged group (9M), 15-month sedentary middle-aged group (15M), and two exercise groups using a voluntary wheel running respectively (9M+EX, 15M+EX). After 3 months, the condition of cardiac apoptosis in different groups was measured by HE dying, TUNEL and DAPI staining, and Western Blot analysis. TUNEL-positive cells were increased in 15M group compared with 9M group, while decreased in 9M+EX and 15M+EX groups compared with their control groups respectively. Protein levels of AIF, Endo G, [[TNF]]-α, [[TNF]]R1, TRAF2, TRADD, Fas, FasL, FADD, activated caspase 8, 3, 9, Bax/Bcl2, Bak/BclxL, and tBid were decreased in 9M+EX and 15M+EX groups compared with their control groups respectively. The protein levels of pBad/Bad, 14-3-3, IGF1, IGFR1, pPI3K/PI3K, and pAKT/AKT were more activated in the 9M+EX and 15M+EX groups than those in their control groups respectively. Significant differences were found between 9M group and 15M group for the protein levels of TRAF2, FADD, Bax/Bcl2, tBid and pAKT/AKT. Voluntary exercise training as an important lifestyle modification may prevent cardiac widely dispersed apoptosis and enhance cardiac survival at middle-aged maturity.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Heart
* In Situ Nick-End Labeling
* Male
* Mice
* Mice, Inbred C57BL
* Mitochondria, Heart
* Muscle, Skeletal
* Physical Conditioning, Animal
* Running
* Sedentary Behavior
|keywords=* Caspase-independent
* Cell death
* Fas dependent
* IGF-related
* Mitochondrial
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.118187
}}
{{medline-entry
|title=Preclinical Evaluation of a Food-Derived Functional Ingredient to Address Skeletal Muscle Atrophy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32751276
|abstract=Skeletal muscle is the metabolic powerhouse of the body, however, dysregulation of the mechanisms involved in skeletal muscle mass maintenance can have devastating effects leading to many metabolic and physiological diseases. The lack of effective solutions makes finding a validated nutritional intervention an urgent unmet medical need. In vitro testing in murine skeletal muscle cells and human macrophages was carried out to determine the effect of a hydrolysate derived from [i]vicia faba[/i] (PeptiStrong: NPN_1) against phosphorylated S6, atrophy gene expression, and tumour necrosis factor alpha ([[TNF]]-α) secretion, respectively. Finally, the efficacy of NPN_1 on attenuating muscle waste in vivo was assessed in an atrophy murine model. Treatment of NPN_1 significantly increased the phosphorylation of S6, downregulated muscle atrophy related genes, and reduced lipopolysaccharide-induced [[TNF]]-α release in vitro. In a disuse atrophy murine model, following 18 days of NPN_1 treatment, mice exhibited a significant attenuation of muscle loss in the soleus muscle and increased the integrated expression of Type I and Type IIa fibres. At the RNA level, a significant upregulation of protein synthesis-related genes was observed in the soleus muscle following NPN_1 treatment. In vitro and preclinical results suggest that NPN_1 is an effective bioactive ingredient with great potential to prolong muscle health.

|keywords=* aging
* bioactive
* functional ingredient
* immobilization
* inflammation
* muscle atrophy
* peptide
* protein synthesis
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469066
}}
{{medline-entry
|title=Childhood survivors of high-risk neuroblastoma show signs of immune recovery and not immunosenescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32744364
|abstract=Neuroblastoma survivors show signs of immunosenescence early after therapy in CD8  T cell compartment and elevated plasma [[TNF]]-α but in later follow-up immune recovery comes into play. Whether the recovery phenotype is long lasting or transient remains to be elucidated, however, late adverse effects often occur in childhood cancer survivors.

|keywords=* adverse late effects
* childhood
* immune recovery
* immunosenescence
* neuroblastoma
|full-text-url=https://sci-hub.do/10.1002/eji.202048541
}}
{{medline-entry
|title=FK506 induces lung lymphatic endothelial cell senescence and downregulates LYVE-1 expression, with associated decreased hyaluronan uptake.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32736525
|abstract=Therapeutic lymphangiogenesis in an orthotopic lung transplant model has been shown to improve acute allograft rejection that is mediated at least in part through hyaluronan drainage. Lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expressed on the surface of lymphatic endothelial cells plays important roles in hyaluronan uptake. The impact of current immunosuppressive therapies on lung lymphatic endothelial cells is largely unknown. We tested the hypothesis that FK506, the most commonly used immunosuppressant after lung transplantation, induces lung lymphatic endothelial cell dysfunction. Lung lymphatic endothelial cells were cultured in vitro and treated with FK506. Telomerase activity was measured using the TRAP assay. Protein expression of LYVE-1 and senescence markers p21 and β-galactosidase was assessed with western blotting. Matrigel tubulation assay were used to investigate the effects of FK506 on [[TNF]]-α-induced lymphangiogenesis. Dual luciferase reporter assay was used to confirm NFAT-dependent transcriptional regulation of LYVE-1. Flow cytometry was used to examine the effects of FK506 on LYVE-1 in precision-cut-lung-slices ex vivo and on hyaluronan uptake in vitro. In vitro, FK506 downregulated telomerase reverse transcriptase expression, resulting in decreased telomerase activity and subsequent induction of p21 expression and cell senescence. Treatment with FK506 decreased LYVE-1 mRNA and protein levels and resulted in decreased LEC HA uptake. Similar result showing reduction of LYVE-1 expression when treated with FK506 was observed ex vivo. We identified a putative NFAT binding site on the LYVE-1 promoter and cloned this region of the promoter in a luciferase-based reporter construct. We showed that this NFAT binding site regulates LYVE-1 transcription, and mutation of this binding site blunted FK506-dependent downregulation of LYVE-1 promoter-dependent transcription. Finally, FK506-treated lymphatic endothelial cells show a blunted response to [[TNF]]-α-mediated lymphangiogenesis. FK506 alters lymphatic endothelial cell molecular characteristics and causes lymphatic endothelial cell dysfunction in vitro and ex vivo. These effects of FK506 on lymphatic endothelial cell may impair the ability of the transplanted lung to drain hyaluronan macromolecules in vivo. The implications of our findings on the long-term health of lung allografts merit more investigation.

|keywords=* Endothelial cells
* Fk506
* Hyaluronan
* LYVE-1
* Lung lymphatic
* Senescence
* TERT
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395348
}}
{{medline-entry
|title=Late-onset hypogonadism: Reductio ad absurdum of the cardiovascular risk-benefit of testosterone replacement therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32737921
|abstract=Low testosterone (T) level is considered a marker of poor cardiovascular health. Ten years ago, the Testosterone in Older Men with Mobility Limitations (TOM) trial was discontinued due to a higher number of adverse events in men receiving T compared with placebo. Since then, several studies have investigated the risks of T replacement therapy (TRT) in late-onset hypogonadism (LOH). To review the mechanism by which TRT could damage the cardiovascular system. Comprehensive literature search of recent clinical and experimental studies. The mechanisms of T-mediated coronary vasodilation were reviewed with emphasis on calcium-activated and ATP-sensitive potassium ion channels. We showed how T regulates endothelial nitric oxide synthase (eNOS) and phosphoinositide 3-kinase/protein kinase B/eNOS signaling pathways in vessel walls and its direct effects on cardiomyocytes via β1-adrenergic and ryanodine receptors and provided data on myocardial infarction and heart failure. Vascular smooth muscle senescence could be explained by the modulation of growth factors, matrix metalloproteinase-2, and angiotensin II by T. Furthermore, leukocyte trafficking, facilitated by changes in [[TNF]]-α, could explain some of the effects of T on atheromatous plaques. Conflicting data on prothrombotic risk linked to platelet aggregation inhibition via NO-triggered arachidonate synthesis or increased aggregability due to enhanced thromboxane A in human platelets provide evidence regarding the hypotheses on plaque maturation and rupture risk. The effects of T on cardiac electrophysiology and oxygen delivery were also reviewed. The effects of TRT on the cardiovascular system are complex. Although molecular studies suggest a potential benefit, several clinical observations reveal neutral or occasionally detrimental effects, mostly due to confounding factors. Attempts to demonstrate that TRT damages the cardiovascular system via systematic analysis of the putative mechanisms led to the contradiction of the initial hypothesis. Current evidence indicates that TRT is safe once other comorbidities are addressed.

|keywords=* aging
* androgen
* heart failure
* myocardial infarction
* testosterone
* thromboembolism
|full-text-url=https://sci-hub.do/10.1111/andr.12876
}}
{{medline-entry
|title=Doxorubicin generates senescent microglia that exhibit altered proteomes, higher levels of cytokine secretion, and a decreased ability to internalize amyloid β.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32738344
|abstract=Cellular senescence is defined by irreversible cell-cycle arrest and is an evolutionarily conserved hallmark of aging. In this study, we generate senescent microglial cells via exposure to the chemotherapy drug doxorubicin. Compared to control cells, doxorubicin-treated microglia exhibited an altered morphology characterized by an enlarged cell size, a flattened appearance, and the development of prominent filaments. Senescent cells harbored elevated levels of senescence associated-β-galactosidase, p16 , and γ-H2AX. Senescent microglia were also less efficient at internalizing amyloid β and pHrodo bioparticles. A detailed proteomic analysis using SWATH-MS identified 201 proteins that were significantly downregulated and 127 that were significantly upregulated in doxorubicin-treated microglia. Proteins involved in processes such as protein synthesis, RNA damage and repair, and protein degradation were largely downregulated while those compromising the integrity of the cell were predominantly upregulated. Various proteins involved in proteasomal processing were among the most significantly downregulated in senescent cells. Relevant to the deleterious senescence-associated secretory phenotype, senescent cells secreted higher levels of the inflammatory cytokines IL-6, IL-8, [[TNF]]-α, and GRO-α. Our data suggest that symptoms of brain aging and age-related neurodegenerative disease may be partially caused by defective phagocytosis, impaired proteasomal processing, and elevated cytokine secretion of senescent microglia.

|keywords=* Aging
* Alzheimer's disease
* Inflammation
* Microglia
* Proteomics
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.yexcr.2020.112203
}}
{{medline-entry
|title=Time restricted feeding provides a viable alternative to alternate day fasting when evaluated in terms of redox homeostasis in rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32717588
|abstract=Intermittent fasting (IF) is a non-pharmacological dietary approach for intervening into aging in different organisms. We evaluated the efficacy of time restricted dietary regimen and alternate-day fasting in rats by measuring redox parameters which are frequently used as signature biomarkers of aging. Wistar rats (8 months) were divided into three groups of six rats each. Group I: Control; Group II: Time-restricted feeding (TRF) (fed and fasted at a ratio of 16:8 h respectively) and Group III. Alternate day feeding (ADF) (fed and fasted on alternate days), for a period of 1 month. The biomarkers of antioxidant defense and oxidative stress: FRAP, GSH, PMRS, ROS, AGE, MDA, PCO, AOPP, [[TNF]]-α and IL-6, were determined. Our results suggest that, based on predominant aging biomarkers, TRF has a similar effect on rats compared with ADF evaluated in terms of redox homeostasis. Observed results defend our purpose that the ADF and TRF methods are reliable dietary restriction regimens and subsequently improve the metabolic profile and redox homeostasis in rats.

|keywords=* Aging
* Alternate day fasting (ADF)
* Intermittent fasting (IF)
* Oxidative stress
* Time-Restricted feeding (TRF)
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104188
}}
{{medline-entry
|title=Associations Between Plasma Immunomodulatory and Inflammatory Mediators With VACS Index Scores Among Older HIV-Infected Adults on Antiretroviral Therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32695109
|abstract=The prevalence of age-related comorbidities is increased in people living with HIV, even in those well-controlled on combination antiretroviral therapy (ART). Persistent immune activation and inflammation may play pivotal roles in the pathogenesis; however, the burden of morbidities in the older HIV infected population may be exacerbated and driven by distinct mechanisms. In a cross sectional study of 45 HIV-infected participants 60 years or older, we examined the relationships between 14 immunomodulatory and inflammatory factors and the Veterans Aging Cohort Study (VACS) Index, a metric of multimorbidity and mortality comprised of age, CD4 count, hemoglobin, Fibrosis-4 [FIB-4], and estimated glomerular filtration rate [eGFR], by linear regression analysis. All participants were virally suppressed (<50 HIV RNA copies/mL), on ART, and primarily Caucasian (86.7%), and male (91.1%). Plasma levels of monocyte/macrophage-associated (neopterin, IP-10, sCD163, sCD14, and MCP-1) and glycan-binding immunomodulatory factors (galectin (Gal)-1, Gal-3, and Gal-9) were assessed, as well as inflammatory biomarkers previously linked to the VACS Index (i.e., CRP, cystatin C, [[TNF]]-α, [[TNF]]RI, IL-6, and D-dimer) for comparison. In regression analysis, higher VACS index scores were associated with higher levels of neopterin, cystatin C, [[TNF]]RI, and Gal-9 (all [i]p[/i] < 0.05), potentially driven by correlations found with individual VACS components, including age, CD4 count, FIB-4, and eGFR. Gal-9, cystatin C, and [[TNF]]RI directly correlated with the extent of multimorbidity. Multiple correlations among markers were observed, suggesting an interplay of overlapping, but distinct, pathways. Collectively, in addition to cystatin C and [[TNF]]RI, both galectin-9 and neopterin, independently emerged as novel fluid markers of the VACS Index and burden of comorbidity and may further guide in understanding pathogenic mechanisms of age-related disorders in older HIV-infected individuals on suppressive ART.

|keywords=* HIV
* aging
* anti-retroviral therapy
* inflammation
* morbidity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338430
}}
{{medline-entry
|title=Chrysin Impact on Oxidative and Inflammation Damages in the Liver of Aged Male Rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32679027
|abstract=The purpose of this research was to investigate the effect of chrysin on one of the natural antioxidants on aging progression in the animal model. Oxidative stress and inflammation increase in hepatic tissue during aging, leading to liver dysfunction. The current research was conducted to show the effect of chrysin on the activities of antioxidant enzyme (catalase, glutathione peroxidase, and superoxide dismutase), serum nitric oxide (NO), and lipid peroxidation as well as inflammatory cytokines ([[TNF]]-α, IL-6, and IL-1β) of aging rats. Male Wistar rats of different ages, 2, 10, and 20 months randomly divided into six groups as follows (n=8, per each group): young control rats (C2), young CH-treated rats (CH2), middle-aged control rats (C10), middle-aged CH-treated group (CH10), aged control group (C20), and aged CH-treated group (CH20). Chrysin (20 mg/kg) was administrated intraperitoneally once a day for 30 days. Present findings indicated that chrysin treatment ameliorated the increased liver levels of lipid peroxidation, [[TNF]]-α, and IL-1β as well as serum levels of NO. The findings suggest that chrysin could be effective against the progression of age-induced damage by modulation oxidant-antioxidant system and inflammatory response.

|keywords=* Aging
* chrysin
* inflammation
* liver
* oxidative stress
* rat.
|full-text-url=https://sci-hub.do/10.2174/1871530320666200717162304
}}
{{medline-entry
|title=Correction of immunosuppression in aged septic rats by human ghrelin and growth hormone through the vagus nerve-dependent inhibition of TGF-β production.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32677895
|abstract=Co-administration of human ghrelin and growth hormone (GH) reverse immunosuppression in septic aged animals, but the mechanism remains elusive. Here, we hypothesize that ghrelin and GH co-treatment restores the immune response in aged septic rats by inhibiting the production of transforming growth factor-β (TGF-β), an immunoregulatory cytokine, through the vagus nerve. Male aged Fischer rats (22-23-month-old) were made septic by cecal ligation and puncture (CLP) with or without dissecting the vagus nerve (vagotomy). Human ghrelin and GH or vehicle (PBS) were administrated subcutaneously at 5 h post CLP. After 20 h of CLP, serum and spleens were harvested. Serum TGF-β levels were increased in septic aged rats, while ghrelin and GH treatment significantly reduced its levels. Expression of TGF-β in the spleen was upregulated after sepsis, while ghrelin and GH treatment significantly inhibited its expression. [[TNF]]-α and IL-6 levels were significantly reduced after ex vivo LPS stimulation of splenocytes from rats that underwent CLP compared to sham rats; while these levels were significantly higher in splenocytes from ghrelin and GH-treated CLP rats compared to vehicle-treated CLP rats. Ghrelin and GH treatment reduced program death receptor-1 (PD-1) expression, increased human leukocyte antigen-DR (HLA-DR) expression, attenuated lymphopenia, and cleaved caspase-3 levels in the spleen of septic aged rats. Vagotomy diminished the beneficial effects of ghrelin and GH treatment in septic rats. In vitro, the addition of ghrelin, GH, or ghrelin and GH together had no effect on restoring immune response in splenocytes from CLP rats following LPS stimulation, indicating the requirement of the vagus nerve for ghrelin and GH's effect. Ghrelin and GH attenuate immunosuppression in aged septic rats through the vagus nerve-dependent inhibition of TGF-β production.

|keywords=* Aging
* Ghrelin
* Immunosuppression
* Sepsis
* Vagus nerve
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364485
}}
{{medline-entry
|title=Epigenetics of neuroinflammation: Immune response, inflammatory response and cholinergic synaptic involvement evidenced by genome-wide DNA methylation analysis of delirious inpatients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32590150
|abstract=Previously our study has shown that the DNA methylation (DNAm) levels at CpG sites in the pro-inflammatory cytokine gene, [[TNF]]-alpha, decrease along with aging, suggesting the potential role of DNAm in aging and heightened inflammatory process leading to increased risk for delirium. However, DNAm differences between delirium cases and non-delirium controls have not been investigated directly. Therefore, we examined genome-wide DNAm differences in blood between patients with delirium and controls to identify useful epigenetic biomarkers for delirium. Data from a total of 87 subjects (43 delirium cases) were analyzed by a genome-wide DNAm case-control association study. A genome-wide significant CpG site near the gene of LDLRAD4 was identified (p = 5.07E-8). In addition, over-representation analysis showed several significant pathways with a false discovery rate adjusted p-value < 0.05. The top pathway with a Gene Ontology term was immune response, and the second top pathway with a Kyoto Encyclopedia of Genes and Genomes term was cholinergic synapse. Significant DNAm differences related to immune/inflammatory response were shown both at gene and pathway levels between patients with delirium and non-delirium controls. This finding indicates that DNAm status in blood has the potential to be used as epigenetic biomarkers for delirium.

|keywords=* Aging
* Delirium
* Genome-wide DNA methylation
* Immune response
* Inflammatory response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486988
}}
{{medline-entry
|title=[i]Andrographis paniculata[/i] and Its Bioactive Diterpenoids Against Inflammation and Oxidative Stress in Keratinocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32560449
|abstract=[i]Andrographis paniculata[/i] was widely used in traditional herbal medicine to treat various diseases. This study explored the potential anti-aging activity of [i]Andrographis paniculata[/i] in cutaneous cells. Human, adult, low calcium, high temperature (HaCaT) cells were treated with methanolic extract (ME), andrographolide (ANDRO), neoandrographolide (NEO), 14-deoxyandrographolide (14DAP) and 14-deoxy-11,12-didehydroandrographolide (14DAP11-12). Oxidative stress and inflammation were induced by hydrogen peroxide and lipopolysaccharide/[[TNF]]-α, respectively. Reactive oxygen species (ROS) production was measured by fluorescence using a 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe and cytokines were quantified by ELISA for interleukin-8 (IL-8) or reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for tumor necrosis factor-α ([[TNF]]-α). Hyaluronic acid (HA) secretion was determined by an ELISA. Our results show a decrease in ROS production and [[TNF]]-α expression by ME (5 µg/mL) in HaCaT under pro-oxidant and pro-inflammatory conditions, respectively. ME protected HaCaT against oxidative stress and inflammation. Our findings confirm that ME can be used for the development of bioactive compounds against epidermal damage.

|keywords=* Andrographis paniculata
* andrographolide
* inflammation
* keratinocytes
* oxidative stress
* skin aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346124
}}
{{medline-entry
|title=Etanercept improves aging-induced cognitive deficits by reducing inflammation and vascular dysfunction in rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32569601
|abstract=Normal aging may lead to cognitive deficits, which is associated with endothelial dysfunction and neuroinflammation. Dysregulation of [[TNF]]α expression contributes to vascular aging and dementia. In this study, we investigated the effects of etanercept, which is a [[TNF]]α inhibitor, on cognitive and endothelial function in aged rats. Male Wistar albino rats were divided into 3 groups: Young (4 month), aged (24 month) aged+ETA (24 month+etanercept). Etanercept (0.8 mg/kg/weekly) was given to the aged+ETA group subcutaneously for 8 weeks. Then passive avoidance test (PAT) and the Morris water maze test (MWMT) were used to evaluate cognitive functions of rats. After the behavioral tests, the rats were subjected to systolic blood pressure (SBP) measurement, and then endothelial function of thoracic aorta was evaluated by isolated organ bath system. Thoracic eNOS expression, hippocampal BDNF expression and serum and hippocampal [[TNF]] levels were also measured. In aged rats, it was shown that cognitive performances in MWMT and PAT were abolished whereas SBP unchanged. Furthermore, aging resulted in endothelial dysfunction, decreased expressions of thoracic eNOS and hippocampal BDNF, and increased level of [[TNF]] in serum and hippocampus. In contrast, ETA improved age-related cognitive deficits and endothelial dysfunction. In addition, ETA reversed changes in protein expression in aged rats. The results of this study indicate that ETA prevents cognitive deficits, endothelial dysfunction, peripheral and neuro-inflammation and decreament of neurotrophin expression in aged rats. These findings suggest that ETA may be beneficial with neuroprotective and vasculoprotective effects in elderly patients.

|keywords=* Aging
* Etanercept
* Inflammation
* Learning
* Memory
* TNFα
* Vascular dementia
|full-text-url=https://sci-hub.do/10.1016/j.physbeh.2020.113019
}}
{{medline-entry
|title=Bacterial antigen translocation and age as BMI-independent contributing factors on systemic inflammation in NAFLD patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32559006
|abstract=Low-grade systemic inflammation is a crucial landmark in NAFLD favouring disease progression and comorbidities. We evaluated the input of circulating bacterial antigens on systemic markers of inflammation in NAFLD patients. Multicenter cross-sectional study including consecutive patients with biopsy-proven NAFLD. Demographic, metabolic and fibrosis-related variables were collected. Circulating bacterial antigens were quantified in blood. Toll-like receptor SNPs were genotyped. Serum cytokine levels were evaluated. Peripheral blood mononuclear cell response to bacterial antigens was evaluated in vitro. Three hundred and fifteen patients from five Spanish hospitals were distributed by BMI. At least, one bacterial antigenic type was found in 66 patients with BMI < 30 (63.4%) and 163 patients with BMI > 30 (77.3%) (P = .014). HOMA-IR was significantly higher in the presence of circulating antigens among patients with BMI < 30. NASH and significant fibrosis in non-obese patients were more frequent in the presence of at least two circulating antigenic types. Allelic frequencies of TLR variants were similar to controls and did not affect clinical or laboratory parameters. Pro-inflammatory cytokines were significantly increased in patients with bacterial antigens, regardless of BMI. TLR gene and protein expression levels were significantly increased in PBMCs from patients with bacterial antigens. Antigen concentrations independently influenced [[TNF]]-α and IL-6, in both BMI subgroups of patients. Age independently influenced [[TNF]]-α and IL-6 in non-obese patients, and [[TNF]]-α in obese patients. Serum circulating bacterial antigens as well as age were BMI-independent factors related to increased systemic inflammation in NAFLD and provides insight on the multifaceted sources of inflammation in these patients.

|keywords=* NAFLD
* aging
* bacterial translocation
* cytokines
* insulin resistance
|full-text-url=https://sci-hub.do/10.1111/liv.14571
}}
{{medline-entry
|title=Bone marrow mesenchymal stem cells improve thymus and spleen function of aging rats through affecting P21/PCNA and suppressing oxidative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32561691
|abstract=Bone marrow mesenchymal stem cells (BMSCs) have been considered to be an important regulator for immune function. We aim to prove the function improvement of aging spleen and thymus induced by BMSCs and unfold the specific mechanisms. Aging animal model was established using D-galactose. The morphological changes of spleen and thymus tissues were observed using hematoxylin-eosin staining and transmission electron microscopy. Key cytokines in the serum were measured with enzyme linked immunosorbent assay. Protein and mRNA levels of P16, P21, and PCNA were detected using western blotting and RT-qPCR. Special markers of BMSCs were identified using flow cytometry, and successful induction of BMSCs to steatoblast and osteoblasts was observed. Compared to aging model, BMSCs significantly increased the spleen and thymus index, improved the histological changes of spleen and thymus tissues. A remarkable increase of ratio between CD4+T cells and CD8+T cells, level of IL-2 was achieved by BMSCs. However, BMSCs markedly inhibited the content of IL-10, [[TNF]]-[i]a[/i], P16, and P21 but promoted PCNA. Significant inhibition of oxidative stress by BMSCs was also observed. We demonstrated that BMSCs significantly improved the tissue damage of aging spleen and thymus, BMSCs may improve aging organs through influencing cytokines, oxidative stress, and P21/PCNA.

|keywords=* BMSCs
* P21/PCNA
* aging
* immune system
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343510
}}
{{medline-entry
|title=Glycolic acid adjusted to pH 4 stimulates collagen production and epidermal renewal without affecting levels of proinflammatory [[TNF]]-alpha in human skin explants.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32583600
|abstract=Glycolic acid (GA) is an effective way of reversing the signs of age and photodamage. GA enhances desquamation of the stratum corneum and induces biological responses that can help restore skin's integrity. GA can, however, cause irritation, especially when its concentration is high, and its pH is low. Thus, most commercially available products for home use contain relatively low GA concentrations and are partially neutralized to a pH around 4. The aim of this study was to determine the biological effects and relative efficacy of cosmetic formulations containing GA at concentrations ranging from 8% to 25% at pH 4 in human ex vivo skin explants. Human skin explants were topically treated with gel formulations and oil-in-water creams containing 8%, 10%, 15%, or 25% GA, adjusted to pH 4, daily for 5 days. The degree of desquamation, their effect on cell proliferation, and their impact upon total collagen levels were determined 24 hours later. Levels of tumor necrosis factor-alpha ([[TNF]]-α) were measured after days 3 and 6. All formulations effectively induced desquamation in a concentration-dependent manner. Total collagen levels were increased at all concentrations, with greatest effects at higher GA concentrations. No effect on [[TNF]]-α expression was observed. These data suggest that partially neutralized GA formulations retain skin rejuvenating properties without causing irritation and inflammation and that their use can be tailored to individual needs based on the concentration of GA in the formulation.

|keywords=* cosmetics
* glycolic acid
* keratolytic agents
* rejuvenation
* skin aging
|full-text-url=https://sci-hub.do/10.1111/jocd.13570
}}
{{medline-entry
|title=A20 of nucleus pulposus cells plays a self-protection role via the nuclear factor-kappa B pathway in the inflammatory microenvironment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32566144
|abstract=Inflammatory response plays a pivotal role in the pathophysiological process of intervertebral disc degeneration (IDD). A20 (also known as tumour necrosis factor alpha-induced protein 3 ([[TNF]]AIP3)) is a ubiquitin-editing enzyme that restricts nuclear factor-kappa B (NF-κB) signalling. A20 prevents the occurrence of multiple inflammatory diseases. However, the role of A20 in the initiation of IDD has not been elucidated. The aim of the study was to investigate the effect of A20 in senescence of [[TNF]] alpha ([[TNF]]-α)-induced nucleus pulposus cells (NPCs). Immunohistochemical staining was performed to observe the expression of A20 in normal and degenerated human intervertebral discs. The NPCs were dissected from the tail vertebrae of healthy male Sprague-Dawley rats and were cultured in the incubator. In the experiment, [[TNF]]-α was used to mimic the inflammatory environment of IDD. The cell viability and senescence were examined to investigate the effect of A20 on [[TNF]]-α-treated NPCs. The expression of messenger RNA (mRNA)-encoding proteins related to matrix macromolecules (collagen II, aggrecan) and senescence markers (p53, p16). Additionally, NF-κB/p65 activity of NPCs was detected within different test compounds. The expression of A20 was upregulated in degenerate human intervertebral discs. The A20 levels of NPCs in [[TNF]]-α inflammatory microenvironments were dramatically higher than those of the control group. [[TNF]]-α significantly decreased cell proliferation potency but increased senescence-associated beta-galactosidase (SA-β-Gal) activity, the expression of senescence-associated proteins, the synthesis of extracellular matrix, and G1 cycle arrest. The senescence indicators and NF-κB/p65 expression of A20 downregulated group treated with [[TNF]]-α were significantly upregulated compared to [[TNF]]-α-treated normal NPCs. A20 has a self-protective effect on the senescence of NPCs induced by [[TNF]]-α. The downregulation of A20 in NPCs exacerbated the senescence of NPCs induced by [[TNF]]-α.  [i]Bone Joint Res.[/i] 2020;9(5):225-235.

|keywords=* A20
* Nuclear factor-kappa B
* Nucleus pulposus
* Senescence
* Tumour necrosis factor alpha
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284293
}}
{{medline-entry
|title=Age-associated decline in neural, endocrine, and immune responses in men and women: Involvement of intracellular signaling pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32563124
|abstract=The aim of this study was to investigate the alterations in the neuroendocrine-immune functions by using human peripheral blood mononuclear cells (hPBMCs) from three age groups (young, middle-aged, and old) of men and women for the analyses of lymphocyte proliferation and cytokine production, expression of cell signaling molecules, nitric oxide (NO) production, and expression of p-tyrosine hydroxylase (TH). Serum was examined for levels of testosterone in men, 17-β-estradiol in women, and cortisol in both sexes. Lymphoproliferation, expression of p-ERK, p-CREB, p-Akt, and p-TH, and levels of serum sex steroid hormones declined with age in men and women. However, [[TNF]]-α production and serum cortisol level increased with age in men and women. mTOR expression was higher in older men while it was lower in older women. IFN-γ and IL-6 production and expression of p-TH and p-mTOR were differentially regulated in men and women. These results suggest that intracellular signaling mediators may be involved in the age-related alterations in the neuroendocrine-immune interactions in men and women.
|mesh-terms=* Adult
* Aging
* Estradiol
* Female
* Humans
* Hydrocortisone
* Immunity, Cellular
* Intracellular Fluid
* Male
* Middle Aged
* Signal Transduction
* Testosterone
* Young Adult
|keywords=* 17β-estradiol
* Cortisol
* Cytokines
* Testosterone
* Tyrosine hydroxylase
|full-text-url=https://sci-hub.do/10.1016/j.jneuroim.2020.577290
}}
{{medline-entry
|title=Classical and lectin complement pathways and markers of inflammation for investigation of susceptibility to infections among healthy older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32536956
|abstract=There is increasing recognition of the significance of chronic, low-level inflammation in older adults, or "inflammaging." Innate immune responses and host-bacterial interactions are recognized as key factors in inflammaging. Inflammatory cytokine IL-6, and complement protein C1q have been identified as biomarkers for the development of frailty and aging-related diseases. Older adults are also susceptible to infections with serotypes of [i]Streptococcus pneumoniae[/i] that bind ficolin-2, a component of the lectin complement pathway, and low ficolin-2 levels could possibly be involved in such susceptibility. The aim of our study was to evaluate complement pathway components and biomarkers for inflammaging among older adults in order to investigate potential innate immune mechanisms that may account for susceptibility to infections in this population. We compared inflammatory markers, as well as components/activity of the classical and lectin complement pathways between healthy older and younger adults. We hypothesized that older adults would have higher levels of inflammatory markers and C1q, and lower levels of lectin pathway components. Older (≥70 years old) and younger (19-54 years old) adults without significant smoking history or chronic medical conditions were eligible for participation. Inflammatory markers (IL-6, [[TNF]]-α, CRP), classical complement pathway activity (CH50) and protein levels (C1q, C3, C4), and lectin pathway (MBL levels/activity, CL-L1, MASP-1/2/3, MAp44, MAp19, and H/M/L-ficolin) were compared between groups. Older adults had significantly higher mean levels of IL-6 and [[TNF]]-α. There were no significant differences in lectin pathway components between older and younger adults. Unexpectedly, mean C1q was significantly higher in the younger group in both unadjusted and adjusted analyses. There was also a significant association between race and C1q levels, but this association did not completely account for the observed differences between age groups. We did not observe deficiencies in lectin pathway components to account for increased susceptibility to ficolin-binding serotypes of [i]S. pneumoniae[/i]. Elevated levels of inflammatory cytokines in older adults are suggestive of inflammaging. However, the observed age and race-associated changes in C1q have not been previously reported in the populations included in our study. These findings are relevant to the investigation of C1q in aging-related pathology, and for its proposed role as a biomarker for frailty and disease.

|keywords=* Aging
* Complement system
* Elderly
* Immune
* Inflammation
* Lectin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285792
}}
{{medline-entry
|title=Activation of FoxO1/SIRT1/RANKL/OPG pathway may underlie the therapeutic effects of resveratrol on aging-dependent male osteoporosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32532246
|abstract=Age-dependent male osteoporosis remains a poorly studied medical problem despite its significance. It is estimated that at least 1 of 5 men will suffer from osteoporotic consequences. Given that multiple mechanisms are involved in the process of senescence, much attention has been given to compounds with polymodal actions. To challenge such a health problem, we tested here the therapeutic potential of resveratrol in male osteoporosis. We also studied the possible molecular mechanisms that may underlie resveratrol effects. Thirty male Wistar albino rats were used in the present study. Rats were divided (10/group) into: control (3-4 months old weighing 150-200 g receiving vehicle), aged (18-20 months old, weighing 350-400 g and receiving vehicle), and resveratrol treated aged (18-20 months old, weighing 350-400 g and receiving resveratrol 20 mg/kg/day for 6 weeks) groups. Assessment of serum calcium, phosphate, bone specific alkaline phosphatase, inflammatory cytokines, oxidative stress markers, and rat femur gene expression of FoxO1, SIRT1, RANKL and OPG proteins was carried out. Histopathological assessment of different levels of rat femur was also performed. Age-dependent osteoporosis resulted in significant increase in serum levels of phosphate, bone specific alkaline phosphatase, hsCRP, IL-1β, IL-6, [[TNF]]-α, MDA, NO, and RANKL gene expression. However, there was significant decrease in serum level of GSH, and gene expression of FoxO1, SIRT1 and OPG. Osteoporotic changes were seen in femur epiphysis, metaphysis and diaphysis. Resveratrol restored significantly age-dependent osteoporotic changes. We concluded that resveratrol can play an important role in the prevention of male osteoporosis. Resveratrol can counter the molecular changes in male osteoporosis via anti-inflammatory, anti-oxidant and gene modifying effects.

|keywords=* Aging
* FoxO1
* Male osteoporosois
* OPG
* RANKL
* Resveratrol
* SIRT1
* Type II osteoporosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293127
}}
{{medline-entry
|title=The senescence-associated secretome as an indicator of age and medical risk.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32554926
|abstract=Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), [[TNF]] receptor superfamily member 6 (FAS), osteopontin (OPN), [[TNF]] receptor 1 ([[TNF]]R1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.

|keywords=* Aging
* Cellular senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406245
}}
{{medline-entry
|title=Exercise Partially Rejuvenates Muscle Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32484032
|abstract=Exercise has long been known to extend health and lifespan in humans and other mammals. However, typically exercise is thought to slow the loss of function that accompanies aging. Brett et al. have now shown that exercise restores functional competency to regenerate muscle stem cells (MuSCs) in mice as well as restore a significant portion of the transcriptional signature associated with young MuSCs. The mechanism involves the likely induction of plasma-borne factors that upregulate cell cycle regulator cyclin D1, which otherwise decreases with increasing age. Cyclin D1, in turn, through its noncanonical attenuation of TGF-beta/Smad3 signaling, helps maintain the regenerative capacity of MuSCs, which is lost as TGF-beta signaling increases with age. Interestingly, elevated levels of some proinflammatory regulators including NF-κB, [[TNF]]-alpha, and interleukin 6 (IL-6) are also reduced by exercise or ectopic expression of cyclin D1. Importantly, the rejuvenation is not complete, as Notch signaling, which also decreases with age, remains at old levels and the rejuvenative effect is not permanent: wearing off in ∼2 weeks after cessation of exercise. Understanding the limitations of the rejuvenative effect of exercise on MuSCs at the molecular level, including changes in the epigenome such as altered DNA methylation age, will be critical in developing more significant rejuvenative therapies including some for aged people wherein morbidities limit exercise.

|keywords=* TGF-beta
* aging
* cyclin D1
* longevity
* regeneration
* stem cells
|full-text-url=https://sci-hub.do/10.1089/rej.2020.2359
}}
{{medline-entry
|title=Brazilian berry extract (Myrciaria jaboticaba): A promising therapy to minimize prostatic inflammation and oxidative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32460430
|abstract=Brazilian berry is a fruit popularly known as "Jaboticaba," rich in bioactive compounds with antioxidant and anti-inflammatory properties. Senescence and overweight are increasing worldwide and are considered risk factors to prostatic pathogenesis mainly due to oxidative and inflammatory processes induction. Thus, this study aimed to evaluate the effect of two increasing doses of the patented jaboticaba peel extract (PJE) on oxidative-stress and inflammation in the prostate of aging or high-fat-fed aging mice. PJE and/or high-fat diet (HFD) treatments started with 11-month-old mice and lasted 60 days. The levels or the immunoexpression of different inflammatory (nuclear factor κB [NFκB], CD3+, cyclooxygenase 2 [COX-2], toll-like receptor 4 [TLR4], phosphorylated signal transducers and activators of transcription 3 [pSTAT-3], tumor necrosis factor α [[[TNF]]-α], interleukin 6 [IL-6], and IL-1β) and oxidative-stress (catalase, superoxide dismutase 2 [SOD2], glutathione reductase [GSR], reduced glutathione, and glutathione peroxidase 3 [GPx3]) related molecules were analyzed by western-blotting, immunohistochemistry, and enzyme-linked immunosorbent assays. Both PJE doses reduced the levels of oxidative-stress-related molecules (GPx3, GSR, catalase), lipid peroxidation (4-hydroxynonenal), inflammatory mediators (COX-2, [[TNF]]-α, and pSTAT-3) and CD3+ T cells number, which were associated with the maintenance of the glandular morphological integrity in aging and HFD-fed-aging mice. Nevertheless, only the high PJE dose reduced the NFκB and TLR4 levels in aging mice; and SOD2, IL-6, and IL-1β levels in HFD-aging mice. Aging itself promoted an oxidative inflammation in the prostate, interfering in the levels of the different oxidative-stress, lipid peroxidation, and inflammatory mediators evaluated, in association with high incidence of prostate epithelial and stromal damages. The HFD intake intensified aging alterations, showing an unfavorable prostatic microenvironment prone to oxidative and inflammatory damages. PJE exerted a dose-dependent effect controlling inflammation and oxidative-stress in aging and HFD-fed aging mice prostate. This fact contributed to prostate microenvironment balance recovery, preserving the tissue architecture of this gland. Thus, the PJE emerges as a potential therapy to prevent inflammation and oxidative stress in the prostate.
|mesh-terms=* Age Factors
* Animals
* Anti-Inflammatory Agents
* Antioxidants
* Cyclooxygenase 2
* Diet, High-Fat
* Dose-Response Relationship, Drug
* Fruit
* Interleukin-1beta
* Interleukin-6
* Lipid Peroxidation
* Male
* Mice
* Myrtaceae
* Oxidative Stress
* Plant Extracts
* Prostatitis
* T-Lymphocytes
|keywords=* aging
* bioactive compounds
* obesity
* overweight
* polyphenols
|full-text-url=https://sci-hub.do/10.1002/pros.24017
}}
{{medline-entry
|title=Potential therapeutic effects of endothelial cells trans-differentiated from Wharton's Jelly-derived mesenchymal stem cells on altered vascular functions in aged diabetic rat model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32426041
|abstract=Diabetes mellitus in elderly represents an exceptional subset in the population vulnerable to cardiovascular events. As aging, diabetes mellitus and hypertension share common pathways, an ideal treatment should possess the ability to counter more than one of, if not all, the underlying mechanisms. Stem cells emerged as a potential approach for complicated medical problems. We tested here the possible role of trans-differentiated endothelial cells (ECs) in the treatment of diabetes mellitus in old rats. Mesenchymal stem cells where isolated from umbilical cord Wharton's Jelly and induced to differentiate into endothelial like-cells using vascular endothelial growth factor-enriched media. Thirty aged male Wistar albino rats were used in the present study. Rats were divided (10/group) into: control group (18-20 months old, weighing 350-400 g, received single intraperitoneal injection as well as single intravenous injection via tail vein of the vehicles), aged diabetic group (18-20 months old, weighing 350-400 g, received single intraperitoneal injection of 50 mg/kg streptozotocin, and also received single intravenous injection of saline via tail vein), and aged diabetic + ECs group (18-20 months old, weighing 350-400 g, received single intraperitoneal injection of 50 mg/kg streptozotocin, and also received single intravenous injection of 2*10  MSC-derived ECs in 0.5 ml saline via tail vein) groups. Assessment of SBP, aortic PWV, and renal artery resistance was performed. Serum levels of ET1, ANG II, IL-6, [[TNF]]-α, MDA, ROS, and VEGF were evaluated, as well as the aortic NO tissue level and eNOS gene expression. Histopathological and immunostaining assessments of small and large vessels were also performed. Induction of diabetes in old rats resulted in significant increase in SBP, aortic PWV, renal artery resistance, and serum levels of ET1, ANG II, IL-6, [[TNF]]-α, MDA, ROS, and VEGF. While there was significant decrease in aortic NO tissue level and eNOS gene expression in the aged diabetic group when compared to aged control group. ECs treatment resulted in significant improvement of endothelial dysfunction, inflammation and oxidative stress. We report here the potential therapeutic role of trans-differentiated ECs in aged diabetics. ECs demonstrated anti-inflammatory, antioxidant, gene modifying properties, significantly countered endothelial dysfunction, and improved vascular insult.

|keywords=* Aging
* Diabetes mellitus
* Endothelial cells
* Hypertension
* Mesenchymal stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216374
}}
{{medline-entry
|title=[Effect of fragmented sleep on postoperative cognitive function and central neuroinflammation].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32375444
|abstract= To investigate the effect of sleep fragmentation on perioperative neurocognitive disorders (PND) and central neuroinflammation by simulating sleep patterns of postoperative patients with sleep fragmentation in aged mice.   Thirty-two elderly ICR mice were randomly divided into four groups ([i]n=[/i]8): normal group (C), surgery group (S), fragmented sleep group (F), and surgery+fragmented sleep group (D). Fragmented sleep was conducted after internal fixation of tibia fractures, cognitive function was evaluated by novel object recognition (NOR) and fear conditioning (FC) test, and changes in expression of inflammatory cytokines in hippocampus were detected by ELISA.   NOR test: the recognition index (RI) of mice in group C, group S, group F and group D was 0.69±0.07, 0.48±0.07, 0.54±0.10 and 0.50±0.12, respectively. The RI of mice in group S, group F and group D was significantly lower than that in group C ([i]t=[/i]4.885, 3.521 and 4.433, all [i]P<[/i]0.01). There was no significant difference in RI between group S and group D ([i]t=[/i]0.967 1, [i]P>[/i]0.05). Contextual FC test: the freezing time of mice in group C, group S, group F and group D was(21.34±6.48), (13.83±4.26), (11.50±6.25) and (6.17±4.77) s, respectively. The freezing time of mice in group S, group F and group D was significantly lower than that in group C ([i]t=[/i]2.722, 3.566, 5.496, [i]P<[/i]0.05 or [i]P<[/i]0.01). The freezing time of mice in group D was significantly lower than that in group S ([i]t=[/i]2.774, [i]P<[/i]0.05). Cue FC test: the freezing time of mice in group C, group S, group F and group D was (74.36±17.09), (43.91±9.71), (46.34±13.43) and (24.90±14.21) s, respectively. The freezing time of mice in group S, group F and group D was significantly lower than that in group C ([i]t=[/i]4.393, 4.043 and 7.136, all [i]P<[/i]0.01). The freezing time of mice in group D was significantly lower than that in group S ([i]t=[/i]2.743, [i]P<[/i]0.05). The levels of [[TNF]]-α, IL-6 and IL-1β in hippocampus of mice in group S, F and D were significantly higher than those in group C, while the levels of [[TNF]]-α and IL-6 in hippocampus of mice in group D were significantly higher than those in group S, with statistically significant differences ([i]P<[/i]0.05 or [i]P<[/i]0.01).   Postoperative fragmented sleep aggravates postoperative cognitive impairment and increases the hippocampal neuroinflammation in aged mice.
|mesh-terms=* Aging
* Animals
* Cognition
* Cognition Disorders
* Fear
* Hippocampus
* Mice
* Mice, Inbred ICR
|keywords=* Central nervous system
* Cognition disorders
* Inflammation
* Postoperative period
* Sleep deprivation
|full-text-url=https://sci-hub.do/10.3760/cma.j.cn112137-20191215-02734
}}
{{medline-entry
|title=Can blocking inflammation enhance immunity during aging?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32386656
|abstract=Aging is a global burden, and the increase in life span does not increase in parallel with health span. Therefore, older adults are currently living longer with chronic diseases, increased infections, and cancer. A characteristic of aging is the presence of chronic low-grade inflammation that is characterized by elevated concentrations of IL-6, [[TNF]]-α, and C-reactive protein, which has been termed inflammaging. Previous studies have demonstrated that chronic inflammation interferes with T-cell response and macrophage function and is also detrimental for vaccine responses. This raises the question of whether therapeutic strategies that reduce inflammation may be useful for improving immunity in older adults. In this review we discuss the potential causes of inflammaging, the cellular source of the inflammatory mediators, and the mechanisms by which inflammation may inhibit immunity. Finally, we describe existing interventions that target inflammation that have been used to enhance immunity during aging.

|keywords=* Inflammaging
* p38-MAP Kinase
* senescence
* senolytics
|full-text-url=https://sci-hub.do/10.1016/j.jaci.2020.03.016
}}
{{medline-entry
|title=[FAS- and [[TNF]]-dependent ways participation in apoptosis mechanisms in hypotalumus in physiological and pathological aging.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32362081
|abstract=The cell resistance to apoptosis can be related to the activity of cytokine-dependent signaling. So, the aim of the work is to investigate the mechanisms of cytokine-dependent FAS/[[TNF]]-mediated regulation of apoptosis of neurosecretory cells in the physiological and pathological (overexpression of the oncogene HER-2/Neu) aging. HER2/Neu transgenic accelerated aged mice of different ages and wild type FVB/N were examined. The apoptosis level of neurons in hypothalamic sections (supraoptic and paraventricular nuclei) (TUNEL) and expression of caspase-8, CD178 (FASL), FAS, FADD, TRADD (Western blotting) was determined. Participation of the proinflammatory component in the aging process is shown. FAS, adapter proteins associated with the death domain (FADD and TRADD), caspase-8 expression is activated in hypothalamus in FVB/N mice (wild type) during aging, and it correlates with an increase in the apoptosis level. HER-2/Neu expression leads to the extrinsic apoptotic pathway suppression. In this case, the reception of an apoptotic signal (FAS-receptor expression) and its further transmission (expression of FADD and TRADD) is suppressed. However, in young transgenic mice, increased expression of TRADD can activate one of the survival ways - NF-κB, ERK or PI3K-AKT cascade. Thus, the HER-2/Neu tyrosine kinase receptor plays a role in the mechanism of cell resistance to age-dependent apoptosis, and the FAS/[[TNF]]-signaling pathway is one of the targets of HER-2/Neu.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Female
* Hypothalamus
* Mice
* Mice, Transgenic
* Signal Transduction
* Tumor Necrosis Factor-alpha
* fas Receptor
|keywords=* FAS-, TNF-dependent pathways
* aging
* apoptosis
* hypothalamus
* neurons

}}
{{medline-entry
|title=Ultrasound-guided continuous thoracic paravertebral block alleviates postoperative delirium in elderly patients undergoing esophagectomy: A randomized controlled trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32332664
|abstract=Delirium is a common postoperative complication in older patients undergoing thoracic surgery and presages poor outcomes. Postoperative pain is an important factor in the progression of delirium. The purpose of this study was to test whether continuous thoracic paravertebral block (PVB), a more effective approach for analgesia, could decrease the incidence of delirium in elderly patients undergoing esophagectomy. A total of 180 geriatric patients undergoing esophagectomy were randomly divided into 2 groups and treated with PVB or patient-controlled analgesia (PCA). Perioperative plasma CRP, IL-1β, IL-6, and [[TNF]]-α levels were detected in all patients. Pain intensity was measured by a numerical rating scale. Delirium was assessed using the confusion assessment method. The incidence of postoperative delirium was significantly lower in the PVB group than in the PCA group. Patients in the PVB group had lower plasma CRP, IL-1β, IL-6, and [[TNF]]-α levels and less pain when coughing after surgery. Ultrasound-guided continuous thoracic paravertebral block improved analgesia, reduced the inflammatory reaction and decreased the occurrence of delirium after surgery.
|mesh-terms=* Aged
* Aged, 80 and over
* Analgesia, Patient-Controlled
* Delirium
* Esophagectomy
* Female
* Geriatrics
* Humans
* Male
* Middle Aged
* Nerve Block
* Postoperative Complications
* Prospective Studies
* Ultrasonography

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440095
}}
{{medline-entry
|title=17β-Estradiol improves insulin signalling and insulin resistance in the aged female hearts: Role of inflammatory and anti-inflammatory cytokines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32311377
|abstract=Aging effects in energy balance in all tissues and organs, including the cardiovascular. The risk of cardiovascular disease is drastically higher in postmenopausal women than in premenopausal women. Estrogen plays an important role in the cardiac function and body's metabolism. The aim of this study was to determine whether 17β-estradiol (E2) has beneficial effects on insulin resistance and some key stages of the insulin signalling pathway in the aged hearts. Young and aged female Wistar rats were ovariectomized and were randomly divided into three groups: young (YS) and aged (AS) sham, young (YV) and aged (AV) vehicle, and young (YE2) and aged (AE2) E2 treatment groups. E2 (1 mg/kg) was administrated every four days for four weeks. Results showed that ovariectomy increased fasting blood glucose, insulin, and HOMAIR in young, while none of these parameters was affected in aged animals. On the other hand, aging itself increased these variables. Furthermore, E2 therapy alleviated these changes in both young and aged animals. Moreover, aging also decreased the p-IRS1, p-Akt level, and translocation of GLUT4 to the plasma membrane. E2 reduced the negative impact of menopause and aging on insulin sensitivity by favoring increase in the level of IL-10 and decrease in the levels of [[TNF]]-α and IL-1β. Our results indicated that the heart response to E2 depended on age, and E2 increased insulin sensitivity in the heart of both young and aged animals by altering inflammatory conditions. Determining the exact mechanism of this action is suggested in future studies.
|mesh-terms=* Aging
* Animals
* Anti-Inflammatory Agents
* Blood Glucose
* Cytokines
* Estradiol
* Female
* Heart
* Insulin
* Insulin Resistance
* Lipid Metabolism
* Menopause
* Ovariectomy
* Rats
* Rats, Wistar
* Signal Transduction
|keywords=* 17β-estradiol
* Aging
* Cytokines
* Heart
* Insulin signalling
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.117673
}}
{{medline-entry
|title=Synergistic Antitumor Efficacy of Magnetohyperthermia and Poly(lactic-co-glycolic acid)-Encapsulated Selol in Ehrlich Breast Adenocarcinoma Treatment in Elderly Swiss Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32252879
|abstract=Nanobiotechnology strategies for cancer treatments are currently being tested with increasing interest, except in elderly groups. It is well established that breast cancer incidence increases with age and that traditional therapies usually generate severe adverse effects, especially for elderly groups. To investigate if the benefits of nanotechnology could be extended to treating cancer in this group, citrate-coated maghemite nanoparticles (NpCit) were used for magnetohyperthermia (MHT) in combination with the administration of PLGA-Selol nanocapsule (NcSel), a formulation with antioxidant and antitumor activity. The combined therapies significantly inhibited breast Ehrlich tumor growth and prevented metastases to the lymph nodes, liver and lungs until 45 days after tumor induction, a better result than the group undergoing conventional drug treatment. The levels of [[TNF]]-α, associated with poor prognosis in Ehrlich tumor, were also normalized. Therefore, the results evidenced the potential use of these therapies for future clinical trials in elderly breast cancer patients.
|mesh-terms=* Adenocarcinoma
* Aging
* Animals
* Cell Line, Tumor
* Glycols
* Humans
* Mice
* Nanoparticles
* Polylactic Acid-Polyglycolic Acid Copolymer
* Selenium Compounds

|full-text-url=https://sci-hub.do/10.1166/jbn.2020.2890
}}
{{medline-entry
|title=Pinitol suppresses [[TNF]]-α-induced chondrocyte senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32200264
|abstract=Osteoarthritis (OA) is a highly prevalent joint disorder that is tightly correlated with age. As the body ages, cell replication and function decline until homeostasis can no longer be maintained. This process involves cellular senescence as well as replicative senescence. Telomere length, cell cycle arrest, expression of p16 and p53, and the release of senescence-associated β-galactosidase (SA-β-Gal) are all markers of cell senescence. In OA joints, chondrocytes undergo cellular senescence prematurely, thereby ceasing to synthesize and maintain cartilage tissue. Upregulation of proinflammatory cytokines, such as tumor necrosis factor-α ([[TNF]]-α), and oxidative stress induced by overproduction of reactive oxygen species (ROS) are key events in the pathogenesis of OA. In the present study, we investigated the effects of pinitol, a naturally occurring compound, on the effects of [[TNF]]-α on chondrocyte senescence and cell cycle arrest. We found that pinitol has a favorable safety profile in terms of cell viability. Pinitol significantly inhibited cellular senescence and cell cycle arrest in the G0/G1 phase induced by [[TNF]]-α. We also found that pinitol could inhibit [[TNF]]-α-induced increased telomerase activity and expression of p16 and p53. Importantly, we found that the effects of pinitol may be mediated through rescue of Nrf2 signaling, which is recognized as a key protective factor in OA. This finding was verified through a Nrf2 silencing experiment using Nrf2 siRNA. Together, our findings reveal the potential of pinitol as a safe therapeutic option for the prevention of OA-associated chondrocyte senescence and oxidative stress.

|keywords=* Cellular senescence
* Nrf2
* Osteoarthritis
* Pinitol
* TNF-α
|full-text-url=https://sci-hub.do/10.1016/j.cyto.2020.155047
}}
{{medline-entry
|title=[Aging of skin fibroblasts: genetic and epigenetic factors.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32160428
|abstract=Gerontocosmetology is the rapid developing knowledge area that has a very large applied meaning. Herewith a lot of information about skin aging and geroprotectors for skin rejuvenation hasn't a scientific background. Thus, understanding the fundamental mechanisms of skin aging becomes the actual task of molecular gerontology. Skin fibroblasts are the polyfunctional cell population that synthesize a number of biologically active substances and participate in maintaining of extracellular matrix homeostasis, skin hydratation and endocrine and immune function. In the review genetic (accumulation of nuclear and mitochondrial DNA mistakes) and epigenetic factors of skin fibroblasts aging are described. Role of AP-1, NF-κB, c-jun, CCN1, TGF-β, [[TNF]]-α, MMP-1, MMP-3, MMP-8, MMP-9 and glycation in skin fibroblasts aging are discussed. There are some data about decreasing of skin fibroblasts ability to migration and synthesis of paxillins and aquaporin-3 (AQP3) during aging. Role of hormonal regulation in skin fibroblasts aging are described. Geroprotective action of melatonin to skin fibroblasts are showed. Reviewed molecular-cellular aspects of skin fibroblasts aging can be take into consideration for scientific background of using of cosmetic products for retarding of skin aging rate.
|mesh-terms=* Cells, Cultured
* Epigenesis, Genetic
* Fibroblasts
* Humans
* Skin Aging
|keywords=* aging
* melatonin
* signal molecules
* skin fibroblasts

}}
{{medline-entry
|title=Functional and traditional training improve muscle power and reduce proinflammatory cytokines in older women: A randomized controlled trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32151735
|abstract=Aging is a natural process that, even in the nonattendance of complex diseases, is associated with a numerous behavioral change that attributes reduced muscle mass, power, strength and function. In addition, aging linked to low-grade inflammatory status, characterized by increased plasma concentrations of inflammatory cytokines such as [[TNF]]-α and IL-6. Physical exercise is the main non-pharmacological strategy for improving the physical fitness of the aged individuals. However, it is still controversial whether exercise can reduce aging-mediated inflammation. To analyze the effects of functional (FT) and traditional (TT) training practice on muscle power and inflammatory profile in physically active older women. The study has been performed for twenty-six weeks in which twenty-four weeks utilized for training sessions and two weeks for physical and biochemical assessments. Forty-three older women (age FT: 64.25 ± 4.70, range: 60-75; TT: 64.90 ± 3.03, range: 60-71; Control: 65.91 ± 5.79, range: 60-75) were randomly divided into three groups: Functional (FT; n = 16); Traditional (TT; n = 16) training groups; and Control Group (CG; n = 11) respectively. Muscle power tests were performed by push (Bench press) and squatting (Squat) actions. The jumping ability was performed through Counter Movement Jump (CMJ). In addition, isometric strength were assessed by Hand Grip Test. Plasma cytokine concentration was measured using flow cytometry. Functional and traditional training sessions subjected to aged women demonstrated a significant enhancement in their physical activity and muscle power. The trained individuals from above two groups showed significant improvements in all analyzed parameters excluding hand-grip. Functional and traditional training exercise reduced the plasma concentrations of [[TNF]]-α (FT: p = 0.0001; TT: p = 0.0410) and whereas FT group has reduced IL-6 (p = 0.0072), but did not affect the alterations of pre and post measurements of IL-2 (FT: p = 0.0651; TT: p = 0.2146) and IL-10 values (FT: p = 0.2658; TT: p = 0.3116). There was no significant difference in any of the test parameters between FT and TT groups. The functional and traditional training practices showed equivalent beneficial outcomes by increasing muscle power and reducing systemic markers associated with inflammation.

|keywords=* Aging
* Cytokines.
* Dynapenia
* Inflamm-aging
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110920
}}
{{medline-entry
|title=Associations of [[TNF]]-α -308 G>A and [[TNF]]-β 252 A>G with Physical Function and BNP-Rugao Longevity and Ageing Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32115620
|abstract=To explore the associations of [[TNF]]-α -308 G>A (rs1800629) and [[TNF]]-β 252 A>G (rs909253) with physical function and plasma B-type natriuretic peptide (BNP). Data of 1747 community-dwelling elders from the ageing arm of the Rugao Longevity and Ageing Study was used. Physical function was measured by handgrip strength, Timed Up and Go (TUG) test and 5-meter walking test (5MWT). AA genotype of the [[TNF]]-α -308 G>A was associated with higher mean time of TUG test and 5MWT (multivariable adjusted β=5.75 and 5.70, respectively, p<0.05), compared with GG genotype. For the [[TNF]]-β 252 A>G polymorphism, GG genotype was associated with higher mean time of TUG test and 5MWT (multivariable adjusted β=1.55 and 0.83, respectively, p<0.05) and lower handgrip strength (multivariable adjusted β=-0.69, p<0.05), compared with AA genotype. Further, GG was associated with greater odds of low handgrip strength (OR=1.47, 95% CI=1.06-2.04), low speed of TUG test (OR=1.87, 95% CI=1.20-2.01) and elevated BNP (OR=1.30, 95% CI=1.08-1.84). GG also interacted with elevated BNP to be associated with greater odds of low handgrip strength and 5MWT. [[TNF]]-β 252 A>G was associated with physical function measurements, plasma BNP level, and odds of elevated BNP in an elderly population. [[TNF]]-β 252 A>G also interacted with elevated BNP to be associated with greater odds of physical function measurements.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Female
* Humans
* Longevity
* Male
* Natriuretic Peptide, Brain
* Tumor Necrosis Factor-alpha
|keywords=* Physical function
* TNF-α -308 G>A polymorphism
* TNF-β 252 A>G polymorphism
* plasma BNP
* population study.
|full-text-url=https://sci-hub.do/10.1007/s12603-020-1336-1
}}
{{medline-entry
|title=3D TECA hydrogel reduces cellular senescence and enhances fibroblasts migration in wound healing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32104405
|abstract=This study was designed to investigate the effect of 3D TECA hydrogel on the inflammatory-induced senescence marker, and to assess the influence of the gel on the periodontal ligament fibroblasts (PDLFs) migration in wound healing [i]in vitro[/i]. PDLFs were cultured with 20 ng/ml [[TNF]]-α to induce inflammation in the presence and absence of 50 µM 3D TECA gel for 14 d. The gel effect on the senescence maker secretory associated-β-galactosidase (SA-β-gal) activity was measured by a histochemical staining. Chromatin condensation and DNA synthesis of the cells were assessed by 4',6-diamidino-2-phenylindole and 5-ethynyl-2'-deoxyuridine fluorescent staining respectively. For evaluating fibroblasts migration, scratch wound healing assay and Pro-Plus Imaging software were used. The activity of senescence marker, SA-β-gal, was positive in the samples with [[TNF]]-α-induced inflammation. SA-β-gal percentage is suppressed (>65%, [i]P[/i] < 0.05) in the treated cells with TECA gel as compared to the non-treated cells. Chromatin foci were obvious in the non-treated samples. DNA synthesis was markedly recognized by the fluorescent staining in the treated compared to non-treated cultures. Scratch wound test indicated that the cells migration rate was significantly higher (14.9 µm /h, [i]P[/i] < 0.05) in the treated versus (11 µm /h) for control PDLFs. The new formula of 3D TECA suppresses the inflammatory-mediated cellular senescence and enhanced fibroblasts proliferation and migration. Therefore, 3D TECA may be used as an adjunct to accelerate repair and healing of periodontal tissues.

|keywords=* 3D TECA
* Cellular senescence
* Fibroblast migration
* SA-β-gal
* TNF-α
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032142
}}
{{medline-entry
|title=Regulatory Effect of Anwulignan on the Immune Function Through Its Antioxidation and Anti-Apoptosis in D-Galactose-Induced Aging Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32099340
|abstract=Aging is a spontaneous and inevitable phenomenon of biology, which can lead to the gradual deterioration of tissues and organs. One of the age-related deterioration processes is immunosenescence, which leads to changes in the function of immune systems, including immune cells and associated cytokines. A proper modulation of immune responses can improve the age-related immunosenescence process and then reach healthy aging. [i]Schisandra sphenanthera[/i], a traditional Chinese medicine, has been used as both a medicine and a nutritional supplement for thousands of years. Anwulignan, a monomer compound of [i]Schisandra sphenanthera[/i] lignans, has been reported to possess an immunomodulatory effect. Therefore, this study was designed to further explore whether Anwulignan could also modulate the immune functions in aging model mice and the underlying mechanism. D-galactose (D-gal) is often used as an inducer of immunosenescence in animals. In this study, a mice model was created by subcutaneous D-gal (220 mg kg ) for successive 42 days. Then, the blood and spleen tissue samples were taken for the analysis and observation of cytokine levels, immunoglobulin levels, leukocyte numbers, and the phagocytic activity of macrophages, as well as the histological changes, the proliferation ability of lymphocytes, and the biochemical parameters in the spleen tissue. Anwulignan significantly increased the serum levels of IL-2, IL-4, IFN-γ, lgG, lgM, and lgA, decreased the content of [[TNF]]-α and IL-6 in the aging mice, and increased the blood leukocyte number, the phagocytic activity, the lymphocyte proliferation, and the spleen index in vitro. Anwulignan also significantly increased the activities of SOD and GSH-Px, decreased the contents of MDA and 8-OHdG in the spleen tissue, up-regulated the expressions of Nrf2, HO-1, and Bcl2, down-regulated the expressions of Keap1, Caspase-3, and Bax in the spleen cells, and reduced the apoptosis of spleen lymphocytes. Anwulignan can restore the immune function that is declined in D-gal-induced aging mice partly related to its antioxidant capacity by activating the Nrf2/ARE pathway and downstream enzymes, as well as its anti-apoptotic effect by regulating Caspase-3 and the ratio of Bcl2 to Bax in the spleen.
|mesh-terms=* Animals
* Antioxidants
* Apoptosis
* Cytokines
* Immunologic Factors
* Immunosenescence
* Male
* Medicine, Chinese Traditional
* Mice
* Models, Animal
* NF-E2-Related Factor 2
* Oxidative Stress
* Phytochemicals
* Schisandra
* Spleen
|keywords=* Anwulignan
* anti-apoptosis
* antioxidation
* immunosenescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996228
}}
{{medline-entry
|title=Pretreatment Frailty Is Independently Associated With Increased Risk of Infections After Immunosuppression in Patients With Inflammatory Bowel Diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32105728
|abstract=Infections are an important adverse effect of immunosuppression for treatment of inflammatory bowel diseases (IBDs). However, risk of infection cannot be sufficiently determined based on patients' ages or comorbidities. Frailty has been associated with outcomes of patients with other inflammatory diseases. We aimed to determine the association between frailty and risk of infections after immunosuppression for IBD. We performed a cohort study of 11,001 patients with IBD, using a validated frailty definition based on International Classification of Disease codes to identify patients who were frail vs fit in the 2 years before initiation of an anti-tumor necrosis factor ([[TNF]]) or immunomodulator therapy, from 1996 through 2010. Our primary outcome was an infection in the first year after treatment. We constructed multivariable logistic regression models, adjusting for clinically pertinent confounders (age, comorbidities, steroid use, and combination therapy) to determine the association between frailty and posttreatment infections. There were 1299 patients treated with an anti-[[TNF]] agent and 2676 patients treated with an immunomodulator. In this cohort, 5% of patients who received anti-[[TNF]] therapy and 7% of patients who received an immunomodulator were frail in the 2 years before immunosuppression. Frail patients were older and had more comorbidities. Higher proportions of frail patients developed infections after treatment (19% after [[TNF]] and 17% after immunomodulators) compared with fit patients (9% after [[TNF]] and 7% after immunomodulators; P < .01 for frail vs fit in both groups). Frail patients had an increased risk of infection after we adjusted for age, comorbidities, and concomitant medications (anti-[[TNF]] adjusted odds ratio, 2.05 [95% confidence interval, 1.07-3.93] and immunomodulator adjusted odds ratio, 1.81 [95% confidence interval, 1.22-2.70]). Frailty was associated with infections after immunosuppression in patients with IBD after we adjust for age and comorbidities. Systematic assessment and strategies to improve frailty might reduce infection risk in patients with IBD.

|keywords=* Aging
* Immunosuppression
* Side Effect
* Thiopurine
|full-text-url=https://sci-hub.do/10.1053/j.gastro.2020.02.032
}}
{{medline-entry
|title=The Citrus Flavonoid Naringenin Protects the Myocardium from Ageing-Dependent Dysfunction: Potential Role of SIRT1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32047577
|abstract=Sirtuin 1 (SIRT1) enzyme plays a pivotal role in the regulation of many physiological functions. In particular, it is implicated in ageing-related diseases, such as cardiac hypertrophy, myocardial infarct, and endothelial dysfunction; moreover, its expression decreases with age. Therefore, an effective strategy to extend the lifespan and improve cardiovascular function is the enhancement of the expression/activity of SIRT1 with exogenous agents. The Citrus flavonoid naringenin (NAR) presents structural similarity with the natural SIRT1 activator resveratrol. In this study, we demonstrate through [i]in vitro[/i] assays that NAR significantly activates SIRT1 enzyme and shows antisenescence effects. The binding mode of NAR into SIRT1 was detailed investigated through [i]in silico[/i] studies. Moreover, chronic administration (for six months) of NAR (100 mg/kg/day) to 6-month-old mice leads to an enhancement of SIRT1 expression and a marked reduction of reactive oxygen species production in myocardial tissue. Furthermore, at the end of the treatment, the plasma levels of two well-known markers of cardiovascular inflammation, [[TNF]]-[i]α[/i] and IL6, are significantly reduced in 12-month-old mice treated with NAR, as well as the cardiovascular risk (total cholesterol/HDL ratio) compared to control mice. Finally, the age-associated fibrotic remodeling, which is well detected through a Mallory trichrome staining in the vehicle-treated 12-month-old mice, is significantly reduced by the chronic treatment with NAR. Moreover, an improvement of myocardium functionality is highlighted by the enhancement of citrate synthase activity and stabilization of the mitochondrial membrane potential after NAR treatment. Taken together, these results suggest that a nutraceutical approach with NAR may have positive impacts on many critical hallmarks of myocardial senescence, contributing to improve the cardiac performance in aged subjects.
|mesh-terms=* Aging
* Animals
* Antioxidants
* Cell Line
* Cellular Senescence
* Citrus
* Cytoprotection
* Disease Models, Animal
* Flavanones
* Humans
* Interleukin-6
* Mice
* Myocardium
* Protein Binding
* Rats
* Reactive Oxygen Species
* Sirtuin 1
* Tumor Necrosis Factor-alpha

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003265
}}
{{medline-entry
|title=In the Absence of a TCR Signal IL-2/IL-12/18-Stimulated γδ T Cells Demonstrate Potent Anti-Tumoral Function Through Direct Killing and Senescence Induction in Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31947966
|abstract=Abundant IFN-γ secretion, potent cytotoxicity, and major histocompatibility complex-independent targeting of a large spectrum of tumors make γδ T cells attractive candidates for cancer immunotherapy. Upon tumor recognition through the T-cell receptor (TCR), NK-receptors, or NKG2D, γδ T cells generate the pro-inflammatory cytokines [[TNF]]-α and IFN-γ, or granzymes and perforin that mediate cellular apoptosis. Despite these favorable potentials, most clinical trials testing the adoptive transfer of pharmacologically TCR-targeted and expanded γδ T cells resulted in a limited response. Recently, the TCR-independent activation of γδ T cells was identified. However, the modulation of γδ T cell's effector functions solely by cytokines remains to be elucidated. In the present study, we systematically analyzed the impact of IL-2, IL-12, and IL-18 in parallel with TCR stimulation on proliferation, cytokine production, and anti-tumor activity of γδ T cells. Our results demonstrate that IL-12 and IL-18, when combined, constitute the most potent stimulus to enhance anti-tumor activity and induce proliferation and IFN-γ production by γδ T cells in the absence of TCR signaling. Intriguingly, stimulation with IL-12 and IL-18 without TCR stimulus induces a comparable degree of anti-tumor activity in γδ T cells to TCR crosslinking by killing tumor cells and driving cancer cells into senescence. These findings approve the use of IL-12/IL-18-stimulated γδ T cells for adoptive cell therapy to boost anti-tumor activity by γδ T cells.

|keywords=* IL-12
* IL-18
* TCR bypass stimulation
* senescence
* γδ T cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017313
}}
{{medline-entry
|title=Aging is associated with loss of beneficial effects of estrogen on leptin responsiveness in mice fed high fat diet: Role of estrogen receptor α and cytokines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31904410
|abstract=Aging causes changes in body composition and energy balance. Estrogen plays an important role in body's metabolism. The aim of this study was to determine whether estrogen has beneficial effects on leptin responsiveness in aged mice. Young 4 months and aged 19-21 female mice fed High Fat Diet (HFD) or Standard Diet (SD) for 12 weeks and following received estrogen for 4 weeks. Responsiveness to leptin was compared by measuring energy balance parameters. Results showed that HFD caused weight gain compared to SD in young, but had no effect on aged animals. Estrogen reduced body weight, energy intake and visceral fat in young, while none of these parameters was affected in aged animals. Although there was leptin sensitivity in aged compared to ovariectomized animals, estrogen only improved the sensitivity of young to leptin. Estrogen prevented increase in [[TNF]]-α and a decrease in IL-10 in HFD young and aged animals. Response to estrogen depended on age, and estrogen increased leptin sensitivity only in young animals. Determining the exact mechanism of this action is suggested in future studies.

|keywords=* Aging
* Cytokines
* ERα
* Estrogen
* Leptin sensitivity
|full-text-url=https://sci-hub.do/10.1016/j.mad.2019.111198
}}
{{medline-entry
|title=Mitochondrial Dysfunction and Alpha-Lipoic Acid: Beneficial or Harmful in Alzheimer's Disease?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31885820
|abstract=Alzheimer's disease (AD) is a neurodegenerative disorder characterised by impairments in the cognitive domains associated with orientation, recording, and memory. This pathology results from an abnormal deposition of the [i]β[/i]-amyloid (A[i]β[/i]) peptide and the intracellular accumulation of neurofibrillary tangles. Mitochondrial dysfunctions play an important role in the pathogenesis of AD, due to disturbances in the bioenergetic properties of cells. To date, the usual therapeutic drugs are limited because of the diversity of cellular routes in AD and the toxic potential of these agents. In this context, alpha-lipoic acid ([i]α[/i]-LA) is a well-known fatty acid used as a supplement in several health conditions and diseases, such as periphery neuropathies and neurodegenerative disorders. It is produced in several cell types, eukaryotes, and prokaryotes, showing antioxidant and anti-inflammatory properties. [i]α[/i]-LA acts as an enzymatic cofactor able to regulate metabolism, energy production, and mitochondrial biogenesis. In addition, the antioxidant capacity of [i]α[/i]-LA is associated with two thiol groups that can be oxidised or reduced, prevent excess free radical formation, and act on improvement of mitochondrial performance. Moreover, [i]α[/i]-LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, [[TNF]]-[i]α[/i], IL-1[i]β[/i], and IL-6. Regarding the pharmacokinetic profile, [i]α[/i]-LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic. However, [i]α[/i]-LA has low risk in prolonged use, although its therapeutic potential, interactions with other substances, and adverse reactions have not been well established in clinical trials with populations at higher risk for diseases of aging. Thus, this review aimed to describe the pharmacokinetic profile, bioavailability, therapeutic efficacy, safety, and effects of combined use with centrally acting drugs, as well as report in vitro and in vivo studies that demonstrate the mitochondrial mechanisms of [i]α[/i]-LA involved in AD protection.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Cytokines
* Humans
* Inflammation Mediators
* Mitochondria
* Neurofibrillary Tangles
* Neurons
* Neuroprotective Agents
* Thioctic Acid

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914903
}}
{{medline-entry
|title=Design, synthesis and evaluation of diosgenin carbamate derivatives as multitarget anti-Alzheimer's disease agents.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31837501
|abstract=In order to produce an effective and multi-targeted clinical drug that could prevent progressive neurodegeneration, a series of diosgenin carbamate derivatives were designed, synthesized and tested for their anti-inflammatory, antioxidant and anti-Aβ activities. The results demonstrated that compound M15 was the most promising derivative against inflammatory (NO inhibition 22.7 ± 2.2%,10 μM) and cellular damage induced by H O  (SH-SY5Y cell protection = 75.3 ± 3.4%, 10 μM) or Aβ (astrocytes protection = 70.2 ± 6.5%, 10 μM). Molecular docking studies revealed the strong binding affinity of M15 to the active site of nNOS, Aβ  and pro-inflammatory proteins. Western blot demonstrated that M15 decreased IL-1β, IL-6 and [[TNF]]-α level, which may contribute to its anti-inflammatory effects. In addition, M15 maintained mitochondrial function as well as cell viability through reducing H O -induced ROS production. The results indicated that oral administration of M15 attenuated memory deficits and played a neuroprotective effect on subcutaneous (s.c.) D-gal aging mice. In summary, M15 could be considered as a potential multifunctional neuroprotective agent due to the effects of anti-inflammatory, antioxidant and anti-Aβ activities.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Anti-Inflammatory Agents, Non-Steroidal
* Astrocytes
* Carbamates
* Cell Line, Tumor
* Cell Survival
* Diosgenin
* Dose-Response Relationship, Drug
* Drug Design
* Galactose
* Humans
* Inflammation
* Male
* Mice
* Mice, Inbred ICR
* Molecular Structure
* Neuroprotective Agents
* Oxidative Stress
* Protein Aggregates
* Structure-Activity Relationship
|keywords=* Alzheimer’s disease
* Anti-Aβ activity
* Anti-inflammatory
* Antioxidant
* Diosgenin
* Multi-target-directed ligands
|full-text-url=https://sci-hub.do/10.1016/j.ejmech.2019.111913
}}
{{medline-entry
|title=Oral Administration of Okara Soybean By-Product Attenuates Cognitive Impairment in a Mouse Model of Accelerated Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31816987
|abstract=The microbiota-gut-brain axis has attracted increasing attention in the last decade. Here, we investigated whether okara, a soybean by-product rich in dietary fiber, can attenuate cognitive impairment in senescence-accelerated mouse prone 8 (SAMP8) mice by altering gut microbial composition. Mice were fed either a standard diet, or a diet containing okara (7.5% or 15%, [i]w[/i]/[i]w[/i]) for 26 weeks. In the memory test, the 7.5% okara-fed mice showed a longer step-through latency and the 15% okara-fed mice had a short escape latency compared with control mice. The 15% okara-fed mice displayed decreased body weight, increased fecal weight, and altered cecal microbiota composition compared with the control group; however, there was no significant difference in the serum lactic acid and butyric acid levels among these mice groups. The 7.5% okara-fed mice had significantly higher NeuN intensity in the hippocampus compared with control mice. Furthermore, a decrease in inflammatory cytokine [[TNF]]- and an increase in brain-derived neurotrophic factor (BDNF) was observed in the 7.5% okara-fed group. The expression of synthesizing enzyme of acetylcholine was increased by the okara diets, and the acetylcholine level in the brain was higher in the 7.5% okara-fed group than in the control. These suggest that oral administration of okara could delay cognitive decline without drastically changing gut microbiota.
|mesh-terms=* Aging
* Animal Feed
* Animals
* Brain-Derived Neurotrophic Factor
* Cognitive Dysfunction
* Diet
* Gastrointestinal Microbiome
* Gene Expression Regulation
* Hippocampus
* Male
* Mice
* Soybeans
* Tumor Necrosis Factor-alpha
|keywords=* BDNF
* SAMP8
* cognitive impairment
* neuroprotection
* okara
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950093
}}
{{medline-entry
|title=Electric vagal nerve stimulation inhibits inflammation and improves early postoperation cognitive dysfunction in aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31759387
|abstract=This study aimed to evaluate effects of electric vagal nerve stimulation on early postoperation cognitive dysfunction in aged rats. A total of 33 male Sprague Dawley rats were selected and assigned randomly to three groups, control group (C, n = 10), splenectomy group (S, n = 10) and splenectomy+vagal nerve stimulation group (SV, n = 13). Behavior and memory of rats were evaluated by Open Field Test and Morris Water Maze. Levels of [[TNF]]-α, IL-6 and IL-10 in serum were measured by ELISA. The level of [[TNF]]-α protein in hippocampus was assessed by Western blotting. rt-PCR was used to detect mRNA expression of NF-κB in hippocampus. During anesthesia/operation, vital life signs of rats were stable. In SV group, vagal nerve stimulation decreased heart rate lower than 10% of basic level and kept it at a stable range by regulating stimulation intensity. After stimulation stop, heart rate returned to the basic level again. This indicated that the model of vagal nerve stimulation was successful. Serum levels of [[TNF]]-α and IL-6 increased by the operation/anesthesia, but they decreased with vagal nerve stimulation (all P < 0.05). [[TNF]]-α protein and mRNA expression of NF-κB in hippocampus were also eliminated by vagal nerve stimulation compared to S group (P < 0.05). Results of Morris Water Maze showed escape latency of postoperation in S group was significantly longer than C group (P < 0.05), and times of crossing platform in S group was lower than that of C group (P < 0.05). Although escape latency of postopration in SV group was shorter than that of S group, there was no significant difference between two groups. Meanwhile there were no significant differences of behavior test in Open Field test between three groups, although vagal nerve stimulation improved partly active explore behavior compared to S group. The inflammation caused by operation and general anesthesia was an important reason of early postoperation cognitive dysfunction, and electric vagal nerve stimulation could inhibit the inflammation. Meanwhile, vagal nerve stimulation could ameliorate early postoperation cognitive dysfunction partly, but its protective effects were not enough and should be studied and improved in future.
|mesh-terms=* Aging
* Anesthesia, General
* Animals
* Behavior, Animal
* Hippocampus
* Inflammation
* Male
* Maze Learning
* NF-kappa B
* Postoperative Cognitive Complications
* Rats
* Rats, Sprague-Dawley
* Splenectomy
* Tumor Necrosis Factor-alpha
* Vagus Nerve Stimulation
|keywords=* Cognitive dysfunction
* General anesthesia
* Inflammation
* Vagus nerve stimulation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875068
}}
{{medline-entry
|title=Metformin decreases LPS-induced inflammatory response in rabbit annulus fibrosus stem/progenitor cells by blocking HMGB1 release.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31772144
|abstract=The present study aimed to investigate the mechanism of intervertebral disc degeneration (IVDD) and identify an efficient treatment for low back pain. Rabbit annulus fibrosus stem cells (AFSCs) were treated with metformin and lipopolysaccharide (LPS). The results indicated that LPS induced HMGB1 release from the nuclei of AFSCs and caused cell senescence in a concentration-dependent manner. The production of PGE2 and HMGB1 was increased in the medium of the LPS-treated AFSCs. Certain inflammation-associated genes ([i]IL-β1[/i], [i]IL-6[/i], [i]COX-2[/i] and [i][[TNF]]-[/i]α) and proteins (IL-β1, COX-2 and [[TNF]]-α) and specific catabolic genes ([i]MMP-3[/i] and [i]MMP-13[/i]) exhibited increased expression in LPS-treated AFSCs. However, the expression levels of other anabolic genes, such as [i]collagen I[/i] and [i]collagen II[/i] were decreased in LPS-treated AFSCs. Following addition of metformin to LPS-containing medium, HMGB1 was retained in the nuclei of AFSCs and the production of PGE2 and HMGB1 was reduced. The expression levels of the catabolic genes and proteins were decreased and those of the anabolic genes were increased. The findings indicated that metformin exerted an anti-inflammatory effect by blocking the HMGB1 translocation and by inhibiting catabolic production and cell senescence in AFSCs. Therefore, metformin may be used as an efficient treatment for the disc degenerative disease.
|mesh-terms=* Animals
* Annulus Fibrosus
* Anti-Inflammatory Agents
* Cellular Senescence
* HMGB1 Protein
* Inflammation
* Intervertebral Disc Degeneration
* Lipopolysaccharides
* Metformin
* Rabbits
* Stem Cells
|keywords=* HMGB1
* annulus fibrosis stem cells
* cell senescence
* intervertebral disc degeneration
* metformin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914423
}}
{{medline-entry
|title=The effects of blueberry and strawberry serum metabolites on age-related oxidative and inflammatory signaling in vitro.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31746877
|abstract=Berry fruits contain a variety of bioactive polyphenolic compounds that exhibit potent antioxidant and anti-inflammatory activities. We have shown that consumption of freeze-dried whole berry powder, equivalent to 1 cup per day of blueberry (BB) or 2 cups per day of strawberry (SB), can differentially improve some aspects of cognition in healthy, older adults, compared to placebo-supplemented controls. We investigated whether fasting and postprandial serum from BB- or SB-supplemented older adults (60-75 years), taken at baseline or after 45 or 90 days of supplementation, would reduce the production of inflammatory and oxidative stress markers compared to serum from a placebo group, in LPS-stressed HAPI rat microglial cells, in vitro. Serum from both BB- and SB-supplemented participants reduced nitrite production, iNOS and COX-2 expression, and [[TNF]]-alpha release relative to serum from placebo controls (p < 0.05). Protection was greatest with serum from the 90-day time-point, suggesting that ongoing supplementation may provide the most health benefits. Serum was protective in both fasted and postprandial conditions, indicating that the effects are not only acute and that the meal did not challenge subjects' ability to regulate oxidative and inflammatory stress. These results suggest that berry metabolites, present in the circulating blood following ingestion, may be mediating the anti-inflammatory effects of dietary berry fruit.
|mesh-terms=* Aged
* Aging
* Animals
* Blueberry Plants
* Double-Blind Method
* Female
* Fragaria
* Fruit
* Humans
* Male
* Microglia
* Middle Aged
* Nitric Oxide
* Nitric Oxide Synthase Type II
* Oxidative Stress
* Postprandial Period
* Rats
* Tumor Necrosis Factor-alpha

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906224
}}
{{medline-entry
|title=Arsenic induces human chondrocyte senescence and accelerates rat articular cartilage aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31734849
|abstract=Arsenic-contaminated drinking water is known to be a serious human health problem. A previous epidemiological study has indicated that arsenic levels in blood were higher in arthritis patients compared to age-matched control subjects. Bone is known as an important arsenic store compartment in the body. Arsenic exposure has been suggested to promote senescence in human mesenchymal stem cells that may affect the balance of adipogenic and osteogenic differentiation. The toxicological effect and mechanism of arsenic exposure on articular chondrocytes still remain unclear. Here, we investigated the arsenic-induced senescence in cultured human articular chondrocytes and long-term arsenic-exposed rat articular cartilage. Arsenic trioxide (As O ; 1-5 μM) significantly induced senescence in human articular chondrocytes by increasing senescence-associated β-galactosidase (SA-β-Gal) activity and protein expression of p16, p53, and p21. Arsenic induced the phosphorylation of p38 and c-Jun N-terminal kinase (JNK) proteins. The inhibitors of p38 and JNK significantly reversed the arsenic-induced chondrocyte senescence. Arsenic could also trigger the induction of GATA4-NF-κB signaling and senescence-associated secretory phenotype (SASP) by increasing IL-1α, IL-1β, TGF-β, [[TNF]]-α, CCL2, PAI-1, and MMP13 mRNA expression. The increased cartilage senescence and abrasion were also observed in a rat model long-term treatment with arsenic (0.05 and 0.5 ppm) in drinking water for 36 weeks as compared to age-matched control rats. The phosphorylation of p38 and JNK and the induction of GATA4-NF-κB signaling and SASP were enhanced in the rat cartilages. Taken together, these findings suggest that arsenic exposure is capable of inducing chondrocyte senescence and accelerating rat articular cartilage aging and abrasion.

|keywords=* Aging
* Arsenic
* Articular cartilage
* Human chondrocyte
* Senescence
* Senescence-associated secretory phenotype
|full-text-url=https://sci-hub.do/10.1007/s00204-019-02607-2
}}
{{medline-entry
|title=Bone Benefits of Fish Oil Supplementation Depend on its EPA and DHA Content.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31717258
|abstract=The preventive effect of high-dose (9%) regular-fish oil (FO) against bone loss during aging has been demonstrated, but the effects of a low-dose (1%-4%) of a highly purified concentrated FO (CFO) has not been elucidated. The aim of this study was to determine the dose-dependent effect of a CFO against bone loss in C57BL/6 female mice during aging. Twelve-month old mice were fed with 1% and 4% CFO and 4% safflower oil (SFO) diets, including a group with a 4% regular-FO diet and a group with a lab chow diet for 12 months. Bone mineral density (BMD) was analyzed by dual-energy x-ray absorptiometry (DXA) before and after the dietary intervention. At the end of dietary intervention, bone resorption markers in serum and inflammatory markers in bone marrow and splenocytes and inflammatory signaling pathways in the bone marrow were analyzed. As compared to the 4% SFO control, 4% CFO maintained higher BMD during aging, while 1% CFO offered only a mild benefit. However, the 1% CFO fed group exhibited slightly better BMD than the 4% regular-FO fed group. BMD loss protection by CFO was accompanied by reduced levels of the bone resorption marker, TRAP, and the osteoclast-stimulating-factor, RANKL, without affecting the decoy-receptor of RANKL, osteoprotegerin (OPG). Further, CFO supplementation was associated with an increase in the production of IL-10, IL-12, and IFN-γ and a decrease in the production of [[TNF]]-α and IL-6, and the activation of NF-κB, p38 MAPK, and JNK signaling pathways. In conclusion, the supplementation of 4% CFO is very efficient in maintaining BMD during aging, whereas 1% CFO is only mildly beneficial. CFO supplementation starting at middle age may maintain better bone health during aging.
|mesh-terms=* Age Factors
* Animals
* Bone Density
* Bone Density Conservation Agents
* Bone Marrow Cells
* Bone Remodeling
* Bone and Bones
* Cells, Cultured
* Cytokines
* Dietary Supplements
* Disease Models, Animal
* Docosahexaenoic Acids
* Eicosapentaenoic Acid
* Female
* JNK Mitogen-Activated Protein Kinases
* Mice, Inbred C57BL
* Osteoporosis
* Signal Transduction
* p38 Mitogen-Activated Protein Kinases
|keywords=* aging
* bone mineral density
* bone resorption
* concentrated fish oil
* cytokines
* inflammation
* omega-3 fatty acids
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893665
}}
{{medline-entry
|title=Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31713098
|abstract=The development of chronic inflammation, called inflammaging, contributes to the pathogenesis of age-related diseases. Although it is known that both B and T lymphocyte compartments of the adaptive immune system deteriorate with advancing age, the impact of aging on immune functions of Th17-type CD161-expressing innate immune cells and their role in inflammaging remain incompletely understood. Here, utilizing the nonhuman primate model of rhesus macaques, we report that a dysregulated Th17-type effector function of CD161  immune cells is associated with leaky gut and inflammatory phenotype of aging. Higher plasma levels of inflammatory cytokines IL-6, [[TNF]]-α, IL-1β, GM-CSF, IL-12, and Eotaxin correlated with elevated markers of gut permeability including LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and sCD14 in aging macaques. Further, older macaques displayed significantly lower frequencies of circulating Th17-type immune cells comprised of CD161  T cell subsets, NK cells, and innate lymphoid cells. Corresponding with the increased markers of gut permeability, production of the type-17 cytokines IL-17 and IL-22 was impaired in CD161  T cell subsets and NK cells, along with a skewing towards IFN-γ cytokine production. These findings suggest that reduced frequencies of CD161  immune cells along with a specific loss in Th17-type effector functions contribute to impaired gut barrier integrity and systemic inflammation in aging macaques. Modulating type-17 immune cell functions via cytokine therapy or dietary interventions towards reducing chronic inflammation in inflammaging individuals may have the potential to prevent or delay age-related chronic diseases and improve immune responses in the elderly population.
|mesh-terms=* Aging
* Animals
* Chronic Disease
* Cytokines
* Disease Models, Animal
* Epithelium
* Flow Cytometry
* Immunity, Innate
* Inflammation
* Macaca mulatta
* NK Cell Lectin-Like Receptor Subfamily B
* Phenotype
* Th17 Cells
|keywords=* CD161+ cells
* I-FABP
* Inflammaging
* LBP
* Leaky gut
* sCD14
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925095
}}
{{medline-entry
|title=Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31719197
|abstract=Supercentenarians, people who have reached 110 y of age, are a great model of healthy aging. Their characteristics of delayed onset of age-related diseases and compression of morbidity imply that their immune system remains functional. Here we performed single-cell transcriptome analysis of 61,202 peripheral blood mononuclear cells (PBMCs), derived from 7 supercentenarians and 5 younger controls. We identified a marked increase of cytotoxic CD4 T cells (CD4 cytotoxic T lymphocytes [CTLs]) as a signature of supercentenarians. Furthermore, single-cell T cell receptor sequencing of 2 supercentenarians revealed that CD4 CTLs had accumulated through massive clonal expansion, with the most frequent clonotypes accounting for 15 to 35% of the entire CD4 T cell population. The CD4 CTLs exhibited substantial heterogeneity in their degree of cytotoxicity as well as a nearly identical transcriptome to that of CD8 CTLs. This indicates that CD4 CTLs utilize the transcriptional program of the CD8 lineage while retaining CD4 expression. Indeed, CD4 CTLs extracted from supercentenarians produced IFN-γ and [[TNF]]-α upon ex vivo stimulation. Our study reveals that supercentenarians have unique characteristics in their circulating lymphocytes, which may represent an essential adaptation to achieve exceptional longevity by sustaining immune responses to infections and diseases.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* B-Lymphocytes
* CD4-Positive T-Lymphocytes
* Case-Control Studies
* Cell Differentiation
* Cells, Cultured
* Clonal Evolution
* Gene Expression Profiling
* Humans
* Interferon-gamma
* Leukocytes, Mononuclear
* Middle Aged
* Single-Cell Analysis
* Tumor Necrosis Factor-alpha
|keywords=* CD4 CTL
* aging
* centenarian
* single-cell transcriptome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883788
}}
{{medline-entry
|title=Gut microbiota combined with metabolomics reveals the metabolic profile of the normal aging process and the anti-aging effect of FuFang Zhenshu TiaoZhi(FTZ) in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31704617
|abstract=The aging process is accompanied by changes in the gut microbiota and metabolites. This study aimed to reveal the relationship between gut microbiota and the metabolome at different ages, as well as the anti-aging effect of FTZ, which is an effective clinical prescription for the treatment of hyperlipidemia and diabetes. In the present study, mice were randomly divided into different age and FTZ treatment groups. The aging-relevant behavioral phenotype the levels of blood glucose, cholesterol, triglycerides, low density lipoprotein cholesterol, free fatty acids, high density lipoprotein-cholesterol and cytokine [[TNF]]-α,IL-6, IL-8 in the serum were measured. Changes of serum metabolties were analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-Q-TOF/MS). Gut microbiota were identified using 16S rDNA sequencing. Our results indicated that with age, the aging-relevant behavioral phenotype appeared, glucose and lipid metabolism disordered, secretion levels of cytokine [[TNF]]-α, IL-6 and IL-8 increased.The Firmicutes/Bacteroidetes ratio changed with age, first increasing and then decreasing, and the microbial diversity and the community richness of the aging mice were improved by FTZ. The abundance of opportunistic bacteria decreased (Lactobacillus murinus, Erysipelatoclostridium), while the levels of protective bacteria such as Butyricimonas, Clostridium and Akkermansia increased. Metabolic analysis identified 24 potential biomarkers and 10 key pathways involving arachidonic acid metabolism, phospholipid metabolism, fatty acid metabolism, taurine and hypotaurine metabolism. Correlation analysis between the gut microbiota and biomarkers suggested that the relative abundance of protective bacteria was negatively correlated with the levels of leukotriene E4, 20-HETE and arachidonic acid, which was different from protective bacteria. Shifts of gut microbiota and metabolomic profiles were observed in the mice during the normal aging process, and treatment with FTZ moderately corrected the aging, which may be mediated via interference with arachidonic acid metabolism, sphingolipid metabolism, glycerophospholipid metabolism, taurine and hypotaurine metabolism and gut microbiota in mice.
|mesh-terms=* Aging
* Animals
* Bacteria
* Biomarkers
* Drugs, Chinese Herbal
* Gastrointestinal Microbiome
* Hyperlipidemias
* Lipid Metabolism
* Male
* Metabolome
* Metabolomics
* Mice
* Mice, Inbred C57BL
|keywords=* Aging
* FTZ
* Gut microbiota
* Metabolomics
|full-text-url=https://sci-hub.do/10.1016/j.biopha.2019.109550
}}
{{medline-entry
|title=Intervertebral disc ageing and degeneration: The antiapoptotic effect of oestrogen.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31669486
|abstract=As an important part of the spinal column, the intervertebral disc (IVD) plays an important role in the intervertebral juncture and spinal movement in general. IVD degeneration (IVDD), which mimics disc ageing but at an accelerated rate, is a common and chronic process that results in severe spinal symptoms, such as lower back pain. It is generally assumed that lower back pain caused by IVDD can also develop secondary conditions, including spinal canal stenosis, spinal segmental instability, osteophyte formation, disc herniation and spinal cord and nerve root compression. Over the past few years, many researchers around the world have widely studied the relevance between oestrogen and IVDD, indicating that oestrogen can effectively alleviate IVDD development by inhibiting the apoptosis of IVD cells. Oestrogen can decrease IVD cell apoptosis in multiple ways, including the inhibition of the inflammatory cytokines IL-1β and [[TNF]]-α, reducing catabolism because of inhibition of matrix metalloproteinases, upregulating integrin α β  and IVD anabolism, activating the PI3K/Akt pathway, decreasing oxidative damage and promoting autophagy. In this article, we perform an overview of the literature regarding the antiapoptotic effect of oestrogen in IVDD.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Cytokines
* Estrogens
* Female
* Humans
* Inflammation
* Intervertebral Disc
* Intervertebral Disc Degeneration
* Intervertebral Disc Displacement
* Male
* Phosphatidylinositol 3-Kinases
* Signal Transduction
|keywords=* Ageing
* Apoptosis
* Intervertebral disc degeneration
* Oestrogen
* Spine
|full-text-url=https://sci-hub.do/10.1016/j.arr.2019.100978
}}
{{medline-entry
|title=MicroRNA 16-5p is upregulated in calorie-restricted mice and modulates inflammatory cytokines of macrophages.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31654705
|abstract=Caloric restriction (CR) has long been known to increase median and maximal lifespans and to decrease mortality and morbidity in short-lived animal models, likely by altering fundamental biological processes that regulate aging and longevity. However, the detailed mechanisms of immunomodulation by CR remain unclear. In this study, we established a mouse model for CR and analyzed the changes of immune cells in these mice. The CR mice fed a calorie-restricted diet for 4 weeks had lower body weight and fat mass compared with control mice. The proportions of CD4 , CD8 , and naïve CD4  T cells in spleen cells from CR mice were higher than those in of control mice. Additionally, the proportion of CD8  T cells was significantly decreased and the mRNA expression of proinflammatory cytokines in the colon of CR mice was significantly decreased compared with those of control mice. To determine the effect of CR on microRNA (miRNA) expression, serum and tissues were collected from mice and the expression level of miRNA was analyzed by real-time RT-PCR. As a result, the expressions of miR-16-5p, miR-196b-5p, and miR-218-5p in serum from CR mice were higher than those in control mice. The expression of miR-16-5p increased in the spleen, thymus, colon, and stomach of CR mice compared with expression in control mice. Furthermore, RAW264 cells transfected with a miR-16-5p mimic significantly decreased the mRNA expression of IL-1β, IL-6, and [[TNF]]-α under LPS stimulation. These results suggested that miR-16-5p might be a critical factor involving the anti-inflammatory effects of calorie-restricted feeding.
|mesh-terms=* Aging
* Animals
* Caloric Restriction
* Cytokines
* Diet Therapy
* Inflammation
* Interleukin-1beta
* Macrophages
* Male
* Mice
* Mice, Inbred C57BL
* MicroRNAs
* Models, Animal
* RAW 264.7 Cells
* Transcriptional Activation
* Tumor Necrosis Factor-alpha
* Up-Regulation
|keywords=* Caloric restriction
* Cellular immunology
* Cytokines
* Macrophages
* microRNA
|full-text-url=https://sci-hub.do/10.1016/j.gene.2019.144191
}}
{{medline-entry
|title=Aerobic exercise modulates cytokine profile and sleep quality in elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31656505
|abstract=Sleep disturbance is a major problem for older adults which can be exacerbated by increased inflammation as aging is associated with increased circulating pro-inflammatory and lower anti-inflammatory cytokines. There is a need to develop alternative medicine techniques to help improve sleep quality in the elderly. To investigate the effects of aerobic exercise training on the sleep quality and inflammatory cytokines in elderly subjects. Forty previously sedentary elderly subjects participated in this study, their age ranged from 61- 67 years. All subjects were randomly assigned to supervised aerobic exercise intervention group (group A, n=25) or control group (group B, n=25). Polysomnographic recordings for sleep quality assessment, interleukin- 6 (IL-6), tumor necrosis factor- alpha ([[TNF]]-α) and interleukin-10 (IL-10) were measured before and after 6 months at the end of the study. There was a significant increase in total sleep duration, sleep efficiency and sleep onset latency in group(A) after 6 months of aerobic exercise training, while, wake time after sleep onset and rapid eye movement (REM) latency significantly reduced after 6 months of aerobic training compared with values obtained prior to aerobic exercise training. Also, the mean values of [[TNF]]- α and IL-6 decreased significantly and the mean value of IL-10 significantly increased in group (A) after the aerobic exercise training, however the results of the control group were not significant. Moreover, there were significant differences between both groups at the end of the study. Exercise training can be considered as a non-pharmacological modality for modifying sleep quality and inflammation among elderly.
|mesh-terms=* Aged
* Cytokines
* Exercise
* Female
* Humans
* Male
* Middle Aged
* Sedentary Behavior
* Sleep Wake Disorders
|keywords=* Sleep quality
* aerobic exercise
* aging
* inflammatory cytokines
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794533
}}
{{medline-entry
|title=Trehalose targets Nrf2 signal to alleviate d-galactose induced aging and improve behavioral ability.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31630800
|abstract=As an important factor leading to aging and chronic diseases, oxidative stress has become a hot research topic. Trehalose is a natural sugar widely found in many edible plants, animals and natural microorganisms, and recent studies have suggested that trehalose is an antioxidant, although its underlying molecular mechanism is unclear. Therefore, we evaluated the protective mechanism of trehalose against oxidative stress-induced senescence. In the mouse model of d-galactose (D-gal) induced aging, we found that trehalose significantly reversed the learning and memory impairment caused by D-gal and improved the ability to explore unknown things, which was associated with a significant reduction in brain tissue damage. Further studies have shown that trehalose activates the expressions of downstream target genes HO-1, NQO1, SOD, GSH and CAT by promoting the nuclear translocation of Nrf2 in the liver. The detoxification ability of organs is increased, antioxidant enzyme activity is enhanced, lipid peroxidation is reduced, and the secretion of inflammatory factors [[TNF]]-α, IL-1β, il-6 is decreased. In conclusion, trehalose play an anti-aging role by activating genes related to Nrf2 pathway.
|mesh-terms=* Aging
* Animals
* Disease Models, Animal
* Dose-Response Relationship, Drug
* Galactose
* Male
* Memory Disorders
* Mice
* Mice, Inbred ICR
* NF-E2-Related Factor 2
* Signal Transduction
* Trehalose
|keywords=* Antioxidant stress
* Cognitive impairment
* Inflammation
* Nrf2
* Trehalose
* d-galactose
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2019.10.088
}}
{{medline-entry
|title=Anti-Inflammatory and Anti-Aging Evaluation of Pigment-Protein Complex Extracted from [i]Chlorella Pyrenoidosa[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31623220
|abstract=Oxidative stress contributes to chronic inflammatory processes implicated in aging, referred to as "inflamm-aging." In this study, the potential anti-inflammatory and anti-aging effects of a pigment-protein complex (PPC) from [i]Chlorella pyrenoidosa[/i] were investigated using lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and D-galactose (D-gal)-induced aging in a murine model. Results indicated that PPC inhibits the production of the inflammatory cytokines [[TNF]]-α and IL-6, and the inflammatory mediator nitric oxide (NO) in LPS-stimulated RAW 264.7 cells. It also protected mice from D-gal induced informatory aging by increasing the activity of the antioxidant enzyme, such as superoxide dismutase (SOD), inhibiting D-gal-induced NF-κB upregulation, and increasing PPARs expression in the brain and gut. The findings indicated that PPC has favorable anti-inflammatory and anti-aging properties, and could be useful in the treatment of acute inflammation and senescence diseases.
|mesh-terms=* Aging
* Animals
* Anti-Inflammatory Agents
* Antioxidants
* Biological Products
* Chlorella
* Cytokines
* Disease Models, Animal
* Galactose
* Inflammation
* Interleukin-6
* Lipopolysaccharides
* Macrophages
* Male
* Mice
* Mice, Inbred C57BL
* NF-kappa B
* Nitric Oxide
* Oxidative Stress
* RAW 264.7 Cells
* Superoxide Dismutase
* Tumor Necrosis Factor-alpha
|keywords=* Chlorella pyrenoidosa
* NF-κB
* PPARs
* anti-aging
* anti-inflammation
* pigment–protein complex
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836285
}}
{{medline-entry
|title=Inflammatory mediators and the risk of falls among older women with acute low back pain: data from Back Complaints in the Elders (BACE)-Brazil.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31606818
|abstract=To investigate the association between plasma levels of inflammatory cytokines (interleukin [IL]-1-β, IL-6, tumor necrosis factor [[[TNF]]]-α, and the soluble [[TNF]] receptor 1 [s[[TNF]]-R1]), disability, and risk of falls in older women with acute low back pain (LBP). This cross-sectional study comprised a subsample of older women from the Back Complaints in the Elders international cohort study. Plasma levels of IL-1-β, IL-6, [[TNF]]-α, and s[[TNF]]-R1 were measured using enzyme-linked immunosorbent assays. Pain was assessed using the Numerical Pain Scale and McGill Pain Questionnaire, while disability was measured using the Roland Morris Questionnaire and gait speed. Risk of falls was estimated using the Physiological Profile Assessment. Linear regression model was used to verify the association between independent variables and fall risk. One hundred and ten women (aged 69.97 ± 5.5 years) with acute LBP were included. The regression model showed an association between the risk of falls and IL-6 levels, pain, gait speed, and years of education. It also explained 21.2% of risk of falls variance. The model equation was: fall risk = 1.28 + (0.19 IL-6) + (0.02 quality of pain) + (- 0.71 gait speed) + (-0 .17 educational level). This study showed an association between risk of falls and IL-6, pain, gait speed, and educational level in older women with LBP. These slides can be retrieved under Electronic Supplementary Material.

|keywords=* Aging
* BACE
* Cytokines
* Disability
* Fall risk
* Low back pain
|full-text-url=https://sci-hub.do/10.1007/s00586-019-06168-x
}}
{{medline-entry
|title=Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31583530
|abstract=Neuroinflammation and cholinergic dysfunction, leading to cognitive impairment, are hallmarks of aging and neurodegenerative disorders, including Alzheimer's disease (AD). Acetylcholinesterase inhibitors (AChEI), the symptomatic therapy in AD, attenuate and delay the cognitive deficit by enhancing cholinergic synapses. The α7 nicotinic acetylcholine (ACh) receptor has shown a double-edged sword feature, as it binds with high affinity Aβ , promoting intracellular accumulation and Aβ-induced tau phosphorylation, but also exerts neuroprotection by stimulating anti-apoptotic pathways. Moreover, it mediates peripheral and central anti-inflammatory response, being the effector player of the activation of the cholinergic anti-inflammatory pathway (CAIP), that, by decreasing the release of [[TNF]]-α, IL-1β, and IL-6, it may have a role in improving cognition. The finding in preclinical models that, in addition to their major function (choline esterase inhibition) AChEIs have neuroprotective properties mediated via α7nAChR and modulate innate immunity, possibly as a result of the increased availability of acetylcholine activating the CAIP, pave the way for new pharmacological intervention in AD and other neurological disorders that are characterized by neuroinflammation. CHRFAM7A is a human-specific gene acting as a dominant negative inhibitor of α7nAChR function, also suggesting a role in affecting human cognition and memory by altering α7nAChR activities in the central nervous system (CNS). This review will summarize the current knowledge on the cholinergic anti-inflammatory pathway in aging-related disorders, and will argue that the presence of the human-restricted CHRFAM7A gene might play a fundamental role in the regulation of CAIP and in the response to AChEI.

|keywords=* Acetylcholinesterase inhibitor
* Aging
* CHRFAM7A
* CHRNA7
* Cholinergic anti-inflammatory pathway
* Neuroinflammation
|full-text-url=https://sci-hub.do/10.1007/s40520-019-01359-4
}}
{{medline-entry
|title=Study on Metabolic Trajectory of Liver Aging and the Effect of Fufang Zhenzhu Tiaozhi on Aging Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31555127
|abstract=The aim of this study was to investigate the metabolic trajectory of liver aging, the effect of FTZ against liver aging in aging mice, and its mechanism using ultraperformance liquid chromatography/quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF/MS).   A total of 80 C57BL/6J Narl mice were randomly divided into five groups: 3-month-old group, 9-month-old group, 14-month-old group, 20-month-old group, and FTZ treatment group (20 months old). The mice in the treatment group received a therapeutic dose of oral FTZ extract (1.0 g/kg, on raw material weight basis) once daily during the experiment. The other groups received the corresponding volume of oral normal saline solution. Liver samples of all five groups were collected after 12 weeks, and UPLC-Q-TOF/MS was used to analyze metabolic changes. Orthogonal partial least squares-discriminant analysis (OPLS-DA) was used to analyze the resulting data. Additionally, cholesterol (TC), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), secretion levels of [[TNF]]-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver were determined.   The levels of TC, TG, AST, and ALT were increased, and liver tissue structure was damaged. The secretion levels of [[TNF]]-α, IL-6, 5-LOX, and COX-2, as well as their relative mRNA expression in the liver also increased with aging. FTZ administration reduced the symptoms of liver aging. The OPLS-DA score plot illustrated the effect of FTZ against liver aging, with N-acetyl-leukotriene E4, 20-hydroxy-leukotriene E4, leukotriene E4, and arachidonic acid among the key biomarkers. The pivotal pathways revealed by pathway analysis included arachidonic acid metabolism and biosynthesis of unsaturated fatty acids. The mechanism by which FTZ reduces the symptoms of liver aging in mice might be related to disorders of the abovementioned pathways.   A metabolomic approach based on UPLC-Q-TOF/MS and multivariate statistical analysis was successfully applied to investigate the metabolic trajectory of liver aging. FTZ has a protective effect against liver aging, which may be mediated [i]via[/i] interference with the metabolism of arachidonic acid, biosynthesis of unsaturated fatty acids, and downregulation of pro-inflammatory factors in the liver in mice [i]in vivo[/i].

|keywords=* Fufang Zhenzhu Tiaozhi
* liver aging
* mass spectrometry
* metabolomics
* ultra-performance liquid chromatography
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722462
}}
{{medline-entry
|title=Systemic Tumor Necrosis Factor-Alpha Trajectories Relate to Brain Health in Typically Aging Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31549145
|abstract=Central nervous system levels of tumor necrosis factor-alpha ([[TNF]]-α), a pro-inflammatory cytokine, regulate the neuroinflammatory response and may play a role in age-related neurodegenerative diseases. The longitudinal relation between peripheral levels of [[TNF]]-α and typical brain aging is understudied. We hypothesized that within-person increases in systemic [[TNF]]-α would track with poorer brain health outcomes in functionally normal adults. Plasma-based [[TNF]]-α concentrations (pg/mL; fasting morning draws) and magnetic resonance imaging were acquired in 424 functionally intact adults (mean age = 71) followed annually for up to 8.4 years (mean follow-up = 2.2 years). Brain outcomes included total gray matter volume and white matter hyperintensities. Cognitive outcomes included composites of memory, executive functioning, and processing speed, as well as Mini-Mental State Examination total scores. Longitudinal mixed-effects models were used, controlling for age, sex, education, and total intracranial volume, as appropriate. [[TNF]]-α concentrations significantly increased over time (p < .001). Linear increases in within-person [[TNF]]-α were longitudinally associated with declines in gray matter volume (p < .001) and increases in white matter hyperintensities (p = .003). Exploratory analyses suggested that the relation between [[TNF]]-α and gray matter volume was curvilinear ([[TNF]]-α 2p = .002), such that initial increases in inflammation were associated with more precipitous atrophy. There was a negative linear relationship of within-person changes in [[TNF]]-α to Mini-Mental State Examination scores over time (p = .036) but not the cognitive composites (all ps >.05). Systemic inflammation, as indexed by plasma [[TNF]]-α, holds potential as a biomarker for age-related declines in brain health.

|keywords=* Brain aging
* Cognition
* Gray matter volume
* Inflammation
* Neuroimaging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457183
}}
{{medline-entry
|title=Targeting senescence improves angiogenic potential of adipose-derived mesenchymal stem cells in patients with preeclampsia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31521202
|abstract=Preeclampsia is a pregnancy-specific hypertensive disorder characterized by impaired angiogenesis. We postulate that senescence of mesenchymal stem cells (MSC), multipotent cells with pro-angiogenic activities, is one of the mechanisms by which systemic inflammation exerts inhibitory effects on angiogenesis in preeclampsia. MSC were isolated from abdominal fat tissue explants removed during medically indicated C-sections from women with preeclampsia (PE-MSC, n = 10) and those with normotensive pregnancies (NP-MSC, n = 12). Sections of the frozen subcutaneous adipose tissue were assessed for inflammation by staining for tumor necrosis factor ([[TNF]])-alpha and monocyte chemoattractant protein (MCP)-1. Viability, proliferation, and migration were compared between PE-MSC vs. NP-MSC. Apoptosis and angiogenesis were assayed before and after treatment with a senolytic agent (1 μM dasatinib) using the IncuCyte S3 Live-Cell Analysis System. Similarly, staining for senescence-associated beta galactosidase (SABG) and qPCR for gene expression of senescence markers, p16 and p21, as well as senescence-associated secretory phenotype (SASP) components, IL-6, IL-8, MCP-1, and PAI-1, were studied before and after treatment with dasatinib and compared between PE and NP. After in vitro exposure to [[TNF]]-alpha, MSC demonstrated upregulation of SASP components, including interleukins-6 and -8 and MCP-1. Staining of the subcutaneous adipose tissue sections revealed a greater inflammatory response in preeclampsia, based on the higher levels of both [[TNF]]-alpha and MCP-1 compared to normotensive pregnancies (p < 0.001 and 0.024, respectively). MSC isolated from PE demonstrated a lower percentage of live MSC cells (p = 0.012), lower proliferation (p = 0.005), and higher migration (p = 0.023). At baseline, PE-MSC demonstrated a senescent phenotype, reflected by more abundant staining for SABG (p < 0.001), upregulation of senescence markers and SASP components, as well as lower angiogenic potential (p < 0.001), compared to NP-MSC. Treatment with dasatinib increased significantly the number of apoptotic PE-MSC compared to NP-MSC (0.011 vs. 0.093) and decreased the gene expression of p16 and six SASP components. The mechanistic link between senescence and impaired angiogenesis in PE was confirmed by improved angiogenic potential of PE-MSC (p < 0.001) after dasatinib treatment. Our data suggest that MSC senescence exerts inhibitory effects on angiogenesis in preeclampsia. Senolytic agents may offer the opportunity for mechanism-based therapies.
|mesh-terms=* Adipose Tissue
* Adult
* Cell Movement
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Dasatinib
* Female
* Humans
* Mesenchymal Stem Cells
* Pre-Eclampsia
* Pregnancy
* Protein Kinase Inhibitors
|keywords=* Angiogenesis, Senolytics, Dasatinib
* Mesenchymal stem cells
* Preeclampsia
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744626
}}
{{medline-entry
|title=Suppression of gut dysbiosis by Bifidobacterium longum alleviates cognitive decline in 5XFAD transgenic and aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31413350
|abstract=To understand the role of commensal gut bacteria on the progression of cognitive decline in Alzheimer's disease via the microbiota-gut-brain axis, we isolated anti-inflammatory Bifidobacterium longum (NK46) from human gut microbiota, which potently inhibited gut microbiota endotoxin production and suppressed NF-κB activation in lipopolysaccharide (LPS)-stimulated BV-2 cells, and examined whether NK46 could simultaneously alleviate gut dysbiosis and cognitive decline in male 5xFAD-transgenic (5XFAD-Tg, 6 months-old) and aged (18 months-old) mice. Oral administration of NK46 (1 × 10  CFU/mouse/day for 1 and 2 months in aged and Tg mice, respectively) shifted gut microbiota composition, particularly Proteobacteria, reduced fecal and blood LPS levels, suppressed NF-κB activation and [[TNF]]-α expression, and increased tight junction protein expression in the colon of 5XFAD-Tg and aged mice. NK46 treatment also alleviated cognitive decline in 5XFAD-Tg and aged mice. Furthermore, NK46 treatment suppressed amyloid-β, β/γ-secretases, and caspase-3 expression and amyloid-β accumulation in the hippocampus of 5XFAD-Tg mice. NK46 treatment also reduced Iba1 , LPS /CD11b , and caspase-3 /NeuN  cell populations and suppressed NF-κB activation in the hippocampus of 5XFAD-Tg and aged mice, while BDNF expression was increased. These findings suggest that the suppression of gut dysbiosis and LPS production by NK46 can mitigate cognitive decline through the regulation of microbiota LPS-mediated NF-κB activation.
|mesh-terms=* Aging
* Animals
* Bifidobacterium longum
* Cognitive Dysfunction
* Dysbiosis
* Feces
* Gastrointestinal Microbiome
* Humans
* Lipopolysaccharides
* Mice
* Mice, Transgenic
* Probiotics

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694197
}}
{{medline-entry
|title=Moderate hyperoxia induces senescence in developing human lung fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31411059
|abstract=Hyperoxia exposure in premature infants increases the risk of subsequent lung diseases, such as asthma and bronchopulmonary dysplasia. Fibroblasts help maintain bronchial and alveolar integrity. Thus, understanding mechanisms by which hyperoxia influences fibroblasts is critical. Cellular senescence is increasingly recognized as important to the pathophysiology of multiple diseases. We hypothesized that clinically relevant moderate hyperoxia (<50% O ) induces senescence in developing fibroblasts. Using primary human fetal lung fibroblasts, we investigated effects of 40% O  on senescence, endoplasmic reticulum (ER) stress, and autophagy pathways. Fibroblasts were exposed to 21% or 40% O  for 7 days with etoposide as a positive control to induce senescence, evaluated by morphological changes, β-galactosidase activity, and DNA damage markers. Senescence-associated secretory phenotype (SASP) profile of inflammatory and profibrotic markers was further assessed. Hyperoxia decreased proliferation but increased cell size. SA-β-gal activity and DNA damage response, cell cycle arrest in G /M phase, and marked upregulation of phosphorylated p53 and p21 were noted. Reduced autophagy was noted with hyperoxia. mRNA expression of proinflammatory and profibrotic factors ([[TNF]]-α, IL-1, IL-8, MMP3) was elevated by hyperoxia or etoposide. Hyperoxia increased several SASP factors (PAI-1, IL1-α, IL1-β, IL-6, LAP, [[TNF]]-α). The secretome of senescent fibroblasts promoted extracellular matrix formation by naïve fibroblasts. Overall, we demonstrate that moderate hyperoxia enhances senescence in primary human fetal lung fibroblasts with reduced autophagy but not enhanced ER stress. The resulting SASP is profibrotic and may contribute to abnormal repair in the lung following hyperoxia.
|mesh-terms=* Autophagy
* CCAAT-Enhancer-Binding Protein-beta
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Damage
* Endoplasmic Reticulum Stress
* Etoposide
* Extracellular Matrix
* Fetus
* Fibroblasts
* G2 Phase Cell Cycle Checkpoints
* Gene Expression Regulation
* Humans
* Hyperoxia
* Interleukin-1
* Interleukin-8
* Lung
* Matrix Metalloproteinase 3
* Oxygen
* Plasminogen Activator Inhibitor 1
* Primary Cell Culture
* Tumor Necrosis Factor-alpha
* Tumor Suppressor Protein p53
|keywords=* autophagy
* endoplasmic reticulum stress
* lung development
* oxygen
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879905
}}
{{medline-entry
|title=Aging-related carcinoembryonic antigen-related cell adhesion molecule 1 signaling promotes vascular dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31389127
|abstract=Aging is an independent risk factor for cardiovascular diseases and therefore of particular interest for the prevention of cardiovascular events. However, the mechanisms underlying vascular aging are not well understood. Since carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is crucially involved in vascular homeostasis, we sought to identify the role of CEACAM1 in vascular aging. Using human internal thoracic artery and murine aorta, we show that CEACAM1 is upregulated in the course of vascular aging. Further analyses demonstrated that [[TNF]]-α is CEACAM1-dependently upregulated in the aging vasculature. Vice versa, [[TNF]]-α induces CEACAM1 expression. This results in a feed-forward loop in the aging vasculature that maintains a chronic pro-inflammatory milieu. Furthermore, we demonstrate that age-associated vascular alterations, that is, increased oxidative stress and vascular fibrosis, due to increased medial collagen deposition crucially depend on the presence of CEACAM1. Additionally, age-dependent upregulation of vascular CEACAM1 expression contributes to endothelial barrier impairment, putatively via increased VEGF/VEGFR-2 signaling. Consequently, aging-related upregulation of vascular CEACAM1 expression results in endothelial dysfunction that may promote atherosclerotic plaque formation in the presence of additional risk factors. Our data suggest that CEACAM1 might represent an attractive target in order to delay physiological aging and therefore the transition to vascular disorders such as atherosclerosis.
|mesh-terms=* Aged
* Aging
* Animals
* Antigens, CD
* Cell Adhesion Molecules
* Cells, Cultured
* Endothelium, Vascular
* Humans
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Middle Aged
* Signal Transduction
|keywords=* aging
* anti-aging
* cytokines
* inflammation
* mouse
* reactive oxygen species
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826129
}}
{{medline-entry
|title=Microglia Express Insulin-Like Growth Factor-1 in the Hippocampus of Aged APP /PS1  Transgenic Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31417357
|abstract=Insulin-like growth factor-1 (IGF-1) is a pleiotropic molecule with neurotrophic and immunomodulatory functions. Knowing the capacity of chronically activated microglia to produce IGF-1 may therefore show essential to promote beneficial microglial functions in Alzheimer's disease (AD). Here, we investigated the expression of IGF-1 mRNA and IGF-1 along with the expression of tumor necrosis factor ([[TNF]]) mRNA, and the amyloid-β (Aβ) plaque load in the hippocampus of 3- to 24-month-old APP /PS1  transgenic (Tg) and wild-type (WT) mice. As IGF-1, in particular, is implicated in neurogenesis we also monitored the proliferation of cells in the subgranular zone (sgz) of the dentate gyrus. We found that the Aβ plaque load reached its maximum in aged 21- and 24-month-old APP /PS1  Tg mice, and that microglial reactivity and hippocampal IGF-1 and [[TNF]] mRNA levels were significantly elevated in aged APP /PS1  Tg mice. The sgz cell proliferation decreased with age, regardless of genotype and increased IGF-1/[[TNF]] mRNA levels. Interestingly, IGF-1 mRNA was expressed in subsets of sgz cells, likely neuroblasts, and neurons in both genotypes, regardless of age, as well as in glial-like cells. By double [i]in situ[/i] hybridization these were shown to be IGF1 mRNA  CD11b mRNA  cells, i.e., IGF-1 mRNA-expressing microglia. Quantification showed a 2-fold increase in the number of microglia and IGF-1 mRNA-expressing microglia in the molecular layer of the dentate gyrus in aged APP /PS1  Tg mice. Double-immunofluorescence showed that IGF-1 was expressed in a subset of Aβ plaque-associated CD11b  microglia and in several subsets of neurons. Exposure of primary murine microglia and BV2 cells to Aβ  did not affect IGF-1 mRNA expression. IGF-1 mRNA levels remained constant in WT mice with aging, unlike [[TNF]] mRNA levels which increased with aging. In conclusion, our results suggest that the increased IGF-1 mRNA levels can be ascribed to a larger number of IGF-1 mRNA-expressing microglia in the aged APP /PS1  Tg mice. The finding that subsets of microglia retain the capacity to express IGF-1 mRNA and IGF-1 in the aged APP /PS1  Tg mice is encouraging, considering the beneficial therapeutic potential of modulating microglial production of IGF-1 in AD.

|keywords=* aging
* cerebral amyloidosis
* insulin-like growth factor
* neurogenesis
* neuroinflammation
* tumor necrosis factor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682662
}}
{{medline-entry
|title=Age- and diet-specific effects of chronic exposure to chlorpyrifos on hormones, inflammation and gut microbiota in rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31400786
|abstract=Chlorpyrifos is a pesticide frequently detected in food and has been reported to disturb endocrine and gut health, which was regulated by gut microbiota and enteroendocrine cells. In this study, newly weaned (3 week) and adult (8 week) male rats fed a normal- or high- fat diet were chronically exposed to 0.3 mg chlorpyrifos/kg bodyweight/day. The effects of chlorpyrifos exposure on serum hormone levels, proinflammatory cytokines and gut microbiota were evaluated. Chronic exposure to chlorpyrifos significantly decreased the concentrations of luteinizing hormone, follicule stimulating hormone and testosterone, which was found only in the normal-fat diet. The counteracted effect of high-fat diet was also found in gut hormones and proinflammatory cytokines. Significantly higher concentrations of glucagon-like peptide-1, pancreatic polypeptide, peptide tyrosine tyrosine (PYY), ghrelin, gastric inhibitory poly-peptide, IL-6, monocyte chemoattractant protein-1, and [[TNF]]-α were found in rats exposed to chlorpyrifos beginning at newly weaned, whereas only the PYY, ghrelin and IL-6 concentrations increased significantly in rats exposed in adulthood. Furthermore, a decrease in epinephrine induced by chlorpyrifos exposure was found in rats exposed to chlorpyrifos beginning at newly weaned, regardless of their diet. Chlorpyrifos-induced disturbances in the microbiome community structure were more apparent in rats fed a high-fat diet and exposed beginning at newly weaned. The affected bacteria included short-chain fatty acid-producing bacteria (Romboutsia, Turicibacter, Clostridium sensu stricto 1, norank_f_Coriobacteriaceae, Faecalibaculum, Parasutterella and norank_f__Erysipelotrichaceae), testosterone-related genus (Turicibacter, Brevibacterium), pathogenic bacteria (Streptococcus), and inflammation-related bacteria (unclassified_f__Ruminococcaceae, Ruminococcaceae_UCG-009, Parasutterella, Oscillibacter), which regulated the endocrine system via the hypothalamic-pituitary-adrenal axis, as well as the immune response and gut barrier. Early exposure accelerated the endocrine-disturbing effect and immune responses of chlorpyrifos, although these effects can be eased or recovered by a high-fat diet. This study helped clarify the relationship between disrupted endocrine function and gut microbiota dysbiosis induced by food contaminants such as pesticides.
|mesh-terms=* Aging
* Animals
* Chlorpyrifos
* Diet, High-Fat
* Gastrointestinal Microbiome
* Hypothalamo-Hypophyseal System
* Inflammation
* Male
* Pituitary-Adrenal System
* RNA, Ribosomal, 16S
* Rats
|keywords=* 16S rRNA gene sequencing
* Gut endocrine
* Gut-brain axis
* Hormone
* Hypothalamic-pituitary-adrenal axis
* Inflammation
|full-text-url=https://sci-hub.do/10.1016/j.pestbp.2019.05.018
}}
==HR==

{{medline-entry
|title=Patients with hip fracture and total hip arthroplasty surgery differ in anthropometric, but not cardiovascular screening abnormalities.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33267795
|abstract=With the rising number of hip surgeries, simple and cost-effective tools for surgery risk assessment are warranted. The analysis of heart rate variability ([[HR]]V) may not only provide critical insights into the general frailty of patients with hip surgery, but also allow for better differentiation of health profiles in different hip surgery groups. Using [[HR]]V analysis, the present study compared cardiovascular as well as anthropometric parameters between patients with hip surgery, the hip fracture surgery group (HFS) and the total hip arthroplasty group (THA), and a control group. 71 participants (56.3% women), aged 60-85 years, took part, divided into three groups-patients after hip surgery (21 HFS and 30 THA patients) and a control group (20 participants). Electrocardiogram was recorded at baseline and after the application of a physical stressor (grip strength). A 3 (group) × 2 (time) repeated measures ANOVA, and a chi square test were carried out to test for group differences. Higher weight (p = .002), body mass index (p = .001), and systolic blood pressure (p = .034) were found in THA patients compared to HFS patients. Lower calf circumference (p = .009) and diastolic blood pressure (p = .048) were observed for the HFS group compared to the control group. For cardiovascular parameters, significant differences emerged between the HFS group and the control group in [[HR]] (p = .005), SDNN (p = .034) and SD2 (p = .012). No significant differences in cardiovascular parameters were observed between the two hip surgery groups: neither at baseline nor during stressor recovery. While [[HR]]V seems to differentiate well between HFS patients and controls, more research with larger samples is needed to scrutinize similaritites and differences in cardiovascular profiles between HFS and THA patients.

|keywords=* Aging
* Cardiovascular reactivity
* Heart rate variability
* Hip fracture
* Total hip arthroplasty
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713041
}}
{{medline-entry
|title=Clinical Role of Lung Ultrasound for the Diagnosis and Prognosis of Coronavirus Disease Pneumonia in Elderly Patients: A Pivotal Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33271558
|abstract=Lung ultrasound (LUS) showed a promising role in the diagnosis and monitoring of patients hospitalized for novel coronavirus disease (COVID-19). However, no data are available on its role in elderly patients. The aim of this study was to evaluate the diagnostic and prognostic role of LUS in elderly patients hospitalized for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pneumonia. Consecutive elderly patients (age >65 years) hospitalized for COVID-19 were enrolled. Demographics, laboratory, comorbidity, and the clinical features of the patients were collected. All patients underwent LUS on admission to the ward. LUS characteristics have been analyzed. Uni- and multivariate analyses to evaluate predictors for in-hospital death were performed. Thirty-seven hospitalized elderly patients (19 men) with a diagnosis of SARS-CoV-2 infection were consecutively enrolled. The median age was 82 years (interquartile range 74.5-93.5). Ultrasound alterations were found in all patients enrolled; inhomogeneous interstitial syndrome with spared areas (91.9%) and pleural alterations (100%) were the most frequent findings. At univariate analysis, LUS score (hazard ratio [[[HR]]] 1.168, 95% CI 1.049-1.301) and pleural effusions ([[HR]] 3.995, 95% CI 1.056-15.110) were associated with in-hospital death. At multivariate analysis, only LUS score ([[HR]] 1.168, 95% CI 1.049-1.301) was independelty associated with in-hospital death. The LUS score's best cutoff for distinguishing patients experiencing in-hospital death was 17 (at multivariate analysis LUS score ≥17, [[HR]] 4.827, 95% CI 1.452-16.040). In-hospital death was significantly different according to the LUS score cutoff of 17 (p = 0.0046). LUS could play a role in the diagnosis and prognosis in elderly patients hospitalized for SARS-CoV-2 infection.

|keywords=* Aging
* Coronavirus disease
* Elderly
* Lung ultrasound
* Severe acute respiratory syndrome-coronavirus-2
|full-text-url=https://sci-hub.do/10.1159/000512209
}}
{{medline-entry
|title=The Relationship of Accelerometer-Assessed Standing Time With and Without Ambulation and Mortality: The WHI OPACH Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33225345
|abstract=Self-reported time spent standing has been associated with lower risk of mortality. No previous studies have examined this association using device-measured standing. This was a prospective cohort study of 5878 older (median age = 80 years), racial/ethnically diverse, community-dwelling women in the WHI Objective Physical Activity and Cardiovascular Health Study (OPACH). Women wore accelerometers for 1 week and were followed for mortality. The study applied previously validated machine learning algorithms to ActiGraph GT3X+ accelerometer data to separately measure time spent standing with and without ambulation. Cox proportional hazards models were used to estimate mortality risk adjusting for potential confounders. Effect modification by age, body mass index, moderate-to-vigorous physical activity, sedentary time, physical functioning, and race/ethnicity was evaluated. There were 691 deaths during 26 649 person-years of follow-up through March 31, 2018 (mean follow-up = 4.8 years). In fully adjusted models, all-cause mortality risk was lower among those with more standing without ambulation (quartile [Q] 4 vs Q1 [[HR]] = 0.63; 95% CI = 0.49-0.81, p-trend = .003) and more standing with ambulation (Q4 vs Q1 [[HR]] = 0.50; 95% CI = 0.35-0.71, p-trend < .001). Associations of standing with ambulation and mortality were stronger among women with above-median sedentary time ([[HR]] = 0.51; 95% CI = 0.38-0.68) compared to women with below-median sedentary time ([[HR]] = 0.80; 95% CI = 0.59-1.07; p-interaction = .02). In this prospective study among older women, higher levels of accelerometer-measured standing were associated with lower risks of all-cause mortality. Standing is an achievable approach to interrupting prolonged sedentary time, and if not contraindicated, is a safe and feasible behavior that appears to benefit health in older ages.

|keywords=* Accelerometer
* Longevity
* Physical activity
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa227
}}
{{medline-entry
|title=Age-related myofiber atrophy in old mice is reversed by ten weeks voluntary high-resistance wheel running.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33181317
|abstract=Age-related loss of muscle mass and function can be attenuated in rodents with life-long voluntary wheel running with moderate resistance. The present study assessed if sarcopenia could be counteracted with ten weeks high intensity training. Old (22-23 months) and middle-aged (11 months) mice were divided into three physical activity groups: Ten weeks of voluntary running in wheels with high ([[HR]]) or low resistance (LR), or no running wheel (SED). The wheel resistance was 0.5-1.5 g in the LR group and progressed from 5 g to 10 g in the [[HR]] group. Six, 8 and 5 old and 8, 9 and 9 middle-aged mice of the SED, LR and [[HR]] groups, respectively, were included in the analysis. Wheel activity was monitored throughout the intervention. Muscle mass of the tibialis anterior, gastrocnemius, soleus and plantaris muscles were measured post-mortem. Fiber type distribution and myofiber cross sectional areal (CSA) were quantified in the gastrocnemius and soleus muscles as well as total number of fibers in the soleus muscle. In the SED, the mass of all individual muscles was reduced in the old vs middle-aged (P < 0.001). In the training groups, the old mice ran significantly less, slower and for shorter bouts than the middle-aged throughout the intervention (P < 0.05). [[HR]] running increased the gastrocnemius and soleus muscle mass by 6% and 18% respectively in the old compared to SED. Fiber CSA was significantly reduced in the old SED mice, whereas fiber CSA in the old [[HR]] gastrocnemius and soleus muscles was comparable to the SED middle-aged. Fiber type shifted from 2b towards 2a in the gastrocnemius muscle of the trained old mice. [[HR]] running was more efficient than LR in maintaining muscle mass and myofiber size, and in shifting fiber types. In the middle-aged mice, similar effects were found, but less pronounced. Interestingly, fiber CSA was unaffected by running in the middle-aged. Ten weeks of [[HR]] running had a positive effect on muscle mass and morphology in both middle-aged and old mice. The old [[HR]] fiber CSA was greater than in old SED and comparable to the middle-aged, and the fibers shifted to a more oxidative composition (2b → 2a). Albeit less pronounced, similar training effects were observed in the middle-aged mice despite running faster and longer than the old.

|keywords=* Aging
* Exercise
* Mouse model
* Muscle morphology
* Skeletal muscle
* Training
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111150
}}
{{medline-entry
|title=Predicted Skeletal Muscle Mass and 4-Year Cardiovascular Disease Incidence in Middle-Aged and Elderly Participants of IKARIA Prospective Epidemiological Study: The Mediating Effect of Sex and Cardiometabolic Factors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33121164
|abstract=The sex-specific effect of skeletal muscle mass (SMM) index (SMI) on 4-year first fatal/non-fatal cardiovascular disease (CVD) event in free-of-disease individuals was examined. In 2009, [i]n[/i] = 1411 inhabitants (mean age = 64(12)) from Ikaria were selected. Follow-up was performed in 2013. SMI was created to reflect SMM through appendicular skeletal muscle mass (indirectly calculated through formulas) divided by body mass index (BMI). Fifteen and six tenths percent of participants exhibited CVD (19.8% in men/12% in women, p = 0.002). Significant U-shape trends were observed in participants >65 years old and women irrespective to age confirmed through multi-adjusted Cox regression analysis; in age >65 years, Hazard Ratio ([[HR]])  = 0.80, 95% Confidence Interval (95%CI) (0.45, 0.96) and in women [[HR]]  = 0.71, 95% CI (0.33, 0.95), while, as for the 3rd SMI tertile, no significant trends were observed. Mediation analysis revealed that mediators of the aforementioned associations in men were the arterial distensibility and total testosterone, while, in women, inflammation, insulin resistance, and arterial distensibility. High SMM accompanied by obesity may not guarantee lower CVD risk. Specific cardiometabolic factors seem to explain this need for balance between lean and fat mass.

|keywords=* aging
* body composition
* gender
* heart disease
* lean mass
* obesity
* primary prevention
* women
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693172
}}
{{medline-entry
|title=Obesity is associated with early hip fracture risk in postmenopausal women: a 25-year follow-up.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33095419
|abstract=Association of body mass index and hip fracture has been controversial. In this study, women with lowest and highest body weight had the highest fracture incidence. A 25-year follow-up indicated that obesity associates with early hip fracture risk and suggested increasing trend in normal-weight women at a later stage. Obesity is a pandemic health issue. Its association with hip fracture risk remains controversial. We studied the long-term relationship of body mass index and hip fracture incidence in postmenopausal women. The cohort of 12,715 Finnish women born in 1932-1941 was followed for 25 years, covering ages from 58 up to 83. Fractures and deaths were obtained from national registries. Women were investigated in deciles of BMI as well as in WHO weight categories (normal, overweight, or obese). The follow-up analysis was carried out in two age strata as "early" (58-70 years) and "late" (> 70 years). Body weight information was updated accordingly. Femoral neck BMD was recorded for a subsample (n = 3163). Altogether, 427 hip fractures were observed. A higher risk of early hip fracture was observed in obese and normal-weight compared with overweight women with hazard ratios ([[HR]]s) of 2.3 ((95% CI) 1.4-3.7) and 2.0 (1.3-3.1) while no difference was observed in late hip fracture risk between the three WHO categories (log rank p = 0.14). All-cause mortality during the follow-up was 19.3%. Compared with normal weight women, the obese women had a higher risk of death with an [[HR]] of 1.6 (1.4-1.8) and higher baseline BMD (p < 0.001). Faster bone loss was observed in the obese compared with other women (p < 0.001). Obesity associates with earlier hip fracture and higher postfracture mortality. The obese women with low BMD have clearly the highest risk of hip fracture. This combination increases hip fracture risk more than either of the factors alone. After 75 years of age, risk appears to increase more in normal weight women, but this trend is in need of further confirmation.

|keywords=* Aging
* Body mass index
* Bone mineral density
* Follow-up study
* General population
* Hip fracture
* Menopause
* Obesity
|full-text-url=https://sci-hub.do/10.1007/s00198-020-05665-w
}}
{{medline-entry
|title=ATM inhibition synergizes with fenofibrate in high grade serous ovarian cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33024871
|abstract=While therapies targeting deficiencies in the homologous recombination ([[HR]]) pathway are emerging as the standard treatment for high grade serous ovarian cancer (HGSOC) patients, this strategy is limited to the ~50% of patients with a deficiency in this pathway. Therefore, patients with [[HR]]-proficient tumors are likely to be resistant to these therapies and require alternative strategies. We found that the [[HR]] gene Ataxia Telangiectasia Mutated (ATM) is wildtype and its activity is upregulated in HGSOC compared to normal fallopian tube tissue. Interestingly, multiple pathways related to metabolism are inversely correlated with [i]ATM[/i] expression in HGSOC specimens, suggesting that combining ATM inhibition with metabolic drugs would be effective. Analysis of FDA-approved drugs from the Dependency Map demonstrated that ATM-low cells are more sensitive to fenofibrate, a PPARα agonist that affects multiple cellular metabolic pathways. Consistently, PPARα signaling is associated with [i]ATM[/i] expression. We validated that combined inhibition of ATM and treatment with fenofibrate is synergistic in multiple HGSOC cell lines by inducing senescence. Together, our results suggest that metabolic changes induced by ATM inhibitors are a potential target for the treatment of HGSOC.

|keywords=* Biochemistry
* Bioinformatics
* Cancer research
* Cell biology
* Cellular metabolism
* Cellular senescence
* Drug combinations
* Homologous recombination
* Metabolite
* Molecular biology
* PPARa
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527645
}}
{{medline-entry
|title=Effectiveness of adjuvant FOLFOX vs 5FU/LV in adults over age 65 with stage II and III colon cancer using a novel hybrid approach.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33015888
|abstract=Estimates of cancer therapy effects can differ in clinical trials and clinical practice, partly due to underrepresentation of certain patient subgroups in trials. We utilize a hybrid approach, combining clinical trial and real-world data, to estimate the comparative effectiveness of two adjuvant chemotherapy regimens for colon cancer. We identified patients aged 66 and older enrolled in the Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer. Similar patients were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, initiating adjuvant chemotherapy with either 5-fluorouracil (5FU) alone or in combination with oxaliplatin (FOLFOX). We used logistic regression to estimate the likelihood of trial enrollment as a function of age, sex, and substage. Using inverse odds of sampling weights (IOSW), we compared 5-year mortality in patients randomized to FOLFOX vs 5FU using weighted Cox proportional hazards regression, the Nelson-Aalen estimator for cumulative hazards, and bootstrapping for 95% confidence intervals (CIs). There were 690 trial participants and 3834 SEER-Medicare patients. The SEER-Medicare population was older and had a higher proportion of stage IIIB and IIIC patients than the trial. After controlling for differences between populations, the IOSW 5-year [[HR]] was 1.21 (0.89, 1.65), slightly farther from the null than the trial estimate ([[HR]] = 1.14, 95%CI: 0.87, 1.49). This study supports mounting evidence of little to no incremental reduction in 5-year mortality for FOLFOX vs 5FU in older adults with stage II-III colon cancer, emphasizing the importance of combining clinical trial and real-world data to support such conclusions.

|keywords=* aging
* cancer
* chemotherapy
* comparative effectiveness research
* pharmacoepidemiology
|full-text-url=https://sci-hub.do/10.1002/pds.5148
}}
{{medline-entry
|title=Age, Frailty, and Comorbidity as Prognostic Factors for Short-Term Outcomes in Patients With Coronavirus Disease 2019 in Geriatric Care.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32978065
|abstract=To analyze whether frailty and comorbidities are associated with in-hospital mortality and discharge to home in older adults hospitalized for coronavirus disease 2019 (COVID-19). Single-center observational study. Patients admitted to geriatric care in a large hospital in Sweden between March 1 and June 11, 2020; 250 were treated for COVID-19 and 717 for other diagnoses. COVID-19 diagnosis was clinically confirmed by positive reverse transcription polymerase chain reaction test or, if negative, by other methods. Patient data were extracted from electronic medical records, which included Clinical Frailty Scale (CFS), and were further used for assessments of the Hospital Frailty Risk Score (HFRS) and the Charlson Comorbidity Index (CCI). In-hospital mortality and home discharge were followed up for up to 25 and 28 days, respectively. Multivariate Cox regression models adjusted for age and sex were used. Among the patients with COVID-19, in-hospital mortality rate was 24% and home discharge rate was 44%. Higher age was associated with in-hospital mortality (hazard ratio [[[HR]]] 1.05 per each year, 95% confidence interval [CI] 1.01‒1.08) and lower probability of home discharge ([[HR]] 0.97, 95% CI 0.95‒0.99). CFS (>5) and CCI, but not HFRS, were predictive of in-hospital mortality ([[HR]] 1.93, 95% CI 1.02‒3.65 and [[HR]] 1.27, 95% CI 1.02‒1.58, respectively). Patients with CFS >5 had a lower probability of being discharged home ([[HR]] 0.38, 95% CI 0.25‒0.58). CCI and HFRS were not associated with home discharge. In general, effects were more pronounced in men. Acute kidney injury was associated with in-hospital mortality and hypertension with discharge to home. Other comorbidities (diabetes, cardiovascular disease, lung diseases, chronic kidney disease and dementia) were not associated with either outcome. Of all geriatric patients with COVID-19, 3 out of 4 survived during the study period. Our results indicate that in addition to age, the level of frailty is a useful predictor of short-term COVID-19 outcomes in geriatric patients.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Betacoronavirus
* COVID-19
* Comorbidity
* Coronavirus Infections
* Female
* Frail Elderly
* Geriatrics
* Humans
* Male
* Models, Statistical
* Outcome Assessment, Health Care
* Pandemics
* Pneumonia, Viral
* Prognosis
* SARS-CoV-2
* Survival Analysis
* Sweden
|keywords=* COVID-19
* aging
* comorbidity
* frailty
* geriatrics
* survival
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427570
}}
{{medline-entry
|title=Clinical and demographic parameters predict the progression from mild cognitive impairment to dementia in elderly patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32918697
|abstract=To evaluate the possibility of predicting the risk of progression from mild cognitive impairment (MCI) to dementia using a combination of clinical/demographic parameters. A total of 462 MCI elderly patients (follow-up: 33 months). Variable measured included cognitive functions, age, gender, MCI type, education, comorbidities, clinical chemistry, and functional status. Amnestic type (aMCI) represented 63% of the sample, non-amnestic (naMCI) 37%; 190 subjects progressed to dementia, 49% among aMCI, and 28% among naMCI. At Cox multivariate regression analysis, only MMSE (one point increase [[HR]] 0.84; 95% CI 0.79-0.90), aMCI ([[HR]] 2.35; 95% CI 1.39-3.98), and age (1 year increase [[HR]] 1.05; 95% CI 1.01-1.10) were independently associated with progression to dementia. A score was created based on these dichotomized variables (score 0-3): age (≥ or < 78 years), MMSE score (≥ or < 25/30) and aMCI type. The conversion rate progressed from 6% in subjects with score 0 (negative predictive value: 0.94), to 31% in individuals with score 1, to 53% in subjects with score 2, to 72% in individuals with score 3 (positive predictive value: 0.72). ROC curve analysis showed an area under the curve of 0.72 (95% CI 0.66-0.75, p 0.0001). We have described a simple score, based on previously recognized predictors such as age, MMSE, and MCI type, which may be useful for an initial stratification of the risk of progression to dementia in patients affected by MCI. The score might help the clinicians to evaluate the need for more expansive/invasive examinations and for a closer follow-up in MCI patients.

|keywords=* Aging
* Cox regression
* Dementia
* Follow-up
* Mild cognitive impairment
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01697-8
}}
{{medline-entry
|title=Plasma Dehydroepiandrosterone Sulfate and Cardiovascular Disease Risk in Older Men and Women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32785663
|abstract=Lower dehydroepiandrosterone-sulfate (DHEA-S) levels have been inconsistently associated with coronary heart disease (CHD) and mortality. Data are limited for heart failure (HF) and association between DHEA-S change and events. Assess associations between low DHEA-S/DHEA-S change and incident HF hospitalization, CHD, and mortality in older adults. DHEA-S was measured in stored plasma from visits 4 (1996-1998) and 5 (2011-2013) of the Atherosclerosis Risk in Communities study. Follow-up for incident events: 18 years for DHEA-S level; 5.5 years for DHEA-S change. General community. Individuals without prevalent cardiovascular disease (n = 8143, mean age 63 years). Associations between DHEA-S and incident HF hospitalization, CHD, or mortality; associations between 15-year change in DHEA-S (n = 3706) and cardiovascular events. DHEA-S below the 15th sex-specific percentile of the study population (men: 55.4 µg/dL; women: 27.4 µg/dL) was associated with increased HF hospitalization (men: hazard ratio [[[HR]]] 1.30, 95% confidence interval [CI], 1.07-1.58; women: [[HR]] 1.42, 95% CI, 1.13-1.79); DHEA-S below the 25th sex-specific percentile (men: 70.0 µg/dL; women: 37.1 µg/dL) was associated with increased death (men: [[HR]] 1.12, 95% CI, 1.01-1.25; women: [[HR]] 1.19, 95% CI, 1.03-1.37). In men, but not women, greater percentage decrease in DHEA-S was associated with increased HF hospitalization ([[HR]] 1.94, 95% CI, 1.11-3.39). Low DHEA-S and change in DHEA-S were not associated with incident CHD. Low DHEA-S is associated with increased risk for HF and mortality but not CHD. Further investigation is warranted to evaluate mechanisms underlying these associations.

|keywords=* DHEA-S
* aging
* heart failure
* mortality
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526732
}}
{{medline-entry
|title=High intensity interval training combined with L-citrulline supplementation: Effects on physical performance in healthy older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32721549
|abstract=The aim of this study was to evaluate the effect of citrulline (CIT) supplementation combined to high intensity interval training (HIIT) on physical performance in healthy older adults. This study is a secondary analysis from a double-blind, randomized trial. Among the participants (sedentary & inactive older adults aged over 65 yrs), 44 were non obese (BMI <30 kg/m ) and completed the intervention: Placebo + HIIT (PLA; n = 21) or CIT + HIIT (n = 23). All participants ingested either 10 g of CIT supplementation/day or placebo and followed HIIT sessions (30 min/session; cycle: 30 s > 85% of maximal heart rate ([[HR]]) and Borg scale >17/20 + 1:50 min at 65% [[HR]] and Borg scale between 13 and 16) on an elliptical device 3 times per week over a 12-week period. Body composition, muscle strength, muscle power, functional capacities (unipodal balance; self-paced and fast Timed Up and Go (nTUG; fTUG); chair test; step tests; 4-meter walking test; 6-minute walking test); dietary intake, energy expenditure and biological markers were measured pre and post-intervention. A repeated-measure analysis of variance was used to estimate time (HIIT intervention), group (PLA vs. CIT) and time*group effects. The decrease in BMI (p = 0.02) and android fat mass (p = 0.05) were significantly greater in the HIIT+CIT group than in the HIIT+PLA group. Finally, a greater increase in self-paced gait speed (nTUG) (p = 0.02) and fast-paced gait speed (fTUG) (p = 0.03) were also observed in the HIIT+CIT group than in the HIIT+PLA group. CIT supplementation combined to HIIT is more effective in improving functional capacities and body composition in healthy older adults than HIIT alone.

|keywords=* Aging
* Body composition
* Exercise
* Mobility
* Nutrition
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111036
}}
{{medline-entry
|title=Associations of blood pressure with risk of injurious falls in old age vary by functional status: A cohort study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32738383
|abstract=We aimed to examine to what extent blood pressure (BP) components are associated with injurious falls in older adults, and whether the possible associations differ by functional status (indicated by physical and cognitive impairment at baseline). This prospective cohort study included 3055 community-living participants of the Swedish National study on Aging and Care in Kungsholmen (aged ≥60 years). At baseline (2001-2004), we measured systolic BP (SBP) and diastolic BP (DBP), mean arterial pressure, pulse pressure (PP), and orthostatic hypotension. Physical function was assessed using tests of balance, chair stands, and walking speed. Cognitive function was assessed with the Mini-Mental State Examination. Injurious falls leading to inpatient or outpatient care during 3 and 10 years of follow-up were identified via patient registers. Data were analyzed using flexible parametric survival models adjusted for potential confounders. During the 10-year follow-up period in people without functional impairment, the multi-adjusted hazard ratios ([[HR]]) of injurious falls were 1.77 (95% CI 1.02-3.07) for having SBP <130 mmHg, 1.73 (95% CI 1.05-2.83) for having SBP ≥160 mmHg (vs. 130-139), and 1.46 (1.05-2.02) for having higher tertile of PP (vs. lower tertile). During the 3-year follow-up period in people with functional impairment, the multi-adjusted [[HR]] of injurious falls was 1.91 (95% CI 1.17-3.13) for having SBP <130 mmHg (vs. 130-139) and 0.74 (0.59-0.94) for having higher tertile of PP (vs. lower tertile). There was no significant association between BP components and injurious falls either in people without functional impairment during the 3-year follow-up period, or in people with functional impairment during the 10-year follow-up period. This large-scale Swedish study provides evidence that the associations between some specific components of BP and risk of injurious falls in older adults vary by functional status. This supports the view that a personalized approach to blood pressure management depending on functional status among older adults might be warranted in clinical settings.

|keywords=* Aging
* Blood pressure
* Falls
* Injury
* Swedish National study on Aging and Care in Kungsholmen (SNAC-K)
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111038
}}
{{medline-entry
|title=Epigenetic age acceleration and clinical outcomes in gliomas.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32692766
|abstract=Epigenetic age acceleration-the difference between an individual's DNA methylation age and chronological age-is associated with many diseases including cancer. This study aims to evaluate epigenetic age acceleration as a prognostic biomarker for gliomas. DNA methylation data of gliomas patients (516 low-grade and intermediate-grade gliomas and 140 glioblastoma) were obtained from The Cancer Genome Atlas (TCGA) and patient epigenetic ages were computed using Horvath's age prediction model. We used multivariate linear regression to assess the association of epigenetic age acceleration with tumor molecular subtypes, including Codel, Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like. Compared with Codel subtype, epigenetic ages in other molecular subtypes show deceleration after controlling age and race. Age deceleration for Classic-like, G-CIMP-high, G-CIMP-low, Mesenchymal-like and PA-like were 15.42 years (CI: 7.98-22.86, p = 5.38E-05), 25.00 years (CI: 20.79-29.22, p = 4.06E-28), 28.56 years (CI: 14.37-42.74, p = 8.75E-05), 45.34 years (CI: 38.80-51.88, p = 2.15E-36), and 53.58 years (CI: 44.90-62.26, p = 4.81E-30), respectively. Then, Cox proportional hazards regression was used to assess the association of epigenetic age acceleration with patient overall survival. Our results show epigenetic age acceleration is positively associated with patient overall survival (per 10-year age acceleration, [[HR]] = 0.89; 95%CI: 0.82-0.97; p = 9.04E-03) in multivariate analysis. When stratified by molecular subtypes, epigenetic age acceleration remains positively associated with patient survival after adjusting age and tumor grade. In conclusion, epigenetic age acceleration is significantly associated with molecular subtypes and patient overall survival in gliomas, indication that epigenetic age acceleration has potential as a quantitative prognostic biomarker for gliomas.
|mesh-terms=* Adult
* Aging
* DNA Methylation
* Epigenesis, Genetic
* Female
* Glioma
* Humans
* Male
* Middle Aged
* Prognosis
* Survival Analysis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373289
}}
{{medline-entry
|title=Do Stairs Inhibit Seniors Who Live on Upper Floors From Going Out?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32666833
|abstract=Walk-up buildings are common in China today since they were almost the only type of residential buildings constructed from the 1950s to the 1990s. This study examined how a vertical mobility obstacle, that is, mandatory stair climbing in walk-up residential buildings, may impact whether seniors go outdoors. We collected and examined 1,608 valid data records from 64 Chinese senior participants in Shanghai wearing Fitbit [[HR]] wristbands that tracked their mobility and physical activity for 31 consecutive days. Multilevel mixed-effects logistic regressions were performed on the binary leaving-home-or-not probability by the level of vertical obstacles controlled for physical-demographic factors, socioeconomic factors, outdoor activity habits, and weather. Our observations revealed that each floor above ground level reduced the likelihood of outdoor trips by approximately one third per floor. After controlling for the physical, demographic, and socioeconomic factors of the participants as well as weather and holidays, we found that significantly fewer going-out incidents were also associated with more frequent outdoor activities within the community, especially in paved areas, but no associations were observed with self-reported visit frequencies to green spaces, senior centers within the community, or other places outside the community. This study offered the in situ observation that seniors' probability of leaving their homes is correlated with the degree of vertical circulation as a mobility barrier (i.e., the number of stairs between their living space and access to the outdoors), which may impact policy making for regulations concerning elevators in residential codes and renovations.

|keywords=* active aging
* activity monitor
* homebound
* mobility
* walk-up buildings
|full-text-url=https://sci-hub.do/10.1177/1937586720936588
}}
{{medline-entry
|title=Age-specific acute changes in carotid-femoral pulse wave velocity with head-up tilt.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32634245
|abstract=Aortic stiffness as measured by carotid-femoral pulse wave velocity (cfPWV) is known to depend on blood pressure (BP), and this dependency may change with age. Therefore, the hydrostatic BP gradient resulting from a change in body posture may elicit a cfPWV change that is age-dependent. We aimed to analyze the relationship between BP gradient - induced by head-up body tilting - and related changes in cfPWV in individuals of varying age. cfPWV and other hemodynamic parameters were measured in 30 healthy individuals at a head-up tilt of 0° (supine), 30°, and 60°. At each angle, the PWV gradient and resulting cfPWV were also estimated (predicted) by assuming a global non-linear, exponential, pressure-diameter relationship characterized by a constant β0, and taking into account that (diastolic) foot-to-foot cfPWV acutely depends on diastolic BP (DBP). cfPWV significantly increased upon body tilting (8.0±2.0 m/s supine, 9.1±2.6 m/s at 30°, 9.5±3.2 m/s at 60°, p for trend <0.01); a positive trend was also observed for heart rate ([[HR]]; p<0.01). When the observed, tilt-induced cfPWV change measured by applanation tonometry was compared with that predicted from the estimated BP hydrostatic gradient, the difference in observed-vs.-predicted PWV change increased non-linearly as a function of age (R2 for quadratic trend=0.38, p<0.01, p vs. linear=0.04). This result was unaffected by [[HR]] tilt-related variations (R2 for quadratic trend=0.37, p<0.01, p vs. linear=0.04). Under a hydrostatic pressure gradient, the pulse wave traveling along the aorta undergoes an age-related, nonlinear PWV increase exceeding the increase predicted from BP dependency.

|keywords=* arterial function
* arterial stiffness
* blood pressure
* early vascular aging
* pressure dependence
|full-text-url=https://sci-hub.do/10.1093/ajh/hpaa101
}}
{{medline-entry
|title=Pre-frailty status increases the risk of rehospitalization in patients after elective cardiac surgery without complication.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32531126
|abstract=It has been demonstrated that patients with pre-frailty have more adverse outcomes after cardiac surgery; however, data on prognosis and long-term evolution in patients with pre-frailty after elective cardiac surgery without postoperative complications are still scarce. To evaluate the impact of pre-frailty status on functional survival in patients after elective cardiac surgery without surgical complications. This was a retrospective study with 141 patients over 65 years old, with an established diagnosis of myocardial infarction or valve disease. Patients were evaluated by Clinical Frailty Scale (CFS) before surgery, according to the hospital protocol, and allocated into two groups: non-frail (CFS, 1-3) and pre-frail (CFS = 4). Patients with adverse cardiovascular events during surgery or at intensive care unit (ICU), mechanical ventilation more than 24 hours, ICU length of stay more than 48 hours, and in-hospital complications were excluded. For all analyses, the statistical significance was set at 5% (P < .05). There were no differences in demographic, anthropometric, surgical procedure, or baseline data on ICU. Pre-frail patients had more adverse events during the 3-year follow-up period with rehospitalization compared to non-frail (39.4% vs 14.3%, respectively). Rehospitalizations in pre-frail patients were in the first year after cardiac surgery (P < .05), and higher cumulative events in pre-frail have occurred with increased odds ratio (OR) (2.828, 95% confidence interval [CI]: 1.298-6.160; P = .001) and hazard ratio ([[HR]]) (3.560, 95% CI: 1.508-84.04; P = .004). The OR and [[HR]] for stroke or death were similar between groups when analyzed separately. Pre-frail patients have more adverse events after elective cardiac surgery without complications when compared to non-frail patients.
|mesh-terms=* Aged
* Cardiac Surgical Procedures
* Elective Surgical Procedures
* Female
* Frailty
* Humans
* Male
* Patient Readmission
* Postoperative Complications
* Retrospective Studies
* Risk
|keywords=* adverse events
* aging
* cardiac surgery
* frailty
* rehospitalization
|full-text-url=https://sci-hub.do/10.1111/jocs.14550
}}
{{medline-entry
|title=Comparative Performance of Creatinine-Based GFR Estimation Equations in Exceptional Longevity: The Rugao Longevity and Ageing Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32546991
|abstract=Reduced kidney function has been associated with an increased risk for adverse outcomes. Accurate assessment of glomerular filtration rate (GFR) is key to diagnosis and management of kidney disfunction. Debate exists on the best GFR estimation equation for elderly people. This study aimed to compare the predictive validity and discriminative ability of four GFR equations in relation to 2-year and 6-year mortality in exceptional longevity (EL) (those over 95 years old with intact health) individuals and is an ideal model to address factors relating to life span and age-related diseases. This study used 6 years' data of 278 EL from the Rugao longevity cohort. Baseline GFR was estimated using four equations: Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, Modification of Diet in Renal Disease Study (MDRD) equation, Berlin Initiative Study-1 (BIS) equation, and modified MDRD equation. Predictive validity was tested using Cox proportional hazards analysis. Overall improvement in reclassification based on estimated GFR (eGFR) was assessed applying net reclassification improvement (NRI). Mean age of participants was 97±2 years with median follow-up of 2.6 years. Median (IQR) eGFR by CKD-EPI, MDRD, BIS, and modified MDRD equations were 73.9 (62.2-77.6), 82.3 (67.4-98.6), 56.4 (47.9-63.9), and 101.5 (83.1-121.6) mL/min per 1.73 m , respectively. Higher eGFR  was associated with lower mortality after multivariate adjustment (for continuous eGFR , [[HR]]  1.018, 95% CI 1.002-1.033, [i]P[/i]=0.023; [[HR]]  1.013, 95% CI 1.002-1.025, [i]P[/i]=0.022), while eGFR from other equations did not show any associations with mortality. NRI for two-year mortality was 0.14 and approximately significant, which may favor the CKD-EPI when compared to BIS equation ([i]P[/i]=0.052). The CKD-EPI equation showed more accurate estimation of kidney function in the elderly with respect to GFR distribution and predictability of mortality risk.
|mesh-terms=* Aged, 80 and over
* Creatinine
* Female
* Glomerular Filtration Rate
* Humans
* Kidney Function Tests
* Longevity
* Male
* Mortality
* Predictive Value of Tests
* Renal Insufficiency
* Reproducibility of Results
* Risk Factors
|keywords=* equation
* exceptional longevity
* glomerular filtration rate
* kidney function
* mortality
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266309
}}
{{medline-entry
|title=Sex-and race-specific associations of protein intake with change in muscle mass and physical function in older adults: the Health, Aging, and Body Composition (Health ABC) Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32520344
|abstract=Protein intake recommendations advise ≥0.8 g/kg body weight (BW)/d, whereas experts propose a higher intake for older adults (1.0-1.2 g/kg BW/d). It is unknown whether optimal protein intake differs by sex or race. We examined the shape of sex- and race-specific associations of dietary protein intake with 3- and 6-y changes in appendicular lean mass (aLM) and gait speed and also 6-y incidence of mobility limitation in community-dwelling older men and women. We used data on men (n = 1163) and women (n = 1237) aged 70-81 y of the Health, Aging, and Body Composition Study. Protein intake was assessed using an FFQ (1998-1999). aLM and gait speed were measured at baseline and at 3 and 6 y. Difficulty walking one-quarter mile or climbing stairs was measured every 6 mo over 6 y. Prospective associations were evaluated with linear and Cox regression models, comparing fit of models with and without spline functions. All analyses were stratified by sex and additionally by race. Mean ± SD protein intake was 0.94 ± 0.36 g/kg adjusted body weight (aBW)/d in men and 0.95 ± 0.36 g/kg aBW/d in women. There were no strong indications of nonlinear associations. In women, higher protein intake was associated with less aLM loss over 3 y (adjusted B per 0.1 g/kg aBW/d: 39.4; 95% CI: 11.6, 67.2), specifically in black women, but not over 6 y or with gait speed decline. In men, protein intake was not associated with changes in aLM and gait speed. Higher protein intake was associated with a lower risk of mobility limitation in men (adjusted [[HR]] per 1.0 g/kg aBW/d: 0.55; 95% CI: 0.34, 0.91) and women (adjusted [[HR]]: 0.56; 95% CI: 0.33, 0.94), specifically white women. Associations between protein intake and physical outcomes may vary by sex and race. Therefore, it is important to consider sex and race in future studies regarding protein needs in older adults.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biomass
* Body Composition
* Body Weight
* Dietary Proteins
* Female
* Humans
* Independent Living
* Male
* Muscle Development
* Muscle Strength
* Muscles
* Prospective Studies
* Sex Factors
|keywords=* appendicular lean body mass
* community-dwelling
* gait speed
* mobility limitation
* old age
* optimal intake
* physical performance
* spline functions
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326591
}}
{{medline-entry
|title=Deterioration of bone microstructure by aging and menopause in Japanese healthy women: analysis by [[HR]]-pQCT.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32519249
|abstract=Second-generation high-resolution peripheral quantitative computed tomography ([[HR]]-pQCT) has provide higher quality of bone images with a voxel size of 61 µm, enabling direct measurements of trabecular thickness. In addition to the standard parameters, the non-metric trabecular parameters such as trabecular morphology (plate to rod-like structures), connectivity, and anisotropy can also be analyzed. The purpose of this study is to investigate deterioration of bone microstructure in healthy Japanese women by measuring standard and non-metric parameters using [[HR]]-pQCT. Study participants were 61 healthy Japanese women (31-70 years). The distal radius and tibia were scanned using second-generation [[HR]]-pQCT, and microstructures of trabecular and cortical bone were measured. Non-metric trabecular parameters included structure model index (SMI), trabecular bone pattern factor (TBPf), connectivity density (Conn.D), number of nodes (N.Nd/TV), degree of anisotropy (DA), and star volume of marrow space (V*ms). Estimated bone strength was evaluated by micro finite element analysis. Associations between bone microstructure, estimated bone strength, age, and menopause were analyzed. Trabecular number declined with age, and trabecular separation increased. SMI and TBPf increased, Conn.D and N.Nd/TV declined, and V*ms increased. Cortical BMD and thickness declined with age, and porosity increased. Stiffness and failure load decreased with age. Cortical thickness and estimated bone strength were affected by menopause. Cortical thickness was most associated with estimated bone strength. Trabecular and cortical bone microstructure were deteriorated markedly with age. Cortical thickness decreased after menopause and was most related to bone strength. Non-metric parameters give additional information about osteoporotic changes of trabecular bone.
|mesh-terms=* Absorptiometry, Photon
* Adult
* Aged
* Aging
* Asian Continental Ancestry Group
* Bone Density
* Bone and Bones
* Cancellous Bone
* Cortical Bone
* Female
* Finite Element Analysis
* Humans
* Japan
* Linear Models
* Menopause
* Middle Aged
* Porosity
* Tomography, X-Ray Computed
|keywords=* Bone microstructure
* Estimated bone strength
* High resolution peripheral quantitative CT (HR-pQCT)
* Japanese women
* Non-metric trabecular parameter
|full-text-url=https://sci-hub.do/10.1007/s00774-020-01115-z
}}
{{medline-entry
|title=Association between Low Protein Intake and Mortality in Patients with Type 2 Diabetes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32492838
|abstract=The aim of this study was to investigate the association between protein intake and mortality risk in patients with type 2 diabetes. We analyzed a pooled data of 2494 diabetic patients from two prospective longitudinal studies. Nutritional intake was assessed using a Food Frequency Questionnaire at baseline. Protein intake per body weight (kg) per day was categorized into quartile groups. Adjusted hazard ratios ([[HR]]s) and 95% confidence interval (CI) were calculated using Cox regression analysis. During the six-year follow-up, there were 152 incidents of all-cause mortality. The [[HR]] for mortality in the lowest quartile of protein intake per body weight compared with the highest quartile was 2.26 (95% CI: 1.34-3.82, [i]p[/i] = 0.002) after adjustment for covariates. Subgroup analyses revealed significant associations between low protein intake and mortality in patients aged over 75 years or under 65 years. After further adjustment of the total energy intake, a significant association between protein intake and mortality remained in patients aged ≥ 75 years, whereas the association was attenuated in those aged < 65 years. Our results suggest that adequate protein intake is necessary in older diabetic patients over 75 years, whereas with diabetes, whereas whole optimal total energy intake is required in younger patients with type 2 diabetes.

|keywords=* aging
* diabetes
* mortality
* nutritional support
* protein intake
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352318
}}
{{medline-entry
|title=CAUSES, mortality rates and risk factors of death in community-dwelling Europeans aged 50 years and over: Results from the Survey of Health, Ageing and Retirement in Europe 2013-2015.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32325305
|abstract=To determine mortality rates and to rank the causes and predictors of mortality using a wide range of sociodemographic and clinical variables. It is a prospective population-based cohort study of adults living in the community, 2013-15 N = 48,691, age ≥50; deceased = 1,944. Clinical and sociodemographic data were obtained from the Survey of Health, Ageing and Retirement in Europe SHARE: Age, Gender, Marital Status, Years of Schooling, Income, Loneliness, Cognition, Self-Rated Health, Diseases, Activities of daily living ADL, and Frailty. Mortality rates were calculated. A Cox proportional hazards model were used to determine risk-adjusted mortality ratios. The crude mortality rate was 18.39 (1000 person-years at risk), (99 % CI, 18.37-18.42). The factors most associated with an increased mortality risk were older age, lower self-rated health, lower cognition, male gender, ADL deficits, higher comorbidity, frailty and loneliness. The diseases with a higher mortality risk were: cancer (Hazard ratio, [[HR]] = 2.67), dementia ([[HR]] = 2.19), depressive symptoms ([[HR]] = 2.10), fractures (hip, femur) ([[HR]] = 1.57), stroke ([[HR]] = 1.55), chronic lung disease ([[HR]] = 1.52), diabetes ([[HR]] = 1.36) and heart attack ([[HR]] = 1.21). The main mortality risk factors, associated independently in the eight diseases were: older age, poor self-rated health, ADL deficits, male gender, lower cognition, comorbidity and the presence of depressive symptoms, with a different influence in the European regions. The need to evaluate and treat the depressive symptoms that accompanies diseases with higher risk of mortality is stressed.
|mesh-terms=* Activities of Daily Living
* Aged
* Aging
* Cohort Studies
* Europe
* Humans
* Independent Living
* Male
* Middle Aged
* Mortality
* Proportional Hazards Models
* Prospective Studies
* Retirement
* Risk Factors
* Surveys and Questionnaires
|keywords=* Aging
* Comorbidity
* Depressive symptoms
* Diseases
* Mortality risk
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104035
}}
{{medline-entry
|title=Estimation of Wave Condition Number From Pressure Waveform Alone and Its Changes With Advancing Age in Healthy Women and Men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32328003
|abstract=The wave condition number (WCN) is a non-dimensional number that determines the state of arterial wave reflections. WCN is equal to [[HR]] × L   /PWV where [[HR]], L   , and PWV are the heart rate, effective length, and pulse wave velocity, respectively. It has been shown that a value of WCN = 0.1 indicates the optimum state of arterial wave reflection in which left ventricle workload is minimized. The pressure wave, flow wave, and PWV are all required to compute WCN, which may limit the potential clinical utility of WCN. The aims of this study are as follows: (1) to assess the feasibility of approximating WCN from the pressure waveform alone (WCN   ), and (2) to provide the proof-of-concept that WCN   can capture age related differences in arterial wave reflection among healthy women and men. Previously published retrospective data composed of seventeen patients (age 19-54 years; 34.3 ± 9.6) were used to assess the accuracy of WCN   . The exact value of WCN was computed from PWV (measured by foot-to-foot method), [[HR]], and L   . A quarter wavelength relationship with minimum impedance modulus were used to compute L   . WCN   was calculated using [[HR]] and the reflected wave arrival time. Previously published analyses from a healthy subset of the Anglo-Cardiff Collaborative Trial (ACCT) study population were used to investigate if non-invasive WCN   captures age related differences in arterial wave reflection among healthy women and men. A strong correlation ([i]r[/i] = 0.83, [i]p[/i]-value <0.0001) between WCN   and WCN was observed. The accuracy of WCN   was independent from relevant physiological parameters such as PWV, pulse pressure (PP), and [[HR]]. Similar changes in WCN   with advancing age were observed in both healthy men and healthy women. In young, healthy individuals (women and men) the WCN   was around 0.1 (the optimum value), and reduced with aging. WCN can be approximated from a single pressure waveform and can capture age related arterial wave reflection alteration. These results are clinically significant since WCN can be extracted from a single non-invasive pressure waveform. Future studies will focus on investigating if WCN is associated with risk for onset of cardiovascular disease events.

|keywords=* arterial wave reflection
* cardiovascular biomarker
* optimum cardiovascular function
* vascular aging
* wave condition number
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161432
}}
{{medline-entry
|title=Extended in vitro culture of primary human mesenchymal stem cells downregulates Brca1-related genes and impairs DNA double-strand break recognition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32333827
|abstract=Mesenchymal stem cells (MSCs) are multilineage adult stem cells with considerable potential for cell-based regenerative therapies. In vitro expansion changes their epigenetic and cellular properties, with a poorly understood impact on DNA damage response (DDR) and genome stability. We report here results of a transcriptome-based pathway analysis of in vitro-expanded human bone marrow-derived mesenchymal stem cell (hBM-MSCs), supplemented with cellular assays focusing on DNA double-strand break (DSB) repair. Gene pathways affected by in vitro aging were mapped using gene ontology, KEGG, and GSEA, and were found to involve DNA repair, homologous recombination ([[HR]]), cell cycle control, and chromosomal replication. Assays for the recognition (γ-H2AX + 53BP1 foci) and repair (pBRCA1 + γ-H2AX foci) of X-ray-induced DNA DSBs in hBM-MSCs show that over a period of 8 weeks of in vitro aging (i.e., about 10 doubling times), cells exhibit a reduced DDR and a higher fraction of residual DNA damage. Furthermore, a distinct subpopulation of cells with impaired DNA DSB recognition was observed. Several genes that participate in DNA repair by [[HR]] (e.g., Rad51, Rad54, BRCA1) show a 2.3- to fourfold reduction of their mRNA expression by qRT-PCR. We conclude that the in vitro expansion of hMSCs can lead to aging-related impairment of the recognition and repair of DNA breaks.

|keywords=* 
BRCA1

* DNA repair
* cellular aging
* homologous recombination
* mesenchymal stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327915
}}
{{medline-entry
|title=Effect of artificial dawn light on cardiovascular function, alertness, and balance in middle-aged and older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32307533
|abstract=When arising in the morning, many older people experience dizziness and difficulty maintaining proper balance, as the cardiovascular system is not able to compensate to the postural shift (standing) and maintain sufficient blood flow to the brain. Such changes in cardiovascular function are observed in young individuals exposed to a dawn simulation light. In this study, we examined whether exposure to a dawn simulation light could impact cardiovascular function and consequent changes in balance in middle-aged and older adults. Twenty-three participants (67.3 ± 8.8 y), 12 of whom reported a history of dizziness in the morning, underwent two overnight stays in our laboratory. During both nights, they slept in complete darkness, except for the last 30 minutes of one of the nights during which a dawn simulation light was used. Continuous blood pressure (BP) and heart rate ([[HR]]) were monitored. Subjective and objective alertness, salivary cortisol, and mobile and standing balance were examined upon arising. Dawn simulation light decreased (33%) the amount of sleep before morning awakening, lowered BP (6.24 mmHg), and increased [[HR]] (0.93 bpm). Despite these changes in physiology, there was no significant impact of dawn simulation on subjective or objective alertness, measures of standing or ambulatory balance, morning cortisol awakening response, or cardiovascular function after awakening. While the dawn simulation did cause an increase in wake and a change in cardiovascular function prior to morning arousal in older adults, we could find no evidence of a functional change in either cardiovascular function or balance upon standing. Registered on Clinicaltrials.gov, #NCT02632318, https://clinicaltrials.gov/ct2/show/NCT02632318.

|keywords=* aging
* alertness
* balance
* blood pressure
* heart rate
* heart rate variability
* light
* sleep inertia
|full-text-url=https://sci-hub.do/10.1093/sleep/zsaa082
}}
{{medline-entry
|title=Heart Rate Performance Curve Is Dependent on Age, Sex, and Performance.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32300582
|abstract= The Heart Rate Performance Curve ([[HR]]PC) is neither linear nor uniform and related to ß1-adrenoceptor sensitivity. As aging and exercise influence ß1-adrenoceptors we suggested age, sex and performance effects on the [[HR]]PC. Aim of the study was to examine the effects of aging on the deflection of the [[HR]]PC in maximal incremental cycle ergometer exercise (CE) in a large cohort of healthy subjects.   Heart rate ([[HR]]) data of 2,980 men (51 ± 15 years) and 1,944 women (52 ± 14 years) were classified into age groups (≤20 up to >80 years). We analyzed age and performance (P  25%-quartile and P  75%-quartile of age predicted power) effects on [[HR]]  and on the degree ([i]k[/i]) and the type (regular downward deflection [i]k[/i] > 0.1, linear -0.1 ≤ [i]k[/i] ≤ 0.1 and atypical upward deflection [i]k[/i] < -0.1) of the [[HR]]PC.   [i]k[/i]-values decreased significantly with age in men and women and were significantly higher in women. Atypical [[HR]]PC's increased by a linear trend from ≤20 to 70 years ([i]m[/i]) respectively 80 years ([i]w[/i]) from 10 to 43% ([i]m[/i]) and 9 to 30% ([i]w[/i]). [[HR]]  of all age groups was lower in P  and overall number of atypical [[HR]]PC's was 21% ([i]m[/i]) and 16% ([i]w[/i]) higher compared to P .   Aging increased the number of atypical [[HR]]PC's with upward deflection in CE tests, which influences exercise intensity prescription especially when using fixed percentages of [[HR]] . Changes in [[HR]]PC's were affected by sex and performance, where women generally and subjects with higher performance presented less atypical [[HR]]PC's even at older age.

|keywords=* aging
* heart rate deflection
* intensity prescription
* maximal heart rate
* sex differences
* ß1-receptor sensitivity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144539
}}
{{medline-entry
|title=Physical activity trajectories, mortality, hospitalization, and disability in the Toledo Study of Healthy Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32163233
|abstract=Physical activity (PA) is a recognized contributor to healthy aging. However, the majority of studies exploring its associations with adverse outcomes in cohorts of older adults use single-time PA estimates, which do not consider its dynamic nature. The aim of the present study is to explore the presence of different PA trajectories in the Toledo Study of Healthy Aging and their association with adverse outcomes. Our hypothesis is that prospectively maintaining or increasing PA is associated with a reduced risk of adverse outcomes. We used data from 1679 participants enrolled in the Toledo Study of Healthy Aging. Trajectories based on the Physical Activity Scale for the Elderly were identified using group-based trajectory modelling. Cox and logistic regression were used to investigate associations between PA trajectories and mortality and hospitalization, and incident and worsening disability, respectively. Mortality was ascertained by linkage to the Spanish National Death Index; disability was evaluated through the Katz Index; and hospitalization was defined as the first admission to Toledo Hospital. Models were adjusted by age, sex, smoking, Charlson Index, education, cognitive impairment, polypharmacy, and Katz Index at Wave 2. We found four PA-decreasing and one PA-increasing trajectories: high PA-consistent (n = 566), moderate PA-mildly decreasing (n = 392), low PA-increasing (n = 237), moderate PA-consistent (n = 191), and low PA-decreasing (n = 293). Belonging to the high PA-consistent trajectory group was associated with reduced risks of mortality as compared with the low PA-decreasing group [hazard ratio ([[HR]]) 1.68; 95% confidence interval (CI) = 1.21-2.31] and hospitalization compared with the low PA-increasing and low PA-decreasing trajectory groups ([[HR]] 1.24; 95% CI = 1.004-1.54 and [[HR]] 1.25; 95% CI = 1.01-1.55, respectively) and with lower rates of incident [odds ratio (OR) 3.14; 95% CI = 1.59-6.19] and worsening disability (OR 2.16; 95% CI = 1.35-3.45) in relation to the low PA-decreasing trajectory group and at follow-up. Increasing PA during late life (low PA-increasing group) was associated with lower incident disability rates (OR 0.38; 95% CI = 0.19-0.82) compared with decreasing PA (low PA-decreasing group), despite similar baseline PA. Our results suggest that sustaining higher PA levels during aging might lead to healthy aging, characterized by a reduction in adverse outcomes. Our study supports the need for enhancing PA participation among older populations, with the goal of reducing personal and economic burden in a worldwide aging population.

|keywords=* Adverse outcomes
* Healthy aging
* Mortality
* Older adults
* Physical activity
* Trajectories
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432572
}}
{{medline-entry
|title=U-Shaped Association of Plasma Testosterone, and no Association of Plasma Estradiol, with Incidence of Fractures in Men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32155267
|abstract=Whether androgens, distinct from estrogen, maintain bone health during male aging has implications for understanding osteoporosis. We assessed associations of different sex hormones with incidence of any bone fracture or hip fracture in older men. Analysis of 3307 community-dwelling men aged 76.8 ± 3.5 years, median follow-up period of 10.6 years. Plasma testosterone (T), dihydrotestosterone (DHT), and estradiol (E2) assayed by mass spectrometry, sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) using immunoassay. Incident fractures determined via data linkage. We analyzed probability of fracture and performed Cox regression adjusted for age, medical comorbidities, and frailty. Incident fractures occurred in 330 men, including 144 hip fractures. Probability plots suggested nonlinear relationships between hormones and risk of any fracture and hip fracture, with higher risk at lower and higher plasma T, lower E2, higher SHBG, and higher LH. In fully adjusted models, there was a U-shaped association of plasma T with incidence of any fracture (Quartile 2 [Q2] versus Q1: fully adjusted hazard ratio [[[HR]]] = 0.69, 95% confidence interval [CI] 0.51-0.94, P = .020; Q3: [[HR]] 0.59, 95% CI 0.42-0.83, P = .002) and hip fracture (Q2 versus Q1: [[HR]] 0.60, 95% CI 0.37-0.93, P = .043; Q3: [[HR]] 0.52, 95% CI 0.31-0.88, P = .015). DHT, E2, and LH were not associated with fracture. Higher SHBG was associated with hip fracture (Q4 versus Q1: [[HR]] 1.76, 95% CI 1.05-2.96, P = .033). Midrange plasma T was associated with lower incidence of any fracture and hip fracture, and higher SHBG with increased risk of hip fracture. Circulating androgen rather than estrogen represents a biomarker for hormone effects on bone driving fracture risk.

|keywords=* estradiol
* fracture
* male aging
* osteoporosis
* sex hormone-binding globulin
* testosterone
|full-text-url=https://sci-hub.do/10.1210/clinem/dgaa115
}}
{{medline-entry
|title=Pregnancy-Related Bone Mineral and Microarchitecture Changes in Women Aged 30 to 45 Years.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32119748
|abstract=At birth, the neonatal skeleton contains 20 to 30 g calcium (Ca). It is hypothesized maternal bone mineral may be mobilized to support fetal skeletal development, although evidence of pregnancy-induced mineral mobilization is limited. We recruited healthy pregnant (n = 53) and non-pregnant non-lactating (NPNL; n = 37) women aged 30 to 45 years (mean age 35.4 ± 3.8 years) and obtained peripheral quantitative computed tomography (pQCT) and high-resolution pQCT ([[HR]]-pQCT) scans from the tibia and radius at 14 to 16 and 34 to 36 weeks of pregnancy, with a similar scan interval for NPNL. Multiple linear regression models were used to assess group differences in change between baseline and follow-up; differences are expressed as standard deviation scores (SDS) ± SEM. Decreases in volumetric bone mineral density (vBMD) outcomes were found in both groups; however, pregnancy-related decreases for pQCT total and trabecular vBMD were -0.65 ± 0.22 SDS and -0.50 ± 0.23 SDS greater (p < .05). [[HR]]-pQCT total and cortical vBMD decreased compared with NPNL by -0.49 ± 0.24 SDS and -0.67 ± 0.23 SDS, respectively; trabecular vBMD decreased in both groups to a similar magnitude. Pregnancy-related changes in bone microarchitecture significantly exceeded NPNL change for trabecular number (0.47 ± 0.23 SDS), trabecular separation (-0.54 ± 0.24 SDS), cortical thickness (-1.01 ± 0.21 SDS), and cortical perimeter (0.78 ± 0.23 SDS). At the proximal radius, cortical vBMD and endosteal circumference increased by 0.50 ± 0.23 SDS and 0.46 ± 0.23 SDS, respectively, compared with NPNL, whereas cortical thickness decreased -0.50 ± 0.22 SDS. Pregnancy-related decreases in total and compartment-specific vBMD exceed age-related change at the distal tibia. Changes at the radius were only evident with pQCT at the cortical-rich proximal site and suggest endosteal resorption. Although the magnitude of these pregnancy-related changes in the appendicular skeleton are small, if they reflect global changes across the skeleton at large, they may contribute substantially to the Ca requirements of the fetus. © 2020 Crown copyright. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article is published with the permission of the Controller of HMSO and the Queen's Printer for Scotland.

|keywords=* AGING
* ANALYSIS/QUANTITATION OF BONE
* BONE QCT/μCT
* EPIDEMIOLOGY
* GENERAL POPULATION STUDIES
|full-text-url=https://sci-hub.do/10.1002/jbmr.3998
}}
{{medline-entry
|title=Analysis of the world record time for combined father and son marathon.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31917623
|abstract=The aim of this study was to examine the physiological profiles and the pacing strategies of the father (59 yr old) and son (34 yr old) who broke the World Record time (4:59:22; father: 2:27:52, son: 2:31:30) for combined father and son marathon in 2019. Oxygen uptake (V̇o ), heart rate ([[HR]]), ventilation (V̇e), blood lactate concentration (La), and running economy (RE) were measured during treadmill-running tests. The total distance of the marathon was divided into eight sections of 5 km and one last section of 2.195 km, and the relative average running velocity on each section was calculated individually. V̇o , [[HR]] , V̇e , and La  were 65.4 mL·kg ·min , 165 beats/min, 115 L/min, 5.7 mmol/L for the father and 66.9 mL·kg ·min , 181 beats/min, 153 L/min, 11.5 mmol/L for the son, respectively. At 17 km/h, RE was 210 mL·kg ·km  for the father and 200 mL·kg ·km  for the son, and % V̇o  sustained was 90.9% for the father and 84.5% for the son, respectively. The father maintained an even running velocity during the marathon (running velocity CV <1%), while the son ran the second half-marathon 7% slower than the first one, and his running velocity markedly dropped from the 35th kilometer. Father and son who broke the World record time for combined father and son marathon had a similar level of performance, but their physiological profiles and pacing strategies during the marathon were different. A more even speed for the son could help them to improve their own record in the near future.  We provide novel data demonstrating that different physiological profiles can lead to the same level of performance in a marathon, even at different ages. The novelty of our study is that we report on the physiological characteristics, training routine, and in-race pacing strategy that allowed a father (59 yr old) and son (34 yr old) to break the World Record time for combined father and son marathon. The father also established a new World record marathon time for the age of 59.

|keywords=* V̇o2max
* aerobic exercise
* aging
* endurance
* oxygen consumption
* running
|full-text-url=https://sci-hub.do/10.1152/japplphysiol.00819.2019
}}
{{medline-entry
|title=Age-related reductions in heart rate variability do not worsen during exposure to humid compared to dry heat: A secondary analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31934605
|abstract=We conducted a secondary analysis to investigate whether age-related attenuations in heart rate variability ([[HR]]V) worsen during exposure to moderate, dry (36.5°C, 20% RH) or humid (36.5°C, 60% RH) heat conditions that resulted in greater body heat storage among older compared to young participants, and during humid compared to dry heat, regardless of age. Six [[HR]]V indices [heart rate ([[HR]]), coefficient of variation (CoV), detrended fluctuation analysis: α1, low frequency power, high frequency power, and low/high frequency ratio] were assessed in 10 young (21 ± 3 y) and 9 older (65 ± 5 y) adults for 15-min prior to (baseline), and at the end of a 120-min exposure to dry and humid heat while seated at rest. Our results demonstrated a condition (dry and humid) x time (baseline and end) interaction effect on [[HR]] (p = 0.047) such that [[HR]] gradually increased during humid heat exposure yet remained similar during dry heat exposure across groups. We also found an age-related attenuation in CoV at baseline for both the dry (young: 0.097 ± 0.023%; older: 0.054 ± 0.016%) and humid (young: 0.093 ± 0.034%; older: 0.056 ± 0.014%) heat conditions (p < 0.02). Those age-related attenuations in CoV, however, were not magnified throughout the exposure nor different between conditions (p > 0.05). While older adults stored more heat during a brief 120-min exposure to dry heat compared to their young counterparts, this was not paralleled by further age-related impairments in [[HR]]V even when body heat storage and cardiovascular strain were exacerbated by exposure to humid heat.

|keywords=* Aging
* autonomic nervous system
* heat stress
* parasympathetic nervous system
* relative humidity
* sympathetic nervous system
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949029
}}
{{medline-entry
|title=Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE-TIMI 58 Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31843945
|abstract=Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio ([[HR]]) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction [i]P[/i] value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with [[HR]] 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction [i]P[/i] value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with [[HR]] 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction [i]P[/i] value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction [i]P[/i] values 0.1058 and 0.8433, respectively). The overall efficacy and safety of dapagliflozin are consistent regardless of age.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Benzhydryl Compounds
* Cardiovascular System
* Diabetes Mellitus, Type 2
* Diabetic Ketoacidosis
* Female
* Glucosides
* Humans
* Hypoglycemia
* Hypoglycemic Agents
* Incidence
* Kidney
* Male
* Middle Aged
* Sodium-Glucose Transporter 2 Inhibitors
* Survival Analysis
* Treatment Outcome
* Urinary Tract Infections

|full-text-url=https://sci-hub.do/10.2337/dc19-1476
}}
{{medline-entry
|title=Validity of Prediction Equations of Maximal Heart Rate in Physically Active Female Adolescents and the Role of Maturation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31766291
|abstract=[i]Background and objectives[/i]: Maximal heart rate ([[HR]] ) is an important training and testing tool, especially in the context of evaluating intensity in exercise prescription; however, few studies have examined the validity of prediction equations of [[HR]]  in physically active female adolescents and the role of maturation level. Therefore, the aim of the present study was to examine the differences between measured and predicted [[HR]]  in a sample of physically active female adolescents. [i]Materials and Methods[/i]: Seventy-one selected volleyball players (age 13.3 ± 0.7 years, body mass 62.0 ± 7.2 kg, height 1.72 ± 0.06 m) performed a 20 m shuttle run endurance test, and the actual [[HR]]  was compared with Tanaka [[HR]]  ('208 - 0.7 × age') and Fox [[HR]]  ('220 - age'). [i]Results[/i]: A large main effect of assessment method on [[HR]]  was found ([i]p[/i] < 0.001, [i]η[/i]  = 0.486) with Fox overestimating actual [[HR]]  by 6.8 bpm (95% confidence intervals, CI; 4.2, 9.3) and Tanaka underestimating actual [[HR]]  by -2.6 bpm (95% CI; -5.1, -0.1). The more matured participants had similar actual [[HR]]  (mean difference -2.4 bpm; 95% CI; -6.5, 1.7; [i]p[/i] = 0.242, d = -0.28), difference Fox - actual [[HR]]  (1.5 bpm; 95% CI; -2.6, 5.6, [i]p[/i] = 0.466, d = 0.17), and difference Tanaka - actual [[HR]]  (1.7 bpm; 95% CI; -2.4, 5.8; [i]p[/i] = 0.414, d = 0.19) to the less matured participants. [i]Conclusions[/i]: These findings suggest that age-based prediction equations of [[HR]]  developed in adult populations should be applied with caution in physically active female adolescents, and Tanaka should be preferred instead of the Fox equation.
|mesh-terms=* Adolescent
* Aging
* Body Mass Index
* Exercise
* Exercise Test
* Female
* Heart Rate
* Humans
|keywords=* cardiac rate
* exercise prescription
* exercise testing
* prediction equations
* training zones
* volleyball
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915545
}}
{{medline-entry
|title=Base excision repair but not DNA double-strand break repair is impaired in aged human adipose-derived stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31782607
|abstract=The decline in DNA repair capacity contributes to the age-associated decrease in genome integrity in somatic cells of different species. However, due to the lack of clinical samples and appropriate tools for studying DNA repair, whether and how age-associated changes in DNA repair result in a loss of genome integrity of human adult stem cells remains incompletely characterized. Here, we isolated 20 eyelid adipose-derived stem cell (ADSC) lines from healthy individuals (young: 10 donors with ages ranging 17-25 years; old: 10 donors with ages ranging 50-59 years). Using these cell lines, we systematically compared the efficiency of base excision repair (BER) and two DNA double-strand break (DSB) repair pathways-nonhomologous end joining (NHEJ) and homologous recombination ([[HR]])-between the young and old groups. Surprisingly, we found that the efficiency of BER but not NHEJ or [[HR]] is impaired in aged human ADSCs, which is in contrast to previous findings that DSB repair declines with age in human fibroblasts. We also demonstrated that BER efficiency is negatively associated with tail moment, which reflects a loss of genome integrity in human ADSCs. Mechanistic studies indicated that at the protein level XRCC1, but not other BER factors, exhibited age-associated decline. Overexpression of XRCC1 reversed the decline of BER efficiency and genome integrity, indicating that XRCC1 is a potential therapeutic target for stabilizing genomes in aged ADSCs.
|mesh-terms=* Adipose Tissue
* Adult
* Aging
* DNA Breaks, Double-Stranded
* DNA End-Joining Repair
* DNA Repair
* Humans
* Middle Aged
* Recombinational DNA Repair
* Stem Cells
* Up-Regulation
* X-ray Repair Cross Complementing Protein 1
* Young Adult
|keywords=* XRCC1
* adipose-derived stem cells
* base excision repair
* genome integrity
* human aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996963
}}
{{medline-entry
|title=Urban-Rural Differences in Hip Fracture Mortality: A Nationwide NOREPOS Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31768493
|abstract=Higher hip fracture incidence in urban than in rural areas has been demonstrated, but urban-rural differences in posthip fracture mortality have been less investigated, and the results are disparate. Hence, the aims of the present register-based cohort study were to examine possible urban-rural differences in short- and long-term mortality in Norwegian hip fracture patients and their potential associations with sociodemographic variables, and to investigate possible urban-rural differences in excess mortality in hip fracture patients compared with the general population. Data were provided from the NOREPOS hip fracture database, the 2001 Population and Housing Census, and the National Registry. The urbanization degree in each municipality was determined by the proportion of inhabitants living in densely populated areas (rural: <1/3, semirural: 1/3 to 2/3, and urban: >2/3). Age-adjusted mortality rates and standardized mortality ratios were calculated for hip fracture patients living in rural, semirural, and urban municipalities. A flexible parametric model was used to estimate age-adjusted average and time-varying [[HR]]s by category of urbanization with the rural category as reference. Among 96,693 hip fracture patients, urban residents had higher mortality than their rural-dwelling counterparts. The [[HR]] of mortality in urban compared with rural areas peaked during the first 1 to 2 years postfracture with a maximum [[HR]] of 1.20 (95% CI, 1.10 to 1.30) in men and 1.15 (95% CI, 1.08 to 1.21) in women. The differences were significant during approximately 5 years after fracture. Adjusting for sociodemographic variables did not substantially change the results. However, absolute 30-day mortality was not significantly different between urban and rural residents, suggesting that health-care quality immediately postfracture does not vary by urbanization. The novel findings of a higher long-term mortality in urban hip fracture patients might reflect disparities in health status or lifestyle, differences in posthip fracture health care or rehabilitation, or a combination of several factors. © 2019 The Authors. [i]JBMR Plus[/i] published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

|keywords=* AGING
* EPIDEMIOLOGY
* GENERAL POPULATION STUDIES
* OSTEOPOROSIS
* STATISTICAL METHODS
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874178
}}
{{medline-entry
|title=Malnutrition as a Strong Predictor of the Onset of Sarcopenia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31783482
|abstract=This study aims to explore the association between malnutrition diagnosed according to both the Global Leadership Initiative of Malnutrition (GLIM) and the European Society of Clinical Nutrition and Metabolism (ESPEN) criteria and the onset of sarcopenia/severe sarcopenia, diagnosed according to the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criterion, in the sarcopenia and physical impairment with advancing age (SarcoPhAge) cohort during a four-year follow-up. Adjusted Cox-regression and Kaplan-Meier curves were performed. Among the 534 community-dwelling participants recruited in the SarcoPhAge study, 510 were free from sarcopenia at baseline, of whom 336 had complete data (186 women and 150 men, mean age of 72.5 ± 5.8 years) to apply the GLIM and ESPEN criteria. A significantly higher risk of developing sarcopenia/severe sarcopenia during the four-year follow-up based on the GLIM [sarcopenia: Adjusted hazard ratio ([[HR]]) = 3.23 (95% confidence interval (CI) 1.73-6.05); severe sarcopenia: Adjusted [[HR]] = 2.87 (95% CI 1.25-6.56)] and ESPEN [sarcopenia: Adjusted [[HR]] = 4.28 (95% CI 1.86-9.86); severe sarcopenia: Adjusted [[HR]] = 3.86 (95% CI 1.29-11.54)] criteria was observed. Kaplan-Meier curves confirmed this relationship (log rank [i]p[/i] < 0.001 for all). These results highlighted the importance of malnutrition since it has been shown to be associated with an approximately fourfold higher risk of developing sarcopenia/severe sarcopenia during a four-year follow-up.
|mesh-terms=* Aged
* Aging
* Cohort Studies
* Female
* Humans
* Independent Living
* Male
* Malnutrition
* Proportional Hazards Models
* Prospective Studies
* Risk Factors
* Sarcopenia
|keywords=* EWGSOP2
* GLIM
* SarcoPhAge
* malnutrition
* sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950107
}}
{{medline-entry
|title=Acclimation to a thermoneutral environment abolishes age-associated alterations in heart rate and heart rate variability in conscious, unrestrained mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31776883
|abstract=Mice are among the most widely used translational models of cardiovascular aging and offer a method to quickly assess lifespan changes in a controlled environment. The standard laboratory temperature (20-22 °C), however, imposes a cold stress on mice that causes an increase in sympathetic nervous system-mediated activation of brown adipose tissue (BAT) to maintain a core body temperature of 36-37 °C. Thus, while physiologic data obtained recapitulate human physiology to a certain degree, interpretations of previous research in mice may have been contaminated by a cold stress, due to housing mice below their thermoneutral zone (30 °C). The purpose of this investigation was to examine how chronic sympathetic stimulation evoked by acclimation to 20 °C might obscure interpretation of changes in autonomic modulation of heart rate ([[HR]]) and heart rate variability ([[HR]]V) that accompany advancing age. [[HR]] and [[HR]]V before and after administration of a dual-autonomic blockade were measured via in-vivo ECG in young (3 months) and aged (30 months) male C57BL/6 telemetry-implanted mice following temperature acclimation for 3 days at 30 °C or 20 °C. Mean basal and intrinsic [[HR]] of both young and aged mice became markedly reduced at 30 °C compared to 20 °C. In both age groups, [[HR]]V parameters in time, frequency, and non-linear domains displayed increased variability at 30 °C compared to 20 °C under basal conditions. Importantly, age-associated declines in [[HR]]V observed at 20 °C were ameliorated when mice were studied at their thermoneutral ambient temperature of 30 °C. Thus, an accurate understanding of autonomic modulation of cardiovascular functions in mice of advanced age requires that they are housed in a metabolically neutral environment.

|keywords=* Aging
* Cardiac autonomic modulation
* Heart rate
* Heart rate variability
* Thermoneutrality
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031176
}}
{{medline-entry
|title=Long-term dementia risk prediction by the LIBRA score: A 30-year follow-up of the CAIDE study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31736136
|abstract=As no causal treatment for dementia is available yet, the focus of dementia research is slowly shifting towards prevention strategies. Therefore, this study aimed to examine the predictive accuracy of the "LIfestyle for BRAin Health" (LIBRA) score, a weighted compound score of 12 modifiable risk and protective factors, for dementia and mild cognitive impairment (MCI) in midlife and late-life, and in individuals with high or low genetic risk based on presence of the apolipoprotein (APOE) ε4 allele. The LIBRA score was calculated for participants from the Finnish Cardiovascular Risk Factors, Aging and Dementia (CAIDE) population-based study examined in midlife (n = 1024) and twice in late-life (n = 604) up to 30 years later. Diagnoses of MCI and dementia were made according to established criteria. Cox proportional hazards models were used to assess the association between LIBRA and risk of dementia and MCI in models adjusted for sex and education (age as timescale). Higher midlife LIBRA scores were related to higher risk of dementia (hazard ratio [[[HR]]] = 1.27; 95% confidence interval [CI], 1.13-1.43) and MCI (unadjusted model: [[HR]] = 1.12; 95% CI, 1.03-1.22) up to 30 years later. Higher late-life LIBRA scores were related to higher risk of MCI ([[HR]] = 1.11; 95% CI, 1.00-1.25), but not dementia ([[HR]] = 1.02; 95% CI, 0.84-1.24). Higher late-life LIBRA scores were related to higher dementia risk among apolipoprotein E (APOE) ε4 non-carriers. Findings emphasize the importance of modifiable risk and protective factors for dementia prevention.
|mesh-terms=* Aged
* Apolipoproteins E
* Cognitive Dysfunction
* Dementia
* Female
* Follow-Up Studies
* Genetic Predisposition to Disease
* Humans
* Life Style
* Male
* Protective Factors
* Risk Assessment
* Risk Factors
|keywords=* cognitive aging
* cohort study
* dementia
* epidemiology
* lifestyle
* prevention
* risk factors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003764
}}
{{medline-entry
|title=Kidney function and its association to imminent, short- and long-term fracture risk-a longitudinal study in older women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31754754
|abstract=Reduced kidney function is associated with an increased fracture risk, although the relationship between an age-related decline and fractures needs further investigation. We followed kidney function and fracture risk for 10 years. A mild-moderate decline in kidney function was associated with fracture, but not in advanced age. With age, kidney function declines. Though well known that chronic kidney disease is associated with increased fracture risk, the extent to which the typical age-related decline contributes is unclear. In the OPRA cohort, a longitudinal study of older non-selected women, we investigated the association between kidney function and fracture. Cystatin C-based kidney function estimates were available at age 75 (n = 981) and 80 (n = 685). Women were categorized by kidney function: normal (CKD stages 1 and 2), mild-moderate (3a), poor (3b-5), and imminent, short- and long-term fracture risk investigated. BMD measurements and kidney function for risk prediction were also evaluated; women were categorized by both reduced kidney function (stages 3-5) and osteoporosis status. In the short term, 2-3 years, mild-moderate kidney dysfunction was associated with the highest risk increase: osteoporotic fractures (2 years [[HR]]  2.21, 95% CI 1.27-3.87) and also up to 5 years (between 75 and 80 years) ([[HR]]  1.51, 1.04-2.18). Hip fracture risk was similarly increased. This association was not observed from age 80 nor for women with poorest kidney function. Reduced kidney function was associated with higher risk even without osteoporosis (osteoporotic fracture; [[HR]]  1.66, 1.08-2.54); risk increased by having both osteoporosis and reduced function ([[HR]]  2.53, 1.52-4.23). Older women with mild-moderate reduction of kidney function are at increased risk of fractures, but not those with the worst function. Our findings furthermore confirm the value of osteoporosis assessment and it is possible that in this age group, age-related decline of kidney function has limited contribution compared with BMD.

|keywords=* Aging
* Bone mineral density
* Chronic kidney disease
* Estimated glomerular filtration rate
* Fracture
* Women
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946753
}}
{{medline-entry
|title=Oxidatively Damaged DNA/RNA and 8-Isoprostane Levels Are Associated With the Development of Type 2 Diabetes at Older Age: Results From a Large Cohort Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31653645
|abstract=Oxidative stress is believed to play an important role in the pathophysiology of type 2 diabetes, but the few cohort studies that have assessed the association of oxidative stress biomarkers with type 2 diabetes incidence were small and reported inconclusive results. We examined the associations of urinary oxidized guanine/guanosine (OxGua) levels (a biomarker of DNA/RNA oxidation) and urinary 8-isoprostane levels (a biomarker of lipid peroxidation) with type 2 diabetes incidence in 7,828 individuals initially without diabetes from a population-based German cohort study with 14 years of follow-up. Hazard ratios ([[HR]]s) (95% CIs) per 1 SD were obtained using multivariable-adjusted Cox proportional hazards regression models. In the total population, weak but statistically significant associations with type 2 diabetes incidence were observed for OxGua levels ([[HR]] [95% CI] per 1 SD 1.05 [1.01; 1.09]) and 8-isoprostane levels (1.04 [1.00; 1.09]). Stratified analyses showed that associations of both biomarkers with type 2 diabetes incidence were absent in the youngest age-group (50-59 years) and strongest in the oldest age-group (65-75 years) of the cohort, with [[HR]] of OxGua levels 1.14 (1.05; 1.23) per 1 SD and of 8-isoprostane levels 1.22 (1.02; 1.45) per 1 SD. These results from a large cohort study support suggestions that an imbalanced redox system contributes to the development of type 2 diabetes but suggest that this association becomes clinically apparent at older ages only, possibly as a result of reduced cellular repair capacity.
|mesh-terms=* Age of Onset
* Aged
* Aging
* Biomarkers
* Cohort Studies
* DNA
* DNA Damage
* Diabetes Mellitus, Type 2
* Dinoprost
* Female
* Follow-Up Studies
* Germany
* Humans
* Incidence
* Lipid Peroxidation
* Male
* Middle Aged
* Oxidation-Reduction
* Oxidative Stress
* RNA

|full-text-url=https://sci-hub.do/10.2337/dc19-1379
}}
{{medline-entry
|title=Associations of vigorous physical activity with all-cause, cardiovascular and cancer mortality among 64 913 adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31548909
|abstract=Physical activity recommendations state that for the same energy expenditure, moderate-to-vigorous physical activities (MVPAs) produce similar health benefits. However, few epidemiological studies have tested this hypothesis. We examined whether, compared with moderate, vigorous activity was associated with larger mortality risk reductions. Data from 11 cohorts of the Health Survey for England and the Scottish Health Survey, collected from 1994 to 2011 (mean (SD) follow-up, 9.0 (3.6) years). Adults aged ≥30 years reported MVPA and linkage to mortality records. Exposure was the proportion of self-reported weighted MVPA through vigorous activity. Outcomes were all-cause, cardiovascular disease (CVD) and cancer mortality. Among 64 913 adult respondents (44% men, 56% women, mean (SD) age, 49.8 (13.6) years), there were 5064 deaths from all-causes, 1393 from CVD and 1602 from cancer during 435 743 person-years of follow-up. Compared with those who reported no vigorous physical activity, and holding constant the volume of weighted MVPA, vigorous activity was associated with additional reductions in mortality risk. For all-cause mortality, the adjusted [[HR]] was [[HR]]=0.84 (95% CI 0.71, 0.99) and [[HR]]=0.84 (95% CI 0.76, 0.94) among those who reported between >0% and<30%, or ≥30% of their activity as vigorous, respectively. For CVD and cancer mortality, point estimates showed similar beneficial associations yet CIs were wider and crossed unity. Vigorous activities were associated with larger reductions in mortality risk than activities of moderate intensity, but no evidence of dose-response effects was found.

|keywords=* cardio-protection
* exercise
* longevity
* non-communicable diseases
* physical activity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733336
}}
{{medline-entry
|title=Reduced cerebrovascular and cardioventilatory responses to intermittent hypoxia in elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31557538
|abstract=The impact of aging on cerebrovascular function and tissue oxygenation during graded hypoxemia is incompletely known. This study compared the age effect on these variables during cyclic hypoxemia-reoxygenation. Hypoxia-induced changes in arterial (SaO ) and cerebral tissue (ScO ) O  saturation, middle cerebral arterial flow velocity (V ), estimated cerebral vascular conductance (CVC), heart rate ([[HR]]) and ventilation were compared between 12 elderly (71 ± 2 yr, 7 women) and 13 young (24 ± 3 yr, 5 women) adults during the first and fifth 5-min exposures to 10% O . Although pre-hypoxia SaO  did not differ between the groups, ScO  was lower (P < 0.05) in the elderly (68.4 ± 1.2%) than young (73.8 ± 0.9%) adults, commensurate with a lower resting V  (P < 0.05). SaO  fell less sharply (P < 0.05) in the elderly subjects during the first and fifth hypoxia exposures. Moreover, the responses of ScO , V , CVC, [[HR]] and breathing frequency to hypoxia were attenuated in the elderly subjects. Systolic and diastolic arterial pressures fell by 2-6 mmHg during hypoxia in both young and elderly. Thus, hypoxemia developed more gradually in elderly than young adults during normobaric hypoxia, concordant with a reduced metabolic demand in the elderly. The elderly adults safely tolerated cyclic, moderate hypoxemia which lowered SaO  by 20-25%, despite dampening of cerebrovascular and cardiac responses to hypoxemia.
|mesh-terms=* Adult
* Aged
* Aging
* Blood Pressure
* Brain
* Cerebrovascular Circulation
* Female
* Heart Rate
* Humans
* Hypoxia
* Male
* Pulmonary Ventilation
* Ultrasonography, Doppler, Transcranial
* Young Adult
|keywords=* Aging
* Arterial oxygen saturation
* Cerebral blood flow
* Cerebral tissue oxygenation
* Heart rate
* Hypoxemia
* Ventilation
|full-text-url=https://sci-hub.do/10.1016/j.resp.2019.103306
}}
{{medline-entry
|title=Vestibulo-sympathetic reflex in patients with bilateral vestibular loss.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31513442
|abstract=This study assessed cardiovascular control during head-down neck flexion (HDNF) in a group of patients suffering from total bilateral idiopathic vestibular loss (BVL) for 7 ± 2 yr. Nine adult patients (age 54 ± 6 yr) with BVL were recruited. Calf blood flow (CBF), mean arterial pressure (MAP), and heart rate ([[HR]]) were measured with subjects' eyes closed in two lying body positions: ventral prone (VP) and lateral (LP) on the left side. Vascular resistance (CVR) was calculated as MAP/CBF. The HDNF protocol consisted in passively changing the head position: head up (HU)-head down (HD)-HU. Measurements were taken twice at each head position. In VP CBF significantly decreased in HD (3.65 ± 0.65 mL·min ·100 mL ) vs. HU (4.64 ± 0.71 mL·min ·100 mL ) ([i]P[/i] < 0.002), whereas CVR in VP significantly rose in HD (31.87 ± 6.93 arbitrary units) vs. HU (25.61 ± 6.36 arbitrary units) ([i]P[/i] < 0.01). In LP no change in CBF or CVR was found between the two head positions. MAP and [[HR]] presented no difference between HU and HD in both body positions. Age of patients did not significantly affect the results. The decrease in CBF of the BVL patients was similar to the decrease observed with the same HDNF protocol in normal subjects. This suggests a sensory compensation for the lost vestibular inputs that could originate from the integration of inputs from trunk graviceptors and proprioceptive and cutaneous receptors. Another possibility is that the HDNF vascular effect is evoked mostly by nonlabyrinthine sensors.  The so-called vestibulo-sympathetic reflex, as demonstrated by the head-down neck flexion (HDNF) protocol, is present in patients with total bilateral vestibular idiopathic loss, equally in young and old subjects. The origin of the sympathetic effect of HDNF is questioned. Moreover, the physiological significance of the vestibulo-sympathetic reflex remains obscure, because it acts in opposition to the orthostatic baroreflex. It may serve to inhibit the excessively powerful baroreflex.
|mesh-terms=* Aging
* Bilateral Vestibulopathy
* Female
* Humans
* Male
* Middle Aged
* Reflex, Abnormal
* Sympathetic Nervous System
|keywords=* bilateral vestibular loss
* compensation
* multisensory integration
* otolithic system
* vestibulo-sympathetic reflex
|full-text-url=https://sci-hub.do/10.1152/japplphysiol.00466.2019
}}
{{medline-entry
|title=Heart rate and blood pressure in male Ts65Dn mice: a model to investigate cardiovascular responses in Down syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31496136
|abstract=Down syndrome (Ds) is the most common chromosomal cause of intellectual disability that results from triplication of chromosome 21 genes. Lower blood pressure (BP) and heart rate ([[HR]]) in response to exercise and other stressors are prevalent in Ds, and are mediated by autonomic dysfunction. The Ts65Dn mouse is a model of Ds that is commonly used in preclinical studies, but has not been formally investigated for cardiovascular responses in conscious mice. Based on human studies of Ds, we hypothesized Ts65Dn would have lower BP and [[HR]], but similar arterial stiffness. BP was quantified in conscious wild-type (WT) and Ts65Dn. A main effect for strain was observed for all BP measures (systolic, diastolic, mean, pulse pressure), with WT higher than Ts65Dn. Pulse wave velocity was similar between WT and Ts65Dn. High-frequency power spectra was higher in WT suggesting autonomic differences between strains. Freely moving [[HR]] was higher in WT versus Ts65Dn in both the dark and light cycles, although a main effect of circadian cycle was also present (dark> light). Similar to what is observed in humans, Ts65Dn has a lower BP which may be attributed to autonomic differences and result in preservation of arterial function with advancing age. Ts65Dn thus appears to capture the Ds cardiovascular phenotype across the lifespan. These data support further use of Ts65Dn to investigate mechanisms that may lead to altered BP and [[HR]] responses in Ds.
|mesh-terms=* Animals
* Autonomic Nervous System
* Blood Pressure
* Circadian Rhythm
* Down Syndrome
* Heart Rate
* Male
* Mice
* Mice, Inbred C57BL
* Vascular Stiffness
|keywords=* Aging
* arterial stiffness
* autonomic nervous system
* circadian
* pulse wave velocity
* spectral analysis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732568
}}
{{medline-entry
|title=Body weight at 10 years of age and change in body composition between 8 and 10 years of age were related to survival in a longitudinal study of 39 Labrador retriever dogs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31500653
|abstract=Overweight and obesity have been adversely associated with longevity in dogs but there is scarce knowledge on the relation between body composition and lifespan. We aimed to investigate the effects of body composition, and within-dog changes over time, on survival in adult Labradors using a prospective cohort study design. The dogs had a median age of 6.5 years at study start and were kept in similar housing and management conditions throughout. The effects of the various predictors, including the effect of individual monthly-recorded change in body weight as a time varying covariate, were evaluated using survival analysis. All dogs were followed to end-of-life; median age at end-of-life was 14.0 years. Body composition was measured annually with dual-energy x-ray absorptiometer (DEXA) scans between 6.2 and 17.0  years. All 39 dogs had DEXA recorded at 8, 9 and 10 years of age. During the study the mean (± SD) percent of fat (PF) and lean mass (PL) was 32.8 (± 5.6) and 64.2 (± 5.5) %, respectively, with a mean lean:fat ratio (LFR) of 2.1 (± 0.6); body weight (BW) varied from 17.5 to 44.0 kg with a mean BW change of 9.9 kg (± 3.0). There was increased hazard of dying for every kg increase in BW at 10 years of age; for each additional kg of BW at 10 years, dogs had a 19% higher hazard ([[HR]] = 1.19, P = 0.004). For the change in both lean mass (LM) and LFR variables, it was protective to have a higher lean and/or lower fat mass (FM) at 10 years of age compared to 8 years of age, although the [[HR]] for change in LM was very close to 1.0. For age at study start, older dogs had an increased hazard. There was no observed effect for the potential confounders sex, coat colour and height at shoulders, or of the time-varying covariate. These results suggest that even rather late-life control efforts on body weight and the relationship between lean and fat mass may influence survival in dogs. Such "windows of opportunity" can be used to develop healthcare strategies that would help promote an increased healthspan in dogs.
|mesh-terms=* Adipose Tissue
* Animals
* Body Composition
* Body Weight
* Dogs
* Longevity
* Longitudinal Studies
* Survival Analysis
|keywords=* Cohort
* Cox
* DEXA
* Dogs
* Fat mass
* Healthspan
* Lean mass
* Lean to fat ratio
* Longevity
* Sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734441
}}
{{medline-entry
|title=Dietary diversity offsets the adverse mortality risk among older indigenous Taiwanese.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31464406
|abstract=The extent to which health and survival inequality between indigenous and nonindigenous older Taiwanese is associated with diet is uncertain. Participants from the Elderly Nutrition and Health Survey in Taiwan (1999-2000) formed this cohort. Dietary information was collected by 24-hr recall and simplified food frequency questionnaire. Dietary quality was assessed by dietary diversity score (DDS, 0-6). Annual medical service utilization and expenditure were derived from National Health Insurance claims until 2006. Survivorship was ascertained from the National Death Registry until 2008. Cox proportional- hazards models were used to determine the association between aboriginality and mortality in conjunction with dietary diversity. Indigenes (n=156) compared with nonindigenes (n=1182) significantly differed in socio-demography, behaviors and chronic disease prevalences. For up to 8 years, indigenes had a higher mortality rate (46.2% vs 33.6%, p=0.003). Indigenes' nutrient intakes were less for polyunsaturated fat, dietary fiber, vitamins and minerals (but more sodium); food intakes more for meat, with less cooking oil, dairy products and fruits; and a lower DDS, (3.61 vs 4.54). They had a 41% higher mortality risk ([[HR]]: 1.41, 95% CI: 1.09-1.81, p=0.008). Control for demographic variables did not change the findings. However, the increase in [[HR]] was substantially attenuated by the inclusion of DDS ([[HR]]: 1.15, 95% CI: 0.88-1.49, p=0.316). There was no significant interaction between aboriginality and DDS on mortality (p=0.673). Older indigenous Taiwanese have a higher mortality risk than their majority counterparts. Irrespective of aboriginality, the more diverse diet is associated with a lower risk of mortality.
|mesh-terms=* Aged
* Aged, 80 and over
* Asian Continental Ancestry Group
* Diet
* Female
* Health Surveys
* Humans
* Indigenous Peoples
* Longevity
* Male
* Mortality
* Nutrition Surveys
* Nutritional Status
* Risk Factors
* Taiwan

|full-text-url=https://sci-hub.do/10.6133/apjcn.201909_28(3).0019
}}
{{medline-entry
|title=Independent and joint effects of vascular and cardiometabolic risk factor pairs for risk of all-cause dementia: a prospective population-based study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31455442
|abstract=To assess independent and joint effects of pairs of vascular and cardiometabolic risk factors (VCMRFs) in relation to risk of all-cause dementia. Population-based longitudinal cohort study of cognitive impairment. We used an algorithm to select pairs of VCMRFs and tested their joint effects in time-dependent Cox models. We used attributable proportions (AP) to measure the proportion of risk from interactions beyond any additive effect. Economically depressed small-town population. Adults age 65+ years with up to 10 yearly study visits (N=1701, median (Q1, Q3) age, 78 (71.0, 83.0), 62.3% female, 94.9% white). Among 1701 participants free from prevalent dementia with at least one follow-up visit, 109 developed incident all-cause dementia. In pairings of APOE*4 with hypertension (HTN) and congestive heart failure (CHF), the variables contributed independently and additively to all-cause dementia risk. In pairings of APOE*4 with stroke and stroke with CHF, the variables demonstrated independent contributions to all-cause dementia risk; their joint effects showed excess detriment demonstrating synergistic interactions (joint [[HR]] [95% CI]: 28.33 [6.74, 119.01] and 50.30 [14.57, 173.57] respectively, fully adjusted models). Physical activity (PA) was independently associated with lower all-cause dementia risk when paired with APOE*4, stroke, and CHF in unadjusted models; these associations did not survive covariate adjustment. The joint effect of low PA and APOE*4 was associated with additively increased all-cause dementia risk (joint [[HR]] [95% CI]: 4.61 [2.07, 10.23], fully adjusted model). Reduction of VCMRFs, including low PA, could be valuable for dementia prevention, especially among APOE*4 carriers.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Apolipoprotein E4
* Cognitive Dysfunction
* Dementia
* Exercise
* Female
* Heart Failure
* Heterozygote
* Humans
* Hypertension
* Male
* Pennsylvania
* Proportional Hazards Models
* Prospective Studies
* Risk Factors
* Stroke
|keywords=* Alzheimer‘s disease (AD)
* apolipoprotein E (APOE)
* cerebral vascular disease (CVD)
* dementia
* epidemiology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948010
}}
{{medline-entry
|title=Work Ability and Job Survival: Four-Year Follow-Up.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31466415
|abstract=Employees with impaired work ability might be at higher risk of remaining shorter in the job than those with adequate work ability. The aim of the study was to establish whether work ability plays a role in job survival. Four-year follow-up (2008-2012) study of 1037 employees of a hospital in São Paulo, Brazil. Work ability was categorized as "adequate" or "impaired". Employment status at the end of follow-up was categorized as active, resignation or dismissal. Survival analysis was performed using the Kaplan-Meier method and the Cox proportional-hazards model. About 78.9% of the participants had adequate and 21.1% impaired work ability. Job survival was longer for the participants with adequate work ability independently from the type of job termination ([i]p[/i] < 0.001). The odds of job termination were higher for the participants with impaired work ability ([i]p[/i] < 0.001) who either resigned (hazard ratio-[[HR]] = 1.58) or were dismissed ([[HR]] = 1.68). Job survival was shorter for the employees with impaired work ability independently from the type of job termination. It was also shorter for the employees who were dismissed compared to those who resigned. Duration in the job might be extended through actions to enhance work ability.
|mesh-terms=* Adult
* Brazil
* Employment
* Female
* Follow-Up Studies
* Hospitals
* Humans
* Male
* Proportional Hazards Models
* Work Capacity Evaluation
|keywords=* aging
* healthcare worker
* life course
* longitudinal studies
* prolonged work career
* work ability
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747402
}}
{{medline-entry
|title=Predictivity of bioimpedance phase angle for incident disability in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31436391
|abstract=Bioelectrical impedance analysis (BIA)-derived phase angle is expected to be an efficient prognostic marker of health adverse events with aging as an alternative of muscle mass. We aimed to examine the predictive ability of phase angle for incident disability in community-dwelling elderly and determine the optimal cut-off values. Community-dwelling elderly aged ≥65 years (n = 4452; mean age = 71.8 ± 5.3 years, 48.3% women) without disability at baseline participated in this prospective cohort study. Phase angle and appendicular skeletal muscle mass (ASM) were examined using a multi-frequency BIA at baseline. Other potential confounding factors (demographics, cognitive function, depressive symptoms, medications, and physical performance) were also assessed. Incident disability was monitored on the basis of long-term care insurance certification. Over a follow-up of 24 months, 4.0% (n = 174) experienced disability, with an overall incidence rate of 20.6 per 1000 person-years. The Cox hazard regression analysis showed that phase angle, as a continuous variable, was independently associated with incident disability after adjusting the covariates [male: hazard ratios ([[HR]]s) = 0.61, 95% confidence interval (CI) = 0.37-0.98; female: [[HR]] = 0.58, 95% CI = 0.37-0.90], although body mass index adjusted ASM was not. Receiver operating characteristic analysis indicated moderate predictive abilities of phase angle for incident disability [male: area under the receiver operating characteristic curve (AUC) = 0.76, 95% CI = 0.70-0.83; female: AUC = 0.71, 95% CI = 0.65-0.76], while those of body mass index adjusted ASM were low (male: AUC = 0.59, 95% CI = 0.521-0.66; female: AUC = 0.58, 95% CI = 0.52-0.63). Multivariate Cox regression analysis showed that low phase angle categorized by cut-off value (male, ≤4.95°; female, ≤4.35°) was independently related to increased risk of incident disability ([[HR]] = 1.95, 95% CI = 1.37-2.78). Lower phase angle independently predicts the incident disability separately from known risk factors. BIA-derived phase angle can be used as a valuable and simple prognostic tool to identify the elderly at risk of disability as targets of preventive treatment.

|keywords=* Aging
* Body composition
* Cellular health
* Muscle mass
* Nutrition
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015240
}}
==APOE==

{{medline-entry
|title=Polygenic risk score of longevity predicts longer survival across an age-continuum.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33216869
|abstract=Studying the genome of centenarians may give insights into the molecular mechanisms underlying extreme human longevity and the escape of age-related diseases. Here, we set out to construct polygenic-risk-scores (PRS) for longevity and to investigate the functions of longevity-associated variants. Using a cohort of centenarians with maintained cognitive health (N=343), a population-matched cohort of older-adults from five cohorts (N=2905), and summary statistics data from a GWAS on parental longevity, we constructed a PRS including 330 variants that significantly discriminated between centenarians and older-adults. This PRS was also associated with longer survival in an independent sample of younger individuals, (p=0.02), leading up to a 4-year difference in survival based on common genetic factors only. We show that this PRS was, in part, able to compensate for the deleterious effect of the [[APOE]]-ε4 allele. Using an integrative framework, we annotated the 330 variants included in this PRS by the genes they associate with. We find that they are enriched with genes associated with cellular differentiation, developmental processes, and cellular response to stress. Together, our results indicate that an extended human lifespan is, in part, the result of a constellation of variants each exerting small advantageous effects on aging-related biological mechanisms that maintain overall health and decrease the risk of age-related diseases.

|keywords=* centenarians
* cognitive health
* genetics
* healthy aging
* longevity
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa289
}}
{{medline-entry
|title=Association Between [[APOE]] Alleles and Change of Neuropsychological Tests in the Long Life Family Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33216038
|abstract=The Long Life Family Study (LLFS) is a family based, prospective study of healthy aging and familial longevity. The study includes two assessments of cognitive function that were administered approximately 8 years apart. To test whether [[APOE]] genotype is associated with change of cognitive function in older adults. We used Bayesian hierarchical models to test the association between [[APOE]] alleles and change of cognitive function. Six longitudinally collected neuropsychological test scores were modelled as a function of age at enrollment, follow-up time, gender, education, field center, birth cohort indicator (≤1935, or >1935), and the number of copies of ɛ2 or ɛ4 alleles. Out of 4,587 eligible participants, 2,064 were male (45.0%), and age at enrollment ranged from 25 to 110 years, with mean of 70.85 years (SD: 15.75). We detected a significant cross-sectional effect of the [[APOE]]ɛ4 allele on Logical Memory. Participants carrying at least one copy of the ɛ4 allele had lower scores in both immediate (-0.31 points, 95% CI: -0.57, -0.05) and delayed (-0.37 points, 95% CI: -0.64, -0.10) recall comparing to non-ɛ4 allele carriers. We did not detect any significant longitudinal effect of the ɛ4 allele. There was no cross-sectional or longitudinal effect of the ɛ2 allele. The [[APOE]]ɛ4 allele was identified as a risk factor for poorer episodic memory in older adults, while the [[APOE]]ɛ2 allele was not significantly associated with any of the cognitive test scores.

|keywords=* APOE
* cognition
* longevity
* longitudinal studies
|full-text-url=https://sci-hub.do/10.3233/JAD-201113
}}
{{medline-entry
|title=The [[APOE]] gene cluster responds to air pollution factors in mice with coordinated expression of genes that differs by age in humans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33215813
|abstract=Little is known of gene-environment interactions for Alzheimer's disease (AD) risk factors. Apolipoprotein E ([[APOE]]) and neighbors on chromosome 19q13.3 have variants associated with risks of AD, but with unknown mechanism. This study describes novel links among the [[APOE]] network, air pollution, and age-related diseases. Mice exposed to air pollution nano-sized particulate matter (nPM) had coordinate responses of Apoe-Apoc1-Tomm40 in the cerebral cortex. In humans, the AD vulnerable hippocampus and amygdala had stronger age decline in [[APOE]] cluster expression than the AD-resistant cerebellum and hypothalamus. Using consensus weighted gene co-expression network, we showed that [[APOE]] has a conserved co-expressed network in rodent and primate brains. SOX1, which has AD-associated single nucleotide polymorphisms, was among the co-expressed genes in the human hippocampus. Humans and mice shared 87% of potential binding sites for transcription factors in [[APOE]] cluster promoter, suggesting similar inducibility and a novel link among environment, [[APOE]] cluster, and risk of AD.

|keywords=* Alzheimer's disease
* aging
* air pollution
* apolipoprotein E
* chromosome 19q13
|full-text-url=https://sci-hub.do/10.1002/alz.12230
}}
{{medline-entry
|title=Homozygosity in the [i][[APOE]][/i] 3 Polymorphism Is Associated With Less Depression and Higher Serum Low-Density Lipoprotein in Chinese Elderly Schizophrenics.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33178131
|abstract= Depressive symptoms are common comorbidities in schizophrenia. However, the effect of [[APOE]] E3 on depressive symptoms has never been investigated in an aging Chinese population with schizophrenia. This cross-sectional study aimed to investigate the effects of [[APOE]] E3 on blood lipid metabolism and depressive symptoms in elderly schizophrenics in China.   Three Hundred and one elderly schizophrenics (161 males, age ranges from 60 to 92 years, with an average age of 67.31 ± 6.667) were included in the study. Depressive symptoms were assessed using the Geriatric Depression Scale (GDS). [[APOE]] gene polymorphism was determined by polymerase chain reaction (PCR). We assessed the correlations of GDS and serum low-density lipoprotein (LDL) with [[APOE]] genotypes.   The concentration of LDL in the Homozygous [[APOE]] E3 group was significantly higher than that in the non-homozygous [[APOE]] E3 group, while the scores of GDS of the Homozygous [[APOE]] E3 group were lower than that in the non-homozygous [[APOE]] E3 group. Using partial correlation analysis and controlling age, gender, duration of disease, and hyperlipidemia, we found that the scores of GDS were significantly correlated with LDL ([i]r[/i] = -0.194, [i]p[/i] = 0.016).   [[APOE]] E3 is associated with less depressive symptoms and higher serum LDL in Chinese elderly patients with schizophrenia, and there is a negative correlation between depressive symptoms and LDL.

|keywords=* APOE E3
* Chinese
* aging
* depressive symptom
* schizophrenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7593819
}}
{{medline-entry
|title=Effect of apolipoprotein E polymorphism on cognition and brain in the Cambridge Centre for Ageing and Neuroscience cohort.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33088920
|abstract=Polymorphisms in the apolipoprotein E ([[APOE]]) gene have been associated with individual differences in cognition, brain structure and brain function. For example, the ε4 allele has been associated with cognitive and brain impairment in old age and increased risk of dementia, while the ε2 allele has been claimed to be neuroprotective. According to the 'antagonistic pleiotropy' hypothesis, these polymorphisms have different effects across the lifespan, with ε4, for example, postulated to confer benefits on cognitive and brain functions earlier in life. In this stage 2 of the Registered Report - https://osf.io/bufc4, we report the results from the cognitive and brain measures in the Cambridge Centre for Ageing and Neuroscience cohort (www.cam-can.org). We investigated the antagonistic pleiotropy hypothesis by testing for allele-by-age interactions in approximately 600 people across the adult lifespan (18-88 years), on six outcome variables related to cognition, brain structure and brain function (namely, fluid intelligence, verbal memory, hippocampal grey-matter volume, mean diffusion within white matter and resting-state connectivity measured by both functional magnetic resonance imaging and magnetoencephalography). We found no evidence to support the antagonistic pleiotropy hypothesis. Indeed, Bayes factors supported the null hypothesis in all cases, except for the (linear) interaction between age and possession of the ε4 allele on fluid intelligence, for which the evidence for faster decline in older ages was ambiguous. Overall, these pre-registered analyses question the antagonistic pleiotropy of [[APOE]] polymorphisms, at least in healthy adults.

|keywords=* Cognition
* ageing
* apolipoprotein E
* brain
* lifespan
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545750
}}
{{medline-entry
|title=Cardiovascular risk factors and [[APOE]]-ε4 status affect memory functioning in aging via changes to temporal stem diffusion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33070365
|abstract=Prior research investigating associations between hypertension, obesity, and apolipoprotein ([[APOE]]) genotype status with memory performance among older adults has yielded inconsistent results. This may reflect, in part, a lack of first accounting for the effects these variables have on structural brain changes, that in turn contribute to age-related memory impairment. The current study sought to clarify the relationships between these factors via path modeling. We hypothesized that higher body mass index (BMI), hypertension, and being an [[APOE]]-ε4 allele carrier would predict poorer memory scores, with much of these effects accounted for by indirect effects operating via differences in the integrity of temporal stem white matter. Participants included 125 healthy older adults who underwent neuropsychological assessment and diffusion-weighted MRI scanning. Direct effects were found for hypertension and demographic variables including age, sex, and education. Importantly, indirect effects were found for BMI, hypertension, [[APOE]]-ε4 status, age, and sex, where these factors predicted memory scores via their impact on temporal stem diffusion measures. There was also a dual effect of sex, with a direct effect indicating that females had better memory performance overall, and an indirect effect indicating that females with greater temporal stem diffusion had poorer memory performance. Results suggest that changes to the integrity of temporal white matter in aging may underpin reduced memory performance. These results highlight that accounting for variables that not only directly impact cognition, but also for those that indirectly impact cognition via structural brain changes, is crucial for understanding the impact of risk factors on cognition.

|keywords=* APOE
* BMI
* RRID:SCR_001398
* RRID:SCR_002403
* RRID:SCR_002823
* RRID:SCR_002865
* RRID:SCR_007037
* aging
* diffusion tensor imaging
* hypertension
* memory
* path modeling
|full-text-url=https://sci-hub.do/10.1002/jnr.24734
}}
{{medline-entry
|title=[[APOE]] [i]ε[/i]4 and resting-state functional connectivity in racially/ethnically diverse older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32999914
|abstract=Numerous neuroimaging studies demonstrated an association between the apolipoprotein E ([[APOE]]) [i]ε[/i]4 allele and resting-state functional connectivity (rsFC) of regions within the default mode network (DMN), both in healthy populations and patients with AD. It remains unclear whether the [[APOE]] [i]ε[/i]4 allele differentially affects the brain's functional network architecture across race/ethnicity. We investigated rsFC within DMN subsystems in 170 [[APOE]] [i]ε[/i]4 carriers compared to 387 [[APOE]] [i]ε[/i]4 non-carriers across three major racial/ethnic groups, including non-Hispanic Whites (n = 166), non-Hispanic Blacks (n = 185), and Hispanics (n = 206) from the Washington Heights-Inwood Columbia Aging Project. Compared to [[APOE]] [i]ε[/i]4 non-carriers, [[APOE]] [i]ε[/i]4 carriers had lower rsFC in temporal DMN, but only in non-Hispanic Whites. Non-Hispanic Black and Hispanic [[APOE]] [i]ε[/i]4 carriers had slightly higher or similar rsFC compared with non-Hispanic White [[APOE]] [i]ε[/i]4 non-carriers. These findings suggest that [[APOE]] [i]ε[/i]4 modulates DMN rsFC differently in non-Hispanic Whites compared with non-Hispanic Blacks and Hispanics.

|keywords=* APOE ε4 differences
* brain aging
* dementia
* neuroimaging
* racial/ethnic differences
* resting‐state functional connectivity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508460
}}
{{medline-entry
|title=Predictors of Olfactory Decline in Aging: A Longitudinal Population-Based Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32886741
|abstract=Olfactory dysfunction is common in aging and associated with dementia and mortality. However, longitudinal studies tracking change in olfactory ability are scarce. We sought to identify predictors of interindividual differences in rate of olfactory identification change in aging. Participants were 1780 individuals, without dementia at baseline and with at least 2 olfactory assessments over 12 years of follow-up (mean age = 70.5 years; 61.9% female), from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Odor identification was assessed with the Sniffin' Sticks. We estimated the impact of demographic, health, and genetic factors on rate of olfactory change with linear mixed effect models. Advancing age, manufacturing profession, history of cerebrovascular disease, higher cardiovascular disease burden, diabetes, slower walking speed, higher number of medications, and the [[APOE]] ε4 allele were associated with accelerated odor identification decline (ps < .014). Multi-adjusted analyses showed unique associations of age, diabetes, and ε4 to olfactory decline (ps < .017). In 1531 participants who remained free of dementia (DSM IV criteria) during follow-up, age, cardiovascular disease burden, and diabetes were associated with accelerated decline (ps < .011). Of these, age and diabetes remained statistically significant in the multi-adjusted model (ps < .001). Demographic, vascular, and genetic factors are linked to rate of decline in odor identification in aging. Although some olfactory loss may be an inevitable part of aging, our results highlight the importance of vascular factors for the integrity of the olfactory system, even in the absence of dementia.

|keywords=*  Cognitive aging
* Epidemiology
* Olfactory
* Olfactory impairment
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662159
}}
{{medline-entry
|title=When Culture Influences Genes: Positive Age Beliefs Amplify the Cognitive-Aging Benefit of [[APOE]] ε2.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32835364
|abstract=Most studies of aging cognition have focused on risk factors for worse performance and on either genetic or environmental factors. In contrast, we examined whether 2 factors known to individually benefit aging cognition may interact to produce better cognition: environment-based positive age beliefs and the [[APOE]] ε2 gene. The sample consisted of 3,895 Health and Retirement Study participants who were 60 years or older at baseline and completed as many as 5 assessments of cognition over 8 years. As predicted, positive age beliefs amplified the cognitive benefit of [[APOE]] ε2. In contrast, negative age beliefs suppressed the cognitive benefit of [[APOE]] ε2. We also found that positive age beliefs contributed nearly 15 times more than [[APOE]] ε2 to better cognition. This study provides the first known evidence that self-perceptions can influence the impact of a gene on cognition. The results underscore the importance of combined psychosocial and biological approaches to understanding cognitive function in older adults.

|keywords=* 
          APOE
        
* Age beliefs
* Cognition
* Gene
* Health and Retirement Study
* Self-perceptions of aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489069
}}
{{medline-entry
|title=Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32817639
|abstract=The ε4 allele of apolipoprotein E ([[APOE]]) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between [[APOE]] genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. This case-control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44-96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer's Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44-94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with [[APOE]] genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one [[APOE]] ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1-5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4-31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65-70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of [[APOE]] ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. In this study, we found that AD diagnosis based on biomarkers was associated with [[APOE]] ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65-70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of [[APOE]] ε4 at the population level.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Apolipoprotein E4
* Biomarkers
* Case-Control Studies
* Cohort Studies
* Female
* Genotype
* Humans
* Male
* Middle Aged

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446786
}}
{{medline-entry
|title=Estimating the potential for dementia prevention through modifiable risk factors elimination in the real-world setting: a population-based study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32767997
|abstract=Preventing dementia onset is one of the global public health priorities: around 35% of dementia cases could be attributable to modifiable risk factors. These estimates relied on secondary data and did not consider the concurrent effect of non-modifiable factors and death. Here, we aimed to estimate the potential reduction of dementia incidence due to modifiable risk factors elimination, controlling for non-modifiable risk factors and for the competing risk of death. Participants from the InveCe.Ab population-based prospective cohort (Abbiategrasso, Italy) without a baseline dementia diagnosis and attending at least one follow-up visit were included (N = 1100). Participants underwent multidimensional assessment at baseline and after 2, 4, and 8 years, from November 2009 to January 2019. Modifiable risk factors were low education, obesity, hypertension, diabetes, depression, smoking, physical inactivity, hearing loss, loneliness, heart disease, stroke, head injury, and delirium. Non-modifiable risk factors were age, sex, and [[APOE]] ε4 genotype. The primary endpoint was dementia diagnosis within the follow-up period (DSM-IV criteria). We performed competing risk regression models to obtain sub-hazard ratio (SHR) for each exposure, with death as competing risk. The exposures associated with dementia were included in a multivariable model to estimate their independent influence on dementia and the corresponding population attributable fraction (PAF). Within the study period (mean follow-up, 82.3 months), 111 participants developed dementia (10.1%). In the multivariable model, [[APOE]] ε4 (SHR = 1.89, 95% CI 1.22-2.92, p = 0.005), diabetes (SHR = 1.56, 95% CI 1.00-2.39, p = 0.043), heart disease (SHR = 1.56, 95% CI 1.03-2.36, p = 0.037), stroke (SHR = 2.31, 95% CI 1.35-3.95, p = 0.002), and delirium (SHR = 8.70, 95% CI 3.26-23.24, p <  0.001) were independently associated with increased dementia risk. In the present cohort, around 40% of dementia cases could be attributable to preventable comorbid diseases. [[APOE]] ε4, diabetes, heart disease, stroke, and delirium independently increased the risk of late-life dementia, controlling for the competing risk of death. Preventive intervention addressed to these clinical populations could be an effective approach to reduce dementia incidence. Further studies on different population-based cohort are needed to obtain more generalizable findings of the potential of dementia prevention in the real-world setting. ClinicalTrials.gov, NCT01345110 .

|keywords=* Aging
* Alzheimer’s disease
* Dementia
* Dementia prevention
* Modifiable risk factors
* Population attributable fraction
* Public health
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414752
}}
{{medline-entry
|title=Machine learning-based estimation of cognitive performance using regional brain MRI markers: the Northern Manhattan Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32740887
|abstract=High dimensional neuroimaging datasets and machine learning have been used to estimate and predict domain-specific cognition, but comparisons with simpler models composed of easy-to-measure variables are limited. Regularization methods in particular may help identify regions-of-interest related to domain-specific cognition. Using data from the Northern Manhattan Study, a cohort study of mostly Hispanic older adults, we compared three models estimating domain-specific cognitive performance: sociodemographics and [[APOE]] ε4 allele status (basic model), the basic model and MRI markers, and a model with only MRI markers. We used several machine learning methods to fit our regression models: elastic net, support vector regression, random forest, and principal components regression. Model performance was assessed with the RMSE, MAE, and R  statistics using 5-fold cross-validation. To assess whether prediction models with imaging biomarkers were more predictive than prediction models built with randomly generated biomarkers, we refit the elastic net models using 1000 datasets with random biomarkers and compared the distribution of the RMSE and R  in models using these random biomarkers to the RMSE and R  from observed models. Basic models explained ~ 31-38% of the variance in domain-specific cognition. Addition of MRI markers did not improve estimation. However, elastic net models with only MRI markers performed significantly better than random MRI markers (one-sided P < .05) and yielded regions-of-interest consistent with previous literature and others not previously explored. Therefore, structural brain MRI markers may be more useful for etiological than predictive modeling.

|keywords=* Biomarkers
* Brain aging
* Cognitive aging
* Machine learning
|full-text-url=https://sci-hub.do/10.1007/s11682-020-00325-3
}}
{{medline-entry
|title=Effects of an [[APOE]] Promoter Polymorphism on Fronto-Parietal Functional Connectivity During Nondemented Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32694990
|abstract=: The rs405509 polymorphism ofthe apolipoprotein E ([[APOE]]) promoter is related to Alzheimer'sdisease (AD). The T/T allele of rs405509 is known to decrease the transcription of the [[APOE]] gene and lead to impairments in specific brain structural networks with aging; thus, it is an important risk factor for AD. However, it remains unknown whether rs405509 affects brain functional connectivity (FC) in aging.  : We investigated the effect of the rs405509 genotype (T/T vs. G-allele) on age-related brain FC using functional magnetic resonance imaging. Forty-five elderly TT carriers and 45 elderly G-allele carriers were scanned during a working memory (WM) task.  : We found that TT carriers showed an accelerated age-related increase in functional activation in the left postcentral gyrus compared with G-allele carriers. Furthermore, the FC between the left postcentral gyrus and some key regions during WM performance, including the right caudal and superior frontal sulcus (SFS), was differentially modulated by age across rs405509 genotype groups.  : These results demonstrate that the rs405509 T/T allele of [[APOE]] causes an age-related brain functional decline in nondemented elderly people, which may be beneficial for understanding the neural mechanisms of rs405509-related cognitive aging and AD pathogenesis.

|keywords=* APOE promoter
* aging
* brain connectome
* fronto-parietal network
* working memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338603
}}
{{medline-entry
|title=The relationship of parental longevity with the aging brain-results from UK Biobank.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32671621
|abstract=A few studies report that parental longevity is associated with preserved cognition and physical function and lower risk of Alzheimer's disease. However, data on structural neuroimaging correlates of parental longevity and its spatial distribution are limited. This study aims to examine relationships of parental longevity with regional brain structure and to explore sex differences. We identified 12,970 UK Biobank participants (mean age = 64.4, 51.5%women) with data on parental longevity, regional gray matter volumes, and white matter microstructure. Participants were categorized based on whether at least one parent lived to age 85 or older or neither parent survived to age 85. Associations of parental longevity, maternal, and paternal longevity with each neuroimaging marker of interest were examined using linear regression, adjusted for demographics, [[APOE]] e4 status, lifestyle, and cardiometabolic conditions. Compared to participants whose both parents died before 85 (43%), those with at least one parent surviving to 85 (57%) had greater volumes in hippocampus, parahippocampal gyrus, middle temporal lobe, and primary sensorimotor cortex and had lower mean diffusivity in posterior thalamic radiation and uncinate fasciculus. Associations were prominent with maternal longevity. Adjustment for cardiometabolic conditions did not affect observed associations except mean diffusivity in posterior thalamic radiation. There were no structural differences in other areas. Parental longevity is associated with preserved brain structure localized in primary sensorimotor cortex and temporal areas including hippocampus. These relationships are prominent with maternal longevity. Longitudinal studies are needed to determine whether changes in these brain structures account for the association between parental longevity and dementia.

|keywords=* Aging
* Brain structure
* DTI
* MRI
* Neuroimaging
* Parental longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525531
}}
{{medline-entry
|title=Alzheimer's Patient Microglia Exhibit Enhanced Aging and Unique Transcriptional Activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32610143
|abstract=Damage-associated microglia (DAM) profiles observed in Alzheimer's disease (AD)-related mouse models reflect an activation state that could modulate AD risk or progression. To learn whether human AD microglia (HAM) display a similar profile, we develop a method for purifying cell types from frozen cerebrocortical tissues for RNA-seq analysis, allowing better transcriptome coverage than typical single-nucleus RNA-seq approaches. The HAM profile we observe bears little resemblance to the DAM profile. Instead, HAM display an enhanced human aging profile, in addition to other disease-related changes such as [[APOE]] upregulation. Analyses of whole-tissue RNA-seq and single-cell/nucleus RNA-seq datasets corroborate our findings and suggest that the lack of DAM response in human microglia occurs specifically in AD tissues, not other neurodegenerative settings. These results, which can be browsed at http://research-pub.gene.com/BrainMyeloidLandscape, provide a genome-wide picture of microglial activation in human AD and highlight considerable differences between mouse models and human disease.

|keywords=* Alzheimer’s disease
* aging
* microglia
* neurodegenerative diseases
* neuroinflammation
* transcriptomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422733
}}
{{medline-entry
|title=Relationships Between Plasma Lipids Species, Gender, Risk Factors, and Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32474467
|abstract=Lipid metabolism is altered in Alzheimer's disease (AD); however, the relationship between AD risk factors (age, [[APOE]]ɛ4, and gender) and lipid metabolism is not well defined. We investigated whether altered lipid metabolism associated with increased age, gender, and [[APOE]] status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals. We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and interaction analysis were used to explore the relationship between risk factors and plasma lipid species. We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, [[APOE]]ɛ4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and [[APOE]]ɛ4 may, in part, be mediated by changes in lipid metabolism. This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways.

|keywords=* APOEɛ4
* Aging
* Alzheimer’s disease
* gender
* lipid 
species

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369125
}}
{{medline-entry
|title=Effects of sex, age, and apolipoprotein E genotype on hippocampal parenchymal fraction in cognitively normal older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32416384
|abstract=Early detection of Alzheimer's disease (AD) is important for timely interventions and developing new treatments. Hippocampus atrophy is an early biomarker of AD. The hippocampal parenchymal fraction (HPF) is a promising measure of hippocampal structural integrity computed from structural MRI. It is important to characterize the dependence of HPF on covariates such as age and sex in the normal population to enhance its utility as a disease biomarker. We measured the HPF in 4239 structural MRI scans from 340 cognitively normal (CN) subjects aged 59-89 years from the AD Neuroimaging Initiative database, and studied its dependence on age, sex, apolipoprotein E ([[APOE]]) genotype, brain hemisphere, intracranial volume (ICV), and education using a linear mixed-effects model. In this CN cohort, HPF was inversely associated with ICV; was greater on the right hemisphere compared to left in both sexes with the degree of right > left asymmetry being slightly more pronounced in men; declined quadratically with age and faster in [[APOE]] ϵ4 carriers compared to non-carriers; and was significantly associated with cognitive ability. Consideration of HPF as an AD biomarker should be in conjunction with other subject attributes that are shown in this research to influence HPF levels in CN older individuals.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Apolipoproteins E
* Biomarkers
* Cognition
* Databases, Factual
* Female
* Genotype
* Hippocampus
* Humans
* Linear Models
* Male
* Middle Aged
* Neuroimaging
* Organ Size
* Parenchymal Tissue
* Reference Values
* Sex Factors
|keywords=* Alzheimer’s disease
* Apolipoprotein E ϵ4
* Atrophy
* Brain
* Healthy aging
* Hippocampal parenchymal fraction
* Hippocampal volumetric integrity
* Hippocampus
* MRI
* Mild cognitive impairment
* Neurodegeneration
* Sex
|full-text-url=https://sci-hub.do/10.1016/j.pscychresns.2020.111107
}}
{{medline-entry
|title=Cognitive Health of Nonagenarians in Southern Italy: A Descriptive Analysis from a Cross-Sectional, Home-Based Pilot Study of Exceptional Longevity (Cilento Initiative on Aging Outcomes Or CIAO).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32380778
|abstract=[i]Background[/i][i]:[/i] Nonagenarians and centenarians (NCs) are an extremely fragile population, particularly in regard to their physical and cognitive function. The aim of this study was to define the neurocognitive profiles among 29 NCs and their 49 younger cohabitants aged 50-75 years from The Cilento Initiative on Aging Outcomes (CIAO) Pilot study in the South of Italy that had provided initial hypotheses regarding positive psychological traits related to exceptional longevity. [i]Methods[/i]: During the home visits, lifestyle information with specific questionnaires, functional autonomy and the neuropsychological Mini Mental Scale Examination (MMSE), and the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog) scale were obtained by qualified study personnel. The total blood oxidative capacity was also determined by testing the reactive derivative of oxygen metabolites (d-ROM) and by the Biological Antioxidant Potential (BAP). In all individuals, the [[APOE]] genotype determination was also performed. [i]Results[/i]: All the subjects in both groups showed high adherence to the Mediterranean Diet. None of the NCs had severe cognitive impairment, and a very low incidence of dementia was found. The data obtained on the Activities ed Instrumental Activities of Daily Living (ADL-IADL) scale showed that the majority of NCs (16/29) were autonomous in daily life activities. The comparative assessment of NCs and cohabitants showed no significant differences in the laboratory assessment of oxidative stress and [[APOE]] genotype. [i]Conclusion:[/i] In the Cilento Region of Southern Italy, NCs seemed to have good cognitive status when compared to younger cohabitants aging 50-65 years without significant differences in oxidative stress markers or [[APOE]] genotype. These results might be related to optimal adherence to the Mediterranean diet, although other lifestyle factors and positive personality traits may also contribute to their healthy aging. Further studies on a larger population should be performed to confirm the results of this pilot study.

|keywords=* Cilento Region
* cognitive health
* lifestyle
* longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279440
}}
{{medline-entry
|title=Apolipoprotein E and Health in Older Men: The Concord Health and Ageing in Men Project.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32342099
|abstract=[[APOE]] genotype has been associated with various age-related outcomes including Alzheimer's disease, frailty, and mortality. In this study, the relationship between health, particularly cognitive function, and [[APOE]] was investigated in older men from the Concord Health and Ageing in Men Project (n = 1,616; age 76.9 ± 5.5 years [range 70-97 years]; Australia). Baseline characteristics and survival up to 12 years were determined. Frailty was measured using Cardiovascular Health study (CHS) criteria and Rockwood frailty index, and cognition using Mini-Mental State Examination (MMSE) and Addenbrookes Cognitive Examination. [[APOE]] ε4 was less common in the oldest men and those born in Mediterranean countries. [[APOE]] ε2 was beneficially associated with cholesterol, creatinine, gamma-glutamyl transaminase, glucose, and HDL cholesterol while [[APOE]] ε4 was adversely associated with cholesterol and albumin. [[APOE]] ε4 was associated with a clinical diagnosis of Alzheimer's disease when adjusted for age and region of birth (ε4 homozygotes Odds ratio (OR) 7.0; ε4 heterozygotes OR 2.4, p < .05), and [[APOE]] ε2 had a small positive association with cognition. On multivariate regression, overall cognitive function in the entire cohort was associated with age, country of birth, education, and frailty (all p < .001). [[APOE]] was not associated with frailty or survival. In conclusion, age and region of birth influenced distribution of [[APOE]] genotype in older men. Although [[APOE]] ε4 was associated with Alzheimer's disease, overall cognitive function in the cohort was associated more strongly with frailty than [[APOE]] genotype.

|keywords=* Aging
* Alzheimer’s disease
* Apolipoprotein E
* Cognition
* Cognitive frailty
* Frailty
* Male
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa105
}}
{{medline-entry
|title=CSF amyloid is a consistent predictor of white matter hyperintensities across the disease course from aging to Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32305782
|abstract=This study investigated the relationship between white matter hyperintensities (WMH) and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Subjects included 180 controls, 107 individuals with a significant memory concern, 320 individuals with early mild cognitive impairment, 171 individuals with late mild cognitive impairment, and 151 individuals with AD, with 3T MRI and CSF Aβ1-42, total tau (t-tau), and phosphorylated tau (p-tau) data. Multiple linear regression models assessed the relationship between WMH and CSF Aβ1-42, t-tau, and p-tau. Directionally, a higher WMH burden was associated with lower CSF Aβ1-42 within each diagnostic group, with no evidence for a difference in the slope of the association across diagnostic groups (p = 0.4). Pooling all participants, this association was statistically significant after adjustment for t-tau, p-tau, age, diagnostic group, and [[APOE]]-ε4 status (p < 0.001). Age was the strongest predictor of WMH (partial R ~16%) compared with CSF Aβ1-42 (partial R ~5%). There was no evidence for an association with WMH and either t-tau or p-tau. These data are supportive of a link between amyloid burden and presumed vascular pathology.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Biomarkers
* Cerebrovascular Disorders
* Cognitive Dysfunction
* Female
* Humans
* Magnetic Resonance Imaging
* Male
* Peptide Fragments
* White Matter
* tau Proteins
|keywords=* Alzheimer's disease
* Amyloid
* Cerebrospinal fluid
* Tau
* Vascular disease
* White matter hyperintensities
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.03.008
}}
{{medline-entry
|title=Association of Cardiovascular Risk Factors with Cerebral Perfusion in Whites and African Americans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32310160
|abstract=Midlife cardiovascular risk factors increase risk for Alzheimer's disease (AD). Despite disproportionately high cardiovascular disease and dementia rates, African Americans are under-represented in studies of AD risk and research-based guidance on targeting vascular risk factors is lacking. This study investigated relationships between specific cardiovascular risk factors and cerebral perfusion in White and African American adults enriched for AD risk. Participants included 397 cognitively unimpaired White (n = 330) and African American (n = 67) adults enrolled in the Wisconsin Alzheimer's Disease Research Center who underwent pseudo-continuous arterial spin labeling MRI. Multiple linear regression models examined independent relationships between cardiovascular risk factors and mean cerebral perfusion. Subsequent interaction and stratified models assessed the role for [[APOE]] genotype and race. When risk factor p-values were FDR-adjusted, diastolic blood pressure was significantly associated with mean perfusion. Tobacco use, triglycerides, waist-to-hip ratio, and a composite risk score were not associated with perfusion. Without FDR adjustment, a relationship was also observed between perfusion and obesity, cholesterol, and fasting glucose. Neither [[APOE]] genotype nor race moderated relationships between risk factors and perfusion. Higher diastolic blood pressure predicted lower perfusion more strongly than other cardiovascular risk factors. This relationship did not vary by racial group or genetic risk for AD, although the African American sample had greater vascular risk burden and lower perfusion rates. Our findings highlight the need to prioritize inclusion of underrepresented groups in neuroimaging studies and to continue exploring the link between modifiable risk factors, cerebrovascular health, and AD risk in underrepresented populations.

|keywords=* Aging
* Alzheimer’s disease
* blood pressure
* cerebrovascular circulation
* neuroimaging
* obesity
|full-text-url=https://sci-hub.do/10.3233/JAD-190360
}}
{{medline-entry
|title=Alzheimer's Risk Factors Age, [[APOE]] Genotype, and Sex Drive Distinct Molecular Pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32199103
|abstract=Evidence suggests interplay among the three major risk factors for Alzheimer's disease (AD): age, [[APOE]] genotype, and sex. Here, we present comprehensive datasets and analyses of brain transcriptomes and blood metabolomes from human apoE2-, apoE3-, and apoE4-targeted replacement mice across young, middle, and old ages with both sexes. We found that age had the greatest impact on brain transcriptomes highlighted by an immune module led by Trem2 and Tyrobp, whereas [[APOE]]4 was associated with upregulation of multiple Serpina3 genes. Importantly, these networks and gene expression changes were mostly conserved in human brains. Finally, we observed a significant interaction between age, [[APOE]] genotype, and sex on unfolded protein response pathway. In the periphery, [[APOE]]2 drove distinct blood metabolome profile highlighted by the upregulation of lipid metabolites. Our work identifies unique and interactive molecular pathways underlying AD risk factors providing valuable resources for discovery and validation research in model systems and humans.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Age Factors
* Aging
* Alzheimer Disease
* Animals
* Apolipoprotein E2
* Apolipoprotein E3
* Apolipoprotein E4
* Apolipoproteins E
* Brain
* Female
* Gene Expression
* Gene Expression Profiling
* Gene Regulatory Networks
* Genotype
* Humans
* Male
* Membrane Glycoproteins
* Membrane Proteins
* Metabolome
* Mice
* Mice, Transgenic
* Protective Factors
* Receptors, Immunologic
* Risk Factors
* Serpins
* Sex Factors
* Unfolded Protein Response
|keywords=* APOE
* Alzheimer’s disease
* Serpina3
* age
* extracellular vesicles
* inflammation
* lipid metabolism
* metabolomics
* sex
* transcriptomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388065
}}
{{medline-entry
|title=Less agreeable, better preserved? A PET amyloid and MRI study in a community-based cohort.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32169357
|abstract=The relationship between personality profiles and brain integrity in old age is still a matter of debate. We examined the association between Big Five factor and facet scores and MRI brain volume changes on a 54-month follow-up in 65 elderly controls with 3 neurocognitive assessments (baseline, 18 months, and 54 months), structural brain MRI (baseline and 54 months), brain amyloid PET during follow-up, and [[APOE]] genotyping. Personality was assessed with the Neuroticism Extraversion Openness Personality Inventory-Revised. Regression models were used to identify predictors of volume loss including time, age, sex, personality, amyloid load, presence of [[APOE]] ε4 allele, and cognitive evolution. Lower agreeableness factor scores (and 4 of its facets) were associated with lower volume loss in the hippocampus, entorhinal cortex, amygdala, mesial temporal lobe, and precuneus bilaterally. Higher openness factor scores (and 2 of its facets) were also associated with lower volume loss in the left hippocampus. Our findings persisted when adjusting for confounders in multivariable models. These data suggest that the combination of low agreeableness and high openness is an independent predictor of better preservation of brain volume in areas vulnerable to neurodegeneration.
|mesh-terms=* Aged
* Aged, 80 and over
* Amyloidogenic Proteins
* Apolipoproteins E
* Brain
* Cognition
* Cohort Studies
* Female
* Follow-Up Studies
* Humans
* Magnetic Resonance Imaging
* Male
* Neuroimaging
* Organ Size
* Personality
* Positron-Emission Tomography
|keywords=* Amyloid load
* Cognitive aging
* Cohort studies
* Personality
* Structural MRI
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.02.004
}}
{{medline-entry
|title=Physical Activity as Moderator of the Association Between [[APOE]] and Cognitive Decline in Older Adults: Results from Three Longitudinal Cohort Studies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32110803
|abstract=Previous studies have suggested that the association between [[APOE]] ɛ 4 and dementia is moderated by physical activity (PA), but the results remain inconclusive and longitudinal data on cognitive decline are missing. In this study, we examine whether there is a gene-environment interaction between [[APOE]] and PA on cognitive decline in older adults using 9-year follow-up data of three cohort studies. We followed 7,176 participants from three longitudinal cohort studies: Longitudinal Aging Study Amsterdam (LASA), InCHIANTI, and Rotterdam Study for 9 years. PA was assessed with self-reported questionnaires and was categorized in low, moderate, and high PA. Cognitive function was assessed with the Mini-Mental State Examination (MMSE) and cognitive decline was defined as a decrease of three points or more on the MMSE during 3 years follow-up. We fitted logistic regression models using generalized estimating equations adjusting for age, sex, education, depressive symptoms, and number of chronic disease. Interaction between [[APOE]] and PA was tested on multiplicative and additive scale. Cohorts were similar in most aspects but InCHIANTI participants were on average older and had lower education. [[APOE]] ɛ 4 carriers had higher odds of cognitive decline (odds ratio [OR] = 1.46, 95% confidence interval [CI]: 1.29-1.64) while PA was not significantly associated with cognitive decline overall (moderate PA: OR = 0.87, 0.67-1.13; high PA: OR = 0.71, 0.36-1.40). There was no evidence for an interaction effect between PA and [[APOE]] ɛ 4 in cognitive decline in older adults ([[APOE]] × moderate PA: p = .83; [[APOE]] × high PA: p = .90). Previous claims of a gene-environment interaction between [[APOE]] ɛ 4 and PA in cognitive decline are not supported by our results.

|keywords=* Gene–environment interaction
* InCHIANTI
* Longitudinal Aging Study Amsterdam
* Rotterdam Study
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518558
}}
{{medline-entry
|title=Longitudinal Maintenance of Cognitive Health in Centenarians in the 100-plus Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32101309
|abstract=Some individuals who reach ages beyond 100 years in good cognitive health may be resilient against risk factors associated with cognitive decline. Exploring the processes underlying resilience may contribute to the development of therapeutic strategies that help to maintain cognitive health while aging. To identify individuals who escape cognitive decline until extreme ages and to investigate the prevalence of associated risk factors. The 100-plus Study is a prospective observational cohort study of community-based Dutch centenarians enrolled between 2013 and 2019 who were visited annually until death or until participation was no longer possible. The centenarians self-reported their cognitive health, as confirmed by a proxy. Of the 1023 centenarians approached for study inclusion, 340 fulfilled the study criteria and were included in analyses. Data analysis was performed from April 2019 to December 2019. Cognition was assessed using the Mini-Mental State Examination (MMSE). To identify centenarians who escape cognitive decline, this study investigated the association of baseline cognition with survivorship and cognitive trajectories for at least 2 years of follow-up using linear mixed models, adjusted for sex, age, and education. This study investigated the prevalence of apolipoprotein E ([[APOE]]) genotypes and cardiovascular disease as risk factors associated with cognitive decline. At baseline, the median age of 340 centenarians was 100.5 years (range, 100.0-108.2 years); 245 participants (72.1%) were female. The maximum survival estimate plateaued at 82% per year (95% CI, 77% to 87%) across centenarians who scored 26 to 30 points on the baseline MMSE (hazard ratio, 0.56; 95% CI, 0.42 to 0.75; P < .001), suggesting that an MMSE score of 26 or higher is representative of both cognitive and physical health. Among the 79 centenarians who were followed up for 2 years or longer, those with baseline MMSE score less than 26 experienced a decline in MMSE score of 1.68 points per year (95% CI, -2.45 to -0.92 points per year; P = .02), whereas centenarians with MMSE scores of 26 or higher at baseline experienced a decline of 0.71 point per year (95% CI, -1.08 to -0.35 points per year). For 73% of the centenarians with baseline MMSE scores of 26 or higher, no cognitive changes were observed, which often extended to ensuing years or until death. It is estimated that this group is representative of less than 10% of Dutch centenarians. In this group, 18.6% carried at least 1 [[APOE]]-ε4 allele, compared with 5.6% of the centenarians with lower and/or declining cognitive performance. Most centenarians who scored 26 or higher on the MMSE at baseline maintained high levels of cognitive performance for at least 2 years, in some cases despite the presence of risk factors associated with cognitive decline. Investigation of this group might reveal the processes underlying resilience against risk factors associated with cognitive decline.
|mesh-terms=* Aged, 80 and over
* Aging
* Apolipoprotein E4
* Cognition
* Female
* Humans
* Longitudinal Studies
* Male
* Mental Status and Dementia Tests
* Prospective Studies

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137688
}}
{{medline-entry
|title=Interaction of [[APOE]], cerebral blood flow, and cortical thickness in the entorhinal cortex predicts memory decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32048144
|abstract=The ε4 allele of the apolipoprotein E ([[APOE]]) gene, a risk factor for cognitive decline, is associated with alterations in medial temporal lobe (MTL) structure and function, yet little research has been dedicated to understanding how these alterations might interact to negatively impact cognition. To bridge this gap, the present study employed linear regression models to determine the extent to which [[APOE]] genotype (ε4+, ε4-) modifies interactive effects of baseline arterial spin labeling MRI-measured cerebral blood flow (CBF) and FreeSurfer-derived cortical thickness/volume (CT/Vo) in two MTL regions of interest (entorhinal cortex, hippocampus) on memory change in 98 older adults who were cognitively normal at baseline. Baseline entorhinal CBF was positively associated with memory change, but only among ε4 carriers with lower entorhinal CT. Similarly, baseline entorhinal CT was positively associated with memory change, but only among ε4 carriers with lower entorhinal CBF. Findings suggest that [[APOE]] ε4 carriers may experience concomitant alterations in neurovascular function and morphology in the MTL that interact to negatively affect cognition prior to the onset of overt clinical symptoms. Results also suggest the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among this group, perhaps reflecting different stages of cerebrovascular compensation (early effective vs. later ineffective).

|keywords=* APOE ε4
* Aging
* Cerebral blood flow
* Cognitive decline
* Cortical thickness
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7165062
}}
{{medline-entry
|title=Determinants of mesial temporal lobe volume loss in older individuals with preserved cognition: a longitudinal PET amyloid study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32057528
|abstract=Mesial temporal lobe (MTL) is prominently affected in normal aging and associated with neurodegeneration in AD. Whether or not MTL atrophy is dependent on increasing amyloid load before the emergence of cognitive deficits is still disputed. We performed a 4.5-year longitudinal study in 75 older community dwellers (48 women, mean age: 79.3 years) including magnetic resonance imaging at baseline and follow-up, positron emission tomography amyloid during follow-up, neuropsychological assessment at 18 and 55 months, and [[APOE]] genotyping. Linear regression models were used to identify predictors of the MTL volume loss. Amyloid load was negatively associated with bilateral MTL volume at baseline explaining almost 10.5% of its variability. In multivariate models including time of follow-up and demographic variables (older age, male gender), this percentage exceeded 35%. The [[APOE]]4 allele independently contributed another 6%. Cognitive changes had a modest but still significant negative association with MTL volume loss. Our data support a multifactorial model including amyloid deposition, older age, male gender, [[APOE]]4 allele, and slight decline of cognitive abilities as independent predictors of MTL volume loss in brain aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alleles
* Amyloidogenic Proteins
* Apolipoprotein E4
* Cognitive Reserve
* Female
* Follow-Up Studies
* Genotype
* Humans
* Longitudinal Studies
* Male
* Neuropsychological Tests
* Organ Size
* Positron-Emission Tomography
* Sex Factors
* Temporal Lobe
|keywords=* APOE
* Amyloid load
* Cognitive changes
* Mesial temporal lobe
* Normal aging
* Structural MRI
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2019.12.002
}}
{{medline-entry
|title=Long-term exposure to ambient air pollution, [[APOE]]-ε4 status, and cognitive decline in a cohort of older adults in northern Manhattan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31926436
|abstract=There is mounting evidence that long-term exposure to air pollution is related to accelerated cognitive decline in aging populations. Factors that influence individual susceptibility remain largely unknown, but may involve the apolipoprotein E genotype E4 ([[APOE]]-ε4) allele. We assessed whether the association between long-term exposure to ambient air pollution and cognitive decline differed by [[APOE]]-ε4 status and cognitive risk factors. The Washington Heights Inwood Community Aging Project (WHICAP) is a prospective study of aging and dementia. Neuropsychological testing and medical examinations occur every 18-24 months. We used mixed-effects models to evaluate whether the association between markers of ambient air pollution (nitrogen dioxide [NO ]), fine [PM ], and coarse [PM ] particulate matter) and the rate of decline in global and domain-specific cognition differed across strata defined by [[APOE]]-ε4 genotypes and cognitive risk factors, adjusting for sociodemographic factors and temporal trends. Among 4821 participants with an average of 6 years follow-up, higher concentrations of ambient air pollution were associated with more rapid cognitive decline. This association was more pronounced among [[APOE]]-ε4 carriers (p < 0.001). A one interquartile range increase in NO  was associated with an additional decline of 0.09 standard deviations (SD) (95%CI -0.1, -0.06) in global cognition across biennial visits among [[APOE]]-ε4 positive individuals and a 0.07 SD (95%CI -0.09, -0.05) decline among [[APOE]]-ε4 negative individuals. Results for PM  PM  and cognitive domains were similar. The association between air pollutants and rate of cognitive decline also varied across strata of race-ethnicity with the association strongest among White non-Hispanic participants. These results add to the body of evidence on the adverse impact of ambient air pollution on cognitive aging and brain health and provide new insights into the genetic and behavioral factors that may impact individual susceptibility.
|mesh-terms=* Aged
* Air Pollutants
* Air Pollution
* Apolipoprotein E4
* Apolipoproteins E
* Cognitive Dysfunction
* Female
* Genotype
* Humans
* Male
* Prospective Studies
* Washington
|keywords=* APOE-ε4 allele
* Aging
* Air pollution
* Cognitive decline
* Cognitive risk factors
* Epidemiology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024003
}}
{{medline-entry
|title=Evidence in support of chromosomal sex influencing plasma based metabolome vs [[APOE]] genotype influencing brain metabolome profile in humanized [[APOE]] male and female mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31917799
|abstract=Late onset Alzheimer's disease (LOAD) is a progressive neurodegenerative disease with four well-established risk factors: age, [[APOE]]4 genotype, female chromosomal sex, and maternal history of AD. Each risk factor impacts multiple systems, making LOAD a complex systems biology challenge. To investigate interactions between LOAD risk factors, we performed multiple scale analyses, including metabolomics, transcriptomics, brain magnetic resonance imaging (MRI), and beta-amyloid assessment, in 16 months old male and female mice with humanized human [[APOE]]3 (h[[APOE]]3) or [[APOE]]4 (h[[APOE]]4) genes. Metabolomic analyses indicated a sex difference in plasma profile whereas [[APOE]] genotype determined brain metabolic profile. Consistent with the brain metabolome, gene and pathway-based RNA-Seq analyses of the hippocampus indicated increased expression of fatty acid/lipid metabolism related genes and pathways in both h[[APOE]]4 males and females. Further, female transcription of fatty acid and amino acids pathways were significantly different from males. MRI based imaging analyses indicated that in multiple white matter tracts, h[[APOE]]4 males and females exhibited lower fractional anisotropy than their h[[APOE]]3 counterparts, suggesting a lower level of white matter integrity in h[[APOE]]4 mice. Consistent with the brain metabolomic and transcriptomic profile of h[[APOE]]4 carriers, beta-amyloid generation was detectable in 16-month-old male and female brains. These data provide therapeutic targets based on chromosomal sex and [[APOE]] genotype. Collectively, these data provide a framework for developing precision medicine interventions during the prodromal phase of LOAD, when the potential to reverse, prevent and delay LOAD progression is greatest.
|mesh-terms=* Age of Onset
* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Apolipoprotein E4
* Apolipoproteins E
* Brain
* Disease Models, Animal
* Female
* Genotype
* Humans
* Magnetic Resonance Imaging
* Male
* Metabolome
* Mice
* Mice, Transgenic
* Sex Characteristics
* Sex Chromosomes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952084
}}
{{medline-entry
|title=[[APOE]] region molecular signatures of Alzheimer's disease across races/ethnicities.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31813627
|abstract=The role of even the strongest genetic risk factor for Alzheimer's disease (AD), the apolipoprotein E ([[APOE]]) ε4 allele, in its etiology remains poorly understood. We examined molecular signatures of AD defined as differences in linkage disequilibrium patterns between AD-affected and -unaffected whites (2673/16,246), Hispanics (392/867), and African Americans (285/1789), separately. We focused on 29 polymorphisms from 5 genes in the [[APOE]] region emphasizing beneficial and adverse effects of the [[APOE]] ε2- and ε4-coding single-nucleotide polymorphisms, respectively, and the differences in the linkage disequilibrium structures involving these alleles between AD-affected and -unaffected subjects. Susceptibility to AD is likely the result of complex interactions of the ε2 and ε4 alleles with other polymorphisms in the [[APOE]] region, and these interactions differ across races/ethnicities corroborating differences in the adverse and beneficial effects of the ε4 and ε2 alleles. Our findings support complex race/ethnicity-specific haplotypes promoting and protecting against AD in this region. They contribute to better understanding of polygenic and resilient mechanisms, which can explain why even homozygous ε4 carriers may not develop AD.
|mesh-terms=* Alleles
* Alzheimer Disease
* Apolipoproteins E
* Continental Population Groups
* Haplotypes
* Heterozygote
* Homozygote
* Humans
* Linkage Disequilibrium
* Polymorphism, Single Nucleotide
* Risk Factors
|keywords=* APOE polymorphism
* Aging
* Alzheimer's disease
* Health span
* Life span
* Neurodegenerative disorders
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064423
}}
{{medline-entry
|title=Varying Effects of [[APOE]] Alleles on Extreme Longevity in European Ethnicities.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31724059
|abstract=[[APOE]] is a well-studied gene with multiple effects on aging and longevity. The gene has three alleles: e2, e3, and e4, whose frequencies vary by ethnicity. While the e2 is associated with healthy cognitive aging, the e4 allele is associated with Alzheimer's disease and early mortality and therefore its prevalence among people with extreme longevity (EL) is low. Using the PopCluster algorithm, we identified several ethnically different clusters in which the effect of the e2 and e4 alleles on EL changed substantially. For example, PopCluster discovered a large group of 1,309 subjects enriched of Southern Italian genetic ancestry with weaker protective effect of e2 (odds ratio [OR] = 1.27, p = .14) and weaker damaging effect of e4 (OR = 0.82, p = .31) on the phenotype of EL compared to other European ethnicities. Further analysis of this cluster suggests that the odds for EL in carriers of the e4 allele with Southern Italian genetic ancestry differ depending on whether they live in the United States (OR = 0.29, p = .009) or Italy (OR = 1.21, p = .38). PopCluster also found clusters enriched of subjects with Danish ancestry with varying effect of e2 on EL. The country of residence (Denmark or United States) appears to change the odds for EL in the e2 carriers.
|mesh-terms=* Aged, 80 and over
* Alleles
* Apolipoproteins E
* Ethnic Groups
* Europe
* European Continental Ancestry Group
* Female
* Humans
* Longevity
* Male
|keywords=* APOE
* Bioinformatics
* Human genetics
* Longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7330482
}}
{{medline-entry
|title=Prospective Evaluation of Cognitive Health and Related Factors in Elderly at Risk for Developing Alzheimer's Dementia: A Longitudinal Cohort Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31686098
|abstract=The CHARIOT PRO Main study is a prospective, non-interventional study evaluating cognitive trajectories in participants at the preclinical stage of Alzheimer's disease (AD) classified by risk levels for developing mild cognitive impairment due to AD (MCI-AD). The study aimed to characterize factors and markers influencing cognitive and functional progression among individuals at-risk for developing MCI-AD, and examine data for more precise predictors of cognitive change, particularly in relation to [[APOE]] ε4 subgroup. This single-site study was conducted at the Imperial College London (ICL) in the United Kingdom. Participants 60 to 85 years of age were classified as high, medium (amnestic or non-amnestic) or low risk for developing MCI-AD based on RBANS z-scores. A series of clinical outcome assessments (COAs) on factors influencing baseline cognitive changes were collected in each of the instrument categories of cognition, lifestyle exposure, mood, and sleep. Data collection was planned to occur every 6 months for 48 months, however the median follow-up time was 18.1 months due to early termination of study by the sponsor. 987 participants were screened, among them 690 participants were actively followed-up post baseline, of whom 165 (23.9%) were [[APOE]] ε4 carriers; with at least one copy of the allele. The mean age was 68.73 years, 94.6% were white, 57.4% were female, and 34.8% had a Family History of Dementia with a somewhat larger percentage in the [[APOE]] ε4 carrier group (42.4%) compared to the non-carrier group (32.4%). Over half of the participants were married and 53% had a Bachelor's or higher degree. Most frequently, safety events typical for this population consisted of upper respiratory tract infection (10.4%), falls (5.2%), hypertension (3.5%) and back pain (3.0%). Conclusion (clinical relevance): AD-related measures collected during the CHARIOT PRO Main study will allow identification and evaluation of AD risk factors and markers associated with cognitive performance from the pre-clinical stage. Evaluating the psycho-biological characteristics of these pre-symptomatic individuals in relation to their natural neurocognitive trajectories will enhance current understanding on determinants of the initial signs of cognitive changes linked to AD.
|mesh-terms=* Aged
* Aged, 80 and over
* Alzheimer Disease
* Anxiety
* Apolipoprotein E4
* Cognition
* Cognitive Dysfunction
* Cohort Studies
* Depression
* Efficiency
* Female
* Healthy Volunteers
* Humans
* Longitudinal Studies
* Male
* Mental Status and Dementia Tests
* Middle Aged
* Neuropsychological Tests
* Prospective Studies
* Risk Factors
* Sleep
* United Kingdom
* Work
|keywords=* Alzheimer Disease
* CHARIOT
* aging registry
* cognitive health
* pre-clinical
|full-text-url=https://sci-hub.do/10.14283/jpad.2019.31
}}
{{medline-entry
|title=Association of Cardiovascular and Alzheimer's Disease Risk Factors with Intracranial Arterial Blood Flow in Whites and African Americans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31658057
|abstract=Alzheimer's disease (AD) has a higher prevalence among African Americans. Targeting cardiovascular and metabolic risk factors may be potential mechanisms to modify AD risk and address racial/ethnic disparities in AD dementia. This study investigated relationships among cardiovascular and metabolic risk factors, [[APOE]] genotype, AD biomarkers, and intracranial arterial blood flow in Whites and African Americans enriched for AD risk. 399 cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center completed physical and neuroimaging examinations. A 4D Flow MRI sequence (phase-contrast vastly under sampled isotropic projection imaging) measured intracranial arterial flow in the Circle of Willis. Linear mixed-effects regression models estimated relationships between risk factors and intracranial arterial flow and tested interactions with racial group, [[APOE]] genotype, and AD biomarkers, with separate models per risk factor. Higher fasting glucose was associated with lower intracranial arterial flow; no additional relationships between flow and risk factors were observed. Main effects of racial group were observed, without an interaction, indicating lower flow in African Americans compared to Whites. In race-stratified analyses, higher glucose and triglycerides were associated with lower flow for African Americans, but not for Whites. No main effects or interactions among risk factors, [[APOE]], or AD biomarkers, and flow were observed. Elevated fasting glucose and triglycerides were associated with lower intracranial arterial flow; these relationships were more prominent in African Americans. Targeting metabolic risk factors may impact intracranial arterial health. Additional research is needed to determine if this will impact disparities in dementia prevalence.
|mesh-terms=* African Americans
* Aged
* Alzheimer Disease
* Biomarkers
* Blood Flow Velocity
* Cardiovascular Diseases
* Cerebrovascular Circulation
* European Continental Ancestry Group
* Female
* Humans
* Male
* Middle Aged
* Risk Factors
|keywords=* African Americans
* Alzheimer’s disease
* Apolipoprotein E4
* aging
* cerebrovascular circulation
* glucose
* metabolic syndrome
* neuroimaging
* risk factors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081660
}}
{{medline-entry
|title=Is Ongoing Anticholinergic Burden Associated With Greater Cognitive Decline and Dementia Severity in Mild to Moderate Alzheimer's Disease?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31613323
|abstract=Use of anticholinergic medication is associated with an increased risk of cognitive impairment and/or dementia. Despite this, the impact of continuing medication with anticholinergic properties in those diagnosed with Alzheimer's Disease (AD) is not clear. Analysis of data from NILVAD, an 18-month randomized controlled trial of Nilvadipine in AD. Effects of ongoing Anticholinergic Cognitive Burden (ACB) on cognition (ADAS-Cog: Alzheimer's Disease Cog Subsection) and dementia severity (CDR-sb: Clinical Dementia Rating - Sum of Boxes/DAD: Disability Assessment for Dementia) over 18 months was evaluated adjusting for important clinical covariates. Just over one-quarter (27.90%, n = 142/510) of patients with mild to moderate AD were prescribed a potential/definite anticholinergic. While ACB score was not associated with greater progression on the ADAS-Cog/CDR-sb over time, a higher total ACB predicted greater dementia severity on the DAD, which persisted after robust covariate adjustment (β Coef: -1.53, 95% CI: -2.83 to -0.23, p = .021). There was a significant interaction between [[APOE]] ε4 status and ACB score, with carriers experiencing greater progression on both the CDR-Sb (β Coef: 0.36, 95% CI: 0.05-0.67, p = .021) and DAD (β Coef: -3.84, 95% CI: -7.65 to 0.03, p = .049). Ongoing use of anticholinergic medication was associated with greater dementia progression on the DAD, but not the CDR-sb. [[APOE]] ε 4 carriers may be particularly vulnerable to the effect of ongoing anticholinergic medication on dementia severity, with significant [[APOE]] ε 4 x ACB score interactions demonstrated on both the DAD and CDR-sb.

|keywords=* Alzheimers
* Cognitive aging
* Drug related
* Medication
|full-text-url=https://sci-hub.do/10.1093/gerona/glz244
}}
{{medline-entry
|title=Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31630996
|abstract=Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY. A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published. Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, [[APOE]] genotype, and center-specific factors. Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Alzheimer Disease
* Amyloid
* Biomarkers
* Cohort Studies
* Europe
* Female
* Humans
* Inflammation
* Male
* Middle Aged
* Parkinson Disease
* Sex Factors
* tau Proteins
|keywords=* Aging
* Alzheimer's disease
* Amyloid
* Biomarker
* Cerebrospinal fluid
* Inflammation
* Mild cognitive impairment
* Multicenter
* Parkinson's disease
* Tau
|full-text-url=https://sci-hub.do/10.1016/j.jalz.2019.07.018
}}
{{medline-entry
|title=Prospective Memory: Age related change is influenced by [[APOE]] genotype.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31578124
|abstract=Non-focal prospective memory (PM) is sensitive to age-related decline; an additional impairment in focal PM is characteristic of mild stage Alzheimer's disease. This research explored whether, by mid-adulthood, the distinct demands of focal and non-focal PM expose differences in carriers of an [i][[APOE]][/i] ε4 allele, a genetic risk factor for Alzheimer's disease. Thirty-three young and 55 mid-age adults, differentiated by [i][[APOE]][/i] genotype, completed a category-decision task with a concurrent focal or non-focal PM demand. Only mid-age ε4 carriers showed a cost of carrying a focal PM intention. In addition, mid-age ε4 carriers showed a significantly greater cost of carrying a non-focal PM intention than young ε4 carriers, supporting a profile of accelerated aging. Consistency in the profile of cost differences observed in mid-age ε4 carriers and pathological aging may indicate premature vulnerability. Future research correlating a shift in PM performance with early genotype differences in brain-based markers of decline is important.

|keywords=*  APOE 
* Alzheimer’s disease
* aging
* mid-adulthood
* prospective memory
|full-text-url=https://sci-hub.do/10.1080/13825585.2019.1671305
}}
{{medline-entry
|title=Education Moderates the Relation Between [[APOE]] ɛ4 and Memory in Nondemented Non-Hispanic Black Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31594222
|abstract=The [[APOE]]ɛ4 allele is a well-known risk factor for Alzheimer's disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. To test if higher educational level buffers the effect of [[APOE]]ɛ4 on cognition among older non-Hispanic Blacks. Participants were 849 non-demented older non-Hispanic Blacks (38.3% [[APOE]]ɛ4+), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between [[APOE]]ɛ4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. Education buffered the effects of the [[APOE]]ɛ4 allele, such that there was no impact of [[APOE]]ɛ4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed-although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment.
|mesh-terms=* Adult
* African Americans
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Apolipoprotein E4
* Cognitive Reserve
* Educational Status
* Executive Function
* Female
* Humans
* Male
* Memory
* Memory, Episodic
* Memory, Short-Term
* Middle Aged
* Neuropsychological Tests
* Sex Characteristics
|keywords=* APOE
* African American
* Alzheimer’s disease
* cognitive reserve
* educational attainment
* episodic memory
* genetic risk
* neuropsychological evaluation
|full-text-url=https://sci-hub.do/10.3233/JAD-190415
}}
{{medline-entry
|title=Apolipoprotein E ε4 allele effects on longitudinal cognitive trajectories are sex and age dependent.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31561966
|abstract=Questions remain about whether apolipoprotein E ([[APOE]])-ε4 effects on cognitive decline are similar in men and women and how [[APOE]]-ε4 and age interact to influence decline in different cognitive domains. In sex-stratified analyses, baseline age-dependent associations between [[APOE]]-ε4 status and longitudinal cognitive trajectories were examined in cognitively normal Caucasian older adults (631 men, 561 women, baseline age range: 50-93, 6733 assessments). In men, older baseline age was associated with greater effects of [[APOE]]-ε4 on longitudinal decline in memory and executive function, detectible from baseline age of 64 and 68, respectively. In women, older baseline age was associated with greater [[APOE]]-ε4 effects on longitudinal decline in attention, detectible at baseline age of 66. No significant [[APOE]]-ε4 effects were found for language, visual-spatial ability, or processing speed. Results highlight the importance of considering sex and age when assessing [[APOE]]-ε4-associated vulnerability to cognitive decline.
|mesh-terms=* Age Factors
* Aged
* Alleles
* Apolipoprotein E4
* Cognition Disorders
* European Continental Ancestry Group
* Executive Function
* Female
* Humans
* Longitudinal Studies
* Male
* Memory
* Neuropsychological Tests
* Sex Factors
|keywords=* Aging
* Alzheimer's disease
* Apolipoprotein E ε4
* Cognitive decline
* Sex
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561018
}}
{{medline-entry
|title=Interactive effect of age and [[APOE]]-ε4 allele load on white matter myelin content in cognitively normal middle-aged subjects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31520917
|abstract=The apolipoprotein E gene ([[APOE]]) ε4 allele has a strong and manifold impact on cognition and neuroimaging phenotypes in cognitively normal subjects, including alterations in the white matter (WM) microstructure. Such alterations have often been regarded as a reflection of potential thinning of the myelin sheath along axons, rather than pure axonal degeneration. Considering the main role of [[APOE]] in brain lipid transport, characterizing the impact of [[APOE]] on the myelin coating is therefore of crucial interest, especially in healthy [[APOE]]-ε4 homozygous individuals, who are exposed to a twelve-fold higher risk of developing Alzheimer's disease (AD), compared to the rest of the population. We examined T1w/T2w ratio maps in 515 cognitively healthy middle-aged participants from the ALFA study (ALzheimer and FAmilies) cohort, a single-site population-based study enriched for AD risk (68 [[APOE]]-ε4 homozygotes, 197 heterozygotes, and 250 non-carriers). Using tract-based spatial statistics, we assessed the impact of age and [[APOE]] genotype on this ratio taken as an indirect descriptor of myelin content. Healthy [[APOE]]-ε4 carriers display decreased T1w/T2w ratios in extensive regions in a dose-dependent manner. These differences were found to interact with age, suggesting faster changes in individuals with more ε4 alleles. These results obtained with T1w/T2w ratios, confirm the increased vulnerability of WM tracts in [[APOE]]-ε4 healthy carriers. Early alterations of myelin content could be the result of the impaired function of the ε4 isoform of the [[APOE]] protein in cholesterol transport. These findings help to clarify the possible interactions between the [[APOE]]-dependent non-pathological burden and age-related changes potentially at the source of the AD pathological cascade.
|mesh-terms=* Age Factors
* Aged
* Aging
* Apolipoprotein E4
* Female
* Humans
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Myelin Sheath
* White Matter
|keywords=* Aging
* Alzheimer
* Apolipoprotein E
* Cognitively normal subjects
* Myelination
* T1w/T2w ratio
* White matter integrity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742967
}}
{{medline-entry
|title=[[APOE]] modifies the interaction of entorhinal cerebral blood flow and cortical thickness on memory function in cognitively normal older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31493534
|abstract=The ε4 allele of the apolipoprotein E ([[APOE]]) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how [[APOE]] ε4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether [[APOE]] genotype (ε4+ vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance. Multiple linear regression models were employed to investigate relationships between [[APOE]] genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4+, 76 ε4-) between the ages of 64 and 89 (mean age = 73). Results indicated that [[APOE]] genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT. Findings suggest that older adult [[APOE]] ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between [[APOE]] ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.
|mesh-terms=* Aged
* Aged, 80 and over
* Apolipoproteins E
* Cerebral Cortex
* Cerebrovascular Circulation
* Entorhinal Cortex
* Female
* Genotype
* Humans
* Linear Models
* Male
* Memory
* Middle Aged
|keywords=* APOE ε4
* Aging
* Alzheimer’s disease
* Cerebral blood flow
* Cognitive decline
* Cortical thickness
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819270
}}
{{medline-entry
|title=When time's arrow doesn't bend: [[APOE]]-ε4 influences episodic memory before old age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31473197
|abstract=Episodic memory impairment is the hallmark symptom of Alzheimer's Disease (AD). However, episodic memory has also been shown to decline across the lifespan. Here, we investigated whether episodic memory is differentially affected relative to other cognitive abilities before old age, and whether being an Apolipoprotein E ([[APOE]]) ε4 carrier -a genetic risk factor for developing AD-exacerbates any such impairments. We used general linear models to test for performance differences within 4 composite measures of cognition - episodic memory, semantic memory, speed of processing, and fluid reasoning-- as a function of age group (young, Mage = 30.21 vs. middle-aged, Mage = 50.84) and [[APOE]]-ε4 genotype status (ε4+ vs. ε4-). We replicated findings of age-related reductions in episodic memory, speed of processing, and fluid reasoning, and age-related increases in semantic memory. However, we also found that [[APOE]] genotype status moderated the age-related declines in episodic memory: [[APOE]]-ε4+ middle-aged adults exhibited impairments relative to both [[APOE]]-ε4- middle-aged participants, and [[APOE]]-ε4+ younger adults. These results suggest specific and dynamic alterations to episodic memory as a function of [[APOE]] allelic variation and age.
|mesh-terms=* Adult
* Alleles
* Alzheimer Disease
* Apolipoprotein E4
* Cognition
* Cognitive Aging
* Female
* Genotype
* Humans
* Linear Models
* Male
* Memory
* Memory, Episodic
* Middle Aged
* Young Adult
|keywords=* Alzheimer's diseas
* Apolipoprotein E
* Cognition
* Episodic memory
* Semantic memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817416
}}
{{medline-entry
|title=Cognitive-Motor Integration Performance Is Affected by Sex, [[APOE]] Status, and Family History of Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31424400
|abstract=Cognitive-motor integration (CMI) involves concurrent thought and action which requires the interaction of large brain networks. Given that early-stage dementia involves neural network dysfunction, deficits in CMI may prove useful for early dementia detection. Our research objective was to investigate sex-related differences in the ability to integrate rules into action. Based on family medical history, we recruited male and female participants both with and without dementia risk factors. Participants did not demonstrate cognitive impairment at the time of testing. Participants were tested on four increasingly dissociated visuomotor tasks (eye and hand movements were made in different spatial planes and/or visual feedback was reversed). We observed significantly greater hand movement endpoint error scores and corrective path lengths in at-risk females compared to at-risk males in the most complex CMI condition (plane-change + feedback reversal). Multiple regression analyses revealed both sex and family history as significant predictors of worse performance in a CMI condition requiring visual feedback reversal. Further, the regression analyses provided preliminary evidence that having an [[APOE]]ɛ4 allele was a significant predictor of poorer CMI performance in the two plane-change CMI conditions. These data suggest that underlying brain networks controlling simultaneous thought and action may differ between the sexes in ways that may be clinically relevant in dementia progression. Preliminary data also suggest an important connection between [[APOE]] variant and CMI performance in individuals at risk of developing dementia.
|mesh-terms=* Aged
* Apolipoproteins E
* Cognition
* Cognitive Dysfunction
* Cross-Sectional Studies
* Dementia
* Female
* Humans
* Male
* Medical History Taking
* Middle Aged
* Photic Stimulation
* Psychomotor Performance
* Sex Characteristics
* Surveys and Questionnaires
|keywords=* Aging
* alzheimer’s disease
* apolipoprotein E4
* dementia risk
* geriatric 
assessment
* motor skills
* movement
* visuomotor integration
|full-text-url=https://sci-hub.do/10.3233/JAD-190403
}}
{{medline-entry
|title=Associations among amyloid status, age, and longitudinal regional brain atrophy in cognitively unimpaired older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31437719
|abstract=The goal of this study was to compare regional brain atrophy patterns in cognitively unimpaired (CU) older adults with and without brain accumulation of amyloid-β (Aβ) to elucidate contributions of Aβ, age, and other variables to atrophy rates. In 80 CU participants from the Alzheimer's Disease Neuroimaging Initiative, we determined effects of Aβ and age on longitudinal, regional atrophy rates, while accounting for confounding variables including sex, [[APOE]] ε4 genotype, white matter lesions, and cerebrospinal fluid total and phosphorylated tau levels. We not only found overlapping patterns of atrophy in Aβ+ versus Aβ- participants but also identified regions where atrophy pattern differed between the 2 groups. Higher Aβ load was associated with increased longitudinal atrophy in the entorhinal cortex, amygdala, and hippocampus, even when accounting for age and other variables. Age was associated with atrophy in insula, fusiform gyrus, and isthmus cingulate, even when accounting for Aβ. We found age by Aβ interactions in the postcentral gyrus and lateral orbitofrontal cortex. These results elucidate the separate and related effects of age, Aβ, and other important variables on longitudinal brain atrophy rates in CU older adults.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Amyloid beta-Peptides
* Atrophy
* Brain
* Cognition
* Cognitive Dysfunction
* Databases, Factual
* Female
* Humans
* Longitudinal Studies
* Male
* Middle Aged
|keywords=* Aging
* Alzheimer's disease
* Amyloid-β
* Brain atrophy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198229
}}
{{medline-entry
|title=Cognitive function and neuropathological outcomes: a forward-looking approach.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31435771
|abstract=To evaluate the risk of Alzheimer's disease-related neuropathology burden at autopsy given older adults' current cognitive state. Participants included 1,303 individuals who enrolled in the Religious Orders Study (ROS) and 1,789 who enrolled in the Rush Memory and Aging Project (MAP). Cognitive status was evaluated via standardized assessments of global cognition and episodic memory. At the time of analyses, about 50% of participants were deceased with the remaining numbers right censored. Using multi-state Cox proportional hazard models, we compared the cognitive status of all subjects alive at a given age and estimated future risk of dying with different AD-related neuropathologies. Endpoints considered were Braak Stages (0-2, 3-4, 5-6), CERAD (0, 1, 2, 3), and TDP-43 (0, 1, 2, 3) level. For all three pathological groupings (Braak, CERAD, TDP-43), we found that a cognitive test score one standard deviation below average put individuals at up to three times the risk for being diagnosed with late stage AD at autopsy according to pathological designations. The effect remained significant after adjusting for sex, [[APOE]]-e4 status, smoking status, education level, and vascular health scores. Applying multi-state modeling techniques, we were able to identify those at risk of exhibiting specific levels of neuropathology based on current cognitive test performance. This approach presents new and approachable possibilities in clinical settings for diagnosis and treatment development programs.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Cognitive Dysfunction
* Female
* Humans
* Male
* Middle Aged
|keywords=* Alzheimer’s disease
* Cognition
* Multi-state model
* Neuropathology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851487
}}
{{medline-entry
|title=[[APOE]] gene-dependent BOLD responses to a breath-hold across the adult lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31408838
|abstract=Age and apolipoprotein E ([[APOE]]) e4 genotype are two of the strongest known risk factors for sporadic Alzheimer's disease (AD). Neuroimaging has shown hemodynamic response changes with age, in asymptomatic carriers of the [[APOE]] e4 allele, and in AD. In this study, we aimed to characterize and differentiate age- and [[APOE]] gene-specific hemodynamic changes to breath-hold and visual stimulation. A further aim was to study whether these responses were modulated by 3-day intake of nitrate, a nitric oxide (NO) source. The study was designed as a randomized, double-blinded, placebo-controlled crossover study, and the study cohort comprised 41 [[APOE]] e4 carriers (e3/e4 or e4/e4 genotype) and 40 non-carriers (e3/e3 genotype) aged 30-70 years at enrollment. The participants underwent two scanning sessions, each preceded by ingestion of sodium nitrate or sodium chloride (control). During functional magnetic resonance imaging (fMRI) sessions, participants performed two concurrent tasks; a breath-hold task to probe cerebrovascular reactivity and a visual stimulation task to evoke functional hyperemia, respectively. We found that the blood oxygenation level dependent (BOLD) hemodynamic response to breath-hold was altered in [[APOE]] e4 carriers relative to non-carriers. Mid-aged (50-60 years of age) e4 carriers exhibited a significantly increased peak time relative to mid-aged e3 carriers, and peak time for younger (30-40 years of age) e4 carriers was significantly shorter than that of mid-aged e4 carriers. The response width was significantly increased for e4 carriers. The response peak magnitude significantly decreased with age. For the visual stimulation task, we found age-related changes, with reduced response magnitude with age but no significant effect of [[APOE]] allele type. We found no effect of nitrate ingestion on BOLD responses evoked by the breath-hold and visual stimulation tasks. The [[APOE]] gene-dependent response to breath-hold may reflect NO-independent differences in vascular function.
|mesh-terms=* Adult
* Aged
* Aging
* Apolipoprotein E3
* Apolipoprotein E4
* Apolipoproteins E
* Breath Holding
* Cerebrovascular Circulation
* Cross-Over Studies
* Double-Blind Method
* Female
* Genotype
* Hemodynamics
* Humans
* Longevity
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Nitrates
|keywords=* Ageing
* Alzheimer's disease
* Apolipoprotein E
* BOLD fMRI
* Breath-hold
* Cerebrovascular reactivity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699560
}}
==MSC==

{{medline-entry
|title=Rejuvenation of Senescent Endothelial Progenitor Cells by Extracellular Vesicles Derived From Mesenchymal Stromal Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33294742
|abstract=Mesenchymal stromal cell ([[MSC]]) transplantation is a form of the stem-cell therapy that has shown beneficial effects for many diseases. The use of stem-cell therapy, including [[MSC]] transplantation, however, has limitations such as the tumorigenic potential of stem cells and the lack of efficacy of aged autologous cells. An ideal therapeutic approach would keep the beneficial effects of [[MSC]] transplantation while circumventing the limitations associated with the use of intact stem cells. This study provides proof-of-concept evidence that [[MSC]]-derived extracellular vesicles represent a promising platform to develop an acellular therapeutic approach that would just do that. Extracellular vesicles are membranous vesicles secreted by [[MSC]]s and contain bioactive molecules to mediate communication between different cells. Extracellular vesicles can be taken up by recipient cells, and once inside the recipient cells, the bioactive molecules are released to exert the beneficial effects on the recipient cells. This study, for the first time to our knowledge, shows that extracellular vesicles secreted by [[MSC]]s recapitulate the beneficial effects of [[MSC]]s on vascular repair and promote blood vessel regeneration after ischemic events. Furthermore, [[MSC]]s from aged donors can be engineered to produce extracellular vesicles with improved regenerative potential, comparable to [[MSC]]s from young donors, thus eliminating the need for allogenic young donors for elderly patients.

|keywords=* BM, bone marrow
* CVD, cardiovascular disease
* EC, endothelial cell
* EPC, endothelial progenitor cell
* EV, extracellular vesicle
* FBS, fetal bovine serum
* MEM, minimum essential medium
* MI, myocardial infarction
* MSC, mesenchymal stromal cell
* NTA, nanotracking analysis
* PBS, phosphate-buffered saline
* TEV, tailored extracellular vesicle
* VEGF, vascular endothelial growth factor
* acellular
* angiogenesis
* extracellular vesicles
* lin− BMC, lineage negative bone marrow cell
* miR, microRNA
* qPCR, quantitative transcription polymerase chain reaction
* regeneration
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691285
}}
{{medline-entry
|title=Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33264634
|abstract=Cortical injury, such as stroke, causes neurotoxic cascades that lead to rapid death and/or damage to neurons and glia. Axonal and myelin damage in particular, are critical factors that lead to neuronal dysfunction and impair recovery of function after injury and can be exacerbated in the aged brain where white matter damage is prevalent. Therapies that can ameliorate myelin damage and promote repair by targeting oligodendroglia, the cells that produce and maintain myelin, may facilitate recovery after injury, especially in the aged brain where these processes are already compromised. We previously reported that a novel therapeutic, Mesenchymal Stem Cell derived extracellular vesicles ([[MSC]]-EVs), administered intravenously at both 24 h and 14 days after cortical injury reduced microgliosis (Go et al. 2019), reduced neuronal pathology (Medalla et al. 2020), and improved motor recovery (Moore et al. 2019) in aged female rhesus monkeys. Here, we evaluated the effect of treatment with [[MSC]]-EVs on changes in oligodendrocyte maturation and associated myelin markers in the sublesional white matter using immunohistochemistry, confocal microscopy, stereology, qRT-PCR, and ELISA. Compared to vehicle-treated control, EV-treated monkeys showed a reduction in the density of damaged oligodendrocytes. Further, EV-treatment was associated with enhanced myelin maintenance, evidenced by upregulation of myelin-related genes and increases in actively-myelinating oligodendrocytes in in sublesional white matter. These changes in myelination correlate with the rate of motor recovery, suggesting that improved myelin maintenance facilitates this recovery. Overall, our results suggest that EVs act on oligodendrocytes to support myelination and likely improve functional recovery after injury in the aged brain. SIGNIFICANCE: We previously reported that after cortical injury in the aged monkey brain, EVs reduce neuronal pathology (Medalla et al. 2020), microgliosis (Go et al. 2019), and facilitate recovery of function. However, the effect of injury on oligodendrocytes and myelination has not been characterized in the primate brain (Dewar et al. 1999; Sozmen et al. 2012; Zhang et al. 2013). In the present study, we assessed changes in myelination after cortical injury in these same aged monkeys. Our results show, for the first time, that [[MSC]]-EVs support recovery of function after cortical injury by enhancing myelin maintenance in the aged primate brain.

|keywords=* Aging
* Cortical injury
* Extracellular vesicles
* Monkeys
* Myelin
* Non-human primates
* Oligodendrocytes
* Stroke
* White matter
|full-text-url=https://sci-hub.do/10.1016/j.expneurol.2020.113540
}}
{{medline-entry
|title=TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33195247
|abstract=Poor cell survival after transplantation restricts the therapeutic potential of mesenchymal stem cell ([[MSC]]) transplantation into infarcted hearts, particularly in older individuals. TPP1, a component of the shelterin complex that is involved in telomere protection, is highly expressed in young [[MSC]]s but declines in aged ones. Here, we explore whether TPP1 overexpression in aged mouse [[MSC]]s improves cell viability [i]in vivo[/i] and [i]in vitro[/i]. Aged mouse [[MSC]]s overexpressing TPP1 were injected into the peri-infarct area of the mouse heart after left anterior descending coronary artery ligation. In parallel, to evaluate cellular-level effects, H O  was applied to [[MSC]]s [i]in vitro[/i] to mimic the microenvironment of myocardial injury. [i]In vivo[/i], the transplantation of aged [[MSC]]s overexpressing TPP1 resulted in improved cell survival, enhanced cardiac function, and reduced fibrosis compared to unmodified aged [[MSC]]s. [i]In vitro[/i], TPP1 overexpression protected aged [[MSC]]s from H O -induced apoptosis and enhanced DNA double-strand break (DSB) repair. In addition, the phosphorylation of AKT and the key DSB repair protein MRE11 were both significantly upregulated in aged [[MSC]]s that overexpressed TPP1. Our results reveal that TPP1 can enhance DNA repair through the AKT/MRE11 pathway, thereby improving the therapeutic effects of aged [[MSC]] transplantation and offering significant potential for the clinical application of autologous transplantation in aged patients.

|keywords=* DNA repair
* aging
* myocardial infarction
* stem cells therapy
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658181
}}
{{medline-entry
|title=Aging-Affected [[MSC]] Functions and Severity of Periodontal Tissue Destruction in a Ligature-Induced Mouse Periodontitis Model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33143068
|abstract=Mesenchymal stem cells ([[MSC]]s) are known to play important roles in the repair of lost or damaged tissues and immunotolerance. On the other hand, aging is known to impair [[MSC]] function. However, little is currently known about how aged [[MSC]]s affect the host response to the local inflammatory condition and tissue deterioration in periodontitis, which is a progressive destructive disease of the periodontal tissue potentially leading to multiple tooth loss. In this study, we examined the relationship between aging-induced impairment of [[MSC]] function and the severity of periodontal tissue destruction associated with the decrease in host immunomodulatory response using a ligature-induced periodontitis model in young and aged mice. The results of micro computerized tomography (micro-CT) and histological analysis revealed a more severe bone loss associated with increased osteoclast activity in aged (50-week-old) mice compared to young (5-week-old) mice. Immunostaining analysis revealed that, in aged mice, the accumulation of inflammatory T and B cells was higher, whereas the percentage of platelet-derived growth factor receptor α (PDGFRα)  [[MSC]]s, which are known to modulate the apoptosis of T cells, was significantly lower than in young mice. In vitro analysis of [[MSC]] function showed that the expression of surface antigen markers for [[MSC]]s (Sca-1, CD90, CD146), colony formation, migration, and osteogenic differentiation of aged [[MSC]]s were significantly declined compared to those of young [[MSC]]s. Moreover, a significantly higher proportion of aged [[MSC]]s were positive for the senescence-associated β galactosidase activity. Importantly, aged [[MSC]]s presented a decreased expression of FAS-L, which was associated with a lower immunomodulatory property of aged [[MSC]]s to induce T cell apoptosis in co-cultures compared with young [[MSC]]s. In summary, this is the first study showing that aging-induced impairment of [[MSC]] function, including immunomodulatory response, is potentially correlated with progressive periodontal tissue deterioration.

|keywords=* aging
* bone resorption
* immunomodulation
* mesenchymal stem cell
* periodontitis
* tissue destruction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663404
}}
{{medline-entry
|title=Human placenta-derived mesenchymal stem cells stimulate ovarian function via miR-145 and bone morphogenetic protein signaling in aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33153492
|abstract=Aging has detrimental effects on the ovary, such as a progressive reduction in fertility and decreased hormone production, that greatly reduce the quality of life of women. Thus, the current study was undertaken to investigate whether human placenta-derived mesenchymal stem cell (hPD-[[MSC]]) treatment can restore the decreases in folliculogenesis and ovarian function that occur with aging. Acclimatized 52-week-old female SD rats were randomly divided into four groups: single hPD-[[MSC]] (5 × 10 ) therapy, multiple (three times, 10-day intervals) hPD-[[MSC]] therapy, control (PBS), and non-treated groups. hPD-[[MSC]] therapy was conducted by tail vein injection into aged rats. The rats were sacrificed 1, 2, 3, and 5 weeks after the last injection. hPD-[[MSC]] tracking and follicle numbers were histologically confirmed. The serum levels of sex hormones and circulating miRNAs were detected by ELISA and qRT-PCR, respectively. TGF-β superfamily proteins and SMAD proteins in the ovary were detected by Western blot analysis. We observed that multiple transplantations of hPD-[[MSC]]s more effectively promoted primordial follicle activation and ovarian hormone (E  and AMH) production than a single injection. After hPD-[[MSC]] therapy, the levels of miR-21-5p, miR-132-3p, and miR-212-3p, miRNAs associated with the ovarian reserve, were increased in the serum. Moreover, miRNAs (miR-16-5p, miR-34a-5p, and miR-191-5p) with known adverse effects on folliculogenesis were markedly suppressed. Importantly, the level of miR-145-5p was reduced after single- or multiple-injection hPD-[[MSC]] therapy, and we confirmed that miR-145-5p targets Bmpr2 but not Tgfbr2. Interestingly, downregulation of miR-145-5p led to an increase in BMPR2, and activation of SMAD signaling concurrently increased primordial follicle development and the number of primary and antral follicles. Our study verified that multiple intravenous injections of hPD-[[MSC]]s led to improved ovarian function via miR-145-5p and BMP-SMAD signaling and proposed the future therapeutic potential of hPD-[[MSC]]s to promote ovarian function in women at advanced age to improve their quality of life during climacterium.

|keywords=* Aging
* Follicular development
* Hormone biosynthesis
* Primordial follicle activation
* Stem cell therapy
* miR-145
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643421
}}
{{medline-entry
|title=Mesenchymal Stromal Cells as Critical Contributors to Tissue Regeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33102483
|abstract=Adult stem cells that are tightly regulated by the specific microenvironment, or the stem cell niche, function to maintain tissue homeostasis and regeneration after damage. This demands the existence of specific niche components that can preserve the stem cell pool in injured tissues and restore the microenvironment for their subsequent appropriate functioning. This role may belong to mesenchymal stromal cells ([[MSC]]s) due to their resistance to damage signals and potency to be specifically activated in response to tissue injury and promote regeneration by different mechanisms. Increased amount of data indicate that activated [[MSC]]s are able to produce factors such as extracellular matrix components, growth factors, extracellular vesicles and organelles, which transiently substitute the regulatory signals from missing niche cells and restrict the injury-induced responses of them. [[MSC]]s may recruit functional cells into a niche or differentiate into missing cell components to endow a niche with ability to regulate stem cell fates. They may also promote the dedifferentiation of committed cells to re-establish a pool of functional stem cells after injury. Accumulated evidence indicates the therapeutic promise of [[MSC]]s for stimulating tissue regeneration, but the benefits of administered [[MSC]]s demonstrated in many injury models are less than expected in clinical studies. This emphasizes the importance of considering the mechanisms of endogenous [[MSC]] functioning for the development of effective approaches to their pharmacological activation or mimicking their effects. To achieve this goal, we integrate the current ideas on the contribution of [[MSC]]s in restoring the stem cell niches after damage and thereby tissue regeneration.

|keywords=* adult stem cells
* aging
* mesenchymal stromal cells (MSC)
* regenerative medicine
* stem cell niche
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546871
}}
{{medline-entry
|title=The biology of human hair greying.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32965076
|abstract=Hair greying (canities) is one of the earliest, most visible ageing-associated phenomena, whose modulation by genetic, psychoemotional, oxidative, senescence-associated, metabolic and nutritional factors has long attracted skin biologists, dermatologists, and industry. Greying is of profound psychological and commercial relevance in increasingly ageing populations. In addition, the onset and perpetuation of defective melanin production in the human anagen hair follicle pigmentary unit (HFPU) provides a superb model for interrogating the molecular mechanisms of ageing in a complex human mini-organ, and greying-associated defects in bulge melanocyte stem cells ([[MSC]]s) represent an intriguing system of neural crest-derived stem cell senescence. Here, we emphasize that human greying invariably begins with the gradual decline in melanogenesis, including reduced tyrosinase activity, defective melanosome transfer and apoptosis of HFPU melanocytes, and is thus a primary event of the anagen hair bulb, not the bulge. Eventually, the bulge [[MSC]] pool becomes depleted as well, at which stage greying becomes largely irreversible. There is still no universally accepted model of human hair greying, and the extent of genetic contributions to greying remains unclear. However, oxidative damage likely is a crucial driver of greying via its disruption of HFPU melanocyte survival, [[MSC]] maintenance, and of the enzymatic apparatus of melanogenesis itself. While neuroendocrine factors [e.g. alpha melanocyte-stimulating hormone (α-MSH), adrenocorticotropic hormone (ACTH), ß-endorphin, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH)], and micropthalmia-associated transcription factor (MITF) are well-known regulators of human hair follicle melanocytes and melanogenesis, how exactly these and other factors [e.g. thyroid hormones, hepatocyte growth factor (HGF), P-cadherin, peripheral clock activity] modulate greying requires more detailed study. Other important open questions include how HFPU melanocytes age intrinsically, how psychoemotional stress impacts this process, and how current insights into the gerontobiology of the human HFPU can best be translated into retardation or reversal of greying.

|keywords=* ageing
* endocrine
* graying
* melanin
* senescence
|full-text-url=https://sci-hub.do/10.1111/brv.12648
}}
{{medline-entry
|title=[i]Tsc1[/i] Regulates the Proliferation Capacity of Bone-Marrow Derived Mesenchymal Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32927859
|abstract=TSC1 is a tumor suppressor that inhibits cell growth via negative regulation of the mammalian target of rapamycin complex (mTORC1). [i]TSC1[/i] mutations are associated with Tuberous Sclerosis Complex (TSC), characterized by multiple benign tumors of mesenchymal and epithelial origin. TSC1 modulates self-renewal and differentiation in hematopoietic stem cells; however, its effects on mesenchymal stem cells ([[MSC]]s) are unknown. We investigated the impact of [i]Tsc1[/i] inactivation in murine bone marrow (BM)-[[MSC]]s, using tissue-specific, transgelin ([i]Tagln[/i])-mediated cre-recombination, targeting both BM-[[MSC]]s and smooth muscle cells. [i]Tsc1[/i] mutants were viable, but homozygous inactivation led to a dwarfed appearance with TSC-like pathologies in multiple organs and reduced survival. In young (28 day old) mice, [i]Tsc1[/i] deficiency-induced significant cell expansion of non-hematopoietic BM in vivo, and [[MSC]] colony-forming potential in vitro, that was normalized upon treatment with the mTOR inhibitor, everolimus. The hyperproliferative BM-[[MSC]] phenotype was lost in aged (1.5 yr) mice, and [i]Tsc1[/i] inactivation was also accompanied by elevated ROS and increased senescence. ShRNA-mediated knockdown of [i]Tsc1[/i] in BM-[[MSC]]s replicated the hyperproliferative BM-[[MSC]] phenotype and led to impaired adipogenic and myogenic differentiation. Our data show that [i]Tsc1[/i] is a negative regulator of BM-[[MSC]] proliferation and support a pivotal role for the Tsc1-mTOR axis in the maintenance of the mesenchymal progenitor pool.

|keywords=* TSC1
* mammalian target of rapamycin (mTOR)
* mesenchymal stem cell
* senescence
* stem cell proliferation
* tuberous sclerosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565438
}}
{{medline-entry
|title=The role of mitochondrial dysfunction in mesenchymal stem cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32803322
|abstract=Mesenchymal stem cells ([[MSC]]s) hold enormous potential for the treatment of immune-related conditions and degenerative diseases, owing to their self-renewal and multilineage differentiation capabilities. Nevertheless, cellular senescence significantly impacts the quantity and quality of [[MSC]]s, limiting their clinical use. Mitochondria play essential roles in energy production by oxidative phosphorylation and metabolism of energy sources via the tricarboxylic acid cycle. Therefore, mitochondrial dysfunction is a primary cause of senescence in [[MSC]]s. Herein, we summarize the current knowledge regarding the mechanisms underlying mitochondrial dysfunction-associated cellular senescence. We also discuss potential methods to prevent or even reverse [[MSC]] senescence.

|keywords=* Mesenchymal stem cells
* Mitochondrial dysfunction
* Mitophagy
* Reactive oxygen species
* Senescence
|full-text-url=https://sci-hub.do/10.1007/s00441-020-03272-z
}}
{{medline-entry
|title=Metabolic syndrome increases senescence-associated micro-RNAs in extracellular vesicles derived from swine and human mesenchymal stem/stromal cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32787856
|abstract=The metabolic syndrome (MetS) is a combination of cardiovascular risk-factors, including obesity, hypertension, hyperglycemia, and insulin resistance. MetS may induce senescence in mesenchymal stem/stromal cells ([[MSC]]) and impact their micro-RNA (miRNA) content. We hypothesized that MetS also alters senescence-associated (SA) miRNAs in [[MSC]]-derived extracellular vesicles (EVs), and interferes with their function. EVs were collected from abdominal adipose tissue-derived [[MSC]]s from pigs with diet-induced MetS or Lean controls (n = 6 each), and from patients with MetS (n = 4) or age-matched Lean controls (n = 5). MiRNA sequencing was performed to identify dysregulated miRNAs in these EVs, and gene ontology to analyze their SA-genes targeted by dysregulated miRNAs. To test for EV function, MetS and Lean pig-EVs were co-incubated with renal tubular cells in-vitro or injected into pigs with renovascular disease (RVD, n = 6 each) in-vivo. SA-b-Galactosidase and trichrome staining evaluated cellular senescence and fibrosis, respectively. Both humans and pigs with MetS showed obesity, hypertension, and hyperglycemia/insulin resistance. In MetS pigs, several upregulated and downregulated miRNAs targeted 5768 genes in [[MSC]]-EVs, 68 of which were SA. In MetS patients, downregulated and upregulated miRNAs targeted 131 SA-genes, 57 of which overlapped with pig-EVs miRNA targets. In-vitro, MetS-[[MSC]]-EVs induced greater senescence in renal tubular cells than Lean-[[MSC]]-EVs. In-vivo, Lean-[[MSC]]-EVs attenuated renal senescence, fibrosis, and dysfunction more effectively than MetS-[[MSC]]-EVs. MetS upregulates SA-miRNAs in swine [[MSC]]-EVs, which is conserved in human subjects, and attenuates their ability to blunt cellular senescence and repair injured target organs. These alterations need to be considered when designing therapeutic regenerative approaches. Video abstract.

|keywords=* EV
* MSC
* Metabolic syndrome
* RNA-sequencing
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425605
}}
{{medline-entry
|title=Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32699947
|abstract=Mesenchymal stem cells ([[MSC]]) are present in all organs and tissues. Several studies have shown the therapeutic potential effect of [[MSC]] or their derived products. However, the functional heterogeneity of [[MSC]] constitutes an important barrier for transferring these capabilities to the clinic. [[MSC]] heterogeneity depends on their origin (biological niche) or the conditions of potential donors (age, diseases or unknown factors). It is accepted that many culture conditions of the artificial niche to which they are subjected, such as O  tension, substrate and extracellular matrix cues, inflammatory stimuli or genetic manipulations can influence their resulting phenotype. Therefore, to attain a more personalized and precise medicine, a correct selection of [[MSC]] is mandatory, based on their functional potential, as well as the need to integrate all the existing information to achieve an optimal improvement of [[MSC]] features in the artificial niche.

|keywords=* Aging diseases
* Conditioned medium
* Diabetes
* Exosomes
* Extracellular vesicles
* Lupus
* Regenerative medicine
* Secretome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375036
}}
{{medline-entry
|title=Functional crosstalk between mTORC1/p70S6K pathway and heterochromatin organization in stress-induced senescence of [[MSC]]s.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32660632
|abstract=Stem cell senescence has been proposed as one of the major drivers of aging, and [[MSC]] senescence contributes to aging-related diseases. Activation of mTORC1 pathway and heterochromatin organization have been characterized as two characteristics of senescent cells; however, whether mTORC1 pathway interacts with heterochromatin organization and contributes to [[MSC]] senescence remains unknown. In this study, we investigated the interaction between heterochromatin organization and mTORC1/p70S6K pathway in stress-induced [[MSC]] senescence. The stress-induced senescence models were established in human umbilical cord-derived [[MSC]]s by doxorubicin (Dox) or H O . Cellular senescence was evaluated by β-Gal activity, upregulation of cell cycle suppressor genes, and expression of SASP. Activation of heterochromatin organization and mTORC1 pathway was determined by Western blot and immunofluorescent staining. A D-galactose (D-Gal)-induced aging model was established in rats to evaluate the crosstalk between heterochromatin and mTORC1 pathway in vivo. We found that heterochromatin organization was provoked at the early stage of Dox- or H O -induced senescence. Disruption of heterochromatin organization led to robust DNA damage response and exacerbated cellular senescence. Suppression of mTORC1/p70S6K pathway by either rapamycin or p70S6K knockdown promoted heterochromatin organization and ameliorated Dox- or H O -induced DNA damage and senescence. In contrast, direct activation of mTORC1 by MHY1485 impaired heterochromatin organization and aggravated stress-induced senescence. Moreover, concomitant activation of mTORC1 pathway and heterochromatin organization was found in D-galactose-induced osteoporosis model in rats. Rapamycin alleviated cellular senescence and promoted heterochromatin organization in B[[MSC]]s derived from D-galactose-treated rats. Altogether, our study indicates the existence of a complex interplay between the mTORC1/p70S6K pathway and the heterochromatin organization during stress-induced [[MSC]] senescence, with important implications for the understanding of aging as well as for its prevention and treatment.

|keywords=* Aging
* Heterochromatin
* MSC senescence
* mTORC1/p70S6K
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359252
}}
{{medline-entry
|title=Increased cellular senescence in the murine and human stenotic kidney: Effect of mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32657444
|abstract=Cell stress may give rise to insuperable growth arrest, which is defined as cellular senescence. Stenotic kidney (STK) ischemia and injury induced by renal artery stenosis (RAS) may be associated with cellular senescence. Mesenchymal stem cells ([[MSC]]s) decrease some forms of STK injury, but their ability to reverse senescence in RAS remains unknown. We hypothesized that RAS evokes STK senescence, which would be ameliorated by [[MSC]]s. Mice were studied after 4 weeks of RAS, RAS treated with adipose tissue-derived [[MSC]]s 2 weeks earlier, or sham. STK senescence-associated β-galactosidase (SA-β-Gal) activity was measured. Protein and gene expression was used to assess senescence and the senescence-associated secretory phenotype (SASP), and staining for renal fibrosis, inflammation, and capillary density. In addition, senescence was assessed as p16+ and p21+ urinary exosomes in patients with renovascular hypertension (RVH) without or 3 months after autologous adipose tissue-derived [[MSC]] delivery, and in healthy volunteers (HV). In RAS mice, STK SA-β-Gal activity increased, and senescence and SASP marker expression was markedly elevated. [[MSC]]s improved renal function, fibrosis, inflammation, and capillary density, and attenuated SA-β-Gal activity, but most senescence and SASP levels remained unchanged. Congruently, in human RVH, p21+ urinary exosomes were elevated compared to HV, and only slightly improved by [[MSC]], whereas p16+ exosomes remained unchanged. Therefore, RAS triggers renal senescence in both mice and human subjects. [[MSC]]s decrease renal injury, but only partly mitigate renal senescence. These observations support exploration of targeted senolytic therapy in RAS.

|keywords=* cellular senescence
* exosomes
* kidney
* mesenchymal stem cells
* renal artery obstruction
|full-text-url=https://sci-hub.do/10.1002/jcp.29940
}}
{{medline-entry
|title=Intrinsic Type 1 Interferon (IFN1) Profile of Uncultured Human Bone Marrow CD45 CD271  Multipotential Stromal Cells (BM-[[MSC]]s): The Impact of Donor Age, Culture Expansion and IFNα and IFNβ Stimulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32679782
|abstract=Skeletal aging is associated with reduced proliferative potential of bone marrow (BM) multipotential stromal cells ([[MSC]]s). Recent data suggest the involvement of type 1 interferon (IFN1) signalling in hematopoietic stem cell (HSC) senescence. Considering that BM-HSCs and BM-[[MSC]]s share the same BM niche, we investigated IFN1 expression profile in human BM-[[MSC]]s in relation to donor age, culture-expansion and IFN1 (α and β) stimulation. Fluorescence-activated cell sorting was used to purify uncultured BM-[[MSC]]s from younger (19-41, [i]n[/i] = 6) and older (59-89, [i]n[/i] = 6) donors based on the CD45 CD271  phenotype, and hematopoietic-lineage cells (BM-HLCs, CD45 CD271 ) were used as controls. Gene expression was analysed using integrated circuits arrays in sorted fractions as well as cultured/stimulated BM-[[MSC]]s and Y201/Y202 immortalised cell lines. IFN1 stimulation led to BM-[[MSC]] growth arrest and upregulation of many IFN1-stimulated genes (ISGs), with IFNβ demonstrating stronger effects. Uncultured [[MSC]]s were characterised by a moderate-level ISG expression similar to Y201 cells. Age-related changes in ISG expression were negligible in BM-[[MSC]]s compared to BM-HLCs, and intracellular reactive oxygen species (ROS) levels in BM-[[MSC]]s did not significantly correlate with donor age. Antiaging genes Klotho and SIRT6 correlated with more ISGs in BM-[[MSC]]s than in BM-HLCs. In patients with osteoarthritis (OA), BM-[[MSC]]s expressed considerably lower levels of several ISGs, indicating that their IFN1 signature is affected in a pathological condition. In summary, BM-[[MSC]]s possess homeostatic IFN1 gene expression signature in health, which is sensitive to in vitro culture and external IFN1 stimulation. IFN signalling may facilitate in vivo BM-[[MSC]] responses to DNA damage and combating senescence and aberrant immune activation.

|keywords=* aging
* bone marrow
* mesenchymal stromal cells
* senescence
* type 1 interferon
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399891
}}
{{medline-entry
|title=Facial rejuvenation using stem cell conditioned media combined with skin needling: A split-face comparative study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32623814
|abstract=The use of stem cells derived growth factors is representing a novel treatment modality in facial rejuvenation. Nowadays, skin needling is considered a very famous treatment of skin aging. However, the addition of such derived products, augments its therapeutic efficacy in the management and delay of skin aging. Comparing the effect of amniotic fluid mesenchymal stem cell derived conditioned media (AF-[[MSC]]-CM) combined with skin needling versus the needling alone in the management of facial aging. Both sides of the face of ten volunteers, suffering from facial aging, were treated with five sessions of skin needling, 2 weeks apart. After skin microneedling, AF-[[MSC]]-CM was added topically to the right side only. Clinical, histological, and morphometrical assessment of the treated skin was done at 1 month after the last session. The percentage of improvement of aged skin increased significantly on the combined treated side (AF-[[MSC]]-CM and dermaroller [DR]), when compared with the other side (DR only) (P < .001). Remodeling of the dermal structures was observed mainly on the combined side. Meanwhile, histometry of the epidermis revealed a significant increase in the epidermal thickness on both treated sides. AF-[[MSC]]-CM combined with skin needling was more efficient in managing facial aging than skin needling alone.

|keywords=* amniotic fluid stem cells products
* dermaroller
* facial aging
* skin needling
|full-text-url=https://sci-hub.do/10.1111/jocd.13594
}}
{{medline-entry
|title=Mesenchymal Stem Cell Senescence and Rejuvenation: Current Status and Challenges.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32582691
|abstract=Over the past decades, mesenchymal stem cell ([[MSC]])-based therapy has been intensively investigated and shown promising results in the treatment of various diseases due to their easy isolation, multiple lineage differentiation potential and immunomodulatory effects. To date, hundreds of phase I and II clinical trials using [[MSC]]s have been completed and many are ongoing. Accumulating evidence has shown that transplanted allogeneic [[MSC]]s lose their beneficial effects due to immunorejection. Nevertheless, the function of autologous [[MSC]]s is adversely affected by age, a process termed senescence, thus limiting their therapeutic potential. Despite great advances in knowledge, the potential mechanisms underlying [[MSC]] senescence are not entirely clear. Understanding the molecular mechanisms that contribute to [[MSC]] senescence is crucial when exploring novel strategies to rejuvenate senescent [[MSC]]s. In this review, we aim to provide an overview of the biological features of senescent [[MSC]]s and the recent progress made regarding the underlying mechanisms including epigenetic changes, autophagy, mitochondrial dysfunction and telomere shortening. We also summarize the current approaches to rejuvenate senescent [[MSC]]s including gene modification and pretreatment strategies. Collectively, rejuvenation of senescent [[MSC]]s is a promising strategy to enhance the efficacy of autologous [[MSC]]-based therapy, especially in elderly patients.

|keywords=* autophagy
* mesenchymal stem cells
* mitochondrial
* rejuvenation
* senescence
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283395
}}
{{medline-entry
|title=The changing epigenetic landscape of Mesenchymal Stem/Stromal Cells during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32445894
|abstract=There is mounting evidence in the literature that mesenchymal stromal/stem cell ([[MSC]]) like populations derived from different tissues, undergo epigenetic changes during aging, leading to compromised connective tissue integrity and function. This body of work has linked the biological aging of [[MSC]] to changes in their epigenetic signatures affecting growth, lifespan, self-renewal and multi-potential, due to deregulation of processes such as cellular senescence, oxidative stress, DNA damage, telomere shortening and DNA damage. This review addresses recent findings examining DNA methylation, histone modifications and miRNA changes in aging [[MSC]] populations. Moreover, we explore how epigenetic factors alter cellular pathways and associated biological networks, contributing to the [[MSC]] aging phenotype. Finally we discuss the crucial areas requiring a greater understanding of these processes, in order to piece together a global picture of the changing epigenetic landscape in [[MSC]] during aging.

|keywords=* Aging
* DNA methylation
* Epigenetics
* Histome modifications
* MSC
* Mesenchymal Stem/Stromal Cells
* Skeleton
* miRNA
|full-text-url=https://sci-hub.do/10.1016/j.bone.2020.115440
}}
{{medline-entry
|title=Dual Role of Autophagy in Regulation of Mesenchymal Stem Cell Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32391362
|abstract=During their development and overall life, mesenchymal stem cells ([[MSC]]s) encounter a plethora of internal and external stress signals and therefore, they need to put in action homeostatic changes in order to face these stresses. To this aim, similar to other mammalian cells, [[MSC]]s are endowed with two crucial biological responses, autophagy and senescence. Sharing of a number of stimuli like shrinkage of telomeres, oncogenic and oxidative stress, and DNA damage, suggest an intriguingly close relationship between autophagy and senescence. Autophagy is at first reported to suppress [[MSC]] senescence by clearing injured cytoplasmic organelles and impaired macromolecules, yet recent investigations also showed that autophagy can promote [[MSC]] senescence by inducing the production of senescence-associated secretory proteins (SASP). These apparently contrary contributions of autophagy may mirror an intricate image of autophagic regulation on [[MSC]] senescence. We here tackle the pro-senescence and anti-senescence roles of autophagy in [[MSC]]s while concentrating on some possible mechanistic explanations of such an intricate liaison. Clarifying the autophagy/senescence relationship in [[MSC]]s will help the development of more effective and safer therapeutic strategies.

|keywords=* SASP
* general autophagy
* mesenchymal stem cell
* selective autophagy
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193103
}}
{{medline-entry
|title=Molecular Aspects of Adipose-Derived Stromal Cell Senescence in a Long-Term Culture: A Potential Role of Inflammatory Pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32314614
|abstract=Long-term culture of mesenchymal stromal/stem cells [i]in vitro[/i] leads to their senescence. It is very important to define the maximal passage to which the mesenchymal stromal/stem cells maintain their regenerative properties and can be used for cellular therapies and construction of neo-organs for clinical application. Adipose-derived stromal/stem cells were isolated from porcine adipose tissue. Immunophenotype, population doubling time, viability using bromodeoxyuridine assay, MTT assay, clonogencity, β-galactosidase activity, specific senescence-associated gene expression, apoptosis, and cell cycle of adipose-derived mesenchymal stromal/stem cells (AD-[[MSC]]s) were analyzed. All analyses were performed through 12 passages (P). Decreasing viability and proliferative potential of AD-[[MSC]]s with subsequent passages together with prolonged population doubling time were observed. Expression of β-galactosidase gradually increased after P6. Differentiation potential of AD-[[MSC]]s into adipogenic, chondrogenic, and osteogenic lineages decreased at the end of culture (P10). No changes in the cell cycle, the number of apoptotic cells and expression of specific AD-[[MSC]] markers during the long-term culture were revealed. Molecular analysis showed increased expression of genes involved in activation of inflammatory response. AD-[[MSC]]s can be cultured for in vivo applications without loss of their properties up to P6.

|keywords=* adipose-derived stromal/stem cell
* aging
* gene expression
* long-term culture
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586277
}}
{{medline-entry
|title=Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32274385
|abstract=Chronic inflammatory conditions like obesity may adversely impact the biological functions underlying the regenerative potential of mesenchymal stromal/stem cells ([[MSC]]). Obesity can impair [[MSC]] function by inducing cellular senescence, a growth-arrest program that transitions cells to a pro-inflammatory state. However, the effect of obesity on adipose tissue-derived [[MSC]] in human subjects remains unclear. We tested the hypothesis that obesity induces senescence and dysfunction in human [[MSC]]. [[MSC]] were harvested from abdominal subcutaneous fat collected from obese and age-matched non-obese subjects ([i]n[/i] = 40) during bariatric or kidney donation surgeries, respectively. [[MSC]] were characterized, their migration and proliferation assessed, and cellular senescence evaluated by gene expression of cell-cycle arrest and senescence-associated secretory phenotype markers. [i]In vitro[/i] studies tested [[MSC]] effect on injured human umbilical vein endothelial cells (HUVEC) function. Mean age was 59 ± 8 years, 66% were females. Obese subjects had higher body-mass index (BMI) than non-obese. [[MSC]] from obese subjects exhibited lower proliferative capacities than non-obese-[[MSC]], suggesting decreased function, whereas their migration remained unchanged. Senescent cell burden and phenotype, manifested as [i]p16[/i], [i]p53[/i], [i]IL-6[/i], and [i]MCP-1[/i] gene expression, were significantly upregulated in obese subjects' [[MSC]]. BMI correlated directly with expression of [i]p16[/i], [i]p21[/i], and [i]IL-6[/i]. Furthermore, co-incubation with non-obese, but not with obese-[[MSC]], restored VEGF expression and tube formation that were blunted in injured HUVEC. Human obesity triggers an early senescence program in adipose tissue-derived [[MSC]]. Thus, obesity-induced cellular injury may alter efficacy of this endogenous repair system and hamper the feasibility of autologous transplantation in obese individuals.

|keywords=* adipose tissue
* cellular dysfunction
* cellular senescence
* mesenchymal stem cells
* obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113401
}}
{{medline-entry
|title=miR-155-5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32196916
|abstract=Aging impairs the functions of human mesenchymal stem cells ([[MSC]]s), thereby severely reducing their beneficial effects on myocardial infarction (MI). MicroRNAs (miRNAs) play crucial roles in regulating the senescence of [[MSC]]s; however, the underlying mechanisms remain unclear. Here, we investigated the significance of miR-155-5p in regulating [[MSC]] senescence and whether inhibition of miR-155-5p could rejuvenate aged [[MSC]]s (A[[MSC]]s) to enhance their therapeutic efficacy for MI. Young [[MSC]]s (Y[[MSC]]s) and A[[MSC]]s were isolated from young and aged donors, respectively. The cellular senescence of [[MSC]]s was evaluated by senescence-associated β-galactosidase (SA-β-gal) staining. Compared with Y[[MSC]]s, A[[MSC]]s exhibited increased cellular senescence as evidenced by increased SA-β-gal activity and decreased proliferative capacity and paracrine effects. The expression of miR-155-5p was much higher in both serum and [[MSC]]s from aged donors than young donors. Upregulation of miR-155-5p in Y[[MSC]]s led to increased cellular senescence, whereas downregulation of miR-155-5p decreased A[[MSC]] senescence. Mechanistically, miR-155-5p inhibited mitochondrial fission and increased mitochondrial fusion in [[MSC]]s via the AMPK signaling pathway, thereby resulting in cellular senescence by repressing the expression of Cab39. These effects were partially reversed by treatment with AMPK activator or mitofusin2-specific siRNA (Mfn2-siRNA). By enhancing angiogenesis and promoting cell survival, transplantation of anti-miR-155-5p-A[[MSC]]s led to improved cardiac function in an aged mouse model of MI compared with transplantation of A[[MSC]]s. In summary, our study shows that miR-155-5p mediates [[MSC]] senescence by regulating the Cab39/AMPK signaling pathway and miR-155-5p is a novel target to rejuvenate A[[MSC]]s and enhance their cardioprotective effects.

|keywords=* mesenchymal stem cells
* miR-155-5p
* myocardial infarction
* rejuvenation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189985
}}
{{medline-entry
|title=Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32154253
|abstract=Aging is associated with high prevalence of chronic degenerative diseases that take a large part of the increasing burden of morbidities in a growing demographic of elderly people. Aging is a complex process that involves cell autonomous and cell non-autonomous mechanisms where senescence plays an important role. Senescence is characterized by the loss of proliferative potential, resistance to cell death by apoptosis and expression of a senescence-associated secretory phenotype (SASP). SASP includes pro-inflammatory cytokines and chemokines, tissue-damaging proteases, growth factors; all contributing to tissue microenvironment alteration and loss of tissue homeostasis. Emerging evidence suggests that the changes in the number and composition of extracellular vesicles (EVs) released by senescent cells contribute to the adverse effects of senescence in aging. In addition, age-related alterations in mesenchymal stem/stromal cells ([[MSC]]s) have been associated to dysregulated functions. The loss of functional stem cells necessary to maintain tissue homeostasis likely directly contributes to aging. In this review, we will focus on the characteristics and role of EVs isolated from senescent [[MSC]]s, the potential effect of [[MSC]]-derived EVs in aging and discuss their therapeutic potential to improve age-related diseases.

|keywords=* aging
* clinical translation
* extracellular vesicles
* mesenchymal stem cells
* regenerative medicine
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047768
}}
{{medline-entry
|title=Molecular Mechanisms Contributing to Mesenchymal Stromal Cell Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32098040
|abstract=Mesenchymal stem/stromal cells ([[MSC]]s) are a reservoir for tissue homeostasis and repair that age during organismal aging. Beside the fundamental in vivo role of [[MSC]]s, they have also emerged in the last years as extremely promising therapeutic agents for a wide variety of clinical conditions. [[MSC]] use frequently requires in vitro expansion, thus exposing cells to replicative senescence. Aging of [[MSC]]s (both in vivo and in vitro) can affect not only their replicative potential, but also their properties, like immunomodulation and secretory profile, thus possibly compromising their therapeutic effect. It is therefore of critical importance to unveil the underlying mechanisms of [[MSC]] senescence and to define shared methods to assess [[MSC]] aging status. The present review will focus on current scientific knowledge about [[MSC]] aging mechanisms, control and effects, including possible anti-aging treatments.

|keywords=* MSC senescence
* in vitro aging
* in vivo aging
* mesenchymal stem/stromal cells (MSC)
* rejuvenating strategies
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072652
}}
{{medline-entry
|title=Inhibition of DNA Methyltransferase by RG108 Promotes Pluripotency-Related Character of Porcine Bone Marrow Mesenchymal Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32125888
|abstract=Mesenchymal stem/stromal cells ([[MSC]]s) have been identified in almost all adult human tissues and been used in numerous clinical trials for a variety of diseases. Studies have shown that [[MSC]]s would undergo cellular senescence when cultured over a long term, which is brought on by increased epigenetic modifications, including DNA methylation. However, the mechanism of [[MSC]]s senescence is not well studied. In this study, the effects of RG108, a DNA methyltransferase inhibitor (DNMTi), on senescence, apoptosis, and pluripotency gene expressions in porcine bone marrow (pBM)-[[MSC]]s were investigated. First, we determined the optimized dose and time of RG108 treatment in pBM-[[MSC]]s to be 10 μM for 48 hours, respectively. Under these conditions, the pluripotency genes ([i]NANOG[/i], [i]POU5F1[/i]), the anti-senescence genes ([i]TERT[/i], [i]bFGF[/i]), and the anti-apoptosis gene ([i]BCL2[/i]) were increased, whereas the apoptotic gene ([i]BAX[/i]) was decreased. RG108 protected against apoptosis when pBM-[[MSC]] induces apoptosis with H O  for 1.5 hours. We also found that RG108 significantly induced the expression of [i]NANOG[/i] and [i]POU5F1[/i] by decreasing DNA methylation in gene promoter regions. These results indicate that an optimized dose of RG108 may promote the pluripotency-related character of pBM-[[MSC]]s through improving cellular anti-senescence, anti-apoptosis, and pluripotency, which provide a better cell origin for stem cell therapy.

|keywords=* RG108
* apoptosis
* pluripotency
* porcine bone marrow mesenchymal stem cells
* senescence
|full-text-url=https://sci-hub.do/10.1089/cell.2019.0060
}}
{{medline-entry
|title=Extracellular Vesicles of Stem Cells to Prevent BRONJ.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32119600
|abstract=Extracellular vesicles (EVs), several tens to hundreds of nanometers in size, are vesicles secreted by cells for intercellular communication. EVs released from mesenchymal stem cells ([[MSC]]-EVs) have the potential to treat multiple diseases. This study aimed to determine the effects of [[MSC]]-EVs on bisphosphonate-related osteonecrosis of the jaw (BRONJ), whose pathogenesis and treatment are not yet established. To this end, zoledronic acid (ZOL) was administered to bone marrow cells and fibroblasts in vitro. In vivo, a BRONJ model was produced by administering ZOL to rats and extracting teeth. Each [[MSC]]-EV-treated and nontreated group was compared histologically and molecularly. In vitro, the nontreated group showed an increased number of β-galactosidase-positive cells and expression of senescence-associated genes [i]p21, pRB[/i] and senescence-related inflammatory cytokines. Conversely, [[MSC]]-EV administration decreased the number of senescent cells and expression levels of [i]p21, pRB[/i] and inflammatory cytokines. In vivo, in the nontreated group, the socket was partially uncovered by the oral epithelium, leaving an exposed bone. Conversely, in the [[MSC]]-EV-treated group, the socket was healed. Besides, in the nontreated group, β-galactosidase-positive cells existed in the socket and colocalized with the CD90 and periostin-positive cells. However, there were few β-galactosidase-positive cells in the [[MSC]]-EV-treated group. Furthermore, gene expression of stem cell markers [i]Bmi1[/i] and [i]Hmga2[/i] and the vascular endothelial marker [i]VEGF[/i] was significantly increased in the [[MSC]]-EV-treated group, compared with that in the nontreated group. These results indicate that [[MSC]]-EVs prevent ZOL-induced senescence in stem cells, osteoblasts, and fibroblasts and reduce inflammatory cytokines. Furthermore, administration of [[MSC]]-EVs prevented senescence of cells involved in wound healing and the spread of chronic inflammation around senescent cells, thereby promoting angiogenesis and bone regeneration and preventing BRONJ.

|keywords=* bisphosphonate-associated osteonecrosis of the jaw
* cellular senescence
* exosomes
* mesenchymal stem cells
* wound healing
* zoledronic acid
|full-text-url=https://sci-hub.do/10.1177/0022034520906793
}}
{{medline-entry
|title=Ginsenoside Rg1 as an Effective Regulator of Mesenchymal Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32038244
|abstract=Recently, breakthroughs have been made in the use of mesenchymal stem cells ([[MSC]]s) to treat various diseases. Several stem cell types have been authorized as drugs by the European Medicines Agency and the U.S. Food and Drug Administration. The Chinese official document "Notification of the management of stem cell clinical research (trial)" was also published in August 2015. Currently, China has approved 106 official stem cell clinical research filing agencies and 62 clinical research projects, which are mostly focused on [[MSC]] therapy. Hence, the optimization and development of stem cell drugs is imperative. During this process, maximizing [[MSC]] expansion, minimizing cell loss during [[MSC]] transplantation, improving the homing rate, precisely regulating the differentiation of [[MSC]]s, and reducing [[MSC]] senescence and apoptosis are major issues in [[MSC]] preclinical research. Similar to artemisinin extracted from the stems and leaves of [i]Artemisia annua[/i], ginsenoside Rg1 (Rg1) is purified from the root or stem of ginseng. In the human body, Rg1 regulates organ function, which is inseparable from its regulation of adult stem cells. Rg1 treatment may effectively regulate the proliferation, differentiation, senescence, and apoptosis of [[MSC]]s in different microenvironments [i]in vitro[/i] or [i]in vivo[/i]. In this review, we discuss recent advances in understanding the effect of Rg1 on [[MSC]]s and describe the issues that must be addressed and prospects regarding Rg1 regulation of [[MSC]]s in preclinical or clinical studies.

|keywords=* apoptosis
* differentiation
* ginsenoside Rg1
* mesenchymal stem cells
* preclinical study
* proliferation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989539
}}
{{medline-entry
|title=The Importance of Stem Cell Senescence in Regenerative Medicine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32026416
|abstract=Mesenchymal stem cells ([[MSC]]s) are an interesting tool in regenerative medicine and a unique cell-based therapy to treat aging-associated diseases. Successful [[MSC]] therapy needs a large-scale cell culture, and requires a prolonged in vitro cell culture that subsequently leads to cell senescence. Administration of senescent [[MSC]]s results in inefficient cell differentiation in the clinical setting. Therefore, it is of utmost importance to enhance our knowledge about the aging process and methods to detect cell senescence in order to overcome this challenge. Numerous studies have addressed senescence in various aspects. Here, we review the characteristics of [[MSC]]s, how aging affects their features, mechanisms involved in aging of [[MSC]]s, and potential approaches to detect [[MSC]] senescence in vitro.

|keywords=* Aging
* Mesenchymal stem cell
* Regenerative medicine
|full-text-url=https://sci-hub.do/10.1007/5584_2020_489
}}
{{medline-entry
|title=Control of mesenchymal stem cell biology by histone modifications.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32025282
|abstract=Mesenchymal stem cells ([[MSC]]s) are considered the most promising seed cells for regenerative medicine because of their considerable therapeutic properties and accessibility. Fine-tuning of cell biological processes, including differentiation and senescence, is essential for achievement of the expected regenerative efficacy. Researchers have recently made great advances in understanding the spatiotemporal gene expression dynamics that occur during osteogenic, adipogenic and chondrogenic differentiation of [[MSC]]s and the intrinsic and environmental factors that affect these processes. In this context, histone modifications have been intensively studied in recent years and have already been indicated to play significant and universal roles in [[MSC]] fate determination and differentiation. In this review, we summarize recent discoveries regarding the effects of histone modifications on [[MSC]] biology. Moreover, we also provide our insights and perspectives for future applications.

|keywords=* Cell biology
* Cell differentiation
* Cellular senescence
* Epigenetics
* Histone modifications
* Mesenchymal stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996187
}}
{{medline-entry
|title=Impact of mesenchymal stem cell senescence on inflammaging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31964472
|abstract=Life expectancy has dramatically increased around the world over the last few decades, and staying healthier longer, without chronic disease, has become an important issue. Although understanding aging is a grand challenge, our understanding of the mechanisms underlying the degeneration of cell and tissue functions with age and its contribution to chronic disease has greatly advanced during the past decade. As our immune system alters with aging, abnormal activation of immune cells leads to imbalance of innate and adaptive immunity and develops a persistent and mild systemic inflammation, inflammaging. With their unique therapeutic properties, such as immunomodulation and tissue regeneration, mesenchymal stem cells ([[MSC]]s) have been considered to be a promising source for treating autoimmune disease or as anti-aging therapy. Although direct evidence of the role of [[MSC]]s in inflammaging has not been thoroughly studied, features reported in senescent [[MSC]]s or the aging process of [[MSC]]s are associated with inflammaging; [[MSC]] niche-driven skewing of hematopoiesis toward the myeloid lineage or oncogenesis, production of pro-inflammatory cytokines, and weakening their modulative property on macrophage polarization, which plays a central role on inflammaging development. This review explores the role of senescent [[MSC]]s as an important regulator for onset and progression of inflammaging and as an effective target for anti-aging strategies. [BMB Reports 2020; 53(2): 65-73].
|mesh-terms=* Aging
* Cellular Senescence
* Cytokines
* Hematopoiesis
* Humans
* Immunomodulation
* Immunosenescence
* Inflammation
* Macrophages
* Mesenchymal Stem Cells

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061209
}}
{{medline-entry
|title=Late Rescue Therapy with Cord-Derived Mesenchymal Stromal Cells for Established Lung Injury in Experimental Bronchopulmonary Dysplasia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31918630
|abstract=Bronchopulmonary dysplasia (BPD), the main complication of extreme prematurity, has lifelong consequences for lung health. Mesenchymal stromal cells ([[MSC]]s) prevent lung injury in experimental BPD in newborn rodents when given in the immediate neonatal period. Whether [[MSC]] therapy can restore normal lung growth after established lung injury in adulthood is clinically relevant, but currently unknown. Experimental BPD was achieved by exposing newborn rats to 95% O  from postnatal days 4-14. Human umbilical cord-derived [[MSC]]s were intratracheally administered to rats (1 × 10 cells/kg body weight) as a single dose at 3 or 6 months of age followed by assessment at 5 or 8 months of age, respectively. Lung alveolar structure and vessel density were histologically analyzed. O -exposed rats exhibited persistent lung injury characterized by arrested alveolar growth with airspace enlargement and a lower vessel density at both 5 and 8 months of age compared with controls. Single-dose [[MSC]] treatment at 3 months partially attenuated O -induced alveolar injury and restored vessel density at 5 months. Treatment with a single dose at 6 months did not attenuate alveolar injury or vessel density at 8 months. However, treatment with multiple [[MSC]] doses at 6, 6.5, 7, and 7.5 months significantly attenuated alveolar injury and improved vessel density at 8 months of age. Treatment of the adult BPD lung with [[MSC]]s has the potential to improve lung injury if administered in multiple doses or at an early stage of adulthood.

|keywords=* COPD
* aging
* lung
* newborn
* regenerative medicine
* stem cells
|full-text-url=https://sci-hub.do/10.1089/scd.2019.0116
}}
{{medline-entry
|title=Low-Level Radiofrequency Exposure Does Not Induce Changes in [[MSC]] Biology: An in vitro Study for the Prevention of NIR-Related Damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31908499
|abstract=The ubiquitous diffusion of radiofrequency (RF) radiation across human living environments has attracted the attention of scientists. Though the adverse health effects of RF exposure remain debatable, it has been reported that the interaction of such radiation with biological macromolecular structures can be deleterious for stem cells, inducing impairment of their main functions involving self-renewal and differentiation. The purpose of this study was to determine whether exposure to RF of 169 megahertz (MHz) that is part of very high radiofrequency (VHF) range 30-300 MHz, could cause damage to stem cells by inducing senescence and loss of regenerative and DNA repair capacity. The study was conducted on mesenchymal stromal cells ([[MSC]]s) containing a subpopulation of stem cells. The [[MSC]]s were exposed to RFs of 169 MHz administered via an open meter 2G "Smart Meter" for different durations of time. We did not observe modifications in [[MSC]] biology as a result of the RF exposure conducted in our experiments. We concluded that [[MSC]]s are insensitive to RF radiation exposure at 169 MHz for various time intervals, including longer durations.

|keywords=* 169 MHz
* CFU
* senescence
* stem cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927227
}}
{{medline-entry
|title=Macrophage migration inhibitory factor rejuvenates aged human mesenchymal stem cells and improves myocardial repair.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31881006
|abstract=The beneficial functions of mesenchymal stem cells ([[MSC]]s) decline with age, limiting their therapeutic efficacy for myocardial infarction (MI). Macrophage migration inhibitory factor (MIF) promotes cell proliferation and survival. We investigated whether MIF overexpression could rejuvenate aged [[MSC]]s and increase their therapeutic efficacy in MI. Young and aged [[MSC]]s were isolated from the bone marrow of young and aged donors. Young [[MSC]]s, aged [[MSC]]s, and MIF-overexpressing aged [[MSC]]s were transplanted into the peri-infarct region in a rat MI model. Aged [[MSC]]s exhibited a lower proliferative capacity, lower MIF level, greater cell size, greater senescence-associated-β-galactosidase activity, and weaker paracrine effects than young [[MSC]]s. Knocking down MIF in young [[MSC]]s induced cellular senescence, whereas overexpressing MIF in aged [[MSC]]s reduced cellular senescence. MIF rejuvenated aged [[MSC]]s by activating autophagy, an effect largely reversed by the autophagy inhibitor 3-methyladenine. MIF-overexpressing aged [[MSC]]s induced angiogenesis and prevented cardiomyocyte apoptosis to a greater extent than aged [[MSC]]s, and had improved heart function and cell survival more effectively than aged [[MSC]]s four weeks after MI. Thus, MIF rejuvenated aged [[MSC]]s by activating autophagy and enhanced their therapeutic efficacy in MI, suggesting a novel [[MSC]]-based therapeutic strategy for cardiovascular diseases in the aged population.
|mesh-terms=* Adolescent
* Aged
* Aged, 80 and over
* Aging
* Animals
* Animals, Newborn
* Cellular Senescence
* Humans
* Macrophage Migration-Inhibitory Factors
* Mesenchymal Stem Cell Transplantation
* Mesenchymal Stem Cells
* Myocardial Infarction
* Myocardium
* Myocytes, Cardiac
* Rats
* Rats, Sprague-Dawley
* Young Adult
|keywords=* macrophage migration inhibitory factor
* mesenchymal stem cells
* myocardial infarction
* rejuvenation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949107
}}
{{medline-entry
|title=Influence of olive oil and its components on mesenchymal stem cell biology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31875868
|abstract=Extra virgin olive oil is characterized by its high content of unsaturated fatty acid residues in triglycerides, mainly oleic acid, and the presence of bioactive and antioxidant compounds. Its consumption is associated with lower risk of suffering chronic diseases and unwanted processes linked to aging, due to the antioxidant capacity and capability of its components to modulate cellular signaling pathways. Consumption of olive oil can alter the physiology of mesenchymal stem cells ([[MSC]]s). This may explain part of the healthy effects of olive oil consumption, such as prevention of unwanted aging processes. To date, there are no specific studies on the action of olive oil on [[MSC]]s, but effects of many components of such food on cell viability and differentiation have been evaluated. The objective of this article is to review existing literature on how different compounds of extra virgin olive oil, including residues of fatty acids, vitamins, squalene, triterpenes, pigments and phenols, affect [[MSC]] maintenance and differentiation, in order to provide a better understanding of the healthy effects of this food. Interestingly, most studies have shown a positive effect of these compounds on [[MSC]]s. The collective findings support the hypothesis that at least part of the beneficial effects of extra virgin olive oil consumption on health may be mediated by its effects on [[MSC]]s.

|keywords=* Aging
* Cellular differentiation
* Cellular niche
* Mediterranean diet
* Mesenchymal stem cells
* Olive oil
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904865
}}
{{medline-entry
|title=Epigenetic Regulation of Mesenchymal Stem Cell Homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31866188
|abstract=Mesenchymal stem cells ([[MSC]]s) have putative roles in maintaining adult tissue health, and the functional decline of [[MSC]]s has emerged as a crucial pathophysiological driver of various diseases. Epigenetic regulation is essential for establishing and preserving [[MSC]] homeostasis in vivo. Furthermore, growing evidence suggests that epigenetic dysregulation contributes to age- and disease-associated [[MSC]] alterations. Epigenetic marks in [[MSC]]s can be amplified through self-renewal divisions and transmitted to differentiated progeny, further perpetuating their role in tissue maintenance and pathogenesis. We review the epigenetic regulation of [[MSC]] homeostasis, emphasizing its contributions to organismal health and disease. Understanding these epigenetic mechanisms could hold promise as targets for [[MSC]]-mediated regenerative therapies.

|keywords=* aging
* epigenetics
* fate decision
* mesenchymal stem cells
* pathogenesis
* regeneration
|full-text-url=https://sci-hub.do/10.1016/j.tcb.2019.11.006
}}
{{medline-entry
|title=Mesenchymal Stem Cells: Allogeneic [[MSC]] May Be Immunosuppressive but Autologous [[MSC]] Are Dysfunctional in Lupus Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31799252
|abstract=Mesenchymal stem cells ([[MSC]]s) have a potently immunosuppressive capacity in both innate and adaptive immune responses. Consequently, [[MSC]]s transplantation has emerged as a potential beneficial therapy for autoimmune diseases even though the mechanisms underlying the immunomodulatory activity of [[MSC]]s is incompletely understood. Transplanted [[MSC]]s from healthy individuals with no known history of autoimmune disease are immunosuppressive in systemic lupus erythematosus (SLE) patients and can ameliorate SLE disease symptoms in those same patients. In contrast, autologous [[MSC]]s from SLE patients are not immunosuppressive and do not ameliorate disease symptoms. Recent studies have shown that [[MSC]]s from SLE patients are dysfunctional in both proliferation and immunoregulation and phenotypically senescent. The senescent phenotype has been attributed to multiple genes and signaling pathways. In this review, we focus on the possible mechanisms for the defective phenotype and function of [[MSC]]s from SLE patients and summarize recent research on [[MSC]]s in autoimmune diseases.

|keywords=* dysfunction
* immunoregulatory
* mesenchymal stem cells
* senescence
* systemic lupus erythematosus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874144
}}
{{medline-entry
|title=Effects of high glucose conditions on the expansion and differentiation capabilities of mesenchymal stromal cells derived from rat endosteal niche.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31752674
|abstract=Mesenchymal stromal cells in the endosteal niche lining compact bone (CB-[[MSC]]s) represent a heterogeneous population, all of which contribute to bone repair and remodelling. Hyperglycaemia associated with type 2 diabetes mellitus (T2DM) can delay and impair the bone healing process. Therefore, this study investigated the influences of high (25 mM) glucose conditions on CB-[[MSC]] populations isolated from male Wistar rats, versus normal (5.5 mM) glucose conditions; in terms of proliferation (population doublings, PDs), senescence characteristics, stem cell marker expression, colony forming efficiencies (CFEs); and osteogenic/adipogenic differentiation, following extended culture in vitro. CB-[[MSC]]s under both normoglycaemic and hyperglycaemic conditions demonstrated similar morphologies and rapid exponential growth to >300PDs, although high glucose conditions promoted more rapid and persistent proliferation beyond ~50PDs, with few indications of senescence. Limited senescence was confirmed by minimal SA-β-galactosidase staining, low senescence marker (p53, p21 , p16 ) expression and positive telomere maintenance marker (rTERT, TR) expression. However, telomere lengths varied throughout culture expansion, with hyperglycaemia significantly reducing telomere lengths at PD50 and PD200. Furthermore, CB-[[MSC]]s expanded in normal and high glucose conditions remained non-transformed, exhibiting similar [[MSC]] (CD73/CD90/CD105), multipotency (CD146) and embryonic (Slug, Snail) markers throughout extended culture, but negligible hematopoietic (CD34/CD45) or pluripotency (Nanog, Oct4) markers. Hyperglycaemia significantly increased CFEs at PD50 and PD100, which decreased at PD200. CB-[[MSC]] osteogenic differentiation was also inhibited by hyperglycaemia at PD15, PD100 and PD200, but not at PD50. Hyperglycaemia inhibited CB-[[MSC]] adipogenic differentiation to a lesser extent at PD15 and PD50, with reduced adipogenesis overall at PD100 and PD200. This study demonstrates the limited negative impact of hyperglycaemia on the proliferative and stem cell characteristics of heterogeneous CB-[[MSC]] populations, although minor sub-population(s) appear more susceptible to these conditions leading to impaired osteogenic/adipogenic differentiation capabilities. Such findings potentially highlight the impact of hyperglycaemia on CB-[[MSC]] bone repair capabilities in situ.
|mesh-terms=* Adipogenesis
* Animals
* Biomarkers
* Bone Regeneration
* Bone and Bones
* Cell Differentiation
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Diabetes Mellitus, Type 2
* Glucose
* Hyperglycemia
* Male
* Mesenchymal Stem Cells
* Osteogenesis
* Rats, Wistar
|keywords=* Bone repair
* Cellular senescence
* Differentiation
* Hyperglycaemia
* Mesenchymal stromal cells; Endosteum
* Type II diabetes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873668
}}
{{medline-entry
|title=Autophagy inhibits the mesenchymal stem cell aging induced by D-galactose through ROS/JNK/p38 signalling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31675454
|abstract=Autophagy and cellular senescence are two critical responses of mammalian cells to stress and may have a direct relationship given that they respond to the same set of stimuli, including oxidative stress, DNA damage, and telomere shortening. Mesenchymal stem cells ([[MSC]]s) have emerged as reliable cell sources for stem cell transplantation and are currently being tested in numerous clinical trials. However, the effects of autophagy on [[MSC]] senescence and corresponding mechanisms have not been fully evaluated. Several studies demonstrated that autophagy level increases in aging [[MSC]]s and the downregulation of autophagy can delay [[MSC]] senescence, which is inconsistent with most studies that showed autophagy could play a protective role in stem cell senescence. To further study the relationship between autophagy and [[MSC]] senescence and explore the effects and mechanisms of premodulated autophagy on [[MSC]] senescence, we induced the up- or down-regulation of autophagy by using rapamycin (Rapa) or 3-methyladenine, respectively, before [[MSC]] senescence induced by D-galactose (D-gal). Results showed that pretreatment with Rapa for 24 hours remarkably alleviated [[MSC]] aging induced by D-gal and inhibited ROS generation. p-Jun N-terminal kinases (JNK) and p-38 expression were also clearly decreased in the Rapa group. Moreover, the protective effect of Rapa on [[MSC]] senescence can be abolished by enhancing the level of ROS, and p38 inhibitor can reverse the promoting effect of H  O  on [[MSC]] senescence. In summary, the present study indicates that autophagy plays a protective role in [[MSC]] senescence induced by D-gal, and ROS/JNK/p38 signalling plays an important mediating role in autophagy-delaying [[MSC]] senescence.

|keywords=* ROS/JNK/p38 signalling
* autophagy
* mesenchymal stem cells
* senescence
|full-text-url=https://sci-hub.do/10.1111/1440-1681.13207
}}
{{medline-entry
|title=Enhancing survival, engraftment, and osteogenic potential of mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31692976
|abstract=Mesenchymal stem cells ([[MSC]]s) are promising candidates for bone regeneration therapies due to their plasticity and easiness of sourcing. [[MSC]]-based treatments are generally considered a safe procedure, however, the long-term results obtained up to now are far from satisfactory. The main causes of these therapeutic limitations are inefficient homing, engraftment, and osteogenic differentiation. Many studies have proposed modifications to improve [[MSC]] engraftment and osteogenic differentiation of the transplanted cells. Several strategies are aimed to improve cell resistance to the hostile microenvironment found in the recipient tissue and increase cell survival after transplantation. These strategies could range from a simple modification of the culture conditions, known as cell-preconditioning, to the genetic modification of the cells to avoid cellular senescence. Many efforts have also been done in order to enhance the osteogenic potential of the transplanted cells and induce bone formation, mainly by the use of bioactive or biomimetic scaffolds, although alternative approaches will also be discussed. This review aims to summarize several of the most recent approaches, providing an up-to-date view of the main developments in [[MSC]]-based regenerative techniques.

|keywords=* Anoikis
* Bioactive scaffolds
* Bone regeneration
* Engraftment
* Homing
* Hypoxia
* Mesenchymal stem cells
* Osteogenesis
* Preconditioning
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828596
}}
{{medline-entry
|title=Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31644429
|abstract=Tissue accumulation of p16 -positive senescent cells is associated with age-related disorders, such as osteoarthritis (OA). These cell-cycle arrested cells affect tissue function through a specific secretory phenotype. The links between OA onset and senescence remain poorly described. Using experimental OA protocol and transgenic [i]Cdkn2a[/i]  and [i]Cdkn2a[/i]  mice, we found that the senescence-driving p16  is a marker of the disease, expressed by the synovial tissue, but is also an actor: its somatic deletion partially protects against cartilage degeneration. We test whether by becoming senescent, the mesenchymal stromal/stem cells ([[MSC]]s), found in the synovial tissue and sub-chondral bone marrow, can contribute to OA development. We established an [i]in vitro[/i] p16 -positive senescence model on human [[MSC]]s. Upon senescence induction, their intrinsic stem cell properties are altered. When co-cultured with OA chondrocytes, senescent [[MSC]] show also a seno-suppressive properties impairment favoring tissue degeneration. To evaluate [i]in vivo[/i] the effects of p16 -senescent [[MSC]] on healthy cartilage, we rely on the SAMP8 mouse model of accelerated senescence that develops spontaneous OA. [[MSC]]s isolated from these mice expressed p16 . Intra-articular injection in 2-month-old C57BL/6JRj male mice of SAMP8-derived [[MSC]]s was sufficient to induce articular cartilage breakdown. Our findings reveal that senescent p16 -positive [[MSC]]s contribute to joint alteration.
|mesh-terms=* Animals
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Chondrocytes
* Coculture Techniques
* Collagenases
* Etoposide
* Gene Expression Regulation
* Humans
* Inflammation
* Luciferases
* Male
* Mesenchymal Stem Cells
* Mice
* Mice, Inbred Strains
* Mice, Transgenic
* Osteoarthritis
* Paracrine Communication
|keywords=* mesenchymal stem cell
* osteoarthritis
* senescence
* tissue homeostasis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834426
}}
{{medline-entry
|title=Embryonic stem cell-derived extracellular vesicles enhance the therapeutic effect of mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31660081
|abstract= Embryonic stem cells (ES) have a great potential for cell-based therapies in a regenerative medicine. However, the ethical and safety issues limit its clinical application. ES-derived extracellular vesicles (ES-EVs) have been reported suppress cellular senescence. Mesenchymal stem cells ([[MSC]]s) are widely used for clinical cell therapy. In this study, we investigated the beneficial effects of ES-EVs on aging [[MSC]]s to further enhancing their therapeutic effects.   [i]In vitro[/i], we explored the rejuvenating effects of ES-EVs on senescent [[MSC]]s by senescence-associated β-gal (SA-β-gal) staining, immunostaining, and DNA damage foci analysis. The therapeutic effect of senescent [[MSC]] pre-treated with ES-EVs was also evaluated by using mouse cutaneous wound model.   We found that ES-EVs significantly rejuvenated the senescent [[MSC]]s [i]in vitro[/i] and improve the therapeutic effects of [[MSC]]s in a mouse cutaneous wound model. In addition, we also identified that the IGF1/PI3K/AKT pathway mediated the antisenescence effects of ES-EVs on [[MSC]]s.   Our results suggested that ES cells derived-extracellular vesicles possess the antisenescence properties, which significantly rejuvenate the senescent [[MSC]]s and enhance the therapeutic effects of [[MSC]]s. This strategy might emerge as a novel therapeutic strategy for [[MSC]]s clinical application.
|mesh-terms=* Animals
* Cell- and Tissue-Based Therapy
* Cellular Senescence
* Disease Models, Animal
* Embryonic Stem Cells
* Extracellular Vesicles
* Humans
* Insulin-Like Growth Factor I
* Mesenchymal Stem Cell Transplantation
* Mesenchymal Stem Cells
* Mice
* Mice, Inbred BALB C
* Phosphatidylinositol 3-Kinases
* Wounds and Injuries
|keywords=* Cellular senescence
* Embryonic stem cells
* Extracellular vesicles
* IGF1/PI3K/AKT pathway
* Mesenchymal stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815953
}}
{{medline-entry
|title=Survival of aging CD264  and CD264  populations of human bone marrow mesenchymal stem cells is independent of colony-forming efficiency.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31612990
|abstract=In vivo mesenchymal stem cell ([[MSC]]) survival is relevant to therapeutic applications requiring engraftment and potentially to nonengraftment applications as well. [[MSC]]s are a mixture of progenitors at different stages of cellular aging, but the contribution of this heterogeneity to the survival of [[MSC]] implants is unknown. Here, we employ a biomarker of cellular aging, the decoy TRAIL receptor CD264, to compare the survival kinetics of two cell populations in human bone marrow [[MSC]] (hBM-[[MSC]]) cultures. Sorted CD264  hBM-[[MSC]]s from two age-matched donors have elevated β-galactosidase activity, decreased differentiation potential and form in vitro colonies inefficiently relative to CD264  hBM-[[MSC]]s. Counterintuitive to their aging phenotype, CD264  hBM-[[MSC]]s exhibited comparable survival to matched CD264  hBM-[[MSC]]s from the same culture during in vitro colony formation and in vivo when implanted ectopically in immunodeficient NIH III mice. In vitro and in vivo survival of these two cell populations were independent of colony-forming efficiency. These findings have ramifications for the preparation of hBM-[[MSC]] therapies given the prevalence of aging CD264  cells in hBM-[[MSC]] cultures and the popularity of colony-forming efficiency as a quality control metric in preclinical and clinical studies with [[MSC]]s.

|keywords=* aging
* decoy TRAIL receptor 2 (CD264)
* mesenchymal stem cells
* survival
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906265
}}
{{medline-entry
|title=Differential effects of extracellular vesicles from aging and young mesenchymal stem cells in acute lung injury.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31575829
|abstract=Old age is a known risk factor for mortality in acute respiratory distress syndrome (ARDS)/acute lung injury. Mesenchymal stem cells ([[MSC]]s) possess potent immunomodulatory properties, while aging [[MSC]]s have reduced capacity. Recent studies have demonstrated that [[MSC]]-derived extracellular vesicles ([[MSC]]-EVs) are able to mimic [[MSC]]s in alleviating acute lung injury. The goals of this study were to determine whether EVs from young and aging [[MSC]]s had differential effects on lipopolysaccharide (LPS)-induced lung injury in young mice and unravel the underlying mechanisms. Our results showed that both aging and young [[MSC]]-EVs had similar physical and phenotypical properties. As their parental cells, young [[MSC]]-EVs alleviated LPS-induced acute lung injury, while aging [[MSC]]-EVs did not exhibit the protective effects. In contrast to young [[MSC]]-EVs, aging [[MSC]]-EVs failed to alter macrophage phenotypes and reduce macrophage recruitment. In addition, the internalization of aging [[MSC]]-EVs by macrophages was significantly lower compared with that of young [[MSC]]-EVs. Furthermore, aging and young [[MSC]]-EVs differed in levels of several miRNAs relating macrophage polarization. In conclusion, aging and young [[MSC]]-EVs have differential effects in alleviating acute lung injury and macrophage polarization, which may be associated with internalization of EVs and their miRNA content.
|mesh-terms=* Acute Lung Injury
* Age Factors
* Animals
* Disease Models, Animal
* Extracellular Vesicles
* Mesenchymal Stem Cell Transplantation
* Mesenchymal Stem Cells
* Mice
* Treatment Outcome
|keywords=* ARDS
* acute lung injury
* aging
* extracellular vesicles
* mesenchymal stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781978
}}
{{medline-entry
|title=Connexin43 is Dispensable for Early Stage Human Mesenchymal Stem Cell Adipogenic Differentiation But is Protective against Cell Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31514306
|abstract=In the last couple of decades, there has been a growing optimism surrounding the potential transformative use of human mesenchymal stem cells ([[MSC]]s) and human-induced pluripotent stem cells (iPSCs) for regenerative medicine and disease treatment. In order for this to occur, it is first essential to understand the mechanisms underpinning their cell-fate specification, which includes cell signaling via gap junctional intercellular communication. Here, we investigated the role of the prototypical gap junction protein, connexin43 (Cx43), in governing the differentiation of iPSCs into [[MSC]]s and [[MSC]] differentiation along the adipogenic lineage. We found that control iPSCs, as well as iPSCs derived from oculodentodigital dysplasia patient fibroblasts harboring a [i]GJA1[/i] (Cx43) gene mutation, successfully and efficiently differentiated into LipidTox and perilipin-positive cells, indicating cell differentiation along the adipogenic lineage. Furthermore, the complete CRISPR-Cas9 ablation of Cx43 from iPSCs did not prevent their differentiation into bona fide [[MSC]]s or pre-adipocytes, strongly suggesting that even though Cx43 expression is upregulated during adipogenesis, it is expendable. Interestingly, late passage Cx43-ablated [[MSC]]s senesced more quickly than control cells, resulting in failure to properly differentiate in vitro. We conclude that despite being upregulated during adipogenesis, Cx43 plays no detectable role in the early stages of human iPSC-derived [[MSC]] adipogenic differentiation. However, Cx43 may play a more impactful role in protecting [[MSC]]s from premature senescence.
|mesh-terms=* Adipogenesis
* Cell Differentiation
* Cellular Senescence
* Connexin 43
* Gene Expression Regulation
* Humans
* Mesenchymal Stem Cells
* Time Factors
|keywords=* CRISPR-Cas9
* adipogenesis
* connexin43
* gap junctional intercellular communication
* mesenchymal stem cells
* oculodentodigital dysplasia
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770901
}}
{{medline-entry
|title=Maintained Properties of Aged Dental Pulp Stem Cells for Superior Periodontal Tissue Regeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31440385
|abstract=Owing to excellent therapeutic potential, mesenchymal stem cells ([[MSC]]s) are gaining increasing popularity with researchers worldwide for applications in tissue engineering, and in treatment of inflammation-related and age-related disorders. However, the senescence of [[MSC]]s over passaging has limited their clinical application owing to adverse effect on physiological function maintenance of tissues as well as disease treatment. An inflammatory microenvironment is one of the key contributors to [[MSC]] senescence, resulting in low regeneration efficiency. Therefore, [[MSC]]s with high resistance to cellular senescence would be a benefit for tissue regeneration. Toward this end, we analyzed the senescence properties of different types of stem cells during culture and under inflammation, including dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), bone marrow mesenchymal stem cells (BM[[MSC]]s), and adipose-derived stem cells (ADSCs). Overall, the DPSCs had higher proliferation rates, lower cellular senescence, and enhanced osteogenesis maintenance compared to those of non-dental [[MSC]]s cultured from passage three to six. The expression profiles of genes related to apoptosis, cell cycle, and cellular protein metabolic process (contributing to the cell self-renewal ability and metabolic processes) significantly differed between DPSCs and BM[[MSC]]s at passage three. Moreover, DPSCs were superior to BM[[MSC]]s with regards to resistance to lipopolysaccharide-induced apoptosis and senescence, with enhanced osteogenesis [i]in vitro[/i], and showed improved periodontal regeneration after injection in a miniature pig periodontitis model [i]in vivo[/i]. Overall, the present study indicates that DPSCs show superior resistance to subculture and inflammation-induced senescence and would be suitable stem cells for tissue engineering with inflammation.

|keywords=* inflammation
* mesenchymal stem cells
* periodontitis
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675537
}}
==SIRT1==

{{medline-entry
|title=Anthocyanins attenuate endothelial dysfunction through regulation of uncoupling of nitric oxide synthase in aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33274583
|abstract=Endothelial dysfunction is one of the main age-related arterial phenotypes responsible for cardiovascular disease (CVD) in older adults. This endothelial dysfunction results from decreased bioavailability of nitric oxide (NO) arising downstream of endothelial oxidative stress. In this study, we investigated the protective effect of anthocyanins and the underlying mechanism in rat thoracic aorta and human vascular endothelial cells in aging models. In vitro, cyanidin-3-rutinoside (C-3-R) and cyanidin-3-glucoside (C-3-G) inhibited the d-galactose (d-gal)-induced senescence in human endothelial cells, as indicated by reduced senescence-associated-β-galactosidase activity, p21, and p16  . Anthocyanins blocked d-gal-induced reactive oxygen species (ROS) formation and NADPH oxidase activity. Anthocyanins reversed d-gal-mediated inhibition of endothelial nitric oxide synthase (eNOS) serine phosphorylation and [[SIRT1]] expression, recovering NO level in endothelial cells. Also, [[SIRT1]]-mediated eNOS deacetylation was shown to be involved in anthocyanin-enhanced eNOS activity. In vivo, anthocyanin-rich mulberry extract was administered to aging rats for 8 weeks. In vivo, mulberry extract alleviated endothelial senescence and oxidative stress in the aorta of aging rats. Consistently, mulberry extract also raised serum NO levels, increased phosphorylation of eNOS, increased [[SIRT1]] expression, and reduced nitrotyrosine in aortas. The eNOS acetylation was higher in the aging group and was restored by mulberry extract treatment. Similarly, [[SIRT1]] level associated with eNOS decreased in the aging group and was restored in aging plus mulberry group. These findings indicate that anthocyanins protect against endothelial senescence through enhanced NO bioavailability by regulating ROS formation and reducing eNOS uncoupling.

|keywords=* NO
* SIRT1
* anthocyanins
* eNOS deacetylation
* senescence
|full-text-url=https://sci-hub.do/10.1111/acel.13279
}}
{{medline-entry
|title=Sirtuins and Their Implications in Neurodegenerative Diseases from a Drug Discovery Perspective.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33280374
|abstract=Sirtuins are class III histone deacetylase (HDAC) enzymes that target both histone and non-histone substrates. They are linked to different brain functions and the regulation of different isoforms of these enzymes is touted to be an emerging therapy for the treatment of neurodegenerative diseases (NDs), including Parkinson's disease (PD), Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS). The level of sirtuins affects brain health as many sirtuin-regulated pathways are responsible for the progression of NDs. Certain sirtuins are also implicated in aging, which is a risk factor for many NDs. In addition to [[SIRT1]]-3, it has been suggested that the less studied sirtuins (SIRT4-7) also play critical roles in brain health. This review delineates the role of each sirtuin isoform in NDs from a disease centric perspective and provides an up-to-date overview of sirtuin modulators and their potential use as therapeutics in these diseases. Furthermore, the future perspectives for sirtuin modulator development and their therapeutic application in neurodegeneration are outlined in detail, hence providing a research direction for future studies.

|keywords=* Aging
* neurodegenerative diseases
* neuroprotective
* sirtuin
* sirtuin activators
* sirtuin inhibitors
|full-text-url=https://sci-hub.do/10.1021/acschemneuro.0c00696
}}
{{medline-entry
|title=Effects of alpha-mangostin on memory senescence induced by high glucose in human umbilical vein endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33149857
|abstract=Hyperglycemia induces cellular senescence in various body cells, such as vascular endothelial cells. Since the vessels are highly distributed in the body and nourish all tissues, vascular damages cause diabetes complications such as kidney failure and visual impairment. Alpha-mangostin is a xanthone found in mangosteen fruit with protective effects in metabolic syndrome and diabetes. This paper has investigated the protective effect of this xanthone against high glucose-induced memory senescence in human vascular endothelial cells (HUVECs) in the presence of metformin, as a positive control. To induce the memory senescence model, HUVECs, after three days incubation with high glucose, were incubated with normal glucose for another three days, and for whole six days, cells were treated with metformin (50 µM) or alpha-mangostin (1.25 µM). On the last day, cell viability by MTT assay, oxidative stress by fluorimetric assay, the number of senescent cells by SA beta-galactosidase staining kit, and secretory interleukin-6 by ELISA kit were measured. [[SIRT1]] and P53 proteins were also evaluated by Western blotting. Metformin and alpha-mangostin significantly increased cell viability, decreased reactive oxygen species, and senescence-associated beta-galactosidase in HUVECs incubated in metabolic memory condition. Generally, metabolic memory increased p53 and acetyl-P53 and decreased [[SIRT1]] proteins in HUVECs, which were reversed by alpha-mangostin and metformin. These data exhibit that alpha-mangostin, comparable to metformin, protects endothelial cells against metabolic memory-induced senescence, which is likely via [[SIRT1]].

|keywords=* Cellular senescence
* Diabetes
* Diabetes complications
* Endothelial cells
* Garcinia mangostana
* Hyperglycemia
* Mangostin
* Metabolic syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585532
}}
{{medline-entry
|title=[[SIRT1]] Activation Using CRISPR/dCas9 Promotes Regeneration of Human Corneal Endothelial Cells through Inhibiting Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33158256
|abstract=Human corneal endothelial cells (hCECs) are restricted in proliferative capacity in vivo. Reduction in the number of hCEC leads to persistent corneal edema requiring corneal transplantation. This study demonstrates the functions of [[SIRT1]] in hCECs and its potential for corneal endothelial regeneration. Cell morphology, cell growth rates and proliferation-associated proteins were compared in normal and senescent hCECs. [[SIRT1]] was activated using the CRISPR/dCas9 activation system ([[SIRT1]]a). The plasmids were transfected into CECs of six-week-old Sprague-Dawley rats using electroporation and cryoinjury was performed. Senescent cells were larger, elongated and showed lower proliferation rates and lower [[SIRT1]] levels. [[SIRT1]] activation promoted the wound healing of CECs. In vivo transfection of [[SIRT1]]a promoted the regeneration of CECs. The proportion of the S-phase cells was lower in senescent cells and elevated upon [[SIRT1]]a activation. [[SIRT1]] regulated cell proliferation, proliferation-associated proteins, mitochondrial membrane potential, and oxidative stress levels. In conclusion, corneal endothelial senescence is related with a decreased [[SIRT1]] level. [[SIRT1]]a promotes the regeneration of CECs by inhibiting cytokine-induced cell death and senescence. Gene function activation therapy using [[SIRT1]]a may serve as a novel treatment strategy for hCEC diseases.

|keywords=* CRISPR/dCas9
* SIRT1
* corneal endothelial cells
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694272
}}
{{medline-entry
|title=Histone Deacetylase [[SIRT1]], Smooth Muscle Cell Function, and Vascular Diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33117155
|abstract=Vascular smooth muscle cells (VSMCs), located in the media of artery, play key roles in maintaining the normal vascular physiological functions. Abnormality in VSMCs is implicated in vascular diseases (VDs), including atherosclerosis, abdominal aortic aneurysm (AAA), aortic dissection, and hypertension by regulating the process of inflammation, phenotypic switching, and extracellular matrix degradation. Sirtuins (SIRTs), a family of proteins containing seven members (from [[SIRT1]] to SIRT7) in mammals, function as NAD -dependent histone deacetylases and ADP-ribosyltransferases. In recent decades, great attention has been paid to the cardiovascular protective effects of SIRTs, especially [[SIRT1]], suggesting a new therapeutic target for the treatment of VDs. In this review, we introduce the basic functions of [[SIRT1]] against VSMC senescence, and summarize the contribution of [[SIRT1]] derived from VSMCs in VDs. Finally, the potential new strategies based on [[SIRT1]] activation have also been discussed with an emphasis on [[SIRT1]] activators and calorie restriction to improve the prognosis of VDs.

|keywords=* SIRT1
* SIRT1 activators
* calorie restriction
* senescence
* vascular diseases
* vascular smooth muscle cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7573826
}}
{{medline-entry
|title=6,4'-dihydroxy-7-methoxyflavanone protects against H O -induced cellular senescence by inducing [[SIRT1]] and inhibiting phosphatidylinositol 3-kinase/Akt pathway activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33111210
|abstract=6, 4'-Dihydroxy-7-methoxyflavanone (DMF) has been shown to possess anti-inflammatory, anti-oxidative, and neuroprotective activities. However, its effect on oxidative stress-induced aging remains undemonstrated. This study aimed at investigating the anti-senescence effect of DMF on hydrogen peroxide (H O )-induced premature senescence, and associated molecular mechanisms in human dermal fibroblasts (HDFs). The cells were DMF pretreated with small interfering RNA (siRNAs) of control or sirtuin 1 ([[SIRT1]]) before H O  exposure, and western blot analysis, senescence-associated β-galactosidase (SA-β-gal) activity, cell counting, gene silencing, and [[SIRT1]] activity assay were performed. Pretreatment with DMF inhibited H O -induced senescence phenotypes, which showed decreased SA-β-gal activity and increased cell growth in comparison with H O -treated HDFs. Meanwhile, the decreases in ac-p53, p21 , and p16  and the increases in pRb and cyclin D1 were observed. DMF was also found to induce [[SIRT1]] expression and activity level concentration- and time-dependently. Moreover, [[SIRT1]] inhibition abrogated DMF senescence prevention. Additionally, Akt and ERK were activated with different kinetics after H O  exposure, and Akt activity inhibition attenuated SA-β-gal activity augmentation. We also found that DMF inhibited H O -induced Akt phosphorylation. This study indicates that DMF effectively protects against oxidative stress-induced premature senescence through [[SIRT1]] expression up-regulation and Akt pathway inhibition in HDFs. These results suggest that DMF can be a potential therapeutic molecule for age-related diseases, or a protective agent against the aging process.

|keywords=* 6,4′-dihydroxy-7-methoxyflavanone
* Akt
* Oxidative stress
* Premature senescence
* SIRT1
|full-text-url=https://sci-hub.do/10.1007/s11010-020-03951-z
}}
{{medline-entry
|title=Isoparvifuran isolated from Dalbergia odorifera attenuates H O -induced senescence of BJ cells through [[SIRT1]] activation and AKT/mTOR pathway inhibition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33010892
|abstract=Isoparvifuran is a benzofuran compound isolated from the heartwood of Dalbergia odorifera. Related research reported that isoparvifuran has antioxidant property. However, it is unclear whether isoparvifuran has anti-aging effects. In this research, we established an aging model, hydrogen peroxide (H O )-induced BJ cell senescence, to explore the protective effect of isoparvifuran on cell senescence and its related mechanisms. Our results revealed that isoparvifuran obviously attenuated H O -induced cell senescence, increased the cell proliferation rate,and reversed senescence-associated molecular markers expression such as cyclin D1, pRb, caveolin-1, ace-p53, p21 and p16. Moreover, isoparvifuran dose and time dependently increased the expression level of Sirtuin 1 ([[SIRT1]]) in BJ cells. The inhibition of [[SIRT1]] obviously reversed the reduction of SA-β-gal activity and the alteration of senescence-associated molecular markers induced by isoparvifuran. Additionally, isoparvifuran also inhibited H O -induced AKT and S6 phosphorylation and increase of SA-β-gal activity. In summary, isoparvifuran protects BJ cells from H O -induced premature senescence, the anti-senescence effect of isoparvifuran is associated with the activation of [[SIRT1]] and the suppression of AKT/mTOR signaling pathway.

|keywords=* AKT/mTOR signaling pathway
* Antioxidant: SIRT1
* Cellular senescence
* Isoparvifuran
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2020.09.096
}}
{{medline-entry
|title=[[SIRT1]] Is the Target Gene for 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-Glucoside Alleviating the HUVEC Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33013385
|abstract=This study aimed to explore the effects of 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-d-glucoside (TSG) on the senescence of human umbilical vein cells (HUVEC) induced by hydrogen peroxide (H O ) and to identify the potential targets mediating its protective action. HUVEC cells pre-treated with TSG for 24 h were exposed to H O  treatment. TSG significantly decreased H O -induced cellular senescence, as indicated by reduced senescence-associated β-galactosidase (SA-β-gal) positive staining, the proportion of cells in the G1 phase, cell apoptosis, p21, and plasminogen activator inhibitor-1 (PAI-1) expression. Moreover, TSG promoted Sirtuin 1 ([[SIRT1]]) expression. When [[SIRT1]] was inhibited by EX527 or [[SIRT1]] siRNA, the effect of TSG is diminished according to the increased proportion of cells in the G1 phase, cell apoptosis, p21, and PAI-1 expression. Overall, our study established TSG as an anti-senescence compound that exerts its protective action by regulating [[SIRT1]] expression.

|keywords=* 2,3,5,4’-tetrahydroxystilbene-2-O-β-d-glucoside
* SIRT1
* human umbilical vein cells
* hydrogen peroxide
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508177
}}
{{medline-entry
|title=The Role of Sirtuins in Kidney Diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32932720
|abstract=Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, [[SIRT1]]-7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

|keywords=* acute kidney injury
* aging kidney
* chronic kidney disease
* diabetic nephropathy
* kidney
* sirtuins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555196
}}
{{medline-entry
|title=The effect of 12-week resistance exercise training on serum levels of cellular aging process parameters in elderly men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32919015
|abstract=Regular physical activity has a positive effect on the prevention of cellular aging. The present study investigated the effect of 12-week resistance training (RT) on serum levels of Sirtuin-1 ([[SIRT1]]), Sirtuin-3 (SIRT3), Sirtuin-6 (SIRT6), Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α), and telomerase enzyme in elderly men. For this purpose, 30 elderly men (age 66.23 ± 0.57 years) were randomly divided into two groups: resistance training group (RET, n = 15) and control group (CTR, n = 15). Participants in RET performed RT protocols with intensity of 60% one-repetition maximum (3×/week, 4 sets of the six exercise circuits). Body composition, physical functioning and, blood samples were assessed before (pre-test) and after (post-test) a 12-week intervention. The results showed that there was a significant increase in serum levels of [[SIRT1]] (P = 0.001), SIRT3 (P = 0.001), SIRT6 (P = 0.02), PGC1-α (P = 0.001), and telomerase enzyme (P = 0.001) in RET. Also, we found a significant difference between the RET and CTR in serum levels of [[SIRT1]] (P = 0.001), SIRT3 (P = 0.001), SIRT6 (P = 0.037), PGC1-α (P = 0.007), and telomerase enzyme (P = 0.001). 12-Week RT increased the levels of proteins associated with the biological aging process in elderly men. It seems that the RT may have beneficial effects on cellular senescence and also improved impaired mitochondrial protein and enzymatic functional induced aging.

|keywords=* Cellular senescence
* Elderly
* Resistance training
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111090
}}
{{medline-entry
|title=Virus-Induced Asthma Exacerbations: [[SIRT1]] Targeted Approach.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32823491
|abstract=The prevalence of asthma has increased worldwide. Asthma exacerbations triggered by upper respiratory tract viral infections remain a major clinical problem and account for hospital admissions and time lost from work. Virus-induced asthma exacerbations cause airway inflammation, resulting in worsening asthma and deterioration in the patients' quality of life, which may require systemic corticosteroid therapy. Despite recent advances in understanding the cellular and molecular mechanisms underlying asthma exacerbations, current therapeutic modalities are inadequate for complete prevention and treatment of these episodes. The pathological role of cellular senescence, especially that involving the silent information regulator 2 homolog sirtuin (SIRT) protein family, has recently been demonstrated in stable and exacerbated chronic respiratory disease states. This review discusses the role of [[SIRT1]] in the pathogenesis of bronchial asthma. It also discusses the role of [[SIRT1]] in inflammatory cells that play an important role in virus-induced asthma exacerbations. Recent studies have hypothesized that [[SIRT1]] is one of major contributors to cellular senescence. [[SIRT1]] levels decrease in Th2 and non-Th2-related airway inflammation, indicating the role of [[SIRT1]] in several endotypes and phenotypes of asthma. Moreover, several models have demonstrated relationships between viral infection and [[SIRT1]]. Therefore, targeting [[SIRT1]] is a novel strategy that may be effective for treating virus-induced asthma exacerbations in the future.

|keywords=* SIRT1
* asthma
* cellular senescence
* exacerbations
* virus infection
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464235
}}
{{medline-entry
|title=Novel resveratrol derivatives have diverse effects on the survival, proliferation and senescence of primary human fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32793997
|abstract=Resveratrol alters the cytokinetics of mammalian cell populations in a dose dependent manner. Concentrations above 25-50 µM typically trigger growth arrest, senescence and/or apoptosis in multiple different cell types. In contrast, concentrations below 10 µM enhance the growth of log phase cell cultures and can rescue senescence in multiple strains of human fibroblasts. To better understand the structural features that regulate these effects, a panel of 24 structurally-related resveralogues were synthesised and evaluated for their capacity to activate [[SIRT1]], as determined by an ex-vivo [[SIRT1]] assay, their toxicity, as measured by lactate dehydrogenase release, and their effects on replicative senescence in MRC5 human fibroblasts as measured by their effects on Ki67 immunoreactivity and senescence-associated β galactosidase activity. Minor modifications to the parent stilbene, resveratrol, significantly alter the biological activities of the molecules. Replacement of the 3,5-dihydroxy substituents with 3,5-dimethoxy groups significantly enhances [[SIRT1]] activity, and reduces toxicity. Minimising other strong conjugative effects also reduces toxicity, but negatively impacts [[SIRT1]] activation. At 100 µM many of the compounds, including resveratrol, induce senescence in primary MRC5 cells in culture. Modifications that reduce or remove this effect match those that reduce toxicity leading to a correlation between reduction in labelling index and increase in LDH release. At 10 µM, the majority of our compounds significantly enhance the growth fraction of log phase cultures of MRC5 cells, consistent with the rescue of a subpopulation of cells within the culture from senescence. [[SIRT1]] activation is not required for rescue to occur but enhances the size of the effect.

|keywords=* Resveratrol
* SIRT1
* Senescence
* Toxicity
|full-text-url=https://sci-hub.do/10.1007/s10522-020-09896-6
}}
{{medline-entry
|title=Glucose restriction delays senescence and promotes proliferation of HUVECs via the AMPK/[[SIRT1]]-FOXA3-Beclin1 pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32768436
|abstract=Caloric restriction (CR) is an important means to delay senescence, and glucose restriction is one of the measures to achieve CR. On the basis of our previous work and bioinformatics analysis, we hypothesized that glucose restriction can up-regulate autophagy, inhibit senescence and promote proliferation via the AMPK/[[SIRT1]]-FOXA3-Beclin1 pathway in human umbilical vein endothelial cells (HUVECs). We found that compared with 5.5 mmol/L and 25 mmol/L glucose, 2.5 mmol/L glucose restriction significantly reduced senescence, enhanced autophagy, increased migration speed, relieved G /G  phase arrest and enhanced proliferation of HUVECs. Furthermore, glucose restriction up-regulated AMPKα1, [[SIRT1]], FOXA3 and Beclin1 expression in HUVECs. Additionally, we demonstrated that AMPKα1 phosphorylated FOXA3 at S170 and S305 in the cytoplasm and promoted FOXA3 nuclear translocation under glucose restriction. FOXA3 in the nucleus was deacetylated by [[SIRT1]] at K214 and K221. Deacetylated FOXA3 specifically bound to +109 C in the Beclin1 transcriptional regulatory region, and significantly enhanced Beclin1 transcription and expression. siRNA knock down of AMPKα1, [[SIRT1]], FOXA3 or Beclin1 expression impaired the glucose restriction-induced inhibition of senescence, enhanced autophagy, increased migration, and induced proliferation of HUVECs. This study confirmed that glucose restriction can enhance autophagy, inhibit senescence, and enhance proliferation of HUVECs through the AMPK/[[SIRT1]]-FOXA3-Beclin1 pathway.

|keywords=* Beclin1
* Endothelial cells
* FOXA3
* Glucose restriction
* Proliferation
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111053
}}
{{medline-entry
|title=Therapeutic Effects of SRT2104 on Lung Injury in Rats with Emphysema via Reduction of Type II Alveolar Epithelial Cell Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32722945
|abstract=Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and severe diseases worldwide with high societal and health care costs. The pathogenesis of COPD is very complicated, and no curative treatment is available. Cellular senescence promotes the development of COPD. Type II alveolar epithelial cells (AECII) play a momentous role in lung tissue repair and maintenance of alveolar homeostasis. Sirtuin 1 ([[SIRT1]]), an antiaging molecule involved in the response to chronic inflammation and oxidative stress, regulates many pathophysiological changes including stress resistance, apoptosis, inflammation, and cellular senescence. This study aimed to investigate whether the pharmacological [[SIRT1]] activator SRT2104 protects against AECII senescence in rats with emphysema. Our findings confirmed that SRT2104 administration reduced the pathological characteristics of emphysema and improved lung function parameters, including pulmonary resistance, pulmonary dynamic compliance, and peak expiratory flow. Moreover, SRT2104 treatment upregulated the expression of surfactant proteins A and C, [[SIRT1]], and forkhead box O 3a (FoxO3a), decreased senescence-associated-β-galactosidase (SA-β-gal) activity, increased [[SIRT1]] deacetylase activity, and downregulated the levels of p53 and p21. Therefore, SRT2104 administration protected against AECII senescence in rats with emphysema via [[SIRT1]]/FoxO3a and [[SIRT1]]/p53 signaling pathways and may provide a novel potential therapeutic strategy for COPD.

|keywords=* Sirtuin 1
* alveolar epithelial cells
* cellular senescence
* chronic obstructive pulmonary disease
* cigarette smoking
|full-text-url=https://sci-hub.do/10.1080/15412555.2020.1797657
}}
{{medline-entry
|title=Latifolin Inhibits Oxidative Stress-Induced Senescence via Upregulation of [[SIRT1]] in Human Dermal Fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32404543
|abstract=Latifolin, a natural flavonoid found in Dalbergia odorifera T. Chen, has been reported to exhibit anti-inflammatory and anticarcinogenic activities in vitro. However, the anti-aging effects of latifolin are unknown. In this study, we selected a model in vitro system, hydrogen peroxide (H O )-induced senescence in human dermal fibroblasts (HDFs), to examine the protective effects of latifolin against senescence and the detailed molecular mechanisms involved. Latifolin reversed the senescence-like phenotypes of the oxidant-challenged model, including senescence-associated β-galactosidase (SA-β-gal) staining, cell proliferation, and the expression of senescence-related proteins, such as caveolin-1, ac-p53, p21 , p16 , pRb, and cyclinD1. We also found that latifolin induced the expression of silent information regulator 1 ([[SIRT1]]) in a concentration- and time-dependent manner, and the anti-senescence effect of latifolin was abrogated by [[SIRT1]] inhibition. Latifolin also suppressed the activation of Akt and S6K1 and attenuated the increase in SA-β-gal activity after H O  exposure. Our results indicate that latifolin exerts protective effects against senescence in HDFs and that induction of [[SIRT1]] and inhibition of the mammalian target of rapamycin (mTOR) pathway are key mediators of its anti-aging effects.

|keywords=* human dermal fibroblast
* latifolin
* mammalian target of rapamycin
* oxidative stress
* senescence
* silent information regulator 1
|full-text-url=https://sci-hub.do/10.1248/bpb.b20-00094
}}
{{medline-entry
|title=SRT1720-induced activation of [[SIRT1]] alleviates vascular smooth muscle cell senescence through PKA-dependent phosphorylation of AMPKα at Ser485.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32421926
|abstract=Aging is a major risk factor for hypertension and atherosclerosis, and vascular smooth muscle cell (VSMC) senescence can promote aging-related vascular diseases. Sirtuin-1 ([[SIRT1]]) and AMP-activated protein kinase (AMPK) were previously reported to modulate vascular senescence; however, its effects have not been well characterized. To determine the nature of the interaction between [[SIRT1]] and AMPK in VSMC senescence, we investigated the effects of SRT1720 on its downstream targets of [[SIRT1]] and the phosphorylation of AMPKα at Ser485. During Adriamycin-induced VSMC senescence, SRT1720 increased the activity of [[SIRT1]] and AMPKα phosphorylation at Ser485 via the cAMP-protein kinase A (PKA) pathway. Telomere length and telomerase reverse transcriptase expression were increased by [[SIRT1]] activation with SRT1720. Taken together, these data show that activation of the [[SIRT1]]/cAMP-PKA/p-AMPKα (Ser485) pathway may be an effective antisenescence mechanism for VSMCs.

|keywords=* SIRT1
* SRT1720
* VSMC senescence
* p-AMPK (Ser485)
* telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327920
}}
{{medline-entry
|title=miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32292498
|abstract=Postmenopausal osteoporosis (PMOP) is a severe health issue faced by postmenopausal women. microRNA-128 (miR-128) is associated with aging, inflammatory signaling, and inflammatory diseases, such as PMOP. It has also been reported to modulate [i]in vitro[/i] osteogenic/adipogenic differentiation. However, its function in osteoclast formation is unknown.  : First, the expression of [i]miR-128[/i] and nuclear factor of activated T cells 1 ([i]Nfatc1,[/i] bone resorption master marker) was investigated in bone tissues derived from PMOP patients, while their correlation to each other was also investigated. The levels of [i]miR-128[/i] and [i]Nfatc1[/i] in bone specimens and bone marrow-derived macrophages (BMMs) from mice subjected to ovariectomy (OVX) were also assayed. Next, we employed mice BMMs modified for overexpression and inhibition of miR-128 levels to determine its effect on osteoclast differentiation. Moreover, we generated osteoclastic miR-128 conditional knockout ([i]miR-128 [/i] ) mice and isolated miR-128 deletion-BMMs to observe its biological function on bone phenotype and osteoclastogenesis [i]in vivo[/i], respectively. The [i]miR-128 [/i] BMMs were used to explore the downstream regulatory mechanisms using pull-down, luciferase reporter, and western-blotting assays. Finally, the impact of miR-128 deficiency on OVX-induced bone loss in mice was evaluated.  : The miR-128 level was found to be positively correlated with the increase in [i]Nfatc1[/i] level in mouse/human bone specimens and mouse primary BMMs. [i]In vitro[/i] experiments demonstrated miR-128 levels that were dependent on activity of osteoclast differentiation and miR-128 overexpression or inhibition in BMMs significantly increased or decreased osteoclastogenesis, respectively. [i]In vivo[/i], we revealed that osteoclastic miR-128 deletion remarkedly increased bone mass through the inhibition of osteoclastogenesis. Mechanistically, we identified sirtuin 1 ([[SIRT1]]) as the direct target of miR-128 at the post-transcriptional level during osteoclast differentiation. Increased levels of [[SIRT1]] reduced nuclear factor κB (NF-κB) activity by decreasing the level of acetylation of Lysine 310, as well as inhibiting tumor necrosis factor-α (Tnf-α) and interleukin 1 (IL-1) expressions. Lastly, osteoclastic deletion of miR-128 significantly suppressed OVX-triggered osteoclastogenesis and exerted a protective effect against bone loss in mice.  : Our findings reveal a critical mechanism for osteoclastogenesis that is mediated by the miR-128/[[SIRT1]]/NF-κB signaling axis, highlighting a possible avenue for the further exploration of diagnostic and therapeutic target molecules in PMOP.

|keywords=* PMOP
* aging
* inflammation
* miR-128
* osteoclastogenesis
* ovariectomy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150474
}}
{{medline-entry
|title=Lymphocyte senescence in COPD is associated with decreased sirtuin 1 expression in steroid resistant pro-inflammatory lymphocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32270742
|abstract=The class III NAD-dependent histone deacetylase (HDAC) sirtuin 1 ([[SIRT1]]) is an important regulator of senescence, aging, and inflammation. [[SIRT1]]de-acetylates chromatin histones, thereby silencing inflammatory gene transcription. We have reported increased steroid-resistant senescent pro-inflammatory CD28nullCD8+ T cells in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that [[SIRT1]] is reduced in these cells in COPD, and that treatment with [[SIRT1]] activators (resveratrol, curcumin) and agents preventing NAD depletion (theophylline) would upregulate [[SIRT1]] and reduce pro-inflammatory cytokine expression in these steroid-resistant cells. Blood was collected from [i]n[/i] = 10 COPD and [i]n[/i] = 10 aged-matched controls. Expression of CD28, [[SIRT1]], and pro-inflammatory cytokines was determined in CD8+ and CD8- T and natural killer T (NKT)-like cells cultured in the presence of ±1 µM prednisolone, ±5 mg/L theophylline, ±1 µM curcumin, ±25 µM resveratrol, using flow cytometry and immunofluorescence. There was an increase in the percentage of CD28nullCD8+ T and NKT-like cells in COPD patients compared with controls. Decreased [[SIRT1]] expression was identified in CD28nullCD8+T and NKT-like cells compared with CD28+ counterparts from both patients and controls (e.g. CD28null 11 ± 3% [i]versus[/i] CD28+ 57 ± 9%). Loss of [[SIRT1]] was associated with increased production of IFNγ and TNFα, steroid resistance, and disease severity. [[SIRT1]] expression was upregulated in the presence of all drugs and was associated with a decrease in steroid resistance and IFNγ and TNFα production by CD28nullCD8+T and NKT-like cells. The presence of the [[SIRT1]] inhibitor, EX-527 negated [by 92 ± 12% (median ± SEM)] the effect of the [[SIRT1]] activator SRT720 on the percentage of CD8+ T cells producing IFNγ and TNFα. Steroid resistance in pro-inflammatory CD28nullCD8+ T and NKT-like cells is associated with decreased [[SIRT1]] expression. Treatment with prednisolone, in combination with theophylline, curcumin or resveratrol increases [[SIRT1]] expression, restores steroid sensitivity, and inhibits pro-inflammatory cytokine production from these cells and may reduce systemic inflammation in COPD. [i]The reviews of this paper are available via the supplemental material section.[/i]

|keywords=* CD28nullCD8+ T and NKT-like cells
* COPD
* IFNγ and TNFα
* SIRT1
* lymphocyte senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153179
}}
{{medline-entry
|title=Therapeutic effects of hydro-alcoholic leaf extract of Withania somnifera on age-induced changes in daily rhythms of Sirt1, Nrf2 and Rev-erbα in the SCN of male Wistar rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32249404
|abstract=The temporal expression pattern of the circadian clock genes are known to be altered/attenuated with advance in age. Withania somnifera (WS) essentially consists of numerous active constituents including withanolides is known to have antioxidant, anti-inflammatory and adaptogenic properties. We have earlier demonstrated therapeutic effects of hydro-alcoholic leaf extract of WS on the age-induced alterations in the levels and daily rhythms of various clock genes such as rBmal1, rPer1, rPer2 and rCry1. We have now studied effects of hydro-alcoholic leaf extract of WS on the age-induced alterations in the levels and daily rhythms of expression of [[SIRT1]] (an NAD  dependent histone deacetylase and a modulator of clock) and NRF2 (a clock controlled gene and a master transcription factor regulating various endogenous antioxidant enzymes) in addition to rRev-erbα in SCN of adult [3 months (m)], middle-aged (12 m) and old-aged (24 m) male Wistar rats. The daily rhythms of rNrf2 expression showed 6 h phase delay in middle age and 12 h phase advance in old age. WS restored rSirt1 daily rhythms and phase in old age whereas it restored the phase of rNrf2 in the SCN of both middle and old aged animals. At protein level, [[SIRT1]] expression showed phase advances in 12 m and 24 m whereas NRF2 daily rhythms were abolished in both the age groups. WS restored the phase and daily rhythms of [[SIRT1]] as well as NRF2 in 12 m old rats. However, rRev-erbα expression was found insensitive to WS treatment in all the age groups studied. Pairwise correlation analysis demonstrated significant stoichiometric interactions among rSirt1, rNrf2 and rRev-erbα in 3 m which altered with aging significantly. WS treatment resulted in differential restorations of such interactions.

|keywords=* Aging
* Ashwagandha
* Circadian clock
* NRF2
* SCN
* SIRT1
|full-text-url=https://sci-hub.do/10.1007/s10522-020-09875-x
}}
{{medline-entry
|title=The Serum Concentration of Anti-Aging Proteins, Sirtuin1 and αKlotho in Patients with End-Stage Kidney Disease on Maintenance Hemodialysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32214805
|abstract=Sirtuin1 ([[SIRT1]]) acts as an anti-aging protein due to anti-apoptotic, anti-oxidative and anti-inflammatory effect and is implicated in several diseases including diabetes or cardiovascular problems. [[SIRT1]] renal overexpression indicates oxidative stress. Similarly, αKlotho was primarily exposed as anti-aging factor. It is primary produced in kidney. It's deficiency is associated with progression of chronic kidney disease and heart disorders. The aim of the study was to assess the serum concentration of sirtuin1 and αKlotho in hemodialysis (HD) patients compared to healthy volunteers in regard to age, blood pressure control, residual kidney function (RKF), diabetes, cardiovascular disease, dialysis vintage and type of dialyzer. The serum level of [[SIRT1]] and αKlotho was evaluated using ELISA tests in 103 HD patients, median age 67 years and in 21 volunteers. Blood pressure, RRF, echocardiography and dialysis parameters were assessed. HD group was divided according to the presence/absence of RKF. The serum [[SIRT1]] level was higher (28.4 vs 2.71ng/mL, p<0.0001) and αKlotho was lower (433.9 vs 756.6pg/mL, p<0.0001) in HD then in control group. αKlotho was lower in those without RKF (387.2 vs 486.2pg/mL, p=0.028). [[SIRT1]] positively correlated with hemodialysis vintage. αKlotho negatively correlated with left ventricular posterior wall thickness. There was no significant relationship between [[SIRT1]] and αKlotho level and age, blood pressure control, type of dialyzer, Kt/V and diabetes. Multivariate analysis revealed association of [[SIRT1]] with ejection fraction (B -0.72; p=0.32). Elevated [[SIRT1]] and lower αKlotho concentration are associated with impaired kidney function. The decrease in levels of αKlotho may also indicate heart hypertrophy in hemodialysis patients. The role of anti-aging proteins, particularly [[SIRT1]] as biomarkers/predictors of oxidative stress, inflammation and cardiovascular diseases need further examination.
|mesh-terms=* Age Factors
* Aged
* Aging
* Biomarkers
* Blood Pressure
* Cardiovascular Diseases
* Case-Control Studies
* Diabetes Complications
* Echocardiography
* Female
* Glucuronidase
* Heart Ventricles
* Humans
* Kidney
* Kidney Failure, Chronic
* Male
* Middle Aged
* Renal Dialysis
* Sirtuin 1
* Stroke Volume
|keywords=* chronic kidney disease
* hemodialysis
* sirtuin1
* αKlotho
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084123
}}
{{medline-entry
|title=Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32158519
|abstract=The role of epigenetics in endothelial cell senescence is a cutting-edge topic in ageing research. However, little is known of the relative contribution to pro-senescence signal propagation provided by microRNAs shuttled by extracellular vesicles (EVs) released from senescent cells. Analysis of microRNA and DNA methylation profiles in non-senescent (control) and senescent (SEN) human umbilical vein endothelial cells (HUVECs), and microRNA profiling of their cognate small EVs (sEVs) and large EVs demonstrated that SEN cells released a significantly greater sEV number than control cells. sEVs were enriched in miR-21-5p and miR-217, which target DNMT1 and [[SIRT1]]. Treatment of control cells with SEN sEVs induced a miR-21/miR-217-related impairment of DNMT1-[[SIRT1]] expression, the reduction of proliferation markers, the acquisition of a senescent phenotype and a partial demethylation of the locus encoding for miR-21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40-100 years showed an inverse U-shaped age-related trend for miR-21-5p, consistent with senescence-associated biomarker profiles. Our findings suggest that miR-21-5p/miR-217 carried by SEN sEVs spread pro-senescence signals, affecting DNA methylation and cell replication.

|keywords=* Cellular senescence
* DNMT1
* SIRT1
* extracellular vesicles
* microRNAs
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048230
}}
{{medline-entry
|title=Spatiotemporal gating of [[SIRT1]] functions by O-GlcNAcylation is essential for liver metabolic switching and prevents hyperglycemia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32152092
|abstract=Inefficient physiological transitions are known to cause metabolic disorders. Therefore, investigating mechanisms that constitute molecular switches in a central metabolic organ like the liver becomes crucial. Specifically, upstream mechanisms that control temporal engagement of transcription factors, which are essential to mediate physiological fed-fast-refed transitions are less understood. [[SIRT1]], a NAD -dependent deacetylase, is pivotal in regulating hepatic gene expression and has emerged as a key therapeutic target. Despite this, if/how nutrient inputs regulate [[SIRT1]] interactions, stability, and therefore downstream functions are still unknown. Here, we establish nutrient-dependent O-GlcNAcylation of [[SIRT1]], within its N-terminal domain, as a crucial determinant of hepatic functions. Our findings demonstrate that during a fasted-to-refed transition, glycosylation of [[SIRT1]] modulates its interactions with various transcription factors and a nodal cytosolic kinase involved in insulin signaling. Moreover, sustained glycosylation in the fed state causes nuclear exclusion and cytosolic ubiquitin-mediated degradation of [[SIRT1]]. This mechanism exerts spatiotemporal control over [[SIRT1]] functions by constituting a previously unknown molecular relay. Of note, loss of [[SIRT1]] glycosylation discomposed these interactions resulting in aberrant gene expression, mitochondrial dysfunctions, and enhanced hepatic gluconeogenesis. Expression of nonglycosylatable [[SIRT1]] in the liver abrogated metabolic flexibility, resulting in systemic insulin resistance, hyperglycemia, and hepatic inflammation, highlighting the physiological costs associated with its overactivation. Conversely, our study also reveals that hyperglycosylation of [[SIRT1]] is associated with aging and high-fat-induced obesity. Thus, we establish that nutrient-dependent glycosylation of [[SIRT1]] is essential to gate its functions and maintain physiological fitness.
|mesh-terms=* Acetylglucosamine
* Aging
* Animals
* Fasting
* Gluconeogenesis
* Glycosylation
* HEK293 Cells
* Homeostasis
* Humans
* Hyperglycemia
* Insulin Resistance
* Liver
* Male
* Mice
* Mice, Inbred C57BL
* Obesity
* Phosphorylation
* Protein Processing, Post-Translational
* Sirtuin 1
* Spatio-Temporal Analysis
|keywords=* PGC1α
* fed–fast cycle
* gluconeogenesis
* insulin signaling
* ubiquitinylation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104039
}}
{{medline-entry
|title=Hydrogen Sulfide Inhibits Homocysteine-Induced Neuronal Senescence by Up-Regulation of [[SIRT1]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32132865
|abstract=Homocysteine (Hcy) accelerates neuronal senescence and induces age-related neurodegenerative diseases. Silence signal regulating factor 1 ([[SIRT1]]) prolongs lifespan and takes neuroprotective effects. We have previously demonstrated that hydrogen sulfide (H S) prevents Hcy-induced apoptosis of neuronal cells and has neuroprotective effect. In the present work, we aimed to investigate whether H S protects HT22 cells against Hcy-induced neuronal senescence and whether [[SIRT1]] mediates this role of H S. We found that Hcy induced cellular senescence in HT22 cells, as determined by β-galactosidase staining, expressions of P16 , P21 , and trypan blue Staining, which are the markers of cellular senescence. However, sodium hydrosulfide (NaHS, the donor of H S) significantly reversed Hcy-induced cellular senescence. Interestingly, NaHS not only up-regulated the expression of [[SIRT1]] in HT22 cells but also reversed Hcy-downregulated the expression of [[SIRT1]] in HT22 cells. Furthermore, we found that pretreatment with Sirtinol (an inhibitor of [[SIRT1]]) markedly reversed the protection of NaHS against Hcy-induced HT22 cells senescence and apoptosis. Our findings illustrated that H S protects HT22 cells against Hcy-induced senescence by up-regulating [[SIRT1]].

|keywords=* SIRT1
* cell senescence
* homocysteine
* hydrogen sulfide
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053352
}}
{{medline-entry
|title=[[SIRT1]] and aging related signaling pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32084459
|abstract=Aging is a biological phenomenon in which the structure and function of organisms declining with the increasing of age. It has become a major risk factor of human diseases, including diabetes, cancers, cardiovascular diseases and neurodegenerative diseases. Silencing information regulator 2 related enzyme 1(sirtuin1, [[SIRT1]]) is an NAD -dependent deacetylase, which has been reported to be involved in the regulation of cellular senescence and aging. The expression of [[SIRT1]] is diminished with aging in mice. By contrast, increased expression of [[SIRT1]] is sufficient to extend lifespan in yeast, caenorhabditis elegans and mice. In this review, the relationship between [[SIRT1]] and aging and various signaling networks associated with aging, including NF-κB, AMPK, mTOR, P53, PGC1α, and FoxOs will be discussed. Meanwhile, the potential therapeutic strategies of targeting [[SIRT1]] to anti-aging are also addressed.

|keywords=* Aging
* Deacetylate
* NAD(+)
* SIRT1
* Signaling pathways
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111215
}}
{{medline-entry
|title=Tropisetron protects against brain aging via attenuating oxidative stress, apoptosis and inflammation: The role of [[SIRT1]] signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32088214
|abstract=The aim of this study was to elucidate the signaling pathway involved in the anti-aging effect of tropisetron and to clarify whether it affects mitochondrial oxidative stress, apoptosis and inflammation in the aging mouse brain by upregulating Sirtuin 1 or silent information regulator 1 ([[SIRT1]]). Aging was induced by d-galactose (DG) at the dose of 200 mg/kg body weight/day subcutaneously injected to male mice for six weeks. Tropisetron was simultaneously administered intraperitoneally once a day at three various doses (1, 3 and 5 mg/kg body weight). Oxidative stress and mitochondrial dysfunction markers were evaluated. Nitric oxide (NO) and pro-inflammatory cytokines levels including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were studied. Besides, the expressions of apoptosis-associated genes (Bax and Bcl-2) and the aging-related gene ([[SIRT1]]) were determined by the real time polymerase chain reaction (RT-PCR). In addition, histopathological alterations were assessed. Tropisetron reversed the induction of oxidative damage, mitochondrial dysfunction and overproduction of inflammatory mediators induced by DG in the brain tissue. In addition, tropisetron suppressed DG-induced apoptosis and found to significantly elevate [[SIRT1]] gene expression. Besides, tropisetron could markedly alleviate DG-induced abnormal changes in the brain morphology. Tropisetron exhibited anti-aging effects in the context of DG-induced senescence in mouse brain through various pathways. Our results suggest that tropisetron may attenuate DG-induced brain aging via [[SIRT1]] signaling activation.
|mesh-terms=* Aging
* Animals
* Antioxidants
* Apoptosis
* Brain
* Drug Administration Schedule
* Galactose
* Gene Expression Regulation
* Inflammation
* Injections, Intraperitoneal
* Injections, Subcutaneous
* Interleukin-6
* Male
* Mice
* Mitochondria
* Neurons
* Nitric Oxide
* Oxidative Stress
* Proto-Oncogene Proteins c-bcl-2
* Reactive Oxygen Species
* Serotonin 5-HT3 Receptor Antagonists
* Sirtuin 1
* Tropisetron
* Tumor Necrosis Factor-alpha
* bcl-2-Associated X Protein
|keywords=* Aging
* Brain
* Neurotoxicity
* Sirtuin 1
* Tropisetron
* d-galactose
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.117452
}}
{{medline-entry
|title=Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of [[SIRT1]] activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32056076
|abstract=Aging-induced structural and functional alterations of the neurovascular unit lead to impairment of neurovascular coupling responses, dysregulation of cerebral blood flow, and increased neuroinflammation, all of which contribute importantly to the pathogenesis of age-related vascular cognitive impairment (VCI). There is increasing evidence showing that a decrease in NAD  availability with age plays a critical role in age-related neurovascular and cerebromicrovascular dysfunction. Our recent studies demonstrate that restoring cellular NAD  levels in aged mice rescues neurovascular function, increases cerebral blood flow, and improves performance on cognitive tasks. To determine the effects of restoring cellular NAD  levels on neurovascular gene expression profiles, 24-month-old C57BL/6 mice were treated with nicotinamide mononucleotide (NMN), a key NAD  intermediate, for 2 weeks. Transcriptome analysis of preparations enriched for cells of the neurovascular unit was performed by RNA-seq. Neurovascular gene expression signatures in NMN-treated aged mice were compared with those in untreated young and aged control mice. We identified 590 genes differentially expressed in the aged neurovascular unit, 204 of which are restored toward youthful expression levels by NMN treatment. The transcriptional footprint of NMN treatment indicates that increased NAD  levels promote [[SIRT1]] activation in the neurovascular unit, as demonstrated by analysis of upstream regulators of differentially expressed genes as well as analysis of the expression of known [[SIRT1]]-dependent genes. Pathway analysis predicts that neurovascular protective effects of NMN are mediated by the induction of genes involved in mitochondrial rejuvenation, anti-inflammatory, and anti-apoptotic pathways. In conclusion, the recently demonstrated protective effects of NMN treatment on neurovascular function can be attributed to multifaceted sirtuin-mediated anti-aging changes in the neurovascular transcriptome. Our present findings taken together with the results of recent studies using mitochondria-targeted interventions suggest that mitochondrial rejuvenation is a critical mechanism to restore neurovascular health and improve cerebral blood flow in aging.

|keywords=* Aging
* Geroscience
* Mitochondria dysfunction
* Transcriptomics
* Vascular cognitive impairment
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206476
}}
{{medline-entry
|title=Deacetylation of MRTF-A by [[SIRT1]] defies senescence induced down-regulation of collagen type I in fibroblast cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32061777
|abstract=Aging provokes both morphological and functional changes in cells, which are accompanied by a fundamental shift in gene expression patterns. One of the characteristic alterations associated with senescence in fibroblast cells is the down-regulation of collagen type I genes. In the present study, we investigated the contribution of myocardin-related transcription factor A, or MRTF-A, in this process. In mouse embryonic fibroblast (MEF) cells and human foreskin fibroblast (HFF) cells, senescence, induced by either progressive passage or treatment with hydrogen peroxide (H O ), led to augmented lysine acetylation of MRTF-A paralleling down-regulation of collagen type I and [[SIRT1]], a lysine deacetylase. [[SIRT1]] interacted with MRTF-A to promote MRTF-A deacetylation. [[SIRT1]] over-expression or activation by selective agonists enhanced trans-activation of the collagen promoters by MRTF-A. On the contrary, [[SIRT1]] depletion or inhibition by specific antagonists suppressed trans-activation of the collagen promoters by MRTF-A. Likewise, mutation of four lysine residues within MRTF-A rendered it more potent in terms of activating the collagen promoters but unresponsive to [[SIRT1]]. Importantly, [[SIRT1]] activation in senescent fibroblasts mitigated repression of collagen type I expression whereas [[SIRT1]] inhibition promoted the loss of collagen type I expression prematurely in young fibroblasts. Mechanistically, [[SIRT1]] enhanced the affinity of MRTF-A for the collagen type I promoters. In conclusion, our data unveil a novel mechanism that underscores aging-associated loss of collagen type I in fibroblasts via [[SIRT1]]-mediated post-translational modification of MRTF-A.
|mesh-terms=* Acetylation
* Animals
* Benzamides
* Carbazoles
* Cellular Senescence
* Collagen Type I
* Down-Regulation
* Embryo, Mammalian
* Fibroblasts
* HEK293 Cells
* Heterocyclic Compounds, 4 or More Rings
* Humans
* Mice
* Mutation
* Naphthols
* Primary Cell Culture
* Promoter Regions, Genetic
* RNA, Small Interfering
* Resveratrol
* Sirtuin 1
* Trans-Activators
|keywords=* Collagen type I
* Fibroblast
* Lysine deacetylation
* Post-translational modification
* Senescence
* Transcriptional regulation
|full-text-url=https://sci-hub.do/10.1016/j.bbadis.2020.165723
}}
{{medline-entry
|title=Chronic Polyphenon-60 or Catechin Treatments Increase Brain Monoamines Syntheses and Hippocampal [[SIRT1]] Levels Improving Cognition in Aged Rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31991916
|abstract=Polyphenolic compounds from green tea have great interest due to its large consumption and therapeutic potential on the age-associated brain decline. The current work compares a similar dose regimen of a whole-green-tea extract and catechin in old rats over the course of 36 days. Results showed a significant improvement in visuo-spatial working memory and episodic memory of old rats after polyphenolic compounds administration assessed by behavioral tests. No effects were observed on the age-associated motor coordination decline. Statistically, results were correlated with significant improvements, mainly in hippocampal and striatal noradrenergic and serotonergic systems, but also with the striatal dopaminergic system. Both polyphenolic treatments also reverted the age-associated reduction of the neuroinflammation by modulating protein sirtuin 1 ([[SIRT1]]) expression in hippocampus, but no effects were observed in the usual reduction of the histone-binding protein RBAP46/48 protein linked to aging. These results are in line with previous ones obtained with other polyphenolic compounds, suggesting a general protective effect of all these compounds on the age-associated brain decline, pointing to a reduction of the oxidative stress and neuroinflammatory status reduction as the leading mechanisms. Results also reinforce the relevance of [[SIRT1]]-mediated mechanism on the neuroprotective effect and rule out the participation of RBAP46/48 protein.
|mesh-terms=* Age Factors
* Animals
* Behavior, Animal
* Biogenic Monoamines
* Catechin
* Cognition
* Cognitive Aging
* Corpus Striatum
* Hippocampus
* Male
* Memory, Episodic
* Memory, Short-Term
* Neuroprotective Agents
* Rats, Sprague-Dawley
* Sirtuin 1
* Time Factors
|keywords=* NF-κB
* RBAP46/48
* SIRT1
* brain aging
* brain monoamine synthesis
* catechin
* green tea
* memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071257
}}
{{medline-entry
|title=Duck Oil-loaded Nanoemulsion Inhibits Senescence of Angiotensin II-treated Vascular Smooth Muscle Cells by Upregulating [[SIRT1]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31970335
|abstract=Cellular senescence is associated with age-related vascular disorders and has been implicated in vascular dysfunctions. Here, we show that duck oil-loaded nanoemulsion (DO-NE) attenuates premature senescence of vascular smooth muscle cells (VSMCs) triggered by angiotensin II (Ang II). Compared with control nanoemulsion (NE), DO-NE significantly inhibited the activity of senescence-associated β-galactosidase, which is a biomarker of cellular senescence, in Ang II-treated VSMCs. [[SIRT1]] protein expression was dose- and time-dependently induced in VSMCs exposed to DO-NE, but not in those exposed to NE, and [[SIRT1]] promoter activity was also elevated. Consistently, DO-NE also dose-dependently rescued Ang II-induced repression of [[SIRT1]] expression, indicating that [[SIRT1]] is linked to the anti-senescence action of DO-NE in VSMCs treated with Ang II. Furthermore, the [[SIRT1]] agonist resveratrol potentiated the effects of DO-NE on VSMCs exposed to Ang II, whereas the [[SIRT1]] inhibitor sirtinol elicited the opposite effect. These findings indicate that DO-NE inhibits senescence by upregulating [[SIRT1]] and thereby impedes vascular aging triggered by Ang II.

|keywords=* SIRT1
* angiotensin II
* duck oil
* nanoemulsion
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957441
}}
{{medline-entry
|title=Two novel [[SIRT1]] activators, SCIC2 and SCIC2.1, enhance [[SIRT1]]-mediated effects in stress response and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31942817
|abstract=[[SIRT1]], a NAD -dependent deacetylase, is the most well-studied member of class III histone deacetylases. Due to its wide range of activities and substrate targets, this enzyme has emerged as a major regulator of different physiological processes. However, [[SIRT1]]-mediated alterations are also implicated in the pathogenesis of several conditions, including metabolic and neurodegenerative disorders, and cancer. Current evidence highlights the potential role of [[SIRT1]] as an attractive therapeutic target for disease prevention and treatment strategies, thus propelling the development of new pharmacological agents. By high-throughput screening of a large library of compounds, we identified SCIC2 as an effective [[SIRT1]] activator. This small molecule showed enzymatic activity of 135.8% at 10 μM, an AC  value of 50 ± 1.8 µM, and bound [[SIRT1]] with a K  of 26.4 ± 0.6 μM. In order to potentiate its [[SIRT1]]-activating ability, SCIC2 was subjected to modelling studies, leading to the identification of a more potent derivative, SCIC2.1. SCIC2.1 displayed higher [[SIRT1]] activity (175%; AC  = 36.83 ± 2.23 µM), stronger binding to [[SIRT1]], and greater cell permeability than SCIC2. At cellular level, both molecules did not alter the cell cycle progression of cancer cells and normal cells, and were able to strengthen [[SIRT1]]-mediated effects in stress response. Finally, SCIC2 and SCIC2.1 attenuated induction of senescence by reducing senescence-associated β-galactosidase activity. Our findings warrant further investigation of these two novel [[SIRT1]] activators in [i]in vivo[/i] and human studies.

|keywords=* Sirtuins
* drug discovery
* epigenetic modulators
* senescence
* stress response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574383
}}
{{medline-entry
|title=Hydrogen sulfide attenuates mitochondrial dysfunction-induced cellular senescence and apoptosis in alveolar epithelial cells by upregulating sirtuin 1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31881011
|abstract=Hydrogen sulfide (H S), an endogenous gaseous signal molecule, regulates many pathologies related to aging. Sirtuin 1 ([[SIRT1]]) has been shown to protect against mitochondrial dysfunction and other pathological processes, including premature senescence. This study was aimed to investigate whether and how H S attenuates senescence and apoptosis of alveolar epithelial cells via a [[SIRT1]]-dependent mechanism. Our results showed that treatment with sodium hydrosulfide (NaHS), a donor of H S, attenuated cigarette smoke extract (CSE)-induced oxidative stress, mitochondrial dysfunction, cellular senescence and apoptosis in A549 cells. This was associated with [[SIRT1]] upregulation. [[SIRT1]] activation by a pharmacological activator, SRT1720, attenuated CSE-induced oxidative stress and mitochondrial dysfunction in A549 cells. While [[SIRT1]] inhibition by EX 527 or silencing by siRNA transfection significantly attenuated or abolished the ability of NaHS to reverse the CSE-induced oxidative stress, mitochondrial dysfunction and the imbalance of mitochondrial fusion and fission. Also, [[SIRT1]] inhibition or silencing abolished the protection of NaHS against CSE-induced cellular senescence and apoptosis. In conclusion, H S attenuates CSE-induced cellular senescence and apoptosis by improving mitochondrial function and reducing oxidative stress in alveolar epithelial cells in a [[SIRT1]]-dependent manner. These findings provide novel mechanisms underlying the protection of H S against cigarette smoke-induced COPD.
|mesh-terms=* A549 Cells
* Alveolar Epithelial Cells
* Apoptosis
* Cellular Senescence
* Humans
* Hydrogen Sulfide
* Mitochondria
* Oxidative Stress
* Sirtuin 1
* Smoke
* Tobacco
* Up-Regulation
|keywords=* alveolar epithelial cell
* cigarette smoke extract
* hydrogen sulfide
* mitochondria injury
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949053
}}
{{medline-entry
|title=The protective role of omentin-1 in IL-1β-induced chondrocyte senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31852248
|abstract=Osteoarthritis is a common type of degenerative joint disease. Inflammation-related chondrocyte senescence plays a major role in the pathogenesis of osteoarthritis. Omentin-1 is a newly identified anti-inflammatory adipokine involved in lipid metabolism. In this study, we examined the biological function of omentin-1 in cultured chondrocytes. The presence of omentin-1 potently suppresses IL-1β-induced cellular senescence as revealed by staining with senescence-associated beta-galactosidase (SA-β-Gal). At the cellular level, omentin-1 attenuates IL-1β-induced G1 phase cell-cycle arrest. Mechanistically, we demonstrate that omentin-1 reduced IL-1β-induced expression of senescent factors including caveolin-1, p21, and PAI-1 as well as p53 acetylation through ameliorating [[SIRT1]] reduction. Notably, silencing of [[SIRT1]] abolishes IL-1β-induced senescence along with the induction of p21 and PAI-1, suggesting that the action of omentin-1 in chondrocytes is dependent on [[SIRT1]]. Collectively, our results revealed the molecular mechanism through which the adipokine omentin-1 exerts a beneficial effect, thereby protecting chondrocytes from senescence. Thus, omentin-1 could have clinical implication in the treatment of osteoarthritis.
|mesh-terms=* Adipokines
* Caveolin 1
* Cell Line, Tumor
* Cellular Senescence
* Chondrocytes
* Cyclin-Dependent Kinase Inhibitor p21
* Cytoprotection
* G1 Phase Cell Cycle Checkpoints
* Humans
* Interleukin-1beta
* Plasminogen Activator Inhibitor 1
* Sirtuin 1
* Transcriptional Activation
|keywords=* IL-1β
* Omentin-1
* SIRT-1
* chondrocyte senescence
|full-text-url=https://sci-hub.do/10.1080/21691401.2019.1699803
}}
{{medline-entry
|title=The Lifespan Extension Ability of Nicotinic Acid Depends on Whether the Intracellular NAD  Level Is Lower than the Sirtuin-Saturating Concentrations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31878234
|abstract=Calorie restriction can extend lifespan by increasing intracellular nicotinamide adenine dinucleotide (NAD ), thereby upregulating the activity of sirtuins ([i]Caenorhabditis elegans[/i] Sir-2.1; human [[SIRT1]]). Nicotinic acid (NA) can be metabolized to NAD ; however, the calorie restriction mimetic (CRM) potential of NA is unclear. This study explored the ability and mechanism of NA to extend the lifespan of human Hs68 cells and C. elegans. We found that NA can efficiently increase the intracellular NAD  levels in Hs68 cells and [i]C. elegans[/i]; however, NA was only able to extend the lifespan of [i]C. elegans[/i]. The steady-state NAD  level in [i]C. elegans[/i] was approximately 55 μM. When intracellular NAD  was increased by a mutation of pme-1 (poly (ADP-ribose) metabolism enzyme 1) or by pretreatment with NAD  in the medium, the lifespan extension ability of NA disappeared. Additionally, the saturating concentration of NAD  required by [[SIRT1]] was approximately 200 μM; however, the steady-state concentration of NAD  in Hs68 cells reached up to 460 μM. These results demonstrate that the lifespan extension ability of NA depends on whether the intracellular level of NAD  is lower than the sirtuin-saturating concentration in Hs68 cells and in [i]C. elegans[/i]. Thus, the CRM potential of NA should be limited to individuals with lower intracellular NAD .
|mesh-terms=* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Caloric Restriction
* Cell Line
* Humans
* NAD
* Niacin
* Sirtuins
* beta-Galactosidase
|keywords=* C. elegans
* Hs68 cells
* NAD+
* calorie restriction mimetic
* lifespan
* nicotinic acid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982340
}}
{{medline-entry
|title=Alpha-mangostin decreased cellular senescence in human umbilical vein endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31792920
|abstract=The hyperglycemic condition in diabetes induces cellular senescence in vascular endothelial cells and causes cardiovascular complications. Alpha-mangostin is a xanthone found in Garcinia mangostana, and has shown protective effects in metabolic syndrome. In this study, the anti-senescence effects of alpha-mangostin in the hyperglycemic condition are investigated. HUVECs were incubated with high glucose for 6 days and co-treated by metformin or alpha-mangostin. After 6 days, cell viability, reactive oxygen species, the percentage of senescent cells, secretory interleukin-6, and the expression of [[SIRT1]], AMPK, p53 and p21 were measured. High glucose (60 mM) significantly decreased cellular viability and increased reactive oxygen species and cellular senescence through the reduction of senescence-associated β-galactosidase activity. Moreover, high glucose increased the protein levels of p53, acetyl-p53 and p21. The protein levels of [[SIRT1]] and total AMPK were decreased by high glucose. High glucose increased the secretion of IL-6. Alpha-mangostin (1.25 μM) and metformin (50 μM) reversed the toxic effects of high glucose in HUVECs. These results show that alpha-mangostin, similar to metformin, has anti-senescence effects in high-glucose conditions, which is probably due to its antioxidant activity through the [[SIRT1]] pathway. Alpha-mangostin has previously shown anti-inflammatory effects and metabolic status improvement in animal and clinical studies. Therefore, this natural agent can be considered as a supplement to prevent vascular complications caused by high glucose in patients with diabetes. Graphical abstract.

|keywords=* Alpha-mangostin
* Diabetes
* HUVEC
* High glucose
* SIRT1
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214571
}}
{{medline-entry
|title=Central nervous system [[SIRT1]] expression is required for cued and contextual fear conditioning memory responses in aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31763496
|abstract=Sirtuin 1 ([[SIRT1]]) is a NAD -dependent enzyme that has important roles in many biological processes involved in aging, including cell growth and repair, inflammation, and energy regulation. [[SIRT1]] activity is modulated in response to certain nutritional interventions that increase healthspan and longevity in rodents, including calorie restriction (CR) and intermittent fasting (IF). In addition to positively influencing cardiometabolic health, [[SIRT1]] is important for brain health and may be critical in the preservation of memory processes that deteriorate during aging. To investigate the role of brain-associated [[SIRT1]] expression in the acquisition of fear memory in mice at 45 and 65 weeks of age. Mice with brain-specific knock-out or overexpression of [i]Sirt1[/i] were assessed on a fear conditioning paradigm to determine the role of [[SIRT1]] in fear memory acquisition. In the current study, mice lacking the expression of brain [[SIRT1]] could not learn the fear conditioning paradigm during training, context, or cue phases. The results of the study indicate that [[SIRT1]] expression in the brain is critical for the formation of fear memory in male mice at two distinct ages, highlighting the essential role of [[SIRT1]] in fear memory acquisition during aging.

|keywords=* Fear conditioning
* SIRT1
* aging
* classically conditioned memory
* hippocampus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839599
}}
{{medline-entry
|title=Does education level protect us from rapid ageing? Sirtuin expression versus age and level of education.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31785216
|abstract=SIR proteins (silent information regulators, sirtuins, [[SIRT1]] - SIRT7, SIR1 - SIR7) belong to NAD+-dependent deacetylases, enzymes taking part in a catalytic reaction of deacetylation, i.e. splitting the rest of acetic acid from protein substrates. Sirtuins play an important role in many cellular processes and are, therefore, involved in the ageing process and in the regulation of cell life. The aim of this paper is to verify the statistical hypothesis assuming the correlation between the age and level of education of examined persons and the expression of selected sirtuins (SIR1 - SIR7, [[SIRT1]] - SIRT7) at the mRNA level in the Polish population. 197 people, aged M = 38.27 (SD = 13.19), in whom expression at the level of mRNA for SIR1 - SIR7 was determined, took part in the study (99 healthy people with a negative history of mental and somatic diseases and 98 people with diagnosed recurrent depressive disorders). A significant correlation was found in the case of age of the examined individuals and the expression of SIR1 - SIR7 at the mRNA level (p < 0.001). Differences in the expression of SIR1 - SIR7 were also found in relation to the level of education (number of years of education) of the examined population (p < 0.001). 1. The higher the number of years of education, the higher the level of SIR1 and SIR6 expression, and the lower the level of SIR2, SIR3, SIR4, SIR5 and SIR7 expression. 2. With age, the level of SIR1 and SIR6 expression decreases and the expression of SIR2, SIR3, SIR4, SIR5 and SIR7 increases.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aging
* Aging, Premature
* Educational Status
* Epigenesis, Genetic
* Female
* Gene Expression Regulation, Enzymologic
* Histones
* Humans
* Learning
* Male
* Middle Aged
* Sirtuins
* Young Adult


}}
{{medline-entry
|title=CO ameliorates endothelial senescence induced by 5-fluorouracil through [[SIRT1]] activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31704100
|abstract=Endothelial senescence is the main risk factor that contributes to vascular dysfunction and the progression of vascular disease. Carbon monoxide (CO) plays an important role in preventing vascular dysfunction and in maintaining vascular physiology or homeostasis. The application of exogenous CO has been shown to confer protection in several models of cardiovascular injury or disease, including hypertension, atherosclerosis, balloon-catheter injury, and graft rejection. However, the mechanism by which CO prevents endothelial senescence has been largely unexplored. The aim of this study was to evaluate the effects of CO on endothelial senescence and to investigate the possible mechanisms underlying this process. We measured the levels of senescence-associated-β-galactosidase activity, senescence-associated secretory phenotype, reactive oxygen species (ROS) production, and stress granule in human umbilical vein endothelial cells and the WI-38 human diploid fibroblast cell line. We found that 5-fluorouracil (5FU)-induced ROS generation was inhibited by CO-releasing molecules (CORM)-A1 treatment, and endothelial senescence induced by 5FU was attenuated by CORM-A1 treatment. The [[SIRT1]] inhibitor EX527 reversed the inhibitory effect of CO on the 5FU-induced endothelial senescence. Furthermore, [[SIRT1]] deficiency abolished the stress granule formation by CO. Our results suggest that CO alleviates the endothelial senescence induced by 5FU through [[SIRT1]] activation and may hence have therapeutic potential for the treatment of vascular diseases.
|mesh-terms=* Antioxidants
* Carbon Monoxide
* Cellular Senescence
* Down-Regulation
* Fluorouracil
* Heme Oxygenase-1
* Human Umbilical Vein Endothelial Cells
* Humans
* Nitric Oxide Synthase Type III
* Reactive Oxygen Species
* Sirtuin 1
|keywords=* 5-Fluorouracil
* Carbon monoxide
* Endothelial senescence
* Reactive oxygen species
* SIRT1
|full-text-url=https://sci-hub.do/10.1016/j.abb.2019.108185
}}
{{medline-entry
|title=Long noncoding RNA GAS5 inhibits cell proliferation and fibrosis in diabetic nephropathy by sponging miR-221 and modulating [[SIRT1]] expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31631065
|abstract=Diabetic nephropathy (DN) is one of the leading causes of end-stage renal diseases worldwide. This study is designed to investigate the underlying function and mechanism of a novel lncRNA GAS5 in the progression of DN. We found that lncRNA GAS5 expression level was decreased in type 2 diabetes (T2D) with DN compared with that in patients without DN. Moreover, lncRNA GAS5 expression level was negatively associated with the severity of DN-related complications. lncRNA GAS5 inhibited MCs proliferation and caused G0/1 phase arrest. lncRNA GAS5 overexpression alleviated the expression of fibrosis-related protein in mesangial cells (MCs). The dual-luciferase reporter assay and RNA binding protein immunoprecipitation (RIP) assay results revealed that lncRNA GAS5 functions as an endogenous sponge for miR-221 via both the directly targeting way and Ago2-dependent manner. Furthermore, [[SIRT1]] was confirmed as a target gene of miR-221. lncRNA GAS5 upregulated [[SIRT1]] expression and inhibited MCs proliferation and fibrosis by acting as an miR-221 sponge. Finally, we found that lncRNA GSA5 suppressed the development of DN in vivo. Thus, lncRNA GAS5 was involved in the progression of DN by sponging miR-221 and contributed to lncRNA-directed diagnostics and therapeutics in DN.
|mesh-terms=* Aging
* Animals
* Argonaute Proteins
* Cell Proliferation
* Diabetes Mellitus, Experimental
* Diabetic Nephropathies
* Fibrosis
* Gene Deletion
* Gene Expression Regulation
* Glucose
* Male
* Mesangial Cells
* Mice
* MicroRNAs
* RAW 264.7 Cells
* RNA, Long Noncoding
* Rats
* Rats, Sprague-Dawley
* Sirtuin 1
|keywords=* diabetic nephropathy
* fibrosis
* lncRNA GAS5
* proliferation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834398
}}
{{medline-entry
|title=The Role of Sirtuin1 in Regulating Endothelial Function, Arterial Remodeling and Vascular Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31572218
|abstract=Sirtuin1 ([[SIRT1]]), which belongs to a highly conserved family of protein deacetylase, is one of the best-studied sirtuins. [[SIRT1]] is involved in a variety of biological processes, including energy metabolism, cell proliferation and survival, chromatin dynamics, and DNA repair. In the vasculature, [[SIRT1]] is ubiquitously expressed in endothelial cells, smooth muscle cells, and perivascular adipose tissues (PVAT). Endothelial [[SIRT1]] plays a unique role in vasoprotection by regulating a large variety of proteins, including endothelial nitric oxide synthase (eNOS). In endothelial cells, [[SIRT1]] and eNOS regulate each other synergistically through positive feedback mechanisms for the maintenance of endothelial function. Recent studies have shown that [[SIRT1]] plays a vital role in modulating PVAT function, arterial remodeling, and vascular aging. In the present article, we summarize recent findings, review the molecular mechanisms and the potential of [[SIRT1]] as a therapeutic target for the treatment of vascular diseases, and discuss future research directions.

|keywords=* PVAT
* SIRT1
* eNOS
* vascular aging
* vascular remodeling
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751260
}}
{{medline-entry
|title=Deacetylation of LAMP1 drives lipophagy-dependent generation of free fatty acids by Abrus agglutinin to promote senescence in prostate cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31544977
|abstract=Therapy-induced senescence in cancer cells is an irreversible antiproliferative state, which inhibits tumor growth and is therefore a potent anti-neoplastic mechanism. In this study, low doses of Abrus agglutinin (AGG)-induced senescence through autophagy in prostate carcinoma cells (PC3) and inhibited proliferation. The inhibition of autophagy with 3-methyl adenine reversed AGG-induced senescence, thus confirming that AGG-triggered senescence required autophagy. AGG treatment also led to lipophagy-mediated accumulation of free fatty acids (FFAs), with a concomitant decrease in the number of lipid droplets. Lalistat, a lysosomal acid lipase inhibitor, abrogated AGG-induced lipophagy and senescence in PC3 cells, indicating that lipophagy is essential for AGG-induced senescence. The accumulation of FFAs increased reactive oxygen species generation, a known facilitator of senescence, which was also reduced in the presence of lalistat. Furthermore, AGG upregulated silent mating type information regulator 2 homolog 1 ([[SIRT1]]), while the presence of sirtinol reduced autophagy flux and the senescent phenotype in the AGG-treated cells. Mechanistically, AGG-induced cytoplasmic [[SIRT1]] deacetylated a Lys residue on the cytoplasmic domain of lysosome-associated membrane protein 1 (LAMP1), an autolysosomal protein, resulting in lipophagy and senescence. Taken together, our findings demonstrate a novel [[SIRT1]]/LAMP1/lipophagy axis mediating AGG-induced senescence in prostate cancer cells.

|keywords=* Abrus agglutinin
* LAMP1
* SIRT1
* free fatty acid
* lipophagy
* reactive oxygen species
* senescence
|full-text-url=https://sci-hub.do/10.1002/jcp.29182
}}
{{medline-entry
|title=Plasma exosomes in OSA patients promote endothelial senescence: effect of long-term adherent continuous positive airway pressure.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31552414
|abstract=Obstructive sleep apnea (OSA) is associated with increased risk for end-organ morbidities, which can collectively be viewed as accelerated aging. Vascular senescence is an important contributor to end-organ dysfunction. Exosomes are released ubiquitously into the circulation, and transfer their cargo to target cells facilitating physiological and pathological processes. Plasma exosomes from 15 patients with polysomnographically diagnosed OSA at baseline (OSA-T1) after 12 months of adherent continuous positive airway pressure (CPAP) treatment (OSA-T2), 13 untreated OSA patients at 12-month intervals (OSA-NT1, OSA-NT2), and 12 controls (CO1 and CO2) were applied on naïve human microvascular endothelialcells-dermal (HMVEC-d). Expression of several senescence gene markers including p16 (CDKN2A), [[SIRT1]], and SIRT6 and immunostaining for β-galactosidase activity (x-gal) were performed. Endothelial cells were also exposed to intermittent hypoxia (IH) or normoxia (RA) or treated with hydrogen peroxide (H2O2), stained with x-gal and subjected to qRT-PCR. Exosomes from OSA-T1, OSA-NT1, and OSA-NT2 induced significant increases in x-gal staining compared to OSA-T2, CO1, and CO2 (p-value < 0.01). p16 expression was significantly increased (p < 0.01), while [[SIRT1]] and SIRT6 expression levels were decreased (p < 0.02 and p < 0.009). Endothelial cells exposed to IH or to H2O2 showed significant increases in x-gal staining (p < 0.001) and in senescence gene expression. Circulating exosomes in untreated OSA induce marked and significant increases in senescence of naïve endothelial cells, which are only partially reversible upon long-term adherent CPAP treatment. Furthermore, endothelial cells exposed to IH or H2O2 also elicit similar responses. Thus, OSA either directly or indirectly via exosomes may initiate and exacerbate cellular aging, possibly via oxidative stress-related pathways.

|keywords=* CPAP
* OSA
* aging
* cardiovascular
* endothelium
* exosomes
* extracellular vesicles
* intermittent hypoxia
* oxidative stress
* senescence
|full-text-url=https://sci-hub.do/10.1093/sleep/zsz217
}}
{{medline-entry
|title=Hydrogen Sulfide Inhibits High Glucose-Induced Neuronal Senescence by Improving Autophagic Flux [i]via[/i] Up-regulation of [[SIRT1]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31481873
|abstract=Hyperglycemia, a key characteristic and risk factor for diabetes mellitus (DM), causes neuronal senescence. Hydrogen sulfide (H S) is a novel neuroprotectant. The present work was to investigate the potential effect of H S on hyperglycemia-induced neuronal senescence and the underlying mechanisms. We found that NaHS, a donor of H S, inhibited high glucose (HG)-induced cellular senescence in HT22 cells (an immortalized mouse hippocampal cell line), as evidenced by a decrease in the number of senescence associated-β-galactosidase (SA-β-gal) positive cells, increase in the growth of cells, and down-regulations of senescence mark proteins, p16  and p21 . NaHS improved the autophagic flux, which is judged by a decrease in the amount of intracellular autophagosome as well as up-regulations of LC3II/I and P62 in HG-exposed HT22 cells. Furthermore, blocked autophagic flux by chloroquine (CQ) significantly abolished NaHS-exerted improvement in the autophagic flux and suppression in the cellular senescence of GH-exposed HT22 cells, which indicated that H S antagonizes HG-induced neuronal senescence by promoting autophagic flux. We also found that NaHS up-regulated the expression of silent mating type information regulation 2 homolog 1 ([[SIRT1]]), an important anti-aging protein, in HG-exposed HT22 cells. Furthermore, inhibition of [[SIRT1]] by sirtinol reversed the protection of H S against HG-induced autophagic flux blockade and cellular senescence in HT22 cells. These data indicated that H S protects HT22 cells against HG-induced neuronal senescence by improving autophagic flux [i]via[/i] up-regulation of [[SIRT1]], suggesting H S as a potential treatment strategy for hyperglycemia-induced neuronal senescence and neurotoxicity.

|keywords=* SIRT1
* autophagic flux
* high glucose
* hydrogen sulfide
* neuronal senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710442
}}
{{medline-entry
|title=Activation of the miR-34a-Mediated [[SIRT1]]/mTOR Signaling Pathway by Urolithin A Attenuates D-Galactose-Induced Brain Aging in Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31420820
|abstract=Despite tremendous advances in modern medicine, effective prevention or therapeutic strategies for age-related neurodegenerative diseases such as Alzheimer's disease (AD) remain limited. Currently, accumulating evidence has demonstrated that microRNAs (miRNAs) are increasingly associated with age-related diseases and are emerging as promising therapeutic targets. Urolithin A, a metabolite compound resulting from the transformation of ellagitannins by gut bacteria, has been reported to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties. The present study primarily focused on the ameliorative effect of urolithin A on aging mice and on the exploration of the potential mechanisms of such an ameliorative effect on cognitive impairment and brain aging. In this study, we first tested the neuroprotective effect of urolithin A using an in vitro H O -induced PC12 cell oxidative damage model. The in vivoD-gal-induced brain aging model showed that urolithin A significantly suppressed the upregulation of miR-34a induced by D-gal. Moreover, target genes associated with miR-34a were also examined. Urolithin A supplementation ameliorated apoptosis induced by D-gal and rescued miR-34a overexpression-induced impaired autophagy in brain aging mice after a 2-month administration. Furthermore, urolithin A activated autophagy by upregulating the [[SIRT1]] signaling pathway and downregulating the mTOR signaling pathway. In conclusion, urolithin A may exert neuroprotective effects and may aid in preventing D-gal-induced brain aging through activation of the miR-34a-mediated [[SIRT1]]/mTOR signaling pathway.
|mesh-terms=* Aging
* Animals
* Brain
* Coumarins
* Galactose
* Male
* Mice
* Mice, Inbred ICR
* MicroRNAs
* PC12 Cells
* Random Allocation
* Rats
* Signal Transduction
* Sirtuin 1
* TOR Serine-Threonine Kinases
|keywords=* D-Gal
* SIRT1/mTOR signal pathway
* Urolithin A
* aging
* autophagy
* miR-34a
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985387
}}
==RPE==

{{medline-entry
|title=Transcriptomic Profiling of Human Pluripotent Stem Cell-derived Retinal Pigment Epithelium over Time.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33307245
|abstract=Human pluripotent stem cell (hPSC)-derived progenies are immature versions of cells, presenting a potential limitation to the accurate modelling of diseases associated with maturity or age. Hence, it is important to characterise how closely cells used in culture resemble their native counterparts. In order to select appropriate time points of retinal pigment epithelium ([[RPE]]) cultures that reflect native counterparts, we characterised the transcriptomic profiles of the hPSC-derived [[RPE]] cells from 1- and 12-month cultures. We differentiated the human embryonic stem cell line H9 into [[RPE]] cells, performed single-cell RNA-sequencing of a total of 16,576 cells to assess the molecular changes of the [[RPE]] cells across these two culture time points. Our results indicate the stability of the [[RPE]] transcriptomic signature, with no evidence of an epithelial-mesenchymal transition, and with the maturing populations of the [[RPE]] observed with time in culture. Assessment of Gene Ontology pathways revealed that as the cultures age, [[RPE]] cells upregulate expression of genes involved in metal binding and antioxidant functions. This might reflect an increased ability to handle oxidative stress as cells mature. Comparison with native human [[RPE]] data confirms a maturing transcriptional profile of [[RPE]] cells in culture. These results suggest that long-term in vitro culture of [[RPE]] cells allows the modelling of specific phenotypes observed in native mature tissues. Our work highlights the transcriptional landscape of hPSC-derived [[RPE]] cells as they age in culture, which provides a reference for native and patient samples to be benchmarked against.

|keywords=* Aging
* Human embryonic stem cell
* Human pluripotent stem cell
* Retinal pigment epithelium
* Single-cell RNA sequencing
|full-text-url=https://sci-hub.do/10.1016/j.gpb.2020.08.002
}}
{{medline-entry
|title=Relationship between Oxygen Uptake, Heart Rate, and Perceived Effort in an Aquatic Incremental Test in Older Women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33187067
|abstract=Different parameters can be used to control the intensity of aerobic exercises, a choice that should consider the population and exercise environment targeted. Therefore, our study aimed to verify the relationship between oxygen uptake (VO ), heart rate (HR), rating of perceived exertion ([[RPE]]), and cadence during an aquatic incremental test in older women. Nine older women (64.3 ± 4.4 years) engaged in a water-based aerobic training performed an aquatic incremental test using the stationary running exercise (cadence increases of 15 b·min  every 2 min) until participants' volitional exhaustion. VO , HR, and [[RPE]] data were measured, and the percentage of peak VO  (%VO ) and percentage of maximal HR (%HR ) were calculated. Linear and polynomial regression analyses were performed (α = 0.05). Polynomial regressions revealed the best adjustments for all analyses. Data showed a significant relationship ([i]p[/i] < 0.001) between %VO  and %HR  ([i]r[/i] = 0.921), %VO  and [[RPE]] ([i]r[/i] = 0.870), and %HR  and [[RPE]] ([i]r[/i] = 0.878). Likewise, significant relationships between cadence ([i]p[/i] < 0.001) and %VO  ([i]r[/i] = 0.873), %HR  ([i]r[/i] = 0.874), and [[RPE]] ([i]r[/i] = 0.910) were also observed. In summary, the physiological, subjective, and mechanical variables investigated were highly associated during an aquatic incremental test to exhaustion in older women. Therefore, these different parameters can be employed to adequately prescribe water-based programs according to preference and availability.

|keywords=* aging
* cardiorespiratory
* maximum test
* rate of perceived exertion
* water aerobics
* water-based exercises
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697777
}}
{{medline-entry
|title=Photoreceptor Degeneration in Homozygous Male Per2  Mice During Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33135952
|abstract=The Per2  mouse model developed by Takahashi laboratory is one of the most powerful models to study circadian rhythms in real time. In this study, we report that photoreceptors degenerate in male Per2  mice during aging. Young (2.5- to 5-month-old) and aged (11- to 13.5-month-old) homozygous male Per2  mice and C57BL/6J mice were used for this study. Retina structure and function were investigated via spectral domain optical coherence tomography (SD-OCT), fundus imaging, and electroretinography (ERG). Zonula occludens-1 (ZO-1) immunofluorescence was used to analyze the retinal pigment epithelium ([[RPE]]) morphology. Fundus examination revealed no difference between young Per2  and wild-type (WT) mice. However, the fundus of aged Per2  mice showed white deposits, suggestive of age-related drusen-like formation or microglia, which were absent in age-matched WT mice. No differences in retinal structure and function were observed between young Per2  and WT mice. However, with age, Per2  mice showed a significant reduction in total retinal thickness with respect to C57BL/6J mice. The reduction was mostly confined to the photoreceptor layer. Consistent with these results, we observed a significant decrease in the amplitude of a- and b-waves of the ERG in aged Per2  mice. Analysis of the [[RPE]] morphology revealed that in aged Per2  mice there was an increase in compactness and eccentricity with a decrease in solidity with respect to the values observed in WT, pointing toward signs of aging in the [[RPE]] of Per2  mice. Our data demonstrate that homozygous Per2  mice show photoreceptor degeneration during aging and a premature aging of the [[RPE]].

|keywords=* Per2luc
* aging
* circadian
* mice
* photoreceptors
* retinal pigment epithelium
|full-text-url=https://sci-hub.do/10.1177/0748730420965285
}}
{{medline-entry
|title=An In-Vitro Cell Model of Intracellular Protein Aggregation Provides Insights into [[RPE]] Stress Associated with Retinopathy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32932802
|abstract=Impaired cargo trafficking and the aggregation of intracellular macromolecules are key features of neurodegeneration, and a hallmark of aged as well as diseased retinal pigment epithelial ([[RPE]]) cells in the eye. Here, photoreceptor outer segments (POS), which are internalized daily by [[RPE]] cells, were modified by UV-irradiation to create oxidatively modified POS (OxPOS). Oxidative modification was quantified by a protein carbonyl content assay. Human A[[RPE]]-19 cells were synchronously pulsed with POS or OxPOS to study whether oxidatively modified cargos can recapitulate features of [[RPE]] pathology associated with blinding diseases. Confocal immunofluorescence microscopy analysis showed that OxPOS was trafficked to LAMP1, LAMP2 lysosomes and to LC3b autophagy vacuoles. Whilst POS were eventually degraded, OxPOS cargos were sequestered in late compartments. Co-localization of OxPOS was also associated with swollen autolysosomes. Ultrastructural analysis revealed the presence of electron-dense OxPOS aggregates in [[RPE]] cells, which appeared to be largely resistant to degradation. Measurement of cellular autofluorescence, using parameters used to assess fundus autofluorescence (FAF) in age-related macular disease (AMD) patients, revealed that OxPOS contributed significantly to a key feature of aged and diseased [[RPE]]. This in vitro cell model therefore represents a versatile tool to study disease pathways linked with [[RPE]] damage and sight-loss.

|keywords=* AMD
* RPE
* aging
* autofluorescence
* autophagy
* diet
* lysosomes
* oxidized POS
* proteolysis
* retina
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555953
}}
{{medline-entry
|title=Short-Term Effect of Self-Selected Training Intensity on Ambulatory Blood Pressure in Hypertensive Older Women: A Randomized Controlled Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32904579
|abstract=To investigate the short-term effect of self-selected training intensity (SSTI) on ambulatory blood pressure (BP) in hypertensive older women. This is a randomized, single-blind, two-arm, parallel-group controlled trial that included 40 medicated hypertensive older women (64.4±3.6 years; resting systolic 118±19 and diastolic BP 68±9 mmHg). SSTI intervention was performed three times per week, 30-50 minutes per session (n=20). The control group participated in health education meetings once per week (n=20). Ambulatory BP (primary outcome) and six-minute walking test performance (secondary outcome) were assessed at baseline and following 8 weeks of intervention. Heart rate (HR), rating of perceived exertion ([[RPE]], 6-20), and affective valence (ie, feeling scale, -5/+5) were recorded during all SSTI sessions. Intention-to-treat and per-protocol analyses were used for data analyses. Fifteen participants from the SSTI group and 17 from the control group completed the study. No differences in ambulatory BP (24-h, awake, and asleep) were observed between SSTI and control groups (intention-to-treat and per-protocol analyses; p>0.05). The SSTI group showed a greater six-minute walking test performance than the control group in the intention-to-treat and per-protocol analyses (p<0.05). The participants exercised at 52±10% of HR reserve reported an [[RPE]] of 11±1 and an affective valence of 3.4±1.1 over the 8-week period. SSTI is a feasible approach to induce a more active lifestyle and increase health-related fitness in hypertensive older women, although it does not improve BP control over a short-term period.

|keywords=* aging
* exercise
* hypertension
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457386
}}
{{medline-entry
|title=Correlation between brain volume and retinal photoreceptor outer segment volume in normal aging and neurodegenerative diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32881874
|abstract=To investigate the association between outer retinal layer metrics, including photoreceptor outer segment volume, on spectral-domain optical coherence tomography (OCT) and brain volume on MRI in normal aging, Alzheimer's disease and Parkinson's disease. This was an exploratory analysis of a cross-sectional cohort study that was approved by the Cleveland Clinic Institutional Review Board to evaluate neurodegenerative disorders. Subjects aged ≥ 50 were recruited. A comprehensive neurological exam, brain MRI with volumetric evaluation, and OCT were performed for each subject. Outer retinal layer parameters, including ellipsoid zone (EZ) to retinal pigment epithelium ([[RPE]]) volume (i.e., surrogate for panmacular photoreceptor outer segment volume), were evaluated with a novel OCT analysis platform. Of 85 subjects, 64 eyes of 64 subjects met MRI and OCT quality control criteria. Total brain volume (%ICV) significantly correlated with EZ-[[RPE]] volume in the normal cognition control group (n = 31, Pearson correlation coefficient 0.514, P < .01), the Parkinson's disease group (n = 19, Pearson correlation coefficient 0.482, P = .04), and the Alzheimer's dementia group (n = 14, Pearson correlation coefficient 0.526, P = .05). Multiple linear regression analysis revealed that photoreceptor outer segment (i.e., EZ-[[RPE]]) volume was an independent, influential factor on total brain volume in all study subjects (Coefficient 15.2, 95% confidence interval 7.8-22.6, P < .001). Outer retinal parameters on OCT may serve as a novel biomarker related to brain volume. This correlation was noted in control subjects suggesting a possible developmental link between retina and brain volume. This relationship was also maintained with atrophic neurodegenerative disorders. Further research is needed to explore possible threshold differences for underlying neurodegenerative disorders.
|mesh-terms=* Aged
* Aging
* Brain
* Female
* Humans
* Linear Models
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Multivariate Analysis
* Neurodegenerative Diseases
* Organ Size
* Retinal Photoreceptor Cell Outer Segment
* Retinal Pigment Epithelium
* Tomography, Optical Coherence

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470418
}}
{{medline-entry
|title=Oxidative stress in the retina and retinal pigment epithelium ([[RPE]]): Role of aging, and DJ-1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32826201
|abstract=High levels of oxidative radicals generated by daily light exposure and high metabolic rate suggest that the antioxidant machinery of the retina and retinal pigment epithelium ([[RPE]]) is crucial for their survival. DJ-1 is a redox-sensitive protein that has been shown to have neuroprotective function in the brain in Parkinson's disease and other neurodegenerative diseases. Here, we analyzed the role of DJ-1 in the retina during oxidative stress and aging. We induced low-level oxidative stress in young (3-month-old) and old (15-month-old) C57BL/6J (WT) and DJ-1 knockout (KO) mice and evaluated effects in the [[RPE]] and retina. Absence of DJ-1 resulted in increased retinal dysfunction in response to low levels of oxidative stress. Our findings suggest that loss of DJ-1 affects the [[RPE]] antioxidant machinery, rendering it unable to combat and neutralize low-level oxidative stress, irrespective of age. Moreover, they draw a parallel to the retinal degeneration observed in AMD, where the occurrence of genetic variants may leave the retina and [[RPE]] unable to fight sustained, low-levels of oxidative stress.

|keywords=* Aging
* DJ-1
* Oxidative stress
* Retina
* Retinal pigment epithelium
* Sodium iodate
|full-text-url=https://sci-hub.do/10.1016/j.redox.2020.101623
}}
{{medline-entry
|title=Direct-Coupled Electroretinogram (DC-ERG) for Recording the Light-Evoked Electrical Responses of the Mouse Retinal Pigment Epithelium.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32744516
|abstract=The retinal pigment epithelium ([[RPE]]) is a specialized monolayer of cells strategically located between the retina and the choriocapillaris that maintain the overall health and structural integrity of the photoreceptors. The [[RPE]] is polarized, exhibiting apically and basally located receptors or channels, and performs vectoral transport of water, ions, metabolites, and secretes several cytokines. In vivo noninvasive measurements of [[RPE]] function can be made using direct-coupled ERGs (DC-ERGs). The methodology behind the DC-ERG was pioneered by Marmorstein, Peachey, and colleagues using a custom-built stimulation recording system and later demonstrated using a commercially available system. The DC-ERG technique uses glass capillaries filled with Hank's buffered salt solution (HBSS) to measure the slower electrical responses of the [[RPE]] elicited from light-evoked concentration changes in the subretinal space due to photoreceptor activity. The prolonged light stimulus and length of the DC-ERG recording make it vulnerable to drift and noise resulting in a low yield of useable recordings. Here, we present a fast, reliable method for improving the stability of the recordings while reducing noise by using vacuum pressure to reduce/eliminate bubbles that result from outgassing of the HBSS and electrode holder. Additionally, power line artifacts are attenuated using a voltage regulator/power conditioner. We include the necessary light stimulation protocols for a commercially available ERG system as well as scripts for analysis of the DC-ERG components: c-wave, fast oscillation, light peak, and off response. Due to the improved ease of recordings and rapid analysis workflow, this simplified protocol is particularly useful in measuring age-related changes in [[RPE]] function, disease progression, and in the assessment of pharmacological intervention.
|mesh-terms=* Aging
* Animals
* Electrophysiological Phenomena
* Electroretinography
* Light
* Mice
* Retinal Pigment Epithelium

|full-text-url=https://sci-hub.do/10.3791/61491
}}
{{medline-entry
|title=High-density lipoproteins are a potential therapeutic target for age-related macular degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32737203
|abstract=Strong evidence suggests that dysregulated lipid metabolism involving dysfunction of the retinal pigmented epithelium ([[RPE]]) underlies the pathogenesis of age-related macular degeneration (AMD), the leading cause of irreversible blindness in the elderly. A hallmark of AMD is the overproduction of lipid- and protein-rich extracellular deposits that accumulate in the extracellular matrix (Bruch's membrane (BrM)) adjacent to the [[RPE]]. We analyzed apolipoprotein A-1 (ApoA-1)-containing lipoproteins isolated from BrM of elderly human donor eyes and found a unique proteome, distinct from high-density lipoprotein (HDL) isolated from donor plasma of the same individuals. The most striking difference is higher concentrations of ApoB and ApoE, which bind to glycosaminoglycans. We hypothesize that this interaction promotes lipoprotein deposition onto BrM glycosaminoglycans, initiating downstream effects that contribute to [[RPE]] dysfunction/death. We tested this hypothesis using two potential therapeutic strategies to alter the lipoprotein/protein profile of these extracellular deposits. First, we used short heparan sulfate oligosaccharides to remove lipoproteins already deposited in both the extracellular matrix of [[RPE]] cells and aged donor BrM tissue. Second, an ApoA-1 mimetic, 5A peptide, was demonstrated to modulate the composition and concentration of apolipoproteins secreted from primary porcine [[RPE]] cells. Significantly, in a mouse model of AMD, this 5A peptide altered the proteomic profile of circulating HDL and ameliorated some of the potentially harmful changes to the protein composition resulting from the high-fat, high-cholesterol diet in this model. Together, these results suggest that targeting HDL interactions with BrM represents a new strategy to slow AMD progression in humans.

|keywords=* age-related macular degeneration
* aging
* apolipoprotein
* complement
* complement factor H
* glycosaminoglycan
* heparan sulfate
* heparan sulfate proteoglycans
* high-density lipoprotein (HDL)
* lipoprotein
* oligosaccharide
* retinal degeneration
* retinal pigmented epithelium
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521644
}}
{{medline-entry
|title=MTOR-initiated metabolic switch and degeneration in the retinal pigment epithelium.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32721041
|abstract=The retinal pigment epithelium ([[RPE]]) is a particularly vulnerable tissue to age-dependent degeneration. Over the life span, the [[RPE]] develops an expanded endo-lysosomal compartment to maintain the high efficiency of phagocytosis and degradation of photoreceptor outer segments (POS) necessary for photoreceptor survival. As the assembly and activation of the mechanistic target of rapamycin complex 1 (mTORC1) occur on the lysosome surface, increased lysosome mass with aging leads to higher mTORC1 activity. The functional consequences of hyperactive mTORC1 in the [[RPE]] are unclear. In the current study, we used integrated high-resolution metabolomic and genomic approaches to examine mice with [[RPE]]-specific deletion of the tuberous sclerosis 1 (Tsc1) gene which encodes an upstream suppressor of mTORC1. Our data show that [[RPE]] cells with constitutively high mTORC1 activity were reprogramed to be hyperactive in glucose and lipid metabolism. Lipolysis was suppressed, mitochondrial carnitine shuttle was inhibited, while genes involved in fatty acid (FA) biosynthesis were upregulated. The metabolic changes occurred prior to structural changes of [[RPE]] and retinal degeneration. These findings have revealed cellular events and intrinsic mechanisms that contribute to lipid accumulation in the [[RPE]] cells during aging and age-related degeneration.

|keywords=* AMD
* Mtor
* aging
* lipid
* metabolism
|full-text-url=https://sci-hub.do/10.1096/fj.202000612R
}}
{{medline-entry
|title=[i]Lactobacillus paracasei[/i] KW3110 Suppresses Inflammatory Stress-Induced Premature Cellular Senescence of Human Retinal Pigment Epithelium Cells and Reduces Ocular Disorders in Healthy Humans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32708511
|abstract=[i]Lactobacillus paracasei[/i] KW3110 (KW3110) has anti-inflammatory effects and mitigates retinal pigment epithelium ([[RPE]]) cell damage caused by blue-light exposure. We investigated whether KW3110 suppresses chronic inflammatory stress-induced [[RPE]] cell damage by modulating immune cell activity and whether it improves ocular disorders in healthy humans. First, we showed that KW3110 treatment of mouse macrophages (J774A.1) produced significantly higher levels of interleukin-10 as compared with other lactic acid bacterium strains (all [i]p[/i] < 0.01). Transferring supernatant from KW3110- and [i]E. coli[/i] 0111:B4 strain and adenosine 5'-triphosphate (LPS/ATP)-stimulated J774A.1 cells to human retinal pigment epithelium (A[[RPE]]-19) cells suppressed senescence-associated phenotypes, including proliferation arrest, abnormal appearance, cell cycle arrest, and upregulation of cytokines, and also suppressed expression of tight junction molecule claudin-1. A randomized, double-blind, placebo-controlled parallel-group study of healthy subjects ([i]n[/i] = 88; 35 to below 50 years) ingesting placebo or KW3110-containing supplements for 8 weeks showed that changes in critical flicker frequency, an indicator of eye fatigue, from the week-0 value were significantly larger in the KW3110 group at weeks 4 ([i]p[/i] = 0.040) and 8 ([i]p[/i] = 0.036). These results suggest that KW3110 protects A[[RPE]]-19 cells against premature senescence and aberrant expression of tight junction molecules caused by chronic inflammatory stress, and may improve chronic eye disorders including eye fatigue.

|keywords=* cellular senescence
* eye fatigue
* inflammation
* lactic acid bacteria
* probiotics
* retina
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403967
}}
{{medline-entry
|title=Retinal pigment epithelium transcriptome analysis in chronic smoking reveals a suppressed innate immune response and activation of differentiation pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32634473
|abstract=Cigarette smoking, a powerful mixture of chemical oxidants, is the strongest environmental risk factor for developing age-related macular degeneration (AMD), the most common cause of blindness among the elderly in western societies. Despite intensive study, the full impact of smoking on the retinal pigment epithelium ([[RPE]]), a central cell type involved in AMD pathobiology, remains unknown. The relative contribution of the known dysfunctional pathways to AMD, at what stage they are most pathogenic, or whether other processes are relevant, is poorly understood, and furthermore, whether smoking activates them, is unknown. We performed global RNA-sequencing of the [[RPE]] from C57BL/6J mice exposed to chronic cigarette smoke for 6 months to identify potential pathogenic and cytoprotective pathways. The [[RPE]] transcriptome induced by chronic cigarette smoking exhibited a mixed response of marked suppression of the innate immune response including type I and II interferons and upregulation of cell differentiation and morphogenic gene clusters, suggesting an attempt by the [[RPE]] to maintain its differentiated state despite smoke-induced injury. Given that mice exposed to chronic smoke develop early features of AMD, these novel findings are potentially relevant to the transition from aging to AMD.

|keywords=* Age-related macular degeneration
* Aging
* Differentiation
* Innate immunity
* RNA sequencing
* Smoking
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434665
}}
{{medline-entry
|title=Differences in Intraretinal Pigment Migration Across Inherited Retinal Dystrophies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32442431
|abstract=To determine whether there are differences in the prevalence of intraretinal pigment migration (IPM) across ages and genetic causes of inherited retinal dystrophies (IRDs). Retrospective cohort study. Patients were evaluated at a single tertiary referral center. All patients with a clinical diagnosis of IRD and confirmatory genetic testing were included in these analyses. A total of 392 patients fit inclusion criteria, and 151 patients were excluded based on inconclusive genetic testing. Patients were placed into 3 groups, ciliary and ciliary-related photoreceptor, nonciliary photoreceptor, and retinal pigment epithelium ([[RPE]]), based on the cellular expression of the gene and the primary affected cell type. The presence of IPM was evaluated by using slit lamp biomicroscopy, indirect ophthalmoscopy, and wide-field color fundus photography. IPM was seen in 257 of 339 patients (75.8%) with mutations in photoreceptor-specific genes and in 18 of 53 patients (34.0%) with mutations in [[RPE]]-specific genes (P < .0001). Pairwise analysis following stratification by age and gene category suggested significant differences at all age groups between patients with mutations in photoreceptor-specific genes and patients with mutations in [[RPE]]-specific genes (P < .05). A fitted multivariate logistic regression model was produced and demonstrated that the incidence of IPM increases as a function of both age and gene category. IPM is a finding more commonly observed in IRDs caused by mutations in photoreceptor-specific genes than [[RPE]]-specific genes. The absence of IPM does not always rule out IRD and should raise suspicion for disease mutations in [[RPE]]-specific genes.
|mesh-terms=* Adult
* Aging
* Cell Movement
* Female
* Follow-Up Studies
* Humans
* Male
* Ophthalmoscopy
* Retinal Dystrophies
* Retinal Pigment Epithelium
* Retrospective Studies
* Slit Lamp Microscopy
* Tomography, Optical Coherence

|full-text-url=https://sci-hub.do/10.1016/j.ajo.2020.05.010
}}
{{medline-entry
|title=Exosomal MiRNA Transfer between Retinal Microglia and [[RPE]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32429541
|abstract=The retinal pigment epithelium ([[RPE]]), the outermost layer of the retina, provides essential support to both the neural retina and choroid. Additionally, the [[RPE]] is highly active in modulating functions of immune cells such as microglia, which migrate to the subretinal compartment during aging and age-related degeneration. Recently, studies have highlighted the important roles of microRNA (miRNA) in the coordination of general tissue maintenance as well as in chronic inflammatory conditions. In this study, we analyzed the miRNA profiles in extracellular vesicles (EVs) released by the [[RPE]], and identified and validated miRNA species whose expression levels showed age-dependent changes in the EVs. Using co-culture of [[RPE]] and retinal microglia, we further demonstrated that miR-21 was transferred between the two types of cells, and the increased miR-21 in microglia influenced the expression of genes downstream of the p53 pathway. These findings suggest that exosome-mediated miRNA transfer is a signaling mechanism that contributes to the regulation of microglia function in the aging retina.

|keywords=* RPE
* aging
* exosome
* inflammation
* microglia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279010
}}
{{medline-entry
|title=Functionally validated imaging endpoints in the Alabama study on early age-related macular degeneration 2 (ALSTAR2): design and methods.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32429847
|abstract=Age-related macular degeneration (AMD), a leading cause of irreversible vision impairment in the United States and globally, is a disease of the photoreceptor support system involving the retinal pigment epithelium ([[RPE]]), Bruch's membrane, and the choriocapillaris in the setting of characteristic extracellular deposits between outer retinal cells and their blood supply. Research has clearly documented the selective vulnerability of rod photoreceptors and rod-mediated (scotopic) vision in early AMD, including delayed rod-mediated dark adaptation (RMDA) and impaired rod-mediated light and pattern sensitivity. The unifying hypothesis of the Alabama Study on Early Macular Degeneration (ALSTAR2) is that early AMD is a disease of micronutrient deficiency and vascular insufficiency, due to detectable structural changes in the retinoid re-supply route from the choriocapillaris to the photoreceptors. Functionally this is manifest as delayed rod-mediated dark adaptation and eventually as rod-mediated visual dysfunction in general. A cohort of 480 older adults either in normal macular health or with early AMD will be enrolled and followed for 3 years to examine cross-sectional and longitudinal associations between structural and functional characteristics of AMD. Using spectral domain optical coherence tomography, the association between (1) subretinal drusenoid deposits and drusen, (2) [[RPE]] cell bodies, and (3) the choriocapillaris' vascular density and rod- and cone-mediated vision will be examined. An accurate map and timeline of structure-function relationships in aging and early AMD gained from ALSTAR2, especially the critical transition from aging to disease, will identify major characteristics relevant to future treatments and preventative measures. A major barrier to developing treatments and prevention strategies for early AMD is a limited understanding of the temporal interrelationships among structural and functional characteristics while transitioning from aging to early AMD. ALSTAR2 will enable the development of functionally valid, structural biomarkers for early AMD, suitable for use in forthcoming clinical trials as endpoint/outcome measures. The comprehensive dataset will also allow hypothesis-testing for mechanisms that underlie the transition from aging to AMD, one of which is a newly developed Center-Surround model of cone resilience and rod vulnerability. ClinicalTrials.gov Identifier NCT04112667, October 7, 2019.

|keywords=* Age-related macular degeneration
* Aging
* Cones
* Dark adaptation
* Light sensitivity
* Macula
* Quantitative autofluorescence
* Retina
* Rods
* Spectral domain optical coherence tomography
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236516
}}
{{medline-entry
|title=Mechanisms of mitochondrial dysfunction and their impact on age-related macular degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32298788
|abstract=Oxidative stress-induced damage to the retinal pigment epithelium ([[RPE]]) is considered to be a key factor in age-related macular degeneration (AMD) pathology. [[RPE]] cells are constantly exposed to oxidative stress that may lead to the accumulation of damaged cellular proteins, lipids, nucleic acids, and cellular organelles, including mitochondria. The ubiquitin-proteasome and the lysosomal/autophagy pathways are the two major proteolytic systems to remove damaged proteins and organelles. There is increasing evidence that proteostasis is disturbed in [[RPE]] as evidenced by lysosomal lipofuscin and extracellular drusen accumulation in AMD. Nuclear factor-erythroid 2-related factor-2 (NFE2L2) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) are master transcription factors in the regulation of antioxidant enzymes, clearance systems, and biogenesis of mitochondria. The precise cause of [[RPE]] degeneration and the onset and progression of AMD are not fully understood. However, mitochondria dysfunction, increased reactive oxygen species (ROS) production, and mitochondrial DNA (mtDNA) damage are observed together with increased protein aggregation and inflammation in AMD. In contrast, functional mitochondria prevent [[RPE]] cells damage and suppress inflammation. Here, we will discuss the role of mitochondria in [[RPE]] degeneration and AMD pathology focused on mtDNA damage and repair, autophagy/mitophagy signaling, and regulation of inflammation. Mitochondria are putative therapeutic targets to prevent or treat AMD.

|keywords=* Age-related macular degeneration
* Aggregation
* Aging
* Autophagy
* Clearance
* Degeneration
* Mitochondria
* Mitophagy
* Retina
* Retinal pigment epithelium
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650008
}}
{{medline-entry
|title=CSF1R blockade induces macrophage ablation and results in mouse choroidal vascular atrophy and [[RPE]] disorganization.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32234210
|abstract=The choroid, which provides vascular supply to the outer retina, demonstrates progressive degeneration in aging and age-related macular degeneration (AMD). However mechanisms that maintain or compromise choroidal homeostasis are obscure. We discovered that the ablation of choroidal macrophages via CSF1R blockade was associated with choroidal vascular atrophy and retinal pigment epithelial ([[RPE]]) changes including structural disruption, downregulation of visual cycle genes, and altered angiogenic factor expression. Suspending CSF1R blockade following ablation enabled spontaneous macrophage regeneration, which fully restored original macrophage distributions and morphologies. Macrophage regeneration was accompanied by arrested vascular degeneration and ameliorated pathological [[RPE]] alterations. These findings suggest that choroidal macrophages play a previously unappreciated trophic role in maintaining choroidal vasculature and [[RPE]] cells, implicating insufficiency in choroidal macrophage function as a factor in aging- and AMD-associated pathology. Modulating macrophage function may constitute a strategy for the therapeutic preservation of the choroid and [[RPE]] in age-related retinal disorders.

|keywords=* RPE disorganization
* aging
* choroid
* choroidal macrophage
* choroidal vasculature
* immunology
* inflammation
* mouse
* neuroscience
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156269
}}
{{medline-entry
|title=Extracellular microparticles exacerbate oxidative damage to retinal pigment epithelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32173468
|abstract=Oxidative stress-induced retinal pigment epithelial cell ([[RPE]]) dysfunction is a primary contributing factor to early dry age-related macular degeneration (AMD). Oxidative injury to the retina may promote extracellular vesicles (EVs) released from [[RPE]]. In this study, we investigated the effects of oxidative-induced [[RPE]] cell-derived microparticles (RMPs) on [[RPE]] cell functions. The oxidative stress induced more RMPs released from [[RPE]] cells in vitro and in vivo, and significant more RMPs were released from aged [[RPE]] cells than that from younger [[RPE]] cells. RMPs were taken up by [[RPE]] cells in a time-dependent manner; however, blockage of CD36 attenuated the uptake process. Furthermore, the decrease of [[RPE]] cell viability by RMPs treatment was associated with an increased expression of cyclin-dependent kinase inhibitors p15 and p21. RMPs enhanced senescence and interrupted phagocytic activity of [[RPE]] cells as well. The present study demonstrated that RMPs produce a strong effect of inducing [[RPE]] cell degeneration. This finding further supports the postulate that RMPs exacerbate oxidative stress damage to [[RPE]] cells, which may uncover a potentially relevant process in the genesis of dry AMD.

|keywords=* Extracellular vesicles
* Oxidative stress
* Phagocytosis
* RPE cell Dysfunction
* RPE cell-Derived microparticles (RMPs)
* Retinal pigment epithelial cell (RPE)
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.yexcr.2020.111957
}}
{{medline-entry
|title=Water-based continuous and interval training in older women: Cardiorespiratory and neuromuscular outcomes (WATER study).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32145293
|abstract=The purpose of this study was to investigate the effects of two water-based aerobic programs on cardiorespiratory and neuromuscular outcomes in older women. Forty-one women (60 to 75 years old) volunteered to participate in the study. Participants were randomized into a water-based continuous (CTG; n = 21; 63.9 ± 2.5 years) or an interval (ITG; n = 20; 64.8 ± 3.6 years) aerobic training group. Both training programs were performed for 12 weeks (45-min sessions twice a week), with exercise intensity based on rating of perceived exertion (Borg's [[RPE]] 6-20 Scale). Pre and post training assessments of cardiorespiratory and neuromuscular outcomes were performed. Data analyses were conducted using Generalized Estimating Equations and Bonferroni post-hoc test (α = 0.05). After the intervention, the CTG and the ITG displayed similar improvements in time to exhaustion (8% vs. 11%), peak oxygen uptake (9% vs. 7%), maximal dynamic knee extension strength (5% vs. 6%), dynamic muscular endurance of knee extensors (10% vs. 11%), maximal vastus lateralis electromyographic signal amplitude (13% vs. 35%), as well as an increase in muscle thickness (5% vs. 6%) and decrease in muscle echo intensity (-2% vs. -3%) of the quadriceps femoris. In conclusion, older women benefited from water-based exercise training prescribed based on participants' [[RPE]], with both the interval and the continuous training programs resulting in similar increases in the cardiorespiratory and neuromuscular parameters.

|keywords=* Aerobic capacity
* Aerobic training
* Aging
* Aquatic exercise
* Interval exercise
* Muscle echo intensity
* Muscle strength
* Muscle thickness
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110914
}}
{{medline-entry
|title=Retrieval Practice Improves Recollection-Based Memory Over a Seven-Day Period in Younger and Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32038382
|abstract=Retrieving information improves subsequent memory performance more strongly than restudying. However, despite recent evidence for this retrieval practice effect ([[RPE]]), the temporal dynamics, age-related changes, and their possible interactions remain unclear. Therefore, we tested 45 young (18-30 years) and 41 older (50 + years) participants with a previously established RP paradigm. Specifically, subjects retrieved and restudied scene images on Day 1; subsequently, their recognition memory for the presented items was tested on the same day of learning and 7 days later using a remember/know paradigm. As main findings we can show that both young and older adults benefited from RP, however, the older participants benefited to a lesser extent. Importantly, the [[RPE]] was present immediately after learning on Day 1 and 7 days later, with no significant differences between time points. Finally, RP improved recollection rates more strongly than familiarity rates, independent of age and retrieval interval. Together, our results provide evidence that the [[RPE]] is reduced but still existing in older adults, it is stable over a period of seven days and relies more strongly on hippocampus-based recollection.

|keywords=* aging
* recollection and familiarity
* retrieval practice
* temporal dynamics
* testing effect
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990689
}}
{{medline-entry
|title=A Comparison of Heart Rate Training Load and Perceptual Effort Between Masters and Young Cyclists
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32000141
|abstract=Due to age-related changes in the psychobiological state of masters athletes, this brief report aimed to compare training load responses using heart rate (HR) and ratings of perceived exertion ([[RPE]]) during standardized training sessions between masters and young cyclists. Masters (n = 10; 55.6 [5.0] y) and young (n = 8; 25.9 [3.0] y) cyclists performed separate endurance and high-intensity interval training sessions. Endurance intensity was set at 95% of ventilatory threshold 2 for 1 hour. High-intensity interval training consisted of 6 × 30-second intervals at 175% peak power output with 4.5-minute rest between intervals. HR was monitored continuously and [[RPE]] collected at standardized time periods during each session. Banister training impulse and summated-HR-zones training loads were also calculated. Despite a significantly lower mean HR in masters cyclists during endurance (P = .04; d = 1.06 [±0.8], moderate) and high-intensity interval training (P = .01; d = 1.34 [±0.8], large), no significant differences were noted (P > .05) when responses were determined relative to maximum HR or converted to training impulse and summated-HR-zone loads. Furthermore, no interaction or between-group differences were evident for [[RPE]] across either session (P > .05). HR and [[RPE]] values were comparable between masters and young cyclists when relative HR responses and HR training load models are used. This finding suggests HR and [[RPE]] methods used to monitor or prescribe training load can be used interchangeably between masters and young athletes irrespective of chronological age.
|mesh-terms=* Adult
* Aging
* Bicycling
* Heart Rate
* High-Intensity Interval Training
* Humans
* Middle Aged
* Perception
* Physical Exertion
|keywords=* age
* endurance training
* high-intensity interval training
* older athlete
|full-text-url=https://sci-hub.do/10.1123/ijspp.2019-0413
}}
{{medline-entry
|title=Retinal Pigment Epithelial Cells: The Unveiled Component in the Etiology of Prpf Splicing Factor-Associated Retinitis Pigmentosa.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31884616
|abstract=Pre-mRNA splicing is a critical step in RNA processing in all eukaryotic cells. It consists of introns removal and requires the assembly of a large RNA-protein complex called the spliceosome. This complex of small nuclear ribonucleoproteins is associated with accessory proteins from the pre-mRNA processing factor (PRPF) family. Mutations in different splicing factor-encoding genes were identified in retinitis pigmentosa (RP) patients. A surprising feature of these ubiquitous factors is that the outcome of their alteration is restricted to the retina. Because of their high metabolic demand, most studies focused on photoreceptors dysfunction and associated degeneration. However, cells from the retinal pigment epithelium ([[RPE]]) are also crucial to maintaining retinal homeostasis and photoreceptor function. Moreover, mutations in [[RPE]]-specific genes are associated with some RP cases. Indeed, we identified major [[RPE]] defects in Prpf31-mutant mice: circadian rhythms of both photoreceptor outer segments (POS) phagocytosis and retinal adhesion were attenuated or lost, leading to ultrastructural anomalies and vacuoles. Taken together, our published and ongoing data suggest that (1) similar molecular events take place in human and mouse cells and (2) these functional defects generate various stress processes.
|mesh-terms=* Animals
* Circadian Rhythm
* Epithelial Cells
* Eye Proteins
* Humans
* Mice
* Phagocytosis
* Photoreceptor Cells, Vertebrate
* RNA Splicing Factors
* Retinal Pigment Epithelium
* Retinitis Pigmentosa
|keywords=* Aging
* Cellular stress
* Circadian rhythm
* Metabolism
* PRPF
* Phagocytosis
* Retinal pigment epithelium
* Retinitis pigmentosa
* Splicing factors
|full-text-url=https://sci-hub.do/10.1007/978-3-030-27378-1_37
}}
{{medline-entry
|title=AMPK May Play an Important Role in the Retinal Metabolic Ecosystem.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31884657
|abstract=Evidence suggests that metabolic dysregulation plays an important role in disease etiology of retinal degenerations. Several studies suggest that preserving the retinal metabolic ecosystem may be protective against retinal degenerations. We investigated whether activation of 5' adenosine monophosphate protein kinase (AMPK) is protective to the retina in several preclinical mouse models of retinal degeneration and found that metformin-induced activation of AMPK was able to delay or prevent retinal degeneration in the rd10 model of retinitis pigmentosa, the NaIO  model of [[RPE]] and retinal injury, and the light damage model of retinal degeneration. This protection was associated with increased mitochondrial DNA copy number, increased levels of ATP, and a reduction in oxidative stress and oxidative DNA damage. We propose that AMPK plays an important role in regulation of the retinal metabolic ecosystem and that activation of AMPK may promote metabolic processes to prevent retinal degeneration.
|mesh-terms=* AMP-Activated Protein Kinases
* Animals
* DNA Damage
* DNA, Mitochondrial
* Disease Models, Animal
* Gene Dosage
* Metformin
* Mice
* Oxidative Stress
* Retina
* Retinal Degeneration
* Retinitis Pigmentosa
|keywords=* AMPK
* Adenosine monophosphate-activated protein kinase
* Aging
* Glycolysis
* Metabolism
* Neuroprotection
* Retina
|full-text-url=https://sci-hub.do/10.1007/978-3-030-27378-1_78
}}
{{medline-entry
|title=Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31840941
|abstract=Modeling age-related macular degeneration (AMD) is challenging, because it is a multifactorial disease. To focus on interactions between the retinal pigment epithelium ([[RPE]]) and Bruch's membrane, we generated [[RPE]] from AMD patients and used an altered extracellular matrix (ECM) that models aged Bruch's membrane. Induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from AMD patients or age-matched (normal) controls. [[RPE]] derived from iPSCs were analyzed by morphology, marker expression, transepithelial electrical resistance (TER), and phagocytosis of rod photoreceptor outer segments. Cell attachment and viability was tested on nitrite-modified ECM, a typical modification of aged Bruch's membrane. DNA microarrays with hierarchical clustering and analysis of mitochondrial function were used to elucidate possible mechanisms for the observed phenotypes. Differentiated [[RPE]] displayed cell-specific morphology and markers. The TER and phagocytic capacity were similar among iPSC-derived [[RPE]] cultures. However, distinct clusters were found for the transcriptomes of AMD and control iPSC-derived [[RPE]]. AMD-derived iPSC-[[RPE]] downregulated genes responsible for metabolic-related pathways and cell attachment. AMD-derived iPSC-[[RPE]] exhibited reduced mitochondrial respiration and ability to attach and survive on nitrite-modified ECM. Cells that did attach induced the expression of complement genes. Despite reprogramming, iPSC derived from AMD patients yielded [[RPE]] with a transcriptome that is distinct from that of age-matched controls. When challenged with an AMD-like modification of Bruch's membrane, AMD-derived iPSC-[[RPE]] activated the complement immune system.

|keywords=* Bruch's membrane
* age-related macular degeneration
* aging
* induced pluripotent stem cells
* nonenzymatic nitration
* retinal pigment epithelium
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031648
}}
{{medline-entry
|title=Elovanoids counteract oligomeric β-amyloid-induced gene expression and protect photoreceptors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31712409
|abstract=The onset of neurodegenerative diseases activates inflammation that leads to progressive neuronal cell death and impairments in cognition (Alzheimer's disease) and sight (age-related macular degeneration [AMD]). How neuroinflammation can be counteracted is not known. In AMD, amyloid β-peptide (Aβ) accumulates in subretinal drusen. In the 5xFAD retina, we found early functional deficiencies (ERG) without photoreceptor cell (PRC) death and identified early insufficiency in biosynthetic pathways of prohomeostatic/neuroprotective mediators neuroprotectin D1 (NPD1) and elovanoids (ELVs). To mimic an inflammatory milieu in wild-type mouse, we triggered retinal pigment epithelium ([[RPE]]) damage/PRC death by subretinally injected oligomeric β-amyloid (OAβ) and observed that ELVs administration counteracted their effects, protecting these cells. In addition, ELVs prevented OAβ-induced changes in gene expression engaged in senescence, inflammation, autophagy, extracellular matrix remodeling, and AMD. Moreover, as OAβ targets the [[RPE]], we used primary human [[RPE]] cell cultures and demonstrated that OAβ caused cell damage, while ELVs protected and restored gene expression as in mouse. Our data show OAβ activates senescence as reflected by enhanced expression of p16 , MMP1, p53, p21, p27, and Il-6, and of senescence-associated phenotype secretome, followed by [[RPE]] and PRC demise, and that ELVs 32 and 34 blunt these events and elicit protection. In addition, ELVs counteracted OAβ-induced expression of genes engaged in AMD, autophagy, and extracellular matrix remodeling. Overall, our data uncovered that ELVs downplay OAβ-senescence program induction and inflammatory transcriptional events and protect [[RPE]] cells and PRC, and therefore have potential as a possible therapeutic avenue for AMD.
|mesh-terms=* Amyloid beta-Peptides
* Animals
* Apoptosis
* Autophagy
* Cells, Cultured
* Docosahexaenoic Acids
* Extracellular Matrix
* Fatty Acids, Omega-3
* Gene Expression Regulation
* Humans
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Photoreceptor Cells
* Retina
* Retinal Pigment Epithelium
* Young Adult
|keywords=* SASP
* age-related macular degeneration
* p16
* retinal pigment epithelial cells
* senescence gene program
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883841
}}
{{medline-entry
|title=Genetic LAMP2 deficiency accelerates the age-associated formation of basal laminar deposits in the retina.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31699817
|abstract=The early stages of age-related macular degeneration (AMD) are characterized by the accumulation of basal laminar deposits (BLamDs). The mechanism for BLamDs accumulating between the retinal pigment epithelium ([[RPE]]) and its basal lamina remains elusive. Here we examined the role in AMD of lysosome-associated membrane protein-2 (LAMP2), a glycoprotein that plays a critical role in lysosomal biogenesis and maturation of autophagosomes/phagosomes. LAMP2 was preferentially expressed by [[RPE]] cells, and its expression declined with age. Deletion of the [i]Lamp2[/i] gene in mice resulted in age-dependent autofluorescence abnormalities of the fundus, thickening of Bruch's membrane, and the formation of BLamDs, resembling histopathological changes occurring in AMD. Moreover, LAMP2-deficient mice developed molecular signatures similar to those found in human AMD-namely, the accumulation of APOE, APOA1, clusterin, and vitronectin-adjacent to BLamDs. In contrast, collagen 4, laminin, and fibronectin, which are extracellular matrix proteins constituting [[RPE]] basal lamina and Bruch's membrane were reduced in [i]Lamp2[/i] knockout (KO) mice. Mechanistically, retarded phagocytic degradation of photoreceptor outer segments compromised lysosomal degradation and increased exocytosis in LAMP2-deficient [[RPE]] cells. The accumulation of BLamDs observed in LAMP2-deficient mice was eventually followed by loss of the [[RPE]] and photoreceptors. Finally, we observed loss of LAMP2 expression along with ultramicroscopic features of abnormal phagocytosis and exocytosis in eyes from AMD patients but not from control individuals. Taken together, these results indicate an important role for LAMP2 in [[RPE]] function in health and disease, suggesting that LAMP2 reduction may contribute to the formation of BLamDs in AMD.
|mesh-terms=* Aging
* Animals
* Basement Membrane
* Bruch Membrane
* Exocytosis
* Humans
* Lysosomal-Associated Membrane Protein 2
* Lysosomes
* Macular Degeneration
* Mice
* Mice, Knockout
* Phagocytosis
* Retina
* Retinal Pigment Epithelium
|keywords=* LAMP2
* aging
* lysosome
* retinal degeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876195
}}
{{medline-entry
|title=Age, lipofuscin and melanin oxidation affect fundus near-infrared autofluorescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31648994
|abstract=Fundus autofluorescence is a non-invasive imaging technique in ophthalmology. Conventionally, short-wavelength autofluorescence (SW-AF) is used for detection of lipofuscin, a byproduct of the visual cycle which accumulates with age or disease in the retinal pigment epithelium ([[RPE]]). Furthermore, near-infrared autofluorescence (NIR-AF) is used as a marker for [[RPE]] and choroidal melanin, but contribution of lipofuscin to the NIR-AF signal is unclear. We employed fluorescence microscopy to investigate NIR-AF properties of melanosomes, lipofuscin and melanolipofuscin granules in histologic sections of wildtype and Abca4  mouse eyes, the latter having increased lipofuscin, as well as aged human donor eyes. Differentiation between these pigments was verified by analytical electron microscopy. To investigate the influence of oxidative and photic stress we used an in vitro model with isolated ocular melanosomes and an in vivo phototoxicity mouse model. We show that NIR-AF is not an intrinsic property of melanin, but rather increases with age and after photic or oxidative stress in mice and isolated melanosomes. Furthermore, when lipofuscin levels are high, lipofuscin granules also show NIR-AF, as confirmed by correlative fluorescence and electron microscopy in human tissue. However, lipofuscin in albino Abca4  mice lacks NIR-AF signals. We suggest that NIR-AF is derived from melanin degradation products that accumulate with time in lipofuscin granules. These findings can help to improve the interpretation of patient fundus autofluorescence data. This work was supported by Bundesministerium für Bildung und Forschung, Deutsche Forschungsgemeinschaft and Chinese Scholarship Council. Major instrumentation used in this work was supported by Deutsche Forschungsgemeinschaft, the European Fund for Regional Development and the state of Baden-Württemberg.
|mesh-terms=* Age Factors
* Animals
* Biomarkers
* Choroid
* Disease Models, Animal
* Female
* Fluorescein Angiography
* Fundus Oculi
* Humans
* Lipofuscin
* Macular Degeneration
* Male
* Melanins
* Melanosomes
* Mice
* Mice, Knockout
* Optical Imaging
* Oxidation-Reduction
* Oxidative Stress
* Protein Transport
* Retinal Pigment Epithelium
* Tomography, Optical Coherence
|keywords=* Aging
* Lipofuscin
* Melanin
* Melanolipofuscin
* Oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838394
}}
{{medline-entry
|title=Relevance of working memory for reinforcement learning in older adults varies with timescale of learning.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31544587
|abstract=In young adults, individual differences in working memory (WM) contribute to reinforcement learning (RL). Age-related RL changes, however, are mostly attributed to decreased reward prediction-error ([[RPE]]) signaling. Here, we investigated the contribution of WM to RL in young (18-35) and older (≥65) adults. Because WM supports maintenance across a limited timescale, we only expected a relation between RL and WM with short delays between stimulus repetitions. Our results demonstrated better learning with short than long delays. A week later, however, long-delay associations were remembered better. Computational modeling corroborated that during learning, WM was more engaged by young adults in the short-delay condition than in any other age-condition combination. Crucially, both model-derived and neuropsychological assessments of WM predicted short-delay learning in older adults, who further benefitted from using self-conceived learning strategies. Thus, depending on the timescale of learning, age-related RL changes may not only reflect decreased [[RPE]] signaling but also WM decline.

|keywords=* Aging
* computational modeling
* individual differences
* reinforcement learning
* working memory
|full-text-url=https://sci-hub.do/10.1080/13825585.2019.1664389
}}
{{medline-entry
|title=Expression and Function of Mas-Related G Protein-Coupled Receptor D and Its Ligand Alamandine in Retina.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31392515
|abstract=A local renin-angiotensin system (RAS) exists in the retina and plays a critical role in retinal neurovascular function. The protective axis of RAS comprising of angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas receptor attenuate the deleterious actions of increased levels of angiotensin II (Ang II), the main effector peptide of RAS. A new peptide, alamandine, and its receptor Mas-related G protein-coupled receptor D (MrgD) have been recently identified that share structural and functional similarity to Ang-(1-7) and its receptor, Mas, establishing another new protective axis of RAS. Here, we examined the expression and cellular localization of MrgD in the retina, the effect of MrgD deficiency on mouse retinal structure and function, as well as the biological function of alamandine in cultured retinal cells. We showed that MrgD is expressed in the retinal neurons, retinal vasculature, Müller glial and [[RPE]] cells, similar to Mas receptor expression. MrgD-deficient mice did not exhibit gross change in retinal morphology and thickness; however, these mice did show a progressive decrease in both scotopic and photopic a-wave and b-wave amplitudes, and increase in retinal capillary loss with age compared to age-matched wild-type mice. In vitro studies in human retinal cells showed that alamandine attenuated the Ang II and LPS-induced increases in inflammatory cytokine gene expression, NF-κB activation, Ang II and hydrogen peroxide-induced production of reactive oxygen species, comparable to that mediated by Ang-(1-7). These results support the notion that alamandine/MrgD may represent another new protective axis of RAS in the retina exerting anti-oxidative and anti-inflammatory effects.
|mesh-terms=* Aging
* Angiotensin II
* Animals
* Cells, Cultured
* Electroretinography
* Humans
* Ligands
* Lipopolysaccharides
* Mice, Inbred C57BL
* Mice, Knockout
* Oligopeptides
* Rats
* Reactive Oxygen Species
* Receptors, G-Protein-Coupled
* Retina
|keywords=* Alamandine
* Angiotensin-(1–7)
* Mas-related G protein-coupled receptor D
* Rennin-angiotensin system
* Retina
|full-text-url=https://sci-hub.do/10.1007/s12035-019-01716-4
}}
==CRP==

{{medline-entry
|title=Omega-3 supplementation improves isometric strength but not muscle anabolic and catabolic signaling in response to resistance exercise in healthy older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33284965
|abstract=Old skeletal muscle exhibits decreased anabolic sensitivity, eventually contributing to muscle wasting. Besides anabolism, also muscle inflammation and catabolism are critical players in regulating the old skeletal muscle's sensitivity. Omega-3 fatty acids (ω-3) are an interesting candidate to reverse anabolic insensitivity via anabolic actions. Yet, it remains unknown whether ω-3 also attenuates muscle inflammation and catabolism. The present study investigates the effect of ω-3 supplementation on muscle inflammation and metabolism (anabolism/catabolism) upon resistance exercise (RE). Twenty-three older adults (OA) (65-84yr;8♀) were randomized to receive ω-3 (~3g·d -1) or corn oil (PLAC) and engaged in a 12-wk RE program (3x·wk -1). Before and after intervention, muscle volume, strength and systemic inflammation were assessed, and muscle biopsies were analysed for markers of anabolism, catabolism and inflammation. Isometric knee-extensor strength increased in ω-3 (+12.2%), but not in PLAC (-1.4%; pinteraction=0.015), whereas leg press strength improved in both conditions (+27.1%; ptime<0.001). RE, but not ω-3, decreased inflammatory (p65NF-κB) and catabolic (FOXO1, LC3b) markers, and improved muscle quality. Yet, muscle volume remained unaffected by RE and ω-3. Accordingly, muscle anabolism (mTORC1) and plasma [[CRP]] remained unchanged by RE and ω-3, whereas serum IL-6 tended to decrease in ω-3 (pinteraction=0.07). These results show that, despite no changes in muscle volume, RE-induced gains in isometric strength can be further enhanced by ω-3. However, ω-3 did not improve RE-induced beneficial catabolic or inflammatory adaptations. Irrespective of muscle volume, gains in strength (primary criterion for sarcopenia) might be explained by changes in muscle quality due to muscle inflammatory or catabolic signaling.

|keywords=* Muscle wasting
* aging
* anabolic resistance
* inflammation
* resistance training
* sarcopenia
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa309
}}
{{medline-entry
|title=Circulating angiopoietin-like protein 2 levels and arterial stiffness in patients receiving maintenance hemodialysis: A cross-sectional study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33197687
|abstract=Chronic low-grade inflammation is receiving much attention as a critical pathology that induces various aging phenotypes, a concept known as "inflammaging". Uremic patients undergoing hemodialysis therapy show vascular aging phenotypes characterized by greater arterial stiffness and calcification compared to healthy controls of the same generation. In the current study, we investigated whether levels of inflammaging markers in the circulation were associated with vascular aging phenotypes in hemodialysis patients, as estimated by the cardio-ankle vascular index (CAVI). We conducted a multicenter cross-sectional study of 412 patients receiving hemodialysis and evaluated the relationship between circulating hs-[[CRP]] or ANGPTL2 levels, as markers of inflammaging, and CAVI. Of 412 patients, 376 were analyzed statistically. While circulating hs-[[CRP]] levels had no significant association with CAVI, generalized linear models revealed that high circulating ANGPTL2 levels were significantly associated with increasing CAVI after adjustment for classical metabolic factors and hemodialysis-related parameters [β 0.63 (95%CI 0.07-1.18)]. Exploratory analysis revealed that high circulating ANGPTL2 levels were also strongly associated with increased CAVI, particularly in patients with conditions of increased vascular mechanical stress, such elevated blood pressure [β 1.00 (95%CI 0.23-1.76)], elevated pulse pressure [β 0.75 (95%CI 0.52-0.98)], or excess body fluid [β 1.25 (95%CI 0.65-1.84)]. We conclude that circulating levels of ANGPTL2 rather than hs-[[CRP]] are positively associated with CAVI in the uremic population and that ANGPTL2 could be a unique marker of progression of vascular aging in patients receiving hemodialysis.

|keywords=* Angiopoietin-like protein (ANGPTL) 2
* Cardio-ankle vascular index (CAVI)
* Chronic inflammation
* Hemodialysis
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.atherosclerosis.2020.10.890
}}
{{medline-entry
|title=Cardiovascular rehabilitation in patients aged 70-year-old or older: benefits on functional capacity, physical activity and metabolic profile in younger [i]vs[/i]. older patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33117418
|abstract=The benefits of exercise-based cardiac rehabilitation (EBCR) programs in post-acute myocardial infarction (AMI) patients have been demonstrated. Our aim was to assess the impact of EBCR in ≥ 70-years-old [i]vs.[/i] younger post-AMI patients. We retrospectively evaluated patients who underwent a supervised EBCR protocol, twice a week during 6-12 weeks. We evaluated changes in several outcomes based on pre- and post-[[CRP]] assessments. Of a total of 1607 patients, 333 (21%) were ≥ 70-years-old. After the EBCR, an overall improvement on functional capacity, daily physical activity, lipid profile, body mass index, glycated hemoglobin (HbA1c), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and C-reactive protein was observed in both younger and older patients ([i]P[/i] < 0.05). Older patients showed a smaller benefit on the increment of daily physical activity and lipid profile improvement, but a larger reduction in NT-pro-BNP. In the multivariate analysis, only improvements on daily physical activity and HbA1c were dependent on age. As their younger counterparts, older patients, significantly improved functional capacity, metabolic parameters and level of daily physical activity after EBCR.

|keywords=* Aging
* Cardiovascular prevention
* Exercise-based cardiac rehabilitation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568038
}}
{{medline-entry
|title=rRT-PCR Results of a Covid-19 Diagnosed Geriatric Patient.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33103060
|abstract=In this study, we aimed to present a geriatric patient with the diagnosis of COVID-19 and with contradictory results in rRT-PCR examinations in short time intervals. A 69-year-old male patient was admitted to the emergency room on the 18th day of May 2020, with the complaints of fever, sweating, myalgia, dry cough that continued for 5 days, and the lack of taste that started on the day he applied to the emergency room. Comorbidity factors include diabetes mellitus, bronchial asthma, and hypertension. The patient has a history of 36 years of smoking 1.5 packs per day. High laboratory findings during hospitalization: monocytes, creatinine, [[CRP]] (C-reactive protein). In the thorax CT, in the parenchyma areas of both lungs, there are increases in attenuation with multilobe distributions (more visible at the level of the upper lobes) in the form of ground-glass opacities. May 19, 2020, was subjected to the rRT-PCR test, repeated twice on the 19th of May which also resulted in positive. Despite rRT-PCR tests, which were negative on 27th of May and positive on 28th of May, the patient, whose symptoms disappeared, and general condition improved, was discharged on June 1, 2020, with the recommendation for home isolation. In our case, unlike the incubation period only, we encountered a negative rRT-PCR result on the 8th day after diagnosis. Therefore, the COVID-19 pandemic control and filiation evaluation with the rRT-PCR test may produce false negative results.

|keywords=* COVID-19
* False negative reactions
* Geriatrics
* Mass screening
* Reverse transcriptase polymerase chain reaction
* SARS-CoV-2
* Tomography
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567648
}}
{{medline-entry
|title=The Association of Aging Biomarkers, Interstitial Lung Abnormalities, and Mortality.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33080140
|abstract=The association between aging and idiopathic pulmonary fibrosis is established. The associations between aging-related biomarkers and interstitial lung abnormalities (ILA) have not been comprehensively evaluated. Evaluate associations between aging biomarkers, ILA, and all-cause mortality. In the Framingham Heart Study (FHS), we evaluated associations between plasma biomarkers (interleukin-6 [IL-6], C-reactive protein [[[CRP]]], tumor necrosis factor alpha receptor II [TNFR], growth differentiation factor 15 [GDF15], cystatin-C, hemoglobin A1C [HGBA1C], insulin, insulin like growth factor [IGF] 1, and IGF binding proteins 1 and 3 [IGFBP1 and 3]), ILA, and mortality. Causal inference analysis was used to determine if biomarkers mediated age. GDF15 results were replicated in COPDGene. In FHS, there was higher odds of ILA per increase in natural log-transformed (ln) GDF15 (OR [95% CI] = 3.4 [1.8-6.4], p=0.0002), TNFR (3.1 [1.6-5.8], p=0.004), IL-6 (1.8 [1.4-2.4], p<0.0001), and [[CRP]] (1.7 [1.3-2.0], p<0.0001). In FHS, after adjustment for multiple comparisons, no biomarker was associated with increased mortality, but GDF15 (HR = 2.0 [1.1-3.5], P=0.02), TNFR (1.8 [1.0-3.3], p=0.05), and IGFBP1 (1.3 [1.1-1.7], P=0.01) approached significance. In COPDGene, higher ln(GDF15) was associated with ILA (OR = 8.1 [3.1-21.4], p<0.0001) and mortality (HR = 1.6 [1.1-2.2], p=0.01). Causal inference analysis showed the association of age with ILA was mediated by IL-6 (p<0.0001), TNFR (p=0.002), and likely GDF15 (p=0.008) in FHS, and by GDF15 (p=0.001) in COPDGene. Some aging-related biomarkers are associated with ILA. GDF15, in particular, may explain some of the association between age, ILA, and mortality.

|keywords=* aging
* growth differentiation factor 15
* idiopathic pulmonary fibrosis
* interstitial lung abnormalities
* mortality
|full-text-url=https://sci-hub.do/10.1164/rccm.202007-2993OC
}}
{{medline-entry
|title=A Novel Fortified Dairy Product and Sarcopenia Measures in Sarcopenic Older Adults: A Double-Blind Randomized Controlled Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33067129
|abstract=To evaluate the efficacy of daily consumption of fortified yogurt with beta-Hydroxy beta-Methyl Butyrate (HMB) and vitamins D and C on measures of sarcopenia, inflammation, and quality of life in sarcopenic older adults. In this 12-week randomized double-blind controlled trial, participants received either yogurt fortified with 3 g HMB, 1000 IU vitamin D, and 500 mg vitamin C in the intervention group (n = 33) or plain yogurt in the control group (n = 33). A total of 66 older adults with sarcopenia recruited from the community in Shiraz, Iran. Body composition, muscle strength, and functionality were measured using Dual-energy-X-ray Absorptiometry (DXA), hydraulic handgrip dynamometer, and usual gait speed, respectively. Serum concentrations of vitamin D, insulin-like growth factor-1 (IGF-1), C-reactive protein (hs-[[CRP]]), malondialdehyde, and insulin were measured at baseline and after 12 weeks. Health-related quality of life (HRQoL) was also evaluated using SF-12 questionnaire. Consumption of fortified yogurt was associated with improvement in handgrip strength [mean change (95% confidence interval) 4.36 (3.35-5.37) vs. 0.97 (-0.04 to 1.99)] and gait speed [0.10 (0.07-0.13) vs. 0.01 (0.00-0.04)] in the intervention group compared with the control group (P < .001). In addition, the results revealed a significant increase in vitamin D and IGF-1 levels in the intervention group (P < .001). The nutritional intervention significantly prevented any increase in the serum concentration of hs-[[CRP]] compared with the control group (P = .033). The results also showed a more significant decrease in the malondialdehyde level in the intervention group compared with the control (P = .008). Moreover, there were significant differences between the 2 groups regarding physical aspects of HRQoL (P = .035). A novel dairy product fortified with HMB, vitamin D, and vitamin C not only could enhance muscle strength and functionality, but also modulate anabolic and inflammatory conditions as well as quality of life. This study suggested that specific nutritional interventions alone could be beneficial, especially for those who are unable to exercise.

|keywords=* Functional food
* aging
* beta-hydroxy beta-methylbutyrate
* muscle strength
* sarcopenia
* vitamin D
|full-text-url=https://sci-hub.do/10.1016/j.jamda.2020.08.035
}}
{{medline-entry
|title=Age-Related Colonic Mucosal Microbiome Community Shifts in Monkeys.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33021628
|abstract=Aging-related changes in gut microbiome changes impacts host health. The interactive relationship between the microbiome and physiological systems in an aged body system remains to be clearly defined, particularly in the context of inflammation. Therefore, we aimed to evaluate systemic inflammation, microbial translocation (MT) and differences between fecal and mucosal microbiomes. Ascending colon mucosal biopsies, fecal and blood samples from healthy young and old female vervet monkeys were collected for 16S rRNA gene sequencing, MT and cytokine analyses, respectively. To demonstrate microbial co-occurrence patterns, we used Kendall's tau correlation measure of interactions between microbes. We found elevated levels of plasma LBP-1, MCP-1 and [[CRP]] in old monkeys, indicative of higher MT and systemic inflammation. Microbiome analysis revealed significant differences specific to age. At the phylum level, abundances of pathobionts such as Proteobacteria were increased in the mucosa of old monkeys. At the family level, Helicobacteriaceae was highly abundant in mucosal samples (old); in contrast, Ruminococcaceae were higher in fecal samples old monkeys. We found significantly lower Firmicutes:Bacteroidetes ratio and lower abundance of butyrate-producing microbes in old monkeys, consistent with less healthy profiles. Microbial community co-occurrence analysis on mucosal samples revealed 13 nodes and 41 associations in the young monkeys, but only 12 nodes and 21 associations in the old monkeys. Our findings provided novel insights into systemic inflammation and gut microbial interactions, highlights the importance of the mucosal niche, and facilitates further understanding of the decline in the stability of the microbial community with aging.

|keywords=* Aging
* Microbial co-occurrences
* Mucosal microbiome
* Systemic inflammation
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa256
}}
{{medline-entry
|title=The relationship between frailty and serum alpha klotho levels in geriatric patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32905907
|abstract=Frailty is a medical syndrome resulting in loss of endurance, strength and physiological function. There is insufficient data to understand the process of frailty formation at the gene level, however one of the product of Klotho gene known as an anti-aging gene with many functions that prolong lifespan is alpha klotho protein. We aimed to investigate the relationship between frailty and the serum alpha klotho protein levels. In this cross-sectional analysis, there were 89 patients aged 65 years old and older, 45 of whom were frail and 44 of whom were not frail, were included in the study. Within the scope of the study, a sociodemographic and clinical information form, the Turkish version of the FRAIL scale and a comprehensive geriatric assessment were evaluated. In addition to routine laboratory tests, plasma alpha klotho protein levels were measured. The mean alpha klotho protein levels of the patients were 0.76 ± 1.01 ng/ml in the control group and 0.54 ± 0.61 ng/ml in the frail group, however, there was no statistically significant difference between the two groups (p = 0.286). C-reactive protein ([[CRP]]) levels were significantly higher and hemoglobin (Hb) levels were significantly lower in the frail patients compared to the control group (p < 0.05). It was observed that alpha klotho protein level was inversly correlated with increased [[CRP]] levels but association was weak (p = 0.022, R: -0.245). Hb levels (p = 0.018, R: 0.250) was weakly correlated with alpha klotho protein level. No significant relationship was found between frailty and alpha klotho protein levels in the geriatric patients. Further comprehensive studies are needed to explore this subject.

|keywords=* Aging
* Biomarkers
* Frailty syndrome
* Geriatric syndrome
* Sarcopenia
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104225
}}
{{medline-entry
|title=ZMPSTE24 Is Associated with Elevated Inflammation and Progerin mRNA.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32872320
|abstract=Lamins are important filaments forming the inner nuclear membrane. Lamin A is processed by zinc metalloproteinase (ZMPSTE24). Failure to cleave a truncated form of prelamin A-also called progerin-causes Hutchinson-Gilford progeria syndrome a well-known premature aging disease. Minor levels of progerin are readily expressed in the blood of healthy individuals due to alternative splicing. Previously, we found an association of increased progerin mRNA with overweight and chronic inflammation (hs-[[CRP]]). Here, we aimed to elucidate correlations of ZMPSTE24, lamin A/C and progerin with the inflammatory marker hs-[[CRP]]. In this retrospective, cross-sectional study we analyzed blood samples from 110 heart failure patients for quantitative mRNA expression of ZMPSTE24, lamin A/C, progerin and hs-[[CRP]] protein. Spearman correlations and linear regression analyses including adjustments for age, gender and ejection fraction showed a significant positive correlation of lnprogerin with lnZMPSTE24 (n = 110; r = 0.33; [i]p[/i] = 0.0004) and lnlamin A/C (n = 110; r = 0.82, [i]p[/i] < 0.0001), whereas no association was observed between lnlamin A/C and lnZMPSTE24 expression. Further analyses showed a significant positive correlation of lnhs-[[CRP]] with lnZMPSTE24 (n = 110; r = 0.21; [i]p[/i] = 0.01) and lnlamin A/C (n = 110; r = 0.24; [i]p[/i] = 0.03). We conclude that chronic inflammation is associated with increased expression of ZMPSTE24 and lamin A/C mRNA. Both markers also positively correlate with increased expression of the premature aging marker progerin which may be linked to cardiovascular aging.

|keywords=* ZMPSTE24
* aging
* inflammation
* lamin A/C
* progerin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563344
}}
{{medline-entry
|title=Cultural and life style practices associated with low inflammatory physiology in Japanese adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32805392
|abstract=Japan is an exceptionally healthy East Asian country with extended longevity. In addition, the typical levels of several proinflammatory proteins, including both C-reactive protein ([[CRP]]) and interleukin-6 (IL-6), are often reported to be low when compared to American and European populations. This analysis determined if blood levels of [[CRP]] and IL-6 were associated with 4 cultural practices reflective of Japanese behavior and customs -- drinking tea, eating seafood, consuming vegetables, and partaking in relaxing baths regularly - among 382 adults living in Tokyo. Regression models controlled for demographic factors, adiposity (BMI), physical exercise, smoking, alcohol use, and chronic illness (e.g., diabetes). Consuming a Japanese diet was associated with significantly lower [[CRP]] and IL-6 levels. More frequent bathing was associated with lower IL-6, but not specifically predictive of low [[CRP]]. This study has confirmed prior evidence for low inflammatory activity in Japanese adults and its association with several behavioral practices common in Japan.

|keywords=* Aging
* Bathing
* C-reactive protein
* Diet
* Inflammation
* Interleukin-6
* Japan
* Tea
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544652
}}
{{medline-entry
|title=Moderate- to high intensity aerobic and resistance exercise reduces peripheral blood regulatory cell populations in older adults with rheumatoid arthritis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32467712
|abstract=Exercise can improve immune health and is beneficial for physical function in patients with rheumatoid arthritis (RA), but the immunological mechanisms are largely unknown. We evaluated the effect of moderate- to high intensity exercise with person-centred guidance on cells of the immune system, with focus on regulatory cell populations, in older adults with RA. Older adults (≥65 years) with RA were randomized to either 20-weeks of moderate - to high intensity aerobic and resistance exercise ([i]n[/i] = 24) or to an active control group performing home-based exercise of light intensity ([i]n[/i] = 25). Aerobic capacity, muscle strength, DAS28 and [[CRP]] were evaluated. Blood samples were collected at baseline and after 20 weeks. The frequency of immune cells defined as adaptive regulatory populations, CD4 + Foxp3 + CD25 + CD127- T regulatory cells (Tregs) and CD19 + CD24hiCD38hi B regulatory cells (Bregs) as well as HLA-DR-/lowCD33 + CD11b + myeloid derived suppressor cells (MDSCs), were assessed using flow cytometry. After 20 weeks of moderate- to high intensity exercise, aerobic capacity and muscle strength were significantly improved but there were no significant changes in Disease Activity Score 28 (DAS28) or [[CRP]]. The frequency of Tregs and Bregs decreased significantly in the intervention group, but not in the active control group. The exercise intervention had no effect on MDSCs. The reduction in regulatory T cells in the intervention group was most pronounced in the female patients. Moderate- to high intensity exercise in older adults with RA led to a decreased proportion of Tregs and Bregs, but that was not associated with increased disease activity or increased inflammation. Improved Ability to Cope With Everyday Life Through a Person-centered Training Program in Elderly Patients With Rheumatoid Arthritis - PEP-walk Study, NCT02397798. Registered at ClinicalTrials.gov March 19, 2015.

|keywords=* Aging
* Breg cells
* Exercise
* IL-10
* Rheumatoid arthritis
* T cells
* Treg cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229606
}}
{{medline-entry
|title=PTSD and the klotho longevity gene: Evaluation of longitudinal effects on inflammation via DNA methylation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32438247
|abstract=Longevity gene klotho (KL) is associated with age-related phenotypes including lifespan, cardiometabolic disorders, cognition, and brain morphology, in part, by conferring protection against inflammation. We hypothesized that the KL/inflammation association might be altered in the presence of psychiatric stress and operate via epigenetic pathways. We examined KL polymorphisms, and their interaction with posttraumatic stress disorder (PTSD) symptoms, in association with KL DNA methylation in blood. We further examined KL DNA methylation as a predictor of longitudinal changes in a peripheral biomarker of inflammation (C-reactive protein; [[CRP]]). The sample comprised 309 white non-Hispanic military veterans (93.5 % male; mean age: 32 years, range: 19-65; 30 % PTSD per structured diagnostic interview); 111 were reassessed approximately two years later. Analyses revealed a methylation quantitative trait locus at rs9527025 (C370S, previously implicated in numerous studies of aging) in association with a Cytosine-phosphate-Guanine site (cg00129557; B = -.65, p =  1.29 X 10 ), located within a DNase hypersensitivity site in the body of KL. There was also a rs9527025 x PTSD severity interaction (B = .004, p = .035) on methylation at this locus such that the minor allele was associated with reduced cg00129557 methylation in individuals with few or no PTSD symptoms while this effect was attenuated in those with elevated levels of PTSD. Path models revealed that methylation at cg00129557 was inversely associated with [[CRP]] over time (B = -.14, p = .005), controlling for baseline [[CRP]]. There was also an indirect effect of rs9527025 X PTSD on subsequent [[CRP]] via cg00129557 methylation (indirect B = -.002, p = .033). Results contribute to our understanding of the epigenetic correlates of inflammation in PTSD and suggest that KL methylation may be a mechanism by which KL genotype confers risk vs. resilience to accelerated aging in those experiencing traumatic stress.

|keywords=* Accelerated aging
* Inflammation
* Klotho
* Methylation
* PTSD
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293549
}}
{{medline-entry
|title=Bereavement is associated with reduced systemic inflammation: C-reactive protein before and after widowhood.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32283288
|abstract=Bereavement is associated with poorer health and early mortality. Increased systemic inflammation is one pathophysiological pathway thought to explain this health risk. However, few studies have examined systemic inflammation before and after widowhood. The current study examined the associations between inflammation and widowhood status before and after bereavement in a sample of married adults who became widowed between assessments in the English Longitudinal Study of Ageing. We examined levels and change over time in systemic inflammation, as assessed by C-reactive protein ([[CRP]]), among participants who became bereaved (n = 199). We then compared these results to a sample of participants whose spouse remained living, selected using a propensity score matching algorithm (n = 199). Contrary to expectations, widowed participants' [[CRP]] decreased following bereavement, d = -0.29, p < 0.001. Change in [[CRP]] was not associated with pre-loss depression levels, caregiving status, marital quality, number of chronic diseases, prescribed medications, body mass index, age, or sex. Compared to continuously married participants, widowed participants' evidenced a significantly greater decrease in [[CRP]] after their spouse's death, β = -0.14, p < 0.001. Widowed adults' systemic inflammation decreased significantly following bereavement, both as a group and compared to people who remained married. We discuss possible explanations for this counterintuitive finding, including the measure of inflammation used in the study and the timing of the study measurements.

|keywords=* Aging
* Bereavement
* C-reactive protein
* Health
* Inflammation
* Widowhood
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415735
}}
{{medline-entry
|title=The Impact of Age on the Prevalence of Sarcopenic Obesity in Bariatric Surgery Candidates.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32249368
|abstract=Sarcopenia pre-dating bariatric surgery (BS) has been suggested as concern for the use of BS in older-adults with morbid obesity. To evaluate the impact of age on the prevalence of sarcopenic obesity (SO) in BS-candidates. Cross-sectional study including 1370 consecutive BS-candidates aged ≥18, and grouped according to age: 18-39 (reference group), 40-49, 50-59 and ≥ 60 years. From body composition analysis data obtained using bioelectrical impedance, skeletal muscle mass (SMM), SMM index (SMMI=SMM/height ), and percentage of SMM (%SMM = SMM/BW*100) were calculated. Class I or class II SO was adjudicated, respectively, when a value between > - 1 and - 2, or > -2 standard deviations from the regression line from the gender-specific distribution of the relationship between BMI and SMMI or the %SMM in the reference group was encountered. According to the SMMI distribution, prevalence of class I and class II SO in the whole cohort was respectively 16.4% and 4.6%. SO was more prevalent in females (p < 0.005). Proportion of subjects with SO positively correlated with older age category in females (Tau-c = 0.149, p < 0.001) but not in males. In females aged ≥60, class I SO was present in 29.1%, and class II in 12.8%. Similar results were obtained when %SMM was used (Cohen's k-coefficient = 0.886, p < 0.001). Age and female gender were identified as independent preditors of SO, whereas [[CRP]] or the presence of obesity-associated comorbidities were not. Age is a risk factor for SO in BS-candidates. SO is fairly common in female subjects aged >60 years that are candidates to BS.

|keywords=* Aging
* Bariatric surgery
* Elderly
* Obesity
* Sarcopenia
|full-text-url=https://sci-hub.do/10.1007/s11695-019-04198-4
}}
{{medline-entry
|title=Intake of dietary advanced glycation end products influences inflammatory markers, immune phenotypes, and antiradical capacity of healthy elderly in a little-studied population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32148813
|abstract=Dietary advanced glycation end products (dAGE) have profound negative effects on overall health, and their intake must be assessed. In this cross-sectional study, we investigated dAGE intake of 337 adult participants (180/157:M/F; age range 50-73 years). Data were collected on anthropometrics, body composition, dietary intake, selected blood biochemistry, immunological parameters, and antiradical capacity (50% hemolysis time; HT ). From the dietary data, dAGEs and phytochemical index (PI) were calculated. Mean BMI, % body fat (%BF), and fasting plasma glucose were all within the accepted normal range. Subjects with high dAGE intake had higher %BF, higher energy intake, and lower PI. They tended to have lower CD4/CD8 ratios and higher proportions of B cells and NK cells, but had significantly higher hs-[[CRP]] levels and lower HT  values. Results on HT  suggested that being >60 years of age enhanced dAGE-associated impairment of defense capacity in both those with low and high HT  compared with those <60 years of age. Thus, overall dAGE consumption was high, but elderly participants had lower dAGE intake than younger adults. Indicators of nutritional status and immunological parameters of the subjects were found to be associated with dAGE intake, suggesting a potential impact on health.

|keywords=* CRP
* advanced glycationed end products
* aging
* dAGE
* immunity
* inflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020308
}}
{{medline-entry
|title=Intentional Switching Between Bimanual Coordination Patterns in Older Adults: Is It Mediated by Inhibition Processes?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32132919
|abstract=The study investigated the consequences of age-related decline in inhibition processes on intentional switching between bimanual coordination patterns. Fifteen young (24±2.8 years) and 20 older adults (69±5.3 years) performed Stroop tasks and bimanual coordination tasks. Stroop tasks included neutral, congruent, and incongruent conditions. Response time and error rate were measured. Bimanual coordination tasks consisted of performing in-phase (IP) and anti-phase (AP) patterns. Participants were requested to switch as quickly as possible from one pattern to the other, resulting in two different switching directions (AP to IP; IP to AP). Mean and standard deviation (SD) of the continuous relative phase ([[CRP]]) were calculated pre- and post-switching for each participant. Total switching time (TST) was measured. The switching phase was also decomposed into reaction time (RT) and reversal time (REvT). Pearson correlation analyses were performed to test for correlations between: (i) SD of [[CRP]] and response time in Stroop tasks, and (ii) switching times (TST, RT, RevT) and response time in Stroop task, respectively. In addition, parallel mediation analyses were conducted. Results showed that: (i) the AP pattern was less stable than the IP pattern in both young and older adults, (ii) coordination patterns were less stable in older adults, (iii) response times in Stroop task were longer in the incongruent condition, and (iv) RespTs were longer in older than in young participants, whatever the condition. In the bimanual coordination task, RT, RevT, and TST increased with age. The stability of the IP pattern was correlated with the response times observed in neutral and congruent conditions, while the stability of the AP pattern was correlated with response time observed in the incongruent condition. Correlation and mediation analyses showed that, in the AP to IP switching direction, RT and RevT were both significantly correlated with response times observed in the incongruent condition of Stroop task. These findings suggest that inhibition processes are involved in switching between bimanual coordination patterns, at least to trigger the early phase of switching. They also support the hypothesis that inhibition processes are more involved in maintaining the AP pattern and switching to the IP pattern. Finally, age-related changes in switching times seem to be prominently mediated by alterations of inhibition processes.

|keywords=* Stroop task
* aging
* bimanual coordination
* inhibition
* mediation analysis
* switching
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041435
}}
{{medline-entry
|title=Shorter Telomere Length in Peripheral Blood Leukocytes Is Associated with Post-Traumatic Chronic Osteomyelitis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32125944
|abstract= This study investigated the association between post-traumatic chronic osteomyelitis (COM) and peripheral leukocyte telomere length (PLTL) and explored factors associated with PLTL in COM.   A total of 56 patients with post-traumatic COM of the extremity and 62 healthy control subjects were recruited. The PLTL was measured by real-time PCR. Binary logistic regression analysis was used to identify factors in correlation with telomere length. Sex, age, white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), C-reactive protein ([[CRP]]), and infection duration were included as independent variables in the logistic regression model.   Post-traumatic COM patients had significantly shorter PLTLs (5.39 ± 0.40) than healthy control subjects (5.69 ± 0.46; p < 0.001). Binary logistic regression analysis showed that PLTL had a statistically significant association with age ([i]B[/i] = -0.072; p = 0.013) and [[CRP]] ([i]B[/i] = -0.061; p = 0.033). The logistic regression model was statistically significant and explained 31.4% (Nagelkerke R ) of the change in telomere length and correctly classified 69.6% of the cases.   Patients with post-traumatic COM have shorter PLTLs than healthy subjects. The PLTL erosion of post-traumatic COM was partially explained by age and [[CRP]].

|keywords=* aging
* post-traumatic chronic osteomyelitis
* telomere
|full-text-url=https://sci-hub.do/10.1089/sur.2019.326
}}
{{medline-entry
|title=Risk Factors of Progression to Frailty: Findings from the Singapore Longitudinal Ageing Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31886815
|abstract=To investigate risk factors of incident physical frailty. A population-based observational longitudinal study. Community-dwelling elderly with age 55 years and above recruited from 2009 through 2011 in the second wave Singapore Longitudinal Ageing Study-2 (SLAS-2) were followed up 3-5 years later. A total of 1297 participants, mean age of 65.6 ±0.19, who were free of physical frailty. Incident frailty defined by three or more criteria of the physical phenotype used in the Cardiovascular Health Study was determined at follow-up. Potential risk factors assessed at baseline included demographic, socioeconomic, medical, psychological factors, and biochemical markers. A total of 204 (15.7%) participants, including 81 (10.87%) of the robust and 123 (22.28%) of the prefrail transited to frailty at follow-up. Age, no education, MMSE score, diabetes, prediabetes and diabetes, arthritis, ≥5 medications, fair and poor self-rated health, moderate to high nutritional risk (NSI ≥3), Hb (g/dL), [[CRP]] (mg/L), low B12, low folate, albumin (g/L), low total cholesterol, adjusted for sex, age and education, were significantly associated (p<0.05) with incident frailty. In stepwise selection models, age (year) (OR=1.07, 95%CI=1.03-1.10, p<0.001), albumin (g/L) (OR=0.85, 95%CI=0.77-0.94, p=0.002), MMSE score (OR=0.88, 95%CI=0.78-0.98, p=0.02), low folate (OR=3.72, 95%CI=1.17-11.86, p=0.03, and previous hospitalization (OR=2.26, 95%CI=1.01-5.04,p=0.05) were significantly associated with incident frailty. The study revealed multiple modifiable risk factors, especially related to poor nutrition, for which preventive measures and early management could potentially halt or delay the development of frailty.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Disease Progression
* Female
* Frail Elderly
* Frailty
* Geriatric Assessment
* Humans
* Independent Living
* Longitudinal Studies
* Male
* Nutrition Assessment
* Nutritional Status
* Physical Examination
* Risk Factors
* Singapore
* Socioeconomic Factors
|keywords=* Frailty
* longitudinal
* risk factors
* transition
|full-text-url=https://sci-hub.do/10.1007/s12603-019-1277-8
}}
{{medline-entry
|title=Physical Function and Strength in Relation to Inflammation in Older Adults with Obesity and Increased Cardiometabolic Risk.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31781724
|abstract=Inflammation is implicated in functional decline and the development of disability in aging. This study aimed to investigate the association of inflammation with physical function and muscle strength in older adults with obesity and increased cardiometabolic risk. In baseline assessments from the CROSSROADS randomized controlled trial, serum interleukin-6 (IL-6), tumor necrosis factor-α (TNFα) and C-reactive protein (hs-[[CRP]]) were assayed in 163 older adults (37% males, 24% African American, BMI 34±3, age 70±5yrs) with hypertension, dyslipidemia and/or diabetes. Physical function was assessed by six-minute walk test (6MWT), chair sit-and-reach (CSR), hand-grip and knee-extension strength; specific-strength as muscle strength/mass ratio. Analyses included ANCOVA and multiple linear regression adjusted for thigh skeletal muscle (MRI), arm lean mass (DXA) and moderate-to-vigorous intensity physical activity (MVPA; accelerometry). Higher hs-[[CRP]] (p<0.01) and IL-6 (p=0.07) were associated with lower 6MWT and CSR, respectively. A composite inflammation score combining all 3 inflammatory markers showed the strongest inverse association with 6MWT (p<0.01). MVPA moderated associations such that amongst participants who engaged in low MVPA, 6MWT distances and CSR scores were significantly lower in those with high IL-6 and TNFα (p<0.05), respectively. In participants with high MVPA, higher hs-[[CRP]] (p<0.05) and TNFα (p=0.07) were associated with poorer upper-extremity specific-strength. Chronic inflammation was associated with poorer physical function and specific strength in older adults with obesity and increased cardiometabolic risk. This association was strongest in participants with multiple elevated inflammatory markers. Physical activity levels below current recommendations mitigated the deleterious effects of inflammation on lower body mobility, underscoring the benefits of exercise for preserving physical function with age.
|mesh-terms=* Aged
* Aging
* Cardiovascular Diseases
* Female
* Humans
* Inflammation
* Male
* Muscle Strength
* Obesity
* Physical Exertion
|keywords=* Inflammation
* cardiovascular disease risk factors
* obesity
* physical activity
* physical function
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996491
}}
{{medline-entry
|title=Key diagnostic characteristics of fever of unknown origin in Japanese patients: a prospective multicentre study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31748308
|abstract=To identify the key diagnostic features and causes of fever of unknown origin (FUO) in Japanese patients. Multicentre prospective study. Sixteen hospitals affiliated with the Japanese Society of Hospital General Medicine, covering the East and West regions of Japan. Patient aged ≥20 years diagnosed with classic FUO (axillary temperature≥38.0°C at least twice within a 3-week period, cause unknown after three outpatient visits or 3 days of hospitalisation). A total of 141 cases met the criteria and were recruited from January 2016 to December 2017. Japanese standard diagnostic examinations. Data collected include usual biochemical blood tests, inflammatory markers (erythrocyte sedimentation rate (ESR), C reactive ([[CRP]]) protein level, procalcitonin level), imaging results, autopsy findings (if performed) and final diagnosis. The most frequent age group was 65-79 years old (mean: 58.6±9.1 years). The most frequent cause of FUO was non-infectious inflammatory disease. After a 6-month follow-up period, 21.3% of cases remained undiagnosed. The types of diseases causing FUO were significantly correlated with age and prognosis. Between patients with and without a final diagnosis, there was no difference in [[CRP]] level between patients with and without a final diagnosis (p=0.121). A significant difference in diagnosis of a causative disease was found between patients who did or did not receive an ESR test (p=0.041). Of the 35 patients with an abnormal ESR value, 28 (80%) had causative disease identified. Age may be a key factor in the differential diagnosis of FUO; the ESR test may be of value in the FUO evaluation process. These results may provide clinicians with insight into the management of FUO to allow adequate treatment according to the cause of the disease.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Female
* Fever of Unknown Origin
* Humans
* Japan
* Male
* Middle Aged
* Prospective Studies
* Young Adult
|keywords=* Japan
* aging population
* elderly
* erythrocyte sedimentation rate
* fever of unknown origin
* prospective studies
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886908
}}
{{medline-entry
|title=Decrease in Serum Vitamin D Level of Older Patients with Fatigue.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31635199
|abstract=Fatigue is characterized by reduced energy level, decreased muscle strength, and a variable degree of cognitive impairment. Recent evidences seem to link vitamin D deficiency to fatigue. The aim of this study was to assess and compare vitamin D status in a cohort of older subjects with and without fatigue. We recruited a total of 480 subjects, 240 patients with fatigue and 240 controls without fatigue, from the Cannizzaro Hospital of Catania (Italy). Fatigue severity was measured by the fatigue severity scale, whereas mental and physical fatigue were measured through the Wessely and Powell fatigue scale, respectively. We also measured several blood parameters and 25-OH vitamin D. Subjects with fatigue showed lower levels of vitamin D as compared with those without fatigue. Blood levels of parameters related to fatigue were normal in both groups of subjects, however, platelet, hemoglobin, hematocrit ([i]p[/i] < 0.05), mean corpuscular volume, C-reactive protein ([[CRP]]), iron, vitamin B12, and folic acid ([i]p[/i] < 0.001) were significantly higher in the fatigue group with respect to the control group. Moreover, compared to controls, patients showed higher scores in the physical ([i]p[/i] < 0.001), mental ([i]p[/i] < 0.001), and severity ([i]p[/i] < 0.001) fatigue scales. Finally, vitamin D inversely correlated with fatigue severity ([i]r[/i] = -0.428, [i]p[/i] < 0.01), whereas creatine kinase and [[CRP]] levels did not correlate with vitamin D. In conclusion, our data showed a direct link between vitamin D and fatigue in older subjects, suggesting translational implications in the diagnosis and management of these patients.
|mesh-terms=* Aged
* Cohort Studies
* Fatigue
* Female
* Humans
* Male
* Middle Aged
* Vitamin D
* Vitamin D Deficiency
|keywords=* aging
* mental fatigue
* older
* physical fatigue
* sex differences
* vitamin D
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836014
}}
{{medline-entry
|title=The Association between Frailty Indicators and Blood-Based Biomarkers in Early-Old Community Dwellers of Thailand.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31533354
|abstract=Thailand has officially reached the status of an "aged society" and become the developing country with the 2nd largest proportion of senior citizens in Southeast Asia. A cross-sectional study of 526 early-old community dwellers was conducted for the Fried frailty phenotype assessment, This included five indicators: Weakness, slowness, physical activity, exhaustion, and weight loss. C-reactive protein ([[CRP]]), interleukin-6 (IL-6), insulin-like growth factor-1, and CD4+:CD8+ Ratio which serve as blood-based biomarkers of frailty. The prevalence of frailty and pre-frail in this population was found to be 15% and 69.6% respectively and was higher among women than men. Frail ([i]n[/i] = 58) and non-frail ([i]n[/i] = 60) participants were evaluated for the associations between the frail indicators and the blood-based biomarkers. Serum levels of IL-6 and [[CRP]] from frail group were significantly elevated when compared with the non-frail counterparts ([i]p[/i] = 0.044 and 0.033, respectively), and were significantly associated with the frailty status with an Odd Ratio  [OR] of 1.554-fold (95% confidence interval [CI], 1.229-1.966) and an OR  of 1.011-fold (95 CI, 1.006-1.016). Decreased hand-grip strength was the only frailty indicator that was significantly associated with both inflammatory biomarkers, (OR  of 1.470-fold and OR  of 1.008-fold). Our study is the first to assess the frailty status among the early-old population in Thailand. These findings will encourage general practitioners to combine frailty indicators and serum biomarkers as early detection tools for at-risk older adults to achieve the goal of healthy aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Biomarkers
* C-Reactive Protein
* CD4-CD8 Ratio
* Cross-Sectional Studies
* Female
* Frail Elderly
* Frailty
* Humans
* Independent Living
* Interleukin-6
* Male
* Middle Aged
* Thailand
|keywords=* C-reactive protein
* Thailand
* aging
* cross-sectional study
* frailty
* frailty biomarkers
* fried’s phenotypes
* interleukin-6
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765843
}}
{{medline-entry
|title=Associations of C-reactive protein and homocysteine concentrations with the impairment of intrinsic capacity domains over a 5-year follow-up among community-dwelling older adults at risk of cognitive decline (MAPT Study).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31493520
|abstract=The World Health Organization (WHO) recently proposed an innovative model of care focusing on functional rather than disease-based perspectives, based on a construct of intrinsic capacity (IC). This study aimed to analyze if low-grade inflammation (LGI) (chronically raised C-reactive protein - [[CRP]]) and hyperhomocysteinemia (HHcy) were associated with variation in IC domains (mobility, cognition, psychological and vitality) and in a combined IC Z-score over a 5-year follow-up among non-demented, community-dwelling older adults at risk of cognitive decline. This observational study included 1516 subjects ≥70 years (64.5% female, mean age 75.4 years, SD = 4.5), volunteers from the interventional study Multidomain Alzheimer Preventive Trial (MAPT). Plasma [[CRP]] (at baseline, 6 and 12 months) and homocysteine (at baseline) concentrations were measured. LGI was defined as having ≥2 consecutively [[CRP]] readings >3 to 10 mg/L between baseline and 12 months, and HHcy was defined as homocysteine >15 μM/L. IC domains were operationalized as follows: Psychological. Depressive symptoms evaluated by the Geriatric Depression Scale (GDS); Mobility. Assessed by the Short Physical Performance Battery (SPPB); Cognitive function. Examined by a Z-score combining four tests; Vitality. Based on hand grip strength. Outcomes were combined into a composite IC Z-score. IC Z-score decreased among groups with no inflammation and LGI after 5 years, but this decrease was more pronounced among the LGI group (unadjusted mean group difference: 0.09, 95%CI: 0.01 to 0.16; p = 0.032). Participants with HHcy also presented IC Z-score decreases over time. Combined conditions provided more pronounced declines, even after adjusting for potential confounders. LGI and HHcy were both related with impairment on the combined IC levels among older adults after a 5-year follow-up. Identifying biomarkers that strongly associate with IC may help to settle strategies aiming to prevent the incidence and slow down the evolution of age-related functional decline and care dependency.
|mesh-terms=* Activities of Daily Living
* Aged
* Biomarkers
* Body Mass Index
* C-Reactive Protein
* Cognitive Dysfunction
* Depression
* Female
* Follow-Up Studies
* Geriatric Assessment
* Hand Strength
* Homocysteine
* Humans
* Independent Living
* Inflammation
* Male
* Mobility Limitation
* Neuropsychological Tests
* Prospective Studies
* Risk Factors
* Time Factors
|keywords=* Aging
* C-reactive protein
* Homocysteine
* Inflammation
* Intrinsic capacity
* Older adults
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110716
}}
{{medline-entry
|title=Longitudinal analysis of loneliness and inflammation at older ages: English longitudinal study of ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31494341
|abstract=Loneliness has been associated with adverse health outcomes, including age-related diseases with an inflammatory etiology such as cardiovascular disease. We aimed to identify potential biological pathways linking loneliness with morbidity and mortality by examining associations of loneliness with biomarkers. Participants in the English Longitudinal Study of Ageing (n = 3239) aged 50 years or older with an average age of 64 years, provided data in waves 4 (2008/2009) and 6 (2012/2013). Linear regression conditional change models had three outcomes: C reactive protein ([[CRP]]) measured in mg/L (log transformed), fibrinogen in g/L and ferritin in g/dL. In men, the onset of loneliness indicated by answering 'no' at wave 4 and 'yes' at wave 6 to question "Much of the time during the past week, you felt lonely?" was associated with a statistically significant increase in levels of [[CRP]] (β = 0.36, 95% confidence interval (0.09 to 0.62)), plasma fibrinogen (0.18 (0.04 to 0.31)) and ferritin (41.04 (6.58 to 75.50)), after full adjustment. A statistically significant increase in [[CRP]] in men was also observed for onset of loneliness assessed with the question "How often do you feel lonely?" (0.20 (0.03 to 0.38)). These associations were not mediated by depressive symptoms. Persistent loneliness (loneliness experienced at both baseline and follow-up) assessed using the University of California Los Angeles (UCLA) loneliness scale was associated with an increase in [[CRP]] (0.11 (0.004 to 0.22)) among men. Associations of the two latter loneliness measures with fibrinogen and ferritin were mainly null. Among women, the only statistically significant association was for persistent loneliness (loneliness at both waves) identified by question "Much of the time during the past week, you felt lonely?" with a reduction in levels of ferritin (-20.62 (-39.78 to -1.46)). Men may be more susceptible to loneliness-associated disease risks signaled by biological changes, including systemic inflammation. Combined social and targeted medical interventions may help to reduce health risks associated with loneliness.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Aging
* C-Reactive Protein
* England
* Female
* Ferritins
* Fibrinogen
* Humans
* Inflammation
* Loneliness
* Longitudinal Studies
* Male
* Middle Aged
|keywords=* C-reactive protein
* Ferritin
* Fibrinogen
* Inflammation
* Loneliness
|full-text-url=https://sci-hub.do/10.1016/j.psyneuen.2019.104421
}}
{{medline-entry
|title=The cortisol burden in elderly subjects with metabolic syndrome and its association with low-grade inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31471891
|abstract=Elderly people are exposed to an increased load of stressful events and neuro-hormonal stimulation is a key finding in metabolic syndrome and its related disorders. To determine the role of cortisol in elderly subjects, with or without metabolic syndrome (MetS), by means of a national multicentre observational study, AGICO (AGIng and Cortisol). From 2012 to 2017, the AGICO study enrolled n.339 subjects (aged > 65), after obtaining their informed consent. The investigators assessed a cardio-metabolic panel (including electrocardiogram, carotid ultrasonography and echocardiography), the presence of MetS (on Adult Treatment Panel III criteria), a neurological examination (including brain imaging), and cortisol activity (using a consecutive collection of diurnal and nocturnal urine). In the patients presenting with MetS, the standardized diurnal and nocturnal cortisol excretion rates were 210.7 ± 145.5 and 173.7 ± 118.1 (mean ± standard deviation) μg/g creatinine/12 h; in those without MetS, the standardized diurnal and nocturnal cortisol excretion rates were 188.7 ± 92.7 and 144.1 ± 82.3 μg/g creatinine/12 h, respectively (nocturnal urinary cortisol in patients with MetS versus those without MetS p = 0.05, female patients with MetS vs female patients without MetS, p < 0.025). A significant positive correlation was found between the [[CRP]] levels and both the diurnal and nocturnal urinary cortisol levels with r = 0.187 (p < 0.025) and r = 0.411 (p < 0.00000001), respectively. The elderly patients with MetS showed a trend towards increased standardized nocturnal cortisol excretions, with particular regard to the female subjects. The positive correlation between cortisol excretion and low-grade inflammation suggests a common mechanism driving both hormonal and inflammatory changes.
|mesh-terms=* Aged
* Aged, 80 and over
* Echocardiography
* Female
* Humans
* Hydrocortisone
* Inflammation
* Male
* Metabolic Syndrome
|keywords=* Aging
* Cortisol
* Inflammation
* Metabolic syndrome
|full-text-url=https://sci-hub.do/10.1007/s40520-019-01322-3
}}
{{medline-entry
|title=Recurrent circadian fasting (RCF) improves blood pressure, biomarkers of cardiometabolic risk and regulates inflammation in men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31426866
|abstract=The effects of fasting on health in non-human models have been widely publicised for a long time and emerging evidence support the idea that these effects can be applicable to human practice. In an open label longitudinal follow-up, a cohort of 78 adult men (aged 20 to 85 years) who fasted for 29 consecutive days from sunrise to sunset (16 h fasting-referred to as recurrent circadian fasting) in Pakistan, were studied. The primary outcomes of the fasting study was weight loss/recovery and the associated changes in blood pressure and circulating levels of surrogate markers linked to organ and system functions-including cardiovascular, metabolic and inflammation. Post-fasting outcomes include the regulation of physiological biomarkers. Recurrent circadian fasting with weight loss reduced blood pressure (140.6 vs. 124.2 mmHg) and markers of cardiovascular risk (~ 4-fold for resistin; triglycerides: p < 0.0001). Reduced glycemia (p < 0.0001) and the associated changes in the regulation of ketosis (β-hydroxybutyrate) were accompanied by a metabolic shift (PPARβ, osteoprotegerin), suggesting the involvement of the different physiological systems tested. Elevated orexin-A levels (p = 0.0183) in participants indicate sleep disturbance and circadian adaptation. All participants had [[CRP]] level < 2 mg/l during the fasting period and a similar trend was observed for TNFα. While most SASP molecules were decreased after the fasting period, heightened levels of IL-8 and IL-6 suggest that some inflammatory markers may be elevated by recurrent circadian fasting. Importantly, older adults reveal similar or more substantial benefits from fasting. Recurrent circadian fasting is beneficial at the cardiometabolic and inflammatory levels, especially for at-risk individuals-this is contingent on compliance towards the recommended dietary behaviour, which controls carbohydrate and caloric intake. These benefits from fasting may be particularly beneficial to older adults as they often exhibit abnormal cardiovascular, metabolic and inflammatory signatures.
|mesh-terms=* Adult
* Biomarkers
* Blood Pressure
* C-Reactive Protein
* Cardiovascular Diseases
* Circadian Rhythm
* Diet
* Energy Intake
* Fasting
* Heart Rate
* Humans
* Inflammation
* Male
* Metabolic Diseases
* Middle Aged
* Nutritional Physiological Phenomena
* Regression Analysis
* Risk Factors
* Young Adult
|keywords=* Aging
* Health benefits
* Inflammation
* Recurrent fasting
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700786
}}
{{medline-entry
|title=Characteristics of patients with rheumatoid arthritis undergoing primary total joint replacement: A 14-year trend analysis (2004-2017).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31393198
|abstract= To examine time trends in the characteristics of patients with rheumatoid arthritis (RA) undergoing primary total joint replacement (TJR).  Biologics were approved in Japan for use in patients with RA in July 2003. A total of 403 large joints in 282 patients who underwent TJR at our institute between 1 January 2004 and 31 December 2017 were retrospectively examined.  A significant decreasing trend was observed in the number of TJRs performed from 2004 to 2017 ([i]p[/i] = 0.013). No significant trend was observed in time from RA onset to TJR ([i]p[/i] = 0.294). Age at RA onset ([i]p[/i] = 0.034) showed a significant increasing trend, and serum C-reactive protein ([[CRP]]) levels showed a significant decreasing trend ([i]p[/i] < 0.001). Negative [[CRP]] (defined as ≤0.3 mg/dl; partial regression coefficient ([i]B[/i]) = 2.44, [i]p[/i] = 0.016) was independently associated with time from RA onset to TJR as well as age at RA onset and juxta-articular osteophyte formation.  The number of TJRs decreased since the approval of biologics in Japan, and changes were observed in the characteristics of patients with RA undergoing TJR. Negative [[CRP]] was an independent factor associated with longer time from RA onset to TJR.
|mesh-terms=* Adult
* Aged
* Antirheumatic Agents
* Arthritis, Rheumatoid
* Arthroplasty, Replacement
* Arthroplasty, Replacement, Knee
* Biological Products
* Drug Utilization
* Female
* Humans
* Japan
* Male
* Middle Aged
* Postoperative Complications
|keywords=* C-reactive protein
* Rheumatoid arthritis
* aging
* arthroplasty
* drug therapy
|full-text-url=https://sci-hub.do/10.1080/14397595.2019.1649111
}}
==CA1==

{{medline-entry
|title=The relation between tau pathology and granulovacuolar degeneration of neurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33069844
|abstract=Neurofibrillary tangles arising from aggregated microtubule-associated protein tau occur in aged brains and are hallmarks of neurodegenerative diseases. A subset of neurons containing aggregated tau displays granulovacuolar degeneration (GVD) that is characterized by membrane-bound cytoplasmic vacuoles, each containing an electron-dense granule (GVB). Tau pathology induces GVBs in experimental models, but GVD does not generally follow tau pathology in the human brain. The entorhinal cortex, DRN, and LC are among the regions that display pathological changes of tau earliest, whereas neurons with GVBs occur first in the hippocampus and have been found in oral raphe nuclei only at the most advanced GVD stage. To date, there is no detailed report about neurons with GVD in aminergic nuclei. We studied the relation between tau pathology and GVD in field [[CA1]] of the hippocampus, entorhinal cortex, dorsal (DRN) and median (MRN) raphe nucleus, and locus coeruleus from elderly subjects with Braak & Braak stages of tau pathology ranging from 0 to VI. Tau pathology and GVBs were visualized by means of immunolabeling and quantified. Percentages of neurons containing GVBs were significantly related to percentages of AT8-positive neurons in the regions examined. GVD and tau pathology were found together in neurons to a different extent in regions of the brain. 53.2% of AT8-immunoreactive neurons in [[CA1]], 19.8% in layer II of the entorhinal cortex, 29.6% in the DRN, and 31.4% in the locus coeruleus contained GVBs. Age-related factors, the percentage of neurons with pretangles in a region of the brain, and the metabolism of a neuron possibly influence the prevalence of neurons with GVBs.

|keywords=* AT8
* Aging
* CA1
* Casein kinase 1δ
* Congo red
* Dorsal raphe nucleus
* Locus coeruleus
* Neurodegeneration
* Tau pathology
|full-text-url=https://sci-hub.do/10.1016/j.nbd.2020.105138
}}
{{medline-entry
|title=Memory and dendritic spines loss, and dynamic dendritic spines changes are age-dependent in the rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32950615
|abstract=Brain aging is a widely studied process, but due to its complexity, much of its progress is unknown. There are many studies linking memory loss and reduced interneuronal communication with brain aging. However, only a few studies compare young and old animals. In the present study, in male rats aged 3, 6, and 18 months, we analyzed the locomotor activity and also short and long-term memory using the novel object recognition test (NORT), in addition to evaluating the dendritic length and the number of dendritic spines in the prefrontal cortex (PFC) and in the [[CA1]], CA3 and DG regions of the dorsal hippocampus using Golgi-Cox staining. We also analyzed the types of dendritic spines in the aforementioned regions. 6- and 18-month old animals showed a reduction in locomotor activity, while long-term memory deficit was observed in 18-month old rats. At 18 months old, the dendritic length was reduced in all the studied regions. The dendritic spine number was also reduced in layer 5 of the PFC, and the [[CA1]] and CA3 of the hippocampus. The dynamics of dendritic spines changed with age, with a reduction of the mushroom spines in all the studied regions, with an increase of the stubby spines in all the studied regions except from the CA3 region, that showed a reduction. Our data suggest that age causes changes in behavior, which may be the result of morphological changes at the dendrite level, both in their length and in the dynamics of their spines.

|keywords=* Aging
* Hippocampus
* Locomotor activity
* Memory and learning
* Prefrontal cortex
* Pyramidal neurons
* dendritic spines
|full-text-url=https://sci-hub.do/10.1016/j.jchemneu.2020.101858
}}
{{medline-entry
|title=Deregulated expression of a longevity gene, Klotho, in the C9orf72 deletion mice with impaired synaptic plasticity and adult hippocampal neurogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32887666
|abstract=Hexanucleotide repeat expansion of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Synergies between loss of C9ORF72 functions and gain of toxicities from the repeat expansions contribute to C9ORF72-mediated pathogenesis. However, how loss of C9orf72 impacts neuronal and synaptic functions remains undetermined. Here, we showed that long-term potentiation at the dentate granule cells and long-term depression at the Schaffer collateral/commissural synapses at the area [[CA1]] were reduced in the hippocampus of C9orf72 knockout mice. Using unbiased transcriptomic analysis, we identified that Klotho, a longevity gene, was selectively dysregulated in an age-dependent manner. Specifically, Klotho protein expression in the hippocampus of C9orf72 knockout mice was incorrectly enriched in the dendritic regions of [[CA1]] with concomitant reduction in granule cell layer of dentate gyrus at 3-month of age followed by an accelerating decline during aging. Furthermore, adult hippocampal neurogenesis was reduced in C9orf72 knockout mice. Taken together, our data suggest that C9ORF72 is required for synaptic plasticity and adult neurogenesis in the hippocampus and Klotho deregulations may be part of C9ORF72-mediated toxicity.

|keywords=* Amyotrophic lateral sclerosis (ALS)
* C9ORF72
* Dentate gyrus, adult neurogenesis
* Frontotemporal dementia (FTD)
* Klotho
* Long-term depression (LTD)
* Long-term potentiation (LTP)
* Longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473815
}}
{{medline-entry
|title=COX5A Plays a Vital Role in Memory Impairment Associated With Brain Aging [i]via[/i] the BDNF/ERK1/2 Signaling Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32754029
|abstract=Cytochrome c oxidase subunit Va (COX5A) is involved in maintaining normal mitochondrial function. However, little is known on the role of COX5A in the development and progress of Alzheimer's disease (Martinez-Losa et al., 2018). In this study, we established and characterized the genomic profiles of genes expressed in the hippocampus of Senescence-Accelerated Mouse-prone 8 (SAMP8) mice, and revealed differential expression of COX5A among 12-month-aged SAMP8 mice and 2-month-aged SAMP8 mice. Newly established transgenic mice with systemic COX5A overexpression (51% increase) resulted in the improvement of spatial recognition memory and hippocampal synaptic plasticity, recovery of hippocampal [[CA1]] dendrites, and activation of the BDNF/ERK1/2 signaling pathway [i]in vivo[/i]. Moreover, mice with both COX5A overexpression and BDNF knockdown showed a poor recovery in spatial recognition memory as well as a decrease in spine density and branching of dendrites in [[CA1]], when compared to mice that only overexpressed COX5A. [i]In vitro[/i] studies supported that COX5A affected neuronal growth [i]via[/i] BDNF. In summary, this study was the first to show that COX5A in the hippocampus plays a vital role in aging-related cognitive deterioration [i]via[/i] BDNF/ERK1/2 regulation, and suggested that COX5A may be a potential target for anti-senescence drugs.

|keywords=* BDNF
* COX5A
* ERK1/2
* brain senescence
* memory impairment
* mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365906
}}
{{medline-entry
|title=Changes of fat-mass and obesity-associated protein expression in the hippocampus in animal models of high-fat diet-induced obesity and D-galactose-induced aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32647628
|abstract=Fat-mass and obesity-associated protein (Fto) is highly expressed in the brain including, the hippocampus, and its expression is significantly decreased in the brain of Alzheimer's disease patients. In the present study, we measured Fto immunoreactivity and protein levels in the hippocampus of obese and aged mice, which were induced by high-fat diet for 12 weeks and D-galactose treatment for 10 weeks, respectively. The obesity and aging phenotypes were assessed by physiological parameters and Morris water maze test, respectively. High fat diet fed mice showed significant increases in body weight and blood glucose levels compared to that in the control or D-galactose-induced aged mice. In addition, treatment with D-galactose significantly decreased the spatial memory. Fto immunoreactivity in the control group was mainly detected in the pyramidal cells of the [[CA1]] and CA3 regions and in the granule cells of the dentate gyrus. In the hippocampus of high-fat diet-fed mice, Fto immunoreactive structures were similarly found in the hippocampus compared to that in the control group, but Fto immunoreactivity in high-fat diet-fed mice was also found in the stratum oriens and radiatum of the [[CA1]] and CA3 regions and the polymorphic layer of the dentate gyrus. In the hippocampus of D-galactose-induced aged mice, fewer Fto immunoreactive structures were detected in the granule cell layer of the dentate gyrus compared to the control group. Fto mRNA and protein levels based on quantitative real-time polymerase chain reaction and western blot assays were slightly increased in the hippocampus of high-fat diet-fed mice compared to that in control mice. In addition, Fto mRNA and protein levels were significantly decreased in the aged hippocampus compared to that in the control group. Fto protein levels are susceptible to the aging process, but not in the hippocampus of high-fat diet-induced obesity. The reduction of Fto in aged mice may be associated with reduced memory impairment in mice.

|keywords=* Aging
* Fto
* Hippocampus
* Mice
* Obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336480
}}
{{medline-entry
|title=Phenylbutyrate ameliorates prefrontal cortex, hippocampus, and nucleus accumbens neural atrophy as well as synaptophysin and GFAP stress in aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32531811
|abstract=Recent reports on brain aging suggest that oxidative stress and inflammatory processes contribute to aging. Interestingly, sodium phenylbutyrate (PBA) is an inhibitor of histone deacetylase, which has anti-inflammatory properties. Several reports have suggested the effect of PBA on learning and memory processes, however there are no studies of the effect of this inhibitor of histone deacetylase on aging. Consequently, in the present study, the effect of PBA was studied in 18-month-old mice. The animals were administered PBA for 2 months after locomotor activity treatment and Morris water maze tests were performed. The Golgi-Cox staining technique and immunohistochemistry for glial fibrillary acidic protein (GFAP) and synaptophysin were performed for the morphological procedures. The administration of PBA improves learning and memory according to the Morris water maze test compared to vehicle-treated animals, which had unchanged locomotor activity. Using Golgi-Cox staining, dendritic length and the number of dendritic spines were measured in limbic regions, such as the nucleus accumbens (NAcc), prefrontal cortex (PFC) layer 3, and the [[CA1]] of the dorsal hippocampus. In addition, PBA increased the number of dendritic spines in the PFC, NAcc, and [[CA1]] subregions of the hippocampus with an increase in dendritic length only in the [[CA1]] region. Moreover, PBA reduced the levels of the GFAP and increased the levels of synaptophysin in the studied regions. Thus, PBA can be a useful pharmacological tool to prevent or delay synaptic plasticity damage and cognitive impairment caused by age.

|keywords=* aging
* dendrites
* hippocampus
* memory and learning
* nucleus accumbens
* prefrontal cortex
* sodium phenylbutyrate
|full-text-url=https://sci-hub.do/10.1002/syn.22177
}}
{{medline-entry
|title=Heterogeneity in brain distribution of activated microglia and astrocytes in a rat ischemic model of Alzheimer's disease after 2 years of survival.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32501292
|abstract=The present study was designed to follow neuroinflammation after ischemic brain injury in the long-term survival rat model. Immunohistochemistry was performed 2 years after 10 min global brain ischemia due to cardiac arrest. For the visualization of the cellular inflammatory reaction microglial marker Iba1 and astrocyte marker GFAP were used. In post-ischemic animals our study revealed significant activation of astrocytes in all tested brain regions (hippocampal [[CA1]] and CA3 areas and dentate gyrus, motor and somatosensory cortex, striatum and thalamus), while microglial activation was only found in [[CA1]] and CA3 areas, and the motor cortex. In the specifically sensitive brain areas microglia and astrocytes showed simultaneously significant activation, while in the resistant brain areas only astrocytes were activated. Thus, there was clear evidence of less intensive neuroinflammation in brain areas resistant to ischemia. Such neuroinflammatory processes are backed by microglia and astrocytes activity even up to 2 years after ischemia-reperfusion brain injury. Our study thus revealed a chronic effect of global cerebral ischemia on the neuroinflammatory reaction in the rat brain even 2 years after the insult.

|keywords=* Alzheimer’s disease
* aging
* brain ischemia
* glia
* neuroinflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343500
}}
{{medline-entry
|title=Hippocampal Subregion Transcriptomic Profiles Reflect Strategy Selection during Cognitive Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32376783
|abstract=Age-related cognitive impairments are associated with differentially expressed genes (DEGs) linked to defined neural systems; however, studies examining multiple regions of the hippocampus fail to find links between behavior and transcription in the dentate gyrus (DG). We hypothesized that use of a task requiring intact DG function would emphasize molecular signals in the DG associated with a decline in performance. We used a water maze beacon discrimination task to characterize young and middle-age male F344 rats, followed by a spatial reference memory probe trial test. Middle-age rats showed increased variability in discriminating two identical beacons. Use of an allocentric strategy and formation of a spatial reference memory were not different between age groups; however, older animals compensated for impaired beacon discrimination through greater reliance on spatial reference memory. mRNA sequencing of hippocampal subregions indicated DEGs in the DG of middle-age rats, linked to synaptic function and neurogenesis, correlated with beacon discrimination performance, suggesting that senescence of the DG underlies the impairment. Few genes correlated with spatial memory across age groups, with a greater number in region [[CA1]]. Age-related [[CA1]] DEGs, correlated with spatial memory, were linked to regulation of neural activity. These results indicate that the beacon task is sensitive to impairment in middle age, and distinct gene profiles are observed in neural circuits that underlie beacon discrimination performance and allocentric memory. The use of different strategies in older animals and associated transcriptional profiles could provide an animal model for examining cognitive reserve and neural compensation of aging.  Hippocampal subregions are thought to differentially contribute to memory. We took advantage of age-related variability in performance on a water maze beacon task and next-generation sequencing to test the hypothesis that aging of the dentate gyrus is linked to impaired beacon discrimination and compensatory use of allocentric memory. The dentate gyrus expressed synaptic function and neurogenesis genes correlated with beacon discrimination in middle-age animals. Spatial reference memory was associated with [[CA1]] transcriptional correlates linked to regulation of neural activity and use of an allocentric strategy. This is the first study examining transcriptomes of multiple hippocampal subregions to link age-related impairments associated with discrimination of feature overlap and alternate response strategies to gene expression in specific hippocampal subregions.
|mesh-terms=* Animals
* Cognitive Aging
* Dentate Gyrus
* Hippocampus
* Maze Learning
* Rats
* Rats, Inbred F344
* Spatial Memory
* Transcriptome
|keywords=* aging
* hippocampus
* pattern separation
* reference memory
* spatial discrimination
* transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326352
}}
{{medline-entry
|title=Associations between pattern separation and hippocampal subfield structure and function vary along the lifespan: A 7 T imaging study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32371923
|abstract=Pattern separation (PS) describes the process by which the brain discriminates similar stimuli from previously encoded stimuli. This fundamental process requires the intact processing by specific subfields in the hippocampus and can be examined using mnemonic discrimination tasks. Previous studies reported different patterns for younger and older individuals between mnemonic discrimination performance and hippocampal subfield activation. Here, we investigated the relationship between the lure discrimination index (LDI) and hippocampal subfield volume and activity across the adult lifespan (20-70 years old). Using ultra-high field functional and structural magnetic resonance imaging at 7 T, we found that lower DG volume and higher CA3 activation was associated with worse LDI performance in individuals (>60 years), suggesting that this higher activation may be an indication of aberrant neurodegenerative-related processes. In fact, higher activation in the [[CA1]] and DG was associated with lower volumes in these subfields. For individuals around 40-50 years old, we observed that greater left and right DG volume, and greater activity in the CA3 was associated with lower LDI performance. Taken together, these results suggest that the relationship between memory and hippocampal subfield structure or function varies nonlinearly and possibly reciprocally with age, with midlife being a critically vulnerable period in life.
|mesh-terms=* Adult
* Age Factors
* Aged
* Brain Mapping
* Female
* Hippocampus
* Humans
* Longevity
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200747
}}
{{medline-entry
|title=Laminarin Pretreatment Provides Neuroprotection against Forebrain Ischemia/Reperfusion Injury by Reducing Oxidative Stress and Neuroinflammation in Aged Gerbils.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32326571
|abstract=Laminarin is a polysaccharide isolated from brown algae that has various biological and pharmacological activities, such as antioxidant and anti-inflammatory properties. We recently reported that pretreated laminarin exerted neuroprotection against transient forebrain ischemia/reperfusion (IR) injury when we pretreated with 50 mg/kg of laminarin once a day for seven days in adult gerbils. However, there have been no studies regarding a neuroprotective effect of pretreated laminarin against IR injury in aged animals and its related mechanisms. Therefore, in this study, we intraperitoneally inject laminarin (50 mg/kg) once a day to aged gerbils for seven days before IR (5-min transient ischemia) surgery and examine the neuroprotective effect of laminarin treatment and the mechanisms in the gerbil hippocampus. IR injury in vehicle-treated gerbils causes loss (death) of pyramidal neurons in the hippocampal [[CA1]] field at five days post-IR. Pretreatment with laminarin effectively protects the [[CA1]] pyramidal neurons from IR injury. Regarding the laminarin-treated gerbils, production of superoxide anions, 4-hydroxy-2-nonenal expression and pro-inflammatory cytokines [interleukin(IL)-1β and tumor necrosis factor-α] expressions are significantly decreased in the [[CA1]] pyramidal neurons after IR. Additionally, laminarin treatment significantly increases expressions of superoxide dismutase and anti-inflammatory cytokines (IL-4 and IL-13) in the [[CA1]] pyramidal neurons before and after IR. Taken together, these findings indicate that laminarin can protect neurons from ischemic brain injury in an aged population by attenuating IR-induced oxidative stress and neuroinflammation.

|keywords=* aging
* laminarin
* neuroinflammation
* neuroprotection
* oxidative stress
* transient cerebral ischemia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230782
}}
{{medline-entry
|title=Age-dependent Alteration in Mitochondrial Dynamics and Autophagy in Hippocampal Neuron of Cannabinoid CB1 Receptor-deficient Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32294520
|abstract=Endocannabinoid system activity contributes to the homeostatic defense against aging and thus may counteract the progression of brain aging. The cannabinoid type 1 (CB1) receptor activity declines with aging in the brain, which impairs neuronal network integrity and cognitive functions. However, the underlying mechanisms that link CB1 activity and memory decline remain unknown. Mitochondrial activity profoundly influences neuronal function, and age-dependent mitochondrial activity change is one of the known hallmarks of brain aging. As CB1 receptor is expressed on mitochondria and may regulate neuronal energy metabolism in hippocampus, we hypothesized that CB1 receptors might influence mitochondria in hippocampal neurons. Here, we found that CB1 receptor significantly affected mitochondrial autophagy (mitophagy) and morphology in an age-dependent manner. Serine 65-phosphorylated ubiquitin, a key marker for mitophagy, was reduced in adult CB1-deficient mice (CB1-KO) compared to those in wild type controls, particularly in [[CA1]] pyramidal cell layer. Transmission electron microscopy (TEM) analysis showed reduced mitophagy-like events in hippocampus of adult CB1-KO. TEM analysis also showed that mitochondrial morphology in adult CB1-KO mice was altered shown by an increase in thin and elongated mitochondria in hippocampal neurons. 3D reconstruction of mitochondrial morphology after scanning electron microscopy additionally revealed an enhanced density of interconnected mitochondria. Altogether, these findings suggest that reduced CB1 signaling in CB1-KO mice leads to reduced mitophagy and abnormal mitochondrial morphology in hippocampal neurons during aging. These mitochondrial changes might be due to the impairments in mitochondrial quality control system, which links age-related decline in CB1 activity and impaired memory.

|keywords=* Aging
* CB1 receptor
* Hippocampus
* Mitochondria
* Mitophagy
|full-text-url=https://sci-hub.do/10.1016/j.brainresbull.2020.03.014
}}
{{medline-entry
|title=Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via [[CA1]]-Frontal Circuit.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32239141
|abstract=The CA3 and [[CA1]] principal cell fields of the hippocampus are vulnerable to aging, and age-related dysfunction in CA3 may be an early seed event closely linked to individual differences in memory decline. However, whether the differential vulnerability of CA3 and [[CA1]] is associated with broader disruption in network-level functional interactions in relation to age-related memory impairment, and more specifically, whether CA3 dysconnectivity contributes to the effects of aging via [[CA1]] network connectivity, has been difficult to test. Here, using resting-state fMRI in a group of aged rats uncontaminated by neurodegenerative disease, aged rats displayed widespread reductions in functional connectivity of CA3 and [[CA1]] fields. Age-related memory deficits were predicted by connectivity between left CA3 and hippocampal circuitry along with connectivity between left [[CA1]] and infralimbic prefrontal cortex. Notably, the effects of CA3 connectivity on memory performance were mediated by [[CA1]] connectivity with prefrontal cortex. We additionally found that spatial learning and memory were associated with functional connectivity changes lateralized to the left CA3 and [[CA1]] divisions. These results provide novel evidence that network-level dysfunction involving interactions of CA3 with [[CA1]] is an early marker of poor cognitive outcome in aging.

|keywords=* aging
* functional connectivity
* hippocampus
* spatial memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325802
}}
{{medline-entry
|title=Integration of qRT-PCR and Immunohistochemical Techniques for mRNA Expression and Localization of m1AChR in the Brain of Aging Rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32219760
|abstract=The neurotransmitter acetylcholine (ACh) is involved in memory and cognitive functions, which normally decline with age. In this chapter, we describe qRT-PCR and immunohistochemical protocols for measurement of muscarinic ACh receptor M1 (m1AChR) levels in the brains of middle-aged rats, with and without administration of grape seed proanthocyanidin extract (GSPE) and exercise training. The analyses revealed that the interventions led to an increase in m1AChR mRNA and protein levels in the [[CA1]] subfield of hippocampus. This would be expected to enhance Ach levels at synapses and thereby boost cognitive ability. The protocols can be applied to m1AChR measurements in neurodegenerative diseases and dementia.

|keywords=* Acetylcholine
* Aging
* Brain
* Immunohistochemistry
* m1AChR
* qRT-PCR
|full-text-url=https://sci-hub.do/10.1007/978-1-0716-0471-7_23
}}
{{medline-entry
|title=Role of Eclipta prostrata extract in improving spatial learning and memory deficits in D-galactose-induced aging in rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32186114
|abstract=To investigate the role of Eclipta prostrata (E. prostrata) extract in improving spatial learning and memory deficits in D-galactose-induced aging in rats. Rats were divided into five groups, with 10 animals in each group. Aging rats were produced by treatment with 100 mg·kg-1·d-1 of D-galactose for 6 weeks. Rats in the E. prostrata treatment groups received an aqueous extract of E. prostrata orally at a concentration of 50, 100, or 200 mg·kg-1·d-1 for 3 weeks. Animals in both the normal and model groups were treated with similar volumes of saline. Spatial memory performance was measured using the Morris water maze. The mRNA levels and enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were analyzed using real-time quantitative PCR and spectrophotometry, respectively. The levels of induced nitric oxide synthase (iNOS), nitric oxide (NO), dopamine (DA), norepinephrine (NE), and serotonin (5-HT) were determined using enzyme-linked immunosorbent assay and spectrophotometry. Compared with the normal group, rats in the D-galactose-treated model group exhibited significant memory loss. There was severe damage to the hippocampal [[CA1]] area, and expression levels of SOD, CAT, GPx, and GR were significantly decreased in the model group compared with the normal group. In the model group, levels of iNOS and NO were significantly increased compared with the normal group. However, treatment with E. prostrata extract reversed the conditions caused by D-galactose-induced aging, especially in the groups with higher treatment concentrations. Compared with the normal group, the levels of DA, NE, and 5-HT were significantly lower in the D-galactose-treated model group. In the E. prostrata extract-treated groups, however, there was a dose-dependent upregulation of DA, NE, and 5-HT expression. Our results suggest that administration of E. prostrata extract can result in an improvement in the learning and memory impairments that are induced by D-galactose treatment in rats. This improvement may be the result of enhanced antioxidative ability, decreased iNOS and NO levels, and the induction of DA, NE, and 5-HT expression in the brain.
|mesh-terms=* Aging
* Animals
* Behavior, Animal
* CA1 Region, Hippocampal
* Catalase
* Dopamine
* Eclipta
* Galactose
* Gene Expression Regulation, Enzymologic
* Glutathione Peroxidase
* Glutathione Reductase
* Male
* Memory Disorders
* Nitric Oxide
* Nitric Oxide Synthase Type II
* Norepinephrine
* Plant Extracts
* RNA, Messenger
* Rats
* Rats, Sprague-Dawley
* Serotonin
* Spatial Learning
* Superoxide Dismutase
|keywords=* Antioxidants
* Eclipta
* Galactose
* Memory disorders
* Spatial learning

}}
{{medline-entry
|title=Differential annualized rates of hippocampal subfields atrophy in aging and future Alzheimer's clinical syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32107063
|abstract=Several studies have investigated the differential vulnerability of hippocampal subfields during aging and Alzheimer's disease (AD). Results were often contradictory, mainly because these works were based on concatenations of cross-sectional measures in cohorts with different ages or stages of AD, in the absence of a longitudinal design. Here, we investigated 327 participants from a population-based cohort of nondemented older adults with a 14-year clinical follow-up. MRI at baseline and 4 years later were assessed to measure the annualized rates of hippocampal subfields atrophy in each participant using an automatic segmentation pipeline with subsequent quality control. On the one hand, CA4 dentate gyrus was significantly more affected than the other subfields in the whole population ([[CA1]]-3: -0.68%/year; subiculum: -0.99%/year; and CA4-DG: -1.39%/year; p < 0.0001). On the other hand, the annualized rate of [[CA1]]-3 atrophy was associated with an increased risk of developing Alzheimer's clinical syndrome over time, independently of age, gender, educational level, and ApoE4 genotype (HR = 2.0; CI 95% 1.4-3.0). These results illustrate the natural history of hippocampal subfields atrophy during aging and AD by showing that the dentate gyrus is the most vulnerable subfield to the effects of aging while the cornu-ammonis is the primary target of AD pathophysiological processes, years before symptom onset.
|mesh-terms=* Aged
* Aging
* Alzheimer Disease
* Atrophy
* Cohort Studies
* Cross-Sectional Studies
* Dentate Gyrus
* Female
* Hippocampus
* Humans
* Magnetic Resonance Imaging
* Male
* Neuropsychological Tests
* Risk
|keywords=* Aging
* Alzheimer's disease
* Hippocampal subfields
* MRI
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.01.011
}}
{{medline-entry
|title=Rectification of radiotherapy-induced cognitive impairments in aged mice by reconstituted Sca-1  stem cells from young donors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32028989
|abstract=Radiotherapy is widely used and effective for treating brain tumours, but inevitably impairs cognition as it arrests cellular processes important for learning and memory. This is particularly evident in the aged brain with limited regenerative capacity, where radiation produces irreparable neuronal damage and activation of neighbouring microglia. The latter is responsible for increased neuronal death and contributes to cognitive decline after treatment. To date, there are few effective means to prevent cognitive deficits after radiotherapy. Here we implanted hematopoietic stem cells (HSCs) from young or old (2- or 18-month-old, respectively) donor mice expressing green fluorescent protein (GFP) into old recipients and assessed cognitive abilities 3 months post-reconstitution. Regardless of donor age, GFP  cells homed to the brain of old recipients and expressed the macrophage/microglial marker, Iba1. However, only young cells attenuated deficits in novel object recognition and spatial memory and learning in old mice post-irradiation. Mechanistically, old recipients that received young HSCs, but not old, displayed significantly greater dendritic spine density and long-term potentiation (LTP) in [[CA1]] neurons of the hippocampus. Lastly, we found that GFP /Iba1  cells from young and old donors were differentially polarized to an anti- and pro-inflammatory phenotype and produced neuroprotective factors and reactive nitrogen species in vivo, respectively. Our results suggest aged peripherally derived microglia-like cells may exacerbate cognitive impairments after radiotherapy, whereas young microglia-like cells are polarized to a reparative phenotype in the irradiated brain, particularly in neural circuits associated with rewards, learning, and memory. These findings present a proof-of-principle for effectively reinstating central cognitive function of irradiated brains with peripheral stem cells from young donor bone marrow.
|mesh-terms=* Animals
* Behavior, Animal
* Cognitive Dysfunction
* Dendritic Spines
* Hematopoietic Stem Cell Transplantation
* Hippocampus
* Humans
* Long-Term Potentiation
* Maze Learning
* Memory
* Mice
* Neurons
* Radiotherapy
* Recovery of Function
* Spinocerebellar Ataxias
* Treatment Outcome
|keywords=* Aging
* Bone marrow stem cells
* Learning and memory
* Microglia
* Radiotherapy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006105
}}
{{medline-entry
|title=Increasing neurogenesis refines hippocampal activity rejuvenating navigational learning strategies and contextual memory throughout life.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31919362
|abstract=Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of [[CA1]] sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain's endogenous reserve of neural stem cells.
|mesh-terms=* Aging
* Animals
* Cyclin D1
* Cyclin-Dependent Kinase 4
* Female
* Hippocampus
* Learning
* Memory
* Memory Consolidation
* Mice
* Mice, Inbred C57BL
* Neural Stem Cells
* Neurogenesis

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952376
}}
{{medline-entry
|title=Memory Performance Correlates of Hippocampal Subfield Volume in Mild Cognitive Impairment Subtype.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31849620
|abstract=The increased understanding that neuropathology begins decades before symptom onset, has led to the conceptualization and widespread utilization of Mild Cognitive Impairment (MCI) as an important transitional state between healthy aging and dementia. Further subcategorization to MCI subtype has led to more distinct prognoses and it is widely considered that amnestic and non-amnestic MCI (aMCI, naMCI) likely have distinct pathophysiologies. Yet, accurately classification remains contentious. Here, we differentiate hippocampal subfield volume between subtypes, diagnosed according to stringent clinical consensus criteria, where aMCI is characterized based on deficits in delayed recall (rather than encoding). We then identify memory performance correlates to subfield volume and associations with long-term cognitive performance and outcome. 3D T1-weighted structural MRI was acquired in 142 participants recruited from the [i]Healthy Brain Aging (HBA) Clinic[/i] and diagnosed with aMCI ([i]n[/i] = 38), naMCI ([i]n[/i] = 84) or subjective memory complaints (SMC; [i]n[/i] = 20). T1-weighted datasets were processed with the cortical and hippocampal subfield processing streams in FreeSurfer (v6.0). Subfield volumes, and associations with baseline and longitudinal objective memory scores were then examined. Subfield volumes were found to differentiate clinical profiles: subiculum, [[CA1]], CA4 and dentate gyrus volumes were significantly reduced in aMCI compared to both naMCI and SMC. [[CA1]] subfield volume was shown to predict concurrent memory performance in aMCI, while dentate gyrus volume significantly predicted longitudinal verbal learning and memory decline in the entire cohort. Our findings demonstrate that using a more stringent diagnostic approach to characterizing aMCI is well justified, as delayed recall deficits are strongly linked to underlying volumetric subfield reductions in [[CA1]], CA4 and the dentate gyrus, subfields known to be associated with mnemonic processes. Further research is now warranted to replicate these findings in other MCI samples.

|keywords=* aging
* hippocampus
* memory
* mild cognitive impairment
* neuroimaging
* subfields
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897308
}}
{{medline-entry
|title=Spermidine protects from age-related synaptic alterations at hippocampal mossy fiber-CA3 synapses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31873156
|abstract=Aging is associated with functional alterations of synapses thought to contribute to age-dependent memory impairment (AMI). While therapeutic avenues to protect from AMI are largely elusive, supplementation of spermidine, a polyamine normally declining with age, has been shown to restore defective proteostasis and to protect from AMI in Drosophila. Here we demonstrate that dietary spermidine protects from age-related synaptic alterations at hippocampal mossy fiber (MF)-CA3 synapses and prevents the aging-induced loss of neuronal mitochondria. Dietary spermidine rescued age-dependent decreases in synaptic vesicle density and largely restored defective presynaptic MF-CA3 long-term potentiation (LTP) at MF-CA3 synapses (MF-CA3) in aged animals. In contrast, spermidine failed to protect CA3-[[CA1]] hippocampal synapses characterized by postsynaptic LTP from age-related changes in function and morphology. Our data demonstrate that dietary spermidine attenuates age-associated deterioration of MF-CA3 synaptic transmission and plasticity. These findings provide a physiological and molecular basis for the future therapeutic usage of spermidine.
|mesh-terms=* Aging
* Animals
* CA3 Region, Hippocampal
* Long-Term Potentiation
* Mice
* Mossy Fibers, Hippocampal
* Spermidine
* Synaptic Transmission
* Synaptic Vesicles

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927957
}}
{{medline-entry
|title=Methylene blue inhibits Caspase-6 activity, and reverses Caspase-6-induced cognitive impairment and neuroinflammation in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31843022
|abstract=Activated Caspase-6 (Casp6) is associated with age-dependent cognitive impairment and Alzheimer disease (AD). Mice expressing human Caspase-6 in hippocampal [[CA1]] neurons develop age-dependent cognitive deficits, neurodegeneration and neuroinflammation. This study assessed if methylene blue (MB), a phenothiazine that inhibits caspases, alters Caspase-6-induced neurodegeneration and cognitive impairment in mice. Aged cognitively impaired Casp6-overexpressing mice were treated with methylene blue in drinking water for 1 month. Methylene blue treatment did not alter Caspase-6 levels, assessed by RT-PCR, western blot and immunohistochemistry, but inhibited fluorescently-labelled Caspase-6 activity in acute brain slice intact neurons. Methylene blue treatment rescued Caspase-6-induced episodic and spatial memory deficits measured by novel object recognition and Barnes maze, respectively. Methylene blue improved synaptic function of hippocampal [[CA1]] neurons since theta-burst long-term potentiation (LTP), measured by field excitatory postsynaptic potentials (fEPSPs) in acute brain slices, was successfully induced in the Schaffer collateral-[[CA1]] pathway in methylene blue-treated, but not in vehicle-treated, Caspase-6 mice. Increased neuroinflammation, measured by ionized calcium binding adaptor molecule 1 (Iba1)-positive microglia numbers and subtypes, and glial fibrillary acidic protein (GFAP)-positive astrocytes, were decreased by methylene blue treatment. Therefore, methylene blue reverses Caspase-6-induced cognitive deficits by inhibiting Caspase-6, and Caspase-6-mediated neurodegeneration and neuroinflammation. Our results indicate that Caspase-6-mediated damage is reversible months after the onset of cognitive deficits and suggest that methylene blue could benefit Alzheimer disease patients by reversing Caspase-6-mediated cognitive decline.
|mesh-terms=* Aging
* Animals
* Caspase 6
* Caspase Inhibitors
* Cognitive Dysfunction
* Female
* Humans
* Inflammation
* Male
* Methylene Blue
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Mice, Transgenic
|keywords=* Alzheimer disease
* Axonal degeneration
* Caspase-6
* Caspase-6 inhibitor
* Hippocampal CA1
* Hippocampal fibres
* Methylene blue
* Synaptic plasticity
* White matter
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6915996
}}
{{medline-entry
|title=Long-term Memory Upscales Volume of Postsynaptic Densities in the Process that Requires Autophosphorylation of αCaMKII.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31800021
|abstract=It is generally accepted that formation and storage of memory relies on alterations of the structure and function of brain circuits. However, the structural data, which show learning-induced and long-lasting remodeling of synapses, are still very sparse. Here, we reconstruct 1927 dendritic spines and their postsynaptic densities (PSDs), representing a postsynaptic part of the glutamatergic synapse, in the hippocampal area [[CA1]] of the mice that underwent spatial training. We observe that in young adult (5 months), mice volume of PSDs, but not the volume of the spines, is increased 26 h after the training. The training-induced growth of PSDs is specific for the dendritic spines that lack smooth endoplasmic reticulum and spine apparatuses, and requires autophosphorylation of αCaMKII. Interestingly, aging alters training-induced ultrastructural remodeling of dendritic spines. In old mice, both the median volumes of dendritic spines and PSDs shift after training toward bigger values. Overall, our data support the hypothesis that formation of memory leaves long-lasting footprint on the ultrastructure of brain circuits; however, the form of circuit remodeling changes with age.

|keywords=* CA1 area
* CaMKII
* IntelliCages
* aging
* dendritic spines
* memory
* postsynaptic density
|full-text-url=https://sci-hub.do/10.1093/cercor/bhz261
}}
{{medline-entry
|title=PACAP27 mitigates an age-dependent hippocampal vulnerability to PGJ2-induced spatial learning deficits and neuroinflammation in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31769222
|abstract=Inflammation in the brain is mediated by the cyclooxygenase pathway, which leads to the production of prostaglandins. Prostaglandin (PG) D2, the most abundant PG in the brain, increases under pathological conditions and is spontaneously metabolized to PGJ2. PGJ2 is highly neurotoxic, with the potential to transition neuroinflammation into a chronic state and contribute to neurodegeneration as seen in many neurological diseases. Conversely, PACAP27 is a lipophilic peptide that raises intracellular cAMP and is an anti-inflammatory agent. The aim of our study was to investigate the therapeutic potential of PACAP27 to counter the behavioral and neurotoxic effects of PGJ2 observed in aged subjects. PGJ2 was injected bilaterally into the hippocampal [[CA1]] region of 53-week-old and 12-week-old C57BL/6N male mice, once per week over 3 weeks (three total infusions) and included co-infusions of PACAP27 within respective treatment groups. Our behavioral assessments looked at spatial learning and memory performance on the 8-arm radial maze, followed by histological analyses of fixed hippocampal tissue using Fluoro-Jade C and fluorescent immunohistochemistry focused on IBA-1 microglia. Aged mice treated with PGJ2 exhibited spatial learning and long-term memory deficits, as well as neurodegeneration in CA3 pyramidal neurons. Aged mice that received co-infusions of PACAP27 exhibited remediated learning and memory performance and decreased neurodegeneration in CA3 pyramidal neurons. Moreover, microglial activation in the CA3 region was also reduced in aged mice cotreated with PACAP27. Our data show that PGJ2 can produce a retrograde spread of damage not observed in PGJ2-treated young mice, leading to age-dependent neurodegeneration of hippocampal neurons producing learning and memory deficits. PACAP27 can remediate the behavioral and neurodegenerative effects that PGJ2 produces in aged subjects. Targeting specific neurotoxic prostaglandins, such as PGJ2, offers great promise as a new therapeutic strategy downstream of cyclooxygenases, to combat the neuronal deficits induced by chronic inflammation.

|keywords=* CA1
* CA3
* Fluoro-Jade C
* aging
* microglia
* radial arm maze
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6955932
}}
{{medline-entry
|title=Inhibition of oxidative stress by testosterone improves synaptic plasticity in senescence accelerated mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31746286
|abstract=It is well known that synaptic plasticity is associated with cognitive performance in Alzheimer's disease (AD). Testosterone (T) is known to exert protective effects on cognitive deficits in AD, but the underlying mechanisms of androgenic action on synaptic plasticity remain unclear. Thus, the aim of this study was to examine the protective mechanism attributed to T on synaptic plasticity in an AD senescence accelerated mouse prone 8 (SAMP8) model. The following parameters were measured: (1) number of intact pyramidal cells in hippocampal [[CA1]] region (2) phosphorylated N-methyl-D-aspartate receptor-1 ([i]p[/i]-NMDAR1) and (3) phosphorylated calmodulin-dependent protein kinase II ([i]p[/i]-CaMKII). In addition, the content of whole brain malondialdehyde (MDA) as well as activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined. Treatment with T significantly elevated the number of intact pyramidal cells in hippocampal [[CA1]] region and markedly increased hippocampal protein and mRNA expression levels of [i]p[/i]-NMDAR1 and [i]p[/i]-CaMK II. Further, T significantly decreased whole brain MDA levels accompanied by elevated activities of SOD and GSH-Px. Data suggest that the protective effects of T on synaptic plasticity in a mouse AD model may be associated with reduction of oxidant stress.
|mesh-terms=* Aging
* Animals
* Male
* Mice
* Neuronal Plasticity
* Oxidative Stress
* Random Allocation
* Receptors, N-Methyl-D-Aspartate
* Testosterone
|keywords=* Alzheimer’s disease
* N-methyl-D-aspartate receptor-1
* Senescence accelerated mouse
* Testosterone
* oxidative stress
|full-text-url=https://sci-hub.do/10.1080/15287394.2019.1683988
}}
{{medline-entry
|title=Restored presynaptic synaptophysin and cholinergic inputs contribute to the protective effects of physical running on spatial memory in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31470103
|abstract=The effects of prolonged physical training on memory performance and underlying presynaptic mechanisms were investigated in old C57BL/6 mice. Training via voluntary running wheels was initiated at 16 months of age and continued for 5 months (1 h per day, 5 days per week), followed by testing of learning and memory functions and counting of presynaptic puncta and cholinergic inputs in the hippocampus. Trained old mice were compared to their age-matched sedentary controls and adult controls. This training strategy improved hippocampal-dependent spatial memory function tested via a novel location task, and enhanced memory was accompanied by restored presynaptic puncta and cholinergic fibers in area [[CA1]] and DG of the hippocampus in old mice. Particularly, the training selectively affected presynaptic vesicle protein synaptophysin but not growth associated protein GAP-43, and the increased number of synaptophysin puncta positively correlates with improved memory performance. To better understand the neurochemical mechanisms by which prolonged physical training protects against aging-related memory deficits, the cholinergic inputs to the hippocampus were compared among the three groups of mice and correlated with memory performance. While the running prevented age-related loss of cholinergic inputs, it has limited impact on the projection source cells in the medial septum-diagonal band (MS-DB). Importantly, cholinergic fibers in area [[CA1]] and DG positively correlated with spatial memory function. These data suggest that the preservation of presynaptic inputs, particularly those involved in the integrity of memory performance, contributes critically to the beneficial effects of physical running initiated at an older age.
|mesh-terms=* Aging
* Animals
* Cholinergic Neurons
* Hippocampus
* Mice
* Mice, Inbred C57BL
* Physical Conditioning, Animal
* Presynaptic Terminals
* Spatial Memory
* Synaptophysin
|keywords=* Aging
* Cholinergic cells
* Hippocampus
* Memory
* Physical training
* Presynaptic terminals
* Synaptophysin
|full-text-url=https://sci-hub.do/10.1016/j.nbd.2019.104586
}}
{{medline-entry
|title=Senescent neurophysiology: Ca  signaling from the membrane to the nucleus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31394200
|abstract=The current review provides a historical perspective on the evolution of hypothesized mechanisms for senescent neurophysiology, focused on the [[CA1]] region of the hippocampus, and the relationship of senescent neurophysiology to impaired hippocampal-dependent memory. Senescent neurophysiology involves processes linked to calcium (Ca ) signaling including an increase in the Ca -dependent afterhyperpolarization (AHP), decreasing pyramidal cell excitability, hyporesponsiveness of N-methyl-D-aspartate (NMDA) receptor function, and a shift in Ca -dependent synaptic plasticity. Dysregulation of intracellular Ca  and downstream signaling of kinase and phosphatase activity lies at the core of senescent neurophysiology. Ca -dysregulation involves a decrease in Ca  influx through NMDA receptors and an increase release of Ca  from internal Ca  stores. Recent work has identified changes in redox signaling, arising in middle-age, as an initiating factor for senescent neurophysiology. The shift in redox state links processes of aging, oxidative stress and inflammation, with functional changes in mechanisms required for episodic memory. The link between age-related changes in Ca  signaling, epigenetics and gene expression is an exciting area of research. Pharmacological and behavioral intervention, initiated in middle-age, can promote memory function by initiating transcription of neuroprotective genes and rejuvenating neurophysiology. However, with more advanced age, or under conditions of neurodegenerative disease, epigenetic changes may weaken the link between environmental influences and transcription, decreasing resilience of memory function.
|mesh-terms=* Aging
* Animals
* CA1 Region, Hippocampal
* Calcium Signaling
* Cell Nucleus
* Epigenesis, Genetic
* Excitatory Postsynaptic Potentials
* Humans
* Membrane Potentials
* Neuronal Plasticity
* Pyramidal Cells
* Receptors, N-Methyl-D-Aspartate
|keywords=* Afterhyperpolarization
* Aging
* Epigenetics
* Hippocampus
* N-methyl-D-aspartate receptor
* Synaptic plasticity
* Transcription
|full-text-url=https://sci-hub.do/10.1016/j.nlm.2019.107064
}}
==GC==

{{medline-entry
|title=Body Size and Cuticular Hydrocarbons as Larval Age Indicators in the Forensic Blow Fly, Chrysomya albiceps (Diptera: Calliphoridae).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33274739
|abstract=Chrysomya albiceps (Wiedemann 1819) is one of the most important insects in forensic entomology. Its larval developmental and survival rates are influenced by nutritional resources, temperature, humidity, and geographical regions. The present study investigated the possibility of relying on body size and cuticular hydrocarbon composition as indicators for age estimation of the different larval instars of C. albiceps. Larvae were maintained in standardized laboratory conditions at different experimental temperatures. All larval instars (first, second, and third) were randomly collected for measuring their body sizes and for estimating their cuticular hydrocarbons at different rearing temperatures (30, 35, 40, and 45°C) using gas chromatography-mass spectrometry ([[GC]]-MS). Results indicated that the duration of larval stage was temperature dependent as it gradually decreased on increasing the rearing temperature (30, 35, and 40°C) except 45°C at which larval development was ceased. In contrary, larval body size, in terms of length, width, and weight, was temperature dependent as it gradually increased with larval development on increasing rearing temperature except at 45°C at which larval development was ceased. The [[GC]]-MS showed a significant difference in the extracted components of cuticular hydrocarbons between different larval instars reared in the same temperature and between the same larval instar that reared at different temperatures. Furthermore, the highest and lowest amounts of cuticular hydrocarbons were detected at 35 and 40°C, respectively. Overall, larval body size and cuticular hydrocarbon components were temperature dependent within the range 30-40°C, which may suggest them as possible reliable age indicators for estimating the postmortem interval in the field of medicolegal entomology.

|keywords=* 
          Chrysomya albiceps
        
* body size
* cuticular hydrocarbon
* forensic
* larval longevity
|full-text-url=https://sci-hub.do/10.1093/jme/tjaa256
}}
{{medline-entry
|title=Composition of peony petal fatty acids and flavonoids and their effect on Caenorhabditis elegans lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33092723
|abstract=The colorful petals of tree peony (Paeonia suffruticosa Andrews) are widely used as a source of additives in food, fragrances, and cosmetics. However, the nutritional composition of peony petals is undetermined, thereby limiting utility and product development. In this work, fresh petals of 15 traditional Chinese tree peony cultivars were selected to analyze the composition of soluble sugars, starch, and soluble protein. Extracted fatty acids (FAs) and flavonoids from petals were characterized by [[GC]]-MS and UPLC-triple-TOF-MS, respectively. The oxidative stress resistance (generated by paraquat) effects of petal extracts of three cultivars were also investigated in the model organism Caenorhabditis elegans. Our results showed that the petals were highly enriched in soluble sugars. 11 FAs were found in tree peony petals, and their compositions were similar to that of tree peony seeds. A total of 56 flavonoids were detected in tree peony petals, 28 of which were reported for the first time in tree peony petals, indicating that UPLC-triple-TOF-MS can improve the identification efficiency of flavonoids. Further analysis of tree peony petal metabolites indicated that anthocyanidin and flavonol composition might be used as specific chemotaxonomic biomarkers for cultivar classification. Flavonoids, linoleic acid, and α-linolenic acid (ALA) in petals might provide antioxidant activity. 150 mg/L of petal extracts of all three tested cultivars increased the lifespan of C. elegans. It was suggested that the petal extracts possessed anti-aging effects and oxidative stress resistance. These results highlight that tree peony petals can serve as natural antioxidant food resources in the future.

|keywords=* Caenorhabditis elegans
* Fatty acid
* Flavonoid identification and composition
* Lifespan extension
* Tree peony petal
|full-text-url=https://sci-hub.do/10.1016/j.plaphy.2020.06.029
}}
{{medline-entry
|title=Photo aging and fragmentation of polypropylene food packaging materials in artificial seawater.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33039831
|abstract=Plastic litters in marine environment usually contain varied types and contents of additives that can significantly affect the photochemical aging and fragmentation process of microplastics (MPs). This study investigated the photo aging process of two common polypropylene (PP) food packaging materials (i.e., meal box and tea cup) in artificial seawater within 12 d of ultraviolet (UV) irradiation. Results revealed that the aging of both plastic materials were critically inhibited compared with pure PP, indicating that PP food packaging materials in natural seawater may share longer aging time than pure ones. [[GC]]-MS analysis revealed that antioxidant Irgafos 168 (tris (2,4-di-tert-butylphenyl) phosphite) was the dominant additive in these plastic materials. Photo reaction between Irgafos 168 and hydroperoxide species on the surface of MPs to prevent the formation of hydroxyl radical was the possible mechanism for the inhibiting effects. After antioxidant was exhausted, its photo degradation products could become the dominant contributor to influence the aging process of MPs. This is the first work exploring the role of antioxidant on the aging process of PP MPs in simulated ocean environment. The findings could be of great help for unraveling the effect of antioxidants on the aging-related environmental risk of hydrocarbon plastics in ocean environment.

|keywords=* Aging
* Antioxidant
* Food packaging materials
* Microplastics
* Polypropylene
* seawater
|full-text-url=https://sci-hub.do/10.1016/j.watres.2020.116456
}}
{{medline-entry
|title=Secretory galectin-3 induced by glucocorticoid stress triggers stemness exhaustion of hepatic progenitor cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32989051
|abstract=Adult progenitor cell populations typically exist in a quiescent state within a controlled niche environment. However, various stresses or forms of damage can disrupt this state, which often leads to dysfunction and aging. We built a glucocorticoid ([[GC]])-induced liver damage model of mice, found that [[GC]] stress induced liver damage, leading to consequences for progenitor cells expansion. However, the mechanisms by which niche factors cause progenitor cells proliferation are largely unknown. We demonstrate that, within the liver progenitor cells niche, Galectin-3 (Gal-3) is responsible for driving a subset of progenitor cells to break quiescence. We show that [[GC]] stress causes aging of the niche, which induces the up-regulation of Gal-3. The increased Gal-3 population increasingly interacts with the progenitor cell marker CD133, which triggers focal adhesion kinase (FAK)/AMP-activated kinase (AMPK) signaling. This results in the loss of quiescence and leads to the eventual stemness exhaustion of progenitor cells. Conversely, blocking Gal-3 with the inhibitor TD139 prevents the loss of stemness and improves liver function. These experiments identify a stress-dependent change in progenitor cell niche that directly influence liver progenitor cell quiescence and function.

|keywords=* AMP-activated kinase (AMPK)
* Cell senescence
* cell cycle
* cellular senescence
* galectin
* galectin-3
* glycoprotein
* liver injury
* proliferation
* protein interaction
* protein-protein interaction
* quiescence
* stem cells
* stemness exhaustion
|full-text-url=https://sci-hub.do/10.1074/jbc.RA120.012974
}}
{{medline-entry
|title=Optimization of Ethanol Detection by Automatic Headspace Method for Cellulose Insulation Aging of Oil-immersed Transformers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32679756
|abstract=The method using ethanol to evaluate the cellulose insulation aging condition of oil-immersed transformers has been proposed. At present, the dominating method for detecting ethanol in insulating oil is to use headspace-gas-chromatography-mass-spectrometry (HS-[[GC]]-MS). However, the problem of quantitative inaccuracy will be sometimes encountered in the actual detection process due to improper instrument parameter setting and improper manual operation. In this study, as an aging marker, ethanol in transformer insulating oil was separated by using VF-624 ms capillary column. The effects of gas-chromatography-mass-spectrometry ([[GC]]-MS) optimization conditions, headspace equilibrium temperature, headspace equilibrium time and standard solution preparation method on the determination of ethanol content in oil were discussed, and optimized measures were proposed. The experimental results showed that the measurement can be more accurate under the headspace temperature of 80 °C and the headspace time of 40 min, and relative standard deviation percentage (RSD%) could reach to 4.62% under this condition. It was also pointed out that, for the preparation of standard solution, the method which controlled the sampling volume of anhydrous ethanol by microliter syringe could make the peak area of ethanol chromatogram have a better linear relationship with the standard curve. Under the similar linear range, the goodness of fitting curve without diluting process could be as high as 0.9993, while the method of preparing the stock solution and diluting stepwise to obtain the fitting curve only had a goodness of 0.9910. The method was validated by standard addition recovery test, and the recovery values obtained were between 90.3% and 95.8%. The optimized method is of great significance for the measurement of ethanol dissolved in insulating oil.

|keywords=* aging
* cellulose insulation
* gas chromatography
* headspace sampling
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407484
}}
{{medline-entry
|title=Sensory, olfactometric and chemical characterization of the aroma potential of Garnacha and Tempranillo winemaking grapes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32569964
|abstract=Reconstituted polyphenolic and aromatic fractions (PAFs) from 33 different Garnacha and Tempranillo grapes were incubated in strict anoxia (75 °C × 24 h). Obtained hydrolyzates were characterized by sensory analysis, gas chromatography-olfactometry ([[GC]]-O) and gas chromatography-mass spectrometry ([[GC]]-MS). Five different aroma categories emerged. Garnacha may develop specific tropical/citrus fruit, kerosene and floral and Tempranillo toasty-woody and red-fruit characteristics. Those notes seem to mask alcoholic and fruit-in-syrup descriptors and the common vegetal background. Twenty-seven odorants were detected by [[GC]]-O. [[GC]]-MS data showed a clustering closely matching the one found by sensory analysis, suggesting the existence of five specific metabolomic profiles behind the five specific sensory profiles. Overall results suggest that 3-mercaptohexanol is responsible for tropical/citrus fruit, TDN for kerosene, volatile phenols for woody/toasty, β-damascenone and massoia lactone, likely with Z-1,5-octadien-3-one for fruit-in-syrup and alcoholic notes. Nine lipid-derived unsaturated aldehydes and ketones may be responsible for the vegetal background.
|mesh-terms=* Fruit
* Gas Chromatography-Mass Spectrometry
* Hexanols
* Norisoprenoids
* Odorants
* Olfactometry
* Principal Component Analysis
* Sulfhydryl Compounds
* Vitis
* Volatile Organic Compounds
|keywords=* Aging
* Aroma precursors
* Glycosides
* Lipid-derived aroma
* Norisoprenoids
* Sensory properties
* Terpenols
* Volatile phenols
|full-text-url=https://sci-hub.do/10.1016/j.foodchem.2020.127207
}}
{{medline-entry
|title=Accelerated Cognitive Ageing in epilepsy: exploring the effective connectivity between resting-state networks and its relation to cognitive decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32529058
|abstract=This study aims at understanding the dynamic functional brain organization in Accelerated Cognitive Ageing (ACA) in epilepsy. We also assess to which extend the (abnormal) effective connectivity between brain networks correlates with the (estimated) decline in IQ scores observed in the ACA patients. Two multi-echo resting-state fMRI scans of 10 ACA patients and 14 age- and education-matched healthy controls were acquired. A task-based fMRI was acquired in-between those two scans, for possible cognitive fatigue effects on reserve capacity. Granger causality ([[GC]]), a measure of effective connectivity between brain regions, was applied on 7 major cognitive networks, and group-wise compared, using permutation testing statistics. This was performed on each of the resting-state sessions independently. We assessed the correlation between the cognitive deterioration scores (representing cognitive decline), and the paired-networks granger causality values. The cingulate cortex appeared to be more engaged in ACA patients. Its dynamics towards the right fronto-parietal cortex, salience network, and the dorsal attention networks (DAN) was stronger than in controls, only in the first resting-state scan session. The Granger causality from the DAN to the default mode network (DMN) and from the ventral attention network (VAN) to the left fronto-parietal network (FPL) was also stronger in ACA patients and again only in the first scans. In the second resting-state scans, only the DMN was more strongly connected with the cingulate cortex in ACA patients. A weaker [[GC]] from DMN to FPL, and stronger [[GC]] from the salience network to cingulate cortex were associated with more decline in the Full-scale IQ and more [[GC]] from DMN to VAN would lead to more decline in the Perceptual Reasoning Index in ACA. The results are in line with the hypothesis of over-recruitment at low cognitive load, and exhaustion at higher cognitive load, as shown by the compensation-related utilization of neural circuits hypothesis (CRUNCH) model for ageing. Moreover, the DMN to VAN directed connectivity strongly correlates with the (estimated) decline in the Perceptual Reasoning Index, which is also in line with a recent study on ageing with mild cognitive impairment in elderly, and the posterior-anterior shift in aging (PASA) model. This study therefore supports the idea that the cognitive decline in our patients resembles the decline observed in healthy ageing, but in an accelerated mode. This study also sheds light on the directions of the impaired connectivity between the main networks involved in the deterioration process, which can be helpful for future development of treatment solutions.

|keywords=* Accelerated cognitive ageing
* Ageing
* Aging
* Biomarkers
* Clinical research
* Cognition
* Cognitive decline
* Cognitive neuroscience
* Effective connectivity
* Epilepsy
* Fmri
* Granger causality
* Image processing
* Medical imaging
* Mental health
* Nervous system
* Neuroscience
* Psychiatry
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283153
}}
{{medline-entry
|title=Characterization of Jinhua ham aroma profiles in specific to aging time by gas chromatography-ion mobility spectrometry ([[GC]]-IMS).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32417671
|abstract=A rapid method for analyzing of Jinhua ham samples in different aging time was created based on gas chromatography-ion mobility spectrometry ([[GC]]-IMS). The [[GC]]-IMS chromatograph provided information regarding the identities and intensities of 37 volatile flavor compounds, including both monomers and dimers. Principal component analysis (PCA) effectively distinguished the variation in the aroma of the Jinhua hams specific to aging time. Alcohol (octanol, 2-methylbutanol), ketones (2-butanone, 2-hexanone, 2-heptanone, acetoin, gamma-butyrolactone), aldehydes (butanal, 3-methylbutanal), ester (propyl acetate) and carboxylic acids (3-methylbutanoic acid) were considered as the main volatile compounds in the Jinhua ham samples. This [[GC]]-IMS method, then, proved to be feasible for the rapid and comprehensive detection of volatile compounds in Jinhua hams, and multivariance analysis (i.e.: PCA) was able to provide information related to aging time.

|keywords=* Aging
* Electronic-nose
* Gas chromatography-ion mobility spectrometry
* Jinhua ham
* Volatiles
|full-text-url=https://sci-hub.do/10.1016/j.meatsci.2020.108178
}}
{{medline-entry
|title=Quantitative Profiling of Lipid Species in Caenorhabditis elegans with Gas Chromatography-Mass Spectrometry.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32410029
|abstract=Gas chromatography-mass spectrometry ([[GC]]-MS) enables sensitive detection and relative quantification of fatty acids. In Caenorhabditis elegans, the use of [[GC]]-MS can corroborate findings from common staining methodologies, providing great resolution on the lipid species altered in abundance in aging, genetic mutants, or with dietary or pharmacologic manipulation. Here we describe a method to quantitate relative abundance of fatty acids in total worm lipid extracts, as well as a method that quantitates fatty acids following separation into neutral lipid pools (triacylglycerols and cholesteryl esters) versus more polar lipids (phospholipids) by solid-phase extraction (SPE).

|keywords=* Aging
* C. elegans
* Fat
* Fatty acids
* Gas chromatography–mass spectrometry
* Lipids
* Phospholipids
* Solid-phase chromatography
* Triglycerides
|full-text-url=https://sci-hub.do/10.1007/978-1-0716-0592-9_10
}}
{{medline-entry
|title=Physicochemical characterization of a polysaccharide from Agrocybe aegirita and its anti-ageing activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32172871
|abstract=The aim of the present study is to characterize the structure of a novel natural polysaccharide from Agrocybe aegirita (AAPS) and evaluate its anti-aging activity. The MALLS and [[GC]]-MS analysis indicated that the AAPS with molecular weights of 1.81 × 10  Da was mainly composed by rhamnose, fucose, mannose, and glucose in a molar ratio of 2.90:10.25:3.70:38.27. The FT-IR and NMR analysis showed that the backbone of AAPS was α-L-Rhap-(1→6)-β-D-Glcp-(1→2)-α-L-Fucp-(1→6)-α-D-Glcp-(1→5)-α-L-Araf-(1→4)-β-D-GlcpA-(1→5)-α-L-Araf-(1→6)-α-D-Manp-(1→6)-α-D-Manp-(1→2)-α-L-Fucp-(1→6)-β-D-Glap-(1→2)-α-L-Rhap-(1→6)-β-D-Galp-(1→, which linked with two side chains α-L-Fucp-(1→6)-β-D-Glcp-(1→6)-β-D-Manp-(1→ and α-D-Xylp-(1→2)-α-L-Fucp-(1→5) -α-D-Araf-(1→6)-β-D-Galp-(1→ at O  at H-4-arabinose and the terminal Galp residues, respectively. The MRC-5 cells induced by H O  were used to explore the anti-ageing effect and its underlying mechanism of AAPS. It showed a potent anti-ageing activity, representing by the increased cell viability and β-Gal viability, prevented G1-phase cell-cycle arrest, and decreased mitochondrial membrane potential. The polysaccharides extracted from A. aegirita might be applied in functional food as anti-ageing ingredient.
|mesh-terms=* Aging
* Agrocybe
* Antioxidants
* Carbohydrate Sequence
* Cell Line
* Chemical Phenomena
* G1 Phase Cell Cycle Checkpoints
* Humans
* Membrane Potential, Mitochondrial
* Mitochondria
* Polysaccharides
|keywords=* Agrocybe aegirita polysaccharide
* Anti-ageing
* Cell cycle
* Mitochondrial membrane potential
* Structure
|full-text-url=https://sci-hub.do/10.1016/j.carbpol.2020.116056
}}
{{medline-entry
|title=Structural characteristics, antioxidant properties and antiaging activities of galactan produced by Mentha haplocalyx Briq.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32070549
|abstract=An antioxidant-active polysaccharide (WMP) with a molecular weight of 26.91 kDa was isolated from Mentha haplocalyx Briq by water extraction, ethanol precipitation and gel filtration. According to HPLC, methylation, [[GC]]-MS, and 1D/2D nuclear magnetic resonance spectroscopy, WMP is a heteropolysaccharide composed of Gal (84.2 %), Glc (9.8 %), Man (2.8 %) and Ara (3.2 %) with (1→6)-α-d-Galp and (1→4, 6)-α-d-Galp residues in the backbone and (1→6)-α-d-Galp and (1→6)-α-d-Glcp residues in the branch. The branch point was located at C-4 of (1→4, 6)-α-d-Galp residue with a branching degree of 19.71 %. WMP showed remarkably high scavenging ability for 1, 1-diphenyl-2-picrylhydrazyl (DPPH) and hydroxyl radicals, ferrous ion chelating activity and ferric reducing powder in vitro. In vivo result showed that WMP oral administration substantially increased the activities of antioxidant enzymes, including SOD, GSH-Px and CAT, and decreased MDA levels in the serum and liver of d-Gal-induced aging mice. Therefore, WMP can be an effective natural antioxidant.
|mesh-terms=* Aging
* Animals
* Antioxidants
* Biphenyl Compounds
* Carbohydrate Conformation
* Galactans
* Male
* Mentha
* Mice
* Mice, Inbred Strains
* Particle Size
* Picrates
* Surface Properties
|keywords=* Anti-aging activity
* Antioxidant activity
* Mentha haplocalyx Briq
* Polysaccharides
|full-text-url=https://sci-hub.do/10.1016/j.carbpol.2020.115936
}}
{{medline-entry
|title=Contribution of Volatile Odorous Terpenoid Compounds to Aged Cognac Spirits Aroma in a Context of Multicomponent Odor Mixtures.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32052967
|abstract=Cognac spirit aromas result from the presence of a wide variety of volatile odorous compounds associated with the modalities of spirit distillation and aging. However, very few studies have been carried out on aging notes of Cognac spirits. An HPLC fractionation approach was used in order to evidence fractions of interest recalling the specific aromatic nuances of aged Cognac. Then, a [[GC]]-O/MS analysis of the selected fractions allowed one to detect odorous zones and identify several volatile compounds. Among them, various well-known volatile compounds representative of the terpenoid family were highlighted, such as geraniol, α-terpinene, nerol, α-terpineol, 1,8-cineole (eucalyptol) and, particularly, piperitone, santalol, and α-campholenal, which have not previously been cited in Cognac. These compounds were quantitated and their detection thresholds were determined. Geraniol, α-terpinene, α-terpineol, and 1,8-cineole concentrations increased while spirits were more aged, while nerol tends to decrease. A sensory contribution of terpenes was observed through perceptual synergic effects, along with β-damascenone and whisky lactone.

|keywords=* Cognac
* aging aroma
* lees
* monoterpenes
* perceptual synergic effects
|full-text-url=https://sci-hub.do/10.1021/acs.jafc.9b06656
}}
{{medline-entry
|title=Plasma Formate Is Greater in Fetal and Neonatal Rats Compared with Their Mothers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31912134
|abstract=Formate can be incorporated into 10-formyl-tetrahydrofolate (10-formyl-THF), which is a substrate for purine synthesis, and after further reduction of the one-carbon group, may be used as a substrate for thymidylate synthesis and for homocysteine remethylation. We examined plasma formate concentrations and the expression of genes involved in the production and utilization of formate in fetal and neonatal rats and in pregnant and virgin female rats. In 1 experiment, plasma formate was measured by [[GC]]-MS in rats aged 1-56 d. In a second experiment, virgin female (adult) rats, 19-d pregnant rats (P) and their male and female fetuses (F), and 3-d-old (N) and 7-d-old (J) offspring had plasma and amniotic fluid analyzed for formate by [[GC]]-MS, mRNA abundance in liver and placenta by qPCR, and several plasma amino acids by HPLC. The plasma formate concentration was significantly higher in fetuses at embryonic day 19 than in the mothers. It was also significantly higher in neonatal rats but slowly returned to adult concentrations by ∼3 wk. The abundance of mitochondrial monofunctional 10-formyl-tetrahydrofolate synthetase (Mthfd1l) mRNA was significantly higher in placenta (PP) and F liver than in liver of N or J. Expression of mitochondrial bifunctional NAD-dependent methylene-tetrahydrofolate dehydrogenase/methenyl-tetrahydrofolate cyclohydrolase (Mthfd2) was significantly enriched in PP and liver of P, intermediate in F liver, and much lower in liver of N and J, relative to PP. Serine hydroxymethyltransferase 2 (Shmt2), methylenetetrahydrofolate dehydrogenase 1 (Mthfd1), and glycine decarboxylase protein of the glycine cleavage system (Gldc) mRNA expression was significantly lower in PP compared with other groups. Cytoplasmic NAD(P)-dependent 10-formyl-tetrahydrofolate dehydrogenase (Aldh1/1) and mitochondrial NAD(P)-dependent 10-formyl-tetrahydrofolate dehydrogenase (Aldh1/2) , genes responsible for the catabolism of 10-formylTHF, were very weakly expressed in PP, low in livers of F and N, and reached the significantly higher adult levels in J. Serine, glycine, and methionine concentrations in plasma of F were significantly higher than in plasma of P. Formate metabolism is highly active in fetuses and in placenta of pregnant rats.
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* Female
* Fetus
* Formates
* Liver
* Maternal-Fetal Exchange
* Mothers
* Placenta
* Pregnancy
* Rats
* Rats, Sprague-Dawley
|keywords=* fetus
* glycine
* methionine
* mitochondria
* one-carbon metabolism
* pregnancy
* serine
* tetrahydrofolate
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198295
}}
{{medline-entry
|title=Development of a new strategy for studying the aroma potential of winemaking grapes through the accelerated hydrolysis of phenolic and aromatic fractions (PAFs).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31882095
|abstract=Current methods for assessing grape aroma potential are based on the fast hydrolysis of precursor fractions but provide hydrolyzates of poor aromatic quality. A new strategy based on the accelerated hydrolysis of reconstituted phenolic and aromatic fractions (PAFs) extracted from grapes is herein developed. PAFs are obtained by solid phase extraction on 10 g-C18 sorbents of partially dealcoholized "mistelle", obtained from grapes treated with ethanol. Under optimal conditions, PAFs contain all aroma precursors but the most polar ones, such as those of DMS, more than 85% of the total phenolics and just traces of metal cations and of amino acids. PAFs reconstituted in model wine, aged in strict anoxia 7 weeks at 45 °C or 24 h at 75 °C, develop strong aromas. At least 30 different odorants including lipid derivatives, volatile phenols, vanillins, norisoprenoids, terpenes, bencenoids and 3-mercaptohexanol were identified by [[GC]]-Olfactometry and [[GC]]-MS. Methodological aspects of the extraction, hydrolysis and analysis are optimized and discussed.

|keywords=* Aging
* Glycosidic precursors
* Grape aroma
* Grape quality
* Hydrolysis
* Polyphenols
* Wine
|full-text-url=https://sci-hub.do/10.1016/j.foodres.2019.108728
}}
{{medline-entry
|title=Compromised steady-state germinal center activity with age in nonhuman primates.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31840398
|abstract=Age-related reductions in vaccine-induced B cells in aging indicate that germinal centers ([[GC]]s), the anatomical site where the development of humoral responses takes place, may lose efficacy with age. We have investigated the baseline follicular and [[GC]] composition in nonhuman primates (NHPs) with respect to their age. There was a marked reduction in follicular area in old animals. We found significantly lower normalized numbers of follicular PD1  CD4 T (Tfh) and proliferating (Ki67  ) [[GC]] B cells with aging, a profile associated with significantly higher numbers of potential follicular suppressor FoxP3  Lag3  CD4 T cells. Furthermore, a positive correlation was found between Tfh and follicular CD8 T cells (fCD8) only in young animals. Despite the increased levels of circulating preinflammatory factors in aging, young animals had higher numbers of monocytes and granulocytes in the follicles, a profile negatively associated with numbers of Tfh cells. Multiple regression analysis showed an altered association between [[GC]] B cells and other [[GC]] immune cell populations in old animals suggesting a differential mechanistic regulation of [[GC]] activity in aging. Our data demonstrate defective baseline [[GC]] composition in old NHPs and provide an immunological base for further understanding the adaptive humoral responses with respect to aging.
|mesh-terms=* Aging
* Animals
* Antigens, CD
* B-Lymphocytes
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Forkhead Transcription Factors
* Germinal Center
* Granulocytes
* Immunity, Humoral
* Inflammation
* Lymph Nodes
* Macaca mulatta
* Monocytes
|keywords=* B cells
* Tfh cells
* aging
* follicles
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996951
}}
{{medline-entry
|title=Endogenous Glucocorticoid Signaling in the Regulation of Bone and Marrow Adiposity: Lessons from Metabolism and Cross Talk in Other Tissues.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31749087
|abstract=The development of adiposity in the bone marrow, known as marrow adipose tissue (MAT), is often associated with musculoskeletal frailty. Glucocorticoids, which are a key component of the biological response to stress, affect both bone and MAT. These molecules signal through receptors such as the glucocorticoid receptor (GR), but the role of the GR in regulation of MAT is not yet clear from previous studies. The purpose of this review is to establish and determine the role of GR-mediated signaling in marrow adiposity by comparing and contrasting what is known against other energy-storing tissues like adipose tissue, liver, and muscle, to provide better insight into the regulation of MAT during times of metabolic stress (e.g., dietary challenges, aging). GR-mediated glucocorticoid signaling is critical for proper storage and utilization of lipids in cells such as adipocytes and hepatocytes and proteolysis in muscle, impacting whole-body composition, energy utilization, and homeostasis through a complex network of tissue cross talk between these systems. Loss of GR signaling in bone promotes increased MAT and decreased bone mass. GR-mediated signaling in the liver, adipose tissue, and muscle is critical for whole-body energy and metabolic homeostasis, and both similarities and differences in GR-mediated [[GC]] signaling in MAT as compared with these tissues are readily apparent. It is clear that [[GC]]-induced pathways work together through these tissues to affect systemic biology, and understanding the role of bone in these patterns of tissue cross talk may lead to a better understanding of MAT-bone biology that improves treatment strategies for frailty-associated diseases.
|mesh-terms=* Adipose Tissue
* Adiposity
* Animals
* Bone Marrow
* Energy Metabolism
* Glucocorticoids
* Homeostasis
* Humans
* Liver
* Muscle, Skeletal
* Receptor Cross-Talk
* Receptors, Glucocorticoid
* Signal Transduction
* Stress, Physiological
|keywords=* Adipocyte
* Aging
* Bone marrow
* Corticosterone
* Cortisol
* Cortisone
* Glucocorticoid
* Osteoblast
|full-text-url=https://sci-hub.do/10.1007/s11914-019-00554-6
}}
{{medline-entry
|title=4,5-Diphenyl-2-methyl picolinate induces cellular senescence by accumulating DNA damage and activating associated signaling pathways in gastric cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31639393
|abstract=Gastric cancer ([[GC]]) is a common cancer with a relatively low survival rate. Cellular senescence, a potent anti-cancer mechanism, is naturally occurred, and can be induced by chemotherapeutic agents. We sought to explore new compounds against [[GC]] cells by inducing cellular senescence. Primary screening of a library of N-heterocyclic compounds identified some with potent inhibitory effects on [[GC]] cells. Furthermore, in vitro effects of the most potent candidate compound on the proliferation and senescence of [[GC]] cells were studied by classical assays, including senescence-associated (SA)-β-galactosidase staining, and immunofluorescence; and in vivo effects of this compound was evaluated in a xenograft tumor mouse model. Among 43 tested compounds, 4,5-diphenyl-2-methyl picolinate (DMP) showed the highest inhibition effects on the growth of [[GC]] cells. In vitro experiments showed that DMP inhibited the proliferation by inducing senescence and DNA-damage associated protein markers and signaling pathways. In vivo experiment confirmed that DMP treatment inhibited tumor growth by promoting DNA-damage signaling. This study set up a platform to identify senescence-inducing anti-cancer compounds, and uncovers that DMP exerted anticancer effects by inducing cellular senescence through targeting DNA damage and associated signaling pathways in [[GC]] cancer.
|mesh-terms=* Animals
* Antineoplastic Agents
* Apoptosis
* Cell Cycle
* Cell Proliferation
* Cellular Senescence
* DNA Damage
* Humans
* Mice
* Mice, Inbred BALB C
* Mice, Nude
* Picolinic Acids
* Signal Transduction
* Stomach Neoplasms
* Tumor Cells, Cultured
* Xenograft Model Antitumor Assays
|keywords=* Cellular senescence
* DNA damage
* Gastric cancer
* N-heterocyclic compound
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2019.116973
}}
{{medline-entry
|title=Relationship Between the Dose Administered, Target Tissue Dose, and Toxicity Level After Acute Oral Exposure to Bifenthrin and Tefluthrin in Young Adult Rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31573616
|abstract=Most pyrethroid insecticides (PYRs) share a similar primary target site in mammals. However, the potency estimates of the lethal and sublethal effects of these compounds differ up to 103-fold. The aim of this study was to evaluate the relationship between the dose administered, the target tissue dose, and the effect of 2 highly toxic PYRs, tefluthrin (TEF; 0.1-9 mg/kg) and bifenthrin (BIF; 0.5-12 mg/kg), by using the oral route, a corn oil vehicle (1 ml/kg) and subcutaneous temperature (Tsc) monitoring assays in adult rats. The Tsc was determined at 30-min intervals for 5 h (TEF) or 4.5 h (BIF) after dosing. Rats were sacrificed at 6 h after dosing, and BIF and TEF concentrations were determined in blood (Bd), liver (Lv), and cerebellum (Cb) by using a [[GC]]-ECD system. The minimal effective dose of BIF (3 mg/kg) affecting Tsc was similar to that found in prior studies using other testing paradigms. Regarding TEF, a very steep relationship between the dose administered and toxicity was observed, with a near-threshold to low-effective range for Tsc at 0.1-6 mg/kg, and a near lethal syndrome at ≥ 7.5 mg/kg. At 6-7.5 mg/kg TEF, the Cb/Bd and Cb/Lv concentration ratios were both > 1. Conversely, for BIF, the Cb concentration was barely over the Bd concentration and the Cb/Lv concentration ratio remained < 1. Our results and previous findings call for more comprehensive consideration to establish the relevance of the distribution into target tissues and the tissue dosimetry for health risks through the exposure to PYRs in humans.
|mesh-terms=* Administration, Oral
* Aging
* Animals
* Body Temperature
* Cerebellum
* Cyclopropanes
* Dose-Response Relationship, Drug
* Hydrocarbons, Fluorinated
* Liver
* Male
* Pyrethrins
* Rats
* Rats, Wistar
* Tissue Distribution
* Toxicokinetics
|keywords=* acute effects
* bifenthrin
* body temperature
* disposition
* rat
* tefluthrin
|full-text-url=https://sci-hub.do/10.1093/toxsci/kfz204
}}
{{medline-entry
|title=Sugar Beet Pectin Supplementation Did Not Alter Profiles of Fecal Microbiota and Exhaled Breath in Healthy Young Adults and Healthy Elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31547291
|abstract=Aging is accompanied with increased frailty and comorbidities, which is potentially associated with microbiome perturbations. Dietary fibers could contribute to healthy aging by beneficially impacting gut microbiota and metabolite profiles. We aimed to compare young adults with elderly and investigate the effect of pectin supplementation on fecal microbiota composition, short chain fatty acids (SCFAs), and exhaled volatile organic compounds (VOCs) while using a randomized, double-blind, placebo-controlled parallel design. Fifty-two young adults and 48 elderly consumed 15 g/day sugar beet pectin or maltodextrin for four weeks. Fecal and exhaled breath samples were collected before and after the intervention period. Fecal samples were used for microbiota profiling by 16S rRNA gene amplicon sequencing, and for analysis of SCFAs by gas chromatography ([[GC]]). Breath was used for VOC analysis by [[GC]]-tof-MS. Young adults and elderly showed similar fecal SCFA and exhaled VOC profiles. Additionally, fecal microbiota profiles were similar, with five genera significantly different in relative abundance. Pectin supplementation did not significantly alter fecal microbiota, SCFA or exhaled VOC profiles in elderly or young adults. In conclusion, aside from some minor differences in microbial composition, healthy elderly and young adults showed comparable fecal microbiota composition and activity, which were not altered by pectin supplementation.
|mesh-terms=* Aged
* Beta vulgaris
* Breath Tests
* Dietary Supplements
* Double-Blind Method
* Exhalation
* Fatty Acids, Volatile
* Feces
* Female
* Gastrointestinal Microbiome
* Healthy Volunteers
* Humans
* Male
* Pectins
* Volatile Organic Compounds
* Young Adult
|keywords=* aging
* dietary fiber
* elderly
* exhaled air
* microbiota
* pectin
* young adults
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770243
}}
{{medline-entry
|title=Identification and analysis of new α- and β-hydroxy ketones related to the formation of 3-methyl-2,4-nonanedione in musts and red wines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31520920
|abstract=The formation of 3-methyl-2,4-nonanedione (MND) during red wine aging can contribute to the premature evolution of aroma, characterized by the loss of fresh fruit and development of dried fruit flavors. The identification of two new hydroxy ketones, 2-hydroxy-3-methylnonan-4-one (syn- and anti-ketol diastereoisomers) and 3-hydroxy-3-methyl-2,4-nonanedione (HMND), prompted the investigation of the precursors and pathways through which MND is produced and evolves. An HS-SPME-[[GC]]-MS method was optimized for their quantitation in numerous must and wine samples, providing insight into the evolution of MND, HMND, and ketols through alcoholic fermentation and wine aging. Alcoholic fermentation resulted in a significant decrease in MND and HMND and the simultaneous appearance of ketol diastereoisomers. The analysis of 167 dry red wines revealed significant increases in MND and anti-ketol contents through aging and a significant positive correlation between MND and anti-ketols. Additional experiments demonstrated that ketols are precursors to MND during red wine oxidation.
|mesh-terms=* Alkanes
* Diacetyl
* Ethanol
* Fruit and Vegetable Juices
* Gas Chromatography-Mass Spectrometry
* Humans
* Hydrogen-Ion Concentration
* Ketones
* Limit of Detection
* Solid Phase Microextraction
* Stereoisomerism
* Time Factors
* Wine
|keywords=* 3-methyl-2,4-nonanedione
* Aroma precursor
* Hydroxy ketones
* Oxidation
* Premature aging
* Wine
|full-text-url=https://sci-hub.do/10.1016/j.foodchem.2019.125486
}}
{{medline-entry
|title=Neonatal T Follicular Helper Cells Are Lodged in a Pre-T Follicular Helper Stage Favoring Innate Over Adaptive Germinal Center Responses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31456798
|abstract=T follicular helper (T ) cells have emerged as a critical limiting factor for controlling the magnitude of neonatal germinal center ([[GC]]) reactions and primary vaccine antibody responses. We compared the functional attributes of neonatal and adult T  cells at the transcriptomic level and demonstrated that the T  cell program is well-initiated in neonates although the T  gene-expression pattern (i.e., [i]CXCR5, IL-21, BCL6, TBK1, STAT4, ASCL2[/i], and [i]c-MAF[/i]) is largely underrepresented as compared to adult T  cells. Importantly, we identified a TH2-bias of neonatal T  cells, with preferential differentiation toward short-lived pre-T  effector cells. Remarkably, adjuvantation with CpG-ODNs redirect neonatal pre-T  cells toward committed [[GC]]-T  cells, as illustrated by increased expression of T  signature genes and reduced expression of TH2-related genes.
|mesh-terms=* Adaptive Immunity
* Adjuvants, Immunologic
* Aging
* Animals
* Animals, Newborn
* Germinal Center
* Immunity, Innate
* Interleukin-13
* Lymphopoiesis
* Mice, Inbred C57BL
* T-Lymphocytes, Helper-Inducer
* Th2 Cells
* Transcriptome
|keywords=* T follicular helper cells
* adjuvant
* neonates
* transcriptional profile analysis
* vaccines
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700230
}}
{{medline-entry
|title=Identification of Dialkylpyrazines Off-Flavors in Oak Wood.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31423769
|abstract=Volatile extractive compounds from high-quality oak wood ([i]Quercus[/i] sp.) are responsible for important pleasant olfactory notes, such as coconut, wood, vanilla, caramel, and spice. Recently, a new off-flavor reminiscent of rancid butter has been detected in oak wood. Using gas chromatography-olfactometry ([[GC]]-O) coupled to several detection modes, such as nitrogen-phosphorus detection ([[GC]]-O-NPD) or mass spectrometry ([[GC]]-O-MS) and multidimensional [[GC]]-O coupled to time-of-flight mass spectrometry, six compounds containing nitrogen atoms were identified. The volatiles were suggested to belong to 2,5-disubstituted pyrazines family, which was confirmed by comparison with synthetic reference compounds. For this purpose, symmetric and dissymmetric 2,5-dialkylpyrazines were prepared from methyl esters of corresponding aliphatic amino acids (Val, Leu, and Ile) by a three-step, one-pot reaction under mild reducing conditions. Organoleptic descriptors and odor detection thresholds were also determined, whereas a bacterial origin explaining these off-flavors was hypothesized.
|mesh-terms=* Flavoring Agents
* Gas Chromatography-Mass Spectrometry
* Odorants
* Olfactometry
* Pyrazines
* Quercus
* Wood
|keywords=* aroma
* barrel aging
* dialkylpyrazine
* oak wood
* off-flavor
* wine
|full-text-url=https://sci-hub.do/10.1021/acs.jafc.9b03185
}}
{{medline-entry
|title=Metabolomics Coupled with Transcriptomics Approach Deciphering Age Relevance in Sepsis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31440390
|abstract=Sepsis is a severe disease frequently occurred in the Intenisive Care Unit (ICU), which has a very high morbidity and mortality, especially in patients aged over 65 years. Owing to the aging effect and the ensuing deterioration of body function, the elder patients may have atypical responses to sepsis. Diagnosis and pathogenesis of sepsis in this population are thus difficult, which hindered effective treatment and management in clinic. To investigated age effects on sepsis, 158 elderly septic patients and 71 non-septic elderly participants were enrolled, and their plasma samples were collected for transcriptomics (RNA-seq) and metabolomics (NMR and [[GC]]-MS) analyses, which are both increasingly being utilized to discover key molecular changes and potential biomarkers for various diseases. Protein-protein interaction (PPI) analysis was subsequently performed to assist cross-platform integration. Real time polymerase chain reaction (RT-PCR) was used for validation of RNA-seq results. For further understanding of the mechanisms, cecal ligation and puncture (CLP) experiment was performed both in young and middle-aged rats, which were subjected to NMR-based metabolomics study and validated for several key inflammation pathways by western blot. Comprehensive analysis of data from the two omics approaches provides a systematic perspective on dysregulated pathways that could facilitate the development of therapy and biomarkers for elderly sepsis. Additionally, the metabolites of lactate, arginine, histamine, tyrosine, glutamate and glucose were shown to be highly specific and sensitive in distinguishing septic patients from healthy controls. Significant increases of arginine, trimethylamine N-oxide and allantoin characterized elderly patient incurred sepsis. Further analytical and biological validations in different subpopulations of septic patients should be carried out, allowing accurate diagnostics and precise treatment of sepsis in clinic.

|keywords=* aging
* biomarker
* metabolomics
* sepsis
* transcriptomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675524
}}
==NLRP3==

{{medline-entry
|title=Innate and Adaptive Immunity in Aging and Longevity: The Foundation of Resilience.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33269094
|abstract=The interrelation of the processes of immunity and senescence now receives an unprecedented emphasis during the COVID-19 pandemic, which brings to the fore the critical need to combat immunosenescence and improve the immune function and resilience of older persons. Here we review the historical origins and the current state of the science of innate and adaptive immunity in aging and longevity. From the modern point of view, innate and adaptive immunity are not only affected by aging but also are important parts of its underlying mechanisms. Excessive levels or activity of antimicrobial peptides, C-reactive protein, complement system, TLR/NF-κB, cGAS/STING/IFN 1,3 and AGEs/RAGE pathways, myeloid cells and [[NLRP3]] inflammasome, declined levels of NK cells in innate immunity, thymus involution and decreased amount of naive T-cells in adaptive immunity, are biomarkers of aging and predisposition factors for cellular senescence and aging-related pathologies. Long-living species, human centenarians, and women are characterized by less inflamm-aging and decelerated immunosenescence. Despite recent progress in understanding, the harmonious theory of immunosenescence is still developing. Geroprotectors targeting these mechanisms are just emerging and are comprehensively discussed in this article.

|keywords=* adaptive immunity
* aging
* innate immunity
* longevity
* resilience
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673842
}}
{{medline-entry
|title=TET2-Loss-of-Function-Driven Clonal Hematopoiesis Exacerbates Experimental Insulin Resistance in Aging and Obesity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33113366
|abstract=Human aging is frequently accompanied by the acquisition of somatic mutations in the hematopoietic system that induce clonal hematopoiesis, leading to the development of a mutant clone of hematopoietic progenitors and leukocytes. This somatic-mutation-driven clonal hematopoiesis has been associated with an increased incidence of cardiovascular disease and type 2 diabetes, but whether this epidemiological association reflects a direct, causal contribution of mutant hematopoietic and immune cells to age-related metabolic abnormalities remains unexplored. Here, we show that inactivating mutations in the epigenetic regulator TET2, which lead to clonal hematopoiesis, aggravate age- and obesity-related insulin resistance in mice. This metabolic dysfunction is paralleled by increased expression of the pro-inflammatory cytokine IL-1β in white adipose tissue, and it is suppressed by pharmacological inhibition of [[NLRP3]] inflammasome-mediated IL-1β production. These findings support a causal contribution of somatic TET2 mutations to insulin resistance and type 2 diabetes.

|keywords=* CHIP
* IL-1β
* TET2
* adipose tissue
* aging
* clonal hematopoiesis
* diabetes
* insulin resistance
* obesity
* somatic mutations
|full-text-url=https://sci-hub.do/10.1016/j.celrep.2020.108326
}}
{{medline-entry
|title=Repeated propofol exposure-induced neuronal damage and cognitive impairment in aged rats by activation of NF-κB pathway and [[NLRP3]] inflammasome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33115643
|abstract=Elderly patients receive propofol at regular intervals for sedation during gastrointestinal endoscopy. However, the link between cognition and intermittent propofol exposure remains unclear. Thus, we used aged rats to investigate the effect of propofol on cognition. The study included two parts. In the first part, aged (18-20 months old) male Sprague-Dawley rats underwent intermittent intraperitoneal injection of propofol (200 mg/kg) or intralipid, every 9 days or once a day. In the second part, some aged rats received intraperitoneal injection of Bay 11-7082 (1 mg/kg), a specific inhibitor of NF-κB, 30 min before propofol injection. Memory tests were performed to evaluate cognition 24 h after the entire treatment. The hippocampal neuronal damage was assessed by TUNEL staining. The hippocampal levels of p-NF-κB p65, [[NLRP3]], caspase-1 p20, and cleaved caspase-3 were detected by western blotting. The hippocampal and serum levels of IL-1β, IL-6, and TNF-α were evaluated using ELISA. There were no differences in the behavioral tests, hippocampal neuronal damage, and neuroinflammation between groups given intralipid and propofol treatment every 9 days. However, repeated propofol treatment once a day promoted activation of NF-κB and the [[NLRP3]] inflammasome, inducing cognitive impairment and neuroinflammation. Interestingly, pretreatment with Bay-11-7082 not only inhibited NF-κB/[[NLRP3]] inflammasome activation, but also attenuated neuronal damage and cognitive dysfunction in aged rats exposed to daily propofol treatment. Intermittent propofol treatment every 9 days may be safe for aged rats. However, propofol treatment once a day could impair the cognition of aged rats, partly through the activation of the NF-κB pathway and [[NLRP3]] inflammasome, which may be a potential targets for the treatment of cognitive impairment in elderly patients.

|keywords=* Aging
* Apoptosis
* NOD-like receptor protein 3 inflammasome
* Neuroinflammation
* Postoperative cognitive dysfunction
* Propofol
|full-text-url=https://sci-hub.do/10.1016/j.neulet.2020.135461
}}
{{medline-entry
|title=A Small Molecule Stabilizer of the MYC G4-Quadruplex Induces Endoplasmic Reticulum Stress, Senescence and Pyroptosis in Multiple Myeloma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33066043
|abstract=New approaches to target MYC include the stabilization of a guanine-rich, G-quadruplex (G4) tertiary DNA structure in the NHE III region of its promoter. Recent screening of a small molecule microarray platform identified a benzofuran, D089, that can stabilize the MYC G4 and inhibit its transcription. D089 induced both dose- and time-dependent multiple myeloma cell death mediated by endoplasmic reticulum induced stress. Unexpectedly, we uncovered two mechanisms of cell death: cellular senescence, as evidenced by increased levels of p16, p21 and γ-H2AX proteins and a caspase 3-independent mechanism consistent with pyroptosis. Cells treated with D089 exhibited high levels of the cleaved form of initiator caspase 8; but failed to show cleavage of executioner caspase 3, a classical apoptotic marker. Cotreatment with the a pan-caspase inhibitor Q-VD-OPh did not affect the cytotoxic effect of D089. In contrast, cleaved caspase 1, an inflammatory caspase downstream of caspases 8/9, was increased by D089 treatment. Cells treated with D089 in addition to either a caspase 1 inhibitor or siRNA-caspase 1 showed increased IC  values, indicating a contribution of cleaved caspase 1 to cell death. Downstream effects of caspase 1 activation after drug treatment included increases in IL1B, gasdermin D cleavage, and HMGB1 translocation from the nucleus to the cytoplasm. Drug treated cells underwent a 'ballooning' morphology characteristic of pyroptosis, rather than 'blebbing' typically associated with apoptosis. ASC specks colocalized with [[NLRP3]] in proximity ligation assays after drug treatment, indicating inflammasome activation and further confirming pyroptosis as a contributor to cell death. Thus, the small molecule MYC G4 stabilizer, D089, provides a new tool compound for studying pyroptosis. These studies suggest that inducing both tumor senescence and pyroptosis may have therapeutic potential for cancer treatment.

|keywords=* ASC and pannexin 1
* MYC G4-quadruplex stabilizer
* NLRP3
* caspase 1
* endoplasmic reticulum stress
* gasdermin D
* inflammasome
* pyroptosis
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650714
}}
{{medline-entry
|title=Interleukin-1β Drives Cellular Senescence of Rat Astrocytes Induced by Oligomerized Amyloid β Peptide and Oxidative Stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33013631
|abstract= Alzheimer's disease (AD) is the leading cause of dementia. With no reliable treatment that delays or reverses the progress of AD, effective medical drugs, and interventions for AD treatment are in urgent need. Clinical success for patients thus relies on gaining a clearer understanding of AD pathogenesis to feed the development of novel and potent therapy strategies. It is well-established that inflammatory processes are involved in the pathology of AD, and recent studies implicated senescence of glial cells as an important player in the progression of AD.   We did a preliminary screen in rat astrocytes for the five most abundant inflammatory factors in neuroinflammation, namely IL-1β, IL-6, IL-8, TGF-β1, and TNF-α, and found that IL-1β could efficiently induce cellular senescence. After that, SA-β-gal staining, immunofluorescence, ELISA, qRT-PCR, and immunoblotting were used to explore the underlying mechanism through which IL-1β mediates cellular senescence of rat astrocytes.   IL-1β-induced cellular senescence of rat astrocytes was accompanied by increased total and phosphorylated tau. Further experiments showed that both oligomerized amyloid β (Aβ) and H O  treatment can induce cellular senescence in rat astrocytes and increase the production and secretion of IL-1β from these cells. Subsequent mechanistic study revealed that activation of [[NLRP3]] mediates Aβ and H O -induced maturation and secretion of IL-1β.   Our results suggest that IL-1β mediates senescence in rat astrocytes induced by several common adverse stimuli in AD, implicating IL-1β and [[NLRP3]] as valuable diagnostic biomarkers and therapeutic targets for AD.

|keywords=* Alzheimer's disease
* amyloid β
* astrocyte
* interleukin-1β
* neuroinflammation
* senescence
* tau
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493674
}}
{{medline-entry
|title=Mechanisms of [[NLRP3]] priming in inflammaging and age related diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32883606
|abstract=The [[NLRP3]] inflammasome is a vital part of the innate immune response, whilst its aberrant activation drives the progression of a number of non-communicable diseases. Thus, [[NLRP3]] inflammasome assembly must be tightly controlled at several checkpoints. The priming step of [[NLRP3]] inflammasome activation is associated with increased [[NLRP3]] gene expression, as well as post-translational modifications that control [[NLRP3]] levels and licence the [[NLRP3]] protein for inflammasome assembly. Increasing life expectancy in modern society is accompanied by a growing percentage of elderly individuals. The process of aging is associated with chronic inflammation that drives and/or worsens a range of age related non-communicable conditions. The [[NLRP3]] inflammasome is known to contribute to pathological inflammation in many settings, but the mechanisms that prime [[NLRP3]] for activation throughout aging and related co-morbidities have not been extensively reviewed. Here we dissect the biochemical changes that occur during aging and the pathogenesis of age related diseases and analyse the mechanisms by which they prime the [[NLRP3]] inflammasome, thus exacerbating inflammation.

|keywords=* Aging
* Inflammaging
* Inflammasome
* NLRP3
* Priming
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571497
}}
{{medline-entry
|title=Lamivudine Inhibits [i]Alu[/i] RNA-induced Retinal Pigment Epithelium Degeneration via Anti-inflammatory and Anti-senescence Activities.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32855848
|abstract=Accumulation of the long noncoding [i]Alu[/i] element RNA activates the [[NLRP3]] inflammasome and leads to retinal pigment epithelium (RPE) cell death, a key event in the pathogenesis of geographic atrophy during late-stage age-related macular degeneration. Lamivudine (3TC) is a nucleoside analog reverse transcriptase inhibitor known to inhibit the [[NLRP3]] inflammasome. Currently, the intracellular response of the senescence marker p16  to the long noncoding RNA is being actively studied. The present study aimed to assess the efficacy of 3TC against [i]Alu[/i] RNA-induced RPE inflammation and senescence by evaluating changes in expression of the proinflammatory cytokines IL-18 and IL-1β and of p16  in RPE cells. Cultured human RPE cells and in vivo mouse RPE cells were transfected with an in vitro-transcribed [i]Alu[/i] RNA, and changes in IL-18, IL-1β, and p16  expression measured in the presences of 3TC or 3,4-(M)CA as a negative control. Treatment with 3TC markedly reduced [i]Alu[/i] RNA-induced expression of IL-18 and IL-1β in human and mouse RPE cells compared with the negative control. Further, [i]Alu[/i] RNA-induced p16  expression was suppressed by 3TC in human RPE cells. Our data suggest that [i]Alu[/i] RNA accumulation contributes to RPE cell senescence in age-related macular degeneration and that this pathogenic process can be suppressed by 3TC. Further verifying this study leads to potential targets for age-related macular degeneration therapy.

|keywords=* NLRP3 inflammasome
* age-related macular degeneration
* lamivudine
* retinal pigment epithelium
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422901
}}
{{medline-entry
|title=The [[NLRP3]] Inflammasome: Metabolic Regulation and Contribution to Inflammaging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32751530
|abstract=In response to inflammatory stimuli, immune cells reconfigure their metabolism and bioenergetics to generate energy and substrates for cell survival and to launch immune effector functions. As a critical component of the innate immune system, the nucleotide-binding and oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3 ([[NLRP3]]) inflammasome can be activated by various endogenous and exogenous danger signals. Activation of this cytosolic multiprotein complex triggers the release of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 and initiates pyroptosis, an inflammatory form of programmed cell death. The [[NLRP3]] inflammasome fuels both chronic and acute inflammatory conditions and is critical in the emergence of inflammaging. Recent advances have highlighted that various metabolic pathways converge as potent regulators of the [[NLRP3]] inflammasome. This review focuses on our current understanding of the metabolic regulation of the [[NLRP3]] inflammasome activation, and the contribution of the [[NLRP3]] inflammasome to inflammaging.

|keywords=* NLRP3 inflammasome
* aging
* inflammation
* metabolism
* mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463618
}}
{{medline-entry
|title=Aging aggravated liver ischemia and reperfusion injury by promoting STING-mediated [[NLRP3]] activation in macrophages.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32666684
|abstract=Although aggravated liver injury has been reported in aged livers post-ischemia and reperfusion (IR), the underlying mechanism of innate immune activation of aged macrophages is not well understood. Here, we investigated whether and how Stimulator of interferon genes (STING) signaling regulated macrophage proinflammatory activation and liver IR injury. Mice were subjected to hepatic IR in vivo. Macrophages isolated from IR-stressed livers and bone marrow-derived macrophages (BMDMs) from young and aged mice were used for in vitro studies. Enhanced nucleotide-binding domain and leucine-rich repeat containing protein 3 ([[NLRP3]]) activation was found in both livers and macrophages of aged mice post-IR. [[NLRP3]] knockdown in macrophages inhibited intrahepatic inflammation and liver injury in both young and aged mice. Interestingly, enhanced activation of the STING/ TANK-binding kinase 1 (TBK1) signaling pathway was observed in aged macrophages post-IR and mitochondria DNA (mtDNA) stimulation. STING suppression blocked over-activation of [[NLRP3]] signaling and excessive secretion of proinflammatory cytokines/chemokines in the mtDNA-stimulated BMDMs from aged mice. More importantly, STING knockdown in macrophages abrogated the detrimental role of aging in aggravating liver IR injury and intrahepatic inflammation. Finally, peripheral blood from the recipients undergoing liver transplantation was collected and analyzed. The results showed that the elderly recipients had much higher levels of TNF-α, IL-6, IL-1β, and IL-18 post-transplantation, indicating increased [[NLRP3]] activation in lR-stressed livers of elderly recipients. In summary, our study demonstrated that the STING-[[NLRP3]] axis was critical for the proinflammatory response of aged macrophages and would be a novel therapeutic target to reduce IR injury in elderly patients.

|keywords=* aging
* and reperfusion injury
* leucine-rich repeat containing protein 3
* liver ischemia
* macrophage immune response
* nucleotide-binding domain
* stimulator of interferon genes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431827
}}
{{medline-entry
|title=Targeting [[NLRP3]] Inflammasome Reduces Age-Related Experimental Alveolar Bone Loss.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32531176
|abstract=The cause of chronic inflammatory periodontitis, which leads to the destruction of periodontal ligament and alveolar bone, is multifactorial. An increasing number of studies have shown the clinical significance of [[NLRP3]]-mediated low-grade inflammation in degenerative disorders, but its causal linkage to age-related periodontitis has not yet been elucidated. In this study, we investigated the involvement of the [[NLRP3]] inflammasome and the therapeutic potential of [[NLRP3]] inhibition in age-related alveolar bone loss by using in vivo and in vitro models. The poor quality of alveolar bones in aged mice was correlated with caspase-1 activation by macrophages and elevated levels of IL-1β, which are mainly regulated by the [[NLRP3]] inflammasome, in periodontal ligament and serum, respectively. Aged mice lacking [i]Nlrp3[/i] showed better bone mass than age-matched wild-type mice via a way that affects bone resorption rather than bone formation. In line with this finding, treatment with MCC950, a potent inhibitor of the [[NLRP3]] inflammasome, significantly suppressed alveolar bone loss with reduced caspase-1 activation in aged mice but not in young mice. In addition, our in vitro studies showed that the addition of IL-1β encourages RANKL-induced osteoclastogenesis from bone marrow-derived macrophages and that treatment with MCC950 significantly suppresses osteoclastic differentiation directly, irrelevant to the inhibition of IL-1β production. Our results suggest that the [[NLRP3]] inflammasome is a critical mediator in age-related alveolar bone loss and that targeting the [[NLRP3]] inflammasome could be a novel option for controlling periodontal degenerative changes with age.

|keywords=* aging
* inflammasomes
* inflammation
* macrophages
* osteoclasts
* periodontitis
|full-text-url=https://sci-hub.do/10.1177/0022034520933533
}}
{{medline-entry
|title=Korean Red Ginseng Suppresses the Expression of Oxidative Stress Response and [[NLRP3]] Inflammasome Genes in Aged C57BL/6 Mouse Ovaries.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32331214
|abstract=Female infertility and subfertility have been increasing in prevalence worldwide. One contributing factor is ovarian function, which is highly age-dependent. Korean red ginseng is widely used as an herbal medicine and has many beneficial properties. We aimed to determine the effect of the Korean red ginseng saponin fraction (KRGSF) on ovarian function in female C57BL/6 mice. Ovaries were isolated from 6- and 12-month-old female mice and treated with KRGSF, and then RNA was extracted and microarray analysis was performed. The expression of key genes was subsequently verified using quantitative RT-PCR. Aging markedly increased the expression of genes encoding oxidative stress factors and [[NLRP3]] inflammasome components, but the expression of these genes was significantly reduced by KRGSF treatment. Thus, the reduction in ovarian health with age is associated with greater oxidative stress response and inflammation, but KRGSF treatment may limit these age-related changes.

|keywords=* Korean ginseng extract
* NLRP3 inflammasome
* aging
* ovary
* oxidative stress response
* subfertility
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231237
}}
{{medline-entry
|title=Cepharanthine promotes the effect of dexmedetomidine on the deposition of β-amyloid in the old age of the senile dementia rat model by regulating inflammasome expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32337948
|abstract=The present study evaluates the synergistic effect of cepharanthine (CP) with dexmedetomidine (DEM) on the deposition of β-amyloid (Aβ) in the brain tissue of senile dementia (SD) rats. Senile dementia was induced by injecting D-gal intraperitoneally 60 mg/kg/day for six weeks and Aβ1-42 (5 µl) intracranially. The effect of cepharanthine and dexmedetomidine was estimated by determining the cognitive function and neurological function score. Moreover, mediators of inflammation, parameters of oxidative stress and reactive oxygen species (ROS) were determined in the brain tissue of senile dementia rats. Mitochondrial membrane permeability and deposition of Aβ1-42 was estimated in senile dementia rats. Western blot assay and reverse transcription polymerase chain reaction (RT-PCR) was performed for the expression of proteins and genes in the brain tissue of senile dementia rats. Data of the study reveal that cepharanthine alone and in combination with dexmedetomidine improves the neurological function score and cognitive function in SD rats. Moreover, parameters of oxidative stress, inflammatory mediators and production of ROS in CP, DEM and CP + DEM treated groups were compared to the SD group of rats. Treatment with CP, DEM and CP + DEM ameliorates the altered expression of [[NLRP3]] pathway and deposition of Aβ in the brain tissue of SD rats. In conclusion, data reveal that cepharanthine ameliorates the deposition of Aβ and [[NLRP3]] pathway in SD rats. Moreover, cepharanthine treatment with dexmedetomidine shows the synergistic effect against the aged SD rat model.
|mesh-terms=* Aging
* Animals
* Benzylisoquinolines
* Brain
* Dexmedetomidine
* Inflammasomes
* Inflammation
* Male
* Mitochondria
* Oxidative Stress
* Rats, Sprague-Dawley
* Reactive Oxygen Species
|keywords=*  dementia
*  dexmedetomidine
*  inflammasomes
*  β-amyloid
* cepharanthine
|full-text-url=https://sci-hub.do/10.5114/fn.2019.89855
}}
{{medline-entry
|title=Ginsenoside Rg1 ameliorates glomerular fibrosis during kidney aging by inhibiting NOX4 and [[NLRP3]] inflammasome activation in SAMP8 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32114413
|abstract=Aging is closely related to the progress of renal fibrosis, which eventually results in renal dysfunction. Ginsenoside Rg1 (Rg1) has been reported to have an extensive anti-aging effect. However, the role and mechanism of Rg1 in aging-related renal fibrosis remain unclear. The present study aimed to evaluate the protective effect and mechanism of Rg1 in renal fibrosis during kidney aging in a model of SAMP8 mice. Taking SAMR1 mice as the control group, SAMP8 mice were administered Apocynin (50 mg/kg), Tempol (50 mg/kg), or Rg1 (5, 10 mg/kg) intragastrically for 9 weeks as treatment groups. The results showed that the elevated levels of blood urea nitrogen, serum creatinine and senescence-associated β-galactosidase (β-Gal) were markedly decreased, the glomerular mesangial proliferation was significantly alleviated and the increased levels of collagen IV and TGF-β1 were significantly downregulated by Rg1 in SAMP8 mice. In addition, the generation of ROS and the expression of NADHP oxidase 4 (NOX4) in the renal cortex were significantly reduced by Rg1 treatment. The expression levels of [[NLRP3]] inflammasome-related proteins and the inflammation-related cytokine IL-1β were also inhibited by Rg1 treatment in the SAMP8 mice. These results suggested that Rg1 could delay kidney aging and inhibit aging-related glomerular fibrosis by reducing NOX4-derived ROS generation and downregulating [[NLRP3]] inflammasome expression.

|keywords=* Ginsenoside Rg1
* Kidney aging
* NADPH oxidase 4 (NOX4)
* NLRP3 inflammasome
* Renal fibrosis
|full-text-url=https://sci-hub.do/10.1016/j.intimp.2020.106339
}}
{{medline-entry
|title=Blockade of the [[NLRP3]] inflammasome improves metabolic health and lifespan in obese mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31975052
|abstract=Aging is the major risk factor for many metabolic chronic diseases. Several metabolic pathways suffer a progressive impairment during aging including body composition and insulin resistance which are associated to autophagy dysfunction and increased inflammation. Many of these alterations are aggravated by non-healthy lifestyle such as obesity and hypercaloric diet which have been shown to accelerate aging. Here, we show that the deleterious effect of hypercaloric diets is reverted by the [[NLRP3]] inflammasome inhibition. [[NLRP3]] deficiency extends mean lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by metabolic health benefits including reduced liver steatosis and cardiac damage, improved glucose and lipid metabolism, and improved protein expression profiles of SIRT-1, mTOR, autophagic flux, and apoptosis. These findings suggest that the suppression of [[NLRP3]] prevented many age-associated changes in metabolism impaired by the effect of hypercaloric diets.

|keywords=* Aging
* Autophagy
* High-fat diet
* Longevity
* NLRP3 inflammasome
* Obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206474
}}
{{medline-entry
|title=Autophagy and [[NLRP3]] inflammasome crosstalk in neuroinflammation in aged bovine brains.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31903559
|abstract=[[NLRP3]] inflammasome is a multiprotein complex that can sense several stimuli such as autophagy dysregulation and increased reactive oxygen species production stimulating inflammation by priming the maturation of proinflammatory cytokines interleukin-1β and interleukin-18 in their active form. In the aging brain, these cytokines can mediate the innate immunity response priming microglial activation. Here, we describe the results of immunohistochemical and molecular analysis carried out on bovine brains. Our results support the hypothesis that the age-related impairment in cellular housekeeping mechanisms and the increased oxidative stress can trigger the inflammatory danger sensor [[NLRP3]]. Moreover, according to the recent scientific literature, we demonstrate the presence of an age-related proinflammatory environment in aged brains consisting in an upregulation of interleukin-1β, an increased microglial activation and increased [[NLRP3]] expression. Finally, we suggest that bovine may potentially be a pivotal animal model for brain aging studies.

|keywords=* NLRP3 inflammasome
* aging
* autophagy
* bovine
* immunosenescence
* neuroinflammation
|full-text-url=https://sci-hub.do/10.1002/jcp.29426
}}
{{medline-entry
|title=[[NLRP3]] Inflammasome Inhibition by MCC950 in Aged Mice Improves Health via Enhanced Autophagy and PPARα Activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31603987
|abstract=The [[NLRP3]] inflammasome has emerged as an important regulator of metabolic disorders and age-related diseases in [[NLRP3]]-deficient mice. In this article, we determine whether, in old mice C57BL6J, the [[NLRP3]] inflammasome inhibitor MCC950 is able to attenuate age-related metabolic syndrome to providing health benefits. We report that MCC950 attenuates metabolic and hepatic dysfunction in aged mice. In addition, MCC950 inhibited the Pi3K/AKT/mTOR pathway, enhanced autophagy, and activated peroxisome proliferator-activated receptor-α in vivo and in vitro. The data suggest that MCC950 mediates the protective effects by the mammalian target of rapamycin inhibition, thus activating autophagy and peroxisome proliferator-activated receptor-α. In conclusion, pharmacological inhibition of [[NLRP3]] in aged mice has a significant impact on health. Thus, [[NLRP3]] may be a therapeutic target of human age-related metabolic syndrome.

|keywords=* Aging
* Autophagy
* MCC950
* NLRP3 inflammasome
* PPARα
|full-text-url=https://sci-hub.do/10.1093/gerona/glz239
}}
{{medline-entry
|title=[[NLRP3]] inflammasome suppression improves longevity and prevents cardiac aging in male mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31625260
|abstract=While [[NLRP3]]-inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation. Here, we investigated the molecular mechanisms through which [[NLRP3]] inhibition may attenuate cardiac aging. Ablation of [[NLRP3]]-inflammasome protected mice from age-related increased insulin sensitivity, reduced IGF-1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the age-dependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old [[NLRP3]] KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt-mediated NAD  levels with increased SIRT1 protein expression. These findings suggest that suppression of [[NLRP3]] prevented many age-associated changes in the heart, preserved cardiac function of aged mice and increased lifespan.

|keywords=* NLRP3-inflammasome
* autophagy
* cardiac aging
* longevity
* morbidity
* mortality
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974709
}}
{{medline-entry
|title=Reduced NRF2 expression suppresses endothelial progenitor cell function and induces senescence during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31494646
|abstract=Aging is associated with an increased risk of cardiovascular disease. Numerical and functional declines in endothelial progenitor cells (EPCs) limit their capacity for endothelial repair and promote the development of cardiovascular disease. We explored the effects of nuclear factor (erythroid-derived 2)-like 2 (NRF2) on EPC activity during aging. Both [i]in vitro[/i] and [i]in vivo[/i], the biological functioning of EPCs decreased with aging. The expression of NRF2 and its target genes ([i]Ho-1[/i], [i]Nqo-1[/i] and [i]Trx[/i]) also declined with aging, while Nod-like receptor protein 3 ([[NLRP3]]) expression increased. Aging was associated with oxidative stress, as evidenced by increased reactive oxygen species and malondialdehyde levels and reduced superoxide dismutase activity. [i]Nrf2[/i] silencing impaired the functioning of EPCs and induced oxidative stress in EPCs from young mice. On the other hand, NRF2 activation in EPCs from aged mice protected these cells against oxidative stress, ameliorated their biological dysfunction and downregulated the [[NLRP3]] inflammasome. These findings suggest NRF2 can prevent the functional damage of EPCs and downregulate the [[NLRP3]] inflammasome through NF-κB signaling.
|mesh-terms=* Aging
* Animals
* Cellular Senescence
* Endothelial Progenitor Cells
* Mice
* NF-E2-Related Factor 2
* NF-kappa B
* NLR Family, Pyrin Domain-Containing 3 Protein
* Neovascularization, Physiologic
* Oxidative Stress
|keywords=* NLRP3 inflammasome
* NRF2
* aging
* endothelial progenitor cells
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756903
}}
{{medline-entry
|title=Effect of Aging on Taurine Transporter (TauT) Expression in the Mouse Brain Cortex.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31468381
|abstract=Taurine content in an older brain is decreased compared to a younger brain and is associated with cognitive deficits. It is not yet known whether the decrease in taurine content is associated with decreased expression of taurine inflow mediating transporters during the aging process. In this study, we investigated whether aging affects taurine transporter and glycine transporter 1 expression in the brain cortex of the mouse. Taurine and glycine transporter expression was compared in the brain cortex of C57BL/6 mice at different ages (2, 12, and 24 months) and to age-matched [[NLRP3]] inflammasome knockout mice. In wild type mice, taurine transporter (TauT) expression in the brain cortex of 12- or 24-month-old mice did not significantly differ from TauT expression in 2-month-old mice. Moreover, TauT expression in the brain cortex of 12- or 24-month-old mice did not significantly differ from age-matched [[NLRP3]] KO mice. This result indirectly suggests that TauT expression may be not affected by aging or age-induced inflammation. In addition, glycine transporter expression was similar to the TauT expression pattern. In conclusion, aging and age-related inflammation might not significantly affect taurine and glycine transporter expression in aged mice. Thus, the decrease of taurine content in an older brain, which is associated with cognitive deficits, may not be significantly related to altered taurine and glycine transporter expression.
|mesh-terms=* Aging
* Animals
* Brain
* Membrane Glycoproteins
* Membrane Transport Proteins
* Mice
* Mice, Inbred C57BL
* Taurine
|keywords=* Age-related diseases
* Glycine Transporter (GLYT)
* NLRP3
* Taurine Transporter (TauT)
|full-text-url=https://sci-hub.do/10.1007/978-981-13-8023-5_1
}}
==SCD==

{{medline-entry
|title=Cognitive training and brain stimulation in prodromal Alzheimer's disease (AD-Stim)-study protocol for a double-blind randomized controlled phase IIb (monocenter) trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33160420
|abstract=Given the growing older population worldwide, and the associated increase in age-related diseases, such as Alzheimer's disease (AD), investigating non-invasive methods to ameliorate or even prevent cognitive decline in prodromal AD is highly relevant. Previous studies suggest transcranial direct current stimulation (tDCS) to be an effective method to boost cognitive performance, especially when applied in combination with cognitive training in healthy older adults. So far, no studies combining tDCS concurrent with an intense multi-session cognitive training in prodromal AD populations have been conducted. The AD-Stim trial is a monocentric, randomized, double-blind, placebo-controlled study, including a 3-week tDCS-assisted cognitive training with anodal tDCS over left DLPFC (target intervention), compared to cognitive training plus sham (control intervention). The cognitive training encompasses a letter updating task and a three-stage Markov decision-making task. Forty-six participants with subjective cognitive decline ([[SCD]]) or mild cognitive impairment (MCI) will be randomized block-wise to either target or control intervention group and participate in nine interventional visits with additional pre- and post-intervention assessments. Performance in the letter updating task after training and anodal tDCS compared to sham stimulation will be analyzed as primary outcome. Further, performance on the second training task and transfer tasks will be investigated. Two follow-up visits (at 1 and 7 months post-training) will be performed to assess possible maintenance effects. Structural and functional magnetic resonance imaging (MRI) will be applied before the intervention and at the 7-month follow-up to identify possible neural predictors for successful intervention. With this trial, we aim to provide evidence for tDCS-induced improvements of multi-session cognitive training in participants with [[SCD]] and MCI. An improved understanding of tDCS effects on cognitive training performance and neural predictors may help to develop novel approaches to counteract cognitive decline in participants with prodromal AD. ClinicalTrials.gov , NCT04265378 . Registered on 07 February 2020. Retrospectively registered. Protocol version: Based on BB 004/18 version 1.2 (May 17, 2019). University Medicine Greifswald.

|keywords=* Aging
* Decision-making
* Mild cognitive impairment
* Subjective cognitive decline
* Transcranial direct current stimulation
* Transfer
* Working memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648990
}}
{{medline-entry
|title=Blood Pressure in Different Dementia Disorders, Mild Cognitive Impairment, and Subjective Cognitive Decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33110409
|abstract=The aim of the study was to investigate whether blood pressure (BP) differed among people with different dementia diagnoses, mild cognitive impairment, and subjective cognitive decline and whether BP differences were observed across age and sex. Our study population comprised clinical data from 6,236 patients (53.5% women) aged 45-97 years ([i]Mean[/i] = 73.9, [i]SD[/i] = 9.6) referred to dementia assessment in 42 outpatient clinics across Norway during 2009-2019. Patients with the following diagnoses were included: Subjective cognitive decline ([[SCD]]), Mild cognitive impairment (MCI), dementia due to Alzheimer's disease (AD), Vascular dementia (VaD), mixed AD and VaD, and dementia in Parkinson's disease/Lewy body disease (PDD/LBD). For all diagnostic groups, SBP increased with age until about 80 years, after which it trended downward, whereas DBP declined after 60 years of age for all diagnostic groups. Patients aged 65 years and younger with [[SCD]] had lower SBP compared to AD patients at the same age, but SBP increased rapidly with increasing age, resulting in a substantially higher SBP at 80 + years compared with all other diagnostic groups. No other differences in SBP or diastolic blood pressure (DBP) were found among patients with the different dementia diagnosis. Neither SBP nor DBP differed between MCI and AD groups. An interaction between age and gender was found for SBP at younger ages, as women started out with a lower pressure than men did but ended up with higher SBP. Among 80+ patients, blood pressure did not differ as a function of the various dementia disorders. The SBP for the [[SCD]] patients of various age groups differed from all other diagnostic groups, indicating either that internal regulation of BP in older people is a risk factor for dementia or that brain damage causing dementia or MCI may led to changes in blood pressure. Brain aging seems to influence SBP differently in men and women.

|keywords=* Alzheimer’s disease
* aging
* blood pressure
* mild cognitive impairment
* subjective cognitive decline
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488384
}}
{{medline-entry
|title=Known-Groups and Convergent Validity of the Telephone Rey Auditory Verbal Learning Test total Learning Scores for Distinguishing Between Older Adults With Amnestic Cognitive Impairment and Subjective Cognitive Decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33067996
|abstract=To examine known-groups validity of a telephone administration of the total learning scores of the Rey Auditory Verbal Learning Test (RAVLT) in discriminating between people with subjective cognitive decline ([[SCD]]) and amnestic mild cognitive impairment (aMCI) and convergent validity of the telephone-RAVLT. In total, 83 older adults (age = 71.4 ± 7.0) with [[SCD]] or aMCI completed the RAVLT learning trials over the telephone and the Hopkins Verbal Learning Test (HVLT) in-person. Telephone-RAVLT total recall significantly correlated with HVLT total recall (r = .49, p < .001). Significant between group differences were found (effect size = 0.94). This study provides support for known-groups and convergent validity of the telephone-RAVLT.

|keywords=* aging
* cognitive impairment
* neuropsychological assessment
|full-text-url=https://sci-hub.do/10.1093/arclin/acaa085
}}
{{medline-entry
|title=Subjective cognitive decline as a predictor of future cognitive decline: a systematic review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32973979
|abstract=Over 44 million people suffer from dementia around the world. Researchers estimated that there will be 48.1 million people with dementia by 2020 and 90.3 million by 2040. In addition to dementia, mild cognitive impairment (MCI) and subjective cognitive decline ([[SCD]]) relate to cognitive impairment. It has been established that MCI precedes dementia, however the significance of [[SCD]] is still unclear. Recent studies suggest that [[SCD]] could be a risk factor for objective cognitive impairment. [[SCD]] is defined as а self-estimated decline in cognitive capacity in comparison to an individual's previous level of functioning, which cannot be determined by neuropsychological tests. To perform a systematic review of prospective longitudinal cohort studies that assessed the risk of MCI and dementia among people with [[SCD]]. A search was carried out for all available peer-reviewed articles in English related to [[SCD]] in PubMed and PsychINFO databases from database initiation through January 2020. The keywords used for the search were 'subjective cognitive (or memory) impairment (or decline or complaints)'. Three authors separately determined the inclusion or exclusion of all articles retrieved for full-text evaluation. The chance of progression to dementia in the [[SCD]] group was 2.17 (95% confidence interval [95%CI] 1.53‒3.07; p<0.05) compared to normal aging. Furthermore, the [[SCD]] group was 2.15 times more likely to progress to MCI than the group without [[SCD]] (95%CI 1.39‒3.30; p=0.005). [[SCD]] might precede cognitive impairment, however, more detailed longitudinal studies should be conducted.

|keywords=* Alzheimer disease.
* aging
* cognition
* cognitive dysfunction
* dementia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500809
}}
{{medline-entry
|title=Geriatric assessment for older adults with sickle cell disease: protocol for a prospective cohort pilot study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32974042
|abstract=The life expectancy for people with sickle cell disease ([[SCD]]) has improved tremendously over the last 50 years. This population experiences hemolysis and vaso-occlusion in multiple organs that lead to complications such as cardiopulmonary disease, strokes, and avascular necrosis. These complications can limit mobility and aerobic endurance, similar to limitations that often occur in geriatric populations. These sickle-cell and age-related events lead to frequent hospitalization, which further increases the risk of functional decline. We have few tools to measure functional decline in people with [[SCD]]. The purpose of this paper is to describe a protocol to evaluate the feasibility of sickle cell disease geriatric assessment ([[SCD]]-GA). We will enroll 40 adults with [[SCD]] (20 age 18-49.99 years and 20 age ≥ 50 years) in a prospective cohort study to assess the feasibility of [[SCD]]-GA. The [[SCD]]-GA includes validated measures from the oncology geriatric assessment enriched with additional physical and cognitive measures. The [[SCD]]-GA will be performed at the first study visit, at 10 to 20 days after hospitalization, and at 12 months (exit visit). With input from a multidisciplinary team of sickle cell specialists, geriatricians, and experts in physical function and physical activity, we selected assessments across 7 domains: functional status (11 measures), comorbid medical conditions (1 measure), psychological state (1 measure), social support (2 measures), weight status (2 measures), cognition (3 measures), and medications (1 measure). We will measure the proportion completing the assessment with feasibility as the primary outcome. Secondary outcomes include the proportion consenting and completing all study visits, duration of the assessment, acceptability, and adverse events. We present the protocol and rationale for selection of the measures included in [[SCD]]-GA. We also outline the methods to determine feasibility and subsequently to optimize the [[SCD]]-GA in preparation for a larger multicenter validation study of the [[SCD]]-GA.

|keywords=* Aging
* Functional assessment
* Geriatric assessment
* Geriatrics
* Older adults
* Sickle cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495855
}}
{{medline-entry
|title=Prevalence and psychosocial correlates of subjectively perceived decline in five cognitive domains: Results from a population-based cohort study in Germany.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32510658
|abstract=Subjective cognitive decline ([[SCD]]) was frequently investigated for memory in healthy aging or in relation to diseases like dementia. It was found to be related to sociodemographic and psychological variables as well as cognitive abilities. The prevalence of [[SCD]] in other cognitive domains and their relation to these variables is largely unknown to date. The present study aimed to fill this gap. A total of 807 subjects (18-85 years of age, M = 57.8 years, female: 43%) completed the Juelich Questionnaire on Subjective Cognitive Decline, to investigate [[SCD]] in memory, attention, language, motor, and executive functions. Logistic regression analyses were used to estimate association of depressive symptomatology, emotionality, and general cognitive performance as well as age, gender, and educational attainment with domain-specific [[SCD]]. The highest prevalence rate was obtained for the memory domain (65.9%), followed by the attention (54.6%), motor (52.9%), executive (39.7%), and language domain (31.5%). Of the psychosocial factors, only age, depressive symptomatology and emotionality were consistently and strongly associated with domain-specific [[SCD]] prevalence. [[SCD]] is prevalent not only in the memory domain, but also in other major cognitive domains. Our results also suggest that the suspicion from previous research, that subjective memory decline might be more strongly associated with depressive symptomatology and emotionality than with actual decline of cognitive performance, might also apply to the attention, motor, executive, and language domain. Further investigations using neuropsychological testing for specific cognitive functions and employing longitudinal designs are required for substantiating this suspicion.

|keywords=* Germany
* cognitive aging
* cognitive complaints
* cohort study
* prevalence
* subjective cognitive decline
|full-text-url=https://sci-hub.do/10.1002/gps.5359
}}
{{medline-entry
|title=SC411 treatment can enhance survival in a mouse model of sickle cell disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32447175
|abstract=Sickle cell disease ([[SCD]]) is one of the most common inherited blood disorder among African Americans affecting 70,000-100,000 individuals in the United States. It is characterized by abnormal hemoglobin (HbS) which develops into severe hemolytic anemia and vaso-occlusive crisis. Therefore, patients with [[SCD]] suffer from a chronic state of inflammation, which is responsible for multiple organ damage, ischemic attacks, and premature death. Another major hallmark of [[SCD]] patients is the abnormally low levels of omega-3 fatty acids, especially docosahexaenoic acid (DHA) in their red blood cell membranes. Treatment with DHA can reduce red blood cell adhesion and enhance cerebral blood flow, thus, our main goal is to investigate the effect of SC411, which is a novel, highly purified DHA ethyl ester formulation with a proprietary delivery platform in [[SCD]]. Utilizing a transgenic mouse model of [[SCD]] (HbSS-Townes) and recurrent hypoxic challenges (10%O , 0.5% CO  and balance N  for 3 h) to mimic ischemic-like conditions, our data suggest that SC411 can elevate blood DHA and eicosapentaenoic acid (EPA) levels after 8 weeks of treatment. SC411 can also decrease arachidonic acid (AA) and sickling of red blood cells. In addition, SC411-treated [[SCD]] mice showed presented with cerebral blood flow, alleviated neuroinflammation, and revived working memory which ultimately enhanced overall survival. In summary, this study suggests that treatment with SC411 improves cellular and functional outcomes in [[SCD]] mice. This finding may provide novel therapeutic opportunities in the treatment against ischemic injury elicited by [[SCD]].

|keywords=* Aging
* Cerebral blood flow
* Docosahexaenoic acid
* Neuroinflammation
* Sickle cell disease
* Working memory
|full-text-url=https://sci-hub.do/10.1016/j.plefa.2020.102110
}}
{{medline-entry
|title=DNA fragmentation of human spermatozoa: Simple assessment of single- and double-strand DNA breaks and their respective dynamic behavioral response.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32416007
|abstract=Procedures to detect sperm DNA fragmentation (SDF), like the sperm chromatin dispersion ([[SCD]]) test, determine the "global" SDF without discriminating between spermatozoa with single-strand DNA breaks only (SDF-SSBs) and those containing double-strand DNA breaks (SDF-DSBs). (a) To validate a test to distinguish human spermatozoa with massive DSBs (DSB-[[SCD]] assay), (b) to study the baseline SDF-SSBs and SDF-DSBs, and (c) to assess their dynamics in vitro. (a) SDF-DSBs were determined by visualization of diffused DNA fragments from spermatozoa lysed under non-denaturing conditions. This was validated by in vitro incubation with DNase I and the comet assay. (b) Baseline SDF-DSBs and SDF-SSBs were determined in ejaculates from 95 males. (c) Their dynamic appearance was studied in samples untreated or exposed to hyperthermia, acidic pH, nitric oxide released by sodium nitroprusside (SNP), and the metabolic energy inhibitors 2-deoxy-D-glucose and antimycin A. (a) DNase I and comet assay experiments confirmed that the assay successfully determined SDF-DSBs. (b) The higher the SDF of the semen sample, the higher the frequency of SSBs, whereas DSBs behaved independently. Abnormal samples showed higher SDF than normozoospermic, the difference being only significant for SDF-SSBs. (c) During the first hours of incubation, the linear rate of increase in SDF-SSBs was 3.7 X higher than that of SDF-DSBs. All hazardous agents accelerated the SDF rate when compared to untreated spermatozoa, primarily being associated with SDF-SSBs. SNP treatment was the most damaging, rapidly inducing spermatozoa with SSBs which progressively evolved to DSBs. Remarkably, this phenomenon was also evidenced after acute SNP exposure, revealing cryptic sperm damage. The DSBs-[[SCD]] is an easy complement for SDF assessment. The dynamic study of SSBs and DSBs may improve the evaluation of sperm quality in clinical settings, particularly "unmasking" the presence of non-specific cryptic sperm damage that might otherwise go undetected.

|keywords=* DNA longevity
* sperm DNA damage
* sperm DNA dynamics
* sperm DNA fragmentation
* sperm chromatin dispersion test
|full-text-url=https://sci-hub.do/10.1111/andr.12819
}}
{{medline-entry
|title=Psychometric Cognitive Decline Precedes the Advent of Subjective Cognitive Decline in the Evolution of Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32388509
|abstract=We have described the clinical stages of the brain aging and Alzheimer's disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology "mild cognitive impairment" (MCI) for the first pre-dementia stage and "subjective cognitive decline" ([[SCD]]) for the pre-MCI stage. We now report the characteristics of a pre-[[SCD]] condition eventuating in likely AD. The aim of this study was to characterize a pre-[[SCD]] condition eventuating in AD. Sixty healthy persons with "no cognitive decline" (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as "decliner," if [[SCD]] or worse, or "nondecliner" if NCD. After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). This is ostensibly the first study to link psychometric cognitive decline to the subsequent [[SCD]] stage of eventual AD.

|keywords=* Alzheimer’s disease
* Brain aging
* Cognitive decline
* Cognitive testing
* Longitudinal studies
* Psychometric cognition
|full-text-url=https://sci-hub.do/10.1159/000507286
}}
{{medline-entry
|title=Serum alkaline phosphatase is elevated and inversely correlated with cognitive functions in subjective cognitive decline: results from the ReGAl 2.0 project.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32363431
|abstract=Alkaline phosphatase has been found on neuronal membranes and plasma alkaline phosphatase (ALP) activity increases during brain injury and cerebrovascular diseases, suggesting that its levels may reflect the neuronal loss. It is known that ALP is higher in subjects affected by Alzheimer's dementia and inversely correlated with cognitive functions. No study has investigated the relationship between ALP and cognitive functions in old-age subject with pre-clinical cognitive impairment. This is a cross-sectional study with data gathered from the ReGAl 2.0 project (Rete Geriatrica Alzheimer-Geriatric Network on Alzheimer's disease), a large Italian multicentric clinical-based study. A cohort of 209 old-age subjects healthy controls (HC), Subjective cognitive decline ([[SCD]]), and Mild Cognitive Impairment (MCI) was included in the study. Cognitive performances were assessed with a large neuropsychological battery. The same day, serum alkaline phosphatase activity was measured in all subjects. We found that the [[SCD]] group had significantly higher ALP levels as compared with HC (p = 0.001). Among all neuropsychological tests, in all population ALP levels negatively correlated with scores at attentional matrices (r =  - 0.243, p = 0.002), Digit Span Forward (r =  - 0.241, p = 0.003) and Letter Fluency Test (r =  - 0.196, p = 0.044). Attentional Matrices (r =  - 0.208, p = 0.014) and Letter Fluency Test (r =  - 0.229, p = 0.019) remained significantly correlated with ALP even after controlling for gender. In the [[SCD]] group, only the Attentional Matrices significantly and negatively correlated with ALP (r =  - 0.344 p = 0.035), while no significant correlations were found in HC or MCI. Results indicate that serum alkaline phosphatase activity is increased in [[SCD]] and inversely correlates with cognitive functions. Further studies are needed to investigate the role of ALP in the progression to AD.

|keywords=* Aging
* Biochemistry
* Cognition
* Dementia
* Geriatric medicine
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01572-6
}}
{{medline-entry
|title=Changes in Activity Participation Among Older Adults With Subjective Cognitive Decline or Objective Cognitive Deficits.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32010049
|abstract=Participation in daily activities is crucial for healthy aging. There is limited research on participation of older adults with subjective cognitive decline ([[SCD]]), defined as the experience of cognitive deficits with no evidence of objective cognitive deficits. Therefore, this study examined perceived changes in participation in this population, and compared it to perceived changes reported by individuals with objective cognitive deficits. The study aimed to: (1) examine the reported changes in activity participation of older with [[SCD]]; (2) investigate differences in the reported changes in participation between individuals with [[SCD]] and those with mild or severe objective cognitive deficits; (3) examine the relationship between activity participation, subjective memory, and objective cognitive status; and (4) explore whether subjective memory explains additional variance in activity participation after accounting for age and objective cognitive deficits. Participants were 115 older adults (60+), divided into three groups based on their Montreal Cognitive Assessment (MoCA) scores: (1) [[SCD]] (MoCA≥26; [i]n[/i] = 66); (2) mild objective cognitive deficits (MoCA = 20-25; [i]n[/i] = 34); and (3) severe objective cognitive deficits (MoCA ≤ 19; [i]n[/i] = 15). The Activity Card Sort was used to measure participation in instrumental activities of daily living, social, and leisure activities. The Multifactorial Memory Questionnaire-Ability subscale was used to assess subjective memory. We found that individuals with [[SCD]], mild cognitive deficits and severe cognitive deficits reported participation withdrawal to a level of 80, 70, and 58% of their past participation, respectively. A significant between group difference was found on participation [χ (2) = 16.44, [i]p[/i] < 0.01], with the [[SCD]] group reporting higher participation than the other two groups. Participation significantly correlated with both cognitive status ([i]r[/i] = 0.40, [i]p[/i] < 0.01) and subjective memory ([i]r[/i] = 0.45, [i]p[/i] < 0.05). A regression analysis revealed that subjective memory contributed significantly to the explained variance in participation, beyond that accounted for by objective cognitive deficits and age. Our findings demonstrate the important role of subjective memory problems in activity participation of older adults, even in the absence of objective cognitive deficits.

|keywords=* activity participation
* aging
* daily functioning
* metamemory
* subjective cognitive decline
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974583
}}
{{medline-entry
|title=Age, gender and drug therapy influences on Tpeak-tend interval and on electrical risk score.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32023499
|abstract=Electrical risk score (ERS) has been proposed as easy, inexpensive test to stratify of sudden cardiac death ([[SCD]]) risk in subjects with normal left ventricular function. Potentially, aging, gender and drugs can influence ERS affecting two on six electrical markers, particularly, those based on the repolarization. Aim of this study was to establish aging, gender and drug therapy possible influences on ERS and mortality in elderly patients. 237 consecutive, low [[SCD]] risk-outpatients with asymptomatic and treated cardiovascular risk factors were analyzed. Six simple ECG markers composed ERS: heart rate (>75 bpm); left ventricular hypertrophy (Sokolow-Lyon criteria); delayed QRS transition zone (≥V4), frontal QRS-T angle (>90°), long QT ; long T peak to T end interval (T ). We obtained ERS in 237 outpatients, grouped according age (<40 ys, ≥40 to <60 ys and ≥60 ys), gender and drug therapy with or without possible influence on the repolarization phase. Two-hundred-thirty-seven patients were grouped respectively in the following age classes: <40 years old; ≥40 to <60 years old and ≥60 years old. ERS (p < 0.05), QT  (p < 0.001), T  (p < 0.001) were higher in older subjects independently from gender, drug therapy and cardiovascular comorbidity. After two years we reported a 7.3% of mortality in the older groups; age (deceased versus survivors: 80 ± 4 versus 73 ± 7 years, p < 0.05) and T  (deceased versus survivors: 117 ± 15 versus 93 ± 21 ms, p < 0.05) were significantly lower in survivors, multivariable logistic regression analysis selected only the T  as significant risk factor for total mortality (odd ratio 1.06, 95% CI: 1.01-1.12, p < 0.05). Aging was associated to the ERS and repolarization phase derangement. T  should be considered a marker of total mortality rather than [[SCD]] in the over sixty years old patients.

|keywords=* Aging
* Electrical risk score
* Gender
* Mortality
* QTc
* Repolarization phase
* T peak-tend interval
|full-text-url=https://sci-hub.do/10.1016/j.jelectrocard.2020.01.009
}}
{{medline-entry
|title=Comorbid Chronic Conditions Among Older Adults with Subjective Cognitive Decline, United States, 2015-2017.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31915725
|abstract=Subjective cognitive decline ([[SCD]]), the self-reported experience of worsening or more frequent confusion or memory loss, may be associated with the development or worsening of chronic conditions or complicating their self-management. The objectives of this study were to (i) establish the prevalence of chronic conditions and multiple chronic conditions among adults with [[SCD]], and (ii) compare the prevalence of chronic conditions among people with and without [[SCD]] and [[SCD]]-related functional limitations. Data were analyzed from the Cognitive Decline module of the Behavioral Risk Factor Surveillance System administered in 49 states, DC, and Puerto Rico during 2015-2017. Analyses included 220,221 respondents aged 45 years or older who answered the [[SCD]] screening question and reported their chronic conditions. Weighted estimates were calculated and chi-square tests were used for comparisons. Persons with a history of stroke, heart disease, and chronic obstructive pulmonary disorder had significantly higher prevalence of [[SCD]] compared to those without. The prevalence of having at least one chronic condition was higher among adults with [[SCD]] compared to adults without [[SCD]] in each age group (45-64 years: 77.4% vs 47.1%, [i]p[/i] < .001; ≥65 years: 86.3% vs 73.5%, [i]p[/i] < .001). Among those with [[SCD]], the prevalence of an [[SCD]]-related functional limitation was higher among those with at least one chronic condition compared to those with none (45-64 years: 63.3% vs 42.4%, [i]p[/i] < .001; ≥65 years: 40.0% vs 25.1%, [i]p[/i] < .001). Only half of adults with [[SCD]] and a chronic condition had discussed their [[SCD]] with a health care professional. [[SCD]] and chronic conditions commonly co-occur. Having a chronic condition was associated with greater [[SCD]]-related functional limitations. [[SCD]] might complicate the management of chronic conditions, and patients and providers should be aware of increased risk for cognitive decline in the presence of chronic diseases.

|keywords=* Aging
* Chronic disease
* Cognitive dysfunction
* Dementia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938465
}}
{{medline-entry
|title=Resting State BOLD Variability Is Linked to White Matter Vascular Burden in Healthy Aging but Not in Older Adults With Subjective Cognitive Decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31920589
|abstract=: Alzheimer's disease (AD) is the leading cause of dementia. A lack of curative treatments and a rapidly aging global population have amplified the need for early biomarkers of the disease process. Recent advances suggest that subjective cognitive decline ([[SCD]]) may be one of the earliest symptomatic markers of the AD cascade. Previous studies have identified changes in variability in the blood-oxygen-level-dependent (BOLD) signal in patients with AD, with a possible association between BOLD variability and cerebrovascular factors in the aging brain. The objective of the current study was to determine whether changes in BOLD variability can be identified in individuals with [[SCD]], and whether this signal may be associated with markers of cerebrovascular integrity in [[SCD]] and older adults without memory complaints.  : Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database from 19 participants with [[SCD]] and 19 similarly-aged controls. For each participant, a map of BOLD signal variability (SD ) was computed as the standard deviation of the BOLD time-series at each voxel. Group comparisons were performed to examine differences in resting-state SD  in [[SCD]] vs. healthy controls. Relationships were then examined between participant SD  maps and neuroimaging markers of white matter vascular infarcts in each group separately.  : Between-group comparisons showed no significant differences in whole-brain SD  in individuals with [[SCD]] and controls. In the healthy aging group, higher white matter hyperintensity (WMH) burden was associated with greater SD  in right temporal regions ([i]p[/i] < 0.05), and lower scores on a measure of global executive functioning. These associations were not identified in individuals with [[SCD]].  : The current study underscores previous evidence for a relationship between SD  and white matter vascular infarcts in the healthy aging brain. The findings also provide evidence for a dissociable relationship between healthy aging and [[SCD]], such that in healthy controls, increased WMH is associated with declines in executive function that is not observed in older adults who present with memory complaints. Further multimodal work is needed to better understand the contributions of vascular pathology to the BOLD signal, and its potential relationship with pathological aging.

|keywords=* Alzheimer’s disease
* aging
* biomarkers
* cerebrovascular health
* signal variability
* subjective cognitive decline
* white matter
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936515
}}
{{medline-entry
|title=Estimated Life Expectancy and Income of Patients With Sickle Cell Disease Compared With Those Without Sickle Cell Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31730182
|abstract=Individuals with sickle cell disease ([[SCD]]) have reduced life expectancy; however, there are limited data available on lifetime income in patients with [[SCD]]. To estimate life expectancy, quality-adjusted life expectancy, and income differences between a US cohort of patients with [[SCD]] and an age-, sex-, and race/ethnicity-matched cohort without [[SCD]]. Cohort simulation modeling was used to (1) build a prevalent [[SCD]] cohort and a matched non-[[SCD]] cohort, (2) identify utility weights for quality-adjusted life expectancy, (3) calculate average expected annual personal income, and (4) model life expectancy, quality-adjusted life expectancy, and lifetime incomes for [[SCD]] and matched non-[[SCD]] cohorts. Data sources included the Centers for Disease Control and Prevention, National Newborn Screening Information System, and published literature. The target population was individuals with [[SCD]], the time horizon was lifetime, and the perspective was societal. Model data were collected from November 29, 2017, to March 21, 2018, and the analysis was performed from April 28 to December 3, 2018. Life expectancy, quality-adjusted life expectancy, and projected lifetime income. The estimated prevalent population for the [[SCD]] cohort was 87 328 (95% uncertainty interval, 79 344-101 398); 998 were male and 952 were female. Projected life expectancy for the [[SCD]] cohort was 54 years vs 76 years for the matched non-[[SCD]] cohort; quality-adjusted life expectancy was 33 years vs 67 years, respectively. Projected lifetime income was $1 227 000 for an individual with [[SCD]] and $1 922 000 for a matched individual without [[SCD]], reflecting a lost income of $695 000 owing to the 22-year difference in life expectancy. One study limitation is that the higher estimates of life expectancy yielded conservative estimates of lost life-years and income. The analysis only considered the value of lost personal income owing to premature mortality and did not consider direct medical costs or other societal costs associated with excess morbidity (eg, lost workdays for disability, time spent in the hospital). The model was most sensitive to changes in income levels and mortality rates. In this simulated cohort modeling study, [[SCD]] had societal consequences beyond medical costs in terms of reduced life expectancy, quality-adjusted life expectancy, and lifetime earnings. These results underscore the need for disease-modifying therapies to improve the underlying morbidity and mortality associated with [[SCD]].
|mesh-terms=* Adolescent
* Adult
* Aged
* Anemia, Sickle Cell
* Child
* Child, Preschool
* Cohort Studies
* Female
* Forecasting
* Humans
* Income
* Infant
* Life Expectancy
* Male
* Middle Aged
* Models, Statistical
* Quality-Adjusted Life Years
* United States
* Young Adult

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902797
}}
{{medline-entry
|title=Does Empirically Derived Classification of Individuals with Subjective Cognitive Complaints Predict Dementia?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31703450
|abstract=(1) Background: Early identification of mild cognitive impairment (MCI) in people reporting subjective cognitive complaints (SCC) and the study of progression of cognitive decline are important issues in dementia research. This paper examines whether empirically derived procedures predict progression from MCI to dementia. (2) Methods: At baseline, 192 participants with SCC were diagnosed according to clinical criteria as cognitively unimpaired (70), single-domain amnestic MCI (65), multiple-domain amnestic MCI (33) and multiple-domain non-amnestic MCI (24). A two-stage hierarchical cluster analysis was performed for empirical classification. Categorical regression analysis was then used to assess the predictive value of the clusters obtained. Participants were re-assessed after 36 months. (3) Results: Participants were grouped into four empirically derived clusters: Cluster 1, similar to multiple-domain amnestic MCI; Cluster 2, characterized by subjective cognitive decline ([[SCD]]) but with low scores in language and working memory; Cluster 3, with specific deterioration in episodic memory, similar to single-domain amnestic MCI; and Cluster 4, with [[SCD]] but with scores above the mean in all domains. The majority of participants who progressed to dementia were included in Cluster 1. (4) Conclusions: Cluster analysis differentiated between MCI and [[SCD]] in a sample of people with SCC and empirical criteria were more closely associated with progression to dementia than standard criteria.

|keywords=* Compostela aging study
* cluster analysis
* cognitive aging
* dementia
* mild cognitive impairment
* screening and diagnosis
* subjective cognitive complaints
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6895967
}}
{{medline-entry
|title=Spatiotemporal Oscillatory Patterns During Working Memory Maintenance in Mild Cognitive Impairment and Subjective Cognitive Decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31522594
|abstract=Working memory (WM) is a crucial cognitive process and its disruption is among the earliest symptoms of Alzheimer's disease. While alterations of the neuronal processes underlying WM have been evidenced in mild cognitive impairment (MCI), scarce literature is available in subjective cognitive decline ([[SCD]]). We used magnetoencephalography during a WM task performed by MCI  , [[SCD]]   and healthy elders   to examine group differences during the maintenance period (0-4000 ms). Data were analyzed using time-frequency analysis and significant oscillatory differences were localized at the source level. Our results indicated significant differences between groups, mainly during the early maintenance (250-1250 ms) in the theta, alpha and beta bands and in the late maintenance (2750-3750 ms) in the theta band. MCI showed lower local synchronization in fronto-temporal cortical regions in the early theta-alpha window relative to controls   and [[SCD]]  , and in the late theta window relative to controls   and [[SCD]]  . Early theta-alpha power was significantly correlated with memory scores   and late theta power was correlated with task performance   and functional activity scores  . In the early beta window, MCI showed reduced power in temporo-posterior regions relative to controls   and [[SCD]]  . Our results may suggest that these alterations would reflect that memory-related networks are damaged.
|mesh-terms=* Aged
* Aging
* Brain Waves
* Cerebral Cortex
* Cognitive Dysfunction
* Cortical Synchronization
* Female
* Humans
* Magnetoencephalography
* Male
* Memory, Short-Term
* Task Performance and Analysis
|keywords=* Alzheimer’s disease (AD)
* Induced oscillatory activity
* magnetoencephalography (MEG)
* mild cognitive impairment (MCI)
* subjective cognitive decline (SCD)
* working memory (WM)
|full-text-url=https://sci-hub.do/10.1142/S0129065719500199
}}
{{medline-entry
|title=Microstructural Correlates and Laterality Effect of Prospective Memory in Non-Demented Adults with Memory Complaints.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31466053
|abstract=An increasing number of studies suggest the importance of prospective memory (ProM) due to its functional relevance and sensitivity to neuropathology. However, its relevant neural substrates have not been sufficiently explored. The present study aimed to investigate the relationship between structural connectivity and both objective and subjective ProM measures in a group of non-demented people with subjective memory complaints, and to examine the potential of ProM measures to detect the difference between subjective cognitive decline ([[SCD]]) and mild cognitive impairment (MCI) in the pre-dementia stage. Thirty-sevennon-dementedparticipants aged above 50 years were recruited from an outpatient Neurology Clinic; 13 of them fulfilled the criteria of MCI and 24 of [[SCD]]. All subjects received comprehensive neuropsychological tests, including the adapted version of the Cambridge Prospective Memory Test, as well as the Taiwan version of the Prospective and Retrospective Memory Questionnaire. The diffusion tensor imaging technique with tract-based spatial statistics was applied to measure cerebral microstructural changes. Time-based ProM performance was significantly correlated with microstructural integrity of the right superior longitudinal fasciculus, while the event-based one was associated with that of the left superior longitudinal fasciculus and the genu of the corpus callosum among all participants and in the [[SCD]] group. After controlling for age, the correlation remained significant between event-based ProM performance and the left superior longitudinal fasciculus among all participants and in the MCI group, as well as between event-based ProM performance and the genu among all participants. Although self-reported ProM failures in real life was associated with fiber disruption of the left superior longitudinal fasciculus among all participants and within the MCI group, an inverse relationship was also observed with that of the corpus callosum in the [[SCD]] group even after controlling for age. As compared to the [[SCD]] group, people with MCI performed significantly worse on time-based ProM tasks and reported more ProM failures in daily life. ProM was related to the integrity of interhemispheric commissural fibers and association fibers that connect the frontal lobe with posterior regions, with a task-specific laterality effect. Time-based ProM tasks and self-reported ProM questionnaire may be sensitive to early pathological cognitive deterioration, while the concomitant aging process and individual awareness level may respectively confound the results of evaluation.
|mesh-terms=* Aged
* Aged, 80 and over
* Corpus Callosum
* Diffusion Tensor Imaging
* Female
* Frontal Lobe
* Functional Laterality
* Humans
* Magnetic Resonance Imaging
* Male
* Memory Disorders
* Middle Aged
* Nerve Fibers
* Neuropsychological Tests
* Retrospective Studies
* Surveys and Questionnaires
* Taiwan
|keywords=* Aging
* Alzheimer’s disease
* Cognitive complaints
* Diffusion tensor imaging
* Lateralization
* Prospective memory
* Tract-based spatial statistics
|full-text-url=https://sci-hub.do/10.1159/000501366
}}
==BDNF==

{{medline-entry
|title=Influence of [i][[BDNF]][/i] Genetic Polymorphisms in the Pathophysiology of Aging-related Diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33269104
|abstract=For the first time in history, most of the population has a life expectancy equal or greater than 60 years. By the year 2050, it is expected that the world population in that age range will reach 2000 million, an increase of 900 million with respect to 2015, which poses new challenges for health systems. In this way, it is relevant to analyze the most common diseases associated with the aging process, namely Alzheimer´s disease, Parkinson Disease and Type II Diabetes, some of which may have a common genetic component that can be detected before manifesting, in order to delay their progress. Genetic inheritance and epigenetics are factors that could be linked in the development of these pathologies. Some researchers indicate that the [i][[BDNF]][/i] gene is a common factor of these diseases, and apparently some of its polymorphisms favor the progression of them. In this regard, alterations in the level of [[BDNF]] expression and secretion, due to polymorphisms, could be linked to the development and/or progression of neurodegenerative and metabolic disorders. In this review we will deepen on the different polymorphisms in the [i][[BDNF]][/i] gene and their possible association with age-related pathologies, to open the possibilities of potential therapeutic targets.

|keywords=* Aging
* BDNF gene
* aging-related diseases
* polymorphism
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673859
}}
{{medline-entry
|title=Moderators of the Impact of (Poly)Phenols Interventions on Psychomotor Functions and [[BDNF]]: Insights from Subgroup Analysis and Meta-Regression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32961777
|abstract=Recent anti-aging interventions have shown contradictory impacts of (poly)phenols regarding the prevention of cognitive decline and maintenance of brain function. These discrepancies have been linked to between-study differences in supplementation protocols. This subgroup analysis and meta-regression aimed to (i) examine differential effects of moderator variables related to participant characteristics and supplementation protocols and (ii) identify practical recommendations to design effective (poly)phenol supplementation protocols for future anti-aging interventions. Multiple electronic databases (Web of Science; PubMed) searched for relevant intervention published from inception to July 2019. Using the PICOS criteria, a total of 4303 records were screened. Only high-quality studies ([i]n[/i] = 15) were included in the final analyses. Random-effects meta-analysis was used, and we calculated standard differences in means (SDM), effect size (ES), and 95% confidence intervals (CI) for two sufficiently comparable items (i.e., psychomotor function and brain-derived neurotrophic factor ([[BDNF]])). When significant heterogeneity was computed ([i]I[/i]  > 50%), a subgroup and meta-regression analysis were performed to examine the moderation effects of participant characteristics and supplementation protocols. The reviewed studies support the beneficial effect of (poly)phenols-rich supplementation on psychomotor functions (ES = -0.677, [i]p[/i] = 0.001) and brain plasticity (ES = 1.168, [i]p[/i] = 0.028). Subgroup analysis revealed higher beneficial impacts of (poly)phenols (i) in younger populations compared to older (SDM = -0.89 vs. -0.47 for psychomotor performance, and 2.41 vs. 0.07 for [[BDNF]], respectively), (ii) following an acute compared to chronic supplementation (SDM = -1.02 vs. -0.43 for psychomotor performance), and (iii) using a phenolic compound with medium compared to low bioavailability rates (SDM = -0.76 vs. -0.68 for psychomotor performance and 3.57 vs. 0.07 for DBNF, respectively). Meta-regressions revealed greater improvement in [[BDNF]] levels with lower percentages of female participants (Q = 40.15, df = 6, [i]p[/i] < 0.001) and a skewed scatter plot toward a greater impact using higher (poly)phenols doses. This review suggests that age group, gender, the used phenolic compounds, their human bioavailability rate, and the supplementation dose as the primary moderator variables relating to the beneficial effects of (poly)phenol consumption on cognitive and brain function in humans. Therefore, it seems more advantageous to start anti-aging (poly)phenol interventions in adults earlier in life using medium (≈500 mg) to high doses (≈1000 mg) of phenolic compounds, with at least medium bioavailability rate (≥9%).

|keywords=* aging
* antioxidant
* brain functions
* brain plasticity
* cognition
* psychomotor functions
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551086
}}
{{medline-entry
|title=Astroglia-Derived [[BDNF]] and MSK-1 Mediate Experience- and Diet-Dependent Synaptic Plasticity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32708382
|abstract=Experience- and diet-dependent regulation of synaptic plasticity can underlie beneficial effects of active lifestyle on the aging brain. Our previous results demonstrate a key role for brain-derived neurotrophic factor ([[BDNF]]) and MSK1 kinase in experience-related homeostatic synaptic scaling. Astroglia has been recently shown to release [[BDNF]] via a calcium-dependent mechanism. To elucidate a role for astroglia-derived [[BDNF]] in homeostatic synaptic plasticity in the aging brain, we explored the experience- and diet-related alterations of synaptic transmission and plasticity in transgenic mice with impairment of the [[BDNF]]/MSK1 pathway (MSK1 kinase dead knock-in mice, MSK1 KD) and impairment of glial exocytosis (dnSNARE mice). We found that prolonged tonic activation of astrocytes caused [[BDNF]]-dependent increase in the efficacy of excitatory synapses accompanied by enlargement of synaptic boutons. We also observed that exposure to environmental enrichment (EE) and caloric restriction (CR) enhanced the Ca  signalling in cortical astrocytes and strongly up-regulated the excitatory and down-regulated inhibitory synaptic currents in old wild-type mice, thus counterbalancing the impact of ageing on astroglial and synaptic signalling. The EE- and CR-induced up-scaling of excitatory synaptic transmission in neocortex was accompanied by the enhancement of long-term synaptic potentiation. Importantly, effects of EE and CR on synaptic transmission and plasticity was significantly reduced in the MSK1 KD and dnSNARE mice. Combined, our results suggest that astroglial release of [[BDNF]] is important for the homeostatic regulation of cortical synapses and beneficial effects of EE and CR on synaptic transmission and plasticity in aging brain.

|keywords=* AMPA receptors
* Arc/Arg3.1
* GABA receptors
* TrkB receptors
* aging
* calcium signalling
* dendritic spines
* diet
* enriched environment
* glia-neuron interactions
* ion conductance microscopy
* synaptic scaling
* synaptic strength
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407492
}}
{{medline-entry
|title=[[BDNF]] reverses aging-related microglial activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32664974
|abstract=Excessive microglial activation is implicated in the pathogenesis of various age-related neurodegenerative diseases. In addition to neurons, brain-derived neurotrophic factor ([[BDNF]]) and its receptor TrkB are also expressed in microglia. However, the direct effect of [[BDNF]] on age-related microglial activation has rarely been investigated. We began to address this question by examining the effect of age on microglial activation and the [[BDNF]]-TrkB pathway in mice. By using pharmacological and genetic approaches, the roles of [[BDNF]] and downstream signaling pathways in microglial activation and related neurotoxicity were examined in microglial cell line and primary microglial cells. We showed that microglial activation was evident in the brains of aged mice. The levels of [[BDNF]] and TrkB in microglia decreased with age and negatively correlated with their activation statuses in mice during aging. Interestingly, aging-related microglial activation could be reversed by chronic, subcutaneous perfusion of [[BDNF]]. Peripheral lipopolysaccharide (LPS) injection-induced microglial activation could be reduced by local supplement of [[BDNF]], while shTrkB induced local microglial activation in naïve mice. In cultured microglial cell line and primary microglial cells, [[BDNF]] inhibited LPS-induced microglial activation, including morphological changes, activations of p38, JNK, and NF-кB, and productions of proinflammatory cytokines. These effects were blocked by shTrkB. [[BDNF]] induced activations of ErK and CREB which then competed with LPS-induced activation of NF-кB for binding to a common coactivator, CREB-binding protein. Decreasing [[BDNF]]-TrkB signaling during aging favors microglial activation, while upregulation [[BDNF]] signaling inhibits microglial activation via the TrkB-Erk-CREB pathway.

|keywords=* Aging
* BDNF
* CREB
* Microglial activation
* NF-кB
* TrkB
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362451
}}
{{medline-entry
|title=High Supervised Resistance Training in Elderly Women: The Role of Supervision Ratio.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32509119
|abstract=The objective of this study was to compare the effects of very high supervision (VHS-RT) versus high supervision (HS-RT) ratio resistance training (RT) on irisin, brain-derived neurotrophic factor (BNDF), muscle strength, functional capacity, and body composition in elderly women. Participants performed daily undulating periodized RT over 16 weeks with two different supervision ratios: VHS-RT at 1:2 (supervisor/subject) or HS-RT at 1:5. Serum was used to analyze brain derived neurotropic factor ([[BDNF]]) and irisin by enzyme-linked immunosorbent assay (ELISA). Body composition was evaluated by dual-energy X-ray absorptiometry, while functional capacity was evaluated using the Six-minute walk test, and Timed Up and Go (TUG). One- repetition maximum (1RM) was determined for bench press and 45° leg press exercises. For both groups, no differences between baseline and post-training were identified for irisin and lean mass ([i]p[/i] > 0.05). Both groups improved bench press 1-RM, 45° leg press 1-RM, and TUG ([i]p[/i] < 0.05). The VHS-RT group displayed higher effect sizes for 1-RM tests. Moreover, only VHS-RT group reduced body fat and body fat percentage ([i]p[/i] < 0.05). In contrast, the HS-RT increased [[BDNF]] ([i]p[/i] < 0.01). In this sense, RT enhances muscle strength and functional capacity in elderly women independent of supervision ratio. A greater supervision ratio during RT may induce more improvements in muscle strength, and body composition than lower supervision ratio during RT.

|keywords=* Aging
* exercise
* functional capacity
* muscle strength
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241618
}}
{{medline-entry
|title=Metformin regulates astrocyte reactivity in Parkinson's disease and normal aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32497590
|abstract=Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, leading to motor symptoms. Despite the remarkable improvements in the management of PD in recent decades, many patients remain significantly disabled. Metformin is a primary medication for the management of type 2 diabetes. We previously showed that co-treatment with metformin and 3,4-dihydroxyphenyl-l-alanine (l-DOPA) prevented the development of l-DOPA-induced dyskinesia in a 6-hydroxydopamine (6-OHDA)-lesioned animal model of PD. However, effects of metformin on PD- and aging-induced genes in reactive astrocytes remain unknown. In this study, we assessed the effect of metformin on motor function, neuroprotection, and reactive astrocytes in the 6-OHDA-induced PD animal model. In addition, the effects of metformin on the genes expressed by specific types of astrocytes were analyzed in PD model and aged mice. Here, we showed that metformin treatment effectively improves the motor symptoms in the 6-OHDA-induced PD mouse model, whereas metformin had no effect on tyrosine hydroxylase-positive neurons. The activation of AMPK and [[BDNF]] signaling pathways was induced by metformin treatment on the 6-OHDA-lesioned side of the striatum. Metformin treatment caused astrocytes to alter reactive genes in a PD animal model. Moreover, aging-induced genes in reactive astrocytes were effectively regulated or suppressed by metformin treatment. Taken together, these results suggest that metformin should be evaluated for the treatment of Parkinson's disease and related neurologic disorders characterized by astrocyte activation.

|keywords=* Aging
* Dorsal striatum
* Metformin
* Parkinson's disease
* Reactive astrocyte
|full-text-url=https://sci-hub.do/10.1016/j.neuropharm.2020.108173
}}
{{medline-entry
|title=Aging-Induced Brain-Derived Neurotrophic Factor in Adipocyte Progenitors Contributes to Adipose Tissue Dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32489703
|abstract=Aging-related adipose tissue dysfunction contributes to the progression of chronic metabolic diseases. We investigated the role of age-dependent expression of a neurotrophin, brain-derived neurotrophic factor ([[BDNF]]) in adipose tissue. Pro-[[BDNF]] expression was elevated in epididymal white adipose tissue (eWAT) with advanced age, which was associated with the reduction in sympathetic innervation. Interestingly, [[BDNF]] expression was enriched in PDGFRα  adipocyte progenitors isolated from eWAT, with age-dependent increase in expression. In vitro pro-[[BDNF]] treatment caused apoptosis in adipocytes differentiated from C3H10T1/2 cells, and siRNA knockdown of sortilin mitigated these effects. Tamoxifen-inducible PDGFRα  cell-specific deletion of [[BDNF]] ([[BDNF]]  KO) reduced pro-[[BDNF]] expression in eWAT, prevented age-associated declines in sympathetic innervation and mitochondrial content in eWAT, and improved insulin sensitivity. Moreover, [[BDNF]]  KO mice showed reduced expression of aging-induced inflammation and senescence markers in eWAT. Collectively, these results identified the upregulation of pro-[[BDNF]] expression in adipocyte progenitors as a feature of visceral white adipose tissue aging and suggested that inhibition of [[BDNF]] expression in adipocyte progenitors is potentially beneficial to prevent aging-related adipose tissue dysfunction.

|keywords=* BDNF
* adipocyte progenitors
* adipose tissue
* aging
* sympathetic innervation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220283
}}
{{medline-entry
|title=The Role of [[BDNF]] on Aging-Modulation Markers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32397504
|abstract=An important link between brain aging and a class of growth/survival factors called neurotrophins has recently been demonstrated. In particular, brain-derived neurotrophic factor ([[BDNF]]) plays a fundamental role during age-related synaptic loss, preventing cerebral atrophy and cognitive decline. The aim of the present study was to investigate whether the use of low dose [[BDNF]] sequentially kinetic activated (SKA) was able to counteract some mechanisms underlying the degeneration and aging of nervous tissue by increasing endogenous protection mechanisms. Both in vitro and in vivo experiments were performed to assess the ability of [[BDNF]] SKA to protect and regenerate survival-related molecular pathways, studying intestinal absorption in vitro and brain function in vivo. Our pioneering results show that [[BDNF]] SKA is able to induce the endogenous production of [[BDNF]], using its receptor TrkB and influencing the apolipoprotein E expression. Moreover, [[BDNF]] SKA exerted effects on β-Amyloid and Sirtuin 1 proteins, confirming the hypothesis of a fine endogenous regulatory effect exerted by [[BDNF]] SKA in maintaining the health of both neurons and astrocytes. For this reason, a change in [[BDNF]] turnover is considered as a positive factor against brain aging.

|keywords=* BBB
* astrocytes
* brain aging
* in vivo model
* low dose BDNF
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287884
}}
{{medline-entry
|title=Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32268299
|abstract=The natural polyamine spermidine and spermine have been reported to ameliorate aging and aging-induced dementia. However, the mechanism is still confused. An aging model, the senescence accelerated mouse-8 (SAMP8), was used in this study. Novel object recognition and the open field test results showed that oral administration of spermidine, spermine and rapamycin increased discrimination index, modified number, inner squares distance and times. Spermidine and spermine increased the activity of SOD, and decreased the level of MDA in the aging brain. Spermidine and spermine phosphorylate AMPK and regulate autophagy proteins (LC3, Beclin 1 and p62). Spermidine and spermine balanced mitochondrial and maintain energy for neuron, with the regulation of MFN1, MFN2, DRP1, COX IV and ATP. In addition, western blot results (Bcl-2, Bax and Caspase-3, NLRP3, IL-18, IL-1β) showed that spermidine and spermine prevented apoptosis and inflammation, and elevate the expression of neurotrophic factors, including NGF, PSD95and PSD93 and [[BDNF]] in neurons of SAMP8 mice. These results indicated that the effect of spermidine and spermine on anti-aging is related with improving autophagy and mitochondrial function.

|keywords=* aging
* autophagy
* mitochondrial dysfunction
* polyamine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185103
}}
{{medline-entry
|title=Microglia senescence occurs in both substantia nigra and ventral tegmental area.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32275335
|abstract=During aging humans lose midbrain dopamine neurons, but not all dopamine regions exhibit vulnerability to neurodegeneration. Microglia maintain tissue homeostasis and neuronal support, but microglia become senescent and likely lose some of their functional abilities. Since aging is the greatest risk factor for Parkinson's disease, we hypothesized that aging-related changes in microglia and neurons occur in the vulnerable substantia nigra pars compacta (SNc) but not the ventral tegmental area (VTA). We conducted stereological analyses to enumerate microglia and dopaminergic neurons in the SNc and VTA of 1-, 6-, 9-, 18-, and 24-month-old C57BL/J6 mice using sections double-stained with tyrosine hydroxylase (TH) and Iba1. Both brain regions show an increase in microglia with aging, whereas numbers of TH+ cells show no significant change after 9 months of age in SNc and 6 months in VTA. Morphometric analyses reveal reduced microglial complexity and projection area while cell body size increases with aging. Contact sites between microglia and dopaminergic neurons in both regions increase with aging, suggesting increased microglial support/surveillance of dopamine neurons. To assess neurotrophin expression in dopaminergic neurons, [[BDNF]] and TH mRNA were quantified. Results show that the ratio of [[BDNF]] to TH decreases in the SNc, but not the VTA. Gait analysis indicates subtle, aging-dependent changes in gait indices. In conclusion, increases in microglial cell number, ratio of microglia to dopamine neurons, and contact sites suggest that innate biological mechanisms compensate for the aging-dependent decline in microglia morphological complexity (senescence) to ensure continued neuronal support in the SNc and VTA.

|keywords=* Parkinson's disease
* aging-dependent neurodegeneration
* dopamine neurons
* microglia complexity
* stereological analyses
* tyrosine hydroxylase; microglia senescence
|full-text-url=https://sci-hub.do/10.1002/glia.23834
}}
{{medline-entry
|title=Towards an understanding of the physical activity-[[BDNF]]-cognition triumvirate: A review of associations and dosage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32171785
|abstract=Physical activity has received substantial research attention due to its beneficial impact on cognition in ageing, particularly via the action of brain-derived neurotrophic factor ([[BDNF]]). It is well established that physical activity can elevate circulating levels of [[BDNF]], and that [[BDNF]] has neurotrophic, neuroprotective and cognitively beneficial properties. Yet, practical implementation of this knowledge is limited by a lack of clarity on context and dose-effect. Against a shifting backdrop of gradually diminishing physical and cognitive capacity in normal ageing, the type, intensity, and duration of physical activity required to elicit elevations in [[BDNF]], and more importantly, the magnitude of [[BDNF]] elevation required for detectable neuroprotection remains poorly characterised. The purpose of this review is to provide an overview of the association between physical activity, [[BDNF]], and cognition, with a focus on clarifying the magnitude of these effects in the context of normative ageing. We discuss the implications of the available evidence for the design of physical activity interventions intended to promote healthy cognitive ageing.
|mesh-terms=* Aging
* Brain-Derived Neurotrophic Factor
* Cognition
* Exercise
* Healthy Aging
* Humans
|keywords=* Ageing
* BDNF
* Brain
* Physical activity
|full-text-url=https://sci-hub.do/10.1016/j.arr.2020.101044
}}
{{medline-entry
|title=Impact of [[BDNF]] and sex on maintaining intact memory function in early midlife.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31948671
|abstract=Sex steroid hormones and neurotrophic factors, such as brain-derived neurotrophic factor ([[BDNF]]), play a significant neuroprotective role in memory circuitry aging. Here, we present findings characterizing the neuroprotective effects of [[BDNF]] on memory performance, as a function of sex and reproductive status in women. Participants (N = 191; mean age = 50.03 ± 2.10) underwent clinical and cognitive testing, fMRI scanning, and hormonal assessments of menopausal staging. Memory performance was assessed with the 6-Trial Selective Reminding Test and the Face-Name Associative Memory Exam. Participants also performed a working memory (WM) N-back task during fMRI scanning. Results revealed significant interactions between menopausal status and [[BDNF]] levels. Only in postmenopausal women, lower plasma [[BDNF]] levels were associated with significantly worse memory performance and altered function in the WM circuitry. [[BDNF]] had no significant impact on memory performance or WM function in pre/perimenopausal women or men. These results suggest that in postmenopausal women, [[BDNF]] is associated with memory performance and memory circuitry function, thus providing evidence of potential sex-dependent factors of risk and resilience for early intervention.
|mesh-terms=* Brain
* Brain-Derived Neurotrophic Factor
* Cognition
* Female
* Humans
* Magnetic Resonance Imaging
* Male
* Memory
* Memory, Short-Term
* Menopause
* Middle Aged
* Neuroprotective Agents
* Neuropsychological Tests
* Reproduction
* Sex Characteristics
|keywords=* Aging
* BDNF
* Hormones
* Memory
* Menopause
* Sex differences
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2019.12.014
}}
{{medline-entry
|title=Testosterone replacement causes dose-dependent improvements in spatial memory among aged male rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31901624
|abstract=Testosterone has been shown to have dose-dependent effects on spatial memory in males, but the effects of aging upon this relationship remain unclear. Additionally, the mechanism by which testosterone regulates memory is unknown, but may involve changes in brain-derived neurotrophic factor ([[BDNF]]) within specific brain regions. We tested the effects of age and testosterone on spatial memory among male rats using two spatial memory tasks: an object-location memory task (OLMT) and the radial-arm maze (RAM). Castration had minimal effect on performance on the RAM, but young rats (2 months) performed significantly fewer working memory errors than aged rats (20 months), and aged rats performed significantly fewer reference memory errors. Both age and castration impaired performance on the OLMT, with only the young rats with intact gonads successfully performing the task. Subsequent experiments involved daily injections of either drug vehicle or one of four doses of testosterone propionate (0.125, 0.250, 0.500, and 1.00 mg/rat) given to castrated aged males. On the RAM, a low physiological dose (0.125 mg) and high doses (0.500-1.000 mg) of testosterone improved working memory, while an intermediate dose (0.250 mg) did not. On the OLMT, only the 0.250 mg T group showed a significant increase in exploration ratios from the exposure trials to the testing trials, indicating that this group remembered the position of the objects. Brain tissue (prefrontal cortex, hippocampus, and striatum) was collected from all subjects to assay [[BDNF]]. We found no evidence that testosterone influenced [[BDNF]], indicating that it is unlikely that testosterone regulates spatial memory through changes in [[BDNF]] levels.

|keywords=* Aging
* BDNF
* Object location memory
* Radial arm maze
* Spatial memory
* Testosterone
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080566
}}
{{medline-entry
|title=The effects of aerobic exercise intensity on memory in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31665610
|abstract=Aerobic exercise may enhance memory in older adults. However, the optimal intensity and underlying mechanism are unclear. This community-based study examined the effect of aerobic exercise intensity on memory and general cognitive abilities. Brain-derived neurotrophic factor ([[BDNF]]) was examined as a potential mechanism. Sixty-four sedentary older adults participated in 1 of 3 groups: ([i]i[/i]) high-intensity interval training (HIIT); ([i]ii[/i]) moderate continuous training (MCT); or ([i]iii[/i]) stretching control (CON). Prior to and following the intervention, high-interference memory was assessed using a Mnemonic Similarity task and executive functions were assessed using Go Nogo and Flanker tasks. HIIT led to the greatest memory performance compared with MCT and CON ([i]F[/i]  = 6.04, [i]p[/i] = 0.004) and greater improvements in memory correlated with greater increases in fitness ([i]r [/i] (46) = 0.27, [i]p[/i] = 0.03). Exercise intensity seemed to matter less for executive functioning, as positive trends were observed for both HIIT and MCT. No significant differences in [[BDNF]] were found between groups. Overall, these results suggest that aerobic exercise may enhance memory in older adults, with the potential for higher intensity exercise to yield the greatest benefit. While our findings suggest that [[BDNF]] does not regulate these adaptations, the mechanisms remain to be determined.   High-intensity interval training results in the greatest memory performance in inactive older adults compared with moderate continuous training or stretching. Improvement in fitness correlates with improvement in memory performance.

|keywords=* BDNF
* activité physique
* aging
* cognition
* entraînement par intervalles de haute intensité
* executive functions
* exercice
* exercise
* fonctions exécutives
* high-intensity interval training
* memory
* mémoire
* physical activity
* vieillissement
|full-text-url=https://sci-hub.do/10.1139/apnm-2019-0495
}}
{{medline-entry
|title=Protective effects of vitamin D on neurophysiologic alterations in brain aging: role of brain-derived neurotrophic factor ([[BDNF]]).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31524100
|abstract= Vitamin D has been hypothesized to be main regulator of the aging rate, alongside evidences support its role in neuroprotection. However, data about the protective role of vitamin D against neurophysiologic alterations associated with brain aging is limited. This study investigated the possible protective effects that vitamin D has on brain-derived neurotrophic factor ([[BDNF]]), cholinergic function, oxidative stress and apoptosis in aging rat brain.   Male Wister albino rats aged 5 months (young), 12 months (middle aged) and 24 months (old) ([i]n[/i] = 20 each) were used. Each age group subdivided to either vitamin D3 supplementation (500 IU/kg/day orally for 5 weeks) or no supplementation (control) group ([i]n[/i] = 10 each). Serum 25-hydroxyvitamin D [25(OH)D], brain [[BDNF]] and malondialdehyde levels and activities of acetylcholinesterase (AChE), antioxidant enzymes (glutathione reductase, glutathione peroxidase and superoxide dismutase) and caspase-3 were quantified.   Vitamin D supplementation significantly mitigated the observed aging-related reduction in brain [[BDNF]] level and activities of AChE and antioxidant enzymes and elevation in malondialdehyde level and caspase-3 activity compared to control groups. Brain [[BDNF]] level correlated positively with serum 25(OH) D level and brain AChE activity and negatively with brain malondialdehyde level and caspase-3 activity in supplemented groups.   Restoring vitamin D levels may, therefore, represent a useful strategy for healthy brain aging. Augmenting brain [[BDNF]] seems to be a key mechanism through which vitamin D counteracts age-related brain dysfunction.

|keywords=* BDNF
* Brain aging
* neurophysiologic alterations
* neuroprotection
* vitamin D supplementation
|full-text-url=https://sci-hub.do/10.1080/1028415X.2019.1665854
}}
{{medline-entry
|title=Differential Effects of Physical Exercise, Cognitive Training, and Mindfulness Practice on Serum [[BDNF]] Levels in Healthy Older Adults: A Randomized Controlled Intervention Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31498125
|abstract=Previous studies have indicated that an active lifestyle is associated with better brain health and a longer life, compared to a more sedentary lifestyle. These studies, both on human and animal subjects, have typically focused on a single activity, usually physical exercise, but other activities have received an increasing interest. One proposed mechanism is that physical exercise increases levels of brain-derived neurotrophic factor ([[BDNF]]) in the brain. For the first time, the long-term effects on serum [[BDNF]] levels were compared in persons who engaged in either physical exercise training, cognitive training, or mindfulness practice during 5 weeks, and compared with an active control group. Two cohorts of healthy older individuals, one from the Boston area in the US and one from the Växjö area in Sweden, participated. A total of 146 participants were randomly assigned to one of the four groups. All interventions were structurally similar, using interactive, computer-based software that directed participants to carry out specified activities for 35 minutes/day, 5 days per week for 5 weeks. Blood samples were obtained at baseline and soon after the completion of the 5-week long intervention program, and serum [[BDNF]] levels were measured using a commercially available ELISA. Only the group that underwent cognitive training increased their serum [[BDNF]] levels after 5 weeks of training (F1,74 = 4.22, p = 0.044, partial η2 = 0.054), corresponding to an average 10% increase. These results strongly suggest that cognitive training can exert beneficial effects on brain health in an older adult population.
|mesh-terms=* Aged
* Brain-Derived Neurotrophic Factor
* Cognition
* Correlation of Data
* Exercise
* Female
* Healthy Aging
* Healthy Lifestyle
* Humans
* Learning
* Male
* Mindfulness
* Neuropsychological Tests
* Outcome Assessment, Health Care
|keywords=* Aging
* brain-derived neurotrophic factor
* cognitive training
* mindfulness
* physical exercise
|full-text-url=https://sci-hub.do/10.3233/JAD-190756
}}
{{medline-entry
|title=Dietary Supplementation with Fish Oil or Conjugated Linoleic Acid Relieves Depression Markers in Mice by Modulation of the Nrf2 Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31398773
|abstract=Inflammation and oxidative stress play an important role in the pathogenesis of depressive disorders and nuclear erythroid related factor 2 (Nrf2), a regulator of RedOx homeostasis and inflammation, is a promising target for depression prevention/treatment. As fish oil (FO) and conjugated linoleic acid (CLA) are known Nrf2 inducers, their protective ability is comparatively evaluated in a murine model of depression (MRL/MpJ-Fas  ). Oxidative stress, fatty acids content, and critical factors reflecting brain functioning-namely brain-derived neurotrophic factor ([[BDNF]]), synaptic markers, and cholinergic signaling-are preliminarily evaluated in the frontal cortex of 8-week (Young) and in 22-week old animals (Old), which are used as model of depression. These markers are measured in Old mice at the end of a 5-week pretreatment with FO or CLA (728 or 650 mg kg  , respectively). Old mice exhibit disrupted Redox homeostasis, compensatory Nrf2 hyperactivation, lower docosaheaxaenoic acid (DHA), and lower [[BDNF]] and synaptic function proteins compared to Young mice. FO and CLA treatment relieves almost all the pathophysiological hallmarks at a level comparable to Young mice. Presented data provide the first evidence for the comparable efficacy of FO or CLA supplementation in preventing depression signs in Old MRL/lpr mice, likely through their ability of improving Nrf2-mediated antioxidant defenses.
|mesh-terms=* Aging
* Animals
* Antidepressive Agents
* Autoimmunity
* Biomarkers
* Brain
* Brain-Derived Neurotrophic Factor
* Depression
* Dietary Supplements
* Docosahexaenoic Acids
* Fatty Acid Elongases
* Fatty Acids
* Fish Oils
* Inflammation
* Linoleic Acids, Conjugated
* Liver
* Male
* Mice, Inbred MRL lpr
* NF-E2-Related Factor 2
* Oxidative Stress
* Stearoyl-CoA Desaturase
* Tumor Necrosis Factor-alpha
|keywords=* brain derived neurotrophic factor
* brain fatty acid profile
* conjugated linoleic acid
* depression
* fish oil
* nuclear erythroid related factor-2
|full-text-url=https://sci-hub.do/10.1002/mnfr.201900243
}}
==TERT==

{{medline-entry
|title=Telomeres and telomerase in risk assessment of cardiovascular diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33171154
|abstract=Telomeres are repetitive nucleoprotein structures located at the ends of chromosomes. Reduction in the number of repetitions causes cell senescence. Cells with high proliferative potential age with each replication cycle. Post-mitotic cells (e.g. cardiovascular cells) have a different aging mechanism. During the aging of cardiovascular system cells, permanent DNA damage occurs in the telomeric regions caused by mitochondrial dysfunction, which is a phenomenon independent of cell proliferation and telomere length. Mitochondrial dysfunction is accompanied by increased production of reactive oxygen species and development of inflammation. This phenomenon in the cells of blood vessels can lead to atherosclerosis development. Telomere damage in cardiomyocytes leads to the activation of the DNA damage response system, histone H2A.X phosphorylation, p53 activation and p21 and p16 protein synthesis, resulting in the SASP phenotype (senescence-associated secretory phenotype), increased inflammation and cardiac dysfunction. Cardiovascular cells show the activity of the [[TERT]] subunit of telomerase, an enzyme that prevents telomere shortening. It turns out that disrupting the activity of this enzyme can also contribute to the formation of cardiovascular diseases. Measurements of telomere length according to the "blood-muscle" model may help in the future to assess the risk of cardiovascular complications in people undergoing cardiological procedures, as well as to assess the effectiveness of some drugs.

|keywords=* Cardiovascular diseases
* Senescence
* Telomerase
* Telomeres
|full-text-url=https://sci-hub.do/10.1016/j.yexcr.2020.112361
}}
{{medline-entry
|title=A 4-Base-Pair Core-Enclosing Helix in Telomerase RNA Is Essential for Activity and for Binding to the Telomerase Reverse Transcriptase Catalytic Protein Subunit.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33046533
|abstract=The telomerase ribonucleoprotein (RNP) counters the chromosome end replication problem, completing genome replication to prevent cellular senescence in yeast, humans, and most other eukaryotes. The telomerase RNP core enzyme is composed of a dedicated RNA subunit and a reverse transcriptase (telomerase reverse transcriptase [[[TERT]]]). Although the majority of the 1,157-nucleotide (nt) [i]Saccharomyces cerevisiae[/i] telomerase RNA, TLC1, is rapidly evolving, the central catalytic core is largely conserved, containing the template, template-boundary helix, pseudoknot, and core-enclosing helix (CEH). Here, we show that 4 bp of core-enclosing helix is required for telomerase to be active [i]in vitro[/i] and to maintain yeast telomeres [i]in vivo[/i], whereas the ΔCEH and 1- and 2-bp alleles do not support telomerase function. Using the CRISPR/nuclease-deactivated Cas9 (dCas9)-based CARRY (CRISPR-assisted RNA-RNA-binding protein [RBP] yeast) two-hybrid assay to assess binding of our CEH mutant RNAs to [[TERT]], we find that the 4-bp CEH RNA binds to [[TERT]] but the shorter-CEH constructs do not, consistent with the telomerase activity and [i]in vivo[/i] complementation results. Thus, the CEH is essential in yeast telomerase RNA because it is needed to bind [[TERT]] to form the core RNP enzyme. Although the 8 nt that form this 4-bp stem at the base of the CEH are nearly invariant among [i]Saccharomyces[/i] species, our results with sequence-randomized and truncated-CEH helices suggest that this binding interaction with [[TERT]] is dictated more by secondary than by primary structure. In summary, we have mapped an essential binding site in telomerase RNA for [[TERT]] that is crucial to form the catalytic core of this biomedically important RNP enzyme.

|keywords=* RNA
* RNP
* TERT
* TLC1
* senescence
* telomerase
* telomerase RNA
* telomere
* two-hybrid screening
* yeast
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685517
}}
{{medline-entry
|title=Angiotensin inhibition and cellular senescence in the developing rat kidney.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33010296
|abstract=Cellular senescence is important for the maintenance of tissue homeostasis during normal development. In this study, we aimed to investigate the effect of renin angiotensin system (RAS) blockade on renal cell senescence in the developing rat kidney. Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for seven days after birth. We investigated the intrarenal expressions of cell cycle regulators p21 and p16 with immunoblots and immunohistochemistry at postnatal day 8. For the determination of renal cellular senescence, immunostaining for senescence-associated β-galactosidase (SA-β-gal) and telomerase reverse transcriptase ([[TERT]]) was also performed. Enalapril treatment showed significant alterations in cellular senescence in neonatal rat kidneys. In the enalapril-treated group, intrarenal p16 and p21 protein expressions decreased compared to controls. The expressions of both p21 and p16 were reduced throughout the renal cortex and medulla of enalapril-treated rats. The immunoreactivity of [[TERT]] in enalapril-treated kidneys was also weaker than that in control kidneys. Control kidneys revealed a clear positive SA-β-gal signal in the cortical tubules; however, SA-β-gal activity was noticeably lower in the enalapril-treated kidneys than in control kidneys. Interruption of the RAS during postnatal nephrogenesis may disrupt physiologic renal cellular senescence in the developing rat kidney.

|keywords=* Apoptosis
* Cellular senescence
* Fetal development
* Kidney
* Renin-angiotensin system
|full-text-url=https://sci-hub.do/10.1016/j.yexmp.2020.104551
}}
{{medline-entry
|title=Decreased expression of [[TERT]] and telomeric proteins as human ovaries age may cause telomere shortening.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32856217
|abstract=Telomeres are repetitive sequences localized at the ends of eukaryotic chromosomes comprising noncoding DNA and telomere-binding proteins. TRF1 and TRF2 both bind to the double-stranded telomeric DNA to regulate its length throughout the lifespan of eukaryotic cells. POT1 interacts with single-stranded telomeric DNA and contributes to protecting genomic integrity. Previous studies have shown that telomeres gradually shorten as ovaries age, coinciding with fertility loss. However, the molecular background of telomere shortening with ovarian aging is not fully understood. The present study aimed to determine the spatial and temporal expression levels of the [[TERT]], TRF1, TRF2, and POT1 proteins in different groups of human ovaries: fetal (n = 11), early postnatal (n = 10), premenopausal (n = 12), and postmenopausal (n = 14). Also, the relative telomere signal intensity of each group was measured using the Q-FISH method. We found that the telomere signal intensities decreased evenly and significantly from fetal to postmenopausal groups (P < 0.05). The [[TERT]], TRF1, TRF2, and POT1 proteins were localized in the cytoplasmic and nuclear regions of the oocytes, granulosa and stromal cells. Furthermore, the expression levels of these proteins reduced significantly from fetal to postmenopausal groups (P < 0.05). These findings suggest that decreased [[TERT]] and telomere-binding protein expression may underlie the telomere shortening of ovaries with age, which may be associated with female fertility loss. Further investigations are required to elicit the molecular mechanisms regulating the gradual decrease in the expression of [[TERT]] and telomere-binding proteins in human oocytes and granulosa cells during ovarian aging.

|keywords=* Ovarian aging
* TERT
* Telomere
* Telomere-binding proteins
|full-text-url=https://sci-hub.do/10.1007/s10815-020-01932-1
}}
{{medline-entry
|title=The secrets of telomerase: Retrospective analysis and future prospects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32698073
|abstract=Telomerase plays a significant role to maintain and regulate the telomere length, cellular immortality and senescence by the addition of guanine-rich repetitive sequences. Chronic inflammation or oxidative stress-induced infection downregulates [[TERT]] gene modifying telomerase activity thus contributing to the early steps of gastric carcinogenesis process. Furthermore, telomere-telomerase system performs fundamental role in the pathogenesis and progression of diabetes mellitus as well as in its vascular intricacy. The cessation of cell proliferation in cultured cells by inhibiting the telomerase activity of transformed cells renders the rationale for culling of telomerase as a target therapy for the treatment of metabolic disorders and various types of cancers. In this article, we have briefly described the role of immune system and malignant cells in the expression of telomerase with critical analysis on the gaps and potential for future studies. The key findings regarding the secrets of the telomerase summarized in this article will help in future treatment modalities for the prevention of various types of cancers and metabolic disorders notably diabetes mellitus.
|mesh-terms=* Aging
* Animals
* Diabetes Mellitus
* Humans
* Neoplasms
* Telomerase
* Telomere Shortening
|keywords=* Cancers
* G-quadruplex formation
* Metabolic disorders
* TERT gene
* Telomere-telomerase system
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.118115
}}
{{medline-entry
|title=Gene expression in human mesenchymal stem cell aging cultures: modulation by short peptides.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32399807
|abstract=Effects of the short peptides Ala-Glu-Asp (AED), Lys-Glu-Asp (KED) and Lys-Glu (KE) on the expression of IGF1, FOXO1, [[TERT]], TNKS2, and NFκB genes were studied in human embryo bone marrow mesenchymal stem cells (line FetMSCs) variously aged in "passages" or "stationary" cultures. Both cell aging models were similar in gene expression. The main difference was in the [[TERT]] gene expression level, which showed an eightfold increase at the "stationary" aging. IGF1 gene expression levels were very similar in both cell culture aging models, being enhanced by 3.5-5.6 fold upon the addition of the peptides. The FOXO1 gene was expressed twice more actively in the "stationary" than in the "passages" aging model. KED peptide inhibited FOXO1 gene expression by 1.6-2.3 fold. KE peptide increased FOXO1 gene expression by about two-fold in the "stationary" aging model but did not affect it in the "passage" aging model. The most striking difference in the peptide effect on cell aging between "passages" and "stationary" aging models was in the KED effects on TNKS2 gene expression; this expression was inhibited by KED in the "passages" model, while stimulation was observed in the "stationary" model. AED, KED, and KE stimulated expression of the NFκB gene in both models. Thus, the peptides studied at nanomolar concentrations modulate the expression of some genes known to be involved in cell aging.

|keywords=* Cell aging
* Genes
* Human mesenchymal stem cells
* Short peptides
|full-text-url=https://sci-hub.do/10.1007/s11033-020-05506-3
}}
{{medline-entry
|title=Unravelling Cellular Mechanisms of Stem Cell Senescence: An Aid from Natural Bioactive Molecules.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32244882
|abstract=Cellular senescence plays a role in the onset of age-related pathologies and in the loss of tissue homeostasis. Natural compounds of food or plants exert an important antioxidant activity, counteracting the formation of harmful free radicals. In the presence of an intense stressing event, cells activate specific responses to counteract senescence or cell death. In the present paper, we aimed at evaluating the levels of expression of specific markers of senescence, in order to demonstrate that extracts from [i]Myrtus Communis L[/i]. can prevent premature senescence in ADSCs exposed to oxidative stress. Cells were cultured in the presence of [i]Myrtus[/i] extracts for 12-24 and 48 h and then incubated with H O  to induce senescence. We then evaluated the expression of senescence-related markers p16, p19, p21, p53, [[TERT]], c-Myc, and the senescence-associated β-Galactoidase activity. Our results showed that pre-treatment with [i]Myrtus[/i] extracts protects cells from premature senescence, by regulating the cell cycle, and inducing the expression of [[TERT]] and c-Myc. These findings suggest a potential application of these natural compounds in the prevention and treatment of various diseases, counteracting premature senescence and preserving tissue functions.

|keywords=* cellular mechanisms
* gene expression
* nutraceuticals
* oxidative stress
* senescence
* stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7150900
}}
{{medline-entry
|title=Expression of telomerase reverse transcriptase positively correlates with duration of lithium treatment in bipolar disorder.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32114208
|abstract=Bipolar disorder (BD) may be associated with accelerated cellular aging. However, previous studies on telomere length (TL), an important biomarker of cellular aging, have yielded mixed results in BD. We aimed to evaluate the hypothesis that BD is associated with telomere shortening and whether this is counteracted by long-term lithium treatment. We also sought to determine whether long-term lithium treatment is associated with increased expression of telomerase reverse transcriptase ([[TERT]]), the catalytic subunit of telomerase. We determined TL and [[TERT]] expression in 100 BD I patients and 100 healthy controls. We also genotyped three single nucleotide polymorphisms associated with TL. [[TERT]] expression was significantly increased in BD I patients currently on lithium treatment. [[TERT]] expression was also significantly positively correlated with duration of lithium treatment in patients treated for 24 months or more. However, we did not find any significant effect of lithium treatment on TL. Neither did we find significant differences in TL between BD patients and controls. We suggest that long-term lithium treatment is associated with an increase in the expression of [[TERT]]. We hypothesize that an increase in [[TERT]] expression may contribute to lithium's mood stabilizing and neuroprotective properties by improving mitochondrial function and decreasing oxidative stress.
|mesh-terms=* Adult
* Aging
* Antimanic Agents
* Bipolar Disorder
* Cellular Senescence
* Female
* Humans
* Lithium
* Lithium Compounds
* Male
* Middle Aged
* Mitochondria
* Oxidative Stress
* Polymorphism, Single Nucleotide
* Real-Time Polymerase Chain Reaction
* Telomerase
* Telomere
* Telomere Homeostasis
* Telomere Shortening
|keywords=* Affective disorder
* Aging
* Mitochondria
* Oxidative stress
* TERT
* Telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334059
}}
{{medline-entry
|title=FAM96B inhibits the senescence of dental pulp stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32039527
|abstract=Dental pulp stem cells (DPSCs) are considered a remarkable source for the regeneration of dental pulp tissues, but their therapeutic effectiveness remains limited, especially in elderly people. Previous studies found that senescence has a negative effect on the proliferation and differentiation potential of DPSCs. Moreover, numerous long non-coding RNA (lncRNA) and messenger RNA were significantly differentially regulated in DPSCs from young and elderly donors. However, the changes in DPSCs protein during senescence have not been addressed. In this study, differences in DPSC protein expression profiles and coexpression of protein and lncRNA were analyzed using proteomics and bioinformatics. The results showed 75 upregulated proteins and 69 downregulated proteins in DPSCs from elderly donors. Vasopressin-regulated water reabsorption, Parkinson's disease, Alzheimer's disease, and protein export were the top four functional pathways associated with DPSCs. High mobility group N1 (HMGN1), HMGN2, UCHL1, and the family with sequence similarity 96 member B homeobox gene (FAM96B) were associated with DPSCs senescence. Then, we investigated FAM96B function in DPSCs. After FAM96B depletion, telomerase reverse transcriptase ([[TERT]]) activity decreased, but the number of senescence-associated β-galactosidase (SA-β-gal) positive cells and the protein levels of p16, p53 were significantly increased. Gain-of-function assays suggested that FAM96B overexpression was positively correlated with [[TERT]] activity, but negatively correlated with the number of SA-β-gal positive cells and the protein levels of P16 and P53. Moreover, after FAM96B overexpression, the results showed a significant increase in alkaline phosphatase activity and an enhanced mineralization ability of DPSCs. The reverse-transcription polymerase chain reaction results also showed that dentin sialophosphoprotein and osteocalcin were expressed at greater levels. The carboxyfluorescein succinimidyl ester (CFSE) results displayed that FAM96B increased the proliferation potential of DPSCs. Our study revealed candidate proteins that might be related to DPSCs senescence and provided information to elucidate the mechanism of the biological changes in DPSCs' aging. Moreover, FAM96B was demonstrated to play an important role in suppressing DPSCs senescence and promoting osteogenic differentiation and proliferation.

|keywords=* FAM96B
* aging
* dental pulp stem cells (DPSCs)
* proteomic analysis
|full-text-url=https://sci-hub.do/10.1002/cbin.11319
}}
{{medline-entry
|title=Aging and biomarkers: Transcriptional levels evaluation of Osteopontin/miRNA-181a axis in hepatic tissue of rats in different age ranges.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32061643
|abstract=Osteopontin (OPN), a novel hepatic damage marker, as well as several non-coding RNA seem to be associated with liver aging, a little studied and not yet defined process. The aim of the study was to evaluate the expression variations of OPN and miRNA-181a, the transcriptional profiling of long non coding (lnc) RNA GAS-5/miRNA-222 axis and lncRNA NEAT-1 in liver tissue of rats. In addition, to monitor the senescence process, the telomere shortening and [[TERT]]/TERC gene expression were also measured. Three groups of male Wistar rats were studied: A (n = 6, young); B (n = 13, adult); C (n = 10, old). Total RNA, including miRNAs, was extracted from liver and analysed by Real-Time PCR. Ultrasound and biochemical evaluation were performed in all rats as well as the histological analysis. OPN mRNA resulted lower in C with respect to A and B while miRNA-181a expression was significantly increased as a function of age. An increasing of both NEAT-1 and miRNA-222 expression as a function of age in parallel with a decreasing of GAS-5 expression in young and old rats, but not in the adults, was observed. A positive correlation was detected between miRNA-181a and miRNA-222. The hepatic ultrasound analysis revealed areas of hyperechogenicity distributed as a function of age. A significant telomere shortening was measured as a function of age while the two subunits [[TERT]] and TERC expressions showed an opposite trend. This work could provide a valid starting point to better understand the physiopathological changes during aging, pinpointing in the OPN/miRNA-181a axis significant predictors of successful aging.

|keywords=* Aging
* Long non-coding RNA
* Osteopontin
* Telomeres
* miRNA
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110879
}}
{{medline-entry
|title=Resveratrol inhibits adipocyte differentiation and cellular senescence of human bone marrow stromal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31978617
|abstract=Bone marrow adipose tissue (BMAT) is a unique adipose depot originating from bone marrow stromal stem cells (BMSCs) and regulates bone homeostasis and energy metabolism. An increased BMAT volume is observed in several conditions e.g. obesity, type 2 diabetes, osteoporosis and is known to be associated with bone fragility and increased risk for fracture. Therapeutic approaches to decrease the accumulation of BMAT are clinically relevant. In a screening experiment of natural compounds, we identified Resveratrol (RSV), a plant-derived antioxidant mediating biological effects via sirtuin- related mechanisms, to exert significant effects of BMAT formation. Thus, we examined in details the effects RSV on adipocytic and osteoblastic differentiation of tolermerized human BMSCs (hBMSC-[[TERT]]). RSV (1.0 μM) enhanced osteoblastic differentiation and inhibited adipocytic differentiation of hBMSC-[[TERT]] when compared with control and Sirtinol (Sirtuin inhibitor). Global gene expression profiling and western blot analysis revealed activation of a number of signaling pathways including focal adhesion kinase (FAK). Pharmacological inhibition of FAK using (PF-573228) and AKT inhibitor (LY-294002) (5μM), diminished RSV-induced osteoblast differentiation. In addition, RSV reduced the levels of senescence-associated secretory phenotype (SASP), gene markers associated with senescence (P53, P16, and P21), intracellular ROS levels and increased gene expression of enzymes protecting cells from oxidative damage (HMOX1 and SOD3). In vitro treatment of primary hBMSCs from aged patients characterized with high adipocytic and low osteoblastic differentiation ability with RSV, significantly enhanced osteoblast and decreased adipocyte formation when compared to hBMSCs from young donors. RSV targets hBMSCs and inhibits adipogenic differentiation and senescence-associated phenotype and thus a potential agent for treating conditions of increased BMAT formation.

|keywords=* Adipogenesis
* Antioxidant
* Bone marrow adiposity
* Bone marrow skeletal stromal cells
* Cellular senescence
* Osteogenesis
|full-text-url=https://sci-hub.do/10.1016/j.bone.2020.115252
}}
{{medline-entry
|title=Characterization of human telomerase reverse transcriptase immortalized anterior cruciate ligament cell lines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31948601
|abstract=The anterior-cruciate-ligament (ACL) contains mesenchymal stem cells (ACL-MSCs), suggesting the feasibility of regenerative treatments of this tissue. The immortalization of isolated cells results in cell-lines applicable to develop cell-based therapies. Immortal cell lines eliminate the need for frequent cell isolation from donor tissues. The objective of this study was to characterize cell lines that were generated from isolated ACL-MSCs using [[TERT]] gene transfer. We isolated ACL-MSCs from human ACLs derived at the time of ACL reconstruction surgery or total knee arthroplasty. We generated cell lines and compared them to non-immortalized ACL-MSCs. We assessed the cellular morphology and we detected surface antigen expression. The resistance to senescence was inferred using the beta galactosidase activity. Histology, immunohistochemistry, and reverse transcriptase polymerase chain reaction (RT-PCR) were used to evaluate the multilineage differentiation capacity. The morphology of h[[TERT]]-ACL-MSCs was similar to ACL up to the last assessment at passage eight. We detected a strong surface expression of CD44, CD90, CD105, and STRO-1 in h[[TERT]]-ACL-MSCs. No substantial reduction in the ATP activity was observed in h[[TERT]]-ACL-MSCs. Cell lines generated from ACL-MSCs maintain their morphology, surface antigen expression profile, and proliferative capacity; while markers of senescence appear to be reduced. These cell-lines maintained their multilineage differentiation capacity. The demonstrated model systems can be used for further development of new cell-based regenerative approaches in anterior cruciate ligament research, which may lead to new therapeutic strategies in the future.
|mesh-terms=* Adolescent
* Aged
* Anterior Cruciate Ligament
* Cell Differentiation
* Cell Separation
* Cells, Cultured
* Humans
* Mesenchymal Stem Cells
* Telomerase
|keywords=* Anterior cruciate ligament
* Immortalization
* Mesenchymal stem cells
* Multilineage differentiation
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962762
}}
{{medline-entry
|title=Mitochondria, Telomeres and Telomerase Subunits.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31781563
|abstract=Mitochondrial functions and telomere functions have mostly been studied independently. In recent years, it, however, has become clear that there are intimate links between mitochondria, telomeres, and telomerase subunits. Mitochondrial dysfunctions cause telomere attrition, while telomere damage leads to reprogramming of mitochondrial biosynthesis and mitochondrial dysfunctions, which has important implications in aging and diseases. In addition, evidence has accumulated that telomere-independent functions of telomerase also exist and that the protein component of telomerase [[TERT]] shuttles between the nucleus and mitochondria under oxidative stress. Our previously published data show that the RNA component of telomerase [i]TERC[/i] is also imported into mitochondria, processed, and exported back to the cytosol. These data show a complex regulation network where telomeres, nuclear genome, and mitochondria are co-regulated by multi-localization and multi-function proteins and RNAs. This review summarizes the connections between mitochondria and telomeres, the mitochondrion-related functions of telomerase subunits, and how they play a role in crosstalk between mitochondria and the nucleus.

|keywords=* TERC
* TERT
* aging
* mitochondria
* telomerase
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851022
}}
{{medline-entry
|title=Towards Therapeutic Alternatives for Mercury Neurotoxicity in the Amazon: Unraveling the Pre-Clinical Effects of the Superfruit Açaí ([i]Euterpe oleracea[/i], Mart.) as Juice for Human Consumption.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31717801
|abstract=Methylmercury (MeHg) exposure is a serious problem of public health, especially in the Amazon. Exposure in riverine populations is responsible for neurobehavioral abnormalities. It was hypothesized that consumption of Amazonian fruits could protect by reducing mercury accumulation. This work analyzed the effects of commercial samples of [i]Euterpe oleracea[/i] (EO) for human consumption (10 μL/g) against MeHg i.p. exposure (2.5 mg/Kg), using neurobehavioral (open field, rotarod and pole tests), biochemical (lipid peroxidation and nitrite levels), aging-related (telomerase reverse transcriptase ([[TERT]]) mRNA expression) and toxicokinetic (MeHg content) parameters in mice. Both the pole and rotarod tests were the most sensitive tests accompanied by increased lipid peroxidation and nitrite levels in brains. MeHg reduced [[TERT]] mRNA about 50% demonstrating a strong pro-aging effect. The EO intake, similar to that of human populations, prevented all alterations, without changing the mercury content, but avoiding neurotoxicity and premature aging of the Central Nervous System (CNS). Contrary to the hypothesis found in the literature on the possible chelating properties of Amazonian fruits consumption, the effect of EO would be essentially pharmacodynamics, and possible mechanisms are discussed. Our data already support the regular consumption of EO as an excellent option for exposed Amazonian populations to have additional protection against MeHg intoxication.
|mesh-terms=* Animals
* Antioxidants
* Behavior, Animal
* Brain Chemistry
* Euterpe
* Fruit and Vegetable Juices
* Lipid Peroxidation
* Male
* Mercury
* Mice
* Motor Skills
* Neurotoxins
* Plant Extracts
* Telomere
|keywords=* Euterpe
* acai
* aging
* antioxidant
* açaí
* extract
* intoxication
* methylmercury
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893510
}}
{{medline-entry
|title=Replication Stress at Telomeric and Mitochondrial DNA: Common Origins and Consequences on Ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31597307
|abstract=Senescence is defined as a stress-induced durable cell cycle arrest. We herein revisit the origin of two of these stresses, namely mitochondrial metabolic compromise, associated with reactive oxygen species (ROS) production, and replicative senescence, activated by extreme telomere shortening. We discuss how replication stress-induced DNA damage of telomeric DNA (telDNA) and mitochondrial DNA (mtDNA) can be considered a common origin of senescence in vitro, with consequences on ageing in vivo. Unexpectedly, mtDNA and telDNA share common features indicative of a high degree of replicative stress, such as G-quadruplexes, D-loops, RNA:DNA heteroduplexes, epigenetic marks, or supercoiling. To avoid these stresses, both compartments use similar enzymatic strategies involving, for instance, endonucleases, topoisomerases, helicases, or primases. Surprisingly, many of these replication helpers are active at both telDNA and mtDNA (e.g., RNAse H1, FEN1, DNA2, RecQ helicases, Top2α, Top2β, TOP3A, DNMT1/3a/3b, SIRT1). In addition, specialized telomeric proteins, such as [[TERT]] (telomerase reverse transcriptase) and TERC (telomerase RNA component), or TIN2 (shelterin complex), shuttle from telomeres to mitochondria, and, by doing so, modulate mitochondrial metabolism and the production of ROS, in a feedback manner. Hence, mitochondria and telomeres use common weapons and cooperate to resist/prevent replication stresses, otherwise producing common consequences, namely senescence and ageing.
|mesh-terms=* Aging
* Animals
* Cellular Senescence
* DNA Damage
* DNA Replication
* DNA, Mitochondrial
* Epigenesis, Genetic
* Humans
* Mitochondria
* Oxidative Stress
* Stress, Physiological
* Telomere
* Telomere Homeostasis
* Telomere Shortening
|keywords=* G-quadruplex
* R-loop
* ageing
* helicase
* mitochondria
* replication stress
* senescence
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801922
}}
{{medline-entry
|title=Telomerase Biology Associations Offer Keys to Cancer and Aging Therapeutics.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31544708
|abstract=Although telomerase has potential for age-related disease intervention, the overexpression of telomerase in about 90% of cancers, and in HIV virus reservoirs, cautions against se in anti-aging telomerase therapeutics. While multiple reviews document the canonical function of telomerase for maintenance of telomeres, as well as an increasing numbers of reviews that reveal new non-canonical functions of telomerase, there was no systematic review that focuses on the array of associates of the subunit of Telomerase Reverse transcriptase protein ([[TERT]]) as pieces of the puzzle to assemble a picture of the how specific [[TERT]] complexes uniquely impact aging and age-related diseases and more can be expected. A structured search of bibliographic data on [[TERT]] complexes was undertaken using databases from the National Center for Biotechnology Information Pubmed with extensive access to biomedical and genomic information in order to obtain a unique documented and cited overview of [[TERT]] complexes that may uniquely impact aging and age-related diseases. The [[TERT]] associations include proper folding, intracellular [[TERT]] transport, metabolism, mitochondrial ROS (Reactive Oxygen Species) regulation, inflammation, cell division, cell death, and gene expression, in addition to the well-known telomere maintenance. While increase of cell cycle inhibitors promote aging, in cancer, the cell cycle check-point regulators are ambushed in favor of cell proliferation, while cytoplasmic [[TERT]] protects a cell cycle inhibitor in oxidative stress. The oncogene cMyc regulates gene expression for overexpression of [[TERT]], and reduction of cell cycle inhibitors-the perfect storm for cancer promotion. [[TERT]] binds with the oncogene RMRP RNA, and [[TERT]]-RMRP function can regulate levels of that oncogene RNA, and [[TERT]] in a TBN complex can regulate heterochromatin. Telomerase benefit and novel function in neurology and cardiology studies open new anti- aging hope. GV1001, a 16 amino acid peptide of [[TERT]] that associates with Heat Shock Proteins (HSP's), bypasses the cell membrane with remarkable anti disease potential. [[TERT]] "associates" are anti-cancer targets for downregulation, but upregulation in antiaging therapy. The overview revealed that unique [[TERT]] associations that impact all seven pillars of aging identified by the Trans-NIH Geroscience Initiative that influence aging and urge research for appropriate targeted telomerase supplements/ stimulation, and inclusion in National Institute on Aging Intervention Testing Program. The preference for use of available "smart drugs", targeted to only cancer, not off-target anti- aging telomerase is implied by the multiplicity of [[TERT]] associates functions.

|keywords=* Aging
* TERT
* associates
* cancer
* cell cycle
* diseases
* oncogenes
* viral infection.
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403649
}}
{{medline-entry
|title=Transient induction of telomerase expression mediates senescence and reduces tumorigenesis in primary fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31481614
|abstract=Telomerase is an enzymatic ribonucleoprotein complex that acts as a reverse transcriptase in the elongation of telomeres. Telomerase activity is well documented in embryonic stem cells and the vast majority of tumor cells, but its role in somatic cells remains to be understood. Here, we report an unexpected function of telomerase during cellular senescence and tumorigenesis. We crossed [i]Tert[/i] heterozygous knockout mice ([i]mTert[/i]   ) for 26 generations, during which time there was progressive shortening of telomeres, and obtained primary skin fibroblasts from [i]mTert[/i]   and [i]mTert[/i]   progeny of the 26th cross. As a consequence of insufficient telomerase activities in prior generations, both [i]mTert[/i]   and [i]mTert[/i]   fibroblasts showed comparable and extremely short telomere length. However, [i]mTert[/i]   cells approached cellular senescence faster and exhibited a significantly higher rate of malignant transformation than [i]mTert[/i]   cells. Furthermore, an evident up-regulation of telomerase reverse-transcriptase ([[TERT]]) expression was detected in [i]mTert[/i]   cells at the presenescence stage. Moreover, removal or down-regulation of [[TERT]] expression in [i]mTert[/i]   and human primary fibroblast cells via CRISPR/Cas9 or shRNA recapitulated [i]mTert[/i]   phenotypes of accelerated senescence and transformation, and overexpression of [[TERT]] in [i]mTert[/i]   cells rescued these phenotypes. Taking these data together, this study suggests that [[TERT]] has a previously underappreciated, protective role in buffering senescence stresses due to short, dysfunctional telomeres, and preventing malignant transformation.
|mesh-terms=* Animals
* Cell Cycle
* Cell Transformation, Neoplastic
* Cells, Cultured
* Cellular Senescence
* Fibroblasts
* Gene Expression
* Gene Expression Regulation
* Gene Knockdown Techniques
* Humans
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Phenotype
* Telomerase
* Telomere
|keywords=* ATM
* senescence
* telomerase
* tumorigenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754593
}}
==PGC==

{{medline-entry
|title=The Aging Stress Response and Its Implication for AMD Pathogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33266495
|abstract=Aging induces several stress response pathways to counterbalance detrimental changes associated with this process. These pathways include nutrient signaling, proteostasis, mitochondrial quality control and DNA damage response. At the cellular level, these pathways are controlled by evolutionarily conserved signaling molecules, such as 5'AMP-activated protein kinase (AMPK), mechanistic target of rapamycin (mTOR), insulin/insulin-like growth factor 1 (IGF-1) and sirtuins, including SIRT1. Peroxisome proliferation-activated receptor coactivator 1 alpha ([[PGC]]-1α), encoded by the [i]PPARGC1A[/i] gene, playing an important role in antioxidant defense and mitochondrial biogenesis, may interact with these molecules influencing lifespan and general fitness. Perturbation in the aging stress response may lead to aging-related disorders, including age-related macular degeneration (AMD), the main reason for vision loss in the elderly. This is supported by studies showing an important role of disturbances in mitochondrial metabolism, DDR and autophagy in AMD pathogenesis. In addition, disturbed expression of [[PGC]]-1α was shown to associate with AMD. Therefore, the aging stress response may be critical for AMD pathogenesis, and further studies are needed to precisely determine mechanisms underlying its role in AMD. These studies can include research on retinal cells produced from pluripotent stem cells obtained from AMD donors with the mutations, either native or engineered, in the critical genes for the aging stress response, including [i]AMPK[/i], [i]IGF1[/i], [i]MTOR[/i], [i]SIRT1[/i] and [i]PPARGC1A[/i].

|keywords=* AMD
* DNA damage response
* PGC-1α
* SIRT1
* age-related macular degeneration
* aging
* autophagy
* insulin/IGF-1
* mitochondrial quality control
* the aging stress response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700335
}}
{{medline-entry
|title=Constitutive [[PGC]]-1α Overexpression in Skeletal Muscle Does Not Contribute to Exercise-Induced Neurogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33200398
|abstract=Physical exercise can improve age-dependent decline in cognition, which in rodent is partly mediated by restoration of an age-dependent decline in neurogenesis. Exercise-inducible myokines in the circulation present a link in muscle-brain crosstalk. The transcription factor [[PGC]]-1α regulates the release of such myokines with neurotrophic properties into the circulation. We study how chronic muscular overexpression of [[PGC]]-1α could contribute to exercise-induced effects on hippocampal neurogenesis and if this effect could be enhanced in a running wheel paradigm. We used 3- and 11-month-old transgenic mice with overexpression of [[PGC]]-1α under the control of muscle creatinine kinase promoter (MCK-[[PGC]]-1α), which have a constitutively developed endurance muscle phenotype. Wild-type and MCK-[[PGC]]-1α mice were single housed with free access to running wheels. Four weeks of running in female animals increased the levels of newborn cells, immature neurons, and, for young animals, new mature neurons, compared to sedentary controls. However, no difference in these parameters was observed between wild-type and transgenic mice under sedentary or running conditions. Multiplex analysis of serum cytokines, chemokines, and myokines suggested several differences in serum protein concentrations between genotypes with musclin found to be significantly upregulated 4-fold in male MCK-[[PGC]]-1α animals. We conclude that constitutive muscular overexpression of [[PGC]]-1α, despite systemic changes and difference in serum composition, does not translate into exercise-induced effects on hippocampal neurogenesis, independent of the age of the animal. This suggests that chronic activation of [[PGC]]-1α in skeletal muscle is by itself not sufficient to mimic exercise-induced effects or to prevent decline of neurogenesis in aging.

|keywords=* Aging
* Hippocampal neurogenesis
* Immunohistochemistry
* PGC-1α
* Transgenic mice
* Voluntary running
|full-text-url=https://sci-hub.do/10.1007/s12035-020-02189-6
}}
{{medline-entry
|title=Dysregulated Autophagy Mediates Sarcopenic Obesity and Its Complications via AMPK and [[PGC]]1α Signaling Pathways: Potential Involvement of Gut Dysbiosis as a Pathological Link.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32961822
|abstract=Sarcopenic obesity (SOB), which is closely related to being elderly as a feature of aging, is recently gaining attention because it is associated with many other age-related diseases that present as altered intercellular communication, dysregulated nutrient sensing, and mitochondrial dysfunction. Along with insulin resistance and inflammation as the core pathogenesis of SOB, autophagy has recently gained attention as a significant mechanism of muscle aging in SOB. Known as important cellular metabolic regulators, the AMP-activated protein kinase (AMPK) and the peroxisome proliferator-activated receptor-gamma coactivator-1 alpha ([[PGC]]-1α) signaling pathways play an important role in autophagy, inflammation, and insulin resistance, as well as mutual communication between skeletal muscle, adipose tissue, and the liver. Furthermore, AMPK and [[PGC]]-1α signaling pathways are implicated in the gut microbiome-muscle axis. In this review, we describe the pathological link between SOB and its associated complications such as metabolic, cardiovascular, and liver disease, falls and fractures, osteoarthritis, pulmonary disease, and mental health via dysregulated autophagy controlled by AMPK and/or [[PGC]]-1α signaling pathways. Here, we propose potential treatments for SOB by modulating autophagy activity and gut dysbiosis based on plausible pathological links.

|keywords=* AMPK signaling pathway
* PGC-1α signaling pathway
* aging
* autophagy
* gut axis
* inflammation
* insulin resistance
* sarcopenic obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7555990
}}
{{medline-entry
|title=Resemblance and differences in dietary restriction nephroprotective mechanisms in young and old rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32970613
|abstract=Dietary restriction (DR) is the strategy ameliorating the morbidity of various pathologies, including age-associated diseases. Acute kidney injury (AKI) remains a problem for the elderly with DR being a promising approach for diminishing its consequences. We evaluated the possible nephroprotective potential of short-term DR in young and old rats. DR in young rats resulted in pronounced beneficial effects normalizing lipid metabolism (triglycerides concentration, adiponectin level) activating autophagic-lysosomal system evaluated by LC3II/LC3I ratio, LAMP1, p62/SQSTM1 levels, and LysoTracker Green staining. DR had a remarkable recovering effect on mitochondrial structure and functions including regaining of mitochondrial membrane potential, the elevation of SIRT-3, [[PGC]]-1α,   levels and partial restoration of ultrastructure. The beneficial effects of DR resulted in the mitigation of oxidative stress including a decrease in levels of protein carbonylation and lipid peroxidation. Aging led to decreased activity of autophagy, elevated oxidative stress and impaired kidney regenerative capacity. Eventually, in old rats, even 8-week DR was not able to ameliorate AKI, but it caused some rejuvenating effects including elevation of mitochondrial membrane potential and Bcl-X  levels, as well as lowered severity of the oxidative stress. Thus, the age-associated decline of protective signaling demands extended DR to achieve nephroprotective potential in old animals.

|keywords=* aging
* caloric restriction
* ischemia/reperfusion
* kidney injury
* mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585108
}}
{{medline-entry
|title=Acute and chronic effects of resistance training on skeletal muscle markers of mitochondrial remodeling in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32748504
|abstract=We investigated the acute and chronic effects of resistance training (RT) on skeletal muscle markers of mitochondrial content and remodeling in older, untrained adults. Sixteen participants (n = 6 males, n = 10 females; age = 59 ± 4 years) completed 10 weeks of full-body RT (2 day/week). Muscle biopsies from the vastus lateralis were obtained prior to RT (Pre), 24 hr following the first training session (Acute), and 72 hr following the last training session (Chronic). Protein levels of mitochondrial electron transport chain complexes I-V (+39 to +180%, p ≤ .020) and markers of mitochondrial fusion Mfn1 (+90%, p = .003), Mfn2 (+110%, p < .001), and Opa1 (+261%, p = .004) increased following chronic RT. Drp1 protein levels also increased (+134%, p = .038), while Fis1 protein levels did not significantly change (-5%, p = .584) following chronic RT. Interestingly, protein markers of mitochondrial biogenesis (i.e., [[PGC]]-1α, TFAM, and NRF1) or mitophagy (i.e., Pink1 and Parkin) were not significantly altered (p > .050) after 10 weeks of RT. In summary, chronic RT promoted increases in content of electron transport chain proteins (i.e., increased protein levels of all five OXPHOS complexes) and increase in the levels of proteins related to mitochondrial dynamics (i.e., increase in fusion protein markers) in skeletal muscle of older adults. These results suggest that chronic RT could be a useful strategy to increase mitochondrial protein content in older individuals.

|keywords=* aging
* mitochondrial dynamics
* mitochondrial function
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399374
}}
{{medline-entry
|title=[[PGC]]-1α-mediated regulation of mitochondrial function and physiological implications.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32516539
|abstract=The majority of human energy metabolism occurs in skeletal muscle mitochondria emphasizing the importance of understanding the regulation of myocellular mitochondrial function. The transcriptional co-activator peroxisome proliferator-activated receptor gamma coactivator 1 alpha ([[PGC]]-1α) has been characterized as a major factor in the transcriptional control of several mitochondrial components. Thus, [[PGC]]-1α is often described as a master regulator of mitochondrial biogenesis as well as a central player in regulating the antioxidant defense. However, accumulating evidence suggests that [[PGC]]-1α is also involved in the complex regulation of mitochondrial quality beyond biogenesis, which includes mitochondrial network dynamics and autophagic removal of damaged mitochondria. In addition, mitochondrial reactive oxygen species production has been suggested to regulate skeletal muscle insulin sensitivity, which may also be influenced by [[PGC]]-1α. This review aims to highlight the current evidence for [[PGC]]-1α-mediated regulation of skeletal muscle mitochondrial function [i]beyond[/i] the effects on mitochondrial biogenesis as well as the potential [[PGC]]-1α-related impact on insulin-stimulated glucose uptake in skeletal muscle.   [[PGC]]-1α regulates mitochondrial biogenesis but also has effects on mitochondrial functions beyond biogenesis. Mitochondrial quality control mechanisms, including fission, fusion, and mitophagy, are regulated by [[PGC]]-1α. [[PGC]]-1α-mediated regulation of mitochondrial quality may affect age-related mitochondrial dysfunction and insulin sensitivity.

|keywords=* aging
* exercise metabolism
* insulin resistance
* mitochondrial metabolism
* muscle metabolism
* muscle physiology
* métabolisme mitochondrial
* métabolisme musculaire
* métabolisme à l’effort
* physiologie musculaire
* résistance à l’insuline
* vieillissement
|full-text-url=https://sci-hub.do/10.1139/apnm-2020-0005
}}
{{medline-entry
|title=Targeting Mitochondrial Network Architecture in Down Syndrome and Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32365535
|abstract=Mitochondria are organelles that mainly control energy conversion in the cell. In addition, they also participate in many relevant activities, such as the regulation of apoptosis and calcium levels, and other metabolic tasks, all closely linked to cell viability. Functionality of mitochondria appears to depend upon their network architecture that may dynamically pass from an interconnected structure with long tubular units, to a fragmented one with short separate fragments. A decline in mitochondrial quality, which presents itself as an altered structural organization and a function of mitochondria, has been observed in Down syndrome (DS), as well as in aging and in age-related pathologies. This review provides a basic overview of mitochondrial dynamics, from fission/fusion mechanisms to mitochondrial homeostasis. Molecular mechanisms determining the disruption of the mitochondrial phenotype in DS and aging are discussed. The impaired activity of the transcriptional co-activator [[PGC]]-1α/PPARGC1A and the hyperactivation of the mammalian target of rapamycin (mTOR) kinase are emerging as molecular underlying causes of these mitochondrial alterations. It is, therefore, likely that either stimulating the [[PGC]]-1α activity or inhibiting mTOR signaling could reverse mitochondrial dysfunction. Evidence is summarized suggesting that drugs targeting either these pathways or other factors affecting the mitochondrial network may represent therapeutic approaches to improve and/or prevent the effects of altered mitochondrial function. Overall, from all these studies it emerges that the implementation of such strategies may exert protective effects in DS and age-related diseases.

|keywords=* Down syndrome
* PGC-1α/PPARGC1A
* aging
* mTOR
* mitochondrial dynamics
* mitochondrial function
* mitochondrial network
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247689
}}
{{medline-entry
|title=Colchicine treatment impairs skeletal muscle mitochondrial function and insulin sensitivity in an age-specific manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32372536
|abstract=The aim of the study was to investigate the impact of autophagy inhibition on skeletal muscle mitochondrial function and glucose homeostasis in young and aged mice. The transcriptional co-activator [[PGC]]-1α regulates muscle oxidative phenotype which has been shown to be linked with basal autophagic capacity. Therefore, young and aged inducible muscle-specific [[PGC]]-1α knockout (iMKO) mice and littermate lox/lox controls were used in three separate experiments performed after either saline or colchicine injections on two consecutive days: (1) Euthanization in the basal state obtaining skeletal muscle for mitochondrial respirometry, (2) whole body glucose tolerance test, and (3) in vivo insulin-stimulated 2-deoxyglucose (2-DG) uptake into skeletal muscle. Muscle [[PGC]]-1α was not required for maintaining basal autophagy flux, regardless of age. Colchicine-induced inhibition of autophagy was associated with impairments of skeletal muscle mitochondrial function, including reduced ADP sensitivity and altered mitochondrial redox balance in both young and aged mice. Colchicine treatment reduced the glucose tolerance in aged, but not young mice, and similarly in iMKO and lox/lox mice. Colchicine reduced insulin-stimulated 2-DG uptake in soleus muscle in aged mice, independently of [[PGC]]-1α, and without affecting insulin-regulated phosphorylation of proximal or distal mediators of insulin signaling. In conclusion, the results indicate that autophagy regulates the mitochondrial ADP sensitivity and redox balance as well as whole body glucose tolerance and skeletal muscle insulin sensitivity in aged mice, with no additional effects of inducible [[PGC]]-1α deletion.

|keywords=* ADP sensitivity
* ROS
* aging
* autophagy
|full-text-url=https://sci-hub.do/10.1096/fj.201903113RR
}}
{{medline-entry
|title=A novel dipeptide from potato protein hydrolysate augments the effects of exercise training against high-fat diet-induced damages in senescence-accelerated mouse-prone 8 by boosting pAMPK / SIRT1/ [[PGC]]-1α/ pFOXO3 pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32335547
|abstract=The pathological effects of obesity are often severe in aging condition. Although exercise training is found to be advantageous, the intensity of exercise performed is limited in aging condition. Therefore in this study we assessed the effect of a combined treatment regimen with a short-peptide IF isolated from alcalase potato-protein hydrolysates and a moderate exercise training for 15 weeks in a 6 month old HFD induced obese senescence accelerated mouse-prone 8 (SAMP8) mice model. Animals were divided into 6 groups (n=6) (C:Control+BSA); (HF:HFD+BSA); (EX:Control+ BSA+Exercise); (HF+IF:HFD+ IF); (HF+EX:HFD+Exercise); (HF+EX+IF:HFD+Exercise+IF). A moderate incremental swimming exercise training was provided for 6 weeks and after 3 weeks of exercise, IF was orally administered (1 mg/kg body Weight). The results show that combined administration of IF and exercise provides a better protection to aging animals by reducing body weight and regulated tissue damage. IF intake and exercise training provided protection against cardiac hypertrophy and maintains the tissue homeostasis in the heart and liver sections. Interestingly, IF and exercise training showed an effective upregulation in pAMPK/ SIRT1/ [[PGC]]-1α/ pFOXO3 mechanism of cellular longevity. Therefore, exercise training with IF intake is a possible strategy for anti-obesity benefits and superior cardiac and hepatic protection in aging condition.

|keywords=* alcalase
* bioactive peptides
* cardio-protection
* hepato-protection
* longevity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202530
}}
{{medline-entry
|title=Mitochondrial nucleoid remodeling and biogenesis are regulated by the p53-p21 -PKCζ pathway in p16 -silenced cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32330121
|abstract=Mitochondrial dysfunction is linked to age-related senescence phenotypes. We report here the pathway increasing nucleoid remodeling and biogenesis in mitochondria during the senescence of foreskin human diploid fibroblasts (fs-HDF) and WI-38 cells. Replicative senescence in fs-HDF cells increased mitochondrial nucleoid remodeling as indicated by 5-bromo-2'-deoxyuridine (BrdU) incorporation and mitochondrial transcription factor A (TFAM) expression in enlarged and fused mitochondria. Mitochondrial nucleoid remodeling was accompanied by mitochondrial biogenesis in old cells, and the expression levels of OXPHOS complex-I, -IV and -V subunits, [[PGC]]-1α and NRF1 were greatly increased compared to young cells. Activated protein kinase C zeta (PKCζ) increased mitochondrial activity and expressed phenotypes of delayed senescence in fs-HDF cells, but not in WI-38 cells. The findings were reproduced in the doxorubicin-induced senescence of young fs-HDF and WI-38 cells [i]via[/i] the PKCζ-LKB1-AMPK signaling pathway, which was regulated by the p53-p21  pathway when p16  was silenced. The signaling enhanced [[PGC]]-1α-NRF1-TFAM axis in mitochondria, which was demonstrated by Ingenuity Pathway Analysis of young and old fs-HDF cells. Activation of the p53-p21  pathway and silencing of p16  are responsible for mitochondrial reprogramming in senescent cells, which may be a compensatory mechanism to promote cell survival under senescence stress.

|keywords=* mitochondria
* nucleoid remodeling
* p16INK4a silence
* p53-p21-PKCζ activation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202532
}}
{{medline-entry
|title=[Metabolic Alteration in Aging Process: Metabolic Remodeling in White Adipose Tissue by Caloric Restriction].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32115557
|abstract=Caloric restriction (CR) improves whole-body metabolism, suppresses various age-related pathophysiological changes, and extends lifespan. The beneficial actions of CR are regulated in growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signal-dependent and -independent manners. To clarify the GH/IGF-1-independent mechanism, we compared gene expression profiles in white adipose tissue (WAT) between CR and GH/IGF-1 suppression, and found that CR upregulated sterol regulatory element-binding protein 1c (SREBP-1c) regulatory gene expression. To validate the impact of SREBP-1c as a beneficial mediator of CR, we compared the responses to CR between wild-type and SREBP-1c knockout (KO) mice. CR extended lifespan, upregulated gene expression involved in FA biosynthesis, activated mitochondrial biogenesis, and suppressed oxidative stress predominantly in WAT. In contrast, most of these findings were not observed in KO mice. Furthermore, SREBP-1c was implicated in CR-associated mitochondrial activation through upregulation of peroxisome proliferator-activated receptor γ coactivator-1α ([[PGC]]-1α), a master regulator of mitochondrial biogenesis. Sirtuin-3 (SIRT3) regulates mitochondrial quality and is also involved in the beneficial actions of CR. We observed that CR upregulated the mature form of SIRT3 protein and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in WAT. MIPEP cleaved precursor form of SIRT3 to mature form, and activated certain mitochondrial matrix proteins, suggesting that MIPEP might contribute to maintenance of mitochondrial quality during CR via SIRT3 activation. Taken together, CR induces SREBP-1c-dependent metabolic remodeling, including enhancement of FA biosynthesis and mitochondrial activation, via [[PGC]]-1α, and improvement of mitochondria quality via Mipep in WAT, resulting in beneficial actions.
|mesh-terms=* Adipose Tissue, White
* Aging
* Animals
* Caloric Restriction
* Gene Expression
* Humans
* Longevity
* Mice
* Organelle Biogenesis
* Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
* Sirtuin 3
* Sterol Regulatory Element Binding Protein 1
* Up-Regulation
|keywords=* caloric restriction (CR)
* fatty acid biosynthesis
* mitochondria
* white adipose tissue (WAT)
|full-text-url=https://sci-hub.do/10.1248/yakushi.19-00193-2
}}
{{medline-entry
|title=Kynurenine aminotransferase isoforms display fiber-type specific expression in young and old human skeletal muscle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32068089
|abstract=Conversion of kynurenine (KYN) to kynurenic acid (KYNA) is the main pathway for free tryptophan degradation in skeletal muscle and has emerged as an important mechanism of how exercise is linked to promotion of mental health. Metabolism of KYN to KYNA mainly depends on the expression of kynurenine aminotransferases (KATs) that is under control of the mitochondria biogenesis regulator [[PGC]]-1α. We therefore hypothesized that expression of KATs would vary between muscle fibers that differ in mitochondrial content, i.e. oxidative type I vs more glycolytic type II muscle fibers. Moreover, we tested the hypothesis that KAT expression differs with age. Single muscle fibers were isolated from biopsies taken from the vastus lateralis muscle in young and old healthy subjects. In young and old subjects the abundance of KAT I, KAT III and KAT IV was greater in Type I than Type II fibers without age-dependent difference in the KAT isoform expressions. The link to mitochondrial content was further seen as the expression of KAT IV correlated to mitochondrial cytochrome c oxidase IV (COX IV) abundance in both fiber types. In conclusion, we describe for the first time the expression pattern of KAT isoforms with respect to specific fiber types and age in human skeletal muscle.

|keywords=* Aging
* Kynurenine aminotransferases
* Mitochondria
* Muscle fiber-type
* Skeletal muscle
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110880
}}
{{medline-entry
|title=Ubiquinol-10 delays postovulatory oocyte aging by improving mitochondrial renewal in pigs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31958774
|abstract=Ubiquinol-10, the reduced form of coenzyme Q10, protects mammalian cells from oxidative damage and enhances mitochondrial activity. However, the protective effect of ubiquinol-10 on mammalian oocytes is not well understood. In this study, we investigated the effect of ubiquinol-10 on porcine oocytes during postovulatory aging. Metaphase II oocytes were selected as fresh oocytes and further cultured for 48 h with different concentrations of ubiquinol-10 (0-400 μM) [i]in vitro[/i] as a postovulatory aging model. After choosing the optimal concentration of ubiquinol-10 (100 μM) that maintained oocyte morphology and developmental competence during the progression of aging, the oocytes were randomly divided into five groups: fresh, control-24 h, ubiquinol-24 h, control-48 h, and ubiquinol-48 h. The results revealed that ubiquinol-10 significantly prevented aging-induced oxidative stress, GSH reduction, cytoskeleton impairment, apoptosis, and autophagy. Mitochondrial biogenesis (SIRT1 and [[PGC]]-1α) and mitophagy (PINK1 and PARKIN)-related proteins were decreased during aging. Addition of ubiquinol-10 prevented the aging-induced reduction of these proteins. Consequently, although mitochondrial content was decreased, the number of active mitochondria and ATP level were significantly increased upon treatment with ubiquinol-10. Thus, ubiquinol-10 has beneficial effects on porcine postovulatory aging oocytes owing to its antioxidant properties and ability to promote mitochondrial renewal.

|keywords=* mitochondria
* oxidative stress
* pig
* postovulatory aging
* ubiquinol-10
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053629
}}
{{medline-entry
|title=Mitochondrial oxidative capacity and NAD  biosynthesis are reduced in human sarcopenia across ethnicities.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31862890
|abstract=The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men from Singapore, Hertfordshire UK and Jamaica. Individuals with sarcopenia reproducibly demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low [[PGC]]-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced mitochondrial respiratory complex expression and activity, and low NAD  levels through perturbed NAD  biosynthesis and salvage in sarcopenic muscle. We provide an integrated molecular profile of human sarcopenia across ethnicities, demonstrating a fundamental role of altered mitochondrial metabolism in the pathological loss of skeletal muscle mass and function in older people.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biopsy
* Case-Control Studies
* Energy Metabolism
* Humans
* Jamaica
* Male
* Middle Aged
* Mitochondria
* Muscle, Skeletal
* NAD
* Oxidation-Reduction
* Oxidative Phosphorylation
* Oxidative Stress
* Proteostasis
* Sarcopenia
* Singapore
* United Kingdom

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925228
}}
{{medline-entry
|title=MicroRNA-34a (miR-34a) Mediates Retinal Endothelial Cell Premature Senescence through Mitochondrial Dysfunction and Loss of Antioxidant Activities.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31443378
|abstract=Stress-associated premature senescence (SAPS) is involved in retinal microvascular injury and diabetic retinopathy. We have investigated the role and mode of action of miR-34a in retinal endothelial cells senescence in response to glucidic stress. Human retinal microvascular endothelial cells (HuREC) were exposed to glucidic stress (high glucose (HG) = 25 mM d-glucose) and compared to cells exposed to normal glucose (NG = 5 mM) or the osmotic control l-glucose (LG = 25 mM). HG stimulation of HuREC increased the expression of miR-34a and induced cellular senescence. HG also increased the expression of p16ink4a and p21waf1, while decreasing the histone deacetylase SIRT1. These effects were associated with diminished mitochondrial function and loss of mitochondrial biogenesis factors (i.e., [[PGC]]-1α, NRF1, and TFAM). Transfection of the cells with miR-34a inhibitor (IB) halted HG-induced mitochondrial dysfunction and up-regulation of senescence-associated markers, whereas miR-34a mimic promoted cellular senescence and mitochondrial dysfunction. Moreover, HG lowered levels of the mitochondrial antioxidants TrxR2 and SOD2, an effect blunted by miR-34a IB, and promoted by miR-34a mimic. 3'-UTR (3'-untranslated region) reporter assay of both genes validated TrxR2 as a direct target of miR-34a, but not SOD2. Our results show that miR-34a is a key player of HG-induced SAPS in retinal endothelial cells via multiple pathways involved in mitochondrial function and biogenesis.

|keywords=* diabetic retinopathy
* miR-34a
* mitochondrial dysfunction
* vascular senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769710
}}
{{medline-entry
|title=Constitutive [[PGC]]-1α overexpression in skeletal muscle does not protect from age-dependent decline in neurogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31444397
|abstract=Aerobic exercise prevents age-dependent decline in cognition and hippocampal neurogenesis. The transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha ([[PGC]]-1α) mediates many of the exercise-induced benefits in skeletal muscle, including the release of factors into the circulation with neurotrophic effects. We use a transgenic mouse model with muscle-specific overexpression of [[PGC]]-1α to study the contribution of chronic muscle activation on exercise-induced effects on hippocampal neurogenesis in aging. Young and old transgenic and wild type animals of both sexes displayed a robust age-related reduction in newborn BrdU -cells, immature neurons (DCX -cells) and new mature BrdU /NeuN -neurons in the dentate gyrus. No differences were detected between genotypes or sexes. Analysis of serum proteins showed a tendency towards increased levels of myokines and reduced levels of pro-inflammatory cytokines for transgenic animals, but only musclin was found to be significantly up-regulated in transgenic animals. We conclude that constitutive muscular overexpression of [[PGC]]-1α, despite potent systemic changes, is insufficient for mimicking exercise-induced effects on hippocampal neurogenesis in aging. Continued studies are required to investigate the complex molecular mechanisms by which circulating signals could mediate exercise-induced effects on the central nervous system in disease and aging, with the aim of discovering new therapeutic possibilities for patients.
|mesh-terms=* Aging
* Animals
* Blood Proteins
* Cytokines
* Female
* Hippocampus
* Male
* Mice, Inbred C57BL
* Mice, Transgenic
* Muscle, Skeletal
* Neurogenesis
* Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
* Reproducibility of Results

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707251
}}
==CD28==

{{medline-entry
|title=Premature CD4  T Cells Senescence Induced by Chronic Infection in Patients with Acute Coronary Syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33269101
|abstract=Acquired immune responses mediated by CD4  T cells contribute to the initiation and progression of acute coronary syndrome (ACS). ACS patients show acquired immune system abnormalities that resemble the characteristics of autoimmune dysfunction described in the elderly. This study aimed to investigate the role of premature CD4  T cells senescence in ACS and the underlying mechanism. We compared the immunological status of 25 ACS patients, 15 young healthy individuals (C1), and 20 elderly individuals with absence of ACS (C2). The percentages of CD4  T lymphocyte subsets (including naïve, regulatory, memory and effector T cells) in peripheral blood were analyzed. In ACS patients, a significant expansion of CD4 [[CD28]]  effector T cells and a decline of CD4 CD25 CD62L Treg cells were observed. In addition, patients with ACS showed an accelerated loss of CD4 CD45RA CD62L  naïve T cells and a compensatory increase in the number of CD4 CD45RO  memory T cells. ACS patients demonstrated no significant difference in frequency of T cell receptor excision circles (TRECs) compared to age-matched healthy volunteers. The expression of p16  was increased while CD62L was decreased in CD4 [[CD28]]  T cells of ACS patients. Compared to healthy donors, ACS patients demonstrated the lowest telomerase activity in both CD4 [[CD28]] and CD4 [[CD28]]  T cells. The serum levels of C-reactive protein, Cytomegalovirus IgG, [i]Helicobactor pylori[/i] IgG and [i]Chlamydia pneumonia[/i] IgG were significantly higher in ACS patients. The results suggested that the percentage of CD4  T cell subpopulations correlated with chronic infection, which contributes to immunosenescence. In conclusion, chronic infection induced senescence of premature CD4 T cells, which may be responsible for the development of ACS.

|keywords=* CD28null T cells
* CD4+ T cells
* acute coronary syndrome
* immunosenescence
* infection
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673853
}}
{{medline-entry
|title=The IMMENSE Study: The Interplay Between iMMune and ENdothelial Cells in Mediating Cardiovascular Risk in Systemic Lupus Erythematosus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33193356
|abstract=Patients with systemic lupus erythematosus (SLE) have a significant increase in cardiovascular (CV) risk although they display a preserved number of circulating angiogenic CD3 CD31 CXCR4  T cells (T ), a subpopulation of T cells which promotes repair of damaged endothelium. This happens due to the concomitant expansion of a T  subset with immunosenescent features, such as the loss of [[CD28]]. Therefore, the aim of this study was to elucidate the interplay between T  subpopulations and endothelial cells in a group of young SLE patients without previous cardiovascular events. Twenty SLE female patients and 10 healthy controls (HCs) were recruited. Flow cytometric analysis of endothelial progenitor cells (EPCs) and T  subsets were performed and serum levels of interleukin (IL)-6, -8, matrix metalloproteinase (MMP)-9 and interferon (IFN)-[i]γ[/i] were measured. Human umbilical vein endothelial cells (HUVECs) proliferation and pro-inflammatory phenotype in response to subjects' serum stimulation were also evaluated. Results showed that the percentage of T  and EPC subsets was reduced in SLE patients compared with HCs, with a marked increase of senescent [[CD28]]  cells among T  subset. SLE disease activity index-2000 (SLEDAI-2K) was inversed related to T  cells percentage. Furthermore, IL-8 serum levels were directly correlated with the percentage of T  and inversely related to the [[CD28]]  T  subsets. We indirectly evaluated the role of the T  subset on the endothelium upon stimulation with serum from subjects with a low percentage of T  CD3  cells in HUVECs. HUVECs displayed pro-inflammatory phenotype with up-regulation of mRNA for IL-6, intercellular adhesion molecule (ICAM)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Cell proliferation rate was directly related to IL-8 serum levels and EPC percentage. In highly selected young SLE patients without previous CV events, we found that the deterioration of T  compartment is an early event in disease course, preceding the development of an overt cardiovascular disease and potentially mediated by SLE-specific mechanisms. The overcome of the [[CD28]]  subset exerts detrimental role over the T  phenotype, where T  could exert an anti-inflammatory effect on endothelial cells and might orchestrate [i]via[/i] IL-8 the function of EPCs, ultimately modulating endothelial proliferation rate.

|keywords=* angiogenic T cells
* cardiovascular risk
* endothelial progenitor cells
* immunosenescence
* systemic lupus erythematosus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658008
}}
{{medline-entry
|title=Emergence of T cell immunosenescence in diabetic chronic kidney disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33088331
|abstract=Type 2 diabetes is an important challenge given the worldwide epidemic and is the most important cause of end-stage renal disease (ESRD) in developed countries. It is known that patients with ESRD and advanced renal failure suffer from immunosenescence and premature T cell aging, but whether such changes develop in patients with less severe chronic kidney disease (CKD) is unclear. 523 adult patients with type 2 diabetes were recruited for this study. Demographic data and clinical information were obtained from medical chart review. Immunosenescence, or aging of the immune system was assessed by staining freshly-obtained peripheral blood with immunophenotyping panels and analyzing cells using multicolor flow cytometry. Consistent with previously observed in the general population, both T and monocyte immunosenescence in diabetic patients positively correlate with age. When compared to diabetic patients with preserved renal function (estimated glomerular filtration rate > 60 ml/min), patients with impaired renal function exhibit a significant decrease of total CD3  and CD4  T cells, but not CD8  T cell and monocyte numbers. Immunosenescence was observed in patients with CKD stage 3 and in patients with more severe renal failure, especially of CD8  T cells. However, immunosenescence was not associated with level of proteinuria level or glucose control. In age, sex and glucose level-adjusted regression models, stage 3 CKD patients exhibited significantly elevated percentages of [[CD28]] , CD127 , and CD57  cells among CD8  T cells when compared to patients with preserved renal function. In contrast, no change was detected in monocyte subpopulations as renal function declined. In addition, higher body mass index (BMI) is associated with enhanced immunosenescence irrespective of CKD status. The extent of immunosenescence is not significantly associated with proteinuria or glucose control in type 2 diabetic patients. T cells, especially the CD8  subsets, exhibit aggravated characteristics of immunosenescence during renal function decline as early as stage 3 CKD. In addition, inflammation increases since stage 3 CKD and higher BMI drives the accumulation of CD8 CD57  T cells. Our study indicates that therapeutic approaches such as weight loss may be used to prevent the emergence of immunosenescence in diabetes before stage 3 CKD.

|keywords=* BMI
* CKD
* Diabetes
* Immunosenescence
* T cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574244
}}
{{medline-entry
|title=The relationship between Chlamydia pneumoniae infection and CD4/CD8 ratio, lymphocyte subsets in middle-aged and elderly individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33068732
|abstract=Chlamydia pneumoniae (C. pneumoniae) is a common respiratory pathogen associated with many inflammatory diseases. There are few data concerning the lymphocyte subsets in middle-aged and elderly individuals with C. pneumoniae infection. A total of 191 patients were included in this study. The study population was categorized into the middle-aged group (40-64 years old) and the elderly group (65-89 years old). Lymphocyte subsets in peripheral blood were examined with multi-colored flow cytometry. Immunological monitoring included lymphocyte subsets, C. pneumoniae IgG and IgM serology. In the middle-aged group, 69.83% individuals presented IgG positivity, which was associated with the inverted CD4/CD8 ratio. Individuals with C. pneumoniae IgG positivity also presented an increased percentage of CD8 [[CD28]]  cells and a decreased CD4/CD8 ratio when compared to weakly-positive individuals. In the elderly group, C. pneumoniae IgG positivity was associated with a significant increase in the percentage of CD3 CD56 CD45  (NKT) cells. In conclusion, altered lymphocyte homeostasis was shown in middle-aged individuals with C. pneumoniae IgG positivity. The senescent phenotypes of T cells might be associated with C. pneumoniae infection in middle-aged individuals.

|keywords=* CD4/CD8 ratio
* Chlamydia pneumoniae
* Immune profile
* Immunosenescence
* Lymphocyte subsets
|full-text-url=https://sci-hub.do/10.1016/j.micpath.2020.104541
}}
{{medline-entry
|title=Next steps in mechanisms of inflammaging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32960694
|abstract=Striking age-related changes occur in the human immune system, beginning in the sixth decade of life. Age is a non-modifiable, universal risk factor that results in the dysregulation of many cellular homeostatic processes. The decline in immune cell macroautophagy/autophagy and the increased generation of proinflammatory cytokines during agingfuels the development of diseases in the elderly. We reported that higher Th17 inflammation during aging was secondary to dysregulation in T cell autophagy. However, the mechanism underlying lower anti-CD3 and anti-[[CD28]] activation-induced T cell autophagy during aging remain unknown. Our data fuel the speculation that dysregulation of the glutathione (GSH) system might cause the decline in T cell autophagy in aging, additionally provoked by reactive oxygen species signaling emanating from the mitochondria.

|keywords=* Aging
* autophagy
* glutathione
* membrane potential
* mitochondria
* oxidative stress
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1822089
}}
{{medline-entry
|title=A randomized pilot trial to evaluate the benefit of the concomitant use of atorvastatin and Raltegravir on immunological markers in protease-inhibitor-treated subjects living with HIV.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32941476
|abstract=Optimization of antiretroviral therapy and anti-inflammatory treatments, such as statins, are among the strategies aimed at reducing metabolic disorders, inflammation and immune activation in people living with HIV (PLWH). We evaluated the potential benefit of combining both strategies. Forty-two PLWH aged ≥40 years receiving a protease inhibitor (PI)-based regimen were randomized (1:1) to switch from PI to Raltegravir (n = 20), or to remain on PI (n = 22). After 24 weeks, all patients received atorvastatin 20mg/day for 48 weeks. We analyzed plasma inflammatory as well as T-cell maturation, activation, exhaustion and senescence markers at baseline, 24 and 72 weeks. Plasma inflammatory markers remained unchanged. Furthermore, no major changes on T-cell maturation subsets, immunoactivation, exhaustion or immunosenescence markers in both CD4 and CD8 T cell compartments were observed. Only a modest decrease in the frequency of CD38+ CD8 T cells and an increase in the frequency of [[CD28]]-CD57+ in both CD4 and CD8 T-cell compartments were noticed in the Raltegravir-switched group. The study combined antiretroviral switch to Raltegravir and Statin-based anti-inflammatory strategies to reduce inflammation and chronic immune activation in PLWH. Although this combination was safe and well tolerated, it had minimal impact on inflammatory and immunological markers. NCT02577042.
|mesh-terms=* Adult
* Anti-HIV Agents
* Anticholesteremic Agents
* Atorvastatin
* CD4-Positive T-Lymphocytes
* CD8-Positive T-Lymphocytes
* Female
* HIV Infections
* HIV Protease Inhibitors
* Humans
* Immunosenescence
* Inflammation
* Lymphocyte Activation
* Male
* Middle Aged
* Pilot Projects
* Raltegravir Potassium

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498036
}}
{{medline-entry
|title=Aging affects responsiveness of peripheral blood mononuclear cells to immunosuppression of periodontal ligament stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32663414
|abstract=The effect of age on the response of peripheral blood mononuclear cells (PBMCs) to immunosuppression induced by human periodontal ligament stem cells (hPDLSCs) is unclear. The identity of the cytokines most effective in inducing the PBMC immune response remains unknown. This study investigated the effects of age on immunophenotype, proliferation, activation, and cytokine secretion capacities of PBMCs following co-culture with hPDLSCs. PBMCs were collected from younger (16-19 years) and older (45-55 years) donors, then co-cultured with confirmed hPDLSCs for various lengths of time. T lymphocyte proliferation and cell surface marker expression were analyzed by flow cytometry. Cytokine expression levels were measured by quantitative polymerase chain reaction assays and enzyme-linked immunosorbent assays. [[CD28]] expression by T lymphocytes decreased with age, indicating reduced proliferation; CD95 expression increased with age, indicating enhanced apoptosis. Moreover, hPDLSCs inhibited T lymphocyte proliferation in both age groups; this inhibition was stronger in cells from older donors than in cells from younger donors. Age reduced the secretion of interleukin-2 and interferon-γ, whereas it increased the secretion of tumor necrosis factor-β by PBMCs cultured with hPDLSCs. Aging may have a robust effect on the response of PBMCs towards hPDLSC-induced immunosuppression.

|keywords=* Periodontal ligament stem cells
* T lymphocytes
* age
* coculture
* cytokines
* immunophenotyping
* immunosenescence
* immunosuppression
* peripheral blood mononuclear cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364836
}}
{{medline-entry
|title=Comparison of Donepezil, Memantine, Melatonin, and Liuwei Dihuang Decoction on Behavioral and Immune Endocrine Responses of Aged Senescence-Accelerated Mouse Resistant 1 Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32477103
|abstract=Aging is a natural biological process associated with cognitive decline and neuroendocrine-immune system changes; the neuroendocrine-immune system plays crucial role in brain aging and neurodegeneration, and it is essential to discern beneficial attempts to delay the aging progress based on immunological aging. In this study, we have investigated the effects of Traditional Chinese Medicine (TCM)-Liuwei Dihuang decoction (LW)-and donepezil, memantine, and melatonin on cognitive decline in aging mice. The aged SAMR1 mice received oral administration of donepezil (1mg/kg), memantine (10 mg/kg), melatonin (10 mg/kg), and LW (10 g/kg) for 3 months. A shuttle box, Morris water maze, and elevated-zero maze were performed to assess cognitive function, and flowcytometry, Luminex, and radioimmunoassay were performed to measure the lymphocyte subsets, inflammatory factors, and hormones. We observed that survival days of mice was increased with melatonin and LW, the anxiety behavior was significantly improved by memantine, melatonin, and LW treatment, active avoidance responses significantly improved by LW, donepezil, and memantine, the spatial learning ability was significantly improved by donepezil, and LW and melatonin were beneficial to the spatial memory of old mice. For immune function, LW increased CD4  and CD4 [[CD28]]  cells and reduced TNF-α, IL-1β, and G-CSF in plasma, and it also promoted the secretion of anti-inflammatory factors IL-4, IL-5, and IL-10 by regulating the active of Th2 cells in spleen. Donepezil and memantine exerted protective effects against CD4 [[CD28]]  cell decrease caused by aging and reduced the pro-inflammatory factors TNF-α, IL-1β, and G-CSF in plasma. Melatonin could reverse CD8 [[CD28]]  cell imbalances and increased B cells. For endocrine factors, LW increased TSH levels in the pituitary, and melatonin increased the GH level in blood. Our findings indicated that LW improved the cognitive decline in aging mice, and this might be associated with modulation of the active T cells and HPG axis hormones as well as increasing anti-inflammatory factors. Meanwhile, donepezil and memantine have advantages in regulating adaptive immunity, melatonin has advantages in the regulation of B cells and pituitary hormones, and LW exhibits a better effect on neuroendocrine immune function compared with the others from a holistic point of view. LW might be a potential therapeutic strategy for anti-aging-related syndromes, and it can also provide a value on medication guidance about drug combinations or treatment in clinic.

|keywords=* Liuwei Dihuang decoction
* aging
* cognition
* immune response
* inflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241684
}}
{{medline-entry
|title=Immunosenescent characteristics of T cells in young patients following haploidentical haematopoietic stem cell transplantation from parental donors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32280463
|abstract=Paediatric and adolescent patients in need of allogeneic haematopoietic stem cell transplantation (HSCT) generally receive stem cells from older, unrelated or parental donors when a sibling donor is not available. Despite encouraging clinical outcomes, it has been suggested that immune reconstitution accompanied by increased replicative stress and a large difference between donor and recipient age may worsen immunosenescence in paediatric recipients. In this study, paired samples were collected at the same time from donors and recipients of haploidentical haematopoietic stem cell transplantation (HaploSCT). We then conducted flow cytometry-based phenotypic and functional analyses and telomere length (TL) measurements of 21 paired T-cell sets from parental donors and children who received T-cell-replete HaploSCT with post-transplant cyclophosphamide (PTCy). Senescent T cells, [[CD28]]  or CD57  cells, were significantly expanded in patients. Further, not only CD4 [[CD28]]  T cells, but also CD4 [[CD28]]  T cells showed reduced cytokine production capacity and impaired polyfunctionality compared with parental donors, whereas their TCR-mediated proliferation capacity was comparable. Of note, the TL in patient T cells was preserved, or even slightly longer, in senescent T cells compared with donor cells. Regression analysis showed that senescent features of CD4  and CD8  T cells in patients were influenced by donor age and the frequency of [[CD28]]  cells, respectively. Our data suggest that in paediatric HaploSCT, premature immunosenescent changes occur in T cells from parental donors, and therefore, long-term immune monitoring should be conducted.

|keywords=* CD28− T cells
* HaploSCT
* immune monitoring
* immunosenescence
* telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142179
}}
{{medline-entry
|title=Diagnosis-independent loss of T-cell costimulatory molecules in individuals with cytomegalovirus infection.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32209361
|abstract=Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n = 98, mean age(SD) = 36(10) years, 74.5% female, 57.1% CMV ) and comparison controls (n = 98, mean age(SD) = 34(10) years, 68.4% female, 51.0% CMV ) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27 [[CD28]] ) cells within CD4  and CD8  T-cell subsets, i.e. naive (CCR7 CD45RA ), effector memory (EM, CCR7 CD45RA ), central memory (CM, CCR7 CD45RA ) and effector memory cells re-expressing CD45RA (EMRA, CCR7 CD45RA ). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27 [[CD28]]  cells within CD4  and CD8  memory T-cell subsets (p's < 0.004), but there was no significant effect of MDD, nor any significant interaction between CMV and diagnosis. Unexpectedly, depressed men were less likely to be CMV  and depressed women were more likely to be CMV  than sex-matched controls suggesting a possible interaction between sex and MDD on CMV susceptibility, but this three-way interaction did not significantly affect the T-cell subtypes. Our findings suggest that depression in young and middle-aged adults does not prematurely advance aging of the T-cell compartment independently of CMV, but there may be significant sex-specific effects on adaptive immunity that warrant further investigation.

|keywords=* Biological aging
* Cytomegalovirus
* Depression
* Immunosenescence
* Major depressive disorder
* Sex differences
* T-cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594105
}}
{{medline-entry
|title=Accelerated immunosenescence in rheumatoid arthritis: impact on clinical progression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32190092
|abstract=Patients with rheumatoid arthritis (RA) develop features of accelerated ageing, including immunosenescence. These changes include decreased thymic functionality, expansion of late-differentiated effector T cells, increased telomeric attrition, and excessive production of cytokines (senescence-associated secretory phenotype). The progression of RA has been associated with the early development of age-related co-morbidities, including osteoporosis, cardiovascular complications, and cognitive impairment. Here I review data supporting the hypothesis that immune-senescence contributes to the aggravation of both articular and extra-articular manifestations. Of note, poor cognitive functions in RA were associated with senescent [[CD28]]- T cells, inflammaging, and autoantibodies against brain antigens. The pathways of immune-to-brain communication are discussed and provide the rationale for the cognitive impairment reported in RA.

|keywords=* Ageing
* Cell senescence
* Cognitive impairment
* Immune ageing
* Rheumatoid arthritis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068869
}}
{{medline-entry
|title=Accelerated immune aging was correlated with lupus-associated brain fog in reproductive-age systemic lupus erythematosus patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32107852
|abstract=Cognitive impairment is common in systemic lupus erythematosus (SLE) patients with substantial adverse effects on function and quality of life. One hypothesis to understand the mechanisms of cognitive impairment in SLE is accelerated immunosenescence. The aim of this study is to observe the correlation between immunosenescence with cognitive impairment in patients with SLE. Sixty-one female SLE patient were measured for CD4 and CD8 T cell-associated senescence markers, including percentage of end-stage differentiated T cells (CD4 and CD8 T cells expressing CD57  or loss of [[CD28]] expression), of naïve T cells (CD4  CD45RA  and CD8  CD45RA  ), memory T cells (CD4  CD45RO  and CD8  CD45RO  ), and antigen-experienced T cells (CD4  KLRG1  and CD8  KLRG1  ) which were measured using flow cytometry. One hallmark of immunosenescence called immune risk profile (IRP) was defined by an inverted ratio of CD4 and CD8. Cognitive functions were measured by Mini-Mental State Examination (MMSE) and Montréal Cognitive Assessment (MOCA) questionnaire. Thirty-six (59.1%) SLE patients who had IRP develop significantly lower attention and recall from both MMSE (P = .005 and P = .000) and MOCA (P = .017 and P = .000) examinations. Decreased visuospatial ability was also found in patients with IRP measured by MOCA (P = .046). There was a negative correlation between memory CD4  CD45RO  T cells with recall and visuospatial domain (R = -0.204, P = .039 and R = -0.250, P = .033; respectively), and negative correlation between CD8  [[CD28]]  T cells with recall and attention domain (R = -0.249, P = .027 and R = -0.145, P = .048, respectively). Systemic lupus erythematosus patients develop an accelerated immunosenescence which contributes to cognitive dysfunction, especially in attention, recall, and visuospatial domains.

|keywords=* immunosenescence
* lupus-associated brain fog
* systemic lupus erythematosus
|full-text-url=https://sci-hub.do/10.1111/1756-185X.13816
}}
{{medline-entry
|title=T cells, aging and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32092501
|abstract=The T cell compartment undergoes characteristic changes with age, which contribute to increased incidence and severity of infections and reduced immunogenicity and efficacy of many vaccines in the older population. Production of naïve T cells is severely impaired due to a decreased output of lymphoid cells from the bone marrow and the involution of the thymus. At the same time, antigen-experienced, highly differentiated T cells accumulate resulting in a diminished T cell receptor repertoire. These cells show some similarities with senescent cells, such as shorter telomers, accumulated DNA damage and metabolic changes. Latent infection with Cytomegalovirus also impacts the T cell compartment and aggravates several of its age-associated changes. Loss of [[CD28]] expression is one hallmark of T cells after repeated antigenic stimulation, but [[CD28]]  T cells cannot be considered truly senescent as e.g. they are still able to proliferate upon adequate stimulation. Several additional markers have been suggested in order to define a potential fully senescent T cell population, but no consensus definition has been reached so far. It has been postulated that highly differentiated senescent-like T cells are unable to eliminate other senescent cell types. Removal of senescent non-immune cells has been shown to be beneficial for the organism and a reliable definition of senescent T cells is essential for an extension of this concept to T cells.

|keywords=* Aging
* Senescence
* T cells
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110887
}}
{{medline-entry
|title=Liver fibrosis and accelerated immune dysfunction (immunosenescence) among HIV-infected Russians with heavy alcohol consumption - an observational cross-sectional study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31892306
|abstract=The multifactorial mechanisms driving negative health outcomes among risky drinkers with HIV may include immunosenescence. Immunosenescence, aging of the immune system, may be accentuated in HIV and leads to poor outcomes. The liver regulates innate immunity and adaptive immune tolerance. HIV-infected people have high prevalence of liver-related comorbidities. We hypothesize that advanced liver fibrosis/cirrhosis is associated with alterations in T-cell subsets consistent with immunosenescence. ART-naïve people with HIV with a recent history of heavy drinking were recruited into a clinical trial of zinc supplementation. Flow cytometry was used to characterize T-cell subsets. The two primary dependent variables were CD8+ and CD4+ T-cells expressing [[CD28]]-CD57+ (senescent cell phenotype). Secondary dependent variables were CD8+ and CD4+ T-cells expressing CD45RO + CD45RA- (memory phenotype), CD45RO-CD45RA+ (naïve phenotype), and the naïve phenotype to memory phenotype T-cell ratio (lower ratios associated with immunosenescence). Advanced liver fibrosis/cirrhosis was defined as FIB-4 > 3.25, APRI≥1.5, or Fibroscan measurement ≥10.5 kPa. Analyses were conducted using multiple linear regression adjusted for potential confounders. Mean age was 34 years; 25% female; 88% hepatitis C. Those with advanced liver fibrosis/cirrhosis (N = 25) had higher HIV-1 RNA and more hepatitis C. Advanced liver fibrosis/cirrhosis was not significantly associated with primary or secondary outcomes in adjusted analyses. Advanced liver fibrosis/cirrhosis was not significantly associated with these senescent T-cell phenotypes in this exploratory study of recent drinkers with HIV. Future studies should assess whether liver fibrosis among those with HIV viral suppression and more advanced, longstanding liver disease is associated with changes in these and other potentially senescent T-cell subsets.
|mesh-terms=* Adult
* Alcoholism
* CD28 Antigens
* CD4-Positive T-Lymphocytes
* CD57 Antigens
* CD8-Positive T-Lymphocytes
* Cross-Sectional Studies
* Female
* HIV Infections
* Hepatitis C
* Humans
* Immunologic Memory
* Immunosenescence
* Leukocyte Common Antigens
* Linear Models
* Liver Cirrhosis, Alcoholic
* Male
* Phenotype
* Randomized Controlled Trials as Topic
* Russia
* Zinc
|keywords=* Alcohol
* HIV
* Immune senescence
* Liver fibrosis
* Russia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938606
}}
{{medline-entry
|title=Effect of Allogenic Bone Marrow Mesenchymal Stem Cell Transplantation on T Cells of Old Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31895587
|abstract=To evaluate age-related changes in T cells and stem cell-related genes in mice and the changes in T cells and stem cell-related genes after allogenic bone marrow mesenchymal stem cell (BMSC) transplantation, BALB/c mice were divided into young (2 months, [i]n[/i] = 5) and old (20 months, [i]n[/i] = 5) groups and 1 × 10  BMSCs from 3-week-old C57BL/6J mice were injected into the old mice ([i]n[/i] = 5). T lymphocytes including CD3 , CD8 , CD8 [[CD28]] , and CD8 CD44 CD62L Sca-1  stem cell-like memory T cells from spleens were analyzed by flow cytometry. mRNA transcriptions of the tumor suppressor [i]p16 [/i] and the senescence inhibiting [i]AUF 1[/i] and stem cell-related [i]ADAM12[/i], [i]GIL3[/i], [i]c-MYC[/i], [i]NANOG[/i], [i]Wnt[/i], [i]HOX11[/i], [i]Sox2[/i], [i]Oct3/4[/i], and [i]KLF4[/i] genes were analyzed by quantitative reverse transcription-polymerase chain reaction for comparison between young and old mice and old mice after BMSC application. Stem cell-related genes were reduced transcribed in old mice, an action that could be partly or completely reversed for some genes by BMSC injections. The proportion of CD8 [[CD28]]  T cells in the spleens of old mice was significantly reduced ([i]p[/i] < 0.01), indicating advanced proliferative T cell senescence. The CD8 CD44 CD62L  cell fraction was significantly reduced and that of CD8 CD44 CD62L Sca-1  increased in splenic CD8  cells of old mice, both actions of which were reversed by BMSC injections. [i]p16 [/i] transcription was enhanced and [i]AUF1[/i] transcription was reduced in old mice, the latter effect partly reversed by BMSC injections. BMSC injections led to recovery of stem cell-related gene activation or BMSC stem cell-related gene expression tolerance in spleens of old mice.

|keywords=* aging
* cellular senescence
* memory T cells
* stem cell
|full-text-url=https://sci-hub.do/10.1089/cell.2019.0055
}}
{{medline-entry
|title=Peripheral antibody concentrations are associated with highly differentiated T cells and inflammatory processes in the human bone marrow.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31462901
|abstract=Antigen-experienced immune cells migrate back to the bone marrow (BM), where they are maintained in BM survival niches for an extended period. The composition of T cell subpopulations in the BM changes with age, leading to an accumulation of highly differentiated T cells and a loss of naïve T cells. While innate immune cells are also affected by age, little is known about interactions between different adaptive immune cell populations maintained in the BM. In this study, the phenotype and function of innate and adaptive immune cells isolated from human BM and peripheral blood (PB) was analysed in detail using flow cytometry, to determine if the accumulation of highly differentiated T and B cells, supported by the BM niches, limits the maintenance of other immune cells, or affects their functions such as providing protective antibody concentrations. Total T cells increase in the BM with age, as do highly differentiated CD8  T cells which no longer express the co-stimulatory molecule [[CD28]], while natural killer T (NKT) cells, monocytes, B cells, and naïve CD8  T cells all decrease in the BM with age. A negative correlation of total T cells with B cells was observed in the BM. The percentage of B cells in the BM negatively correlated with highly differentiated CD8 [[CD28]]  T cells, replicative-senescent CD8 CD57  T cells, as well as the CD8 [[CD28]] CD57  population. Similar correlations were seen between B cells and the frequency of highly differentiated T cells producing pro-inflammatory molecules in the BM. Interestingly, plasma concentrations of diphtheria-specific antibodies negatively correlated with highly differentiated CD8 CD57  T cells as well as with exhausted central memory CD8  and CD4  T cells in the BM. A negative impact on diphtheria-specific antibodies was also observed for CD8  T cells expressing senescence associated genes such as the cell cycle regulator p21 (CDKN1A), KLRG-1, and elevated levels of reactive oxygen species (ROS). Our data suggest that the accumulation and maintenance of highly differentiated, senescent, and exhausted T cells in the BM, particularly in old age, may interfere with the survival of other cell populations resident in the BM such as monocytes and B cells, leading to reduced peripheral diphtheria antibody concentrations as a result. These findings further highlight the importance of the BM in the long-term maintenance of immunological memory.

|keywords=* Aging
* Antibodies
* B cells
* Bone marrow
* Exhaustion
* Immunosenescence
* Inflammation
* Pro-inflammatory
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706884
}}
==HGS==

{{medline-entry
|title=Handgrip strength asymmetry is associated with future falls in older Americans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33247424
|abstract=Examining handgrip strength ([[HGS]]) asymmetry could extend the utility of handgrip dynamometers for screening future falls. We sought to determine the associations of [[HGS]] asymmetry on future falls in older Americans. The analytic sample included 10,446 adults aged at least 65 years from the 2006-2016 waves of the Health and Retirement Study. Falls were self-reported. A handgrip dynamometer measured [[HGS]]. The highest [[HGS]] on each hand was used for determining [[HGS]] asymmetry ratio: (non-dominant [[HGS]]/dominant [[HGS]]). Those with [[HGS]] asymmetry ratio < 1.0 had their ratio inverted to make all [[HGS]] asymmetry ratios ≥ 1.0. Participants were categorized into asymmetry groups based on their inverted [[HGS]] asymmetry ratio: (1) 0.0-10.0%, (2) 10.1-20.0%, (3) 20.1-30.0%, and (4) > 30.0%. Generalized estimating equations were used for the analyses. Every 0.10 increase in [[HGS]] asymmetry ratio was associated with 1.26 (95% confidence interval (CI) 1.07-1.48) greater odds for future falls. Relative to those with [[HGS]] asymmetry 0.0-10.0%, participants with [[HGS]] asymmetry > 30.0% had 1.15 (CI 1.01-1.33) greater odds for future falls; however, the associations were not significant for those with [[HGS]] asymmetry 10.1-20.0% (odds ratio: 1.06; CI 0.98-1.14) and 20.1-30.0% (odds ratio: 1.10; CI 0.99-1.22). Compared to those with [[HGS]] asymmetry 0.0-10.0%, participants with [[HGS]] asymmetry > 10.0% and > 20.0% had 1.07 (CI 1.01-1.16) and 1.12 (CI 1.02-1.22) greater odds for future falls, respectively. Asymmetric [[HGS]], as a possible biomarker of impaired neuromuscular function, may help predict falls. We recommend that [[HGS]] asymmetry be considered in [[HGS]] protocols and fall risk assessments.

|keywords=* Aging
* Functional laterality
* Geriatric assessment
* Geriatrics
* Muscle strength dynamometer
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01757-z
}}
{{medline-entry
|title=Examining Additional Aspects of Muscle Function with a Digital Handgrip Dynamometer and Accelerometer in Older Adults: A Pilot Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33142897
|abstract=Background  Maximal handgrip strength ([[HGS]]) could be an incomplete and unidimensional measure of muscle function. This pilot study sought to examine the relationships between maximal [[HGS]], radial and ulnar digit grip strength, submaximal [[HGS]] force control, [[HGS]] fatigability, neuromuscular [[HGS]] steadiness, and [[HGS]] asymmetry in older adults. Methods: A digital handgrip dynamometer and accelerometer was used to collect several [[HGS]] measurements from 13 adults aged 70.9 ± 4.0 years: maximal strength, radial and ulnar digit grip strength, submaximal force control, fatigability, neuromuscular steadiness, and asymmetry. Pearson correlations determined the relationships between individual [[HGS]] measurements. A principal component analysis was used to derive a collection of new uncorrelated variables from the [[HGS]] measures we examined. Results: The individual [[HGS]] measurements were differentially correlated. Maximal strength (maximal [[HGS]], radial digit strength, ulnar digits strength), contractile steadiness (maximal [[HGS]] steadiness, ulnar digit grip strength steadiness), and functional strength (submaximal [[HGS]] force control, [[HGS]] fatigability, [[HGS]] asymmetry, [[HGS]] fatigability steadiness) emerged as dimensions from the [[HGS]] measurements that we evaluated.  : Our findings suggest that these additional measures of muscle function may differ from maximal [[HGS]] alone. Continued research is warranted for improving how we assess muscle function with more modern technologies, including handgrip dynamometry and accelerometry.

|keywords=* aging
* geriatric assessment
* muscle strength
* muscle weakness
* physical functional performance
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709634
}}
{{medline-entry
|title=The Relationship between Muscular Strength and Depression in Older Adults with Chronic Disease Comorbidity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32962093
|abstract=Older adults with disease and disability are particularly vulnerable to experiencing more severe consequences of depression. The purpose of the present study is to investigate the relationship between disease comorbidities (number of disease: ND0, 1 disease: ND1 and 2 or more diseases: ND ≥ 2), hand grip strength (low [[HGS]] and high [[HGS]]), and the prevalence of depression in Korean older adults. Data from the living profiles of older people survey that was conducted by the ministry of health and welfare in Korea were utilized. Data for 6107 females and 4347 males were appropriate for statistical tests. The results demonstrated that depression was more prevalent as ND increased ([i]p[/i] < 0.01). In addition, [[HGS]] appeared lower as ND increased in both male ([i]p[/i] < 0.01) and female subjects ([i]p[/i] < 0.01). Furthermore, relative to ND0 and low [[HGS]], ND0 and high [[HGS]] showed a ~65% reduction in the prevalence of depression ([i]p[/i] < 0.01). After adjusting for age, the prevalence of depression was reduced by ~60% in the subgroup with ND0 and high [[HGS]] relative to ND0 and low [[HGS]] ([i]p[/i] < 0.01). These data demonstrate that muscular strength indices such as [[HGS]] may be useful when assessing depression in older adults. Further research in this area is warranted.

|keywords=* aging
* depression
* disease comorbidities
* muscular strength
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558624
}}
{{medline-entry
|title=Handgrip Strength in the Korean Population: Normative Data and Cutoff Values.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32743310
|abstract=We aimed to report the age- and sex-specific normative data of Korean handgrip strength ([[HGS]]) and to establish the cutoffs values of low [[HGS]] in Korean populations. We analyzed the [[HGS]] data of 23,716 Koreans (10,793 men and 12,923 women) from the Korea National Health and Nutrition Examination Survey from 2014 to 2017. The means with standard deviations (SDs) of [[HGS]] were calculated for each 5-year interval starting from 10 years of age. To determine the relationship between [[HGS]] and body mass index (BMI), correlation analysis was also performed. The sex-specific cutoff values for low [[HGS]] were presented by deriving the -2 SD values of healthy young adults. The mean [[HGS]] was 39.5±9.3 kg in men and 24.4±5.3 kg in women. The mean [[HGS]] increased from 10 to 39 years and peaked at 35-39 years in both men (46.0±7.2 kg) and women (27.2±4.6 kg). Men showed a higher correlation between [[HGS]] and BMI (r=0.378) than did women (r=0.134). The cutoff values for low [[HGS]] were 29.6 kg for men and 16.8 kg for women for -2 SD below the reference for healthy young adults. In Koreans, the mean [[HGS]] peaked at 35-39 years in both men and women, and the aging curve of [[HGS]] was steeper in men than in women. The cutoff values for low [[HGS]] were 29.6 kg and 16.8 kg for men and women, respectively.

|keywords=* Aging
* Hand strength
* Muscle strength
* Nutrition surveys
* Sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370763
}}
{{medline-entry
|title=Handgrip Strength Asymmetry and Weakness Are Associated with Lower Cognitive Function: A Panel Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32473060
|abstract=Examining handgrip strength ([[HGS]]) asymmetry and weakness together may extend the predictive capacity of [[HGS]] for capturing possible health problems such as cognitive impairment. The purpose of this study was to determine the associations of [[HGS]] asymmetry and weakness on lower cognitive functioning in a national sample of aging Americans. Longitudinal panel. Participant residences. The analytic sample included 17,163 Americans aged 65.0 years (standard deviation = 10.1 years) who participated in the 2006 to 2016 waves of the Health and Retirement Study (HRS). A handgrip dynamometer was used to measure [[HGS]]; weakness was defined as [[HGS]] below 26 kg (men) or below 16 kg (women). Persons with [[HGS]] above 10% stronger on either hand were considered as having any [[HGS]] asymmetry. Those with [[HGS]] that was more than 10% stronger on their dominant or nondominant hand were considered as having dominant or nondominant [[HGS]] asymmetry, respectively. The Telephone Interview of Cognitive Status determined lower cognitive functioning (≤11 for ages 50-64 years; ≤10 for ages ≥65 years). Covariate-adjusted linear mixed-effects models analyzed the associations of each [[HGS]] asymmetry and weakness group on lower cognitive functioning. Relative to those with symmetric [[HGS]] and no weakness, each [[HGS]] asymmetry and weakness group had greater odds for lower cognitive functioning: 1.15 (95% confidence interval [CI] = 1.03-1.27) for any [[HGS]] asymmetry alone, 1.64 (95% CI = 1.21-2.23) for weakness alone, and 1.95 (95% CI = 1.51-2.53) for any [[HGS]] asymmetry and weakness. Each [[HGS]] asymmetry dominance and weakness group also had greater odds for lower cognitive functioning: 1.12 (95% CI = 1.01-1.25) for asymmetric dominant [[HGS]] alone, 1.27 (95% CI = 1.05-1.53) for asymmetric nondominant [[HGS]] alone, 1.64 (95% CI = 1.21-2.23) for weakness alone, 1.89 (95% CI = 1.39-2.57) for weakness and asymmetric dominant [[HGS]], and 2.10 (95% CI = 1.37-3.20) for weakness and asymmetric nondominant [[HGS]]. The presence of both [[HGS]] asymmetry and weakness may predict accelerated declines in cognitive functioning.

|keywords=* aging
* functional laterality
* geriatric assessment
* geriatrics
* muscle strength dynamometer
|full-text-url=https://sci-hub.do/10.1111/jgs.16556
}}
{{medline-entry
|title=Handgrip Strength Asymmetry and Weakness are Differentially Associated with Functional Limitations in Older Americans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32384713
|abstract=[i]Background:[/i] Handgrip strength ([[HGS]]) is a convent measure of strength capacity and associated with several age-related health conditions such as functional disability. Asymmetric strength between limbs has been linked to diminished function. Therefore, both [[HGS]] asymmetry and weakness could be associated with functional disability. We examined the associations of [[HGS]] asymmetry and weakness on functional limitations in a nationally representative sample of older Americans. [i]Methods[/i]: Data were analyzed from 2689 adults ≥ 60 years who participated in the 2011-2012 and 2013-2014 waves of the National Health and Nutrition Examination Survey. Weakness was defined as [[HGS]] < 26 kg for men and < 16 kg for women. Asymmetry was determined from the ratio of the dominant and non-dominant [[HGS]]. Those with [[HGS]] ratio 0.9-1.1 were considered as having [[HGS]] symmetry, and those outside this range had asymmetry. [i]Results:[/i] Compared to those with symmetric [[HGS]] and were not weak, those with weakness alone, and both weakness and [[HGS]] asymmetry had 2.47 (95% confidence interval [CI]: 1.14-5.35) and 3.93 (CI: 1.18-13.07) greater odds for functional limitations, respectively. However, [[HGS]] asymmetry alone was not associated with functional limitations (odds ratio: 0.80; CI: 0.62-1.03). [i]Conclusion:[/i] The use of [[HGS]] asymmetry in protocols could improve the prognostic value of handgrip dynamometers.
|mesh-terms=* Aged
* Aged, 80 and over
* Female
* Geriatric Assessment
* Hand Strength
* Humans
* Male
* Middle Aged
* Muscle Strength
* Muscle Strength Dynamometer
* Muscle Weakness
* Odds Ratio
* United States
|keywords=* aging
* geriatrics
* muscle strength
* muscle strength dynamometer
* nutrition surveys
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246814
}}
{{medline-entry
|title=Absolute and Body Mass Index Normalized Handgrip Strength Percentiles by Gender, Ethnicity, and Hand Dominance in Americans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31930203
|abstract=Gender and ethnicity are factors which influence strength, and hand dominance could be a critical component of handgrip strength ([[HGS]]) testing. Providing such [[HGS]] percentiles across the lifespan may help to identify weakness-related health concerns. We sought to generate growth charts and curves for [[HGS]] by gender and ethnicity in a nationally-representative sample of Americans aged 6-80 years. Data from 13,617 participants in the 2011-2012 and 2013-2014 waves of the National Health and Nutrition Examination Survey were analyzed. [[HGS]] was measured with a handgrip dynamometer. Age, gender, ethnicity, and hand dominance were self-reported. Body Mass Index (BMI) was calculated from height and body mass. Measures of absolute [[HGS]] and [[HGS]] normalized to BMI were separately included in parametric quantile regression analyses for determining the 10th-90th percentiles across ages by gender and ethnicity. Similar models were also conducted by hand dominance. Differences in absolute [[HGS]] and [[HGS]] normalized to BMI quantiles across ages existed for each ethnicity regardless of gender. In men, absolute [[HGS]] generally increased until about 25 years of age, began to decline around age 30 years, and regressed into older adulthood. In women, absolute [[HGS]] appeared to rise starting at age 6 years, peaked between 20 and 30 years of age, but was maintained into mid-life before declining in older adulthood. Similar results were found for [[HGS]] normalized to BMI. Our findings provide percentile charts for [[HGS]] capacity that could be utilized for comparing individual measures of [[HGS]] to those from a United States population-representative sample.

|keywords=* aging
* epidemiology
* hand strength
* human development
* muscle weakness
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954001
}}
{{medline-entry
|title=Hand grip strength variability during serial testing as an entropic biomarker of aging: a Poincaré plot analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31931730
|abstract=The Poincaré plot method can be used for both qualitative and quantitative assessment of self-similarity in usually periodic functions, hence the idea of applying it to the study of homeostasis of living organisms. From the analysis of numerous scientific data, it can be concluded that hand functionality can be correlated with the state of the human body as a biological system exposed to various forms of ontogenetic stress. We used the Poincaré plot method to analyze the variability of hand grip strength ([[HGS]]), as an entropic biomarker of aging, during 60 repetitive tests of the dominant and nondominant hand, in young and older healthy subjects. An observational cross-sectional study was performed on 80 young adults (18-22 years old, mean age 20.01 years) and 80 older people (65-69 years old, mean age 67.13 years), with a sex ratio of 1:1 for both groups. For statistical analysis, we applied univariate descriptive statistics and inferential statistics (Shapiro-Wilk test, Mann-Whitney U-test for independent large samples, with the determination of the effect size coefficient r, and simple linear regression. We calculated the effect of fatigue and the Poincaré indices SD , SD , SD /SD  and the area of the fitting ellipse (AFE) for the test values of each subject. The analysis of the differences between groups revealed statistically significant results for most [[HGS]]-derived indices (p ≤ 0.05), and the magnitude of the differences indicated, in most situations, a large effect size (r > 0.5). Our results demonstrate that the proposed repetitive [[HGS]] testing indicates relevant differences between young and older healthy subjects. Through the mathematical modeling of data and the application of the concept of entropy, we provide arguments supporting this new design of [[HGS]] testing. Our results indicate that the variability of [[HGS]] during serial testing, which reflects complex repetitive biomechanical functions, represents an efficient indicator for differentiation between young and older hand function patterns from an entropic perspective. In practical terms, the variability of [[HGS]], evaluated by the new serial testing design, can be considered an attractive and relatively simple biomarker to use for gerontological studies.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Cross-Sectional Studies
* Entropy
* Female
* Hand Strength
* Heart Rate
* Humans
* Male
|keywords=* Aging
* Entropy
* Hand grip strength
* Nonlinear dynamics
* Poincaré plot
* Time series
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958685
}}
{{medline-entry
|title=Physical Activity and Fitness in White- and Blue-Collar Retired Men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31849269
|abstract=The average life expectancy has increased and despite a distinct feminization of aging, the number of older males continues to grow. Physical activity has a positive effect on health and helps to slow down the negative consequences of aging. The aim of the study was to evaluate possible relationships between physical fitness, physical activity and type of work during occupational activity among retired men (aged ≥65 years), no longer professionally active. The study included 104 men (aged from 65 to 90 years), further stratified into blue- and white-collar groups (66 and 38 subjects, respectively). The International Physical Activity Questionnaire (IPAQ) was used to assess their physical activity levels. Physical performance was assessed using the Short Physical Performance Battery test (SPPB) and handgrip strength ([[HGS]]) measurement. Geriatric Depression Scale (GDS) was used to identify the risk for depression. Mean physical activity in the study population was moderate in almost 70%, high in 19% and low in 11% of the subjects. Men with high physical activity levels had better SPPB and GDS scores ([i]p[/i] = .01 and [i]p[/i] = .001, respectively). In the blue-collar group, the IPAQ scores were lower than in the white-collar group, although the differences were statistically insignificant. The SPPB scores and mean [[HGS]] for the dominant hand were similar in both groups. Occupational physical activity should not substitute other forms of physical activity. Regardless of the type of work performed before retirement, the men obtained similar results in terms of their physical activity.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Body Mass Index
* Exercise
* Geriatric Assessment
* Humans
* Longitudinal Studies
* Male
* Men's Health
* Occupations
* Physical Fitness
* Poland
* Retirement
* Social Class
* Surveys and Questionnaires
* Task Performance and Analysis
|keywords=* Retirement
* occupation
* old men
* physical activity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920597
}}
{{medline-entry
|title=Association between Hand Grip Strength and Self-Rated Health in Middle- and Old-Aged Korean Citizens.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31842533
|abstract=To investigate the relationship between hand grip strength ([[HGS]]) and self-rated health in middleand old-aged Korean subjects. The data used for this study were derived from the Korean Longitudinal Study of Aging. A total of 9,132 participants were enrolled using the year 2006 as the baseline, with additional data collected throughout the followup period until 2016. Chi-square test and generalized estimating equation regression models were used for data analysis. [[HGS]] was measured in a sitting position with the elbow fixed at 90° on both sides using a dynamometer, and calculated using the values measured from both sides. Relative [[HGS]] was measured by dividing [[HGS]] by the subject's body mass index. Self-rated health was assessed with the question "How would you rate your current health in general?" and answers were categorized as "excellent," "moderate," or "poor." [[HGS]] was shown to be inversely associated with self-rated health (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.93-0.94; P<0.0001). Patients aged 65 years or older with lower scores were more likely to report poor self-rated health. Similar results were obtained with relative [[HGS]] (OR, 0.40; 95% CI, 0.36-0.45; P<0.0001), but standard [[HGS]] had better model fitting (quasi-likelihood under independence model criteria=33,890). [[HGS]] may be considered an index for the diagnosis of sarcopenia and may also affect self-rated health, which is a multidimensional indicator of an individual's health status and can identify patients who may require special attention.

|keywords=* Hand Grip Strength
* Korean Longitudinal Study of Aging
* Self-Rated Health
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987025
}}
{{medline-entry
|title=Weakness May Have a Causal Association With Early Mortality in Older Americans: A Matched Cohort Analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31786197
|abstract=Quantifying the association between muscle weakness and mortality with carefully matched cohorts will help to better establish the impact of weakness on premature death. We used a matched cohort analysis in a national sample of older Americans to determine if those who were weak had a higher risk for mortality compared with control groups with incrementally higher strength capacities. Longitudinal panel. Detailed interviews that included physical measures were conducted in person, whereas core interviews were often performed over the telephone. Data from 19,729 Americans aged at least 50 years from the 2006-2014 waves of the Health and Retirement Study were analyzed. A handgrip dynamometer was used to assess handgrip strength ([[HGS]]) in each participant. Men with [[HGS]] <26 kg were considered weak, ≥26 kg were considered not weak, and ≥32 kg were considered strong. Women with [[HGS]] <16 kg were classified as weak, ≥16 kg were classified as not-weak, and ≥20 kg were classified as strong. The National Death Index and postmortem interviews determined the date of death. The greedy matching algorithm was used to match cohorts. Of the 1077 weak and not-weak matched pairs, 401 weak (37.2%) and 296 not-weak (27.4%) older Americans died over an average 4.4 ± 2.5-year follow-up. There were 392 weak (37.0%) and 243 strong (22.9%) persons who died over a mean 4.5 ± 2.5-year follow-up from the 1057 weak and strong matched pairs. Those in the weak cohort had a 1.40 [95% confidence interval (CI) 1.19, 1.64] and 1.54 (CI 1.30, 1.83) higher hazard for mortality relative to persons in the not-weak and strong control cohorts, respectively. Our findings may indicate a causal association between muscle weakness and mortality in older Americans. Health care providers should include measures of [[HGS]] as part of routine health assessments and discuss the health risks of muscle weakness with their patients.

|keywords=* Aging
* Epidemiology
* Geriatrics
* hand strength
* muscle strength
* sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186143
}}
{{medline-entry
|title=Associations Between Dietary Patterns and Handgrip Strength: The Korea National Health and Nutrition Examination Survey 2014-2016.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31743070
|abstract= The age-related decline in handgrip strength ([[HGS]]) is an important indicator of weakening muscle strength concomitant with aging and sarcopenia. This study was to investigate the association between dietary patterns and [[HGS]].  In this cross-sectional study of 7,624 adults aged 19-64 years who were enrolled in the Korea National Health and Nutrition Examination Survey 2014-2016, we assessed [[HGS]] with a digital hand dynamometer while the participants adopted a standing position with their arms lowered. Their diets were examined with a food frequency questionnaire which included 112 food items and were categorized into 26 food groups. To determine the associations between dietary patterns and [[HGS]], we employed a weighted multivariable linear regression model.  We identified two dietary patterns: the Prudent and the Western dietary patterns. Individuals in the highest tertile of the Prudent dietary pattern had the highest [[HGS]] scores ([i]β[/i] = 0.54, [i]p[/i] < 0.001). No difference was found among the tertiles of the Western dietary pattern. Sex-specific stratification (2,953 men, 4,671 women) indicated that both sexes showed significant associations with [[HGS]] according to the tertiles of their factor loading scores in the Prudent dietary pattern (men, [i]β[/i] = 0.49, [i]p[/i] = 0.014; women, [i]β[/i] = 0.51, [i]p[/i] < 0.001).  This cross-sectional study of 7,624 adults revealed a significantly positive association between [[HGS]] and the Prudent dietary pattern, even after adjusting for potential confounding factors.

|keywords=* Dietary patterns
* Korea National Health and Nutrition Examination Survey
* aging
* diet
* handgrip strength
|full-text-url=https://sci-hub.do/10.1080/07315724.2019.1691955
}}
{{medline-entry
|title=Effect of relative handgrip strength on cardiovascular disease among Korean adults aged 45 years and older: Results from the Korean Longitudinal Study of Aging (2006-2016).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31574451
|abstract=Aging causes both structural and functional changes in the skeletal muscle, and is associated with changes in body composition form, which results in an increased incidence of cardiovascular death. Handgrip strength ([[HGS]]) is a simple, fast, reliable, and cost-effective tool for measuring muscle strength. We aimed to investigate which index was most suitable for predicting cardiovascular disease (CVD), and suggested the optimal cut-off points based on the handgrip strength index. In addition, we aimed to identify the effects of weak [[HGS]], as determined by applying the optimal cut point on the occurrence of CVD. A total of 8494 older men and women aged over 45 years from the Korean Longitudinal Study of Aging (KLoSA) were included in this study at baseline. We performed general estimating equations (GEE) with independent correlation structure to assess whether handgrip strength is longitudinally related to occurrence of CVDs such as heart disease or stroke reported from 1 st to 6th wave of KLoSA. The relative [[HGS]] was strongly associated with CVD in both sexes, and the best fit model was in that in comparison to dominant [[HGS]] and absolute [[HGS]]. In addition, we calculated the optimal cut point for CVD based on the relative [[HGS]] in this study (men: 2.52 and women: 1.55, respectively), and demonstrated that low [[HGS]], as determined by applying relative [[HGS]] cut points, was associated with a higher OR for CVD compared to normal [[HGS]]; the associations observed were consistent between the sexes. Our findings suggest that [[HGS]] has the potential to be a valuable screening tool for cardiovascular risk in clinical settings; this is advantageous in situations where blood sampling is not possible since [[HGS]] is easily measured and highly reproducible. It is necessary to pay attention to weak grip strength against body size in the elderly population.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Cardiovascular Diseases
* Female
* Hand Strength
* Humans
* Longitudinal Studies
* Male
* Middle Aged
* Muscle Strength
* Muscle, Skeletal
* Republic of Korea
* Risk Factors
|keywords=* Cardiovascular disease
* KLoSA
* Relative handgrip strength
|full-text-url=https://sci-hub.do/10.1016/j.archger.2019.103937
}}
{{medline-entry
|title=Weakness and cognitive impairment are independently and jointly associated with functional decline in aging Americans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31520335
|abstract=Discovering how certain health factors contribute to functional declines may help to promote successful aging. To determine the independent and joint associations of handgrip strength ([[HGS]]) and cognitive function with instrumental activities of daily living (IADL) and activities of daily living (ADL) disability decline in aging Americans. Data from 18,391 adults aged 50 years and over who participated in at least one wave of the 2006-2014 waves of the Health and Retirement Study were analyzed. A hand-held dynamometer assessed [[HGS]] and cognitive functioning was examined with a modified version of the Telephone Interview of Cognitive Status. IADL and ADL abilities were self-reported. Participants were stratified into four distinct groups based on their [[HGS]] and cognitive function status. Separate covariate-adjusted multilevel models were conducted for the analyses. Participants who were weak, had a cognitive impairment, and had both weakness and a cognitive impairment had 1.70 (95% confidence interval (CI) 1.57-1.84), 1.97 (CI 1.74-2.23), and 3.13 (CI 2.73-3.59) greater odds for IADL disability decline, respectively, and 2.26 (CI 2.03-2.51), 1.26 (CI 1.05-1.51), and 4.48 (CI 3.72-5.39) greater odds for ADL disability decline, respectively. [[HGS]] and cognitive functioning were independently and jointly associated with IADL and ADL disability declines. Individuals with both weakness and cognitive impairment demonstrated substantially higher odds for functional decline than those with either risk factor alone. Including measures of both [[HGS]] and cognitive functioning in routine geriatric assessments may help to identify those at greatest risk for declining functional capacity.
|mesh-terms=* Activities of Daily Living
* Aged
* Aging
* Cognitive Dysfunction
* Geriatric Assessment
* Hand Strength
* Humans
* Middle Aged
|keywords=* Dementia
* Epidemiology
* Geriatrics
* Muscle strength
* Nervous system
|full-text-url=https://sci-hub.do/10.1007/s40520-019-01351-y
}}
{{medline-entry
|title=Association of phase angle with sarcopenia and its components in physically active older women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31463928
|abstract=The aim of the present study was to associate phase angle (PhA) with sarcopenia and its components in physically active older women. A cross-sectional study was performed with 94 physically active older women. PhA and muscle mass were assessed by bioelectrical impedance. Muscle strength was measured by handgrip strength ([[HGS]]) and functional capacity was evaluated by 4-meter walk test. Sarcopenia was diagnosed according to the European Consensus on Definition and Diagnosis of Sarcopenia (2010). Participants were evaluated according to the PhA tercile. The individuals were divided into two groups: 1st vs. 2nd and 3rd terciles. The individuals in the first tercile were considered having low PhA (< 5.7º). Low PhA was not associated with sarcopenia (OR = 1.50 (0.520-4.319)), low muscle mass index (OR = 1.50 (0.520-4.319)), low [[HGS]] (OR = 3.15 (0.954-10.401)) and low walk speed (OR = 1.46 (0.384-5.534)). In addition, PhA had a weak correlation with walk speed (r = 0.24, p = 0.023) and walk speed was able to predict the PhA variations by 3.9%. PhA was not associated with sarcopenia and its components in physically active older women. Although PhA was correlated with walk speed, the biological meaning of this association is questionable, since the power of the prediction was low.
|mesh-terms=* Aged
* Cross-Sectional Studies
* Electric Impedance
* Female
* Hand Strength
* Humans
* Muscle Strength
* Sarcopenia
* Walking Speed
|keywords=* Aging
* Bioimpedance
* Muscle function
* Muscle mass
|full-text-url=https://sci-hub.do/10.1007/s40520-019-01325-0
}}
==CS==

{{medline-entry
|title=Acute effect of bodyweight-based strength training on blood pressure of hypertensive older adults: A randomized crossover clinical trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33198514
|abstract=: Strength Training (ST) reduces the cardiovascular risk of hypertensive elderly people; however, there is a need for efficient and low-cost ST programs that aim to reduce blood pressure (BP) in elderly people with adherence and affectivity in this population.  : Evaluate the acute effect on BP and satisfaction with the practice of bodyweight-based strength training (BWST) in hypertensive older adults.  : Participants performed a BWST session and a control session ([[CS]]). The BWST consisted of six exercises, with three sets of 30 seconds. In the [[CS]], no activity was performed. BP was measured before and at 0, 10, 20, and 30 minutes post-session. Participants' satisfaction was assessed.  : Eleven older adults (65.8 ± 4.6 years; 7 men) participated in the study. There was an increase ([i]p[/i] = .028) in systolic BP immediately after BWST, returning to baseline values in the intervals 10, 20, and 30 post-section. In the [[CS]] there was an increase ([i]p[/i] = .009) 30 minutes post-session compared to 20 minutes. Between sessions, a lower systolic BP was found in BWST (-6.54 ± 3.31; [i]p[/i] = .048) 30 minutes post-sessions. For satisfaction, 82% of participants were "totally satisfied" with BWST.  : The SBP is lower 30 minutes after BWST session than control session, and BWST promoted a pleasant affective response in hypertensive older adults.

|keywords=* Exercise
* aging
* hypertension
* hypotension
* resistance training
|full-text-url=https://sci-hub.do/10.1080/10641963.2020.1847130
}}
{{medline-entry
|title=Particle growth with photochemical age from new particle formation to haze in the winter of Beijing, China.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33207435
|abstract=Secondary aerosol formation in the aging process of primary emission is the main reason for haze pollution in eastern China. Pollution evolution with photochemical age was studied for the first time at a comprehensive field observation station during winter in Beijing. The photochemical age was used as an estimate of the timescale attributed to the aging process and was estimated from the ratio of toluene to benzene in this study. A low photochemical age indicates a fresh emission. The photochemical age of air masses during new particle formation (NPF) days was lower than that on haze days. In general, the strongest NPF events, along with a peak of the formation rate of 1.5 nm (J ) and 3 nm particles (J ), were observed when the photochemical age was between 12 and 24 h while rarely took place with photochemical ages less than 12 h. When photochemical age was larger than 48 h, haze occurred and NPF was suppressed. The sources and sinks of nanoparticles had distinct relation with the photochemical age. Our results show that the condensation sink ([[CS]]) showed a valley with photochemical ages ranging from 12 to 24 h, while H SO  concentration showed no obvious trend with the photochemical age. The high concentrations of precursor vapours within an air mass lead to persistent nucleation with photochemical age ranging from 12 to 48 h in winter. Coincidently, the fast increase of PM  mass was also observed during this range of photochemical age. Noteworthy, [[CS]] increased with the photochemical age on NPF days only, which is the likely reason for the observation that the PM  mass increased faster with photochemical age on NPF days compared with other days. The evolution of particles with the photochemical age provides new insights into understanding how particles originating from NPF transform to haze pollution.

|keywords=* Condensation sink
* Haze
* New particle formation
* Photochemical aging
* Pollution evolution
|full-text-url=https://sci-hub.do/10.1016/j.scitotenv.2020.142207
}}
{{medline-entry
|title=Effect of aging on stabilization of Cd and Ni by biochars and enzyme activities in a historically contaminated alkaline agricultural soil simulated with wet-dry and freeze-thaw cycling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33143976
|abstract=Natural aging alters the surface physicochemical properties of biochars, which can affect the retention of heavy metals. This work investigated the effect of biochar aging on stabilization of heavy metals (Cd and Ni) and soil enzyme activities simulated with laboratory wet-dry (WD) and freeze-thaw (FT) cycling. A wheat straw (WS) biochar and a corn straw ([[CS]]) biochar were subjected to 30 WD or FT cycles, and Cd- and Ni-contaminated alkaline soils amended with the two fresh biochars (at 5% w/w) were subjected to 30-day constant moisture incubation and 30 WD or FT cycles. WD and FT aging caused slight reduction in the pH of the biochars, significant increases in their O contents and surface areas, and formation of new carbonate minerals. WS biochar was more effective than [[CS]] biochar at reducing the phytoavailable Cd in the soil, with reduction of 12.1%, 14.6%, and 12.9% under constant moisture incubation, WD aging, and FT aging, respectively. Reduction in phytoavailability of Ni by the addition of biochars was observed only under WD aging, by 17.0% and 18.5% in the presence of WS and [[CS]] biochars, respectively. Biochar amendment also reduced the distribution of Cd in the acid soluble and reducible fractions in all aging regimes. The addition of biochars decreased catalase activity in almost all aging regimes and invertase activity under FT aging, but increased urease activity under FT aging. Comparison of the enzyme activities in the soils amended with biochars under constant moisture and accelerated aging conditions indicates WD aging significantly decreased the activities of catalase, invertase, and urease in all treatments, while FT aging significantly increased urease activity in all treatments. These findings suggest that biochars can stabilize Cd in alkaline soils under changing environmental conditions, although the activities of some soil enzymes could be negatively impacted.

|keywords=* Accelerated aging
* Biochar
* Cadmium
* Enzyme activity
* Heavy metal stabilization
* Soil remediation
|full-text-url=https://sci-hub.do/10.1016/j.envpol.2020.115846
}}
{{medline-entry
|title=Cockayne syndrome proteins [[CS]]A and [[CS]]B maintain mitochondrial homeostasis through NAD  signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33166073
|abstract=Cockayne syndrome ([[CS]]) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the [[CS]]A or [[CS]]B proteins. [[CS]] patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The [[CS]] proteins are involved in transcription and DNA repair, with the latter including transcription-coupled nucleotide excision repair (TC-NER). However, there is also evidence for mitochondrial dysfunction in [[CS]], which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with [[CS]]B deficiency, such changes in the [[CS]] nematode model and [[CS]] patients are not fully known. Our cross-species transcriptomic analysis in [[CS]] postmortem brain tissue, [[CS]] mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in [[CS]]. Restoration of mitochondrial dysfunction through NAD  supplementation significantly improved lifespan and healthspan in the [[CS]] nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of [[CS]]. In cerebellar samples from [[CS]] patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for [[CS]]A or [[CS]]B, this dysfunction can be corrected with supplementation of NAD  precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD  restoration.

|keywords=* AMPK
* Cockayne syndrome
* NAD+
* accelerated ageing
* aging
* mitochondrial maintenance
* mitophagy
|full-text-url=https://sci-hub.do/10.1111/acel.13268
}}
{{medline-entry
|title=Vision Impairment and Participation in Cognitively Stimulating Activities: The Health ABC Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32710546
|abstract=Engagement in cognitively stimulating activities is associated with decreased rates of cognitive decline in older adults. However, most cognitively stimulating tasks require good vision, potentially affecting the ability of visually impaired adults to engage in these activities. We examined the relationship between vision and participation in cognitively stimulating activities. Data from the Health, Aging and Body Composition study (1999-2005) were analyzed. Associations between visual function (visual acuity (VA), contrast sensitivity ([[CS]]), and stereo acuity (SA) impairments) and annual rates of change in number of cognitively stimulating activities (by self-report) performed at least once a month, were examined. Analyses included 924 participants aged 75.2 ±2.8 years. At baseline, impaired [[CS]] (27%), and SA (29%) was associated with participation in fewer cognitive activities (β=-0.33, 95%CI=-0.63,-0.03; β=-0.32, 95%CI=-0.61,-0.03, respectively) while VA ( 8%) was not (β=-0.34, 95%CI=-0.81,0.13). In longitudinal models, groups with and without VA, [[CS]], and SA impairments exhibited declines in monthly cognitive activities over time. Annual rates of decline were relatively higher in the VA (β=-0.16, 95%CI=-0.26,-0.05) and [[CS]] (β=-0.14, 95%CI=-0.19,-0.09) impaired groups than observed in the respective unimpaired groups (No VA: β=-0.12, 95%CI=-0.15,-0.10; No [[CS]]: β=-0.12, 95%CI=-0.15,-0.09), but did not achieve statistical significance. SA (β=-0.13, 95%CI=-0.17,-0.09) and no SA (β=-0.13, 95%CI=-0.16,-0.10) groups had similar rates of decline. Visually impaired older adults participate in fewer cognitive activities and although participation decline is similar to the non-impaired, lower overall participation indicates a need to identify cognitively stimulating activities accessible to visually impaired older adults.

|keywords=* Cognition
* Cognitive Aging
* Sensory
* Vision loss
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa184
}}
{{medline-entry
|title=Suspension training vs. traditional resistance training: effects on muscle mass, strength and functional performance in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32700098
|abstract=We compared the effects of suspension training (ST) with traditional resistance training (TRT) on muscle mass, strength and functional performance in older adults. Forty-two untrained older adults were randomized in TRT, ST (both performed 3 sets of whole body exercises to muscle failure) or control group (CON). Muscle thickness (MT) of biceps brachii (MT ) and vastus lateralis (MT ), maximal dynamic strength test (1RM) for biceps curl (1RM ) and leg extension exercises (1RM ), and functional performance tests (chair stand [[[CS]]], timed up and go [TUG] and maximal gait speed [MGS]) were performed before and after 12 weeks of training. MT  increased significantly and similarly for all training groups (TRT 23.35%; ST 21.56%). MT  increased significantly and similarly for all training groups (TRT 13.03%; ST 14.07%). 1RM  increased significantly and similarly for all training groups (TRT 16.06%; ST 14.33%). 1RM  increased significantly and similarly for all training groups (TRT 14.89%; ST 18.06%). MGS increased significantly and similarly for all groups (TRT 6.26%; ST 5.99%; CON 2.87%). [[CS]] decreased significantly and similarly for all training groups (TRT - 20.80%; ST - 15.73%). TUG decreased significantly and similarly for all training groups (TRT - 8.66%; ST - 9.16%). Suspension training (ST) promotes similar muscle mass, strength and functional performance improvements compared to TRT in older adults.

|keywords=* Aging
* Functionality
* Instability resistance training
* Muscle hypertrophy
* TRX training
|full-text-url=https://sci-hub.do/10.1007/s00421-020-04446-x
}}
{{medline-entry
|title=Generational Differences in the 10-year Incidence of Impaired Contrast Sensitivity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32693658
|abstract=To determine if incidence of contrast sensitivity ([[CS]]) impairment differs by generation and identify factors to explain these differences. The Beaver Dam Eye Study (BDES) and Beaver Dam Offspring Study (BOSS) are cohort studies of aging adults in Beaver Dam, Wisconsin. Baseline examinations occurred from 1993 to 1995 (BDES) and 2005-2008 (BOSS). Follow-up examinations occurred in five-year intervals. [[CS]] testing was conducted with Pelli-Robson letter sensitivity charts; Incident impairment was a log [[CS]] score <1.55 in either eye at follow-up. Associations of incidence with generation were investigated using estimated hazard ratios (HR) with 95% confidence intervals (CI). Participants (N = 3185) had a mean age of 51.9 years at baseline (standard deviation = 9.9) and 51.9% were female. Ten-year cumulative incidence of [[CS]] impairment was 40.1%, was higher among women (41.7%) than men (38.8%), and increased by age group. The risk of incident [[CS]] impairment decreased by 39% per generation. In multivariable models, the Baby Boom Generation (HR = 0.42, 95%CI = 0.31, 0.58) and Generation X (HR = 0.56, 95%CI = 0.34, 0.91) had a significantly decreased risk of [[CS]] impairment compared to the Greatest Generation. Results were similar in sensitivity analyses excluding those with cataract, age-related macular degeneration, or visual acuity impairment. The risk of incident [[CS]] impairment decreased by birth cohort, with the greatest reduction in the Baby Boom Generation. The difference in risk suggests that there are unknown modifiable risk factors that may help to further explain the etiology of [[CS]] impairment and provide potential pathways for prevention in the future.

|keywords=* Aging
* Birth Cohort Effect
* Contrast Sensitivity
* Epidemiology
* Visual Function
|full-text-url=https://sci-hub.do/10.1080/09286586.2020.1791909
}}
{{medline-entry
|title=Inducible aging in Hydra oligactis implicates sexual reproduction, loss of stem cells, and genome maintenance as major pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32578072
|abstract=Freshwater polyps of the genus Hydra do not age. However, temperature stress induces aging and a shift from reproduction by asexual budding to sexual gamete production in a cold-sensitive ([[CS]]) strain of H. oligactis. We sequenced the transcriptome of a male [[CS]] strain before and after this life history shift and compared changes in gene expression relative to those seen in a cold-resistant (CR) strain that does not undergo a life history shift in response to altered temperature. We found that the switch from non-aging asexual reproduction to aging and sexual reproduction involves upregulation of genes not only involved in gametogenesis but also genes involved in cellular senescence, apoptosis, and DNA repair accompanied by a downregulation of genes involved in stem cell maintenance. These results suggest that aging is a byproduct of sexual reproduction-associated cellular reprogramming and underscore the power of these H. oligactis strains to identify intrinsic mechanisms of aging.

|keywords=* Aging
* Cold-sensitive
* DNA repair
* Gametogenesis
* Hydra oligactis
* Transcriptome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394996
}}
{{medline-entry
|title=Noradrenergic Responsiveness Supports Selective Attention across the Adult Lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32317388
|abstract=Selectively attending to relevant information while blocking out distractors is crucial for goal-directed behavior, yet with advancing age, deficits emerge in attentional selectivity. Decrements in attention have been associated with altered noradrenergic activity in animals. However, research linking noradrenergic functioning to attention in aging humans is scarce, likely reflecting long-standing methodological challenges in noninvasive assessments. We studied whether age-related differences in the noradrenergic system predict differences in attention. We measured pupil dilation, a noninvasive marker of arousal-related norepinephrine (NE) release, while concurrently recording the EEG of male younger ([i]N[/i] = 39; 25.2 ± 3.2 years) and older adults ([i]N[/i] = 38; 70.6 ± 2.7 years). Arousal was modulated on a trial-by-trial basis using fear-conditioned ([[CS]] ) stimuli. During conditioning, pupil and EEG markers related to heightened arousal were identified. Afterward, in a dichotic listening task, participants were cued to direct attention to either the left or right ear while highly similar syllable pairs were presented simultaneously to both ears. During the dichotic listening task, presentation of fear-conditioned stimuli reinstated the acquired arousal response, as reflected in pupil and EEG α-β band responses. Critically, pupil dilation to [[CS]]  was correlated with stronger EEG α-β desynchronization, suggesting a common dependence on NE release. On a behavioral level, stronger arousal reactions were associated with better attention. In particular, structural equation modeling revealed that the responsiveness of the NE system is associated with attention on a latent construct level, measured by several indicator tasks. Overall, our results suggest that the responsiveness of the NE system supports attention across the lifespan.  In old age, the ability to selectively process relevant aspects of the environment fades. Animal research suggests that the neuromodulator norepinephrine helps to maintain selective attention. We tested younger and older adults across a variety of attention tasks. In addition, we used arousing stimuli to experimentally activate participants' noradrenergic system while recording pupillometry and EEG to infer its functional capacity. Older adults showed compromised attention and reduced noradrenergic responsiveness as indicated by interrelated pupil and EEG markers. Crucially, in both age groups, a more responsive noradrenergic system was strongly associated with attention. Our findings link animal and human studies on the neural underpinning of attention in aging and underscore the importance of the noradrenergic system in late-life cognition.
|mesh-terms=* Adult
* Aged
* Aging
* Attention
* Brain Waves
* Cortical Synchronization
* Humans
* Male
* Norepinephrine
* Reflex, Pupillary
|keywords=* cognitive aging
* locus coeruleus
* noradrenaline
* norepinephrine
* rhythmic neural activity
* selective attention
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252473
}}
{{medline-entry
|title=Cellular senescence: from anti-cancer weapon to anti-aging target.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32060861
|abstract=Cellular senescence ([[CS]]) is a state of stable cell cycle arrest characterized by the production and secretion of inflammatory molecules. Early studies described oncogene-induced senescence (OIS) as a barrier to tumorigenesis, such that the therapeutic induction of [[CS]] might represent a rational anti-cancer strategy. Indeed, the validity of this approach has been borne out by the development and approval of the cyclin-dependent kinase (CDK) inhibitor palbociclib for the treatment of breast cancer. Apart from tumors, senescent cells have also been shown to accumulate during natural mammalian aging, where they produce detrimental effects on the physiology of surrounding tissues. Thus, pharmacological senescent cell depletion has been proposed as an approach to delay age-related functional decline; this has been formally demonstrated in animal models. In this review article, we describe the current mechanistic understanding of cellular senescence at the molecular level and how it informs the development of new therapeutic strategies to combat cancer and aging.
|mesh-terms=* Aging
* Animals
* Antineoplastic Agents
* Breast Neoplasms
* Cell Proliferation
* Cell Transformation, Neoplastic
* Cellular Senescence
* Cyclin-Dependent Kinases
* Drug Discovery
* Female
* Humans
* Piperazines
* Protein Kinase Inhibitors
* Pyridines
|keywords=* cancer
* cellular senescence
* healthy aging
* pro-senescence cancer therapy
* senolytic therapies
|full-text-url=https://sci-hub.do/10.1007/s11427-019-1629-6
}}
{{medline-entry
|title=Extra-mitochondrial citrate synthase initiates calcium oscillation and suppresses age-dependent sperm dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31857692
|abstract=Men and women become infertile with age, but the mechanism of declining male fertility, more specifically, the decrease in in sperm quality, is not well known. Citrate synthase ([[CS]]) is a core enzyme of the mitochondrial tricarboxylic acid (TCA) cycle, which directly controls cellular function. Extra-mitochondrial [[CS]] (e[[CS]]) is produced and abundant in the sperm head; however, its role in male fertility is unknown. We investigated the role of e[[CS]] in male fertility by producing eCs-deficient (eCs-KO) mice. The initiation of the first spike of Ca  oscillation was substantially delayed in egg fused with eCs-KO sperm, despite normal expression of sperm factor phospholipase C zeta 1. The eCs-KO male mice were initially fertile, but the fertility dropped with age. Metabolomic analysis of aged sperm revealed that the loss of e[[CS]] enhances TCA cycle in the mitochondria with age, presumably leading to depletion of extra-mitochondrial citrate. The data suggest that e[[CS]] suppresses age-dependent male infertility, providing insights into the decline of male fertility with age.
|mesh-terms=* Aging
* Animals
* Calcium Signaling
* Citrate (si)-Synthase
* Citric Acid Cycle
* Female
* Infertility, Male
* Male
* Metabolome
* Mice
* Ovum
* Spermatozoa

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096335
}}
{{medline-entry
|title=Pathogenesis of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31737341
|abstract=Chronic obstructive pulmonary disease (COPD) is a common respiratory disease that is characterized by functional and structural alterations primarily caused by long-term inhalation of harmful particles. Cigarette smoke ([[CS]]) induces airway inflammation in COPD, which is known to persist even after smoking cessation. This review discusses the basic pathogenesis of COPD, with particular focus on an endogenous protective mechanism against oxidative stress via Nrf2, altered immune response of the airway inflammatory cells, exaggerated cellular senescence of the lung structural cells, and cell death with expanded inflammation. Recently, [[CS]]-induced mitochondria autophagy is reported to initiate programmed necrosis (necroptosis). Necroptosis is a new concept of cell death which is driven by a defined molecular pathway along with exaggerated inflammation. This new cell death mechanism is of importance due to its ability to produce more inflammatory substances during the process of epithelial death, contributing to persistent airway inflammation that cannot be explained by apoptosis-derived cell death. Autophagy is an auto-cell component degradation system executed by lysosomes that controls protein and organelle degradation for successful homeostasis. As well as in the process of necroptosis, autophagy is also observed during cellular senescence. Aging of the lungs results in the acquisition of senescence-associated secretory phenotypes (SASP) that are known to secrete inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases resulting in chronic low-grade inflammation. In future research, we intend to highlight the genetic and epigenetic approaches that can facilitate the understanding of disease susceptibility. The goal of precision medicine is to establish more accurate diagnosis and treatment methods based on the patient-specific pathogenic characteristics. This review provides insights into [[CS]]-induced COPD pathogenesis, which contributes to a very complex disease. Investigating the mechanism of developing COPD, along with the availability of the particular inhibitors, will lead to new therapeutic approaches in COPD treatment.

|keywords=* Airway inflammation
* autophagy
* cellular senescence
* chronic obstructive pulmonary disease (COPD)
* necroptosis
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6831915
}}
{{medline-entry
|title=Possible Role of Amyloid Cross-Seeding in Evolvability and Neurodegenerative Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31524179
|abstract=Aging-related neurodegenerative disorders are frequently associated with the aggregation of multiple amyloidogenic proteins (APs), although the reason why such detrimental phenomena have emerged in the post-reproductive human brain across evolution is unclear. Speculatively, APs might provide physiological benefits for the human brain during developmental/reproductive stages. Of relevance, it is noteworthy that cross-seeding ([[CS]]) of APs has recently been characterized in cellular and animal models of neurodegenerative disease, and that normal physiological [[CS]] of multiple APs has also been observed in lower organisms, including yeast and bacteria. In this context, our main objective is to discuss a possible involvement of the [[CS]] of APs in promoting evolvability, a hypothetical view regarding the function of APs as an inheritance of acquired characteristics against human brain stressors, which are transgenerationally transmitted to offspring via germ cells. Mechanistically, the protofibrils formed by the [[CS]] of multiple APs might confer hormesis more potently than individual APs. By virtue of greater encoded stress information in parental brains being available, the brains of offspring can cope more efficiently with forth-coming stressors. On the other hand, subsequent neurodegeneration caused by APs in parental brain through the antagonistic pleiotropy mechanism in aging, may suggest that synergistically, multiple APs might be more detrimental compared to singular AP in neurodegeneration. Taken together, we suggest that the [[CS]] of multiple APs might be involved in both evolvability and neurodegenerative disease in human brain, which may be mechanistically and therapeutically important.
|mesh-terms=* Aging
* Amyloidogenic Proteins
* Animals
* Biological Evolution
* Brain
* Female
* Humans
* Inheritance Patterns
* Models, Neurological
* Neurodegenerative Diseases
* Pregnancy
* Stress, Physiological
|keywords=* Alzheimer’s disease
* Parkinson’s disease
* amyloid cascade hypothesis
* amyloidogenic proteins
* antimicrobial protection model
* cross-seeding
* evolvability hypothesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839461
}}
{{medline-entry
|title=Targeting p16-induced senescence prevents cigarette smoke-induced emphysema by promoting IGF1/Akt1 signaling in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31428695
|abstract=Senescence is a mechanism associated with aging that alters tissue regeneration by depleting the stem cell pool. Chronic obstructive pulmonary disease (COPD) displays hallmarks of senescence, including a diminished stem cell population. DNA damage from cigarette smoke ([[CS]]) induces senescence via the p16 pathway. This study evaluated the contribution of p16 to [[CS]]-associated lung pathologies. p16 expression was prominent in human COPD lungs compared with normal subjects. [[CS]] induces impaired pulmonary function, emphysema, and increased alveolar epithelial cell (AECII) senescence in wild-type mice, whereas [[CS]]-exposed p16  mice exhibit normal pulmonary function, reduced emphysema, diminished AECII senescence, and increased pro-growth IGF1 signaling, suggesting that improved lung function in p16  mice was due to increased alveolar progenitor cell proliferation. In conclusion, our study suggests that targeting senescence may facilitate alveolar regeneration in COPD emphysema by promoting IGF1 proliferative signaling.
|mesh-terms=* Alveolar Epithelial Cells
* Animals
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cytokines
* Emphysema
* Insulin-Like Growth Factor I
* Lung
* Mice, Inbred C57BL
* Models, Biological
* Promoter Regions, Genetic
* Proto-Oncogene Proteins c-akt
* Pulmonary Disease, Chronic Obstructive
* RNA, Messenger
* Signal Transduction
* Smoking
|keywords=* Molecular biology
* Senescence
* Stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689060
}}
==ACE2==

{{medline-entry
|title=How Does SARS-CoV-2 Affect the Central Nervous System? A Working Hypothesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33304284
|abstract=Interstitial pneumonia was the first manifestation to be recognized as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, in just a few weeks, it became clear that the coronavirus disease-2019 (COVID-19) overrun tissues and more body organs than just the lungs, so much so that it could be considered a systemic pathology. Several studies reported the involvement of the conjunctiva, the gut, the heart and its pace, and vascular injuries such as thromboembolic complications and Kawasaki disease in children and toddlers were also described. More recently, it was reported that in a sample of 214 SARS-CoV-2 positive patients, 36.4% complained of neurological symptoms ranging from non-specific manifestations (dizziness, headache, and seizures), to more specific symptoms such hyposmia or hypogeusia, and stroke. Older individuals, especially males with comorbidities, appear to be at the highest risk of developing such severe complications related to the Central Nervous System (CNS) involvement. Neuropsychiatric manifestations in COVID-19 appear to develop in patients with and without pre-existing neurological disorders. Growing evidence suggests that SARS-CoV-2 binds to the human Angiotensin-Converting Enzyme 2 ([[ACE2]]) for the attachment and entrance inside host cells. By describing [[ACE2]] and the whole Renin Angiotensin Aldosterone System (RAAS) we may better understand whether specific cell types may be affected by SARS-CoV-2 and whether their functioning can be disrupted in case of an infection. Since clear evidences of neurological interest have already been shown, by clarifying the topographical distribution and density of [[ACE2]], we will be able to speculate how SARS-CoV-2 may affect the CNS and what is the pathogenetic mechanism by which it contributes to the specific clinical manifestations of the disease. Based on such evidences, we finally hypothesize the process of SARS-CoV-2 invasion of the CNS and provide a possible explanation for the onset or the exacerbation of some common neuropsychiatric disorders in the elderly including cognitive impairment and Alzheimer disease.

|keywords=* ACE2
* Alzheimer disease
* Ang(1-7)/Mas
* COVID-19
* RAAS
* SARS-CoV
* brain aging
* neurodegenerative and psychiatric disorders abstract
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701095
}}
{{medline-entry
|title=Bioinformatic characterization of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33112891
|abstract=The World Health Organization declared the COVID-19 epidemic a public health emergency of international concern on March 11th, 2020, and the pandemic is rapidly spreading worldwide. COVID-19 is caused by a novel coronavirus SARS-CoV-2, which enters human target cells via angiotensin converting enzyme 2 ([[ACE2]]). We used a number of bioinformatics tools to computationally characterize [[ACE2]] by determining its cell-specific expression in trachea, lung, and small intestine, derive its putative functions, and predict transcriptional regulation. The small intestine expressed higher levels of [[ACE2]] mRNA than any other organ. By immunohistochemistry, duodenum, kidney and testis showed strong signals, whereas the signal was weak in the respiratory tract. Single cell RNA-Seq data from trachea indicated positive signals along the respiratory tract in key protective cell types including club, goblet, proliferating, and ciliary epithelial cells; while in lung the ratio of [[ACE2]]-expressing cells was low in all cell types (<2.6%), but was highest in vascular endothelial and goblet cells. Gene ontology analysis suggested that, besides its classical role in the renin-angiotensin system, [[ACE2]] may be functionally associated with angiogenesis/blood vessel morphogenesis. Using a novel tool for the prediction of transcription factor binding sites we identified several putative binding sites within two tissue-specific promoters of the [[ACE2]] gene as well as a new putative short form of [[ACE2]]. These include several interferon-stimulated response elements sites for STAT1, IRF8, and IRF9. Our results also confirmed that age and gender play no significant role in the regulation of [[ACE2]] mRNA expression in the lung.
|mesh-terms=* Aging
* Angiotensin-Converting Enzyme 2
* Betacoronavirus
* Binding Sites
* COVID-19
* Carrier Proteins
* Computational Biology
* Coronavirus Infections
* Female
* Gene Expression Regulation, Enzymologic
* Gene Ontology
* Humans
* Interferons
* Lung
* Male
* Metalloproteases
* Neovascularization, Physiologic
* Organ Specificity
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* Promoter Regions, Genetic
* RNA, Messenger
* Receptors, Virus
* Renin-Angiotensin System
* SARS-CoV-2
* Sex Characteristics
* Single-Cell Analysis
* Transcription Factors
* Transcription Initiation Site
* Virus Attachment

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592753
}}
{{medline-entry
|title=A mouse-adapted model of SARS-CoV-2 to test COVID-19 countermeasures.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32854108
|abstract=Coronaviruses are prone to transmission to new host species, as recently demonstrated by the spread to humans of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the coronavirus disease 2019 (COVID-19) pandemic . Small animal models that recapitulate SARS-CoV-2 disease are needed urgently for rapid evaluation of medical countermeasures . SARS-CoV-2 cannot infect wild-type laboratory mice owing to inefficient interactions between the viral spike protein and the mouse orthologue of the human receptor, angiotensin-converting enzyme 2 ([[ACE2]]) . Here we used reverse genetics  to remodel the interaction between SARS-CoV-2 spike protein and mouse [[ACE2]] and designed mouse-adapted SARS-CoV-2 (SARS-CoV-2 MA), a recombinant virus that can use mouse [[ACE2]] for entry into cells. SARS-CoV-2 MA was able to replicate in the upper and lower airways of both young adult and aged BALB/c mice. SARS-CoV-2 MA caused more severe disease in aged mice, and exhibited more clinically relevant phenotypes than those seen in Hfh4-[[ACE2]] transgenic mice, which express human [[ACE2]] under the control of the Hfh4 (also known as Foxj1) promoter. We demonstrate the utility of this model using vaccine-challenge studies in immune-competent mice with native expression of mouse [[ACE2]]. Finally, we show that the clinical candidate interferon-λ1a (IFN-λ1a) potently inhibits SARS-CoV-2 replication in primary human airway epithelial cells in vitro-both prophylactic and therapeutic administration of IFN-λ1a diminished SARS-CoV-2 replication in mice. In summary, the mouse-adapted SARS-CoV-2 MA model demonstrates age-related disease pathogenesis and supports the clinical use of pegylated IFN-λ1a as a treatment for human COVID-19 .
|mesh-terms=* Aging
* Angiotensin-Converting Enzyme 2
* Animals
* Betacoronavirus
* COVID-19
* COVID-19 Vaccines
* Coronavirus Infections
* Disease Models, Animal
* Female
* Forkhead Transcription Factors
* Humans
* Interferon-alpha
* Interferons
* Interleukins
* Male
* Mice
* Mice, Inbred BALB C
* Mice, Transgenic
* Models, Molecular
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* Receptors, Virus
* SARS-CoV-2
* Viral Vaccines

|full-text-url=https://sci-hub.do/10.1038/s41586-020-2708-8
}}
{{medline-entry
|title=COVID-19 and Senotherapeutics: Any Role for the Naturally-occurring Dipeptide Carnosine?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32765939
|abstract=It is suggested that the non-toxic dipeptide carnosine (beta-alanyl-L-histidine) should be examined as a potential protective agent against COVID-19 infection and inflammatory consequences especially in the elderly. Carnosine is an effective anti-inflammatory agent which can also inhibit CD26 and [[ACE2]] activity. It is also suggested that nasal administration would direct the peptide directly to the lungs and escape the attention of serum carnosinase.

|keywords=* acetyl-carnosine
* aging
* carnosine
* inflammation
* lungs
* olfaction
* virus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390525
}}
{{medline-entry
|title=The dual impact of [[ACE2]] in COVID-19 and ironical actions in geriatrics and pediatrics with possible therapeutic solutions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32653522
|abstract=The novel corona virus disease has shaken the entire world with its deadly effects and rapid transmission rates, posing a significant challenge to the healthcare authorities to develop suitable therapeutic solution to save lives on earth. The review aims to grab the attention of the researchers all over the globe, towards the role of [[ACE2]] in COVID-19 disease. [[ACE2]] serves as a molecular target for the SARS-CoV-2, to enter the target cell, by interacting with the viral glycoprotein spikes. However, the complexity began when numerous studies identified the protective response of [[ACE2]] in abbreviating the harmful effects of vasoconstrictor, anti-inflammatory peptide, angiotensin 2, by mediating its conversion to angiotensin-(1-7), which exercised antagonistic actions to angiotensin 2. Furthermore, certain investigations revealed greater resistance among children as compared to the geriatrics, towards COVID-19 infection, despite the elevated expression of [[ACE2]] in pediatric population. Based upon such evidences, the review demonstrated possible therapeutic interventions, targeting both the protective and deleterious effects of [[ACE2]] in COVID-19 disease, primarily inhibiting [[ACE2]]-virus interactions or administering soluble [[ACE2]]. Thus, the authors aim to provide an opportunity for the researchers to consider RAAS system to be a significant element in development of suitable treatment regime for COVID-19 pandemic.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Angiotensin-Converting Enzyme 2
* Anti-Inflammatory Agents
* Betacoronavirus
* COVID-19
* Child
* Child, Preschool
* Coronavirus
* Coronavirus Infections
* Female
* Geriatrics
* Humans
* Infant
* Infant, Newborn
* Male
* Pandemics
* Pediatrics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* Protein Binding
* Receptors, Virus
* Renin-Angiotensin System
* SARS-CoV-2
* Severe Acute Respiratory Syndrome
* Virus Internalization
|keywords=* ACE2
* Angiotensin 2
* Angiotensin-(1–7)
* Corona virus
* Glycoprotein spikes
* RAAS system
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347488
}}
{{medline-entry
|title=The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of "inflame-aging".
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32529477
|abstract=Novel Coronavirus disease 2019 (COVID-19), is an acute respiratory distress syndrome (ARDS), which is emerged in Wuhan, and recently become worldwide pandemic. Strangely, ample evidences have been shown that the severity of COVID-19 infections varies widely from children (asymptomatic), adults (mild infection), as well as elderly adults (deadly critical). It has proven that COVID-19 infection in some elderly critical adults leads to a cytokine storm, which is characterized by severe systemic elevation of several pro-inflammatory cytokines. Then, a cytokine storm can induce edematous, ARDS, pneumonia, as well as multiple organ failure in aged patients. It is far from clear till now why cytokine storm induces in only COVID-19 elderly patients, and not in young patients. However, it seems that aging is associated with mild elevated levels of local and systemic pro-inflammatory cytokines, which is characterized by "inflamm-aging". It is highly likely that "inflamm-aging" is correlated to increased risk of a cytokine storm in some critical elderly patients with COVID-19 infection. A systematic search in the literature was performed in PubMed, Scopus, Embase, Cochrane Library, Web of Science, as well as Google Scholar pre-print database using all available MeSH terms for COVID-19, Coronavirus, SARS-CoV-2, senescent cell, cytokine storm, inflame-aging, [[ACE2]] receptor, autophagy, and Vitamin D. Electronic database searches combined and duplicates were removed. The aim of the present review was to summarize experimental data and clinical observations that linked the pathophysiology mechanisms of "inflamm-aging", mild-grade inflammation, and cytokine storm in some elderly adults with severe COVID-19 infection.
|mesh-terms=* Adipocytes
* Age Factors
* Aged
* Aging
* Angiotensin II Type 2 Receptor Blockers
* Autophagy
* Betacoronavirus
* COVID-19
* Cellular Senescence
* Coronavirus Infections
* Cytokine Release Syndrome
* Cytokines
* Humans
* Immune System
* Inflammation
* Pandemics
* Pneumonia, Viral
* Reactive Oxygen Species
* Receptor, Angiotensin, Type 2
* SARS-CoV-2
* Vitamin D
* Vitamin D Deficiency
|keywords=* ACE2 receptor
* Autophagy
* COVID-19
* Cytokine storm
* Senescent cell
* Vitamin D
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289226
}}
{{medline-entry
|title=Decoding SARS-CoV-2 hijacking of host mitochondria in COVID-19 pathogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32510973
|abstract=Because of the ongoing pandemic around the world, the mechanisms underlying the SARS-CoV-2-induced COVID-19 are subject to intense investigation. Based on available data for the SARS-CoV-1 virus, we suggest how CoV-2 localization of RNA transcripts in mitochondria hijacks the host cell's mitochondrial function to viral advantage. Besides viral RNA transcripts, RNA also localizes to mitochondria. SARS-CoV-2 may manipulate mitochondrial function indirectly, first by [[ACE2]] regulation of mitochondrial function, and once it enters the host cell, open-reading frames (ORFs) such as ORF-9b can directly manipulate mitochondrial function to evade host cell immunity and facilitate virus replication and COVID-19 disease. Manipulations of host mitochondria by viral ORFs can release mitochondrial DNA (mtDNA) in the cytoplasm and activate mtDNA-induced inflammasome and suppress innate and adaptive immunity. We argue that a decline in [[ACE2]] function in aged individuals, coupled with the age-associated decline in mitochondrial functions resulting in chronic metabolic disorders like diabetes or cancer, may make the host more vulnerable to infection and health complications to mortality. These observations suggest that distinct localization of viral RNA and proteins in mitochondria must play essential roles in SARS-CoV-2 pathogenesis. Understanding the mechanisms underlying virus communication with host mitochondria may provide critical insights into COVID-19 pathologies. An investigation into the SARS-CoV-2 hijacking of mitochondria should lead to novel approaches to prevent and treat COVID-19.
|mesh-terms=* Adaptive Immunity
* Angiotensin-Converting Enzyme 2
* Animals
* Betacoronavirus
* COVID-19
* Coronavirus Infections
* DNA, Mitochondrial
* Gene Expression Regulation, Viral
* Host Microbial Interactions
* Humans
* Immunity, Innate
* Mitochondria
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* RNA, Viral
* SARS-CoV-2
* Virus Replication
|keywords=* COVID-19
* SARS-CoV
* aging
* coronavirus
* mitochondria
* mitochondrial DNA
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381712
}}
{{medline-entry
|title=A Mouse Model of SARS-CoV-2 Infection and Pathogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32485164
|abstract=Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought an urgent need for an animal model. Human angiotensin-converting enzyme II ([[ACE2]]) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human [[ACE2]] (h[[ACE2]]) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged h[[ACE2]] mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged h[[ACE2]] mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in h[[ACE2]] mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.
|mesh-terms=* Aging
* Angiotensin-Converting Enzyme 2
* Animals
* Betacoronavirus
* Brain
* COVID-19
* CRISPR-Cas Systems
* Coronavirus Infections
* Cytokines
* Disease Models, Animal
* Gene Knock-In Techniques
* Lung
* Lung Diseases, Interstitial
* Mice, Inbred C57BL
* Nose
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* RNA, Viral
* SARS-CoV-2
* Stomach
* Trachea
* Viral Load
* Virus Replication
|keywords=* SARS-CoV-2
* angiotensin-converting enzyme II
* hACE2-KI/NIFDC
* mouse model
* pathogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250783
}}
{{medline-entry
|title=COVID-19-associated cardiovascular morbidity in older adults: a position paper from the Italian Society of Cardiovascular Researches.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32430627
|abstract=Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects host cells following binding with the cell surface [[ACE2]] receptors, thereby leading to coronavirus disease 2019 (COVID-19). SARS-CoV-2 causes viral pneumonia with additional extrapulmonary manifestations and major complications, including acute myocardial injury, arrhythmia, and shock mainly in elderly patients. Furthermore, patients with existing cardiovascular comorbidities, such as hypertension and coronary heart disease, have a worse clinical outcome following contraction of the viral illness. A striking feature of COVID-19 pandemics is the high incidence of fatalities in advanced aged patients: this might be due to the prevalence of frailty and cardiovascular disease increase with age due to endothelial dysfunction and loss of endogenous cardioprotective mechanisms. Although experimental evidence on this topic is still at its infancy, the aim of this position paper is to hypothesize and discuss more suggestive cellular and molecular mechanisms whereby SARS-CoV-2 may lead to detrimental consequences to the cardiovascular system. We will focus on aging, cytokine storm, NLRP3/inflammasome, hypoxemia, and air pollution, which is an emerging cardiovascular risk factor associated with rapid urbanization and globalization. We will finally discuss the impact of clinically available CV drugs on the clinical course of COVID-19 patients. Understanding the role played by SARS-CoV2 on the CV system is indeed mandatory to get further insights into COVID-19 pathogenesis and to design a therapeutic strategy of cardio-protection for frail patients.
|mesh-terms=* Age Factors
* Aged
* Betacoronavirus
* COVID-19
* Cardiovascular Diseases
* Coronavirus Infections
* Female
* Humans
* Italy
* Male
* Middle Aged
* Pandemics
* Pneumonia, Viral
* Risk Factors
* SARS-CoV-2
|keywords=* Acute myocardial injury
* Aging
* COVID-19
* Cardiovascular system
* Frailty
* SARS-CoV-2
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237344
}}
{{medline-entry
|title=Gut microbiota and Covid-19- possible link and implications.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32430279
|abstract=Covid-19 is a major pandemic facing the world today caused by SARS-CoV-2 which has implications on our understanding of infectious diseases. Although, SARS-Cov-2 primarily causes lung infection through binding of [[ACE2]] receptors present on the alveolar epithelial cells, yet it was recently reported that SARS-CoV-2 RNA was found in the faeces of infected patients. Interestingly, the intestinal epithelial cells particularly the enterocytes of the small intestine also express [[ACE2]] receptors. Role of the gut microbiota in influencing lung diseases has been well articulated. It is also known that respiratory virus infection causes perturbations in the gut microbiota. Diet, environmental factors and genetics play an important role in shaping gut microbiota which can influence immunity. Gut microbiota diversity is decreased in old age and Covid-19 has been mainly fatal in elderly patients which again points to the role the gut microbiota may play in this disease. Improving gut microbiota profile by personalized nutrition and supplementation known to improve immunity can be one of the prophylactic ways by which the impact of this disease can be minimized in old people and immune-compromised patients. More trials may be initiated to see the effect of co-supplementation of personalized functional food including prebiotics/probiotics along with current therapies.
|mesh-terms=* Aging
* Betacoronavirus
* COVID-19
* Coronavirus Infections
* Diet
* Dysbiosis
* Gastrointestinal Microbiome
* Gastrointestinal Tract
* Homeostasis
* Humans
* Immunity
* Lung
* Pandemics
* Pneumonia, Viral
* SARS-CoV-2
|keywords=* Covid-19
* Diet
* Dysbiosis
* Gut microbiome
* Immunity
* Lung microbiota
* SARS-CoV-2
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217790
}}
{{medline-entry
|title=Inflamm-aging: Why older men are the most susceptible to SARS-CoV-2 complicated outcomes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32389499
|abstract=Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. In most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. The aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). Here, we advance the hypothesis that four well-recognized features of aging contribute to the disproportionate SARS-CoV-2 mortality suffered by elderly men: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type I interferon response due to the chronic inflammation; iii. the downregulation of [[ACE2]] (i.e. the SARS-CoV-2 receptor); and iv. accelerated biological aging. The high mortality rate of SARS-CoV-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also SARS-CoV-2 infection.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Angiotensin-Converting Enzyme 2
* Antibodies, Monoclonal, Humanized
* Betacoronavirus
* COVID-19
* Comorbidity
* Coronavirus Infections
* Female
* Humans
* Inflammation
* Interferon Type I
* Interleukin-6
* Male
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* SARS-CoV-2
* Severe Acute Respiratory Syndrome
|keywords=* COVID-19
* Cardiovascular diseases
* Host-directed therapies
* Inflamm-aging
* SARS-CoV-2
* interleukin-6
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252014
}}
{{medline-entry
|title=Restoration of the Renin-Angiotensin System Balance Is a Part of the Effect of Fasting on Cardiovascular Rejuvenation: Role of Age and Fasting Models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31571520
|abstract=Intermittent fasting (IF) is an intervention that can be beneficial for health span and mitigate the risk of developing age-related cardiovascular diseases; however, the involved mechanisms are not well understood. The present study investigated the effects of IF regimens on the plasma level of angiotensin II (Ang II), and the expression of Ang II receptors (AT1aR and AT2R) and angiotensin-converting enzyme 2 ([[ACE2]]) in the heart and aorta of male, 3-, 12-, and 24-month-old Wistar rats fed [i]ad libitum[/i] (AL), fed [i]ad libitum[/i] and fasted 1 day per week (FW), or fasted every other day (EOD) for 3 months. Aging was associated with high circulating levels of Ang II, high level of AT1aR protein expression in the heart and aorta, and low level of AT2R protein expression in the heart and aorta. Both FW and EOD decreased Ang II levels ([i]p[/i] < 0.01, [i]p[/i] < 0.001) and AT1aR protein expression in the heart ([i]p[/i] < 0.01, [i]p[/i] < 0.001) and aorta ([i]p[/i] < 0.001) of old rats. Both FW and EOD increased the expression of AT2R protein in the heart ([i]p[/i] < 0.05 and [i]p[/i] < 0.001, respectively). However, only EOD increased the expression of AT2R protein ([i]p[/i] < 0.05) in the aorta. In the old group, both the FW and EOD regimens induced a significant increase in the expression of [[ACE2]] protein in the heart ([i]p[/i] < 0.01, [i]p[/i] < 0.001 vs. age-matched AL group, respectively). The results suggest that a part of the recovery effect of fasting on cardiovascular system in old rats is mediated through restoration of the balance of renin-angiotensin system.

|keywords=* aging
* cardiac hypertrophy index
* intermittent fasting
* renin–angiotensin system (RAS)
|full-text-url=https://sci-hub.do/10.1089/rej.2019.2254
}}
{{medline-entry
|title=Angiotensin 1-7 alleviates aging-associated muscle weakness and bone loss, but is not associated with accelerated aging in [[ACE2]]-knockout mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31519791
|abstract=The angiotensin-converting enzyme 2 ([[ACE2]])-angiotensin 1-7 (A1-7)-A1-7 receptor (Mas) axis plays a protective role in the renin-angiotensin system (RAS). We recently found that [[ACE2]] knockout ([[ACE2]]KO) mice exhibit earlier aging-associated muscle weakness, and that A1-7 alleviates muscle weakness in aging mice. In the present study, we investigated the role of the A1-7-Mas pathway in the effect of [[ACE2]] on physiological aging. Male wild-type, [[ACE2]]KO, and Mas knockout (MasKO) mice were subjected to periodical grip strength measurement, followed by administration of A1-7 or vehicle for 4 weeks at 24 months of age. [[ACE2]]KO mice exhibited decreased grip strength after 6 months of age, while grip strength of MasKO mice was similar to that of wild-type mice. A1-7 improved grip strength in [[ACE2]]KO and wild-type mice, but not in MasKO mice. Muscle fibre size was smaller in [[ACE2]]KO mice than that in wild-type and MasKO mice, and increased with A1-7 in [[ACE2]]KO and WT mice, but not in MasKO mice. Centrally nucleated fibres (CNFs) and expression of the senescence-associated gene [i]p16INK4a[/i] in skeletal muscles were enhanced only in [[ACE2]]KO mice and were not altered by A1-7. [[ACE2]]KO mice, but not MasKO mice, exhibited thinning of peripheral fat along with increased adipose expression of [i]p16INK4a[/i] A1-7 significantly increased bone volume in wild-type and [[ACE2]]KO mice, but not in MasKO mice. Our findings suggest that the impact of [[ACE2]] on physiological aging does not depend on the endogenous production of A1-7 by [[ACE2]], while overactivation of the A1-7-Mas pathway could alleviate sarcopenia and osteoporosis in aged mice.
|mesh-terms=* Adipose Tissue
* Aging
* Angiotensin I
* Angiotensin-Converting Enzyme 2
* Animals
* Body Weight
* Bone Resorption
* Cyclin-Dependent Kinase Inhibitor p16
* Forelimb
* Gene Deletion
* Hand Strength
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Muscle Weakness
* Muscles
* Organ Size
* PAX3 Transcription Factor
* Peptide Fragments
* Peptidyl-Dipeptidase A
* Proto-Oncogene Proteins
* Receptors, G-Protein-Coupled
* Renin-Angiotensin System
* Time Factors
|keywords=* Angiotensin 1-7
* Angiotensin Converting Enzyme 2
* Mas receptor
* Muscle weakness
* osteoporosis
|full-text-url=https://sci-hub.do/10.1042/CS20190573
}}
==STAT3==

{{medline-entry
|title=Dietary Restriction Suppresses Steatosis-Associated Hepatic Tumorigenesis in Hepatitis C Virus Core Gene Transgenic Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33083279
|abstract=Dietary restriction (DR) is a preventive strategy for obesity, metabolic syndrome, cardiovascular disease, and diabetes. Although an interconnection between obesity, metabolic syndrome, fatty liver, and hepatocellular carcinoma has been documented, the mechanism and impact of DR on steatosis-derived hepatocarcinogenesis are not fully understood. This study aimed to evaluate whether DR can prevent hepatic tumorigenesis. Male hepatitis C virus core gene transgenic (HCVcpTg) mice that develop spontaneous age-dependent insulin resistance, hepatic steatosis, and ensuing liver tumor development without apparent hepatic fibrosis, were fed with either a control diet ad libitum (control group) or 70% of the same control diet (DR group) for 15 months, and liver phenotypes were investigated. DR significantly reduced the number and volume of liver tumors. DR attenuated hepatic oxidative and endoplasmic reticulum stress and markedly suppressed nuclear factor-κB, signal transducer and activator of transcription 3 ([[STAT3]]) and STAT5, and phosphorylation of extracellular signal-regulated kinase, leading to downregulation of several pro-oncogenic mediators, such as cyclin D1. Serum insulin and insulin-like growth factor 1 levels, as well as hepatic expression of insulin receptor substrate 1/2, phosphatidylinositol-3 kinase, and serine/threonine-protein kinase AKT, were downregulated by DR. A transcriptome analysis revealed that [[STAT3]] signaling and lipogenesis were the most suppressed hepatocarcinogenic pathways affected by DR. Additionally, DR stimulated autophagy and p62/sequestosome 1 degradation, enhanced phosphorylation of AMP-activated protein kinase α, increased fibroblast growth factor 21 expression, and attenuated expression of senescence-associated secretory phenotypes. DR suppressed steatosis-associated hepatic tumorigenesis in HCVcpTg mice, mainly due to attenuation of pathways involved in inflammation, cellular stress, cell proliferation, insulin signaling, and senescence. These findings support the notion that persistent 30% reduction of daily food intake is beneficial for preventing steatosis-associated hepatocarcinogenesis caused by HCV core protein.

|keywords=* Cyclin D1
* NF-κB
* STAT3
* Senescence
* p62/SQSTM1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548900
}}
{{medline-entry
|title=Skeletal glucocorticoid signalling determines leptin resistance and obesity in aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33045434
|abstract=Aging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging. Mice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2 -tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus [[STAT3]] phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured. As they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2 -tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic [[STAT3]], from 6 months of age onwards. In contrast, HSD2 -tg mice remained leptin-sensitive throughout the study. Compared to HSD2 -tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2 -tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2 -tg mice, compared to wild-type mice. Skeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.

|keywords=* Aging
* Appetite
* Glucocorticoid
* Leptin
* Obesity
* Osteoblast
* Osteocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596342
}}
{{medline-entry
|title=AMPK alleviates oxidative stress‑induced premature senescence via inhibition of NF-κB/[[STAT3]] axis-mediated positive feedback loop.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32882228
|abstract=Stress-induced premature senescence (SIPS) is characterized by the secretion of a variety of inflammatory cytokines, chemokines, and proteases, which are defined collectively as the senescence-associated secretory phenotype (SASP). AMP-activated protein kinase (AMPK) activation contributes to SIPS prevention, and the impact of AMPK on SASP may be included, but the mechanisms governing this phenomenon have not elucidated. In this study, we showed that SIPS is accompanied by a dynamic fluctuation of NF-κB activation, which induces SASP production, whilst reinforcing and amplifying local [[STAT3]] signalling and subsequently enhancing downstream senescence. NF-κB and [[STAT3]] inhibitors attenuate oxidative stress-induced senescence in a time-dependent manner. Conditioned medium (CM) from senescent cells rich in SASP factors can induce growth arrest and promote senescence in healthy cells; accordingly, a [[STAT3]] inhibitor blunts the SASP-induced senescence, indicating a positive feedback mechanism via the NF-κB/[[STAT3]] pathway that sustains SASP production and promotes senescence. In addition, we confirmed that AMPK negatively regulates SASP production and senescence development associated with NF-κB/[[STAT3]] inhibition. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence development via inhibiting the NF-κB/SASP/[[STAT3]] signalling mediated positive feedback loop.

|keywords=* AMPK
* NF-κB/STAT3 signalling
* Oxidative stress
* SASP
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111347
}}
{{medline-entry
|title=Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through [[STAT3]] activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32848054
|abstract=Increased neural stem cell (NSC) quiescence is a major determinant of age-related regenerative decline in the adult hippocampus. However, a coextensive model has been proposed in which division-coupled conversion of NSCs into differentiated astrocytes restrict the stem cell pool with age. Here we report that age-related loss of the posttranslational modification, O-linked β-[i]N[/i]-acetylglucosamine (O-GlcNAc), in NSCs promotes a glial fate switch. We detect an age-dependent decrease in NSC O-GlcNAc levels coincident with decreased neurogenesis and increased gliogenesis in the mature hippocampus. Mimicking an age-related loss of NSC O-GlcNAcylation in young mice reduces neurogenesis, increases astrocyte differentiation, and impairs associated cognitive function. Using RNA-sequencing of primary NSCs following decreased O-GlcNAcylation, we detected changes in the [[STAT3]] signaling pathway indicative of glial differentiation. Moreover, using O-GlcNAc-specific mass spectrometry analysis of the aging hippocampus, together with an in vitro site-directed mutagenesis approach, we identify loss of [[STAT3]] O-GlcNAc at Threonine 717 as a driver of astrocyte differentiation. Our data identify the posttranslational modification, O-GlcNAc, as a key molecular regulator of regenerative decline underlying an age-related NSC fate switch.
|mesh-terms=* Aging
* Animals
* Cell Differentiation
* Cell Proliferation
* Computational Biology
* Gene Expression Regulation
* Glucosamine
* Hippocampus
* Mice
* Neural Stem Cells
* Neurogenesis
* Neuroglia
* STAT3 Transcription Factor
* Sequence Analysis, RNA
|keywords=* O-GlcNAcylation
* aging
* gliogenesis
* neural stem cells
* neurogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486730
}}
{{medline-entry
|title=Cell Death by Gallotannin Is Associated with Inhibition of the JAK/STAT Pathway in Human Colon Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32714471
|abstract=Gallotannin (GT) is a polyphenol that possesses interesting anticancer properties. However, the mechanisms underlying its antitumor effects have not been well defined. This study was designed to clarify the mechanisms underlying GT antitumor effects in colon cancer cell lines. Three isogenic HCT116 cell lines (p53 , p53 , and p21 ) were treated with GT for different time points then Western blot, flow cytometry, and senescence analysis were performed to examine the effect of GT on Mitogen-activated protein kinase (MAPK) and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) effectors, [[STAT3]] downstream apoptotic targets, Sub-G1 phase, and programmed cell death induction. Transfection using Invitrogen Lipofectamine 2000 Transfection Reagent (Thermo Fisher Scientific, Waltham, Massachusetts) were used to identify the role of p53 and p21 in the p53  and p21  cell lines. Both low and high GT concentrations caused MAPKs activation marked by upregulation of extracellular signal-regulated kinase (p-ERK). The preincubation with the antioxidant Tiron (Sigma-Aldrich, St Louis, Missouri) showed that GT's antitumor effects were not mediated by reactive oxygen species. We then examined the effect of GT on the JAK/STAT pathway, which is known to be activated in colorectal cancer. GT totally inhibited the JAK/STAT pathway effectors JAK2, STAT1, and [[STAT3]] and their downstream apoptotic regulators B-cell lymphoma-extra large (Bcl-x ) and c-Myc in all 3 cell lines. HCT116 cancer cells exhibited differential sensitivity to GT with p21  cells being the most sensitive and p53  cells that express p21 protein being the least sensitive. In p53  cells, GT induced senescence, whereas in p53  and p21  cells, GT induced apoptosis in a caspase independent manner marked by Poly(ADP-Ribose) Polymerase (PARP) cleavage, Bcl-2 downregulation, and upregulation of the Bcl-2 associated X (Bax) to B-cell lymphoma 2 (Bcl-2) ratio. In addition, the sub-G1 phase exceeded 50% in p21  cells. Considered together, our results indicate that GT is potent inhibitor of the JAK/STAT pathway in colon cancer irrespective of the p53 and p21 status, which provides insights into its mechanism of anticancer activities and future potential for clinical translation. ([i]Curr Ther Res Clin Exp[/i]. 2020; 81:XXX-XXX).

|keywords=* Apoptosis
* JAK/STAT
* caspase
* colon cancer
* gallotannin
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378856
}}
{{medline-entry
|title=The effect of interleukin 6 deficiency on myocardial signal transduction pathways activation induced by bacterial lipopolysaccharide in young and old mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32693349
|abstract=Exaggerated release of proinflammatory mediators during sepsis contributes to inadequate vasodilatation and depressed myocardial contractility, which lead to development of shock and circulatory collapse. The aim of the study was to evaluate the effect of IL-6 and aging on activation of intracellular signaling pathways in the myocardium induced by bacterial lipopolysaccharide (LPS) administration. LPS was injected intraperitoneally to male 3- and 24-month old mice with systemic IL-6 gene knock-out (IL-6KO) and the reference strain (WT). LPS was given intraperitoneally in single low (0.1 mg/kg) or high (10 mg/kg) dose, or in two doses (0.1 + 10 mg/kg) with 24-h delay. The expression and phosphorylation of [[STAT3]], ERK1/2, Akt1/2/3 proteins in the left ventricular myocardium was evaluated after 24 h using Western blotting. Low LPS dose induced higher [[STAT3]] phosphorylation only in old IL-6KO mice, not affecting ERK1/2 and Akt1/2/3 phosphorylation in any group. High LPS dose upregulated [[STAT3]] phosphorylation similarly in all groups, reduced ERK1/2 expression in young WT mice and upregulated Akt1/2/3 expression and phosphorylation in young IL-6KO mice. Pretreatment with low LPS dose attenuated phosphorylation of [[STAT3]] in both old groups and phosphorylation of Akt1/2/3 in young IL-6KO group. Two-dose approach also significantly potentiated ERK1/2 phosphorylation in both old groups. Obtained results show that IL-6 deficiency alters the activity of intracellular signaling pathways: JAK/STAT in old and Akt in young LPS-treated mice. This may indicate that lack of IL-6 attenuates Akt-related cytoprotective effect of pretreatment with low LPS dose in young but not in aged animals.

|keywords=* Aging
* For review: bacterial lipolisacharide (LPS)
* Heart
* Inflammation
* Interleukin-6
* Signal transduction
|full-text-url=https://sci-hub.do/10.1016/j.advms.2020.06.006
}}
{{medline-entry
|title=Silibinin and SARS-CoV-2: Dual Targeting of Host Cytokine Storm and Virus Replication Machinery for Clinical Management of COVID-19 Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32517353
|abstract=COVID-19, the illness caused by infection with the novel coronavirus SARS-CoV-2, is a rapidly spreading global pandemic in urgent need of effective treatments. Here we present a comprehensive examination of the host- and virus-targeted functions of the flavonolignan silibinin, a potential drug candidate against COVID-19/SARS-CoV-2. As a direct inhibitor of [[STAT3]]-a master checkpoint regulator of inflammatory cytokine signaling and immune response-silibinin might be expected to phenotypically integrate the mechanisms of action of IL-6-targeted monoclonal antibodies and pan-JAK1/2 inhibitors to limit the cytokine storm and T-cell lymphopenia in the clinical setting of severe COVID-19. As a computationally predicted, remdesivir-like inhibitor of RNA-dependent RNA polymerase (RdRp)-the central component of the replication/transcription machinery of SARS-CoV-2-silibinin is expected to reduce viral load and impede delayed interferon responses. The dual ability of silibinin to target both the host cytokine storm and the virus replication machinery provides a strong rationale for the clinical testing of silibinin against the COVID-19 global public health emergency. A randomized, open-label, phase II multicentric clinical trial (SIL-COVID19) will evaluate the therapeutic efficacy of silibinin in the prevention of acute respiratory distress syndrome in moderate-to-severe COVID-19-positive onco-hematological patients at the Catalan Institute of Oncology in Catalonia, Spain.

|keywords=* IL-6
* JAK
* coronavirus
* cytokine storm
* remdesivir
* senescence
* stat3
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356916
}}
{{medline-entry
|title=Implication of JAK1/[[STAT3]]/SOCS3 Pathway in Aging of Cerebellum of Male Rat: Histological and Molecular study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32483368
|abstract=Aging causes morphological and functional changes in the cerebellum. This work aimed to demonstrate the implication of JAK1/[[STAT3]]/SOCS3 on aging-induced changes of rat cerebellum. Thirty male rats were divided into: adult (12 months), early senile (24 months) and late senile (32 months) groups. Immunohistochemical reaction of the cerebellum to GFAP and caspase-3 was assessed and the expression of JAK1, [[STAT3]], SOCS3 proteins was also evaluated. TNFα as well as the activities of malondialdehyde (MDA) and reduced glutathione (GSH) in cerebellar tissue were also measured. The cerebellum of late senile rats revealed more degenerative changes than early senile rats in the form of increase in GFAP and caspase-3 immunoreaction. Additionally, there was decrease in JAK1and [[STAT3]] expression in early and late senile rats and increase in SOCS3 when compare early and late senile groups with adult one. Enhancement of TNFα was noticed with aging as well as significant decrease in GSH and increase in MDA in early senile group. Moreover, late senile group revealed significant decrease in GSH and increase in MDA. It could be concluded that aging resulting in variable changes of the cerebellum as detected by morphological changes, immunohistochemical reactions of caspase-3 and GFAP and expression of JAK1/[[STAT3]]/SOCS3 proteins. Additionally, inflammatory marker TNFα and the activity of oxidative/antioxidative stress markers; malondialdehyde (MDA) and reduced glutathione (GSH) were also affected with aging.
|mesh-terms=* Aging
* Animals
* Caspase 3
* Cerebellum
* Glial Fibrillary Acidic Protein
* Glutathione
* Immunohistochemistry
* Janus Kinase 1
* Male
* Malondialdehyde
* Microscopy, Electron
* Rats
* Rats, Wistar
* STAT3 Transcription Factor
* Signal Transduction
* Suppressor of Cytokine Signaling 3 Protein
* Tumor Necrosis Factor-alpha

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264275
}}
{{medline-entry
|title=Atorvastatin-induced senescence of hepatocellular carcinoma is mediated by downregulation of hTERT through the suppression of the IL-6/[[STAT3]] pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32257389
|abstract=Hepatocellular carcinoma (HCC), a hepatic malignancy, has a poor prognosis and contributes to cancer-related death worldwide. Cellular senescence is an anticancer therapeutic strategy that causes irreversible cell cycle arrest and enables immune-mediated clearance of cancer cells. Atorvastatin, an HMG-CoA reductase inhibitor, has been shown to inhibit tumor growth and induce apoptosis or autophagy in malignant tumors. However, whether atorvastatin can induce HCC cell senescence and the mechanisms involved are poorly understood. The effects of atorvastatin-induced senescence were examined in both HCC cells and mouse xenograft models. The phenomenon and mechanism of senescence were examined by cell cycle analysis, senescence-associated β-galactosidase (SA-β-gal) staining and western blotting in HCC cells, and HCC tissues from mice were analyzed by immunohistochemical (IHC) staining. We demonstrated that atorvastatin induced cell growth inhibition and G0/G1 phase cell cycle arrest, leading to senescence in HCC cells. Atorvastatin-induced senescence was independent of p53, p14, and p16, and atorvastatin not only decreased the secretion of IL-6, a major senescence-associated secretory phenotype (SASP) factor, and the phosphorylation of [[STAT3]] but also inhibited the expression of hTERT, a catalytic subunit of telomerase. Supplementation with exogenous IL-6 reversed both atorvastatin-induced suppression of [[STAT3]] phosphorylation and hTERT expression and atorvastatin-induced senescence. Overexpression of constitutively activated [[STAT3]] rescued HCC cells from atorvastatin-induced hTERT suppression and senescence. Moreover, atorvastatin decreased tumor growth in mouse xenograft models. Consistent with these results, atorvastatin decreased the IL-6, p-[[STAT3]], and hTERT levels and increased β-gal expression in tumor sections. Taken together, these data indicate that atorvastatin can induce atypical cellular senescence in HCC cells to inhibit tumor growth, an effect mediated by downregulation of hTERT through suppression of the IL-6/[[STAT3]] pathway.

|keywords=* Cancer therapy
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105491
}}
{{medline-entry
|title=Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32012719
|abstract=Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA--Gal, -H2A.X), growth-arrest in the G  phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-B, and [[STAT3]] pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored.

|keywords=* aging biomarkers
* cancer biology
* cellular senescence
* epithelial ovarian cancer
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072138
}}
{{medline-entry
|title=Persistent Activation of [[STAT3]] Pathway in the Retina Induced Vision Impairment and Retinal Degenerative Changes in Ageing Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31884637
|abstract=Neurotrophic factors can promote the survival of degenerating retinal cells through the activation of [[STAT3]] pathway. Thus, augmenting [[STAT3]] activation in the retina has been proposed as potential therapy for retinal dystrophies. On the other hand, aberrant activation of [[STAT3]] pathway is oncogenic and implicated in diverse human diseases. Furthermore, the [[STAT3]]/SOCS3 axis has been shown to induce the degradation of rhodopsin during retinal inflammation. In this study, we generated and used mice with constitutive activation of [[STAT3]] pathway in the retina to evaluate the safety and consequences of enhancing [[STAT3]] activities in the retina as a potential treatment for retinal degenerative diseases. We show that long-term activation of the [[STAT3]] pathway can induce retinal degenerative changes and also exacerbate uveitis and other intraocular inflammatory diseases. Mechanisms underlying the development of vision impairment in the [[STAT3]]c-Tg mice derived in part from [[STAT3]]-mediated inhibition of rhodopsin and overexpression of SOCS3 in the retina. These results suggest that much caution should be exercised in the use of [[STAT3]] augmentation therapy for retinal dystrophies.
|mesh-terms=* Aging
* Animals
* Mice
* Mice, Inbred C57BL
* Retina
* Retinal Degeneration
* STAT3 Transcription Factor
* Suppressor of Cytokine Signaling 3 Protein
* Suppressor of Cytokine Signaling Proteins
* Uveitis
|keywords=* EAU
* Experimental autoimmune uveitis
* Retinal dystrophies
* SOCS3
* STAT3
* Transgenic mouse
* Uveitis
|full-text-url=https://sci-hub.do/10.1007/978-3-030-27378-1_58
}}
{{medline-entry
|title=Interleukin-10 induces senescence of activated hepatic stellate cells via [[STAT3]]-p53 pathway to attenuate liver fibrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31730896
|abstract=Hepatic fibrosis is a wound healing process which results in deposition of excessive abnormal extracellular matrix (ECM) in response to various liver injuries. Activated hepatic stellate cells (HSCs) are the major sources of ECM and induction of senescence of activated HSCs is an attractive therapeutic strategy for liver fibrosis. Our previous studies have shown that interleukin-10 (IL-10) attenuates the carbon tetrachloride (CCL ) - and porcine serum-induced liver fibrosis in rats. However, little is known about the mechanisms of IL-10 regulating the senescence of activated HSCs. The aim of this study is to uncover the underlying pathway by which IL-10 mediates activated HSCs senescence to attenuate liver fibrosis. In vivo, we found that IL-10 gene by hydrodynamics-based transfection attenuated CCL -induced liver fibrosis associated with senescence of activated HSCs in rats. In vitro experiment confirmed that IL-10 could induce senescence of activated HSCs via inhibiting cell proliferation, inducing cell cycle arrest, increasing the SA-β-Gal activity and enhancing expression of senescence marker protein p53 and p21. Treatment with Pifithrin-α, a specific inhibitor of p53, could abrogate IL-10-increased SA-β-Gal activity and expression of P53 and P21in activated HSCs. Lastly, IL-10 also increased the expression of total and phosphorylated signal transducers and activators of transcription 3([[STAT3]]) and promoted phosphorylated [[STAT3]] translocation from cytoplasm to nucleus. Treatment with cryptotanshinone, a specific inhibitor of [[STAT3]], could inhibit the phosphorylation of [[STAT3]] and its downstream proteins p53 and p21 expression and decrease the activity of SA-β-Gal in activated HSCs induced by IL-10. Taken together, IL-10 induced senescence of activated HSCs via [[STAT3]]-p53 pathway to attenuate liver fibrosis in rats and present study will provide a new mechanism of antifibrotic effects of IL-10.

|keywords=* Hepatic stellate cells
* Interleukin-10
* Liver fibrosis
* Senescence
* Signal pathway
|full-text-url=https://sci-hub.do/10.1016/j.cellsig.2019.109445
}}
==CP==

{{medline-entry
|title=A Life Course Perspective on Growing Older With Cerebral Palsy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33213304
|abstract=Despite most children with cerebral palsy ([[CP]]) now living within typical life spans, little is known about how the effects of [[CP]] unfold across the life course and impact participation in everyday life during adulthood. In this study, we explored the experiences of 38 adults growing older with [[CP]]. Data were gathered using semi-structured interviews focused on participants' engagement in activities in their community and analyzed using a life course perspective to deepen our understanding of the experiences of our participants. We found that individual agency, family and social contexts, as well as larger sociocultural contexts all shaped participants' experiences as they grew older. The findings highlight the usefulness of the life course perspective for understanding how the effects of a diagnosis of [[CP]] unfold over time. Further use of this perspective can better inform health care services to meet the needs of adults with [[CP]] aging with a lifelong disability.

|keywords=* aging
* cerebral palsy
* midlife
* neurological disorders
* neurology
* qualitative descriptive
|full-text-url=https://sci-hub.do/10.1177/1049732320971247
}}
{{medline-entry
|title=The molecular anatomy and functions of the choroid plexus in healthy and diseased brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32750317
|abstract=The choroid plexus ([[CP]]) is located in the ventricular system of the brain (one in each ventricle), and the [[CP]] epithelial cells form an important barrier between the blood and the cerebrospinal fluid (CSF). Their main function comprises CSF secretion, maintenance of brain homeostasis, signalling, and forming a neuroprotective barrier against harmful external and internal compounds. The [[CP]]s mature early and demonstrate expressional changes of barrier-specific genes and proteins related to location and developmental stage of the [[CP]]. Important proteins for the barrier function include tight junction proteins, numerous transporters and enzymes. Natural senescence leads to structural changes in the [[CP]] cells and reduced or loss of function, while further loss of [[CP]] function and changes in immune status may be relevant in neurodegenerative diseases such as Alzheimer's disease and Multiple Sclerosis. Neuroprotective genes expressed at [[CP]]s may be unexplored targets for new therapies for neurodegenerative diseases.

|keywords=* Aging
* Alzheimer's disease
* Choroid plexus
* Development
* Multiple sclerosis
* Neuroprotection
|full-text-url=https://sci-hub.do/10.1016/j.bbamem.2020.183430
}}
{{medline-entry
|title=The effects and mechanism of collagen peptide and elastin peptide on skin aging induced by D-galactose combined with ultraviolet radiation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32717457
|abstract=The content of collagen and elastin occupies a large proportion of skin evaluation, and collagen peptide ([[CP]]) and elastin peptide (EP) are widely used drugs, which have anti-inflammatory effects. In addition, [[CP]] and EP can also be used as therapeutic agents for skin repair. However, previous studies have never thoroughly verified the effects of oral administration of [[CP]] and EP on skin repair. To study the effects and mechanism of oral administration of [[CP]] and EP on skin aging induced by combinatorial treatment with D-galactose and ultraviolet radiation. In animal experiments, the combined oral administration of [[CP]] and EP increased the contents of collagen and elastin in animal skin, accompanying with significantly upregulated expression of hyaluronic acid and hydroxyproline, as well as significantly reduced expression of MMP-3 and IL-1α. In addition, the combined therapy also significantly increased the expression of seven collagen and elastin synthesis-related factors including IGF-1, LOX, SMAD2, JNK, SP1, TβRII and TGF-β. Oral administration of [[CP]] and EP can repair skin aging induced by the combined treatment with D-galactose and ultraviolet radiation and the effects of [[CP]] and EP appeared synergistic.

|keywords=* Collagen
* D-galactose
* Elastin
* Skin aging
* Ultraviolet
|full-text-url=https://sci-hub.do/10.1016/j.jphotobiol.2020.111964
}}
{{medline-entry
|title=Model based strategies towards protein A resin lifetime optimization and supervision.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32709318
|abstract=The high cost of protein A resins drives the biopharmaceutical industry to maximize its lifetime, which is limited by several processes, usually referred to as resin aging. In this work, two model based strategies are presented, aiming to control and improve the resin lifetime. The first approach, purely statistical, enables qualitative monitoring of the column state and prediction of column performance indicators (e.g. yield, purity and dynamic binding capacity) from chromatographic on-line data (e.g. UV signal). The second one, referred to as hybrid modeling, is based on a lumped kinetic model, which includes two aging parameters fitted on several resin cycling experimental campaigns with varying cleaning procedures ([[CP]]). The first aging parameter accounts for binding capacity deterioration (caused by ligand degradation, leaching, and pore occlusion), while the second accounts for a decreased mass transfer rate (mainly caused by fouling). The hybrid model provides important insights into the prevailing aging mechanism as a function of the different [[CP]]s. In addition, it can be applied to model based [[CP]] optimization and yield forecasting with the capability of state estimation corrections based on on-line process information. Both approaches show promising results, which could help to significantly extend the resin lifetime. This comes along with increased understanding, reduced experimental effort, decreased cost of goods, and improved process robustness.
|mesh-terms=* Algorithms
* Chromatography
* Kinetics
* Least-Squares Analysis
* Ligands
* Models, Theoretical
* Principal Component Analysis
* Resins, Plant
* Staphylococcal Protein A
* Statistics as Topic
|keywords=* Cleaning procedures
* Hybrid modeling
* Multivariate data analysis
* Protein A chromatography
* Resin aging
* Resin lifetime
|full-text-url=https://sci-hub.do/10.1016/j.chroma.2020.461261
}}
{{medline-entry
|title=The influence of age and environmental conditions on supplement intake by beef cattle winter grazing northern mixed-grass rangelands.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32658282
|abstract=This study evaluated the influence of cow age and temperature adjusted for wind chill (Twindchill) on supplement intake behavior of beef cattle winter grazing northern mixed grass prairie rangelands. A commercial herd of 272 (year 1) and 302 (year 2) bred cows (Angus, Simmental × Angus) ranging in age from 1- to 12-yr-old grazed a 329-ha rangeland pasture (~1.5 ha animal unit month- 1) from November to January. Cows were grouped into seven age classes (1 yr old, 2 yr old, 3 yr old, 4 yr old, 5 yr old, 6 yr old, and ≥ 7 yr old) and were provided free-choice access to a 30% [[CP]] self-fed canola meal-based pelleted supplement with 25% salt to limit intake. The target daily intake was 0.91 kg cow- 1 d- 1. Supplement was provided in a SmartFeed Pro self-feeder system to measure individual animal supplement intake and behavior. An Onset HOBO U30-NRC Weather Station was placed near the supplement feeders to collect weather data for the entirety of the grazing period. Average daily supplement intake and the coefficient variation in supplement intake displayed a Twindchill × cow age × year interaction (P ≤ 0.02). There was a negative linear effect of age on supplement intake (kg cow- 1 d- 1) for days with below average Twindchill conditions in both years (P < 0.01). There was also negative linear effect of age on supplement intake (g kg of BW- 1 d- 1) at average Twindchill in year 1 and below average Twindchill in year 2 (P < 0.01). Cow age had a quadratic effect on supplement intake for days with below average Twindchill in year 1 (P = 0.02); however, this was a curvilinear response where yearlings and 2-yr-olds consumed more supplement per kilogram of BW than other age cattle (P < 0.01). Cow age had positive linear effects on variation in supplement intake at below average Twindchill conditions in both years (P < 0.01). Daily visits to the supplement feeders displayed a Twindchill × cow age interaction (P < 0.01), where there was a linear decrease in visits with increasing age at below average Twindchill conditions (P < 0.01). In summary, both cow age and the winter environmental conditions interacted to influence animal supplement intake behavior and, as a result, nutrient delivery efficacy in winter grazing beef cattle.
|mesh-terms=* Aging
* Animal Feed
* Animal Husbandry
* Animals
* Cattle
* Diet
* Dietary Supplements
* Ecosystem
* Female
* Poaceae
* Seasons
* Weather
|keywords=* beef cattle
* cow age
* environment
* supplement intake
* winter grazing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455287
}}
{{medline-entry
|title=Cyclophosphamide, a cancer chemotherapy drug-induced early onset of reproductive senescence and alterations in reproductive performance and their prevention in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32536211
|abstract=Although, cyclophosphamide ([[CP]]) treatment is known to cause degeneration of the ovarian follicular reserve, which may have a serious consequence of the onset of early reproductive senescence, thus far there is no experimental study either to demonstrate [[CP]]-induced early onset of reproductive senescence or its prevention. Intraperitoneal administration (ip) of [[CP]] [100 mg/kg body weight (bw)/mouse] resulted in a drastic reduction in reproductive life span as shown by the onset of reproductive senescence at a significantly early age (258 days) compared to controls (349 days), whereas treatment with the root extract of the herb [i]Decalepis hamiltonii[/i] (DH) (200 mg/Kg bw/day for 7 days), a cocktail of anti-oxidants prior to [[CP]] administration maintained normal reproductive life span in mice. Further, the [[CP]] treated mice showed a significant increase in pre-coital interval and a significant reduction in parturition index coupled with regressive changes in the uterine endometrium, whereas DH co-treatment prevented these changes. The results for the first time, demonstrate that the ovarian toxicity of [[CP]] could be prevented by an anti-oxidant to maintain a normal reproductive life span as well as reproductive outcome using mice model.

|keywords=* Cyclophosphamide
* Decalepis hamiltonii
* premature ovarian failure
* reproductive performance
* reproductive senescence
* uterus
|full-text-url=https://sci-hub.do/10.1080/01480545.2020.1774773
}}
{{medline-entry
|title=Asymptomatic [i]Clostridium perfringens[/i] Inhabitation in Intestine Can Cause Inflammation, Apoptosis, and Disorders in Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31928429
|abstract=[i]Clostridium perfringens[/i] ([[CP]]) is a foodborne pathogen. The bacterium can also inhabit human gut without symptoms of foodborne illness. However, the clinical symptoms of long-term inhabitation have not been known yet. Therefore, the objective of this study was to elucidate the relationship between intestinal [[CP]] and other internal organs. Phosphate-buffered saline (PBS) and [[CP]] were orally injected into 5-week-old (YOUNG) and 12-month-old C57BL6/J (ADULT) mice. Gene expression levels related to inflammation (tumor necrosis factor-α [[i]TNF-α[/i]], interleukin [[i]IL[/i]]-[i]1β[/i], and [i]IL-6[/i]) and oxidative stress (superoxide dismutase [[i]SOD[/i]][i]1[/i], [i]SOD2[/i], [i]SOD3[/i], glutathione reductase [[i]GSR[/i]], glutathione peroxidase [[i]GPx[/i]][i]3[/i], and catalase [[i]CAT[/i]]) responses were evaluated in the brain, small intestine, and liver. In addition, apoptosis-related (BCL2-associated X [[i]BAX[/i]][i]1[/i] and high-mobility group box-1 [[i]HMGB1[/i]]) and brain disorder-related genes (CCAAT-enhancer-binding protein [[i]C/EBP[/i]][i]-β[/i], [i]C/EBPδ[/i], C/EBP homologous protein [[i]CHOP[/i]], and amyloid precursor protein [[i]APP[/i]]) as brain damage markers were examined. The protein expressions in the brain were also measured. Gene expression levels of inflammation and oxidative stress responses were higher ([i]p[/i] < 0.05) in brains of [[CP]]-YOUNG and [[CP]]-ADULT mice, compared with PBS-YOUNG and PBS-ADULT, and the gene expression levels were higher ([i]p[/i] < 0.05) in brains of [[CP]]-ADULT mice than [[CP]]-YOUNG mice. Apoptosis-related ([i]BAX1[/i] and [i]HMGB1[/i]) and brain disorder-related genes ([i]C/EBPβ, C/EBPδ, CHOP,[/i] and [i]APP[/i]) were higher ([i]p[/i] < 0.05) in brains of [[CP]]-challenged mice, compared with PBS-challenged mice. Even oxidative stress response (GPx and SOD2), cell damage-related (HMGB1), and β-amyloid proteins were higher ([i]p[/i] < 0.05) in brains of [[CP]]- than in PBS-challenged mice. C/EBP protein was higher ([i]p[/i] < 0.05) in [[CP]]-YOUNG, compared with PBS-YOUNG mice. However, these clinical symptoms were not observed in small intestine and liver. These results indicate that although asymptomatic intestinal [[CP]] do not cause foodborne illness, their inhabitation may cause brain inflammation, oxidative stress, apoptosis, and cell damage, which may induce disorders, especially for the aged group.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Asymptomatic Infections
* Brain
* Brain Diseases
* Clostridium Infections
* Clostridium perfringens
* Disease Models, Animal
* Feces
* Food Microbiology
* Gene Expression
* Humans
* Inflammation
* Intestines
* Liver
* Male
* Mice
* Mice, Inbred C57BL
* Organ Size
* Oxidative Stress
* Risk Factors
* Spleen
|keywords=* Clostridium perfringens
* brain damage
* brain disorder
* gut microbiota
|full-text-url=https://sci-hub.do/10.1089/fpd.2019.2677
}}
{{medline-entry
|title=The Role of the Clinical Pharmacist in the Management of People Living with HIV in the Modern Antiretroviral Era.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31834321
|abstract=As the HIV epidemic has evolved, so too has the role of the clinical pharmacist ([[CP]]) in the management of people living with HIV (PLWH). The modern antiretroviral therapy (ART) era has resulted in PLWH living normal life spans with resulting increased comorbidities. [[CP]]s have long been a part of the multidisciplinary management of ART. However, with the changing demographics of PLWH and health-care system dynamics, [[CP]]s have had the opportunity to expand their role. This includes involvement in managing increasing comorbidities with expanding and more complicated medication regimens, drug interaction monitoring, and optimizing transitions of care, all while recognizing and addressing barriers to successful HIV and hepatitis C virus (HCV) treatment. In addition, with the expansion of HIV prevention and pre-exposure prophylaxis (PrEP) services, [[CP]]s have the opportunity to be involved in HIV prevention. This study summarizes the literature evaluating the impact of [[CP]]s in the management of PLWH in the era of modern ART. We conducted a literature search to identify studies that assessed the [[CP]] role in HIV clinical practice since 2006. The identified studies were grouped into two categories. The first was HIV related outcomes, including interventions on regimen selection, adherence, regimen optimization, and management of treatment failure. The second group of studies pertained to aging and vulnerable populations, including management of comorbidities, transitions of care, medication-assisted treatment, hepatitis C, and HIV screening and PrEP. We concluded that the evidence supports the expanding role of [[CP]]s to positively impact a variety of aspects related to the care of PLWH.
|mesh-terms=* Aged
* Aged, 80 and over
* Anti-Retroviral Agents
* Disease Management
* Disease Transmission, Infectious
* Female
* HIV Infections
* Humans
* Male
* Medication Adherence
* Middle Aged
* Pharmacists
* Professional Role
* Treatment Outcome
|keywords=* Aging
* Antiretroviral therapy
* Clinical pharmacist
* Comorbidities
* HIV
|full-text-url=https://sci-hub.do/10.24875/AIDSRev.19000089
}}
{{medline-entry
|title=A clinically feasible method for the assessment and characterization of pain in patients with chronic pancreatitis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31787527
|abstract=Pain is the primary symptom of chronic pancreatitis ([[CP]]), but methods for sensory testing and pain characterization have not previously been validated for clinical use. We present a clinically feasible method for the assessment and characterization of pain mechanisms in patients with [[CP]] based on quantitative sensory testing (QST). This was a cross-sectional, multicenter study of 122 control subjects without pancreatic disease and another 60 patients with painful [[CP]]. All subjects underwent standardized QST assessments including a cold pressor test, a conditioned pain modulation paradigm, repetitive pin-prick stimuli (temporal summation) and pressure stimulation of the upper abdominal (pancreatic) and control dermatomes. The effects of age and gender on QST assessment parameters were investigated and normative reference values based on quartile regression were derived and implemented in algorithms to categorize patients according to their patterns of central pain processing (normal vs. segmental sensitization vs. widespread sensitization). Absolute pressure thresholds were subject to clinically relevant gender effects (all p < 0.001), while the remainder of QST parameters were unaffected by age and gender. The algorithm with the best discriminatory capacity showed good separation between patients and controls (p < 0.001); 50% of patients had normal central pain processing, 23% had evidence of segmental sensitization and 27% had evidence of widespread sensitization. We show normative reference values for a clinically feasible method for assessment and characterization of pain mechanisms in patients with [[CP]]. Application of this method streamlines the evaluation of pancreatic pain and may be used to inform treatment. CLINICALTRIALS. NCT03434392.
|mesh-terms=* Adult
* Aging
* Case-Control Studies
* Cross-Sectional Studies
* Humans
* Middle Aged
* Pain
* Pain Measurement
* Pancreatitis, Chronic
* Sex Factors
|keywords=* Central sensitization
* Chronic pancreatitis
* Nociception
* Pain
|full-text-url=https://sci-hub.do/10.1016/j.pan.2019.11.007
}}
{{medline-entry
|title=Differences in geometric strength at the contralateral hip between men with hip fracture and non-fractured comparators.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31812699
|abstract=Older men sustain excess bone mineral density (BMD) declines after hip fracture; however, BMD provides no information on mechanical structure and strength. The aim was to assess whether changes in hip bone geometry in older men after hip fracture differ than that expected with aging. Two cohorts were used: Baltimore Hip Studies 7th cohort (BHS-7) and Baltimore Men's Osteoporosis Study (MOST). The sample (N = 170) included older Caucasian men with hip fracture that were propensity score matched (1:1) to community-dwelling non-fractured comparators. Hip Structural Analysis (HSA) calculated aerial BMD and metrics of bone structural strength: cross-sectional bone area (CSA), cortical outer diameter (OD), section modulus (SM), and centroid position ([[CP]]). Mixed-effect models estimated changes in HSA parameters and adjusted robust regression models evaluated between-cohort differences in annual percent change at the narrow neck (NN), intertrochanteric (IT), and femoral shaft (FS). Hip fracture was associated with statistically greater declines in NN CSA (β = -2.818; 95% CI: -3.300%, -2.336%), SM (β = -1.896%; 95% CI: -2.711%, -1.080%) and [[CP]] (β = -0.884%; 95% CI: -0.889%, -0.880%) and significantly larger increases in NN OD (β = 0.187%; 95% CI: 0.185%, 0.190%). Differences in IT HSA parameters were like the NN but larger in magnitude, while there were favorable changes in FS geometry where fragility fractures are rare. Findings indicate there are declines in bone structure and strength at the NN and IT regions of the proximal femur in older men during hip fracture recovery that far exceed what occurs during normal aging.

|keywords=* Aging
* DXA
* Fracture prevention
* Injury/fracture healing
* Osteoporosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7037571
}}
{{medline-entry
|title=Factors associated with the number of clinical pharmacy recommendations: findings from an observational study in geriatric inpatients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31642397
|abstract=: Drug-related problems are prevalent in older inpatients and can be reduced by providing clinical pharmacy ([[CP]]) services. Details concerning implementation in clinical practice are frequently lacking. The aim was to describe the output of one such [[CP]] program and to identify factors associated with [[CP]] recommendations.  : A [[CP]] program was installed at three acute geriatric wards in a teaching hospital. A convenience sample was collected, consisting of inpatients who received a [[CP]] consultation at discharge. Medical conditions, patient demographics, and drug use were evaluated retrospectively. Number and type of the [[CP]] recommendations were determined. A Poisson regression analysis was performed to determine factors associated with the number of [[CP]] recommendations.  : A cohort of 524 patients, aged 85 (interquartile range (IQR): 82-89) years was included. On admission, 10.31 (standard deviation: 4.49) drugs were taken. Three (IQR: 2-4) [[CP]] recommendations were provided per patient, of which 70.2% targeted drug discontinuation. A model was derived, containing the following factors: number of drugs on admission (incidence rate ratio (IRR): 1.063; 95% confidence interval (CI): 1.052-1.074), number of previous contacts with the geriatric department (IRR: 0.869; 95%CI: 0.816-0.926), presence of left-ventricular dysfunction (IRR: 1.179, 95% CI: 1.023-1.360), the number of new drugs (IRR: 1.046; 95% CI: 1.021-1.071) and use of colecalciferol (IRR: 1.22; 95% CI: 1.088-1.367).  : Five factors were associated with the number of [[CP]] recommendations at discharge. This could allow for further patient stratification to increase the efficiency of the [[CP]] program.

|keywords=* Clinical pharmacy
* geriatrics
* inpatients
* polypharmacy
* risk stratification
|full-text-url=https://sci-hub.do/10.1080/17843286.2019.1683128
}}
{{medline-entry
|title=Protection against oxidative stress and anti-aging effect in Drosophila of royal jelly-collagen peptide.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31622731
|abstract=Dietary peptide has been of great interest because of its perspective in nutrition and health of human body. The aim of this study was to develop a dietary nutritional supplement exerting both antioxidant and anti-aging effects. Peptide, named as ERJ-[[CP]], was prepared by mixing enzyme-treated royal jelly (ERJ) with collagen peptide ([[CP]]), showing stronger antioxidant activity in vitro. Drosophila was used as model animal to investigate anti-aging effect of ERJ-[[CP]] in vivo. ERJ-[[CP]] significantly prolonged the average life span of Drosophila treated with H O  and paraquat, reducing malondialdehyde (MDA) and protein carbonyl (PCO) levels in Drosophila. In addition, 3 mg/mL of ERJ-[[CP]] could prolong the lifespan of natural aging Drosophila by 11.16%. ERJ-[[CP]] could up-regulate the levels of total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and down-regulate the contents of MDA and PCO. Moreover, the intake of ERJ-[[CP]] increased the food consumption, weight gain and exercise capacity of Drosophila. The results showed that ERJ-[[CP]] played a protective role in both antioxidant and anti-aging effects on Drosophila, and the anti-aging effect may be achieved by alleviating oxidative damage. It suggests that ERJ-[[CP]] could be developed as a health-promoting ingredient with antioxidant and anti-aging effects for human body.
|mesh-terms=* Aging
* Amino Acids
* Animals
* Body Weight
* Collagen
* Drosophila
* Fatty Acids
* Feeding Behavior
* Hydrogen Peroxide
* Longevity
* Molecular Weight
* Oxidative Stress
* Paraquat
|keywords=* Anti-aging
* Antioxidant activity
* Collagen
* Drosophila
* Royal jelly
|full-text-url=https://sci-hub.do/10.1016/j.fct.2019.110881
}}
==APP==

{{medline-entry
|title=Pre-symptomatic Caspase-1 inhibitor delays cognitive decline in a mouse model of Alzheimer disease and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32917871
|abstract=Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein ([[APP]] ) J20 and wild-type mice with VX-765 delays both [[APP]] - and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Behavior, Animal
* Cognitive Dysfunction
* Cytokines
* Dipeptides
* Disease Models, Animal
* Encephalitis
* Female
* Humans
* Inflammation
* Male
* Memory Disorders
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Serpins
* Spatial Memory
* Viral Proteins
* para-Aminobenzoates

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486940
}}
{{medline-entry
|title=Regorafenib Regulates AD Pathology, Neuroinflammation, and Dendritic Spinogenesis in Cells and a Mouse Model of AD.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32660121
|abstract=The oral multi-target kinase inhibitor regorafenib, which targets the oncogenic receptor tyrosine kinase (RTK), is an effective therapeutic for patients with advanced gastrointestinal stromal tumors or metastatic colorectal cancer. However, whether regorafenib treatment has beneficial effects on neuroinflammation and Alzheimer's disease (AD) pathology has not been carefully addressed. Here, we report the regulatory function of regorafenib in neuroinflammatory responses and AD-related pathology in vitro and in vivo. Regorafenib affected AKT signaling to attenuate lipopolysaccharide (LPS)-mediated expression of proinflammatory cytokines in BV2 microglial cells and primary cultured microglia and astrocytes. In addition, regorafenib suppressed LPS-induced neuroinflammatory responses in LPS-injected wild-type mice. In 5x FAD mice (a mouse model of AD), regorafenib ameliorated AD pathology, as evidenced by increased dendritic spine density and decreased Aβ plaque levels, by modulating [[APP]] processing and [[APP]] processing-associated proteins. Furthermore, regorafenib-injected 5x FAD mice displayed significantly reduced tau phosphorylation at T212 and S214 (AT100) due to the downregulation of glycogen synthase kinase-3 beta (GSK3β) activity. Taken together, our results indicate that regorafenib has beneficial effects on neuroinflammation, AD pathology, and dendritic spine formation in vitro and in vivo.

|keywords=* aging
* amyloid beta
* dendritic spine
* neuroinflammation
* regorafenib
* tau
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408082
}}
{{medline-entry
|title=An agnostic reevaluation of the amyloid cascade hypothesis of Alzheimer's disease pathogenesis: The role of [[APP]] homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32588983
|abstract=To reassess the role of amyloid beta (Aβ) and the amyloid precursor protein ([[APP]]) system in the pathogenesis of Alzheimer's disease (AD). [[APP]] is a cell adhesion molecule that has been highly conserved over the course of phylogeny that has critical roles in brain development, synaptic plasticity, and the brain's intrinsic immune system. The amyloid cascade hypothesis describes a relatively linear, deterministic sequence of events triggered by a gain of Aβ peptide fragment toxicity that results in neurodegeneration and cognitive loss, yet well designed immunotherapy and beta secretase inhibitor trials that have successfully targeted Aβ have failed to have any consistent effects on the steady decline of cognition. Mutations of the [[APP]] and presenilin genes not only alter the ratio of longer to shorter Aβ fragments (resulting in a gain of Aβ toxicity), but also disrupt the normal homeostatic roles of their respective proteins. The evolutionary history, physiological importance, and complexity of the [[APP]] and presenilin systems, as well as other critical components including tau and apolipoprotein E (APOE) imply that altered function of such systems could have severe consequences that include but need not be limited to a gain of Aβ toxicity and would more generally result in altered homeostasis of [[APP]]-related functions. Challenges that a loss of [[APP]] homeostasis addresses better than the more limited gain of Aβ toxicity model include the topographic mismatches between Aβ and tau pathology, the profile and chronology of cognitive and biomarker changes that precede the clinical expression of mild cognitive impairment and dementia, and the disappointments of Aβ targeted therapeutics among others. The importance of [[APP]], α- and β-secretases, the presenilins and γ-secretase, as well as tau was recognized by the authors of the amyloid cascade hypothesis, and has since led multiple investigators to propose alternative, more balanced hypotheses including reduced homeostasis and frank loss-of-function of key components that include but go beyond the currently envisioned linear model of Aβ toxicity.

|keywords=* aging
* amyloid hypothesis
* amyloid precursor protein homeostasis
* late onset Alzheimer's disease
* young onset Alzheimer's disease
|full-text-url=https://sci-hub.do/10.1002/alz.12124
}}
{{medline-entry
|title=Transcriptomic profiling of microglia and astrocytes throughout aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32238175
|abstract=Activation of microglia and astrocytes, a prominent hallmark of both aging and Alzheimer's disease (AD), has been suggested to contribute to aging and AD progression, but the underlying cellular and molecular mechanisms are largely unknown. We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and [[APP]]-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles. Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). And most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes. Overall, our RNA-seq data provide a valuable resource for future investigations into the roles of microglia and astrocytes in aging- and amyloid-β-induced AD pathologies.

|keywords=* Aging
* Alzheimer’s disease (AD)
* Astrocyte
* Microglia
* RNA-seq
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115095
}}
{{medline-entry
|title=Platelets in Amyloidogenic Mice Are Activated and Invade the Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32194368
|abstract=Alzheimer's disease (AD) is a neurodegenerative disease with a complex and not fully understood pathogenesis. Besides brain-intrinsic hallmarks such as abnormal deposition of harmful proteins, i.e., amyloid beta in plaques and hyperphosphorylated Tau in neurofibrillary tangles, blood-derived elements, in particular, platelets have been discussed to be involved in AD pathogenesis. The underlying mechanisms, however, are rather unexplored. Here, we investigate a potential role of platelets in an AD transgenic animal model with severe amyloid plaque formation, the [[APP]]-PS1 transgenic mice, and analyzed the presence, spatial location and activation status of platelets within the brain. In [[APP]]-PS1 mice, a higher number of platelets were located within the brain parenchyma, i.e., outside the cerebral blood vessels compared to WT controls. Such platelets were activated according to the expression of the platelet activation marker CD62P and to morphological hallmarks such as membrane protrusions. In the brain, platelets were in close contact exclusively with astrocytes suggesting an interaction between these two cell types. In the bloodstream, although the percentage of activated platelets did not differ between transgenic and age-matched control animals, [[APP]]-PS1 blood-derived platelets showed remarkable ultrastructural peculiarities in platelet-specific organelles such as the open canalicular system (OCS). This work urges for further investigations on platelets and their yet unknown functional roles in the brain, which might go beyond AD pathogenesis and be relevant for various age-related neurodegenerative diseases.

|keywords=* Alzheimer’s disease
* aging
* astrocytes
* platelets
* vascular pathology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063083
}}
{{medline-entry
|title=CHIP modulates [[APP]]-induced autophagy-dependent pathological symptoms in Drosophila.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31777182
|abstract=Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether autophagy is a cause or consequence of AD. We have previously expressed the full-length human [[APP]] in Drosophila and established a fly AD model that exhibits multiple AD-like symptoms. Here we report that depletion of CHIP effectively palliated [[APP]]-induced pathological symptoms, including morphological, behavioral, and cognitive defects. Mechanistically, CHIP is required for [[APP]]-induced autophagy dysfunction, which promotes Aβ production via increased expression of BACE and Psn. Our findings suggest that aberrant autophagy is not only a consequence of abnormal [[APP]] activity, but also contributes to dysregulated [[APP]] metabolism and subsequent AD pathogenesis.
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Aspartic Acid Endopeptidases
* Autophagy
* Brain
* Cognitive Dysfunction
* Disease Models, Animal
* Dopaminergic Neurons
* Down-Regulation
* Drosophila
* Drosophila Proteins
* Eye
* Learning Disabilities
* Locomotion
* Longevity
* Nuclear Proteins
* Presenilins
* RNA Interference
* Wings, Animal
|keywords=* 
CHIP

* APP
* Alzheimer’s disease
* Aβ
* autophagy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996943
}}
{{medline-entry
|title=Studies on [[APP]] metabolism related to age-associated mitochondrial dysfunction in [[APP]]/PS1 transgenic mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31744937
|abstract=The aging brain with mitochondrial dysfunction and a reduced adenosine 5'-triphosphate (ATP) has been implicated in the onset and progression of β-Amyloid (Aβ)-induced neuronal toxicity in AD. To unravel the function of ATP and the underlying mechanisms on AD development, [[APP]]/PS1 double transgenic mice and wild-type (WT) C57 mice at 6 and 10 months of age were studied. We demonstrated a decreased ATP release in the hippocampus and platelet of [[APP]]/PS1 mice, comparing to C57 mice at a relatively early age. Levels of Aβ were raised in both hippocampus and platelet of [[APP]]/PS1 mice, accompanied by a decrease of α-secretase activity and an increase of β-secretase activity. Moreover, our results presented an age-dependent rise in mitochondrial vulnerability to oxidation in [[APP]]/PS1 mice. In addition, we found decreased pSer473-Akt levels, increased GSK3β activity by inhibiting phosphorylation at Ser9 in aged [[APP]]/PS1 mice and these dysfunctions probably due to down-regulation of Bcl-2 and up-regulation of cleaved caspase-3. Therefore, we demonstrate that PI3K/Akt/GSK3β signaling pathway could be involved in Aβ-associated mitochondrial dysfunction of [[APP]]/PS1 mice and [[APP]] abnormal metabolism in platelet might provide potential biomarkers for early diagnosis of AD.
|mesh-terms=* Adenosine Triphosphate
* Aging
* Alzheimer Disease
* Amyloid beta-Protein Precursor
* Animals
* Blood Platelets
* Disease Models, Animal
* Hippocampus
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Mitochondria
* Presenilin-1
|keywords=* APP/PS1 mice
* Amyloid-beta
* adenosine 5’-triphosphate
* mitochondria dysfunction
* platelets
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6914425
}}
{{medline-entry
|title=Intermittent Hypoxia-Hyperoxia Training Improves Cognitive Function and Decreases Circulating Biomarkers of Alzheimer's Disease in Patients with Mild Cognitive Impairment: A Pilot Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31671598
|abstract=Alzheimer's disease (AD) affects not only the central nervous system, but also peripheral blood cells including neutrophils and platelets, which actively participate in pathogenesis of AD through a vicious cycle between platelets aggregation and production of excessive amyloid beta (Aβ). Platelets adhesion on amyloid plaques also increases the risk of cerebral microcirculation disorders. Moreover, activated platelets release soluble adhesion molecules that cause migration, adhesion/activation of neutrophils and formation of neutrophil extracellular traps (NETs), which may damage blood brain barrier and destroy brain parenchyma. The present study examined the effects of intermittent hypoxic-hyperoxic training (IHHT) on elderly patients with mild cognitive impairment (MCI), a precursor of AD. Twenty-one participants (age 51-74 years) were divided into three groups: Healthy Control ([i]n[/i] = 7), MCI+Sham ([i]n[/i] = 6), and MCI+IHHT ([i]n[/i] = 8). IHHT was carried out five times per week for three weeks (total 15 sessions). Each IHHT session consisted of four cycles of 5-min hypoxia (12% F O ) and 3-min hyperoxia (33% F O ). Cognitive parameters, Aβ and amyloid precursor protein ([[APP]]) expression, microRNA 29, and long non-coding RNA in isolated platelets as well as NETs in peripheral blood were investigated. We found an initial decline in cognitive function indices in both MCI+Sham and MCI+IHHT groups and significant correlations between cognitive test scores and the levels of circulating biomarkers of AD. Whereas sham training led to no change in these parameters, IHHT resulted in the improvement in cognitive test scores, along with significant increase in [[APP]] ratio and decrease in Aβ expression and NETs formation one day after the end of three-week IHHT. Such effects on Aβ expression and NETs formation remained more pronounced one month after IHHT. In conclusion, our results from this pilot study suggested a potential utility of IHHT as a new non-pharmacological therapy to improve cognitive function in pre-AD patients and slow down the development of AD.
|mesh-terms=* Aged
* Alzheimer Disease
* Biomarkers
* Case-Control Studies
* Cognition
* Cognitive Dysfunction
* Female
* Humans
* Hyperoxia
* Hypoxia
* Male
* Middle Aged
* Pilot Projects
* Respiratory Therapy
* Treatment Outcome
|keywords=* Alzheimer’s disease
* adaptation
* aging
* amyloid beta
* biomarker
* cognitive function
* hyperoxia
* intermittent hypoxia
* platelets
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862463
}}
{{medline-entry
|title=The Implication of Androgens in the Presence of Protein Kinase C to Repair Alzheimer’s Disease-Induced Cognitive Dysfunction
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31677609
|abstract=Aging, as a major risk factor of memory deficiency, affects neural signaling pathways in hippocampus. In particular, age-dependent androgens deficiency causes cognitive impairments. Several enzymes like protein kinase C (PKC) are involved in memory deficiency. Indeed, PKC regulatory process mediates α-secretase activation to cleave [[APP]] in β-amyloid cascade and tau proteins phosphorylation mechanism.  Androgens and cortisol regulate PKC signaling pathways, affecting the modulation of receptor for activated C kinase 1. Mitogen-activated protein kinase/ERK signaling pathway depends on CREB activity in hippocampal neurons and is involved in regulatory processes via PKC and androgens. Therefore, testosterone and PKC contribute in the neuronal apoptosis. The present review summarizes the current status of androgens, PKC, and their influence on cognitive learning. Inconsistencies in experimental investigations related to this fundamental correlation are also discussed, with emphasis on the mentioned contributors as the probable potent candidates for learning and memory improvement.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Amyloid Precursor Protein Secretases
* Amyloid beta-Peptides
* Androgens
* Aspartic Acid Endopeptidases
* Cognition
* Cognitive Dysfunction
* Cyclic AMP Response Element-Binding Protein
* Female
* Hippocampus
* Humans
* Learning
* MAP Kinase Signaling System
* Male
* Middle Aged
* Neoplasm Proteins
* Phosphorylation
* Protein Kinase C
* Receptors for Activated C Kinase
* tau Proteins
|keywords=* Androgens
* Cognition
* Hippocampus
* Protein kinase C
* Spatial memory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984714
}}
{{medline-entry
|title=Modulation of Neural and Muscular Adaptation Processes During Resistance Training by Fish Protein Ingestions in Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31596471
|abstract=Assessments of both neural and muscular adaptations during interventions would provide valuable information for developing countermeasures to age-related muscle dysfunctions. We investigated the effect of fish protein ingestion on training-induced neural and muscular adaptations in older adults. Twenty older adults participated 8 weeks of isometric knee extension training intervention. The participants were divided into two groups who took fish protein (n = 10, Alaska pollack protein, [[APP]]) or casein (n = 10, CAS). Maximal muscle strength during knee extension, lower extremity muscle mass (body impedance method), and motor unit firing pattern of knee extensor muscle (high-density surface electromyography) were measured before, during, and after the intervention. Muscle strength were significantly increased in both CAS (124.7 ± 5.8%) and [[APP]] (117.1 ± 4.4%) after intervention (p < .05), but no significant differences between the groups were observed (p > .05). Significant increases in lower extremity muscle mass from 0 to 8 weeks were demonstrated only for [[APP]] (102.0 ± 3.2, p < .05). Greater changes in motor unit firing pattern following intervention were represented in CAS more than in [[APP]]. These results suggest that nutritional supplementations could modulate neural and muscular adaptations following resistance training and fish protein ingestion preferentially induces muscular adaptation without the detectable neural adaptation in older adults.

|keywords=* Aging
* Alaska pollack protein
* Motor unit identification
* Multichannel surface electromyography
* Nutritional supplementation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7164534
}}
{{medline-entry
|title=Antipsychotic Polypharmacy in Older Adult Asian Patients With Schizophrenia: Research on Asian Psychotropic Prescription Pattern.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31480982
|abstract=Antipsychotic polypharmacy ([[APP]]) is a controversial topic in the treatment of older adults with schizophrenia. The objective of this study was to examine the use of [[APP]] in older adult Asian patients with schizophrenia and its associated demographic and clinical factors. This study was based on the fourth survey of the consortium known as the Research on Asian Psychotropic Prescription Pattern for Antipsychotics. Fifteen Asian countries/territories participated in this survey, including Bangladesh, Mainland China, Hong Kong, India, Indonesia, Japan, Korea, Malaysia, Myanmar, Pakistan, Singapore, Sri Lanka, Taiwan, Thailand, and Vietnam. Basic demographic and clinical characteristics were collected using a standardized data collection form. Among the 879 older adults with schizophrenia included in the survey, the rate of [[APP]] was 40.5%. Multiple logistic regression analysis revealed that higher antipsychotic doses ([i]P[/i] < .001, odds ratio [OR] = 1.003, 95% confidence interval [CI]: 1.002-1.003), longer duration of illness ([i]P[/i] = .02, OR = 1.845, 95% CI: 1.087-3.132), and the prescription of anticholinergics ([i]P[/i] < .001, OR = 1.871, 95% CI: 1.329-2.635), second-generation antipsychotics ([i]P[/i] = .001, OR = 2.264, 95% CI: 1.453-3.529), and first-generation antipsychotics ([i]P[/i] < .001, OR = 3.344, 95% CI: 2.307-4.847) were significantly associated with [[APP]]. Antipsychotic polypharmacy was common in older adult Asian patients with schizophrenia. Compared to the results of previous surveys, the use of [[APP]] showed a declining trend over time. Considering the general poor health status of older patients with schizophrenia and their increased risk of drug-induced adverse events, the use of [[APP]] in this population needs careful consideration.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Antipsychotic Agents
* Asian Continental Ancestry Group
* Female
* Humans
* Male
* Middle Aged
* Polypharmacy
* Schizophrenia
|keywords=* Asian
* antipsychotic polypharmacy
* older adult patients
* schizophrenia
|full-text-url=https://sci-hub.do/10.1177/0891988719862636
}}
{{medline-entry
|title=A pleiotropic role for exosomes loaded with the amyloid β precursor protein carboxyl-terminal fragments in the brain of Down syndrome patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31479861
|abstract=Down syndrome (DS) is characterized by cognitive deficits throughout the life span and with the development of aging-dependent Alzheimer's type neuropathology, which is related to the triplication of the amyloid β precursor protein ([[APP]]) gene. A dysfunctional endosomal system in neurons is an early characteristic of DS and [[APP]] metabolites accumulate in endosomes in DS neurons. We have previously shown enhanced release of exosomes in the brain of DS patients and the mouse model of DS Ts[Rb(12.17 )]2Cje (Ts2), and by DS fibroblasts, as compared with diploid controls. Here, we demonstrate that exosome-enriched extracellular vesicles (hereafter called EVs) isolated from DS and Ts2 brains, and from the culture media of human DS fibroblasts are enriched in [[APP]] carboxyl-terminal fragments ([[APP]]-CTFs) as compared with diploid controls. Moreover, [[APP]]-CTFs levels increase in an age-dependent manner in EVs isolated from the brain of Ts2 mice. The release of [[APP]]-CTFs-enriched exosomes may have a pathogenic role by transporting [[APP]]-CTFs into naïve neurons and propagating these neurotoxic metabolites, which are also a source of amyloid β, throughout the brain, but also provides a benefit to DS neurons by shedding [[APP]]-CTFs accumulated intracellularly.
|mesh-terms=* Amyloid beta-Protein Precursor
* Brain
* Down Syndrome
* Exosomes
* Humans
|keywords=* APP
* APP-CTFs
* Aging
* Brain
* Down syndrome
* Exosomes
* Extracellular vesicles
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960325
}}
==ATM==

{{medline-entry
|title=S[[ATM]]F Suppresses the Premature Senescence Phenotype of the [[ATM]] Loss-of-Function Mutant and Improves Its Fertility in [i]Arabidopsis[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33143308
|abstract=Leaf senescence is the final stage of leaf development. It is accompanied by the remobilization of nutrients from senescent leaves to developing organs. The occurrence of senescence is the consequence of integrating intrinsic and environmental signals. DNA damage triggered by stresses has been regarded as one of the reasons for senescence. To prevent DNA damage, cells have evolved elaborate DNA repair machinery. The ataxia telangiectasia mutated ([[ATM]]) functions as the chief transducer of the double-strand breaks (DSBs) signal. Our previous study suggests that [[ATM]] functions in lifespan regulation in [i]Arabidopsis[/i]. However, [[ATM]] regulatory mechanism on plant longevity remains unclear. Here, we performed chemical mutagenesis to identify the components involved in [[ATM]]-mediated longevity and obtained three dominant mutants [i]satmf1~3[/i], [i]suppressor of atm in fertility[/i], displaying delayed senescence and restored fertility in comparison with [i]atm[/i] mutant. Molecular cloning and functional analysis of S[[ATM]]F (suppressor of atm in fertility) will help to understand the underlying regulatory mechanism of [[ATM]] in plants, and shed light on developing new treatments for the disease Ataxia-telangiectasia.

|keywords=* ATM
* DNA damage
* SATMF
* fertility
* leaf senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662627
}}
{{medline-entry
|title=[[ATM]] mediated-p53 signaling pathway forms a novel axis for senescence control.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32949791
|abstract=Previously, we uncovered a novel mechanism in which senescence is controlled by mitochondrial functional recovery upon Ataxia-telangiectasia mutated ([[ATM]]) inhibition. However, it remains elusive how [[ATM]] controls signaling pathways to achieve restorative effect. In this study, we performed microarray and found that p53 pathway was differentially expressed upon [[ATM]] inhibition. We found that [[ATM]] inhibition yields senescence amelioration through p53-dependent manner. The restorative effect was also afforded by direct p53 inhibition. Furthermore, mitochondrial metabolic reprogramming via p53 inhibition was a prerequisite for senescence amelioration. Taken together, our data indicated that p53 pathway functions as potential target for [[ATM]]-mediated senescence amelioration.

|keywords=* ATM inhibition
* Metabolic reprogrammer
* Mitochondria
* P53
* Senescence alleviation
|full-text-url=https://sci-hub.do/10.1016/j.mito.2020.09.002
}}
{{medline-entry
|title=Non-canonical [[ATM]]/MRN activities temporally define the senescence secretory program.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32785991
|abstract=Senescent cells display senescence-associated (SA) phenotypic programs such as stable proliferation arrest (SAPA) and a secretory phenotype (SASP). Senescence-inducing persistent DNA double-strand breaks (pDSBs) cause an immediate DNA damage response (DDR) and SAPA, but the SASP requires days to develop. Here, we show that following the immediate canonical DDR, a delayed chromatin accumulation of the [[ATM]] and MRN complexes coincides with the expression of SASP factors. Importantly, histone deacetylase inhibitors (HDACi) trigger SAPA and SASP in the absence of DNA damage. However, HDACi-induced SASP also requires [[ATM]]/MRN activities and causes their accumulation on chromatin, revealing a DNA damage-independent, non-canonical DDR activity that underlies SASP maturation. This non-canonical DDR is required for the recruitment of the transcription factor NF-κB on chromatin but not for its nuclear translocation. Non-canonical DDR further does not require [[ATM]] kinase activity, suggesting structural [[ATM]] functions. We propose that delayed chromatin recruitment of SASP modulators is the result of non-canonical DDR signaling that ensures SASP activation only in the context of senescence and not in response to transient DNA damage-induced proliferation arrest.

|keywords=* DNA damage response
* MRN complex
* NF-κB
* chromatin
* senescence secretome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534619
}}
{{medline-entry
|title=[[ATM]] is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32201398
|abstract=NF-κB is a transcription factor activated in response to inflammatory, genotoxic and oxidative stress and important for driving senescence and aging. Ataxia-telangiectasia mutated ([[ATM]]) kinase, a core component of DNA damage response signaling, activates NF-κB in response to genotoxic and oxidative stress via post-translational modifications. Here we demonstrate that [[ATM]] is activated in senescent cells in culture and murine tissues from [i]Ercc1[/i]-deficient mouse models of accelerated aging, as well as naturally aged mice. Genetic and pharmacologic inhibition of [[ATM]] reduced activation of NF-κB and markers of senescence and the senescence-associated secretory phenotype (SASP) in senescent [i]Ercc1 [/i] MEFs. [i]Ercc1 [/i] mice heterozygous for [i]Atm[/i] have reduced NF-κB activity and cellular senescence, improved function of muscle-derived stem/progenetor cells (MDSPCs) and extended healthspan with reduced age-related pathology especially age-related bone and intervertebral disc pathologies. In addition, treatment of [i]Ercc1[/i]  mice with the [[ATM]] inhibitor KU-55933 suppressed markers of senescence and SASP. Taken together, these results demonstrate that the [[ATM]] kinase is a major mediator of DNA damage-induced, NF-κB-mediated cellular senescence, stem cell dysfunction and aging and thus represents a therapeutic target to slow the progression of aging.

|keywords=* ATM
* DNA damage response
* NF-κB
* aging
* cellular senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138542
}}
{{medline-entry
|title=[[ATM]] suppresses leaf senescence triggered by DNA double-strand break through epigenetic control of senescence-associated genes in Arabidopsis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32163596
|abstract=All living organisms are unavoidably exposed to various endogenous and environmental stresses that trigger potentially fatal DNA damage, including double-strand breaks (DSBs). Although a growing body of evidence indicates that DNA damage is one of the prime drivers of aging in animals, little is known regarding the importance of DNA damage and its repair on lifespan control in plants. We found that the level of DSBs increases but DNA repair efficiency decreases as Arabidopsis leaves age. Generation of DSBs by inducible expression of I-PpoI leads to premature senescence phenotypes. We examined the senescence phenotypes in the loss-of-function mutants for 13 key components of the DNA repair pathway and found that deficiency in ATAXIA TELANGIECTASIA MUTATED ([[ATM]]), the chief transducer of the DSB signal, results in premature senescence in Arabidopsis. [[ATM]] represses DSB-induced expression of senescence-associated genes, including the genes encoding the WRKY and NAC transcription factors, central components of the leaf senescence process, via modulation of histone lysine methylation. Our work highlights the significance of [[ATM]] in the control of leaf senescence and has significant implications for the conservation of aging mechanisms in animals and plants.

|keywords=* 
Arabidopsis thaliana

* ATM
* DNA repair
* double-strand breaks
* histone methylation
* leaf senescence
|full-text-url=https://sci-hub.do/10.1111/nph.16535
}}
{{medline-entry
|title=Glioblastoma Cells Do Not Affect Axitinib-Dependent Senescence of HUVECs in a Transwell Coculture Model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32098270
|abstract=Axitinib is an orally available inhibitor of tyrosine kinases, with high specificity for vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. It is approved for the treatment of advanced renal cell carcinoma and is in phase II clinical trials for recurrent glioblastoma (GBM). GBM is a brain tumor peculiar in its ability to induce neoangiogenesis. Since both GBM tumor cells and endothelial cells of tumor vasculature express VEGFRs, Axitinib exerts its inhibitory action on both tumor and endothelial cells. We and others previously demonstrated that Axitinib triggers cellular senescence. In particular, Axitinib-dependent senescence of HUVECs (human umbilical vein endothelial cells) is accompanied by intracellular reactive oxygen species(ROS) increase and early ataxia telangiectasia mutated([[ATM]]) activation. Here we wondered if the presence of glioblastoma tumor cells could affect the HUVEC senescence upon Axitinib exposure. To address this issue, we cocultured HUVECs together with GBM tumor cells in transwell plates. HUVEC senescence did not result in being affected by GBM cells, neither in terms of β galactosidase activity nor of proliferation index or [[ATM]] phosphorylation. Conversely, Axitinib modulation of HUVEC gene expression was altered by cocultured GBM cells. These data demonstrate that the GBM secretome modifies HUVECs' transcriptomic profile upon Axitinib exposure, but does not prevent drug-induced senescence.
|mesh-terms=* Ataxia Telangiectasia Mutated Proteins
* Axitinib
* Cell Line, Tumor
* Cellular Senescence
* Coculture Techniques
* Gene Expression Profiling
* Glioblastoma
* Human Umbilical Vein Endothelial Cells
* Humans
* Phosphorylation
|keywords=* Axitinib
* endothelial cells
* glioblastoma
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073100
}}
{{medline-entry
|title=Declining BRCA-Mediated DNA Repair in Sperm Aging and its Prevention by Sphingosine-1-Phosphate.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31916095
|abstract=Recent data suggest that paternal age can have major impact on reproductive outcomes, and with increased age, there is increased likelihood of chromosomal abnormalities in the sperm. Here, we studied DNA damage and repair as a function of male aging and assessed whether sphingosine-1-phosphate (S1P), a ceramide-induced death inhibitor, can prevent sperm aging by enhancing DNA double-strand breaks (DSB) repair. We observed a significant increase in DNA damage with age and this increase was associated with a decline in the expression of key DNA DSB repair genes in mouse sperm. The haploinsufficiency of BRCA1 male mice sperm showed significantly increased DNA damage and apoptosis, along with decreased chromatin integrity when compared to similar age wild type (WT) mice. Furthermore, haploinsufficiency of BRCA1 male mice had lower sperm count and smaller litter size when crossed with WT females. The resulting embryos had a higher probability of growth arrest and reduced implantation. S1P treatment decreased genotoxic-stress-induced DNA damage in sperm and enhanced the expressions of key DNA repair genes such as BRCA1. Co-treatment with an [[ATM]] inhibitor reversed the effects of S1P, implying that the impact of S1P on DNA repair is via the [[ATM]]-mediated pathway. Our findings indicate a key role for DNA damage repair mechanism in the maintenance of sperm integrity and suggest that S1P can improve DNA repair in sperm. Further translational studies are warranted to determine the clinical significance of these findings and whether S1P can delay male reproductive aging. There is mounting evidence that sperm quality declines with age, similar to that of the oocyte. However, the reasons behind this decline are poorly understood and there is no medical intervention to improve sperm quality. Our study suggests a strong role for DNA damage repair in maintenance of sperm quality, and for the first time, a potential pharmaceutical approach to prevent sperm aging.

|keywords=* Aging
* DNA fragmentation
* Gene expression
* Sperm
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065969
}}
{{medline-entry
|title=BRCA-related [[ATM]]-mediated DNA double-strand break repair and ovarian aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31822904
|abstract=Oocyte aging has significant clinical consequences, and yet no treatment exists to address the age-related decline in oocyte quality. The lack of progress in the treatment of oocyte aging is due to the fact that the underlying molecular mechanisms are not sufficiently understood. BRCA1 and 2 are involved in homologous DNA recombination and play essential roles in ataxia telangiectasia mutated ([[ATM]])-mediated DNA double-strand break (DSB) repair. A growing body of laboratory, translational and clinical evidence has emerged within the past decade indicating a role for BRCA function and [[ATM]]-mediated DNA DSB repair in ovarian aging. Although there are several competing or complementary theories, given the growing evidence tying BRCA function and [[ATM]]-mediated DNA DSB repair mechanisms in general to ovarian aging, we performed this review encompassing basic, translational and clinical work to assess the current state of knowledge on the topic. A clear understanding of the mechanisms underlying oocyte aging may result in targeted treatments to preserve ovarian reserve and improve oocyte quality. We searched for published articles in the PubMed database containing key words, BRCA, BRCA1, BRCA2, Mutations, Fertility, Ovarian Reserve, Infertility, Mechanisms of Ovarian Aging, Oocyte or Oocyte DNA Repair, in the English-language literature until May 2019. We did not include abstracts or conference proceedings, with the exception of our own. Laboratory studies provided robust and reproducible evidence that BRCA1 function and [[ATM]]-mediated DNA DSB repair, in general, weakens with age in oocytes of multiple species including human. In both women with BRCA mutations and BRCA-mutant mice, primordial follicle numbers are reduced and there is accelerated accumulation of DNA DSBs in oocytes. In general, women with BRCA1 mutations have lower ovarian reserves and experience earlier menopause. Laboratory evidence also supports critical role for BRCA1 and other [[ATM]]-mediated DNA DSB repair pathway members in meiotic function. When laboratory, translational and clinical evidence is considered together, BRCA-related [[ATM]]-mediated DNA DSB repair function emerges as a likely regulator of ovarian aging. Moreover, DNA damage and repair appear to be key features in chemotherapy-induced ovarian aging. The existing data suggest that the BRCA-related [[ATM]]-mediated DNA repair pathway is a strong candidate to be a regulator of oocyte aging, and the age-related decline of this pathway likely impairs oocyte health. This knowledge may create an opportunity to develop targeted treatments to reverse or prevent physiological or chemotherapy-induced oocyte aging. On the immediate practical side, women with BRCA or similar mutations may need to be specially counselled for fertility preservation.
|mesh-terms=* Aging
* Animals
* Ataxia Telangiectasia
* BRCA1 Protein
* BRCA2 Protein
* DNA Breaks, Double-Stranded
* DNA Repair
* Female
* Fertility
* Fertility Preservation
* Humans
* Mice
* Oocytes
* Ovarian Follicle
* Ovarian Reserve
* Ovary
|keywords=* 
          BRCA
        
* 
          BRCA1/2
        
* DNA repair
* anti-Mullerian hormone
* chemotherapy
* mutations
* oocyte
* ovarian aging
* ovarian reserve
* ovarian response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935693
}}
{{medline-entry
|title=[[ATM]] Deficiency Accelerates DNA Damage, Telomere Erosion, and Premature T Cell Aging in HIV-Infected Individuals on Antiretroviral Therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31781094
|abstract=HIV infection leads to a phenomenon of inflammaging, in which chronic inflammation induces an immune aged phenotype, even in individuals on combined antiretroviral therapy (cART) with undetectable viremia. In this study, we investigated T cell homeostasis and telomeric DNA damage and repair machineries in cART-controlled HIV patients at risk for inflammaging. We found a significant depletion of CD4 T cells, which was inversely correlated with the cell apoptosis in virus-suppressed HIV subjects compared to age-matched healthy subjects (HS). In addition, HIV CD4 T cells were prone to DNA damage that extended to chromosome ends-telomeres, leading to accelerated telomere erosion-a hallmark of cell senescence. Mechanistically, the DNA double-strand break (DSB) sensors MRE11, RAD50, and NBS1 (MRN complex) remained intact, but both expression and activity of the DNA damage checkpoint kinase ataxia-telangiectasia mutated ([[ATM]]) and its downstream checkpoint kinase 2 (CHK2) were significantly suppressed in HIV CD4 T cells. Consistently, [[ATM]]/CHK2 activation, DNA repair, and cellular functions were also impaired in healthy CD4 T cells following [[ATM]] knockdown or exposure to the [[ATM]] inhibitor KU60019 [i]in vitro[/i], recapitulating the biological effects observed in HIV-derived CD4 T cells [i]in vivo[/i]. Importantly, ectopic expression of [[ATM]] was essential and sufficient to reduce the DNA damage, apoptosis, and cellular dysfunction in HIV-derived CD4 T cells. These results demonstrate that failure of DSB repair due to [[ATM]] deficiency leads to increased DNA damage and renders CD4 T cells prone to senescence and apoptotic death, contributing to CD4 T cell depletion or dysfunction in cART-controlled, latent HIV infection.
|mesh-terms=* Anti-Retroviral Agents
* Ataxia Telangiectasia Mutated Proteins
* Cellular Senescence
* DNA Damage
* HIV Infections
* Humans
* T-Lymphocytes
* Telomere
|keywords=* ATM
* DNA damage repair
* HIV
* T cell homeostasis
* apoptosis
* immune aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856652
}}
{{medline-entry
|title=SMG1 heterozygosity exacerbates haematopoietic cancer development in Atm null mice by increasing persistent DNA damage and oxidative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31565865
|abstract=Suppressor of morphogenesis in genitalia 1 (SMG1) and ataxia telangiectasia mutated ([[ATM]]) are members of the PI3-kinase like-kinase (PIKK) family of proteins. [[ATM]] is a well-established tumour suppressor. Loss of one or both alleles of [[ATM]] results in an increased risk of cancer development, particularly haematopoietic cancer and breast cancer in both humans and mouse models. In mice, total loss of SMG1 is embryonic lethal and loss of a single allele results in an increased rate of cancer development, particularly haematopoietic cancers and lung cancer. In this study, we generated mice deficient in Atm and lacking one allele of Smg1, Atm  Smg1  mice. These mice developed cancers more rapidly than either of the parental genotypes, and all cancers were haematopoietic in origin. The combined loss of Smg1 and Atm resulted in a higher level of basal DNA damage and oxidative stress in tissues than loss of either gene alone. Furthermore, Atm  Smg1  mice displayed increased cytokine levels in haematopoietic tissues compared with wild-type animals indicating the development of low-level inflammation and a pro-tumour microenvironment. Overall, our data demonstrated that combined loss of Atm expression and decreased Smg1 expression increases haematopoietic cancer development.
|mesh-terms=* Animals
* Ataxia Telangiectasia Mutated Proteins
* Carcinogenesis
* Cells, Cultured
* DNA Damage
* Embryo, Mammalian
* Fibroblasts
* Gamma Rays
* Hematologic Neoplasms
* Heterozygote
* Kaplan-Meier Estimate
* Longevity
* Lymphoma
* Mice, Inbred C57BL
* Mice, Knockout
* Oxidative Stress
* Protein-Serine-Threonine Kinases
|keywords=* DNA damage
* cancer
* inflammation
* lymphoma
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6850945
}}
{{medline-entry
|title=LncRNA RP11-670E13.6, interacted with hnRNPH, delays cellular senescence by sponging microRNA-663a in UVB damaged dermal fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31444317
|abstract=Ultraviolet (UV) irradiation from the sunlight is a major etiologic factor for premature skin aging. Long noncoding RNAs (lncRNAs) are involved in various biological processes, and their roles in UV irradiation-induced skin aging have recently been described. Previously, we found that the lncRNA [i]RP11-670E13.6[/i] was up-regulated and delayed cellular senescence in UVB-irradiated primary human dermal fibroblasts. Here, we performed further investigations of [i]RP11-670E13.6[/i] function. The results showed that this lncRNA directly bound to [i]miR-663a[/i] and functioned as a sponge for [i]miR-663a[/i] to modulate the derepression of Cdk4 and Cdk6, thereby delaying cellular senescence during UV irradiation-induced skin photoaging. Moreover, we found that [i]RP11-670E13.6[/i] may facilitate DNA damage repair by increasing [[ATM]] and γH2A.X levels. In addition, heterogeneous nuclear ribonucleoprotein H physically interacted with [i]RP11-670E13.6[/i] and blocked its expression. Collectively, our results suggested that the [i]RP11-670E13.6/miR-663a[/i]/[i]CDK4[/i] and [i]RP11-670E13.6/miR-663a[/i]/[i]CDK6[/i] axis, which may function as competitive endogenous RNA networks, played important roles in UVB-induced cellular senescence.
|mesh-terms=* Cell Proliferation
* Cellular Senescence
* Fibroblasts
* Heterogeneous-Nuclear Ribonucleoprotein Group F-H
* Humans
* MicroRNAs
* RNA, Long Noncoding
* Skin
* Skin Aging
* Ultraviolet Rays
|keywords=* cellular senescence
* dermal fibroblast
* lncRNA
* microRNA
* ultraviolet B
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738423
}}
{{medline-entry
|title=Tel1/[[ATM]] Signaling to the Checkpoint Contributes to Replicative Senescence in the Absence of Telomerase.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31391264
|abstract=Telomeres progressively shorten at every round of DNA replication in the absence of telomerase. When they become critically short, telomeres trigger replicative senescence by activating a DNA damage response that is governed by the Mec1/ATR and Tel1/[[ATM]] protein kinases. While Mec1/ATR is known to block cell division when extended single-stranded DNA (ssDNA) accumulates at eroded telomeres, the molecular mechanism by which Tel1/[[ATM]] promotes senescence is still unclear. By characterizing a Tel1-hy184 mutant variant that compensates for the lack of Mec1 functions, we provide evidence that Tel1 promotes senescence by signaling to a Rad9-dependent checkpoint. Tel1-hy184 anticipates senescence onset in telomerase-negative cells, while the lack of Tel1 or the expression of a kinase-defective (kd) Tel1 variant delays it. Both Tel1-hy184 and Tel1-kd do not alter ssDNA generation at telomeric DNA ends. Furthermore, Rad9 and (only partially) Mec1 are responsible for the precocious senescence promoted by Tel1-hy184. This precocious senescence is mainly caused by the F1751I, D1985N, and E2133K amino acid substitutions, which are located in the FRAP-[[ATM]]-TRAPP domain of Tel1 and also increase Tel1 binding to DNA ends. Altogether, these results indicate that Tel1 induces replicative senescence by directly signaling dysfunctional telomeres to the checkpoint machinery.
|mesh-terms=* Amino Acid Substitution
* Ataxia Telangiectasia Mutated Proteins
* Cell Cycle Checkpoints
* Cell Division
* Cellular Senescence
* DNA Damage
* DNA Replication
* DNA, Single-Stranded
* DNA-Binding Proteins
* Intracellular Signaling Peptides and Proteins
* Mutant Proteins
* Protein-Serine-Threonine Kinases
* Saccharomyces cerevisiae
* Saccharomyces cerevisiae Proteins
* Telomerase
* Telomere
* Telomere Shortening
|keywords=* Tel1
* checkpoint
* replicative senescence
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781906
}}
==GFAP==

{{medline-entry
|title=Immunohistological Detection of Active Satellite Cellsin Rat Dorsal Root Ganglia after Parenteral Administration of Lipopolysaccharide and during Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32990851
|abstract=Immunohistochemical reaction to glial fibrillar acid protein ([[GFAP]]) is widely used for identification of activated satellite cells in sensory ganglia. We used this marker in studies of satellite cells activation in dorsal root ganglia during aging and under conditions of experimental systemic inflammation: in young (4 months) and aged (18-19 months) rats and animals with experimental LPS-induced systemic inflammation. The number of [[GFAP]]  satellite cells increased significantly after parenteral injection of LPS and during aging, which can indicate similarity of mechanisms of reactive glial changes during aging and systemic inflammation.

|keywords=* aging
* dorsal root ganglion
* satellite cells
* systemic inflammation
|full-text-url=https://sci-hub.do/10.1007/s10517-020-04950-2
}}
{{medline-entry
|title=Transgenic Mice Expressing Human α-Synuclein in Noradrenergic Neurons Develop Locus Ceruleus Pathology and Nonmotor Features of Parkinson's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32868457
|abstract=Degeneration of locus ceruleus (LC) neurons and dysregulation of noradrenergic signaling are ubiquitous features of Parkinson's disease (PD). The LC is among the first brain regions affected by α-synuclein (asyn) pathology, yet how asyn affects these neurons remains unclear. LC-derived norepinephrine (NE) can stimulate neuroprotective mechanisms and modulate immune cells, while dysregulation of NE neurotransmission may exacerbate disease progression, particularly nonmotor symptoms, and contribute to the chronic neuroinflammation associated with PD pathology. Although transgenic mice overexpressing asyn have previously been developed, transgene expression is usually driven by pan-neuronal promoters and thus has not been selectively targeted to LC neurons. Here we report a novel transgenic mouse expressing human wild-type asyn under control of the noradrenergic-specific dopamine β-hydroxylase promoter ([i]DBH-hSNCA[/i]). These mice developed oligomeric and conformation-specific asyn in LC neurons, alterations in hippocampal and LC microglial abundance, upregulated [[GFAP]] expression, degeneration of LC fibers, decreased striatal DA metabolism, and age-dependent behaviors reminiscent of nonmotor symptoms of PD that were rescued by adrenergic receptor antagonists. These mice provide novel insights into how asyn pathology affects LC neurons and how central noradrenergic dysfunction may contribute to early PD pathophysiology.  ɑ-Synuclein (asyn) pathology and loss of neurons in the locus ceruleus (LC) are two of the most ubiquitous neuropathologic features of Parkinson's disease (PD). Dysregulated norepinephrine (NE) neurotransmission is associated with the nonmotor symptoms of PD, including sleep disturbances, emotional changes such as anxiety and depression, and cognitive decline. Importantly, the loss of central NE may contribute to the chronic inflammation in, and progression of, PD. We have generated a novel transgenic mouse expressing human asyn in LC neurons to investigate how increased asyn expression affects the function of the central noradrenergic transmission and associated behaviors. We report cytotoxic effects of oligomeric and conformation-specific asyn, astrogliosis, LC fiber degeneration, disruptions in striatal dopamine metabolism, and age-dependent alterations in nonmotor behaviors without inclusions.

|keywords=* Parkinson's disease
* aging
* locus ceruleus
* nonmotor
* norepinephrine
* α-synuclein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511194
}}
{{medline-entry
|title=ApoE Genotype-Dependent Response to Antioxidant and Exercise Interventions on Brain Function.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32630431
|abstract=This study determined whether antioxidant supplementation is a viable complement to exercise regimens in improving cognitive and motor performance in a mouse model of Alzheimer's disease risk. Starting at 12 months of age, separate groups of male and female mice expressing human Apolipoprotein E3 ([[GFAP]]-ApoE3) or E4 ([[GFAP]]-ApoE4) were fed either a control diet or a diet supplemented with vitamins E and C. The mice were further separated into a sedentary group or a group that followed a daily exercise regimen. After 8 weeks on the treatments, the mice were administered a battery of functional tests including tests to measure reflex and motor, cognitive, and affective function while remaining on their treatment. Subsequently, plasma inflammatory markers and catalase activity in brain regions were measured. Overall, the [[GFAP]]-ApoE4 mice exhibited poorer motor function and spatial learning and memory. The treatments improved balance, learning, and cognitive flexibility in the [[GFAP]]-ApoE3 mice and overall the [[GFAP]]-ApoE4 mice were not responsive. The addition of antioxidants to supplement a training regimen only provided further benefits to the active avoidance task, and there was no antagonistic interaction between the two interventions. These outcomes are indicative that there is a window of opportunity for treatment and that genotype plays an important role in response to interventions.

|keywords=* Alzheimer’s disease
* ApoE
* aging
* antioxidants
* cognition
* exercise
* motor
* oxidative stress
* vitamin C
* vitamin E
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346214
}}
{{medline-entry
|title=Age-Dependent Heterogeneity of Murine Olfactory Bulb Astrocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32581775
|abstract=Astrocytes have a high impact on the structure of the central nervous system, as they control neural activity, development, and plasticity. Heterogeneity of astrocytes has been shown before, but so far only a few studies have demonstrated heterogeneous morphology of astrocytes concerning aging. In this study, we examined morphologic differences of astrocyte subpopulations in adult mice and the progression of these differences with age. We surveyed astrocytes in olfactory bulb slices of mice aged 3 months, 1 year and 2 years (three animals each age group), based on their appearance in anti-[[GFAP]] immunostaining. Based on this data we established three different types of astrocytes: type I (stellate), type II (elliptic), and type III (squid-like). We found that with the advanced age of the mice, astrocytes grow in size and complexity. Major changes occurred between the ages of 3 months and 1 year, while between 1 and 2 years no significant development in cell size and complexity could be detected. Our results show that astrocytes in the olfactory bulb are heterogeneous and undergo morphological transformation until late adolescence but not upon senescence. Structural plasticity is further substantiated by the expression of vimentin in some astrocyte processes in all age groups.

|keywords=* Sholl analysis
* aging
* astrocyte
* cell morphology
* heterogeneity
* olfactory bulb
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296154
}}
{{medline-entry
|title=Neuroinflammation in Aged Brain: Impact of the Oral Administration of Ellagic Acid Microdispersion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32455600
|abstract=The immune system and the central nervous system message each other to preserving central homeostasis. Both systems undergo changes during aging that determine central age-related defects. Ellagic acid (EA) is a natural product which is beneficial in both peripheral and central diseases, including aging. We analyzed the impact of the oral administration of a new oral ellagic acid micro-dispersion (EAm), that largely increased the EA solubility, in young and old mice. Oral EAm did not modify animal weight and behavioral skills in young and old mice, but significantly recovered changes in "ex-vivo, in vitro" parameters in old animals. Cortical noradrenaline exocytosis decreased in aged mice. EAm administration did not modify noradrenaline overflow in young animals, but recovered it in old mice. Furthermore, [[GFAP]] staining was increased in the cortex of aged mice, while IBA-1 and CD45 immunopositivities were unchanged when compared to young ones. EAm treatment significantly reduced CD45 signal in both young and old cortical lysates; it diminished [[GFAP]] immunopositivity in young mice, but failed to affect IBA-1 expression in both young and old animals. Finally, EAm treatment significantly reduced IL1beta expression in old mice. These results suggest that EAm is beneficial to aging and represents a nutraceutical ingredient for elders.

|keywords=* CD45
* EA microdispersion (EAm)
* GFAP
* aging
* behavioral skills
* ellagic acid (EA)
* mice
* noradrenaline
* oral administration
* principal component analysis (PCA)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279224
}}
{{medline-entry
|title=Long-term treatment with spermidine increases health span of middle-aged Sprague-Dawley male rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32285289
|abstract=Let alone calorie restriction, life span extension in higher organisms has proven to be difficult to achieve using simple drugs. Previous studies have shown that the polyamine spermidine increased the maximum life span in C. elegans and the median life span in mice. However, younger subjects (< 40 years of age) are infrequently prescribed nor self-medicating with antiaging drugs. Therefore, in the present study, we aimed at assessing the effect of long-term treatment with spermidine given in the drinking water on behavioral performance and longevity of male, middle-aged Sprague-Dawley rats. We report that spermidine given in the drinking water did not extend neither the median nor the maximum life span of the middle-aged male Sprague-Dawley rats. However, spermidine treatment had a beneficial effect on the body weight and the kidney tubules, liver, and heart morphology. Behaviorally, spermidine led to a reduction in anxiety and an increase in curiosity, as assessed by exploratory behavior. Moreover, long-term treatment with spermidine enhanced autophagy in the brain and led to a diminished expression of the inflammatory markers, Tgfb, CD11b, Fcgr1, Stat1, CR3, and [[GFAP]] mRNAs in several cortical region and hippocampus of the treated rats suggesting that one beneficial effect of the long-term treatment with spermidine is an attenuated proinflammatory state in the aged brain. Our results suggest that long-term treatment with spermidine increases health span of middle-aged rats by attenuating neuroinflammation and improving anxiety and exploratory behavior.

|keywords=* Autophagy
* Behavior
* Longevity
* Middle-aged rats
* Neuroinflammation
* Spermidine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287009
}}
{{medline-entry
|title=Meta-analysis of human prefrontal cortex reveals activation of [[GFAP]] and decline of synaptic transmission in the aging brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32138778
|abstract=Despite ongoing research efforts, mechanisms of brain aging are still enigmatic and need to be elucidated for a better understanding of age-associated cognitive decline. The aim of this study is to investigate aging in the prefrontal cortex region of human brain in a meta-analysis of transcriptome datasets. We analyzed 591 gene expression datasets pertaining to female and male human prefrontal cortex biopsies of distinct ages. We used hierarchical clustering and principal component analysis (PCA) to determine the influence of sex and age on global transcriptome levels. In sex-specific analysis we identified genes correlating with age and differentially expressed between groups of young, middle-aged and aged. Pathways and gene ontologies (GOs) over-represented in the resulting gene sets were calculated. Potential causal relationships between genes and between GOs were explored employing the Granger test of gene expression time series over the range of ages. The most outstanding results were the age-related decline of synaptic transmission and activated expression of glial fibrillary acidic protein ([[GFAP]]) in both sexes. We found an antagonistic relationship between calcium/calmodulin dependent protein kinase IV (CAMK4) and [[GFAP]] which may include regulatory mechanisms involving cAMP responsive element binding protein (CREB) and mitogen-activated protein kinase (MAPK, alias ERK). Common to both sexes was a decline in synaptic transmission, neurogenesis and an increased base-level of inflammatory and immune-related processes. Furthermore, we detected differences in dendritic spine morphogenesis, catecholamine signaling and cellular responses to external stimuli, particularly to metal (Zinc and cadmium) ions which were higher in female brains.

|keywords=* Aging
* Meta-analysis
* Prefrontal cortex
* Sex-specific
* Transcriptome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059712
}}
{{medline-entry
|title=Astroglial biotin deprivation under endoplasmic reticulum stress uncouples BCAA-mTORC1 role in lipid synthesis to prolong autophagy inhibition in the aging brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32030764
|abstract=Autophagy delays the onset of endoplasmic reticulum (ER) stress by recycling cellular debris. However, the cues that elicit autophagy under the emergence of ER stress and their dysregulation during aging remains obscure. Amino acids, notably branched-chain amino acids (BCAA), get accumulated in the cells once protein synthesis is inhibited by ER stress. The BCAA mimic satiety to inhibit autophagy via mechanistic targets of rapamycin complex 1 (mTORC1) activation and, in contrast, their catabolism supplements de novo lipogenesis for the formation of autophagosome membranes. Thus promoting BCAA utilization is hypothesized to induce autophagy to alleviate ER stress. Nevertheless, except protein synthesis, the rest of BCAA utilization and lipogenesis depends on the co-enzyme biotin. Hence, the levels of biotinylated carboxylases and lipids were assessed in the aging brain of Wistar rats. Despite the increased levels of biotinylated carboxylases and lipids, the aging brain accumulates BCAA. Since astrocytes are the primary site of BCAA and lipid metabolism and the increased expression of glial fibrillary acidic protein ([[GFAP]]) denotes astroglial ER stress, co-localization studies were performed to determine the extent of biotinylation in [[GFAP]] positive cells. Although total biotin intensity was higher in aged brain slices, the astrocytes specific decrease in biotinylation is attributed to BCAA accumulation, mTORC1 overactivation, autophagy inhibition, and ER stress in the aging brain. The ER stress in primary astrocytes using tunicamycin also mimic the in vivo phenotype. Biotin supplementation ameliorated the changes observed in vitro, corroborating the significance of astrocytes biotin availability to promote autophagy under ER stress in aging.

|keywords=* BCAA
* ER stress
* aging
* autophagy
* lipogenesis
* mTORC1
|full-text-url=https://sci-hub.do/10.1111/jnc.14979
}}
{{medline-entry
|title=Long-lived mice with reduced growth hormone signaling have a constitutive upregulation of hepatic chaperone-mediated autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32013718
|abstract=Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis. CMA modulates proteomic organization through selective protein degradation, with targets including metabolic enzymes, cell growth regulators, and neurodegeneration-related proteins. CMA activity is low in [i]ad libitum[/i]-fed rodents but is increased by prolonged fasting. AKT negatively regulates CMA at the lysosomal membrane by phosphorylating and inhibiting the CMA regulator [[GFAP]]. We have previously reported that long-lived [i]Pou1f1/Pit1[/i] mutant (Snell) mice and [i]ghr[/i] (growth hormone receptor) knockout mice ([i]ghr[/i] KO) have lower AKT activity when fed compared to littermate controls, suggesting the hypothesis that these mice have increased baseline CMA activity. Here, we report that liver lysosomes from fed Snell dwarf mice and [i]ghr[/i] KO mice have decreased [[GFAP]] phosphorylation and increased CMA substrate uptake activity. Liver lysosomes isolated from fed Snell dwarf mice and [i]ghr[/i] KO mice injected with the protease inhibitor leupeptin had increased accumulation of endogenous CMA substrates, compared to littermate controls, suggesting an increase in CMA [i]in vivo[/i]. Mice with liver-specific ablation of GH (growth hormone) signaling did not have increased liver CMA, suggesting that a signaling effect resulting from a loss of growth hormone in another tissue causes enhanced CMA in Snell dwarf and [i]ghr[/i] KO mice. Finally, we find Snell dwarf mice have decreased protein levels (in liver and kidney) of CIP2A, a well-characterized CMA target protein, without an associated change in [i]Cip2a[/i] mRNA. Collectively, these data suggest that CMA is enhanced downstream of an endocrine change resulting from whole-body ablation of GH signaling.  CMA: chaperone-mediated autophagy; GH: growth hormone; [i]ghr[/i] KO: growth hormone receptor knockout; LAMP2A: splice variant 1 of [i]Lamp2[/i] transcript; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; Li[i]-ghr[/i] KO: liver-specific [i]ghr[/i] knockout; MA: macroautophagy; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; PBS: phosphate-buffered saline.

|keywords=* Aging
* chaperone-mediated autophagy
* endocrine control of autophagy
* endocrine signaling
* growth hormone
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1725378
}}
{{medline-entry
|title=Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer-like behavioral and neuropathological changes in CD-1 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31997558
|abstract=Infections could contribute to Alzheimer's disease (AD) neuropathology in human. However, experimental evidence for a causal relationship between infections during the prenatal phase and the onset of AD is lacking. CD-1 mothers were intraperitoneally received lipopolysaccharide (LPS) with two doses (25 and 50 μg/kg) or normal saline every day during gestational days 15-17. A battery of behavioral tasks was used to assess the species-typical behavior, sensorimotor capacity, anxiety, locomotor activity, recognition memory, and spatial learning and memory in 1-, 6-, 12-, 18-, and 22-month-old offspring mice. An immunohistochemical technology was performed to detect neuropathological indicators consisting of amyloid-β (Aβ), phosphorylated tau (p-tau), and glial fibrillary acidic protein ([[GFAP]]) in the hippocampus. Compared to the same-aged controls, LPS-treated offspring had similar behavioral abilities and the levels of Aβ42, p-tau, and [[GFAP]] at 1 and 6 months old. From 12 months onward, LPS-treated offspring gradually showed decreased species-typical behavior, sensorimotor ability, locomotor activity, recognition memory, and spatial learning and memory, and increased anxieties and the levels of Aβ42, p-tau, and [[GFAP]] relative to the same-aged controls. Moreover, this damage effect (especially cognitive decline) persistently progressed onwards. The changes in these neuropathological indicators significantly correlated with impaired spatial learning and memory. Prenatal exposure to low doses of LPS caused AD-related features including behavioral and neuropathological changes from midlife to senectitude.

|keywords=* Alzheimer's disease
* aging
* lipopolysaccharide
* memory
* mice
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066339
}}
{{medline-entry
|title=Increased levels of Aβ42 decrease the lifespan of ob/ob mice with dysregulation of microglia and astrocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31907998
|abstract=Clinical studies have indicated that obesity and diabetes are associated with Alzheimer's disease (AD) and neurodegeneration. Although the mechanisms underlying these associations remain elusive, the bidirectional interactions between obesity/diabetes and Alzheimer's disease (AD) may be involved in them. Both obesity/diabetes and AD significantly reduce life expectancy. We generated App  knock-in; ob/ob mice by crossing App  knock-in mice and ob/ob mice to investigate whether amyloid-β (Aβ) affects the lifespan of ob/ob mice. App  knock-in; ob/ob mice displayed the shortest lifespan compared to wild-type mice, App  knock-in mice, and ob/ob mice. Notably, the Aβ42 levels were increased at minimum levels before deposition in App  knock-in mice and App  knock-in; ob/ob mice at 18 months of age. No differences in the levels of several neuronal markers were observed between mice at this age. However, we observed increased levels of glial fibrillary acidic protein ([[GFAP]]), an astrocyte marker, in App  knock-in; ob/ob mice, while the levels of several microglial markers, including CD11b, TREM2, and DAP12, were decreased in both ob/ob mice and App  knock-in; ob/ob mice. The increase in [[GFAP]] levels was not observed in young App  knock-in; ob/ob mice. Thus, the increased Aβ42 levels may decrease the lifespan of ob/ob mice, which is associated with the dysregulation of microglia and astrocytes in an age-dependent manner. Based on these findings, the imbalance in these neuroinflammatory cells may provide a clue to the mechanisms by which the interaction between obesity/diabetes and early AD reduces life expectancy.
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Peptides
* Animals
* Astrocytes
* Gene Knock-In Techniques
* Longevity
* Mice
* Mice, Knockout
* Mice, Obese
* Microglia
* Peptide Fragments
|keywords=* Alzheimer's disease
* astrocytes
* diabetes
* lifespan
* microglia
* obesity
|full-text-url=https://sci-hub.do/10.1096/fj.201901028RR
}}
{{medline-entry
|title=Selective brain neuronal and glial losses without changes in [[GFAP]] immunoreactivity: Young versus mature adult Wistar rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31404554
|abstract=Normal ageing results in brain selective neuronal and glial losses. In the present study we analyze neuronal and glial changes in Wistar rats at two different ages, 45 days (young) and 420 days (mature adult), using Nissl staining and glial fibrillary acidic protein ([[GFAP]]) immunohistochemistry associated to the Sholl analysis. Comparing mature adults with young rats we noted the former present a decrease in neuronal density in the cerebral cortex, corpus callosum, pyriform cortex, L.D.D.M., L.D.V.L., central medial thalamic nucleus and zona incerta. A decrease in glial density was found in the dorsomedial and ventromedial hypothalamic nuclei. Additionally, the neuron/glia ratio was reduced in the central medial thalamic nucleus and increased in the habenula. No changes were found in the neuronal and glial densities or neuron/glia ratio in the other studied regions. The number of astrocytic primary processes and the number of intersections counted in the Sholl analysis presented no significant difference in any of the studied regions. Overall, neither [[GFAP]] positive astrocytic density nor [[GFAP]] immunoreactivity showed alteration.
|mesh-terms=* Aging
* Animals
* Brain
* Glial Fibrillary Acidic Protein
* Male
* Neuroglia
* Neurons
* Rats
* Rats, Wistar
|keywords=* Ageing
* Astrocytes
* GFAP
* Glia
* Neurons
|full-text-url=https://sci-hub.do/10.1016/j.mad.2019.111128
}}
==CGA==

{{medline-entry
|title=Safety and efficacy of preoperative chemoradiotherapy in fit older patients with intermediate or locally advanced rectal cancer evaluated by comprehensive geriatric assessment: A planned interim analysis of a multicenter, phase II trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33160954
|abstract=Comprehensive geriatric assessment ([[CGA]]) is a diagnostic method to assess the physical and mental health status of older patients. The purpose of this study was to assess the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for intermediate or locally advanced rectal cancer in older people who were classified as "fit" by [[CGA]]. The interim analysis focusing on safety was reported here as the first part of this trial. This is a single arm, multicenter, phase II trial. The eligible patients for this study were aged 70 years or above that fulfilled the standard of intermediate or locally advanced risk category, and met the standard of fit (SIOG1) evaluated by [[CGA]]. All patients received preCRT (50 Gy) with Raltitrexed (3 mg/m  on d1 and d22). Qualitative and quantitative variables were described using descriptive statistics. The surgery adherence predicting was analyzed by multivariate logistic regression. Thirty-nine fit patients were enrolled. All patients except one finished radiotherapy without dose reduction. Thirty-two patients finished the prescribed Raltitrexed therapy as scheduled. A serious toxicity was observed in 12 patients (30.8%), and only six patients (15.4%) experienced non-hematological side effects. Overall, our results showed that preCRT was feasible and safe in older patients with rectal cancer who were evaluated as fit based on [[CGA]], supporting the use of [[CGA]] to tailor oncological treatment and predict the tolerance of a specific therapy. Completing this trial as planned would provide further valuable insights.

|keywords=* Comprehensive geriatric assessment
* Geriatrics
* Preoperative chemoradiotherapy
* Rectal cancer
|full-text-url=https://sci-hub.do/10.1016/j.jgo.2020.10.016
}}
{{medline-entry
|title=The Protective Effect of Chlorogenic Acid on Vascular Senescence via the Nrf2/HO-1 Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32630570
|abstract=The world faces the serious problem of aging. In this study, we aimed to investigate the effect of chlorogenic acid ([[CGA]]) on vascular senescence. C57/BL6 female mice that were 14 ± 3 months old were infused with either Angiotensin II (AngII) or saline subcutaneously for two weeks. These mice were administered [[CGA]] of 20 or 40 mg/kg/day, or saline via oral gavage. AngII infusion developed vascular senescence, which was confirmed by senescence associated-β-galactosidase (SA-β-gal) staining. [[CGA]] administration attenuated vascular senescence in a dose-dependent manner, in association with the increase of Sirtuin 1 (Sirt1) and endothelial nitric oxide synthase (eNOS), and with the decrease of p-Akt, PAI-1, p53, and p21. In an in vitro study, with or without pre-treatment of [[CGA]], Human Umbilical Vein Endothelial Cells (HUVECs) were stimulated with H O  for an hour, then cultured in the absence or presence of 0.5-5.0 μM [[CGA]] for the indicated time. Endothelial cell senescence was induced by H O , which was attenuated by [[CGA]] treatment. Pre-treatment of [[CGA]] increased Nrf2 in HUVECs. After H O  treatment, translocation of Nrf2 into the nucleus and the subsequent increase of Heme Oxygenase-1 (HO-1) were observed earlier in [[CGA]]-treated cells. Furthermore, the HO-1 inhibitor canceled the beneficial effect of [[CGA]] on vascular senescence in mice. In conclusion, [[CGA]] exerts a beneficial effect on vascular senescence, which is at least partly dependent on the Nuclear factor erythroid 2-factor 2 (Nrf2)/HO-1 pathway.

|keywords=* chlorogenic acid
* heme oxygenase-1
* nuclear factor erythroid 2-related factor 2
* vascular senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350250
}}
{{medline-entry
|title=Association between comprehensive geriatric assessment and short-term outcomes among older adult patients with stroke: A nationwide retrospective cohort study using propensity score and instrumental variable methods.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32566923
|abstract=Comprehensive geriatric assessment ([[CGA]]) is a multidimensional and multidisciplinary method to identify geriatric conditions among older patients. The aim of the present study was to examine the associations between [[CGA]] and short-term outcomes among older adult inpatients with stroke. The study was a nationwide, retrospective cohort study. We used the Diagnosis Procedure Combination database, a national Japanese inpatient database, to identify older adult stroke patients from 2014 to 2017. The associations between [[CGA]] and in-hospital mortality, length of hospital stay, readmission rate, rehabilitation intervention, and introduction of home health care were evaluated using propensity score matching and instrumental variable analysis. We identified 338,720 patients, 21·3% of whom received [[CGA]]. A propensity score-matched analysis of 53,861 pairs showed that in-hospital mortality was significantly lower in the [[CGA]] group than in the non-[[CGA]] group (3·6% vs. 4·1%, [i]p[/i] < 0·001). The rate of long-term hospitalization (> 60 days) was significantly lower in the [[CGA]] group than in the non-[[CGA]] group (8·7% vs. 10·1%, [i]p[/i] < 0·001), and the rates of rehabilitation intervention (30·3% vs. 24·9%, [i]p[/i] < 0·001) and home health care (8·3% vs. 7·6%, [i]p[/i] = 0·001) were both higher in the [[CGA]] group than in the non-[[CGA]] group. Instrumental variable analysis showed similar results. [[CGA]] was significantly associated with the examined short-term outcomes. These findings from Japan, one of the most aged countries worldwide, highlight the possible benefits of [[CGA]] for short-term outcomes and can be of use for health policy in other international contexts. This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (19AA2007 and H30-Policy-Designated-004) and the Ministry of Education, Culture, Sports, Science and Technology, Japan (17H04141).

|keywords=* Comprehensive geriatric assessment
* Geriatrics
* Japanese diagnosis procedure combination database
* Length of stay
* Mortality
* Stroke
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298723
}}
{{medline-entry
|title=Interventions to Improve Clinical Outcomes in Older Adults Admitted to a Surgical Service: A Systematic Review and Meta-analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32417101
|abstract=Managing older patients with surgical conditions is a major challenge for hospitals. There is therefore a growing interest in providing geriatric perioperative services. The aim of this systematic review and meta-analysis was to characterize and assess the impact of targeted perioperative geriatric interventions on clinical outcomes of older adults admitted to nonorthopedic surgical teams. A systematic review and meta-analysis of studies of perioperative geriatric interventions in older adults hospitalized under nonorthopedic surgical teams. Ovid MEDLINE, EMBASE, PsycINFO, Scopus, Cochrane Central Register of Controlled Trials, CINAHL, and trial registry databases were searched. Primary outcomes were change in functional status and length of stay (LOS). Fifteen randomized controlled trials (RCTs) and 9 prospective before-and-after studies met the inclusion criteria (n = 3026 participants). Perioperative geriatric interventions included preoperative comprehensive geriatric assessment and management ([[CGA]]) (5 studies), multicomponent inpatient geriatric programs (8 studies), cognitive training (1 study), exercise (5 studies), and prehabilitation (5 studies). Exercise therapy [mean difference (MD) -1.90, 95% confidence interval (CI) -3.01, -0.80], multicomponent inpatient geriatric programs (MD -1.98, 95% CI -3.09, -0.88), and prehabilitation (MD -1.32, 95% CI -2.75, 0.11) reduced LOS. Functional decline was highly heterogeneous, with 4 of 8 studies reporting significantly less functional decline. Geriatric perioperative interventions reduced complications [exercise therapy risk ratio (RR) 0.74, 95% CI 0.48, 1.15; prehabilitation RR 0.61, 95% CI 0.47, 0.80] and delirium (multicomponent inpatient geriatric programs RR 0.49, 95% CI 0.27, 0.90; preoperative [[CGA]] RR 0.54, 95% CI 0.33, 0.89). There was no significant impact on mortality or readmissions. Perioperative geriatric interventions targeted at older nonorthopedic surgical patients improve some clinically relevant outcomes. There is a need for these interventions to be further evaluated in high-quality studies, and future research should explore how to effectively implement these interventions within complex health care systems.

|keywords=* Aging
* comprehensive geriatric assessment
* delirium
* functional status
* outcomes
* surgery
|full-text-url=https://sci-hub.do/10.1016/j.jamda.2020.03.023
}}
{{medline-entry
|title=A Computerized Frailty Assessment Tool at Points-of-Care: Development of a Standalone Electronic Comprehensive Geriatric Assessment/Frailty Index (eFI-[[CGA]]).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32296673
|abstract= Frailty is characterized by loss of biological reserves and is associated with an increased risk of adverse health outcomes. Frailty can be operationalized using a Frailty Index (FI) based on the accumulation of health deficits; items under health evaluation in the well-established Comprehensive Geriatric Assessment ([[CGA]]) have been used to generate an FI-[[CGA]]. Traditionally, constructing the FI-[[CGA]] has relied on paper-based recording and manual data processing. As this can be time-consuming and error-prone, it limits widespread uptake of this proven type of frailty assessment. Here, we report the development of an electronic tool, the eFI-[[CGA]], for use on personal computers by frontline healthcare providers, to collect [[CGA]] data and automate FI-CFA calculation. The ultimate goal is to support early identification and management of frailty at points-of-care, and make uptake in Electronic Medical Records (EMR) feasible and transparent.   An electronic [[CGA]] (e[[CGA]]) form was implemented to operate on Microsoft's WinForms platform and coded using C# programming language. Users complete the e[[CGA]] form, from which items under the [[CGA]] evaluation are automatically retrieved and processed to output an eFI-[[CGA]] score. A user-friendly interface and secured data saving methods were implemented. The software was debugged and tested using systematically designed simulation data, addressing different logic, syntax, and application errors, and then tested with clinical assessment. The user manual and manual scoring were used as ground truth to compare eFI-[[CGA]] input and automated eFI score calculations. Frontline health-provider user feedback was incorporated to improve the end-user experience.   The Standalone eFI-[[CGA]] software tool was developed and optimized for use on personal computers. The user interface adapted the design of paper-based [[CGA]] form to facilitate familiarity for clinical users. Compared to known scores, the software tool generated eFI-[[CGA]] scores with 100% accuracy to four decimal places. The eFI-[[CGA]] allowed secure data storage and retrieval of multiple types, including user input, completed e[[CGA]] form, coded items, and calculated eFI-[[CGA]] scores. It also permitted recording of actions requiring clinical follow-up, facilitating care planning. Application bugs were identified and resolved at various stages of the implementation, resulting in efficient system performance.   Accurate, robust, and reliable computerized frailty assessments are needed to promote effective frailty assessment and management, as a key tool in health care systems facing up to frailty. Our research has enabled the delivery of the standalone eFI-[[CGA]] software technology to empower effective frailty assessment and management by various healthcare providers at points-of-care, facilitating integrated care of older adults.

|keywords=* aging
* comprehensive geriatric assessment (CGA)
* electronic assessment tools
* frailty
* frailty index
* healthcare
* older adults
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137764
}}
{{medline-entry
|title=Allocating patients to geriatric medicine wards in a tertiary university hospital in England: A service evaluation of the Specialist Advice for the Frail Elderly (SAFE) team.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31942488
|abstract=The number of older patients admitted to acute hospitals has increased; however, their needs are heterogeneous and there is no gold-standard method of triaging them towards practicing comprehensive geriatric assessment ([[CGA]]). In our hospital, the SAFE (Specialist Advice for the Frail Elderly) team provide an initial geriatric assessment of all emergency admissions of patients aged ≥75 years (with some assessments also occurring in those aged 65 to 74 years) and recommend as to whether [[CGA]] in a dedicated Department of Medicine for the Elderly (DME) ward may be required. SAFE assessments include routine screening for geriatric syndromes using validated tools. Our aim was to compare the characteristics (age, gender, acute illness severity on admission as per modified early warning score (MEWS), Charlson Comorbidity Index, Clinical Frailty Scale (CFS), presence of dementia and delirium) and outcomes (length of stay, delayed discharge, inpatient mortality, discharge to usual place of residence, and new institutionalization) of patients listed to a DME ward, to those not listed. We analyzed all SAFE team assessments of patients admitted nonelectively between February 2015 and November 2016. Of 6192 admissions, 16% were listed for a DME ward. Those were older, had higher MEWS and CFS score, were more often affected by cognitive impairment, had longer hospital stay, higher inpatient mortality, and more often required new institutionalization. Higher CFS and presence of dementia and delirium were the strongest predictors of DME ward recommendation. Routine measurement of markers of geriatric complexity may help maximize access to finite inpatient [[CGA]] resources.

|keywords=* clinical frailty scale
* frail older adults
* geriatrics
* hospital medicine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880728
}}
{{medline-entry
|title=Role of Frailty on Risk Stratification in Cardiac Surgery and Procedures.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31894551
|abstract=The number of older people candidates for interventional cardiology, such as PCI but especially for transcatheter aortic valve implantation (TAVI) , would increase in the future. Generically, the surgical risk, the amount of complications in the perioperative period, mortality and severe disability remain significantly higher in the elderly than in younger. For this reason it's important to determine the indication for surgical intervention, using tools able to predict not only the classics outcome (length of stay, mortality), but also those more specifically geriatrics, correlate to frailty: delirium, cognitive deterioration, risk of institutionalization and decline in functional status. The majority of the most used surgical risks scores are often specialist-oriented and many variables are not considered. The need of a multidimensional diagnostic process, focused on detect frailty, in order to program a coordinated and integrated plan for treatment and long term follow up, led to the development of a specific geriatric tool: the Comprehensive Geriatric Assessment ([[CGA]]). The [[CGA]] has the aim to improve the prognostic ability of the current risk scores to capture short long term mortality and disability, and helping to resolve a crucial issue providing solid clinical indications to help physician in the definition of on interventional approach as futile. This tool will likely optimize the selection of TAVI older candidates could have the maximal benefit from the procedure.
|mesh-terms=* Aged
* Aged, 80 and over
* Cardiac Surgical Procedures
* Frail Elderly
* Frailty
* Geriatric Assessment
* Humans
* Percutaneous Coronary Intervention
* Risk Assessment
* Transcatheter Aortic Valve Replacement
|keywords=* Cardiac surgery
* Comprehensive geriatric assessment
* Disability
* Elderly
* Frailty
* Geriatrics
* Surgical risk scores
* TAVI
|full-text-url=https://sci-hub.do/10.1007/978-3-030-33330-0_11
}}
{{medline-entry
|title=Developing an objective structured clinical examination in comprehensive geriatric assessment - A pilot study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31745004
|abstract=Acquiring medical competencies alone does not necessarily lead to the delivery of quality clinical care. Many UK training programs are soon to be based on the curricula of entrustable professional capabilities (EPCs). These are tasks carried out in practice requiring proficiency in several competencies for quality practice. Assessments to evaluate EPCs for independent practice are needed. Comprehensive geriatric assessment ([[CGA]]) is an EPC in geriatric medicine. We describe the development of an assessment of [[CGA]] as an example of examining EPCs. A [[CGA]] station was introduced in the Diploma in Geriatric Medicine clinical examination. Candidates rotate through four stations: three single competency-based stations (history, communication/ethics and physical examination) and an EPC-based station in [[CGA]]. One hundred and seventy-eight (female: 96 [53.9%]) candidates took it. There was a weak but significantly positive correlation between the score at [[CGA]] and the total score in the other stations (r = 0.46; P < 0.001). Most candidates passing the station passed the examination. Correlation with other stations similarly showed weak significant correlations (Station 1: r = 0.38; P < 0.001, Station 3: r = 0.28; P < 0.001, and Station 4: r = 0.37; P < 0.001). There was 61.4% (kappa: 0.61; P = 0.000) agreement between examiners whether a candidate passed or failed. Agreement was higher for the other stations, i.e. Station 1 (kappa: 0.85; P < 0.001), Station 3 (kappa: 0.72; P < 0.001), and Station 4 (kappa: 0.85; P < 0.001). Performance on the station correlated positively with overall performance, suggesting that it has discriminatory value in differentiating candidates with varying ability and the more able candidates pass the examination.
|mesh-terms=* Aged
* Clinical Competence
* Education, Medical, Graduate
* Educational Measurement
* Female
* Geriatric Assessment
* Geriatrics
* Humans
* Male
* Pilot Projects
* United Kingdom
|keywords=* Comprehensive geriatric assessment
* development
* entrustable professional capabilities
* objective structured clinical examination
* summative assessment
|full-text-url=https://sci-hub.do/10.4103/efh.EfH_111_18
}}
{{medline-entry
|title=How do doctors choose treatment for older gynecological cancer patients? A Japanese Gynecologic Oncology Group survey of gynecologic oncologists.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31728682
|abstract=The proportion of elderly Japanese people (age ≥ 65 years) is currently 27.7%, and the average life span of women is 87.14 years, both of which are unprecedented. In gynecologic cancer, evidence of treatment for the elderly is scarce, and treatment policies are determined by each facility. The aim of the present study was to investigate the status of treatment policies for elderly patients with gynecologic cancer. A web-based questionnaire regarding how treatment strategies are currently determined for elderly patients with gynecologic cancer was conducted on gynecologic oncologists to develop a tool for the objective evaluation of treatment policy decisions for elderly patients. The responses showed that 48% of the gynecologic oncologists were aware of comprehensive geriatric assessment ([[CGA]]), but only 6% had actually conducted [[CGA]]. Age, comorbidities, performance status, and pretreatment evaluations were regarded as important in determining the treatment strategy. Invasive treatments such as radical hysterectomy and para-aortic lymph node dissection tended to have age limits. These findings suggest that awareness of [[CGA]] is low in Japan, and that elderly people may not be given standard therapy, which highlights the importance of building on these findings by gathering further evidence and developing a new tool for predicting treatment outcomes for elderly patients with gynecologic cancer.
|mesh-terms=* Aged
* Aged, 80 and over
* Comorbidity
* Female
* Genital Neoplasms, Female
* Geriatric Assessment
* Gynecology
* Humans
* Hysterectomy
* Japan
* Lymph Node Excision
* Oncologists
* Surveys and Questionnaires
|keywords=* Comprehensive geriatric assessment
* Elderly
* Geriatrics
* Gynecologic cancer
|full-text-url=https://sci-hub.do/10.1007/s10147-019-01574-z
}}
{{medline-entry
|title=Validation of the Pictorial Fit-Frail Scale in a memory clinic setting.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31524122
|abstract=To assess the feasibility, reliability, and validity of the Pictorial Fit-Frail Scale (PFFS) among patients, caregivers, nurses, and geriatricians in an outpatient memory clinic. Observational study. A Canadian referral-based outpatient memory clinic. Fifty-one consecutive patients and/or their caregivers, as well as attending nurses and geriatricians. Participants (patients, caregivers, nurses, and geriatricians) were asked to complete the PFFS based on the patient's current level of functioning. Time-to-complete and level of assistance required was recorded. Participants also completed a demographic survey and patients' medical history (including the Mini-Mental State Examination [MMSE], and Comprehensive Geriatric Assessment [[[CGA]]]) was obtained via chart review. Patient participants had a mean age of 77.3±10.1 years, and average MMSE of 22.0±7.0, and 53% were female. Participants were able to complete the PFFS with minimal assistance, and their average times to completion were 4:38±2:09, 3:11±1:16, 1:05±0:19, and 0:57±0:30 (mins:sec) for patients, caregivers, nurses, and geriatricians, respectively. Mean PFFS scores as rated by patients, caregivers, nurses, and geriatricians were 9.0±5.7, 13.1±6.6, 11.2±4.5, 11.9±5.9, respectively. Patients with low MMSE scores (0-24) took significantly longer to complete the scale and had higher PFFS scores. Inter-rater reliability between nurses and geriatricians was 0.74, but it was lower when assessments were done for patients with low MMSE scores (0.47, p<0.05). The correlation between PFFS and a Frailty Index based on the [[CGA]] was moderately high and statistically significant for caregivers, nurses, and geriatricians (r=0.66, r=0.59, r=0.64, respectively), but not patients. The PFFS is feasible, even among people with some slight cognitive impairment, though it may be less useful when patients with severe dementia administer it to themselves. Further, the PFFS may help inform clinicians about areas of concern as identified by patients, enabling them to contribute more to diagnostic and treatment decisions or helping with health tracking and care planning.

|keywords=* aging
* dementia
* frail elderly
* frailty
* psychometrics
|full-text-url=https://sci-hub.do/10.1017/S1041610219000905
}}
{{medline-entry
|title=Impact of Resolution of Hyponatremia on Neurocognitive and Motor Performance in Geriatric Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31467370
|abstract=This observational study investigated the impact of hyponatremia resolution on the results of a comprehensive geriatric assessment ([[CGA]]) in 150 patients with age ≥70 years and serum sodium <130 mEq/L. The test battery including Barthel index of Activities of Daily Living (ADL) and various tests of neurocognitive function, motor performance and mood stability was applied on admission and at discharge. Changes of individual test results (Δ) were analyzed and normonatremic patients matched for age, gender, and ADL served as reference group. Most [[CGA]] test results improved. The improvement was more pronounced in the hyponatremia group with respect to ADL (ΔADL: 14.3 ± 17.1 vs. 9.8 ± 14.7; p = 0.002) and MMSE (ΔMMSE: 1.8 ± 3.0 vs. 0.7 ± 1.9; p = 0.002). Effect sizes were small (i.e., >0.2) in the overall analysis for ΔADL and ΔMMSE and moderate (i.e., >0.5) for ΔMMSE in the euvolemic subgroup. Beneficial effects on ΔADL and ΔMMSE were only observed in the subgroup of patients in which [Na ] was raised by >5 mEq/L and multivariable linear regression analysis confirmed [Na ] increase to be an independent predictor of MMSE improvement. Resolution of hyponatremia has a beneficial impact on the geriatric patients' overall functional status, in particular in euvolemic cases.
|mesh-terms=* Activities of Daily Living
* Aged
* Aged, 80 and over
* Aging
* Cognition
* Female
* Geriatrics
* Humans
* Hyponatremia
* Male
* Mental Status and Dementia Tests
* Middle Aged
* Motor Activity
* Sodium

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715723
}}
{{medline-entry
|title=Health outcome of older hospitalized patients in internal medicine environments evaluated by Identification of Seniors at Risk (ISAR) screening and geriatric assessment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31412787
|abstract=Hospitals are in need of valid and economic screening and assessment tools that help identifying older patients at risk for complications which require intensified support during their hospital stay. Five hundred forty-seven internal medicine in-patients (mean age 78.14 ± 5.96 years; 54.7% males) prospectively received Identification of Seniors at Risk (ISAR) screening. If screening results were positive (ISAR score ≥ 2), a comprehensive geriatric assessment ([[CGA]]) was performed. We explored sensitivity and specificity of different ISAR and [[CGA]] cutoffs. Further, we analyzed the risk of falls and how patients got discharged from hospital. ISAR+/[[CGA]] abnormal patients spent more days in hospital (16.1 ± 14.5), received more nursing hours per day (3.0 ± 2.3), more hours of physiotherapy during their hospital stay (2.2 ± 3.2), and had more falls (10.1%) compared to ISAR+/[[CGA]] normal (10.9 ± 12.3, 2.0 ± 1.2, 1.2 ± 4.3, and 2.8%, respectively, all p ≤ 0.016) and ISAR- (9.6 ± 11.5, 2.3 ± 4.5, 0.7 ± 2.0, and 2.2%, respectively, all p ≤ 0.002) patients. ISAR+/[[CGA]] abnormal patients terminated their treatment regularly with being discharged back home less often (59.6%) compared to ISAR+/[[CGA]] normal (78.5%, p = 0.002) and ISAR- (78.2%, p = 0.056) patients. ISAR cutoff≥2 and [[CGA]] defined as abnormal in case of impairment of ADL plus another [[CGA]] domain achieved best sensitivity/specificity. Abnormal geriatric risk screening and assessment are associated with longer hospital stay and higher amount of nursing and physiotherapy during hospital stay, greater risk of falling, and a lower percentage of successfully terminated treatment in older in-patients.
|mesh-terms=* Accidental Falls
* Aged
* Aged, 80 and over
* Cohort Studies
* Emergency Service, Hospital
* Female
* Geriatric Assessment
* Health Status
* Hospitalization
* Humans
* Internal Medicine
* Length of Stay
* Male
* Mass Screening
* Patient Discharge
* Risk Assessment
|keywords=* CGA
* Cutoff
* Geriatrics
* ISAR
* Internal medicine
* Older in-patients
* Risk screening
* Sensitivity
* Specificity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694685
}}
==TH==

{{medline-entry
|title=Thyroid hormone signaling is associated with physical performance, muscle mass, and strength in a cohort of oldest-old: results from the Mugello study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33219914
|abstract=Thyroid hormones ([[TH]]s) play a crucial role in the homeostasis of muscle function, such as myogenesis and energy metabolism, suggesting that the thyroid may be also involved in the entropic processes of muscle aging. The aim of the present study is to evaluate the effect of [[TH]] signaling on physical performance, muscle mass, and strength in a cohort of community-dwelling oldest-old subjects (> 90 years). The study population was selected in a rural area of central Italy (Mugello, Tuscany), and the design was cross-sectional. Four hundred seventy-five subjects (130 males and 345 females) were enrolled, representing about 65% of all the nonagenarians living in the Mugello area. After adjusting for multiple confounding factors (sex, age, diabetes, and levothyroxine administration), the lowest quartile of FT3/FT4 ratio distribution showed lower physical performance compared to the other quartiles (β ± SE: - 0.49 ± 0.12; p < 0.001), whereas the highest quartile of FT3/FT4 ratio was associated with higher skeletal muscle index (β ± SE: 1.11 ± 0.42; p = 0.009). In addition, the lowest quartile of FT4 showed a statistically significant higher handgrip strength (β ± SE: 1.78 ± 0.68; p = 0.009) compared to all other quartiles. This study demonstrates that nonagenarians with higher FT3/FT4 ratios had better preserved muscle function, therefore successfully overcoming the imbalance of homeostatic and entropic processes involved in muscle aging. However, we could not establish a cause-effect relationship due to the cross-sectional design of the study.

|keywords=* Aging
* Muscle mass
* Muscle strength
* Oldest-old
* Physical performance
* Rehabilitation
* Thyroid hormone signaling
|full-text-url=https://sci-hub.do/10.1007/s11357-020-00302-0
}}
{{medline-entry
|title=Social Environment Ameliorates Behavioral and Immune Impairments in Tyrosine Hydroxylase Haploinsufficient Female Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32772235
|abstract=The social environment can influence the functional capacity of nervous and immune systems, and consequently the state of health, especially in aged individuals. Adult female tyrosine hydroxylase haploinsufficient ([[TH]]-HZ) mice exhibit behavioral impairments, premature immunosenescence and oxidative- inflammatory stress. All these deteriorations are associated with a lower lifespan than wild type (WT) counterparts. The aim was to analyze whether the cohabitation with WT animals could revert or at least ameliorate the deterioration in the nervous and immune systems that female [[TH]]-HZ mice show at adult age. Female [[TH]]-HZ and WT mice at age of 3-4 weeks were divided into following groups: control [[TH]]-HZ (5 [[TH]]-HZ mice in the cage; [[TH]]-HZ100%), control WT (5 WT mice in the cage; WT100%), [[TH]]-HZ > 50% and WT < 50% (5 [[TH]]-HZ with 2 WT mice in each cage) as well as [[TH]]-HZ < 50% and WT > 50% (2 [[TH]]-HZ and 5 WT mice in each cage). At the age of 37-38 weeks, all mice were submitted to a battery of behavioral tests, evaluating sensorimotor abilities, exploratory capacities and anxiety-like behaviors. Subsequently, peritoneal leukocytes were extracted and several immune functions as well as oxidative and inflammatory stress parameters were analyzed. The results showed that the [[TH]]-HZ < 50% group had improved behavioral responses, especially anxiety-like behaviors, and the immunosenescence and oxidative stress of their peritoneal leukocytes were ameliorated. However, WT mice that cohabited with [[TH]]-HZ mice presented higher anxiety-like behaviors and deterioration in immune functions and in their inflammatory stress parameters. Thus, this social environment is capable of ameliorating the impairments associated with a haploinsufficiency of the th gene. Graphical Abstract.

|keywords=* Behavioral responses
* Immunosenescence
* Oxidative-inflammatory stress
* Social environmental strategy
* Tyrosine hydroxylase haploinsufficient mice
|full-text-url=https://sci-hub.do/10.1007/s11481-020-09947-2
}}
{{medline-entry
|title=Mechanism of thyroid hormone signaling in skeletal muscle of aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32720201
|abstract=Skeletal muscle (SM) has been shown as a target of thyroid hormones ([[TH]]s). However, the status of [[TH]] signaling in aged SM remains unclear. This study aimed to explore the mechanism of [[TH]] signaling in SM of aging mice. Thirty C57BL/6J male mice were divided into 6-, 15- and 22-month (6, 15 and 22M) groups according to different age. Physical parameters were evaluated by analytical balance, grip strength test and histological analysis. Thyroid function was detected by enzyme-linked immunosorbent assay. [[TH]] signaling was compared among the three groups by real-time PCR and western blotting analysis. p16, p21, and p53 mRNA levels in SM increased in age-dependent manner. The muscle weight and strength decreased in 22M group compared to 6 and 15M groups. Concentrations of thyroid hormones, including free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) in 22 M mice were not shown significant difference compared to 6M or 15M mice, although FT3 showed slightly decrease and TSH appeared a mild increase accompanying with age. mRNA levels of [[TH]] transporters, including MCT8 and MCT10, as well as iodothyronine deiodinase type 2 (DIO2) and type 3 (DIO3), were higher in 22M, while [[TH]] receptor α (TRα) mRNA and protein expression was lower in 22M, compared to the other groups. Type-I myosin heavy chain (MyHC I), MyHC IIx, and MyHC IIa were upregulated and Type-IIb MyHC (MyHC IIb) was downregulated in SM with advancing age. [[TH]] signaling in SM changes with aging.

|keywords=* Aging
* Mice
* Skeletal muscle
* Thyroid hormone signaling
|full-text-url=https://sci-hub.do/10.1007/s12020-020-02428-9
}}
{{medline-entry
|title=Longitudinal changes in bone mineral density and trabecular bone score in Korean adults: a community-based prospective study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32621253
|abstract=The bone mineral densities (BMDs) of the femoral neck and total hip, and the lumbar spine trabecular bone score (TBS), tended to decrease with age in both men and women, whereas the lumbar spine BMD tended to increase. Lumbar spine BMD is thus inappropriate for evaluating longitudinal changes in bone loss; the lumbar spine TBS is an alternative measure. Aging is associated with a decrease in bone mass and quality. This community-based prospective cohort study investigated longitudinal changes in bone phenotype in Korean adults. We analyzed data from a prospective community-based cohort study, the Korean Genome and Epidemiology Study. Postmenopausal women and men who underwent dual-energy X-ray absorptiometry at least twice from 2007 to 2014 were included. Longitudinal changes in bone mineral density (BMD) and trabecular bone score (TBS) over 6 years were analyzed by sex, age, and body mass index. A total of 1895 subjects were enrolled (men 965; postmenopausal women 929). The femoral neck (FN) BMD, total hip ([[TH]]) BMD, and lumbar spine (LS) TBS decreased significantly over time, but the LS BMD increased significantly. In men, the average annual changes were 0.3% in LS BMD (p < 0.001), - 0.33% in FN BMD (p < 0.001), - 0.26% in [[TH]] BMD (p = 0.001), and - 0.27% in LS TBS (p < 0.001). In women, the average annual changes were 0.27% in LS BMD (p < 0.001), - 0.67% in FN BMD (p < 0.001), - 0.66% in [[TH]] BMD (p < 0.001), and - 0.27% in LS TBS (p < 0.001). The longitudinal decrease in [[TH]] BMD over time was significantly greater in women (versus men) and those who were older (versus younger). The FN and [[TH]] BMDs decreased with aging. But, the LS BMD was inappropriate to evaluate longitudinal changes of bone loss. The LS TBS could be alterative.
|mesh-terms=* Absorptiometry, Photon
* Adult
* Bone Density
* Cancellous Bone
* Cohort Studies
* Female
* Humans
* Lumbar Vertebrae
* Male
* Prospective Studies
* Republic of Korea
|keywords=* Aging
* Bone mineral density
* Natural history
* Osteoporosis
|full-text-url=https://sci-hub.do/10.1007/s11657-020-00731-6
}}
{{medline-entry
|title=Quantitative proteomic profiling of the rat substantia nigra places glial fibrillary acidic protein at the hub of proteins dysregulated during aging: Implications for idiopathic Parkinson's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32270889
|abstract=There is a strong correlation between aging and onset of idiopathic Parkinson's disease, but little is known about whether cellular changes occur during normal aging that may explain this association. Here, proteomic and bioinformatic analysis was conducted on the substantia nigra (SN) of rats at four stages of life to identify and quantify protein changes throughout aging. This analysis revealed that proteins associated with cell adhesion, protein aggregation and oxidation-reduction are dysregulated as early as middle age in rats. Glial fibrillary acidic protein (GFAP) was identified as a network hub connecting the greatest number of proteins altered during aging. Furthermore, the isoform of GFAP expressed in the SN varied throughout life. However, the expression levels of the rate-limiting enzyme for dopamine production, tyrosine hydroxylase ([[TH]]), were maintained even in the oldest animals, despite a reduction in the number of dopamine neurons in the SN pars compact(SNc) as aging progressed. This age-related increase in [[TH]] expression per neuron would likely to increase the vulnerability of neurons, since increased dopamine production would be an additional source of oxidative stress. This, in turn, would place a high demand on support systems from local astrocytes, which themselves show protein changes that could affect their functionality. Taken together, this study highlights key processes that are altered with age in the rat SN, each of which converges upon GFAP. These findings offer insight into the relationship between aging and increased challenges to neuronal viability, and indicate an important role for glial cells in the aging process.

|keywords=* RRID:AB_11145309
* RRID:AB_2109791
* RRID:AB_228307
* RRID:AB_228341
* RRID:AB_2336820
* RRID:AB_2631098
* RRID:AB_390204
* RRID:MGI:5651135
* RRID:SCR_001881
* RRID:SCR_002798
* RRID:SCR_003070
* RRID:SCR_004946
* RRID:SCR_005223
* aging
* dopaminergic neuron
* glial fibrillary acidic protein
* proteome
* proteomics
* substantia nigra
|full-text-url=https://sci-hub.do/10.1002/jnr.24622
}}
{{medline-entry
|title=Withaferin-A Protects the Nigral Dopamine Neuron and Recovers Motor Activity in Aged Rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31982873
|abstract=Withaferin-A (WA) was evaluated for its neuroprotective efficacy on the dopamine (DA) neurons of the substantia nigra (SN) and striatum (ST) in aged rats. Wistar albino rats were divided into group I, young (3 months old); group II, aged (24 months old); group III, aged rats supplemented with WA (50 mg/kg bodyweight once per day for 30 days), and group IV, young rats supplemented with WA (50 mg/kg bodyweight). At the end of the experiment period, the animals were subjected to various motor behavior analyses, and were sacrificed by transcardial perfusion. The brains were dissected out and subjected to various analyses, including histological, histomorphometrical, and immunolocalization of the tyrosine hydroxylase ([[TH]]) enzyme. The data of rotarod analysis (p < 0.001) showed a significant motor impairment in aged rats (number of falls 10.2 ± 0.86) and reduction in retention time (31.23 ± 2.56 s) compared to young controls (2.41 ± 0.35 and 84.05 ± 5.15 s). The stride length was significantly reduced (p < 0.001) in aged rats (4.21 ± 0.57 and 4.38 ± 0.61 cm) when compared to young control rats (6.98 ± 0.25 and 7.13 ± 0.70 cm). The histomorphometric data of the aged animals showed a significant reduction in the neuronal diameter (p < 0.001), density (p < 0.001), and volume (p < 0.001) in the SN of aged rats when compared to young rats. Immunohistology demonstrated a marked reduction in the levels of [[TH]] enzyme in both the SN and ST of aged animals when compared to young rats. Both structural and functional impairments were reversed in the aged animals after the supplementation of WA (p < 0.001). The present study clearly indicates that WA attenuates the ageing-mediated motor degenerative changes in the SN and ST of aged rats and ascertains its neuroprotective potential.
|mesh-terms=* Aging
* Animals
* Brain
* Corpus Striatum
* Dopaminergic Neurons
* Male
* Motor Activity
* Neuroprotective Agents
* Rats
* Rats, Wistar
* Substantia Nigra
* Tyrosine 3-Monooxygenase
* Withanolides
|keywords=* Ageing
* Dopamine
* Striatum
* Substantia nigra
* Withaferin-A
|full-text-url=https://sci-hub.do/10.1159/000505183
}}
{{medline-entry
|title=Effects of physical activity on bone mineral density in older adults: Korea National Health and Nutrition Examination Survey, 2008-2011.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31655946
|abstract=We compared the relationship between physical activity (PA) and bone mineral density (BMD) in men and women aged over 50 years. Only moderate-to-vigorous PA was positively associated with hip BMD in men. There was no association between PA and BMD at any site in women. Physical activity (PA) is widely recommended for osteoporosis. However, epidemiological data regarding the intensity or volume of PA required for bone health are lacking. We aimed to investigate and compare the relationship between PA and bone mineral density (BMD) in men and women. This population-based cross-sectional study used data from the 4th and 5th Korea National Health and Nutrition Examination Surveys and included 2767 men and 2753 women aged > 50 years. The intensity, frequency, and duration of PA were assessed using a questionnaire, and the participants were divided into the no activity, walking-only, moderate PA, and vigorous PA groups. BMD was measured at the lumbar spine (LS), femur neck (FN), and total hip ([[TH]]) using dual-energy X-ray absorptiometry. Adjusted-BMDs of the hip were higher in men and women in the moderate and vigorous PA groups than those in men and women in the walking-only and no activity groups, while frequency and duration of PA were not associated with BMD at any site. The odds ratios for osteoporosis were the lowest at the FN and [[TH]] in men in the vigorous PA group (0.354, 95% confidence interval (CI) 0.139-0.901, P < 0.002, and 0.072, 95% CI 0.007-0.766, P < 0.003, respectively), while it was not significant in women. Only moderate-to-vigorous PA was positively associated with the hip BMD in men. There was no association between PA and BMD at any site in women. It is necessary to assess the PA intensity for bone health based on the site and sex.
|mesh-terms=* Absorptiometry, Photon
* Aged
* Bone Density
* Cross-Sectional Studies
* Exercise
* Female
* Femur Neck
* Humans
* Lumbar Vertebrae
* Male
* Middle Aged
* Nutrition Surveys
* Osteoporosis
* Republic of Korea
* Surveys and Questionnaires
|keywords=* Aging
* Bone mineral density
* Exercise
* Gender
* Osteoporosis
* Physical activity
|full-text-url=https://sci-hub.do/10.1007/s11657-019-0655-5
}}
{{medline-entry
|title=Age-Related Resistance to Thyroid Hormone Action.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31512083
|abstract=The age-related resistance to thyroid hormones ([[TH]]s) explains the paucity of symptoms and signs of hyperthyroidism in older adults and may partly explain the myriad of symptoms and signs of hypothyroidism in biochemically euthyroid older people. This review considers the available data on the mechanisms underlying [[TH]] resistance with aging and compares these physiologic changes with the changes observed in congenital [[TH]] resistance syndromes. Aging is associated with alterations in [[TH]] economy along with a host of changes in the responsiveness of various tissues to [[TH]]s. The age-related resistance to [[TH]]s can be attributed to decreased [[TH]] transport to tissues, decreased nuclear receptor occupancy, decreased activation of thyroxine to triiodothyronine, and alterations in [[TH]] responsive gene expression. Although an increase in serum [[TH]] levels is expected in syndromes of [[TH]] resistance, unchanged serum [[TH]] levels in the euthyroid elderly is the result of increased sensitivity to [[TH]] negative feedback with increased suppression of thyroid-stimulating hormone, decreased thyroidal sensitivity to thyroid-stimulating hormone, and decreased [[TH]] production and secretion. The current clinical evidence suggests that the age-related [[TH]] resistance is mostly an adaptive response of the aging organism. It is tempting to speculate that similar changes can occur prematurely in a group of younger people who present with signs and symptoms of hypothyroidism despite normal serum thyroid function tests.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Animals
* Humans
* Hyperthyroidism
* Hypothyroidism
* Iodide Peroxidase
* Male
* Receptors, Thyroid Hormone
* Thyroid Hormones
* Thyroxine
* Triiodothyronine

|full-text-url=https://sci-hub.do/10.1007/s40266-019-00711-7
}}
{{medline-entry
|title=Age-Dependent Changes in Glucose Homeostasis in Male Deiodinase Type 2 Knockout Zebrafish.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31504428
|abstract=Thyroid hormones ([[TH]]s) are crucial regulators of glucose metabolism and insulin sensitivity. Moreover, inactivating mutations in type 2 deiodinase (DIO2), the major [[TH]]-activating enzyme, have been associated with type 2 diabetes mellitus in both humans and mice. We studied the link between Dio2 deficiency and glucose homeostasis in fasted males of two different Dio2 knockout (KO) zebrafish lines. Young adult Dio2KO zebrafish (6 to 9 months) were hyperglycemic. Both insulin and glucagon expression were increased, whereas β and α cell numbers in the main pancreatic islet were similar to those in wild-types. Insulin receptor expression in skeletal muscle was decreased at 6 months, accompanied by a strong downregulation of hexokinase and pyruvate kinase expression. Blood glucose levels in Dio2KO zebrafish, however, normalized around 1 year of age. Older mutants (18 to 24 months) were normoglycemic, and increased insulin and glucagon expression was accompanied by a prominent increase in pancreatic islet size and β and α cell numbers. Older Dio2KO zebrafish also showed strongly decreased expression of glucagon receptors in the gastrointestinal system as well as decreased expression of glucose transporters GLUT2 and GLUT12, glucose-6-phosphatase, and glycogen synthase 2. This study shows that Dio2KO zebrafish suffer from transient hyperglycemia, which is counteracted with increasing age by a prominent hyperplasia of the endocrine pancreas together with decreases in hepatic glucagon sensitivity and intestinal glucose uptake. Further research on the mechanisms allowing compensation in older Dio2KO zebrafish may help to identify new therapeutic targets for ([[TH]] deficiency-related) hyperglycemia.
|mesh-terms=* Aging
* Animals
* Animals, Genetically Modified
* Glucose
* Glucose Transport Proteins, Facilitative
* Homeostasis
* Hyperglycemia
* Iodide Peroxidase
* Islets of Langerhans
* Male
* Proglucagon
* Proinsulin
* Receptor, Insulin
* Receptors, Glucagon
* Zebrafish

|full-text-url=https://sci-hub.do/10.1210/en.2019-00445
}}
{{medline-entry
|title=Age effect on thyroid hormone brain response in male mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31494803
|abstract=Thyroid hormones ([[TH]]) are important for brain development and central nervous system (CNS) function. Disturbances of thyroid function occur with higher prevalence in the ageing population and may negatively impact brain function. We investigated the age impact on behavior in young adult and old male mice (5 vs. 20 months) with chronic hypo- or hyper-thyroidism as well as in sham-treated controls. Expression of [[TH]] transporters and [[TH]] responsive genes was studied in CNS and pituitary by in situ hybridization and qRT-PCR, whereas [[TH]] serum concentrations were determined by immunoassay. Serum [[TH]] levels were lower in old compared with young hyperthyroid mice, suggesting a milder hyperthyroid phenotype in the aged group. Likewise, elevated plus maze activity was reduced in old hyperthyroid animals. Under hypothyroid conditions, thyroxine serum concentrations did not differ in young and old mice. Both groups showed a comparable decline in activity and elevated anxiety levels. However, an attenuated increase in hypothalamic thyrotropin releasing hormone and pituitary thyroid stimulating hormone transcript expression was found in old hypothyroid mice. Brain expression of monocarboxylate transporter 8 and organic anion transporting polypeptide 1c1 was not affected by age or [[TH]] status. In summary, ageing attenuates neurological phenotypes in hyperthyroid but not hypothyroid mice, which fits with age effects on [[TH]] serum levels in the animals. In contrast no changes in [[TH]] transporter expression were found in aged mouse brains with hyper- or hypo-thyroid state.
|mesh-terms=* Aging
* Animals
* Brain
* Gene Expression
* Hyperthyroidism
* Hypothyroidism
* Male
* Maze Learning
* Mice, Inbred C57BL
* Monocarboxylic Acid Transporters
* Organic Cation Transport Proteins
* Rotarod Performance Test
* Symporters
* Thyroid Hormones
* Thyrotropin
* Thyrotropin-Releasing Hormone
|keywords=* Ageing
* Hyperthyroidism
* Hypothyroidism
* Male mice
* Thyroid hormones
|full-text-url=https://sci-hub.do/10.1007/s12020-019-02078-6
}}
{{medline-entry
|title=Aging Is Associated with Low Thyroid State and Organ-Specific Sensitivity to Thyroxine.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31441387
|abstract= Serum thyroid state in older adults correlates with extended longevity. We hypothesized that age impacts not only systemic but also organ-specific thyroid state and response to thyroxine (T4).   Young (3 months) and old (23 months) male mice were analyzed at baseline and after acute T4 challenge. Age effects on circulating thyrotropin (TSH) and thyroid hormone ([[TH]]) concentrations, transcript expression in the pituitary and thyroid were compared with organ-specific responses characterized by hepatic and cardiac content of [[TH]] and [[TH]] metabolites and expression of [[TH]]-target genes, as well as hepatic deiodinase 1 activity.   Circulating [[TH]] concentrations and hepatic and cardiac [[TH]] content were lower in old versus young mice. After injection with T4, conversion of T4 to triiodothyronine was decreased in old mice while [[TH]] transport in liver and heart was not affected. Organ-specific [[TH]] response was augmented in old mice in liver but not heart, indicating age- and tissue-specific sensitivity to [[TH]]. A compensatory increase of [i]thyroid stimulating hormone subunit beta[/i] expression in the pituitary and increased serum TSH concentrations, but reduced expression of thyroid differentiation markers were found in old mice.   We suggest that a reduced activity of the aged thyroid is responsible for the systemic low [[TH]] state in old mice. Further, divergent [[TH]] metabolism and tissue response in liver and heart occur after T4 treatment in an aged organism. These rodent data are in agreement with a much narrower window for T4 substitution in the older adults to avoid overtreatment.
|mesh-terms=* Aging
* Animals
* DNA-Binding Proteins
* Hypothalamo-Hypophyseal System
* Liver
* Male
* Mice
* Mice, Inbred C57BL
* Myocardium
* Pituitary Gland
* Thyroid Gland
* Thyroid Hormones
* Thyrotropin
* Thyroxine
* Transcription Factors
|keywords=* HPT-axis
* aging
* mice
* thyroid gland
* thyroid hormones
|full-text-url=https://sci-hub.do/10.1089/thy.2018.0377
}}
==SOD2==

{{medline-entry
|title=Astaxanthin Counteracts Vascular Calcification In Vitro Through an Early Up-Regulation of [[SOD2]] Based on a Transcriptomic Approach.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33198315
|abstract=Vascular calcification (VC) is a critical contributor to the rising cardiovascular risk among at-risk populations such as those with diabetes or renal failure. The pathogenesis of VC involves an uprising of oxidative stress, for which antioxidants can be theoretically effective. However, astaxanthin, a potent antioxidant, has not been tested before for the purpose of managing VC. To answer this question, we tested the efficacy of astaxanthin against VC using the high phosphate (HP)-induced vascular smooth muscle cell (VSMC) calcification model. RNAs from treated groups underwent Affymetrix microarray screening, with intra-group consistency and inter-group differential expressions identified. Candidate hub genes were selected, followed by validation in experimental models and functional characterization. We showed that HP induced progressive calcification among treated VSMCs, while astaxanthin dose-responsively and time-dependently ameliorated calcification severities. Transcriptomic profiling revealed that 3491 genes exhibited significant early changes during VC progression, among which 26 potential hub genes were selected based on closeness ranking and biologic plausibility. [[SOD2]] was validated in the VSMC model, shown to drive the deactivation of cellular senescence and enhance antioxidative defenses. Astaxanthin did not alter intracellular reactive oxygen species (ROS) levels without HP, but significantly lowered ROS production in HP-treated VSMCs. [[SOD2]] knockdown prominently abolished the anti-calcification effect of astaxanthin on HP-treated VSMCs, lending support to our findings. In conclusion, we demonstrated for the first time that astaxanthin could be a potential candidate treatment for VC, through inducing the up-regulation of [[SOD2]] early during calcification progression and potentially suppressing vascular senescence.

|keywords=* aortic calcification
* astaxanthin
* chronic kidney disease
* chronic kidney disease-mineral bone disorder
* oxidative stress
* reactive oxygen species
* senescence
* vascular calcification
* vascular smooth muscle cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698184
}}
{{medline-entry
|title=Alginate Oligosaccharide Prevents against D-galactose-mediated Cataract in C57BL/6J Mice via Regulating Oxidative Stress and Antioxidant System.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33153341
|abstract=Alginate oligosaccharides (AOS), obtained from depolymerizing alginate, has multiple pharmacological benefits. Cataract is a common disease caused by turbidity of the lens protein due to lens metabolism disorders. This study aimed to test the effects and the underlying mechanisms of AOS on D-galactose (D-gal)-mediated cataract. A total of 45 8-week-old C57BL/6 J male mice were randomly divided into 5 groups. After eight weeks' intervention, the score of cataract was calculated depending on the turbidity of the lens. Hematoxylin and eosin (HE) and transmission electron microscope (TEM) images [i]were observed. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) level were measured by corresponding[/i] detection kits, respectively. SOD1, [[SOD2]], catalase (CAT) and p53 protein expressions were examined by Western blot. Nuclear factor erythroid-2 related factor (Nrf2) and heme oxygenase-1 (HO-1) mRNA expressions were examined by Quantitative Real Time-PCR (RT-qPCR). The score of the turbidity of the lens showed that AOS significantly delayed the cataractogenesis. HE staining and TEM imaging showed that AOS decreased the damage and senescence of lenses in D-gal-induced C57BL/6 J mice. We further detected aging marker p53 expression in crystalline lenses, and our result showed that AOS significantly inhibited p53 protein expression in D-gal-induced mice. In addition, SOD activity and MDA level detection results showed that AOS significantly increased the activity of SOD, and decreased the level of MDA in crystalline lenses homogenates of D-gal-induced aging mice. Western blot results showed that AOS attenuated the damage of D-gal in the protein expressions of antioxidative enzymes SOD1, [[SOD2]] and CAT. RT-qPCR results showed that AOS suppressed the down-regulation of Nrf2 and HO-1 mRNA expressions induced by D-gal. AOS prevents against D-gal-mediated cataract in C57BL/6 J mice via inhibiting oxidative stress and up-regulating antioxidant system. Consequently, our results suggest that AOS may be an effective therapeutic strategy against cataract.

|keywords=* Cataract
* D-galactose
* aging
* alginate oligosaccharide
* oxidative stress
|full-text-url=https://sci-hub.do/10.1080/02713683.2020.1842456
}}
{{medline-entry
|title=Protoflavones in melanoma therapy: Prooxidant and pro-senescence effect of protoapigenone and its synthetic alkyl derivative in A375 cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32931795
|abstract=In our study, the anticancer effects of a semisynthetic p-quinol, protoapigenone 1'-O-butyl ether (PABut), were tested in human melanoma A375 cells also in comparison with natural congener, protoapigenone (PA). The cytotoxic effect of PABut and PA was determined using MTT assay. Flow cytometry analysis was used to evaluate the influence of the compounds tested on ROS generation and cell cycle distribution in A375 cells. Moreover, apoptosis was evaluated by AO/EB dual staining as well as by flow cytometry. Markers of senescence were quantified by spectrofluorimetry and by Western blot analysis. Both PABut and PA showed significant cytotoxicity against melanoma A375 cells at sub-micromolar concentrations. Both protoflavones induced comparable cell cycle arrest in G2/M phase. However, a more profound upregulation of intracellular ROS levels was found following PABut treatment. An increased apoptosis in the cells following 48 h treatment with both protoflavones tested was also confirmed. Both compounds tested remarkably upregulated p21 protein levels in A375 cells. Unlike PA, PABut significantly decreased protein levels of NAD -dependent deacetylase SirT1 and β-actin accompanied by mild significant upregulation of mitochondrial [[SOD2]] and senescence markers, p16 protein and SA-β-Gal activity. However, a significant upregulation of p53 only following PA treatment was found. These results suggest that PABut and PA confer high chemotherapeutic potential in melanoma cells and are suitable for further testing. Furthermore, modification of protoapigenone with 1'-O-butyl ether moiety can be associated with improved senescence-inducing effect and, thus, enhanced chemotherapeutic potency of PABut compared to the unmodified natural protoflavone.
|mesh-terms=* Antineoplastic Agents, Phytogenic
* Autophagy
* Biomarkers
* Cell Cycle
* Cell Line, Tumor
* Cellular Senescence
* Cyclohexanones
* Flavones
* Humans
* Melanoma
* Reactive Oxygen Species
* Superoxide Dismutase
* beta-Galactosidase
|keywords=* Alkyl protoflavone
* Flavonoid
* Melanoma
* Protoapigenone
* Semi-synthesis
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.118419
}}
{{medline-entry
|title=Ginsenoside Rg1 protects against Sca-1  HSC/HPC cell aging by regulating the SIRT1-FOXO3 and SIRT3-[[SOD2]] signaling pathways in a γ-ray irradiation-induced aging mice model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32765665
|abstract=Aging is characterized by a progressive deterioration in metabolic functions. The present study aimed to investigate the antagonistic effects of ginsenoside Rg1 (Rg1) on the γ-ray irradiation-induced aging of mixed hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs). C57BL/6 mice were divided into a control group, a γ-ray irradiation group that served as an aging mouse model, and an Rg1 group. The Rg1 group was treated with Rg1 at dosage of 20 mg/kg/day for 7 days prior to γ-ray irradiation. The aging mouse model was established by exposing the mice to 6.5-Gy γ-ray total-body irradiation. Stem cell antigen 1 positive (Sca-1 ) HSC/HPCs isolated from the mice were examined using a senescence-associated β-galactosidase (SA-β-Gal) staining assay. The cell cycle of the HSC/HPCs was examined using flow cytometry. A mixed hematopoietic progenitor cell colony-forming unit (CFU-mix) assay was also conducted. The mRNA and protein expression levels of sirtuin 1 (SIRT1), SIRT3, forkhead box O3 (FOXO3) and superoxide dismutase ([[SOD2]]) were evaluated using western blot and reverse transcription-quantitative PCR assays. The results indicated that Rg1 treatment significantly increased white blood cell, red blood cell and platelet counts in peripheral blood compared with those in the γ-ray irradiation group (P<0.05). However, Rg1 significantly attenuated the senescence of Sca-1  HSC/HPCs in the γ-ray irradiation aging mice model. The proportion of SA-β-Gal stained HSC/HPCs was significantly decreased and CFU-Mix counts were significantly increased in the Rg1 group compared with the γ-ray irradiation group (P<0.05). Rg1 significantly increased the mRNA and protein levels of SIRT1, SIRT3, FOXO3 and [[SOD2]] in the Sca-1  HSC/HPCs compared with those in the γ-ray irradiation group (P<0.05). The percentage of Sca-1  HSC/HPCs arrested at the G1 phase in the Rg1 group was significantly decreased compared with that in the γ-ray irradiation group (P<0.05). In conclusion, the present study indicates that Rg1 exerts anti-aging effects via the regulation of SIRT1-FOXO3 and SIRT3-[[SOD2]] signaling pathways, and triggering the progression of Sca-1  HSC/HPCs from the G1 phase to the S phase in γ-ray irradiation-induced aging mice.

|keywords=* SIRT1
* SIRT3
* aging
* ginsenoside Rg1
* hematopoietic progenitor cells
* hematopoietic stem cells
* senescence
* γ-ray irradiation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388550
}}
{{medline-entry
|title=Almond Skin Extracts and Chlorogenic Acid Delay Chronological Aging and Enhanced Oxidative Stress Response in Yeast.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32481725
|abstract=Almond ([i]Prunus dulcis[/i] (Mill.) D.A.Webb) is one of the largest nut crops in the world. Recently, phenolic compounds, mostly stored in almond skin, have been associated with much of the health-promoting behavior associated with their intake. The almond skin enriched fraction obtained from cold-pressed oil residues of the endemic Moroccan [i]Beldi[/i] ecotypes is particularly rich in chlorogenic acid. In this study, both almond skin extract (AE) and chlorogenic acid (CHL) supplements, similar to traditional positive control resveratrol, significantly increased the chronological life-span of yeast compared to the untreated group. Our results showed that AE and CHL significantly reduced the production of reactive oxygen and nitrogen species (ROS/RNS), most likely due to their ability to maintain mitochondrial function during aging, as indicated by the maintenance of normal mitochondrial membrane potential in treated groups. This may be associated with the observed activation of the anti-oxidative stress response in treated yeast, which results in activation at both gene expression and enzymatic activity levels for [[SOD2]] and SIR2, the latter being an upstream inducer of [i][[SOD2]][/i] expression. Interestingly, the differential gene expression induction of mitochondrial [i][[SOD2]][/i] gene at the expense of the cytosolic [i]SOD1[/i] gene confirms the key role of mitochondrial function in this regulation. Furthermore, AE and CHL have contributed to the survival of yeast under UV-C-induced oxidative stress, by reducing the development of ROS/RNS, resulting in a significant reduction in cellular oxidative damage, as evidenced by decreased membrane lipid peroxidation, protein carbonyl content and 8-oxo-guanine formation in DNA. Together, these results demonstrate the interest of AE and CHL as new regulators in the chronological life-span and control of the oxidative stress response of yeast.

|keywords=* 8-Oxo-guanine
* aging
* almond
* chlorogenic acid
* lipid peroxidation
* mitochondria
* oxidative stress
* protein carbonylation
* sirtuin
* superoxide dismutase
* yeast
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345664
}}
{{medline-entry
|title=Opposing p53 and mTOR/AKT promote an in vivo switch from apoptosis to senescence upon telomere shortening in zebrafish.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32427102
|abstract=Progressive telomere shortening during lifespan is associated with restriction of cell proliferation, genome instability and aging. Apoptosis and senescence are the two major outcomes upon irreversible cellular damage. Here, we show a transition of these two cell fates during aging of telomerase deficient zebrafish. In young telomerase mutants, proliferative tissues exhibit DNA damage and p53-dependent apoptosis, but no senescence. However, these tissues in older animals display loss of cellularity and senescence becomes predominant. Tissue alterations are accompanied by a pro-proliferative stimulus mediated by AKT signaling. Upon AKT activation, FoxO transcription factors are phosphorylated and translocated out of the nucleus. This results in reduced [[SOD2]] expression causing an increase of ROS and mitochondrial dysfunction. These alterations induce p15/16 growth arrest and senescence. We propose that, upon telomere shortening, early apoptosis leads to cell depletion and insufficient compensatory proliferation. Following tissue damage, the mTOR/AKT is activated causing mitochondrial dysfunction and p15/16-dependent senescence.

|keywords=* AKT
* aging
* apoptosis
* cell biology
* p53
* regenerative medicine
* senescence
* stem cells
* telomeres
* zebrafish
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237213
}}
{{medline-entry
|title=Bioactive peptides derived from crimson snapper and in vivo anti-aging effects on fat diet-induced high fat Drosophila melanogaster.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31844865
|abstract=Crimson snapper is an important marine economy fish, and its scales are rich in collagen. Crimson snapper scale peptides (CSSPs) obtained from crimson snapper scales by enzymatic hydrolysis exhibited significantly antioxidant activities to DPPH, ABTS and hydroxyl radicals in vitro. In vivo antioxidant and anti-aging effects of CSSPs on the Drosophila melanogaster aging model constructed by lard were investigated in this study. The results showed that CSSPs could prolong the mean lifespan, 50% survival days and the maximum lifespan of Drosophila, and especially when the concentration of CSSPs was increased to 6 mg mL-1, the mean lifespan of male and female Drosophila increased by 21.2% and 26.2%, respectively, indicating the effective life extension effect of CSSPs. Meanwhile, the addition of CSSPs effectively reduced the contents of malondialdehyde (MDA) and protein carbonylation (PCO) and increased the levels of total superoxide dismutase (T-SOD) and catalase (CAT) in Drosophila, which showed a significant dose dependence. Besides, the antioxidant-related genes SOD1, [[SOD2]] and CAT were up-regulated in Drosophila when fed with diets containing CSSPs. In conclusion, CSSPs played an antioxidant and anti-aging role by reducing the accumulation of peroxide products and improving the activity of antioxidant enzymes, as well as by up-regulating the expression of antioxidant-related genes. The results suggest that CSSPs have potential to be used in the food and healthcare industries as potential food-borne antioxidant and anti-aging agents.
|mesh-terms=* Aging
* Animal Scales
* Animals
* Catalase
* Diet, High-Fat
* Disease Models, Animal
* Drosophila Proteins
* Drosophila melanogaster
* Female
* Fish Proteins
* Fishes
* Humans
* Longevity
* Male
* Malondialdehyde
* Oxidative Stress
* Peptides
* Superoxide Dismutase

|full-text-url=https://sci-hub.do/10.1039/c9fo01414d
}}
{{medline-entry
|title=Ellagic acid prolongs the lifespan of Drosophila melanogaster.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31786733
|abstract=Wild-type Canton-S flies of Drosophila melanogaster were treated with ellagic acid at 100 μM and 200 μM concentrations. Longevity assay showed male flies fed with 200 μM ellagic acid displayed longer mean lifespan and maximum lifespan than control flies. Female flies fed with 200 μM ellagic acid laid less number of eggs than control. The eclosion time was less in female flies fed with 200 μM ellagic acid. Ellagic acid fed female flies performed better than male flies and control flies for heat shock tolerance and starvation stress. Male flies treated with 100 μM ellagic acid recovered faster from cold shock compared with control flies. Male and female flies treated with ellagic acid displayed increased survival following exposure to 5% hydrogen peroxide. Gene expression studies displayed upregulated expressions of CAT, dFOXO, ATG1, and [[SOD2]] in ellagic acid-treated male flies, and upregulated expressions of dFOXO, CAT, and [[SOD2]] in ellagic acid-treated female flies. Results from these studies show the pro-longevity effect of ellagic acid on Drosophila melanogaster.

|keywords=* Drosophila melanogaster
* Ellagic acid
* Gene expression
* Longevity
* Stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031466
}}
{{medline-entry
|title=Chlorella vulgaris modulates the expression of senescence-associated genes in replicative senescence of human diploid fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31642042
|abstract=Human diploid fibroblasts (HDFs) cultured in vitro have limited capacity to proliferate after population doubling is repeated several times, and they enter into a state known as replicative senescence or cellular senescence. This study aimed to investigate the effect of Chlorella vulgaris on the replicative senescence of HDFs by determining the expression of senescence-associated genes. Young and senescent HDFs were divided into untreated control and C. vulgaris-treated groups. A senescence-associated gene transcription analysis was carried out with qRT-PCR. Treatment of young HDFs with C. vulgaris reduced the expression of SOD1, CAT and CCS (p < 0.05). In addition, the expression of the [[SOD2]] gene was increased with C. vulgaris treatment in young, pre-senescent and senescent HDFs (p < 0.05). Treatment of senescent HDFs with C. vulgaris resulted in the downregulation of TP53 gene expression. The expression of the CDKN2A gene was significantly decreased upon C. vulgaris treatment in young and senescent HDFs. C. vulgaris treatment was also found to significantly upregulate the expression of the MAPK14 gene in pre-senescent HDFs. In addition, the expression of MAPK14 was significantly upregulated compared to that in the untreated senescent HDFs (p < 0.05). In summary, the expression of senescence-associated genes related to antioxidants and the insulin/insulin-like growth factor-1 signalling, DNA damage-associated signalling, cell differentiation and cell proliferation pathways was modulated by C. vulgaris during replicative senescence of human diploid fibroblasts.
|mesh-terms=* Antioxidants
* Catalase
* Cell Differentiation
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Chlorella vulgaris
* DNA Damage
* Diploidy
* Fibroblasts
* Gene Expression
* Genes, p53
* Humans
* Male
* Mitogen-Activated Protein Kinase 14
* Molecular Chaperones
* Primary Cell Culture
* Signal Transduction
* Superoxide Dismutase
* Superoxide Dismutase-1
|keywords=* Chlorella vulgaris
* Fibroblasts
* Replicative senescence
* Senescence-associated genes
|full-text-url=https://sci-hub.do/10.1007/s11033-019-05140-8
}}
{{medline-entry
|title=Age-Associated Changes in Antioxidants and Redox Proteins of Rat Heart.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31647296
|abstract=Oxidative stress and decline in cellular redox regulation have been hypothesized to play a key role in cardiovascular aging; however, data on antioxidant and redox regulating systems in the aging heart are controversial. The aim of the present study was to examine the effect of aging on critical antioxidant enzymes and two major redox-regulatory systems glutathione (GSH) and thioredoxin (Trx) system in hearts from adult (6-month-old), old (15-month-old), and senescent (26-month-old) rats. Aging was associated with a non-uniform array of changes, including decline in contents of reduced GSH and total mercaptans in the senescent heart. The activities of Mn-superoxide dismutase ([[SOD2]]), glutathione peroxidase (GPx), glutathione reductase (GR), and thioredoxin reductase (TrxR) exhibited an age-related decline, whereas catalase was unchanged and Cu,Zn-superoxide dismutase (SOD1) displayed only slight decrease in old heart and was unchanged in the senescent heart. GR, Trx, and peroxiredoxin levels were significantly reduced in old and/or senescent hearts, indicating a diminished expression of these proteins. In contrast, [[SOD2]] level was unchanged in the old heart and was slightly elevated in the senescent heart. Decline in GPx activity was accompanied by a loss of GPx level only in old rats, the level in senescent heart was unchanged. These results indicate age-related posttranslational protein modification of [[SOD2]] and GPx. In summary, our data suggest that changes are more pronounced in senescent than in old rat hearts and support the view that aging is associated with disturbed redox balance that could alter cellular signaling and regulation.
|mesh-terms=* Aging
* Animals
* Antioxidants
* Glutathione Peroxidase
* Male
* Myocardium
* Oxidation-Reduction
* Rats
* Rats, Wistar
* Superoxide Dismutase

|full-text-url=https://sci-hub.do/10.33549/physiolres.934170
}}
{{medline-entry
|title=Impact of curcumin on replicative and chronological aging in the Saccharomyces cerevisiae yeast.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31659616
|abstract=Curcumin is a biologically active compound of vegetable origin which has a hormetic effect. Pro-health and anti-aging properties of curcumin have been known for years. The main benefit of curcumin is thought to be its anti-oxidative action. Despite vast amount of data confirming age-delaying activity of curcumin in various groups of organisms, so far little has been discovered about curcumin's impact on cell aging in the experimental model of the Saccharomyces cerevisiae budding yeast. We have been able to demonstrate that curcumin significantly increases oxidative stress and accelerates replicative and chronological aging of yeast cells devoid of anti-oxidative protection (with SOD1 and [[SOD2]] gene deletion) and deprived of DNA repair mechanisms (RAD52). Interestingly, curcumin delays aging, probably through hormesis, of the wild-type strain BY4741.

|keywords=* Aging
* Curcumin
* Hypertrophy
* Oxidative stress
* Yeast
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942599
}}
==MB==

{{medline-entry
|title=Probing menstrual bloodstain aging with fluorescence spectroscopy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33279406
|abstract=Menstrual blood ([[MB]]) is a common and important type of forensic evidence, especially in sexual assault cases. [[MB]] is composed of peripheral blood (PB), vaginal fluid, and endometrial cells of the uterine wall. In forensic investigations, the differentiation of [[MB]] and PB can determine whether the blood present is a result of tissue damage from an assault or a natural cause and thus help to reconstruct the event. Understanding how menstrual blood changes is necessary to develop a method for bloodstain aging. Fluorescence spectroscopy, a promising spectroscopic method for bloodstain analysis, was used to probe the biochemical changes that occur over time in menstrual bloodstains. It was found that steady-state fluorescence spectra underwent significant changes over first nine hours post deposition. The underlying mechanism of fluorescence changes was proposed to involve the kinetic transformation of three fluorophores: tryptophan, nicotinamide adenine dinucleotide and flavins.

|keywords=* Aging
* Analytical methods
* Blood
* Fluorescence spectroscopy
* Forensics
|full-text-url=https://sci-hub.do/10.1016/j.saa.2020.119172
}}
{{medline-entry
|title=Effect of physical exercise and medication on enhancing cognitive function in older adults with vascular risk.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32989840
|abstract=To examine the association of physical exercise (PE) and medication on cognitive function in older adults with vascular risk. This was a cross-sectional study of 478 non-demented participants aged ≥60 years with vascular risk. Management strategy included PE (mind-body exercise and/or strenuous exercise), medication, PE combined with medication and no management at all. Participation of PE was determined by self-reporting exercise engagement in the past year. Cognitive preservation was defined as a global composite z-score that was equal to or above the age and educational adjusted mean of cognitively normal older adults. Binary logistic regression was carried out to examine the association between management strategy and cognitive preservation in each exercise modality adjusted by sociodemographic, physical, mental and genetic factors. An association was found in preserved cognitive function for those who managed their vascular risk through PE (OR 2.5, 95% CI 1.2-5.3, P = 0.015) and in combination with medication (OR 2.1, 95% CI 1.0-4.6, P = 0.05). A similar pattern was also found in each exercise subtype. A significant short-term (OR 3.6, 95% CI 1.0-12.4, P = 0.042) to lifelong (OR 3.5, 95% CI 1.4-8.5, P = 0.006) cognitive benefit was found in [[MB]] exercise. Medication alone may be insufficient to preserve cognitive function in older adults with vascular risk. In our sample, medication in combined with PE is found to have significant impact on cognitive improvement. Mind-body exercise might be better than strenuous exercise, as a more sustainable cognitive effect is observed. Geriatr Gerontol Int 2020; 20: 1067-1071..
|mesh-terms=* Aged
* Aged, 80 and over
* Cognition
* Cross-Sectional Studies
* Exercise
* Exercise Therapy
* Female
* Humans
* Male
* Middle Aged
* Risk Factors
* Vascular Diseases
|keywords=* active aging
* cognitive preservation
* exercise habit
* lifestyle advice
* vascular care
|full-text-url=https://sci-hub.do/10.1111/ggi.14048
}}
{{medline-entry
|title=A novel indenone derivative selectively induces senescence in MDA-[[MB]]-231 (breast adenocarcinoma) cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32956706
|abstract=Triple-negative breast cancer is the most aggressive form of breast cancer with limited intervention options. Moreover, a number of belligerent therapeutic strategies adopted to treat such aggressive forms of cancer have demonstrated detrimental side effects. This necessitates exploration of targeted chemotherapeutics. We assessed the efficacy of a novel indenone derivative (nID) [(±)-N-(2-(-5-methoxy-1-oxo-3-(2-oxo-2-phenylethyl)-2,3-dihydro-1H-inden-2-yl)ethyl)-4-methylbenzenesulfonamide], synthesized by a novel internal nucleophile-assisted palladium-catalyzed hydration-olefin insertion cascade; against triple-negative breast cancer cells (MDA-[[MB]]-231). On 24 h treatment, the nID caused decline in the viability of MDA-[[MB]]-231 and MDA-[[MB]]-468 cells, but did not significantly (P < 0.05) affect WRL-68 (epithelial-like) cells. In fact, the nID demonstrated augmentation of p53 expression, and consequent p53-dependent senescence in both MDA-[[MB]]-231 and MDA-[[MB]]-468 cells, but not in WRL-68 cells. The breast cancer cells also exhibited reduced proliferation, downregulated p65/NF-κB and survivin, along with augmented p21  expression, on treatment with the nID. This ensued cell cycle arrest at G1 stage, which might have driven the MDA-[[MB]]-231 cells to senescence. We observed a selectivity of the nID to target MDA-[[MB]]-231 cells, whereas WRL-68 cells did not show any considerable effect. The results underscored that the nID has potential to be developed into a cancer therapeutic.
|mesh-terms=* Antineoplastic Agents
* Breast Neoplasms
* Catalysis
* Cell Line, Tumor
* Cell Survival
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Down-Regulation
* Female
* G1 Phase Cell Cycle Checkpoints
* Humans
* Palladium
* Sulfonamides
* Survivin
* Tumor Suppressor Protein p53
* Up-Regulation
|keywords=* Cell cycle arrest
* Novel indenone derivative
* Senescence
* Triple-negative breast cancer
|full-text-url=https://sci-hub.do/10.1016/j.cbi.2020.109250
}}
{{medline-entry
|title=Improved Autophagic Flux in Escapers from Doxorubicin-Induced Senescence/Polyploidy of Breast Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32846959
|abstract=The induction of senescence/polyploidization and their role in cancer recurrence is still a poorly explored issue. We showed that MDA-[[MB]]-231 and MCF-7 breast cancer cells underwent reversible senescence/polyploidization upon pulse treatment with doxorubicin (dox). Subsequently, senescent/polyploid cells produced progeny (escapers) that possessed the same amount of DNA as parental cells. In a dox-induced senescence/polyploidization state, the accumulation of autophagy protein markers, such as LC3B II and p62/SQSTM1, was observed. However, the senescent cells were characterized by a very low rate of new autophagosome formation and degradation, estimated by autophagic index. In contrast to senescent cells, escapers had a substantially increased autophagic index and transcription factor EB activation, but a decreased level of an autophagy inhibitor, Rubicon, and autophagic vesicles with non-degraded cargo. These results strongly suggested that autophagy in escapers was improved, especially in MDA-[[MB]]-231 cells. The escapers of both cell lines were also susceptible to dox-induced senescence. However, MDA-[[MB]]-231 cells which escaped from senescence were characterized by a lower number of γH2AX foci and a different pattern of interleukin synthesis than senescent cells. Thus, our studies showed that breast cancer cells can undergo senescence uncoupled from autophagy status, but autophagic flux resumption may be indispensable in cancer cell escape from senescence/polyploidy.

|keywords=* DNA damage
* Rubicon
* SQSTM1/p62
* TFEB
* autophagic index
* autophagy
* cancer
* polyploidy
* senescence
* senescence escape
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504443
}}
{{medline-entry
|title=Lifespan regulation in α/β posterior neurons of the fly mushroom bodies by Rab27.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32627932
|abstract=Brain function has been implicated to control the aging process and modulate lifespan. However, continuous efforts remain for the identification of the minimal sufficient brain region and the underlying mechanism for neuronal regulation of longevity. Here, we show that the Drosophila lifespan is modulated by rab27 functioning in a small subset of neurons of the mushroom bodies ([[MB]]), a brain structure that shares analogous functions with mammalian hippocampus and hypothalamus. Depleting rab27 in the α/βp neurons of the [[MB]] is sufficient to extend lifespan, enhance systemic stress responses, and alter energy homeostasis, all without trade-offs in major life functions. Within the α/βp neurons, rab27KO causes the mislocalization of phosphorylated S6K thus attenuates TOR signaling, resulting in decreased protein synthesis and reduced neuronal activity. Consistently, expression of dominant-negative S6K in the α/βp neurons increases lifespan. Furthermore, the expression of phospho-mimetic S6 in α/βp neurons of rab27KO rescued local protein synthesis and reversed lifespan extension. These findings demonstrate that inhibiting TOR-mediated protein synthesis in α/βp neurons is sufficient to promote longevity.

|keywords=* Drosophila
* Rab27
* S6K
* TOR
* lifespan extension
* mushroom body
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431830
}}
{{medline-entry
|title=Tailored Functionalized Magnetic Nanoparticles to Target Breast Cancer Cells Including Cancer Stem-Like Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32485849
|abstract=Nanotechnology-based approaches hold substantial potential to avoid chemoresistance and minimize side effects. In this work, we have used biocompatible iron oxide magnetic nanoparticles (MNPs) called MF66 and functionalized with the antineoplastic drug doxorubicin (DOX) against MDA-[[MB]]-231 cells. Electrostatically functionalized MNPs showed effective uptake and DOX linked to MNPs was more efficiently retained inside the cells than free DOX, leading to cell inactivation by mitotic catastrophe, senescence and apoptosis. Both effects, uptake and cytotoxicity, were demonstrated by different assays and videomicroscopy techniques. Likewise, covalently functionalized MNPs using three different linkers-disulfide (DOX-S-S-Pyr, called MF66-S-S-DOX), imine (DOX-I-Mal, called MF66-I-DOX) or both (DOX-I-S-S-Pyr, called MF66-S-S-I-DOX)-were also analysed. The highest cell death was detected using a linker sensitive to both pH and reducing environment (DOX-I-S-S-Pyr). The greatest success of this study was to detect also their activity against breast cancer stem-like cells (CSC) from MDA-[[MB]]-231 and primary breast cancer cells derived from a patient with a similar genetic profile (triple-negative breast cancer). In summary, these nanoformulations are promising tools as therapeutic agent vehicles, due to their ability to produce efficient internalization, drug delivery, and cancer cell inactivation, even in cancer stem-like cells (CSCs) from patients.

|keywords=* apoptosis
* cancer stem-like cells
* doxorubicin
* magnetic iron oxide nanoparticles
* mitotic catastrophe
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352336
}}
{{medline-entry
|title="Mitotic Slippage" and Extranuclear DNA in Cancer Chemoresistance: A Focus on Telomeres.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32316332
|abstract=Mitotic slippage (MS), the incomplete mitosis that results in a doubled genome in interphase, is a typical response of [i]TP53[/i]-mutant tumors resistant to genotoxic therapy. These polyploidized cells display premature senescence and sort the damaged DNA into the cytoplasm. In this study, we explored MS in the MDA-[[MB]]-231 cell line treated with doxorubicin (DOX). We found selective release into the cytoplasm of telomere fragments enriched in telomerase reverse transcriptase (hTERT), telomere capping protein TRF2, and DNA double-strand breaks marked by γH2AX, in association with ubiquitin-binding protein SQSTM1/p62. This occurs along with the alternative lengthening of telomeres (ALT) and DNA repair by homologous recombination (HR) in the nuclear promyelocytic leukemia (PML) bodies. The cells in repeated MS cycles activate meiotic genes and display holocentric chromosomes characteristic for inverted meiosis (IM). These giant cells acquire an amoeboid phenotype and finally bud the depolyploidized progeny, restarting the mitotic cycling. We suggest the reversible conversion of the telomerase-driven telomere maintenance into ALT coupled with IM at the sub-telomere breakage sites introduced by meiotic nuclease SPO11. All three MS mechanisms converging at telomeres recapitulate the amoeba-like agamic life-cycle, decreasing the mutagenic load and enabling the recovery of recombined, reduced progeny for return into the mitotic cycle.

|keywords=* ALT
* SQSTM1/p62
* amoeboid conversion
* budding of mitotic progeny
* cellular senescence
* extranuclear DNA
* genotoxic treatment
* inverted meiosis
* mtTP53 cancer
* polyploidization
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215480
}}
{{medline-entry
|title=Diversity of the Senescence Phenotype of Cancer Cells Treated with Chemotherapeutic Agents.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31771226
|abstract=It is acknowledged that cancer cells are able to undergo senescence in response to clinically used chemotherapeutics. Moreover, recent years have provided evidence that some drugs can selectively remove senescent cells. Therefore, it is essential to properly identify and characterize senescent cells, especially when it comes to cancer. Senescence was induced in various cancer cell lines (A549, SH-SY-5Y, HCT116, MDA-[[MB]]-231, and MCF-7) following treatment with doxorubicin, irinotecan, methotrexate, 5-fluorouracil, oxaliplatin, or paclitaxel. Treatment with tested chemotherapeutics resulted in upregulation of p21 and proliferation arrest without cytotoxicity. A comparative analysis with the use of common senescence markers (i.e., morphology, SA-β-galactosidase, granularity, secretory phenotype, and the level of double-stranded DNA damage) revealed a large diversity in response to the chemotherapeutics used. The strongest senescence inducers were doxorubicin, irinotecan, and methotrexate; paclitaxel had an intermediate effect and oxaliplatin and 5-fluorouracil did not induce senescence. In addition, different susceptibility of cancer cells to senescence was observed. A statistical analysis aimed at finding any relationship between the senescence markers applied did not show clear correlations. Moreover, increased SA-β-gal activity coupled with p21 expression proved not to be an unequivocal senescence marker. This points to a need to simultaneously analyze multiple markers, given their individual limitations.
|mesh-terms=* Antineoplastic Agents
* Cell Proliferation
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* Doxorubicin
* Fluorouracil
* Humans
* Irinotecan
* Methotrexate
* Neoplasms
* Oxaliplatin
* Paclitaxel
* Phenotype
* Tumor Cells, Cultured
|keywords=* DNA damage
* SASP
* cancer
* chemotherapy
* senescence
* senescence markers
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952928
}}
{{medline-entry
|title=Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long-lived and cancer-resistant subterranean wild rodent, Spalax.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31605433
|abstract=The blind mole rat (Spalax) is a wild, long-lived rodent that has evolved mechanisms to tolerate hypoxia and resist cancer. Previously, we demonstrated high DNA repair capacity and low DNA damage in Spalax fibroblasts following genotoxic stress compared with rats. Since the acquisition of senescence-associated secretory phenotype (SASP) is a consequence of persistent DNA damage, we investigated whether cellular senescence in Spalax is accompanied by an inflammatory response. Spalax fibroblasts undergo replicative senescence (RS) and etoposide-induced senescence (EIS), evidenced by an increased activity of senescence-associated beta-galactosidase (SA-β-Gal), growth arrest, and overexpression of p21, p16, and p53 mRNAs. Yet, unlike mouse and human fibroblasts, RS and EIS Spalax cells showed undetectable or decreased expression of the well-known SASP factors: interleukin-6 (IL6), IL8, IL1α, growth-related oncogene alpha (GROα), SerpinB2, and intercellular adhesion molecule (ICAM-1). Apparently, due to the efficient DNA repair in Spalax, senescent cells did not accumulate the DNA damage necessary for SASP activation. Conversely, Spalax can maintain DNA integrity during replicative or moderate genotoxic stress and limit pro-inflammatory secretion. However, exposure to the conditioned medium of breast cancer cells MDA-[[MB]]-231 resulted in an increase in DNA damage, activation of the nuclear factor κB (NF-κB) through nuclear translocation, and expression of inflammatory mediators in RS Spalax cells. Evaluation of SASP in aging Spalax brain and intestine confirmed downregulation of inflammatory-related genes. These findings suggest a natural mechanism for alleviating the inflammatory response during cellular senescence and aging in Spalax, which can prevent age-related chronic inflammation supporting healthy aging and longevity.

|keywords=* 
Spalax

* DNA damage
* DNA repair
* cellular senescence
* interleukin-1 alpha (IL1α)
* nuclear factor κB (NF-κB)
* senescence-associated secretory phenotype (SASP)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974727
}}
{{medline-entry
|title=Quantification of the health-status of the Dutch Labrador retriever population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31494529
|abstract=Health issues in purebred dogs are currently considered one of the biggest problems in companion animal health. The Labrador retriever (LR) is one of the most popular dog breeds. The aim of this study was to quantify LR breed health in comparison with mixed-breed dogs ([[MB]]), by using four different data sources: a veterinary practice management system (appr. 35,000 unique individuals LR + [[MB]]), data from two animal insurance companies (appr. 15,500 and 4500 individuals respectively), and a histopathological laboratory (appr. 4000 individuals). After extensive recoding of the data, health parameters utilised to quantify breed health were longevity, frequency of practice visits and insurance expense claims, and diagnostic codes. A Kaplan-Meier univariate and multivariable Cox proportional hazard model were used to evaluate longevity. A negative binomial model was used to analyse the frequency of visits, claims, and diagnostic codes in both sets of insurance data. Logistic regression was used to look into the categorical diagnostic codes in the laboratory data. The median lifespan of the LR was similar (12 years, practice data) or longer (10 versus 8 years, insurance data) than [[MB]] for individuals with a known birth and death date. When including censored individuals, survival time in the LR was comparable to [[MB]] individuals up to 10 years of age. Above 10 years of age, the LR lived a similar length as [[MB]] with a medium to large body size, but shorter than all [[MB]]. The LR visited the veterinary practice more often (risk ratio (RR) 1.2, 95% confidence interval 1.2-1.3), and also showed a higher frequency of insurance expense claims (RR 2.2 (2.1-2.3) and RR 1.2 (1.1-1.3) respectively for the two insurance data sets). The largest difference in organ systems between the LR and [[MB]] in insurance claims was related to ears (RR 5.3 (4.8-5.8) and RR 2.6 (2.3-3.1)), followed by airways (RR 2.6 (2.4-2.8)), tendons & muscles (RR 2.4 (2.2-2.6) and RR 1.4 (1.1-1.7)), and joints (RR 1.7 (1.3-2.1)), without a difference in median age at diagnosis. The data from the histopathological laboratory suggested a higher disease burden related to oncology for the LR compared to [[MB]] (OR 1.2, 95% CI 1.0-1.3). Oncological diagnoses were made at a younger age in the LR (8.8 versus 9.4 years). The disease burden was significantly higher for the LR than [[MB]], but these results may suffer from substantial bias such as selection bias towards the database, and different behaviour of LR versus [[MB]] owners with regards to veterinary care. In the future, longer term population data can corroborate these results.
|mesh-terms=* Animals
* Dog Diseases
* Dogs
* Female
* Health Status
* Insurance
* Laboratories
* Longevity
* Male
* Netherlands
* Proportional Hazards Models
* Risk Factors
|keywords=* Canine health
* Data analysis
* Health parameters
* Labrador retriever
* Lifespan
* Oncology
|full-text-url=https://sci-hub.do/10.1016/j.prevetmed.2019.104764
}}
{{medline-entry
|title=Conjugated Physiological Resveratrol Metabolites Induce Senescence in Breast Cancer Cells: Role of p53/p21 and p16/Rb Pathways, and ABC Transporters.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31441212
|abstract=Recent evidence demonstrates that resveratrol (RSV) metabolites, but not free RSV, reach malignant tumors (MT) in breast cancer (BC) patients. Since these metabolites, as detected in MT, do not exert short-term antiproliferative or estrogenic/antiestrogenic activities, long-term tumor-senescent chemoprevention has been hypothesized. Consequently, here, for the first time, whether physiologically relevant RSV metabolites can induce senescence in BC cells is investigated. Human BC MCF-7 (wild-type p53) and MDA-[[MB]]-231 (mutant p53), and non-tumorigenic MCF-10A cells are treated with free RSV and physiological-derived metabolites (RSV 3-O-glucuronide, RSV 3-O-sulfate, RSV 4'-O-sulfate, dihydroresveratrol (DH-RSV), and DH-RSV 3-Oglucuronide). Cellular senescence is measured by SA-β-gal activity and senescence-associated markers (p53, p21  , p16  , and phosphorylation status of retinoblastoma (pRb/tRb)). Although no effect is observed in MDA-[[MB]]-231 and normal cells, RSV metabolites induce cellular senescence in MCF-7 cells by reducing their clonogenic capacity and arresting cell cycle at G  M/S phase, but do not induce apoptosis. Senescence is induced through the p53/p21  and p16  /Rb pathways, depending on the RSV metabolite, and requires ABC transporters, but not estrogen receptors. These data suggest that RSV metabolites, as found in MT from BC patients, are not de-conjugated to release free RSV, but enter the cells and may exert long-term tumor-senescent chemoprevention.
|mesh-terms=* ATP-Binding Cassette Transporters
* Breast Neoplasms
* Cell Cycle Checkpoints
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Female
* Glucuronides
* Humans
* MCF-7 Cells
* Resveratrol
* Retinoblastoma Protein
* Signal Transduction
* Stilbenes
* Tumor Suppressor Protein p53
|keywords=* ABC transporters
* breast cancer
* deconjugation
* resveratrol metabolites
* senescence
|full-text-url=https://sci-hub.do/10.1002/mnfr.201900629
}}
==PC==

{{medline-entry
|title=Blended home-based exercise and dietary protein in community-dwelling older adults: a cluster randomized controlled trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33103379
|abstract=Effective and sustainable interventions are needed to counteract the decline in physical function and sarcopenia in the growing aging population. The aim of this study was to determine the 6 and 12 month effectiveness of blended (e-health + coaching) home-based exercise and a dietary protein intervention on physical performance in community-dwelling older adults. This cluster randomized controlled trial allocated 45 clusters of older adults already engaged in a weekly community-based exercise programme. The clusters were randomized to three groups with ratio of 16:15:14; (i) no intervention, control (CON); (ii) blended home-based exercise intervention (HBex); and (iii) HBex with dietary protein counselling (HBex-Pro). Both interventions used a tablet [[PC]] with app and personalized coaching and were targeting on behaviour change. The study comprised coached 6 month interventions with a 6 month follow-up. The primary outcome physical performance was assessed by modified Physical Performance Test (m-PPT). Secondary outcomes were gait speed, physical activity level (PAL), handgrip muscle strength, protein intake, skeletal muscle mass, health status, and executive functioning. Linear mixed models of repeated measured were used to assess intervention effects at 6 and 12 months. The population included 245 older adults (mean age 72 ± 6.5 (SD) years), 71% female, and 54% co-morbidities observed. Dropout of the intervention was 18% at 6 months and 26% at 12 months. Participants were well functioning, based on an m-PPT score of 33.9 (2.8) out of 36. For the primary outcome m-PPT, no significant intervention effects (HBex, +0.03, P = 0.933; HBex-Pro, -0.13, P = 0.730) were found. Gait speed (+0.20 m/s, P = 0.001), PAL (+0.06, P = 0.008), muscle strength (+2.32 kg, P = 0.001), protein intake (+0.32 g/kg/day, P < 0.001), and muscle mass (+0.33 kg, P = 0.017) improved significantly in the HBex-Pro group compared with control group after 6 month intervention. The protein intake, muscle mass, and strength remained significantly improved after 12 months as compared with those of control. Health change and executive functioning improved significantly in both intervention groups after 6 months. This HBex and dietary protein interventions did not change the physical performance (m-PPT) in community-dwelling older adults. Changes were observed in gait speed, PAL, muscle mass, strength, and dietary protein intake, in response to this combined intervention.

|keywords=* Aging
* Behaviour change
* Physical functioning
* Protein
* Sarcopenia
* e-Health
|full-text-url=https://sci-hub.do/10.1002/jcsm.12634
}}
{{medline-entry
|title=Right ventricular diastolic function in aging: a head-to-head comparison between phase-contrast MRI and Doppler echocardiography.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32980983
|abstract=To evaluate right ventricle (RV) diastolic function from phase-contrast MRI ([[PC]]-MRI) in aging. 89 healthy individuals (50 men, 43 ± 15 years) underwent cardiac MRI including 2D [[PC]]-MRI (1.5T) and reference Doppler echocardiography of both ventricles on the same day. Conventional echocardiographic parameters were estimated: early (E, cm/s) and atrial (A) peak velocities as well as myocardial early peak longitudinal velocity (E'). [[PC]]-MRI images were analyzed using custom software, providing: E', E and A waves along with respective peak flow rates (Ef, Af, mL/s) and filling volume (mL), for both ventricles. Intra- and inter-observer reproducibility was studied in 30 subjects and coefficients of variation (CoV) as well as intra-class correlation coefficients (ICC) were provided. RV diastolic function indices derived from [[PC]]-MRI data were reproducible (CoV ≤ 21%, ICC ≥ 0.75) and reliable as reflected by significant associations with left ventricular diastolic function indices assessed using both echocardiography (linear regression Pearson correlation coefficient r ≤ 0.59) and [[PC]]-MRI (r ≤ 71). Despite the fair associations between RV echocardiography and [[PC]]-MRI (r ≤ 0.25), the highest correlation with age was obtained for MRI Ef/Af ratio (r = - 0.64, p < 0.0001 vs. r = - 0.40, p = 0.0001 for echocardiographic E/A). Among [[PC]]-MRI E/A ratios, highest correlations with age were observed for flow rate and mean velocity ratios (r = - 0.61, p < 0.0001) as compared to maximal velocity ratios (r = - 0.56, p < 0.0001). Associations with age for E' were equivalent between [[PC]]-MRI (mean velocity: r = - 0.40, p < 0.0001; maximal velocity: r = - 0.36, p = 0.0005) and echocardiography (r = - 0.36, p = 0.0006). Finally, the significant and age-independent associations between RV mass/end-diastolic volume and E' were stronger for [[PC]]-MRI (mean velocity: r = - 0.36, p = 0.0006; maximal velocity: r = - 0.28, p = 0.007) than echocardiography (r = - 0.09, p = 0.38). [[PC]]-MRI tricuspid inflow and annulus myocardial velocity parameters were reproducible and able to characterize age-related variations in RV diastolic function.

|keywords=* Aging
* Diastolic function
* Phase-contrast MRI
* Right ventricle
|full-text-url=https://sci-hub.do/10.1007/s10554-020-02040-y
}}
{{medline-entry
|title=Pulse Width and Implantable Pulse Generator Longevity in Pallidal Deep Brain Stimulation for Dystonia: A Population-Based Comparative Effectiveness Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32668433
|abstract=A wide range of pulse widths (PWs) has been used in globus pallidus internus (GPi) deep brain stimulation (DBS) for dystonia. However, no specific PW has demonstrated clinical superiority, and the paradigm may differ among DBS centers. To investigate how different paradigms of PWs in GPi DBS for dystonia affect implantable pulse generator (IPG) longevities and energy consumption. Thirty-nine patients with dystonia treated with bilateral GPi DBS at 2 Swedish DBS centers from 2005 to 2015 were included. Different PW paradigms were used at the 2 centers, 60-90 µs (short PWs) and 450 µs (long PW), respectively. The frequency of IPG replacements, pulse effective voltage (PEV), IPG model, pre-/postoperative imaging, and clinical outcome based on the clinical global impression (CGI) scale were collected from the medical charts and compared between the 2 groups. The average IPG longevity was extended for the short PWs (1,129 ± 50 days) compared to the long PW (925 ± 32 days; χ2 = 12.31, p = 0.0005, log-rank test). IPG longevity correlated inversely with PEV (Pearson's r = -0.667, p < 0.0001). IPG longevities did not differ between Kinetra® and Activa® [[PC]] in the short (p = 0.319) or long PW group (p = 0.858). Electrode distances to the central sensorimotor region of the GPi did not differ between the short or long PW groups (p = 0.595). Pre- and postoperative CGI did not differ between groups. Short PWs were associated with decreased energy consumption and increased IPG longevity. These effects were not dependent on the IPG model or the anatomic location of the electrodes. PWs did not correlate with symptom severities or clinical outcomes. The results suggest that the use of short PWs might be more energy efficient and could therefore be preferred initially when programming patients with GPi DBS for dystonia.

|keywords=* Deep brain stimulation
* Dystonia
* Globus pallidus internus
* Pulse generator longevity
* Pulse width
|full-text-url=https://sci-hub.do/10.1159/000508794
}}
{{medline-entry
|title=Gemcitabine plus nab-paclitaxel with initial dose reduction for older patients with advanced pancreatic cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32576518
|abstract=For older patients with pancreatic cancer ([[PC]]), the benefits of gemcitabine plus nab-paclitaxel (GnP) are still uncertain, and the toxicity may be excessive. We aimed to examine the efficacy and safety of modified GnP (m-GnP), which is a nab-paclitaxel reduced regimen, for older patients (≥75 years) with advanced [[PC]]. In total, 34 patients met the eligibility criteria for study inclusion between 2015 and 2020. We evaluated the overall survival (OS), progression-free survival (PFS), best response, and adverse events associated with m-GnP treatment. The median OS and PFS were 15.4 months and 5.9 months, respectively. The best response was partial response in 29% (10/34), stable disease in 53% (18/34), and progressive disease in 15% of patients (5/34); one patient was not evaluated. Among the grade 3 or higher hematological adverse events, neutropenia was the most frequent, occurring in 38% of patients (13/34), whereas febrile neutropenia occurred in 3% (1/34). Grade 3 or higher non-hematological adverse events occurred in 12% of patients (4/34). Early discontinuation owing to intolerable adverse events occurred in one patient, and there were no chemotherapy-related deaths. The present study demonstrated that m-GnP exhibited good efficacy with acceptable toxicity. To avoid early discontinuation and maintain dose intensities, initial dose reduction may be a good option for older patients with [[PC]] when receiving GnP.

|keywords=* Adverse events
* Chemotherapy
* Gemcitabine
* Geriatrics
* Nab-paclitaxel
* Pancreatic cancer
|full-text-url=https://sci-hub.do/10.1016/j.jgo.2020.06.017
}}
{{medline-entry
|title=Protective effects of 17-β-oestradiol and phytoestrogen on age-induced oxidative stress and inhibition of surfactant synthesis in rat type II pneumocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32314935
|abstract=Epidemiological data suggest protective effects of oestrogen and phytoestrogen on lung tissue. This study aimed to elucidate the role of 17-β-oestradiol and phytoestrogen in age-related inhibition of surfactant synthesis and oxidative stress in rat type II pneumocytes. Forty male and 66 female Wistar rats were used. Female rats were randomly kept intact or ovariectomized at age 12 months. At age 22 months, ovariectomized rats received 17-β-oestradiol, soy extract, or no treatment. Oxidative stress markers CO, NO, cGMP and lipid peroxide (LPO), antioxidant enzymes and phosphatidylcholine ([[PC]]) were measured in cultured type II pneumocytes isolated at ages 2, 14, 18, 22 and 24 months. Old, male and ovariectomized rats showed significantly higher CO, NO, cGMP and LPO and lower [[PC]] content and antioxidant enzymes. 17-β-oestradiol and phytoestrogen significantly reversed these effects. In conclusion, aging and oestrogen deprivation decreased [[PC]] synthesis and altered the redox status in type II pneumocytes, which were partially restored by 17-β-oestradiol or soy supplementation.

|keywords=* 17-β-Oestradiol
* aging
* oxidative stress
* phytoestrogen
* surfactant
* type ii pneumocytes
|full-text-url=https://sci-hub.do/10.1080/09637486.2020.1757044
}}
{{medline-entry
|title=Pacing During 200-m Competitive Masters Swimming.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32271289
|abstract=Breen, D, Powell, C, and Anderson, R. Pacing during 200-m competitive masters swimming. J Strength Cond Res 34(7): 1903-1910, 2020-Pacing strategies are key to overall performance outcome, particularly in swimming given the large resistive properties of water. However, no studies examining how swimming stroke, gender, age, or performance level affect pacing strategies during 200-m races. This study aimed to examine masters athletes pacing strategies categorized by stroke, gender, age, and performance level. Data were retrieved from World and European masters swimming championships and contained data for 4,272 performances. Performances were coded for stroke, gender, age, and performance classification ([[PC]]). Performance classification was based on comparison to the appropriate masters world record. Performances were then normalized, with split times being expressed as a percentage faster or slower than average 50-m split time to determine relative pace. Coefficient of variation (CV) of 50-m time was examined across splits. The main effect for stroke was examined at each split, whereas gender, age, and [[PC]] were examined for split-1 pace and CV. An alpha level of 0.05 was set to denote statistical significance. A main effect for stroke was identified at each split (all p < 0.001; (Equation is included in full-text article.)-split-1 = 0.292; (Equation is included in full-text article.)-split-2 = 0.040; (Equation is included in full-text article.)-split-3 = 0.058; (Equation is included in full-text article.)-split-4 = 0.162). A main effect for [[PC]] was identified for split-1 pace and CV within all strokes (all p < 0.001), except for breaststroke (both p > 0.775). Masters athletes exhibit different pacing patterns across strokes, whereas lower ranked athletes also display less even pacing and a faster relative start compared with higher-ranked athletes. Individual analyses of pacing strategies may be necessary.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Athletes
* Athletic Performance
* Competitive Behavior
* Female
* Humans
* Male
* Middle Aged
* Sex Factors
* Swimming

|full-text-url=https://sci-hub.do/10.1519/JSC.0000000000003621
}}
{{medline-entry
|title=Prostate cancer in Pennsylvania: The role of older age at diagnosis, aggressiveness, and environmental risk factors on treatment and mortality using data from the Pennsylvania Cancer Registry.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32212232
|abstract=To assess: (a) cancer treatment in prostate cancer survivors ([[PC]]S) by age at diagnosis (ADx) and prostate cancer ([[PC]]) aggressiveness; (b) potential impact on [[PC]] mortality; and (c) these results in the context of environmental/behavioral risk factors on [[PC]]S in Pennsylvania. Prostate cancer survivors ages ≥40 years were identified from the 2004-2014 Pennsylvania Cancer Registry ([[PC]]R). Demographic/clinical descriptors and [[PC]] treatment were extracted from [[PC]]R. Prostate cancer aggressiveness was defined by clinical/pathologic Gleason score and tumor stage. Logistic and Cox regression analyses tested associations between treatment received and [[PC]]-specific mortality. County-level data from the Pennsylvania BRFSS were used to estimate cancer-related behavioral risk factors (eg, smoking, physical inactivity, fruit/vegetable consumption [FV], alcohol use) and used as covariates. There were 90 694 [[PC]]S ages 40-105 years (mean age = 66.19 years, SD = 9.25) included. Most were non-Hispanic white men (83%). Prostate cancer survivors ≥75 years were least likely to receive any treatment but men ages 65-74 were more likely to receive combined therapies (OR = 1.47; 95% CI 1.28, 1.69) vs [[PC]]S ages 40-54 years, controlling for covariates. Prostate cancer survivors 55-75+ with aggressive [[PC]] who received any treatment vs no definitive treatment had significantly reduced mortality. Men from counties with high obesity and smoking rates were significantly less likely to receive any treatment than men living in counties with lower rates of these risk factors. Prostate cancer survivors who lived in counties with high rates of physical inactivity and had high rates of sufficient FV consumption were slightly more likely to receive cancer treatment vs no definitive treatment compared to men who lived in counties with high rates of physical activity and lower FV consumption. We observed a general age-related decline in receipt of treatment. Prostate cancer survivors ages ≥75 years were significantly less likely to get any cancer treatment compared to younger [[PC]]S. However, most men with more aggressive disease who received any treatment had greatly reduced [[PC]] mortality, regardless of age. Considering environmental/behavioral risk factors may attenuate [[PC]] risk and inform treatment options.

|keywords=* aging
* behavioral risk factors
* geriatric oncology
* healthy aging
* prostate cancer survivorship
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221418
}}
{{medline-entry
|title=Extracranial versus intracranial hydro-hemodynamics during aging: a [[PC]]-MRI pilot cross-sectional study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31931818
|abstract=Both aging and changes in blood flow velocity between the extracranial (intraspinal) and intracranial regions of cerebral vessels have an impact on brain hydro-hemodynamics. Arterial and venous cerebral blood flows interact with cerebrospinal fluid (CSF) in the both the cranial and spinal systems. Studies suggest that increased blood and CSF flow pulsatility plays an important role in certain neurological diseases. Here, we investigated the changes in blood-CSF flow pulsatility in the cranial and spinal systems with age as well as the impact of the intracranial compartment on flow patterns. Phase-contrast magnetic resonance imaging ([[PC]]-MRI) was performed in 16 young and 19 elderly healthy volunteers to measure the flows of CSF and blood. CSF stroke volume (SV), blood SV, and arterial and venous pulsatility indexes (PIs) were assessed at intra- and extracranial levels in both samples. Correlations between ventricular and spinal CSF flow, and between blood and CSF flow during aging were also assessed. There was a significant decrease in arterial cerebral blood flow and intracranial venous cerebral blood flow with aging. We also found a significant increase of intracranial blood SV, spinal CSF SV and arterial/venous pulsatility indexes with aging. In regard to intracranial compartment impact, arterial and venous PIs decreased significantly at intracranial level in elderly volunteers, while young adults exhibited decrease in venous PI only. Intracranial venous PI was paradoxically lower than extracranial venous PI, regardless of age. In both sample groups, spinal CSF SV and aqueductal CSF SV were positively correlated, and so were extracranial blood and spinal CSF SVs. The study demonstrates that aging changes blood flow but preserves blood and CSF interactions. We also showed that many parameters related to blood and CSF flows differ between young and elderly adults.
|mesh-terms=* Aged
* Aged, 80 and over
* Brain
* Cerebral Ventricles
* Cerebrospinal Fluid
* Cerebrovascular Circulation
* Cross-Sectional Studies
* Female
* Hemodynamics
* Humans
* Magnetic Resonance Imaging
* Male
* Middle Aged
|keywords=* Aging
* Arterial cerebral blood flow
* CSF flow
* PC-MRI
* Pulsatility
* Venous cerebral blood flow
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958565
}}
{{medline-entry
|title=Age-specific health-related quality of life in disease-free long-term prostate cancer survivors versus male population controls-results from a population-based study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31736000
|abstract=Prostate cancer ([[PC]]) and its treatment may affect [[PC]] survivors differently with respect to age. However, little is known regarding age-specific health-related quality of life (HRQoL) in [[PC]] survivors 5 years or even ≥ 10 years post-diagnosis. The sample included 1975 disease-free [[PC]] survivors (5-16 years post-diagnosis) and 661 cancer-free population controls, recruited from two German population-based studies (CAESAR+, LinDe). HRQoL in both populations was assessed using the EORTC QLQ-C30 questionnaire. Additionally, [[PC]] survivors completed the [[PC]]-specific EORTC QLQ-PR25 questionnaire. Differences in HRQoL between survivors and controls, as well as differences according to age and time since diagnosis were analyzed with multiple regression after adjustment for age, education, stage, and time since diagnosis, where appropriate. In general, [[PC]] survivors reported HRQoL and symptom-burden levels comparable to the general population, except for significantly poorer social functioning and higher burden for diarrhea and constipation. In age-specific analyses, [[PC]] survivors up to 69 years indicated poorer global health and social functioning than population controls. Stratification by time since diagnosis revealed little difference between the subgroups. On [[PC]]-specific symptoms, burden was highest for urinary bother and symptoms, and lowest for bowel symptoms. Younger age was associated with less urinary symptoms but higher urinary bother. Long-term disease-free [[PC]] survivors reported overall good HRQoL, but experienced persistent specific detriments. Our data suggest that these detriments do not improve substantially with increasing time since diagnosis. Targeted interventions are recommended to prevent [[PC]]-related and treatment-related symptoms becoming chronic and to enhance social functioning.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aging
* Cancer Survivors
* Case-Control Studies
* Disease-Free Survival
* Germany
* Humans
* Male
* Middle Aged
* Prostatic Neoplasms
* Quality of Life
* Surveys and Questionnaires
* Young Adult
|keywords=* Health-related quality of life
* Long-term survivor
* Population-based
* Prostate cancer
|full-text-url=https://sci-hub.do/10.1007/s00520-019-05120-5
}}
{{medline-entry
|title=Cross-Linked Polyphenol-Based Drug Nano-Self-Assemblies Engineered to Blockade Prostate Cancer Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31553876
|abstract=Cellular senescence is one of the prevailing issues in cancer therapeutics that promotes cancer relapse, chemoresistance, and recurrence. Patients undergoing persistent chemotherapy often develop drug-induced senescence. Docetaxel, an FDA-approved treatment for prostate cancer, is known to induce cellular senescence which often limits the overall survival of patients. Strategic therapies that counter the cellular and drug-induced senescence are an unmet clinical need. Towards this an effort was made to develop a novel therapeutic strategy that targets and removes senescent cells from the tumors, we developed a nanoformulation of tannic acid-docetaxel self-assemblies (DSAs). The construction of DSAs was confirmed through particle size measurements, spectroscopy, thermal, and biocompatibility studies. This formulation exhibited enhanced [i]in vitro[/i] therapeutic activity in various biological functional assays with respect to native docetaxel treatments. Microarray and immunoblot analysis results demonstrated that DSAs exposure selectively deregulated senescence associated TGFβR1/FOXO1/p21 signaling. Decrease in β-galactosidase staining further suggested reversion of drug-induced senescence after DSAs exposure. Additionally, DSAs induced profound cell death by activation of apoptotic signaling through bypassing senescence. Furthermore, [i]in vivo[/i] and [i]ex vivo[/i] imaging analysis demonstrated the tumor targeting behavior of DSAs in mice bearing [[PC]]-3 xenograft tumors. The antisenescence and anticancer activity of DSAs was further shown [i]in vivo[/i] by inhibiting TGFβR1 proteins and regressing tumor growth through apoptotic induction in the [[PC]]-3 xenograft mouse model. Overall, DSAs exhibited such advanced features due to a natural compound in the formulation as a matrix/binder for docetaxel. Overall, DSAs showed superior tumor targeting and improved cellular internalization, promoting docetaxel efficacy. These findings may have great implications in prostate cancer therapy.
|mesh-terms=* Animals
* Antineoplastic Agents
* Apoptosis
* Cell Line, Tumor
* Cellular Senescence
* Docetaxel
* Forkhead Box Protein O1
* Humans
* Male
* Mice
* Mice, Nude
* Nanostructures
* Polyphenols
* Prostatic Neoplasms
* Receptor, Transforming Growth Factor-beta Type I
* Signal Transduction
* Tannins
* Transplantation, Heterologous
|keywords=* DSAs
* apoptosis
* docetaxel
* nanoassemblies
* prostate cancer
* senescence
|full-text-url=https://sci-hub.do/10.1021/acsami.9b14738
}}
{{medline-entry
|title=An Immersive Virtual Reality Platform for Assessing Spatial Navigation Memory in Predementia Screening: Feasibility and Usability Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31482851
|abstract=Traditional methods for assessing memory are expensive and have high administrative costs. Memory assessment is important for establishing cognitive impairment in cases such as detecting dementia in older adults. Virtual reality (VR) technology can assist in establishing better quality outcome in such crucial screening by supporting the well-being of individuals and offering them an engaging, cognitively challenging task that is not stressful. However, unmet user needs can compromise the validity of the outcome. Therefore, screening technology for older adults must address their specific design and usability requirements. This study aimed to design and evaluate the feasibility of an immersive VR platform to assess spatial navigation memory in older adults and establish its compatibility by comparing the outcome to a standard screening platform on a personal computer ([[PC]]). VR-CogAssess is a platform integrating an Oculus Rift head-mounted display and immersive photorealistic imagery. In a pilot study with healthy older adults (N=42; mean age 73.22 years, SD 9.26), a landmark recall test was conducted, and assessment on the VR-CogAssess was compared against a standard [[PC]] (S[[PC]]) setup. Results showed that participants in VR were significantly more engaged (P=.003), achieved higher landmark recall scores (P=.004), made less navigational mistakes (P=.04), and reported a higher level of presence (P=.002) than those in S[[PC]] setup. In addition, participants in VR indicated no significantly higher stress than S[[PC]] setup (P=.87). The study findings suggest immersive VR is feasible and compatible with S[[PC]] counterpart for spatial navigation memory assessment. The study provides a set of design guidelines for creating similar platforms in the future.

|keywords=* cognition
* dementia
* healthy aging
* memory
* virtual reality
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6751096
}}
==TLR4==

{{medline-entry
|title=Age-Dependent Changes of Adipokine and Cytokine Secretion From Rat Adipose Tissue by Endogenous and Exogenous Toll-Like Receptor Agonists.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32973755
|abstract=White adipose tissue but recently also brown adipose tissue have emerged as endocrine organs. Age-associated obesity is accompanied by prolonged and elevated lipopolysaccharide (LPS)-induced sickness symptoms and increased cytokine and adipokine levels in the circulation partially originating from adipose tissue. In the present study, [i]ex vivo[/i] fat explants were used to investigate how the exogenous pathogen-associated molecular pattern (PAMP) LPS or the endogenous danger-associated molecular patterns (DAMPs) high mobility group box-1 protein (HMGB1) and biglycan modulate the release of cytokines and adipokines/batokines and, thus, could influence systemic and/or local inflammation. The response of adipose tissue (epididymal, retroperitoneal, subcutaneous, and brown) was compared between young lean and old obese rats (2 vs. 24 months old). LPS induced a strong interleukin (IL)-6 and tumor necrosis factor (TNF) alpha release into the supernatant of all adipose tissue types investigated. HMGB1 (subcutaneous) and biglycan (retroperitoneal) led to an increased release of IL-6 and TNFalpha (HMGB1) and decreased visfatin and adiponectin (biglycan) secretion from epididymal adipose tissue (young rats). Visfatin was also decreased by HMGB1 in retroperitoneal adipose tissue of old rats. We found significantly higher leptin (all fat pads) and adiponectin (subcutaneous) levels in supernatants of adipose tissue from old compared to young rats, whereas visfatin secretion showed the opposite. The expression of the biglycan receptor Toll-like receptor (TLR) 2 as well as the LPS and HMGB1 receptors [[TLR4]] and receptor for advanced glycation end products (RAGE) were reduced with age ([[TLR4]]/RAGE) and by stimulation with their ligands (subcutaneous). Overall, we revealed that adipokines/adipose-tissue released cytokines show some modulation of their release caused by mediators of septic (batokines) and sterile inflammation with potential implication for acute and chronic disease. Moreover, aging may increase or decrease the release of fat-derived mediators. These data show that DAMPS and LPS locally modulate cytokine secretion while only DAMPS but not LPS can locally alter adipokine secretion during inflammation.

|keywords=* adipokines
* aging
* batokines
* biglycan
* cytokines
* fat explant cultures
* high mobility group box-1 protein
* lipopolysaccharide
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466552
}}
{{medline-entry
|title=Role of Toll Like Receptor 4 in Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32983082
|abstract=Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer's disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecular players of the innate immune system have recently been proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. [[TLR4]] mediated signaling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proven to be key players in the pathology of AD. Among others, Aβo promote Ca  entry and mitochondrial Ca  overload leading to cell death in neurons. [[TLR4]] has recently been found to be involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a [[TLR4]] receptor agonist, increases cytosolic Ca  concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were significantly prevented by pharmacological blockade of [[TLR4]] receptor signaling. Moreover, [[TLR4]] expression in rat hippocampal neurons increased significantly in aged neurons [i]in vitro[/i]. Therefore, molecular patterns associated with infection and/or brain cell damage may activate [[TLR4]] and Ca  signaling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of [[TLR4]] in AD.

|keywords=* Alzheimer’s disease
* TLR4
* aging
* amyloid beta oligomers
* calcium
* hippocampal neurons
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479089
}}
{{medline-entry
|title=Commentary on Some Recent Theses Relevant to Combating Aging: August 2020.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32718230
|abstract=Theses reviewed in this issue include "Characterization and Purification of Putative Stem Cells from the Adult Murine Pancreas," "Inhibition of [[TLR4]] Minimizes Islet Damage due to Sterile Inflammation and Improves Islet Transplant Outcomes," "Liquefaction of the Brain Following Stroke Shares Multiple Characteristics with Atherosclerosis and Mediates Secondary Neurodegeneration in an Osteopontin-Dependent Mechanism," "Manipulating the Segregation of Human Mitochondrial DNA," "Role of Mitochondria in Plasma Membrane Repair and Pathogenesis of Muscular Dystrophy," and "The Role of Cytosolic Accumulation of Nuclear DNA in Retinal-Pigment Epithelium Dysfunction and Age-Related Macular Degeneration."

|keywords=* aging
* dissertations
* theses
|full-text-url=https://sci-hub.do/10.1089/rej.2020.2378
}}
{{medline-entry
|title=Sialylation and Galectin-3 in Microglia-Mediated Neuroinflammation and Neurodegeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32581723
|abstract=Microglia are brain macrophages that mediate neuroinflammation and contribute to and protect against neurodegeneration. The terminal sugar residue of all glycoproteins and glycolipids on the surface of mammalian cells is normally sialic acid, and addition of this negatively charged residue is known as "sialylation," whereas removal by sialidases is known as "desialylation." High sialylation of the neuronal cell surface inhibits microglial phagocytosis of such neurons, via: (i) activating sialic acid receptors (Siglecs) on microglia that inhibit phagocytosis and (ii) inhibiting binding of opsonins C1q, C3, and galectin-3. Microglial sialylation inhibits inflammatory activation of microglia via: (i) activating Siglec receptors CD22 and CD33 on microglia that inhibit phagocytosis and (ii) inhibiting Toll-like receptor 4 ([[TLR4]]), complement receptor 3 (CR3), and other microglial receptors. When activated, microglia release a sialidase activity that desialylates both microglia and neurons, activating the microglia and rendering the neurons susceptible to phagocytosis. Activated microglia also release galectin-3 (Gal-3), which: (i) further activates microglia via binding to [[TLR4]] and TREM2, (ii) binds to desialylated neurons opsonizing them for phagocytosis via Mer tyrosine kinase, and (iii) promotes Aβ aggregation and toxicity [i]in vivo[/i]. Gal-3 and desialylation may increase in a variety of brain pathologies. Thus, Gal-3 and sialidases are potential treatment targets to prevent neuroinflammation and neurodegeneration.

|keywords=* aging
* desialylation
* galectin-3
* microglia
* neurodegeneration
* phagocytosis
* sialic acid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296093
}}
{{medline-entry
|title=Chemerin facilitates intervertebral disc degeneration via [[TLR4]] and CMKLR1 and activation of NF-kB signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32526705
|abstract=Now days, obesity is a major risk factor for intervertebral disc degeneration (IDD). However, adipokine, such as chemerin is a novel cytokine, which is secreted by adipose tissue, and are thought to be played major roles in various degenerative diseases. Obese individuals are known to have high concentration of serum chemerin. Our purpose was to study whether chemerin acts as a biochemical relationship between obesity, and IDD. In this study, we found that the expression level of chemerin was significantly increased in the human degenerated nucleus pulposus (NP) tissues, and had higher level in the obese people than the normal people. Chemerin significantly increased the inflammatory mediator level, contributing to ECM degradation in nucleus pulposus cells (NPCs). Furthermore, chemerin overexpression aggravates the puncture-induced IVDD progression in rats, while knockdown CMKLR1 reverses IVDD progression. Chemerin activates the NF-kB signaling pathway via its receptors CMKLR1, and [[TLR4]] to release inflammatory mediators, which cause matrix degradation, and cell aging. These findings generally provide novel evidence supporting the causative role of obesity in IDD, which is essentially important to literally develop novel preventative or generally therapeutic treatment in the disc degenerative disorders.

|keywords=* chemerin
* inflammation
* intervertebral disc
* nucleus pulposus
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343479
}}
{{medline-entry
|title=Toll-like receptor 4 differentially regulates adult hippocampal neurogenesis in an age- and sex-dependent manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32343455
|abstract=Toll-like receptor 4 ([[TLR4]]) is primarily responsible for initiating an immune response following pathogen recognition. However, [[TLR4]] is also expressed on neural progenitor cells and has been reported to regulate hippocampal neurogenesis as young male [[TLR4]] knockout mice show increases in cell proliferation and doublecortin positive cells. Whether these effects occur in both sexes and are sustained with normal aging is currently unknown. The present study evaluated whether [[TLR4]] deficiency alters adult hippocampal neurogenesis in young (3-4 months) and aged (18-20 months), male and female, [[TLR4]] deficient ([[TLR4]]-/-; B6.B10ScN-Tlr4lps-del/JthJ) and wild type (WT) mice. Additionally, neurogenesis within the dorsal and the ventral hippocampal subdivisions was evaluated to determine if [[TLR4]] has differential effects across the hippocampus. Bromodeoxyuridine (BrdU) was administered to quantify new cell survival as well as cell differentiation. Ki-67 was measured to evaluate cell proliferation. Results show that young [[TLR4]]-/- females had higher rates of proliferation and neuronal differentiation in both the dorsal and ventral hippocampus relative to WT females. Young [[TLR4]]-/- males show elevated proliferation and neuronal differentiation mainly in the ventral hippocampus. While young [[TLR4]]-/- mice show enhanced neurogenesis compared to young WT mice, the increase was not apparent in the aged [[TLR4]]-/- mice. Both aged WT and [[TLR4]]-/- mice showed a decrease in proliferation, new cell survival, and neuronal differentiation compared to young WT and [[TLR4]]-/- mice. The data collectively indicate that [[TLR4]] regulates hippocampal neurogenesis in young adults, but that these effects are region-specific in males and that females show broader changes in neurogenesis throughout the hippocampus.

|keywords=* TLR4
* adult hippocampal neurogenesis
* aging
* proliferation
* sex differences
|full-text-url=https://sci-hub.do/10.1002/hipo.23209
}}
{{medline-entry
|title=Aging-associated immunosenescence via alterations in splenic immune cell populations in rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31838133
|abstract=Immunosenescence is the decline of the host immune system due to aging, resulting in various complications. The splenic lymphoid nodule is the pivotal compartment involved in immunosenescence. In this study, we investigated the important changes in the splenic immune cell populations of aged rats (18-24 months) in comparison with young rats (3-5 months). We, also, studied the effects of aging on the activities of total superoxide dismutase (T-SOD) and malondialdehyde (MDA) levels in spleen of both groups, besides the changes of the splenic architecture. Furthermore, immunohistochemical staining was performed to detect the aging effects in T cells, B cells, macrophages, granulocytes, mast cells, proliferating cells, apoptotic cells, and cells positive for interleukin-1β (IL-1β), interleukin-6 (IL-6), and Toll-like receptor 4 ([[TLR4]]). The aged rats had significantly lower spleen/body weight ratios and smaller splenic nodules, indicating a decline in general immunity in them. With aging, T-SOD activities were decreased, while MDA levels were increased, exhibiting that oxidative stress increases in spleens. In addition, the aged group also had significantly fewer T and B cells, macrophages, granulocytes, IL-6 and [[TLR4]] immuno-positive cells, and proliferating cells in the periarterial lymphatic sheaths, marginal zone, and lymphoid follicles compared with the young group. On the other hand, the number of mast cells and apoptotic cells was significantly increased with age. Therefore, we can conclude that cellular immunity and humoral immunity were crumpled with age.
|mesh-terms=* Animals
* B-Lymphocytes
* Cells, Cultured
* Immunity, Cellular
* Immunosenescence
* Male
* Malondialdehyde
* Oxidative Stress
* Rats
* Rats, Wistar
* Spleen
* Superoxide Dismutase
* T-Lymphocytes
|keywords=* Aging
* Immunohistochemistry
* Immunosenescence
* Oxidative stress
* Spleen
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2019.117168
}}
{{medline-entry
|title=Leptin induces immunosenescence in human B cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31831137
|abstract=Leptin is an adipokine secreted primarily by the adipocytes. Leptin has endocrine and immune functions and increases the secretion of pro-inflammatory cytokines by immune cells. Here we show that incubation of B cells from young lean individuals with leptin increases the frequencies of pro-inflammatory B cells and induces intrinsic B cell inflammation, characterized by mRNA expression of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (IL-8), micro-RNAs (miR-155 and miR-16), [[TLR4]] and p16, a cell cycle regulator associated with immunosenescence. We have previously shown that the expression of these pro-inflammatory markers in unstimulated B cells is negatively associated with the response of the same B cells after in vivo or in vitro stimulation. B cells from young lean individuals, after in vitro incubation with leptin, show reduced class switch and influenza vaccine-specific IgG production. Our results altogether show that leptin makes B cells from youn lean individuals similar to those from young obese and elderly lean individuals, suggesting that leptin may be a mechanisms of immunosenescence in human B cells.
|mesh-terms=* Adult
* Aged
* B-Lymphocytes
* Humans
* Immunoglobulin Class Switching
* Immunosenescence
* Leptin
* Middle Aged
* Obesity
|keywords=* B cells
* Immunosenescence
* Leptin
* Obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002206
}}
{{medline-entry
|title=Genetic Variation in the Magnitude and Longevity of the IgG Subclass Response to a Diphtheria-Tetanus-Acellular Pertussis (DTaP) Vaccine in Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31547158
|abstract=The type of IgG subclasses induced by vaccination is an important determinant of vaccine efficacy because the IgG subclasses vary in their biological function. The goal of this study was to determine the influence of the genetic background on the production and duration of vaccine-induced IgG subclasses. IgG1, IgG2b, and IgG3 titers against diphtheria toxoid (DT), pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (Prn) were measured in mice from 28 different inbred and wild-derived strains vaccinated with an aluminum hydroxide-adjuvanted DTaP vaccine. The titers and duration of vaccine-specific IgG subclass responses were different among mouse strains, indicating that genetic factors contribute to this variation. Statistical associations were used to identify potential mechanisms that contribute to antibody production and longevity. This analysis showed that the mechanisms guiding the magnitude of antibody production were antigen-dependent for IgG1 but antigen-independent for IgG2b and IgG3. However, the mechanisms driving the longevity of antibody titers were antigen-independent for IgG1, IgG2b, and IgG3. The ratio of IgG1 and IgG3 titers identified Th1 and Th2-prone mouse strains. [[TLR4]]-deficient C3H/HeJ mice had an enhanced IgG1 response compared with C3H/HeOuJ mice with intact [[TLR4]]. This work demonstrates that the genetic background contributes significantly to the magnitude and longevity of vaccine-induced IgG1, IgG2b, and IgG3 titers in mice.

|keywords=* DTaP
* IgG subclass
* antibody longevity
* antibody magnitude
* genetics
* vaccine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963843
}}
{{medline-entry
|title=Rapamycin improves sevoflurane‑induced cognitive dysfunction in aged rats by mediating autophagy through the [[TLR4]]/MyD88/NF‑κB signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31432123
|abstract=The present study was aimed to observe the protective effect of rapamycin on cognitive dysfunction induced by sevoflurane in aged rats and its effect on autophagy‑related proteins, and to investigate the regulatory mechanism of the Toll‑like receptor 4/myeloid differentiation primary response 88/nuclear factor‑κB ([[TLR4]]/MyD88/NF‑κB) signaling pathway. Fifty Sprague‑Dawley rats were randomly assigned to a control group, a sevoflurane group, a rapamycin pretreatment group, a [[TLR4]] inhibitor group and a 3MA autophagy inhibitor group. A water maze test was used to evaluate the cognition and memory of rats. Hematoxylin and eosin (H&E) staining was performed to observe pathological changes of brain tissue. A TUNEL assay was used to detect the apoptosis of brain tissue. ELISA was used to assess changes in brain injury markers and inflammatory factors. A western blot assay or quantitative reverse transcription PCR (RT‑qPCR) were performed to determine the expression of autophagy‑related proteins and the [[TLR4]]/MyD88/NF‑κB signaling pathway in brain tissue. The results revealed that rapamycin could improve cognitive dysfunction of aged rats induced by sevoflurane. Rapamycin was identified to play a therapeutic role, including mitigating brain tissue damage, inhibiting apoptosis, and activating autophagy in a sevoflurane‑treated aged rat model. This function of rapamycin was demonstrated to depend on the [[TLR4]]/MyD88/NF‑κB signaling pathway.
|mesh-terms=* Aging
* Animals
* Autophagic Cell Death
* Cognitive Dysfunction
* Male
* Myeloid Differentiation Factor 88
* NF-kappa B
* Rats
* Rats, Sprague-Dawley
* Sevoflurane
* Signal Transduction
* Sirolimus
* Toll-Like Receptor 4

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755174
}}
==FEV==

{{medline-entry
|title=Prediction of Lung Function in Adolescence Using Epigenetic Aging: A Machine Learning Approach.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33182250
|abstract=Epigenetic aging has been found to be associated with a number of phenotypes and diseases. A few studies have investigated its effect on lung function in relatively older people. However, this effect has not been explored in the younger population. This study examines whether lung function in adolescence can be predicted with epigenetic age accelerations (AAs) using machine learning techniques. DNA methylation based AAs were estimated in 326 matched samples at two time points (at 10 years and 18 years) from the Isle of Wight Birth Cohort. Five machine learning regression models (linear, lasso, ridge, elastic net, and Bayesian ridge) were used to predict [[FEV]]  (forced expiratory volume in one second) and FVC (forced vital capacity) at 18 years from feature selected predictor variables (based on mutual information) and AA changes between the two time points. The best models were ridge regression (R  = 75.21% ± 7.42%; RMSE = 0.3768 ± 0.0653) and elastic net regression (R  = 75.38% ± 6.98%; RMSE = 0.445 ± 0.069) for [[FEV]]  and FVC, respectively. This study suggests that the application of machine learning in conjunction with tracking changes in AA over the life span can be beneficial to assess the lung health in adolescence.

|keywords=* epigenetic aging
* feature selection
* hyperparameter tuning
* lung function
* machine learning
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712054
}}
{{medline-entry
|title=Effect of Age on the Efficacy and Safety of Once-Daily Single-Inhaler Triple Therapy Fluticasone Furoate/Umeclidinium/Vilanterol in Patients With Chronic Obstructive Pulmonary Disease: A Post Hoc Analysis of the IMPACT Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33031829
|abstract=In the IMPACT trial, single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduced moderate/severe exacerbation rates versus FF/VI and UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease (COPD) and a history of exacerbations, with a similar safety profile. Research Question Does age have an effect on trial outcomes? IMPACT was a Phase III, double-blind, 52-week trial. Patients ≥40 years of age with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 mcg, FF/VI 100/25 mcg, or UMEC/VI 62.5/25 mcg. Endpoints assessed by age included annual rate of moderate/severe exacerbations, change from baseline (CFB) in trough forced expiratory volume in 1 second ([[FEV]] ), proportion of St George's Respiratory Questionnaire (SGRQ) responders (≥4 units decrease from baseline in SGRQ total score) and safety. The intent-to-treat population comprised 10,355 patients; 4724 (46%), 4225 (41%), and 1406 (14%) were ≤64, 65-74, and ≥75 years of age, respectively. FF/UMEC/VI reduced on-treatment moderate/severe exacerbation rates versus FF/VI (% reduction [95% confidence interval (CI)], ≤64 years: 8% [-1, 16], p=0.070; 65-74 years: 22% [14, 29], p<0.001; ≥75 years 18% [3, 31], p=0.021) and versus UMEC/VI (≤64 years: 16% [7, 25], p=0.002; 65-74 years: 33% [25, 41], p<0.001; ≥75 years 24% [6, 38], p=0.012), with greatest rate reduction seen in the 65-74 and ≥75 years subgroups. Post hoc analyses of CFB in trough [[FEV]] , and proportion of SGRQ responders at Week 52 were significantly greater with FF/UMEC/VI than FF/VI or UMEC/VI in all subgroups. No new safety signals were identified. FF/UMEC/VI reduced the rate of moderate/severe exacerbations and improved lung function and health status versus FF/VI and UMEC/VI irrespective of age for most endpoints, with a similar safety profile. GSK (CTT116855/NCT02164513).

|keywords=* COPD
* aging
* exacerbations
* safety
* single-inhaler triple therapy
|full-text-url=https://sci-hub.do/10.1016/j.chest.2020.09.253
}}
{{medline-entry
|title=A comprehensive analysis of factors related to lung function in older adults: Cross-sectional findings from the Canadian Longitudinal Study on Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33010732
|abstract=Maintenance of lung function is an often underappreciated, yet critical component of healthy aging. Given the unprecedented shift in the average age of Canadians over the next half century, it will be important to investigate the determinants of lung function in the elderly. In the following study, we estimated the association between lung function and a broad array of factors related to sociodemographics, lifestyle, chronic medical conditions and psychosocial factors in older adults aged 45-86 years old using cross-sectional data from the Canadian Longitudinal Study of Aging (n = 21,338). In addition to examining the entire cohort, we also performed stratified analyses within men/women, adults aged 45-64/65+, and healthy/comorbid. In multivariable regression, our explanatory factors (excluding age, sex, height and ethnicity) were able to explain 17% and 11% of the total variance in [[FEV]]  and [[FEV]] /FVC, respectively. Notable and significant contributions were observed for respiratory disease, smoking, obesity, income, and physical activity, while psychosocial factors mainly exhibited non-significant associations. Generally, these associations were stronger for males than females, and adults 65 and older as compared to those aged 45-64. Our findings indicate that there are pervasive and generally under-recognized sociodemographic and lifestyle factors that exhibit significant associations with [[FEV]]  and [[FEV]] /FVC in older adults. While implication of causality in these relationships is not possible due to the cross-sectional nature of the study, future work aiming to investigate determinants of lung health in older adults may choose to target these factors, given that many are modifiable.

|keywords=* Aging
* Determinants
* Lung function
* Sex
* Spirometry
|full-text-url=https://sci-hub.do/10.1016/j.rmed.2020.106157
}}
{{medline-entry
|title=Risk factors associated with the detection of pulmonary emphysema in older asymptomatic respiratory subjects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32517728
|abstract=Several lung structural and functional abnormalities may occur associated with aging, including emphysema. In this study, we evaluated the frequency and risk factors associated with emphysema in respiratory asymptomatic individuals enrolled in our Lung Aging Program. From a cohort of 687 subjects, we found by high-resolution computed tomography (HRCT) 29 individuals (4%) with emphysematous changes that were compared with 87 controls (3:1) randomly selected from the same cohort. This was a transversal, observational, case-control study where we examined demographics and functional characteristics, as well as telomere length and serum Klotho concentration, two conditions that have been associated with aging and some aging-associated diseases including emphysema. Individuals with subclinical pulmonary emphysema were older (72 ± 9 versus 67 ± 6 years), and primarily smoker males with low body mass index. Despite that they were asymptomatic, two of them exhibited a decrease of forced expiratory volume in 1 s ([[FEV]] ), with a lower [[FEV]] /FVC suggesting airway obstruction. Cigarette smoking (OR = 5.43, CI95% 1.8-16.7), family history of lung disease (OR = 4.32, CI95% 1.0-19.0) and lower body mass index (OR 7.22, CI95% 1.2-3.5) were risk factors for the development of lung emphysematous changes. No association was found with telomere length and Klotho serum concentration. Our findings reveal that a small but important percentage of older people without respiratory symptoms, present pulmonary emphysema and indicate that smoking exposure and genetic background may contribute to etiological factors.

|keywords=* Aging
* COPD
* Klotho
* Pulmonary emphysema
* Risk factors
* Telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285611
}}
{{medline-entry
|title=Tiotropium Respimat Efficacy and Safety in Asthma: Relationship to Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32320797
|abstract=Data are limited on the differential response to long-acting bronchodilators in older versus younger adults with asthma. To determine whether the response to tiotropium Respimat differed in older versus younger patients with asthma. Post hoc analyses of 4 randomized, double-blind, placebo-controlled studies in adults with asthma were carried out. Two studies compared tiotropium Respimat 5 μg once daily with placebo, both added to high-dose inhaled corticosteroid (ICS) plus long-acting β -agonist (ie, severe asthma). The other 2 evaluated tiotropium Respimat 2.5 or 5 μg once daily, salmeterol 50 μg twice daily, or placebo, all added to medium-dose ICS (moderate asthma). Data were analyzed in 2 pools: (1) severe and (2) moderate asthma. Efficacy end points: trough and peak [[FEV]] ; trough forced vital capacity; Asthma Control Questionnaire total score and responder percentage, all at week 24. One set of analyses was performed with age as a continuous covariate; the second was conducted in categories less than 40, 40 to 60, and more than 60 years, with treatment-by-age subgroup interaction P values obtained. Safety was analyzed in age categories. Across the age categories, treatment-by-age subgroup interaction P values for trough [[FEV]]  were .13 and .77 for patients with severe and moderate asthma, respectively, not indicating significant impact of age on overall treatment effect, with this observation replicated in the 2 continuum analyses. The other end points (including safety) were also not impacted by age. Once-daily tiotropium Respimat add-on to ICS or ICS/long-acting β -agonist therapy was effective and well tolerated in patients with asthma independent of age.

|keywords=* Aging
* Asthma
* Long-acting muscarinic antagonist
* Long-acting β(2)-agonists
* Pharmacotherapy
|full-text-url=https://sci-hub.do/10.1016/j.jaip.2020.04.013
}}
{{medline-entry
|title=Current Bronchodilator Responsiveness Criteria Underestimate Asthma in Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32071132
|abstract=Asthma is common in older adults and is confirmed by demonstration of variable expiratory air-flow limitations, typically evaluated by spirometric assessment of bronchodilator responsiveness. However, many patients with clinically suspected asthma and documented air-flow obstruction do not exhibit a post-bronchodilator response that meets or exceeds current established guidelines. We investigated if extending the time from bronchodilator administration to assessment of bronchodilator response increases the yield of spirometry for the diagnosis of asthma in older adults. This was a cross-sectional study. The subjects were non-smokers, ≥ 60 y old, and with suspected asthma. Subjects were characterized as (1) those with a positive bronchodilator response on the 30-min post-bronchodilator spirometry, (2) those with a positive bronchodilator response on the 60-min post-bronchodilator spirometry, and (3) those without a positive bronchodilator response but with a positive methacholine challenge test. Factors associated with a late response to bronchodilator were evaluated by using bivariate analysis and by multivariate analysis by using a logistic regression model. This study enrolled 165 subjects. Of these, 81 (49.1%) had a positive bronchodilator response on 30-min post-bronchodilator spirometry; 25 (15.2%) had a positive bronchodilator response on the 1-h post-bronchodilator spirometry; and 59 (35.8%) had no positive bronchodilator response but had a positive methacholine challenge test. On multivariable regression analysis, those with a higher baseline percentage of predicted [[FEV]] , higher scores on a standard asthma control test, and wheezing and/or cough after exercise were more likely to either have a late bronchodilator response or no bronchodilator response. Our study showed that a late positive response to bronchodilator use was more common than previously presumed in older subjects with suspected asthma. Pulmonary function testing laboratories should consider routinely reassessing spirometry at 1 h after bronchodilator use if the earlier assessment did not reveal a significant response.

|keywords=* aging
* albuterol
* asthma
* bronchodilator effect
* lung diseases
* older adult
* spirometry
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538007
}}
{{medline-entry
|title=Physical performances show conflicting associations in aged manual workers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32042126
|abstract=Ageing is associated with a decrease in physical performance implying that aged manual workers may be unable to match the physical requirements of their jobs. In this cross-sectional study, 96 male manual workers aged 51-72 years were recruited. Outcomes included handgrip strength (HGS), fat-free mass (FFM), fat percentage, cardiorespiratory fitness ([Formula: see text]O max), forced vital capacity (FVC), forced expiratory volume after 1 s ([[FEV]] ), spinal flexibility, sit-to-stand test performance and static balance. Covariates included height, smoking habits, leisure-time physical activity and systemic inflammation from blood samples. Outcomes were also compared with general populations. Age was negatively related to FFM and [[FEV]] , whereas static balance (velocity of displacement) was positively associated with age. Greater HGS, but poorer [Formula: see text]O max and [[FEV]] /[[FEV]] ratio were found compared with general populations. Age was negatively related with physical performances although a large part of the variance in performance could be explained by factors other than age such as smoking and systemic inflammation. The manual workers had greater muscle strength but had poorer cardiorespiratory fitness and lung function when compared with general populations. Specific health interventions targeting specifically cardiorespiratory fitness, lung function, and balance may be needed to maintain physical performances among manual workers.
|mesh-terms=* Aged
* Aging
* Body Composition
* Body Mass Index
* Cardiorespiratory Fitness
* Cross-Sectional Studies
* Hand Strength
* Humans
* Lung
* Male
* Middle Aged
* Physical Functional Performance

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010773
}}
{{medline-entry
|title=[[FEV]]  as a Standalone Spirometric Predictor and the Attributable Fraction for Death in Older Persons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31662447
|abstract=Commonly used thresholds for staging [[FEV]]  have not been evaluated as standalone spirometric predictors of death in older persons. Specifically, the proportion of deaths attributed to a reduced [[FEV]] , when staged by commonly used thresholds in L, percent of predicted (% pred), and Z scores, has not been previously reported. In 4,232 white persons ≥ 65 y old, sampled from the Cardiovascular Health Study, [[FEV]]  was stratified as stage 1 ([[FEV]]  ≥ 2.00 L, ≥80% pred, and Z score ≥-1.64), stage 2 ([[FEV]]  1.50-1.99 L, 50-79%pred, and Z score -2.55 to -1.63), and stage 3 ([[FEV]]  < 1.50 L, < 50% pred, and Z score < -2.55). Notably, a Z score threshold of -1.64 defines normal-for-age lung function as the lower limit of normal (ie, 5th percentile of distribution), and accounts for differences in age, sex, height, and ethnicity. Next, adjusted odds ratios and average attributable fractions for 10-y all-cause mortality were calculated, comparing [[FEV]]  stages 2 and 3 against stage 1, expressed in L, % pred, and Z scores. The average attributable fraction estimates the proportion of deaths attributed to a predictor by combining the prevalence of the predictor with the relative risk of death conferred by that predictor. [[FEV]]  stage 2 and 3 in L, % pred, and Z scores yielded similar adjusted odds ratios of death: 1.40-1.51 for stage 2 and 2.35-2.66 for stage 3. Conversely, [[FEV]]  stages 2 and 3 in L, % pred, and Z scores differed in prevalence: 12.8-28.6% for stage 2 and 6.4-17.5% for stage 3, and also differed in the adjusted average attributable fraction for death: 3.2-6.4% for stage 2 and 4.5-9.1% for stage 3. In older persons, the proportion of deaths attributed to a reduced [[FEV]]  is best stratified by Z score staging thresholds because these yield a similar relative risk of death but a more age- and sex-appropriate prevalence of [[FEV]]  stage.

|keywords=* aging
* average attributable fraction
* death
* relative risk
* spirometry
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055488
}}
{{medline-entry
|title=An Individualized Prediction Model for Long-term Lung Function Trajectory and Risk of COPD in the General Population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31542453
|abstract=Prediction of future lung function will enable the identification of individuals at high risk of developing COPD, but the trajectory of lung function decline varies greatly among individuals. This study involved the development and validation of an individualized prediction model of lung function trajectory and risk of airflow limitation in the general population. Data were obtained from the Framingham Offspring Cohort, which included 4,167 participants ≥ 20 years of age and who had ≥ 2 valid spirometry assessments. The primary outcome was prebronchodilator [[FEV]] ; the secondary outcome was the risk of airflow limitation (defined as [[FEV]] /FVC less than the lower limit of normal). Mixed effects regression models were developed for individualized prediction, and a machine learning algorithm was used to determine essential predictors. The model was validated in two large, independent multicenter cohorts (N = 2,075 and 12,913, respectively). With 20 common predictors, the model explained 79% of the variation in [[FEV]]  decline in the derivation cohort. In two validation datasets, the model had low error in predicting [[FEV]]  decline (root mean square error range, 0.18-0.22 L) and high discriminative power in predicting risk of airflow limitation (C-statistic range, 0.86-0.87). This model was implemented in a freely accessible website-based application, which allows prediction based on flexible sets of predictors (http://resp.core.ubc.ca/ipress/Framingham[[FEV]]1). The individualized predictor is an accurate tool to predict long-term lung function trajectories and risk of airflow limitation in the general population. This model enables identifying individuals at higher risk of COPD, who can then be targeted for preventive therapies.
|mesh-terms=* Adult
* Age Factors
* Aging
* Alcohol Drinking
* Algorithms
* Alkaline Phosphatase
* Body Height
* Bronchodilator Agents
* Cigarette Smoking
* Cohort Studies
* Cough
* Dyspnea
* Electrocardiography
* Female
* Forced Expiratory Volume
* Hematocrit
* Humans
* Leukocyte Count
* Longitudinal Studies
* Lung
* Machine Learning
* Male
* Middle Aged
* Pulmonary Disease, Chronic Obstructive
* Risk Assessment
* Serum Albumin
* Serum Globulins
* Sex Factors
* Spirometry
* Triglycerides
* Vital Capacity
|keywords=* COPD
* FEV(1)
* FEV(1)/FVC
* airflow limitation
* lung function
* predictive modeling
|full-text-url=https://sci-hub.do/10.1016/j.chest.2019.09.003
}}
{{medline-entry
|title=Telomere length and lung function in a population-based cohort of children and mid-life adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31456360
|abstract=Telomere length is associated with poorer lung health in older adults, possibly from cumulative risk factor exposure, but data are lacking in pediatric and population-based cohorts. We examined associations of telomere length with lung function in children and mid-life adults. Data were drawn from a population-based cross-sectional study of 11 to 12 year-olds and mid-life adults. Lung function was assessed by spirometric [[FEV]]  , FVC, [[FEV]]   /FVC ratio, and MMEF   . Telomere length was measured by quantitative polymerase chain reaction from blood and expressed as the amount of telomeric genomic DNA to the beta-globin gene (T/S ratio). Associations of telomere length with spirometric parameters were tested by linear and logistic regression models, adjusting for potential confounders of sex, age, body mass index, socioeconomic position, physical activity, inflammation, asthma, pubertal status, and smoking. Mean T/S ratio was 1.09 (n = 1206; SD 0.55) in children and 0.81 (n = 1343; SD 0.38) in adults. In adults, for every additional unit in T/S ratio, [[FEV]]   /FVC and MMEF   z-scores were higher (β 0.21 [95% confidence interval, CI; 0.06-0.36] and 0.23 [95% CI; 0.08-0.38], respectively), and the likelihood of being in the lowest quartile for [[FEV]]   /FVC and MMEF   z-scores was lower (odds ratios 0.59 [95% CI, 0.39-0.89] and 0.64 [95% CI, 0.41-0.99], respectively). No evidence of association was seen for adult [[FEV]]   or FVC, or any childhood spirometric index after adjustments. Shorter telomere length showed moderate associations with poorer airflow parameters, but not vital capacity (lung volume) in mid-life adults. However, there was no convincing evidence of associations in children.
|mesh-terms=* Aged
* Asthma
* Body Mass Index
* Child
* Cohort Studies
* Cross-Sectional Studies
* Exercise
* Female
* Forced Expiratory Volume
* Humans
* Lung
* Male
* Respiratory Function Tests
* Risk Factors
* Smoking
* Spirometry
* Telomere
* Vital Capacity
|keywords=* aging
* cell senescence
* life course
* national cohort
* spirometry
|full-text-url=https://sci-hub.do/10.1002/ppul.24489
}}
==LPA==

{{medline-entry
|title=Ginseng gintonin, aging societies, and geriatric brain diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32817818
|abstract=A dramatic increase in aging populations and low birth rates rapidly drive aging societies and increase aging-associated neurodegenerative diseases. However, functional food or medicinal formulations to prevent geriatric brain disorders are not readily available. [i]Panax ginseng[/i] is a candidate, since ginseng has long-been consumed as a rejuvenating agent. However, the underlying molecular mechanisms and the components of ginseng that are responsible for brain rejuvenation and human longevity are unknown. Accumulating evidence shows that gintonin is a candidate for the anti-aging ingredient of ginseng, especially in brain senescence. Gintonin, a glycolipoprotein complex, contains three lipid-derived G protein-coupled receptor ligands: lysophosphatidic acids ([[LPA]]s), lysophosphatidylinositols (LPIs), and linoleic acid (LA). [[LPA]], LPI, and LA act on six [[LPA]] receptor subtypes, GPR55, and GPR40, respectively. These G protein-coupled receptors are distributed within the nervous and non-nervous systems of the human body. Gintonin-enriched fraction (GEF) exhibits anti-brain senescence and effects against disorders such as Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD). Oral administration of gintonin in animal models of d-galactose-induced brain aging, AD, HD, and PD restored cognitive and motor functions. The underlying molecular mechanisms of gintonin-mediated anti-brain aging and anti-neurodegenerative diseases include neurogenesis, autophagy stimulation, anti-apoptosis, anti-oxidative stress, and anti-inflammatory activities. This review describes the characteristics of gintonin and GEF, and how gintonin exerts its effects on brain aging and brain associated-neurodegenerative diseases. Finally, we describe how GEF can be applied to improve the quality of life of senior citizens in aging societies.

|keywords=* Brain aging
* Gintonin
* Neurodegenerative diseases
* Panax ginseng
* Rejuvenation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426447
}}
{{medline-entry
|title=Late-life related subtypes of depression - a data-driven approach on cognitive domains and physical frailty.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32442243
|abstract=With increasing age, symptoms of depression may increasingly overlap with age-related physical frailty and cognitive decline. We aim to identify late-life related subtypes of depression based on measures of depressive symptom dimensions, cognitive performance and physical frailty. A clinical cohort study of 375 depressed older patients with a DSM-IV depressive disorder (acronym NESDO). A latent profile analysis ([[LPA]]) was applied on the three subscales of the Inventory of Depressive Symptomatology, as well as performance in five cognitive domains and two proxies for physical frailty. For each class, we investigated remission, dropout and mortality at two-year follow-up as well as change over time of depressive symptom severity, cognitive performance, and physical frailty. An [[LPA]] model with 5 classes best described the data, yielding two subgroups suffering from pure depression ('mild' and 'severe' depression, 55% of all patients) and three subgroups characterized by a specific profile of cognitive and physical frailty features, labelled as 'amnestic depression', 'frail-depressed, physically dominated' and 'frail-depressed, cognitively dominated'. The prospective analyses showed that patients in the subgroup of "mild depression" and "amnestic depression" had the highest remission rates, while patients in both frail-depressed subgroups had the highest mortality rates. Late-life depression can be subtyped by specific combinations of age-related clinical features, which seems to have prospective relevance. Subtyping according the cognitive profile and physical frailty may be relevant for studies examining underlying disease processes as well as to stratify treatment studies on the effectiveness of antidepressants, psychotherapy and augmentation with geriatric rehabilitation.

|keywords=* cognitive aging
* depression
* frailty
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa110
}}
{{medline-entry
|title=Does sedentary time increase in older adults in the days following participation in intense exercise?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32130714
|abstract=Older adults have the highest sedentary time across all age groups, and only a small portion is meeting the minimum recommendations for weekly physical activity. Little research to date has looked at how changes in one of these behaviours influences the other. To assess changes in 24-h movement behaviours (sedentary time, light intensity physical activity ([[LPA]]), moderate-vigorous PA (MVPA) and sleep) over three consecutive days, following acute bouts of exercise of varying intensity in older adults. Participants (n = 28, 69.7 ± 6.5 years) completed a maximal exercise test and the following exercise protocols in random order: moderate continuous exercise (MOD), high-intensity interval exercise (HI) and sprint interval exercise (SPRT). A thigh-worn device (ActivPAL™) was used to measure movement behaviours at baseline and the 3 days following each exercise session. Repeated measures analysis of variance indicated that compared to baseline, participants decreased MVPA in the 3 days following all exercise sessions and decreased [[LPA]] following HI and SPRT (p < 0.05). Over half of the sample had clinically meaningful increases in sedentary time (30 min/day) in the days following exercise participation. Older adults who compensate for exercise participation by reducing physical activity and increasing sedentary time in subsequent days may require behavioural counseling to ensure that incidental and recreational physical activities are not reduced. It appears that older adults compensate for acute exercise by decreasing MVPA and [[LPA]], and increasing sedentary time in the days following exercise. Future research is needed to determine whether compensation persists with regular engagement.
|mesh-terms=* Accelerometry
* Aged
* Exercise
* Exercise Test
* Humans
* Sedentary Behavior
* Sleep
|keywords=* Aging
* Compensation
* High intensity
* Movement behaviours
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01502-6
}}
{{medline-entry
|title=Association of Long-term Exposure to Elevated Lipoprotein(a) Levels With Parental Life Span, Chronic Disease-Free Survival, and Mortality Risk: A Mendelian Randomization Analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32108890
|abstract=Elevated lipoprotein(a) (Lp[a]) levels are associated with atherosclerotic cardiovascular diseases. The association between high Lp(a) levels and human longevity phenotypes is, however, controversial. To examine whether genetically determined Lp(a) levels are associated with parental life span and chronic disease-free survival (health span) and the association between Lp(a) levels and long-term, all-cause mortality risk. In this genetic association study, cross-sectional mendelian randomization (UK Biobank [2006-2010] and LifeGen Consortium) and prospective analyses (European Prospective Investigation Into Cancer and Nutrition (EPIC)-Norfolk [1993-1997, with patients followed up to 2016]) were conducted using individual-level data on 139 362 participants. The association between a weighted genetic risk score of 26 independent single-nucleotide polymorphisms at the [[LPA]] locus on parental life span using individual participant data from the UK Biobank, as well as with summary statistics of a genome-wide association study of more than 1 million life spans (UK Biobank and LifeGen), were examined. The association between these single-nucleotide polymorphisms and the age at the end of the health span was tested using summary statistics of a previous genome-wide association study in the UK Biobank. The association between Lp(a) levels and all-cause mortality in the EPIC-Norfolk study was also investigated. Data were analyzed from December 2018 to December 2019. Genetically determined and measured Lp(a) levels. Parental life span, health span, and all-cause mortality. In 139 362 white British participants (mean [SD] age, 62.8 [3.9] years; 52% women) from the UK Biobank, increases in the genetic risk score (weighted for a 50-mg/dL increase in Lp[a] levels) were inversely associated with a high parental life span (odds ratio, 0.92; 95% CI, 0.89-0.94; P = 2.7 × 10-8). Using the Egger-mendelian randomization method, a negative association between [[LPA]] single-nucleotide polymorphisms and parental life span (mean [SD] Egger-mendelian randomization slope, -0.0019 [0.0002]; P = 2.22 × 10-18) and health span (-0.0019 [0.0003]; P = 3.00 × 10-13) was noted. In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064]). The results of this study suggest a potential causal effect of absolute Lp(a) levels on human longevity as defined by parental life span, health span, and all-cause mortality. The results also provide a rationale for trials of Lp(a)-lowering therapy in individuals with high Lp(a) levels.
|mesh-terms=* Aged
* Case-Control Studies
* Cross-Sectional Studies
* Female
* Humans
* Lipoprotein(a)
* Longevity
* Male
* Mendelian Randomization Analysis
* Middle Aged
* Parents
* Phenotype
* Prospective Studies
* Risk Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049087
}}
{{medline-entry
|title=Elevated Autotaxin and [[LPA]] Levels During Chronic Viral Hepatitis and Hepatocellular Carcinoma Associate with Systemic Immune Activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31769428
|abstract=Circulating autotaxin (ATX) is elevated in persons with liver disease, particularly in the setting of chronic hepatitis C virus (HCV) and HCV/HIV infection. It is thought that plasma ATX levels are, in part, attributable to impaired liver clearance that is secondary to fibrotic liver disease. In a discovery data set, we identified plasma ATX to be associated with parameters of systemic immune activation during chronic HCV and HCV/HIV infection. We and others have observed a partial normalization of ATX levels within months of starting interferon-free direct-acting antiviral (DAA) HCV therapy, consistent with a non-fibrotic liver disease contribution to elevated ATX levels, or HCV-mediated hepatocyte activation. Relationships between ATX, lysophosphatidic acid ([[LPA]]) and parameters of systemic immune activation will be discussed in the context of HCV infection, age, immune health, liver health, and hepatocellular carcinoma (HCC).

|keywords=* Aging
* Autotaxin
* Hepatitis
* Hepatocellular Carcinoma
* Immune Activation
* Immunity
* Inflammation
* Liver
* Lysophosphatidic Acid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966516
}}
{{medline-entry
|title=Lysophosphatidic acid receptor [[LPA]]  prevents oxidative stress and cellular senescence in Hutchinson-Gilford progeria syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31714004
|abstract=Hutchinson-Gilford progeria syndrome (HGPS) is a rare laminopathy that produces a mutant form of prelamin A, known as Progerin, resulting in premature aging. HGPS cells show morphological abnormalities of the nuclear membrane, reduced cell proliferation rates, accumulation of reactive oxygen species (ROS), and expression of senescence markers. Lysophosphatidic acid ([[LPA]]) is a growth factor-like lipid mediator that regulates various physiological functions via activating multiple [[LPA]] G protein-coupled receptors. Here, we study the roles of [[LPA]] and [[LPA]] receptors in premature aging. We report that the protein level of [[LPA]]  was highly downregulated through internalization and the lysosomal degradation pathway in Progerin-transfected HEK293 cells. By treating Progerin HEK293 cells with an [[LPA]]  agonist (OMPT, 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate) and performing shRNA knockdown of the Lpa3r transcript in these cells, we showed that [[LPA]]  activation increased expression levels of antioxidant enzymes, consequently inhibiting ROS accumulation and ameliorating cell senescence. [[LPA]]  was shown to be downregulated in HGPS patient fibroblasts through the lysosomal pathway, and it was shown to be crucial for ameliorating ROS accumulation and cell senescence in fibroblasts. Moreover, in a zebrafish model, [[LPA]]  deficiency was sufficient to cause premature aging phenotypes in multiple organs, as well as a shorter lifespan. Taken together, these findings identify the decline of [[LPA]]  as a key contributor to the premature aging phenotypes of HGPS cells and zebrafish.

|keywords=* 1-Oleoyl-2-O-methyl-rac-glycerophosphothionate
* Hutchinson-Gilford progeria syndrome
* LPA3
* cell senescence
* lysophosphatidic acid
* reactive oxygen species
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974717
}}
{{medline-entry
|title=Associations of Sedentary and Physically-Active Behaviors With Cognitive-Function Decline in Community-Dwelling Older Adults: Compositional Data Analysis From the NEIGE Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31656243
|abstract=Physical activity can help to protect against cognitive decline in older adults. However, little is known about the potential combined relationships of time spent in sedentary behavior (SB), light-intensity physical activity ([[LPA]]), and moderate-to-vigorous physical activity (MVPA) with indices of cognitive health. We examined the cross-sectional associations of objectively-determined sedentary and physically-active behaviors with an indicator of cognitive function decline (CFD) in older adults. A randomly-recruited sample of 511 Japanese older adults (47% male; aged 65-84 years) wore a tri-axial accelerometer for 7 consecutive days in 2017. Cognitive function was assessed by interviewers using the Japanese version of Mini-Mental State Examination, with a score of ≤23 indicating CFD. Associations of sedentary and physically-active behaviors with CFD were examined using a compositional logistic regression analysis based on isometric log-ratio transformations of time use, adjusting for potential confounders. Forty one (9.4%) of the participants had an indication of CFD. Activity compositions differed significantly between CFD and normal cognitive function (NCF); the proportion of time spent in MVPA was 39.1% lower, relative to the overall mean composition in those with CFD, and was 5.3% higher in those with NCF. There was a significant beneficial association of having a higher proportion of MVPA relative to other activities with CFD. [[LPA]] and SB were not associated with CFD when models were corrected for time spent in all activity behaviors. Larger relative contribution of MVPA was favorably associated with an indicator of CFD in older adults.

|keywords=* accelerometry
* aging
* exercise
* neurocognitive disorders
* sedentary lifestyle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557173
}}
{{medline-entry
|title=Validation and comparison of two automated methods for quantifying brain white matter hyperintensities of presumed vascular origin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31612759
|abstract=White matter hyperintensities (WMH) are a common imaging finding indicative of cerebral small vessel disease. Lesion segmentation algorithms have been developed to overcome issues arising from visual rating scales. In this study, we evaluated two automated methods and compared them to visual and manual segmentation to determine the most robust algorithm provided by the open-source Lesion Segmentation Toolbox (LST). We compared WMH data from visual ratings (Scheltens' scale) with those derived from algorithms provided within LST. We then compared spatial and volumetric WMH data derived from manually-delineated lesion maps with WMH data and lesion maps provided by the LST algorithms. We identified optimal initial thresholds for algorithms provided by LST compared with visual ratings (Lesion Growth Algorithm (LGA): initial κ and lesion probability thresholds, 0.5; Lesion Probability Algorithm ([[LPA]]) lesion probability threshold, 0.65). LGA was found to perform better then [[LPA]] compared with manual segmentation. LGA appeared to be the most suitable algorithm for quantifying WMH in relation to cerebral small vessel disease, compared with Scheltens' score and manual segmentation. LGA offers a user-friendly, effective WMH segmentation method in the research environment.

|keywords=* White matter hyperintensity
* brain aging
* cerebral small vessel disease
* lesion segmentation
* methodology
* validation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607266
}}
{{medline-entry
|title=The Sedentary Time and Physical Activity Levels on Physical Fitness in the Elderly: A Comparative Cross Sectional Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31581429
|abstract=Ageing is a life-long process characterized by a progressive loss of physical fitness compromising strength, flexibility, and agility. The purpose of this study was to use accelerometry to examine the relationship between sedentary time, light physical activity ([[LPA]]), and moderate to vigorous physical activity (MVPA) with the elderly's physical fitness. Additionally, we aimed to examine the association between the aforementioned variables on older adults who fulfilled global recommendations on physical activity for health and on those who did not fulfil these recommendations. Eighty-three elderly (mean ± SD: 72.14 ± 5.61 years old) of both genders volunteered to participate in this cross-sectional study, being divided into an active group (n = 53; 71.02 ± 5.27 years old) and an inactive group (n = 30; 74.13 ± 5.72 years old) according to the established guidelines. Sedentary and physical activity times were assessed using an ActiGraph  GT1M accelerometer, whereas physical fitness was evaluated with the Senior Fitness Test. MVPA time was correlated with lower body mass index (BMI) ((r  = -0.218; [i]p[/i] = 0.048; -0.3 < r ≤ -0.1 (small)) and shorter time to complete the agility test ((r  = -0.367; [i]p[/i] = 0.001; -0.5 < r ≤ -0.3 (low)). Moreover, MVPA time was positively correlated with aerobic endurance ((r  = 0.397; [i]p[/i] = 0.000; 0.5 < r ≤ 0.3 (low)) and strength ((r  = 0.243; [i]p[/i] = 0.027; 0.3 < r ≤ 0.1 (small)). In the inactive group, MVPA time was positively correlated with upper limb flexibility ((rs = 0.400; [i]p[/i] = 0.028; 0.5 < r ≤ 0.3 (low)); moreover, sedentary time was negatively correlated with upper limb flexibility ((r = -0.443; [i]p[/i] = 0.014; -0.5 < r ≤ -0.3 (low)), and [[LPA]] time was negatively correlated with BMI ((r = -0.423; [i]p[/i] = 0.020; -0.5 < r ≤ -0.3 (low)). In the active group, MVPA time was correlated with lower BMI ((rs = -0.320; [i]p[/i] = 0.020; -0.5 < r ≤ -0.3 (low)), and shorter time to complete agility test ((rs = -0.296; [i]p[/i] = 0.031; -0.3 < r ≤ -0.1 (small)). Our results reinforce the importance of promoting MVPA practice among the elderly, thereby allowing physical fitness maintenance or improvement.
|mesh-terms=* Accelerometry
* Aged
* Aged, 80 and over
* Aging
* Body Mass Index
* Cross-Sectional Studies
* Exercise
* Female
* Humans
* Male
* Physical Fitness
* Sedentary Behavior
|keywords=* accelerometry
* ageing
* health
* physical fitness
* sedentary behaviour
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801920
}}
{{medline-entry
|title=Light-Intensity Physical Activity in a Large Prospective Cohort of Older US Adults: A 21-Year Follow-Up of Mortality.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31600755
|abstract=Studies show that regular moderate to vigorous physical activity is associated with a lower risk of cardiovascular disease, certain cancers, and premature death, but few studies have examined associations of light-intensity physical activity ([[LPA]]) and mortality, especially among older adults. The aim of this study was to investigate the association of [[LPA]] with the risks of death from all causes, cancer, cardiovascular diseases, and respiratory diseases among older adults in the Cancer Prevention Study-II Nutrition Cohort (CPS-II NC). Analyses included 123,232 participants in CPS-II NC, among whom 46,829 died during follow-up (1993-2014). Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for self-reported leisure time [[LPA]] associated with mortality. Engaging in little or no [[LPA]] (<3 metabolic equivalent [MET]-h/week) was associated with a 16% higher risk of all-cause mortality (HR 1.16, 95% CI 1.12-1.20) compared to engaging in some [[LPA]] (3 to <9 MET-h/week) after adjusting for moderate to vigorous physical activity. However, there was no evidence of a dose-response relationship. A statistically significant interaction with age suggested that more [[LPA]] was associated with a lower risk of respiratory disease mortality only among participants aged ≥70 years (21+ vs. 3 to <9 MET-h/week, HR 0.78, 95% CI 0.66-0.91; pint = 0.003). In this prospective study of older adults, accumulating little/no leisure time [[LPA]] was associated with a higher risk of mortality. It is of substantial public health value to demonstrate the potential benefits of engaging in any activity, even if light in intensity, among older adults given the aging US population.
|mesh-terms=* Aged
* Cardiovascular Diseases
* Cohort Studies
* Exercise
* Female
* Follow-Up Studies
* Humans
* Leisure Activities
* Male
* Middle Aged
* Mortality
* Neoplasms
* Proportional Hazards Models
* Prospective Studies
* Respiratory Tract Diseases
* Risk Factors
* Surveys and Questionnaires
* United States
|keywords=* Aging
* Cancer prevention study
* Leisure time physical activity
* Light-intensity physical activity
|full-text-url=https://sci-hub.do/10.1159/000502860
}}
==SIRT6==

{{medline-entry
|title=Association between [[SIRT6]] Methylation and Human Longevity in a Chinese Population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33238266
|abstract=Sirtuin 6 gene ([[SIRT6]]) is a longevity gene that is involved in a variety of metabolic pathways, but the relationship between [[SIRT6]] methylation and longevity has not been clarified. We conducted a case-control study on 129 residents with a family history of longevity (1 of parents, themselves, or siblings aged ≥90 years) and 86 individuals without a family history of exceptional longevity to identify the association. DNA pyrosequencing was performed to analyze the methylation status of [[SIRT6]] promoter CpG sites. qRT-PCR and ELISA were used to estimate the [[SIRT6]] messenger RNA (mRNA) levels and protein content. Six CpG sites (P1-P6) were identified as methylation variable positions in the [[SIRT6]] promoter region. At the P2 and P5 CpG sites, the methylation rates of the longevity group were lower than those of the control group (p < 0.001 and p = 0.009), which might be independent determinants of longevity. The mRNA and protein levels of [[SIRT6]] decreased in the control group (p < 0.0001 and p = 0.038). The mRNA level negatively correlated with the methylation rates at the P2 (rs = -0.173, p = 0.011) and P5 sites (rs = -0.207, p = 0.002). Furthermore, the protein content positively correlated with the methylation rate at the P5 site (rs = 0.136, p = 0.046) but showed no significant correlation with the methylation rate at the P2 site. The low level of [[SIRT6]] methylation may be a potential protective factor of Chinese longevity.

|keywords=* DNA Methylation
* Longevity
* Messenger RNA
* SIRT6
|full-text-url=https://sci-hub.do/10.1159/000508832
}}
{{medline-entry
|title=The [[SIRT6]] activator MDL-800 improves genomic stability and pluripotency of old murine-derived iPS cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33089974
|abstract=Cellular reprogramming is an emerging strategy for delaying the aging processes. However, a number of challenges, including the impaired genome integrity and decreased pluripotency of induced pluripotent stem cells (iPSCs) derived from old donors, may hinder their potential clinical applications. The longevity gene, Sirtuin 6 ([[SIRT6]]), functions in multiple biological processes such as the maintenance of genome integrity and the regulation of somatic cell reprogramming. Here, for the first time, we demonstrate that MDL-800, a recently developed selective [[SIRT6]] activator, improved genomic stability by activating two DNA repair pathways-nonhomologous end joining (NHEJ) and base excision repair (BER) in old murine-derived iPSCs. More interestingly, we found that pretreating old murine iPSCs, which normally exhibit a restricted differentiation potential, with MDL-800 promoted the formation of teratomas comprised of all three germ layers and robustly stimulated chimera generation. Our findings suggest that pharmacological activation of [[SIRT6]] holds great promise in treating aging-associated diseases with iPSC-based cell therapy.

|keywords=* DNA repair
* MDL-800
* SIRT6
* aging
* genome integrity
* pluripotency
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431819
}}
{{medline-entry
|title=Sirtuins as Possible Predictors of Aging and Alzheimer's Disease Development: Verification in the Hippocampus and Saliva.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33098511
|abstract=Verification of signaling molecules in the saliva is a non-invasive method of diagnosis and evaluation of treatment effectiveness in different pathologies. Sirtuins (SIRT), proteins from NAD-dependent histone deacetylases, are supposed to be involved in the pathogenesis of Alzheimerэs disease. Age-related decrease in sirtuins expression induces many pathophysiological processes that could lead to neurodegeneration. We studied the expression of SIRT1, SIRT3, SIRT5, and [[SIRT6]] in the hippocampus and saliva of humans without neurological pathologies and in patients with Alzheimer's disease of elderly and senile age. In elderly and senile patients, the expression of SIRT1, SIRT3, and [[SIRT6]] in the hippocampus and saliva was 1.5-4.9-fold reduced in comparison with healthy individuals of the corresponding age. In healthy senile persons, the expression of [[SIRT6]] in the hippocampus and saliva was 2.5-4.5-fold lower than in healthy elderly individuals. Measurement of SIRT1, SIRT3, and [[SIRT6]] concentration in the saliva can be used as an additional method for intravital non-invasive diagnosis of Alzheimer's disease in patients of advanced age. [[SIRT6]] concentration in the saliva can be recommended as a marker for assessment of the rate of aging.

|keywords=* Alzheimer’s disease
* aging
* intravital diagnosis
* saliva
* sirtuins
|full-text-url=https://sci-hub.do/10.1007/s10517-020-04986-4
}}
{{medline-entry
|title=Age-related epigenetic drift deregulates [i][[SIRT6]][/i] expression and affects its downstream genes in human peripheral blood mononuclear cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32573339
|abstract=Sirtuin 6 ([[SIRT6]]) exerts a protective effect on health and extends the lives of model organisms. We, therefore, aimed to clarify whether age-related epigenetic drift is responsible for differences in [i][[SIRT6]][/i] expression in peripheral blood mononuclear cells (PBMCs) of healthy young (n = 55, mean age 27.5 ± 4.4 years), middle-aged (n = 51, 65.4 ± 3.3 years), and long-lived (n = 51, 93.9 ± 3.6 years) humans. [i]In silico[/i] analysis was performed using the STRING network. No age-related differences were observed in the percentage of [i][[SIRT6]][/i] CpG island methylation. However, the age affected the expression of miR-34a-5p, miR-125a-5p, miR-186-5p, miR-342-5p and miR-766-3p (all p < 0.0001), miR-181-2-3p and Let-7c (both p = 0.0003), and miR-103a-3p (p = 0.0069). A negative association was observed between [i][[SIRT6]][/i] mRNA and miR-186-5p (r  = -0.25, p = 0.026), and a positive association was observed with miR-34a-5p (r  = 0.31, p = 0.0055) and miR-181a-2-3p (r  = 0.39, p = 0.0002). [i][[SIRT6]][/i] mRNA also negatively correlated with the expression of [i]TP53[/i] (r  = -0.41, p = 0.0126) and [i]MYC[/i] (r  = -0.35, p = 0.0448). Notably, the expression of several miRNAs and genes was similar in young and long-lived groups but different from the middle-aged group. We conclude that age-related epigenetic changes can affect the expression of [[SIRT6]] in PBMCs and, in this way, possibly influence immunosenescence. Moreover, molecular events could differentiate 'normal' ageing from that of long-lived individuals.

|keywords=* SIRT6
* aging
* interaction network
* longevity
* methylation
* miRNA
* peripheral blood mononuclear cells (PBMCs)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678931
}}
{{medline-entry
|title=Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32518153
|abstract=Sirtuin 6 ([[SIRT6]]) is a nuclear NAD -dependent deacetylase of histone H3 that regulates genome stability and gene expression. However, nonhistone substrates and additional catalytic activities of [[SIRT6]], including long-chain deacylation and mono-ADP-ribosylation of other proteins, have also been reported, but many of these noncanonical roles remain enigmatic. Genetic studies have revealed critical homeostatic cellular functions of [[SIRT6]], underscoring the need to better understand which catalytic functions and molecular pathways are driving [[SIRT6]]-associated phenotypes. At the physiological level, [[SIRT6]] activity promotes increased longevity by regulating metabolism and DNA repair. Recent work has identified natural products and synthetic small molecules capable of activating the inefficient [i]in vitro[/i] deacetylase activity of [[SIRT6]]. Here, we discuss the cellular functions of [[SIRT6]] with a focus on attributing its catalytic activity to its proposed biological functions. We cover the molecular architecture and catalytic mechanisms that distinguish [[SIRT6]] from other NAD -dependent deacylases. We propose that combining specific [[SIRT6]] amino acid substitutions identified in enzymology studies and activity-selective compounds could help delineate [[SIRT6]] functions in specific biological contexts and resolve the apparently conflicting roles of [[SIRT6]] in processes such as tumor development. We further highlight the recent development of small-molecule modulators that provide additional biological insight into [[SIRT6]] functions and offer therapeutic approaches to manage metabolic and age-associated diseases.

|keywords=* SIRT6
* activator
* aging
* cancer
* cell metabolism
* chromatin
* gene expression
* histone deacetylase (HDAC)
* longevity
* metabolic disorder
* sirtuin
* small molecule
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415977
}}
{{medline-entry
|title=Age-dependent role of [[SIRT6]] in jawbone via regulating senescence and autophagy of bone marrow stromal cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32002721
|abstract=Age-related jawbone loss directly impact the function of oral cavity resulted from tooth loss, implant failure, and jaw fracture. Numerous evidences show that age-related senescence of bone marrow stromal cells (BMSCs) play a critical role in bone loss, but little attention has been paid to jawbone. Here, we delineated the critical role of sirtuin family protein 6 ([[SIRT6]]) in senescence, autophagy, and osteogenesis of BMSCs from jawbones. Radiography analysis showed less jawbone quality in elderly than young people. We also showed that [[SIRT6]] expression decreased in bone tissue and BMSCs from the elderly by immunochemical staining. BMSCs from the elderly exhibited decreased osteogenic differentiation and inclined senescence which these phenotypes could be simulated by [[SIRT6]] knockdown. Furthermore, accompanied with the inhibition of [[SIRT6]], the autophagy level and ostogenesis of BMSCs was also decreased. However, using rapamycin, an autophagy activator, could rescue these adverse effects of BMSCs caused by [[SIRT6]] inhibition. Mechanistically, [[SIRT6]] regulated the autophagy and osteogenesis of BMSCs by activating AKT-mTOR pathway, at least in part. Finally, a decreased jawbone quality was shown in [[SIRT6]] haploinsufficiency mice by Wnt1 specific tissue knockdown (Wnt1-Cre;[[SIRT6]] ) model. Taken together, our data revealed that [[SIRT6]] adjusted senescence and osteogenesis of BMSCs via altering autophagy level, and associated with age-related bone loss. [[SIRT6]] could be as a promising therapeutic target for age-related osteoporosis of jawbone.
|mesh-terms=* Adult
* Aged
* Aging
* Animals
* Bone Marrow Cells
* Humans
* Jaw
* Male
* Mesenchymal Stem Cells
* Mice
* Mice, Knockout
* Middle Aged
* Osteogenesis
* Sirtuins
|keywords=* Autophagy
* Bone marrow stromal cells
* Jawbone
* Osteoporosis
* SIRT6
* Senescence
|full-text-url=https://sci-hub.do/10.1007/s10735-020-09857-w
}}
{{medline-entry
|title=Mechanism of activation for the sirtuin 6 protein deacylase.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31822559
|abstract=The histone deacetylase sirtuin 6 ([[SIRT6]]) regulates numerous biological functions, including transcriptional repression, DNA repair, and telomere maintenance. Recombinant [[SIRT6]] displays catalytic efficiencies 2 orders of magnitude greater for long-chain deacylation than deacetylation against peptide substrates; however, deacetylation can be enhanced by allosteric small-molecule activators. Here, we investigated the mechanisms of activated lysine deacetylation and enhanced long-chain acyl-group removal by [[SIRT6]]. Activity-based screening identified compounds that activated histone peptide deacetylation 18-48-fold. Chemical optimization based on structure-activity relationships yielded an activator with improved potency and selectivity for [[SIRT6]]. Using this novel activator, we conducted biochemical and kinetic analyses revealing that [[SIRT6]] is activated via acceleration of a catalytic step occurring after substrate binding but before NAD  cleavage. We identified a [[SIRT6]] variant, R65A, that maintains basal deacetylase activity but cannot be activated and failed to enhance long-chain deacylation. Additional biochemical studies revealed that Arg-65 is critical for activation by facilitating a conformational step that initiates chemical catalysis. This work suggests that [[SIRT6]] activation of deacetylation involves a similar mechanism to improved catalysis as that of long-chain deacylation. The identification of novel [[SIRT6]] activators and the molecular insights into activation and catalysis presented here provide a foundational understanding for physiological [[SIRT6]] activation and for rational design of activating molecules.
|mesh-terms=* Allosteric Regulation
* Biocatalysis
* Fatty Acids
* HEK293 Cells
* Histones
* Humans
* Hydrophobic and Hydrophilic Interactions
* Kinetics
* Lipids
* Mutagenesis
* Mutation
* NAD
* Peptides
* Protein Binding
* Protein Conformation
* Sirtuins
* Small Molecule Libraries
|keywords=* SIRT6
* activator
* cancer
* chromatin
* deacetylation
* epigenetics
* histone
* histone deacetylase (HDAC)
* lifespan
* long chain acyl substrate
* longevity
* sirtuin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996886
}}
{{medline-entry
|title=Proteomics of Long-Lived Mammals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31737995
|abstract=Mammalian species differ up to 100-fold in their aging rates and maximum lifespans. Long-lived mammals appear to possess traits that extend lifespan and healthspan. Genomic analyses have not revealed a single pro-longevity function that would account for all longevity effects. In contrast, it appears that pro-longevity mechanisms may be complex traits afforded by connections between metabolism and protein functions that are impossible to predict by genomic approaches alone. Thus, metabolomics and proteomics studies will be required to understand the mechanisms of longevity. Several examples are reviewed that demonstrate the naked mole rat (NMR) shows unique proteomic signatures that contribute to longevity by overcoming several hallmarks of aging. [[SIRT6]] is also discussed as an example of a protein that evolves enhanced enzymatic function in long-lived species. Finally, it is shown that several longevity-related proteins such as Cip1/p21, FOXO3, TOP2A, AKT1, RICTOR, INSR, and [[SIRT6]] harbor posttranslational modification (PTM) sites that preferentially appear in either short- or long-lived species and provide examples of crosstalk between PTM sites. Prospects of enhancing lifespan and healthspan of humans by altering metabolism and proteoforms with drugs that mimic changes observed in long-lived species are discussed.

|keywords=* SIRT6
* aging
* long-lived mammals
* naked mole rats
* proteomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7117992
}}
{{medline-entry
|title=Sirtuins and [[SIRT6]] in Carcinogenesis and in Diet.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31591350
|abstract=Sirtuins are a highly conserved family of nicotinamide adenine dinucleotide (NAD)-dependent protein lysine modifying enzymes. They are key regulators for a wide variety of cellular and physiological processes such as cell proliferation, differentiation, DNA damage and stress response, genome stability, cell survival, metabolism, energy homeostasis, organ development and aging. Aging is one of the major risk factors of cancer, as many of the physiological mechanisms and pathologies associated with the aging process also contribute to tumor initiation, growth and/or metastasis. This review focuses on one the mammalian sirtuins, [[SIRT6]], which has emerged as an important regulator of longevity and appears to have multiple biochemical functions that interfere with tumor development and may be useful in cancer prevention and for site-specific treatment. The recent evidence of the role of [[SIRT6]] in carcinogenesis is also discussed, focusing on the potential use of [[SIRT6]] modulators in cancer nanomedicine.
|mesh-terms=* Aging
* Animals
* Carcinogenesis
* Diet
* Gene Expression Regulation, Neoplastic
* Humans
* Nanomedicine
* Organ Specificity
* Sirtuins
|keywords=* SIRT6
* cancer
* chemotherapy
* diet
* modulator
* sirtuins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801518
}}
{{medline-entry
|title=[[SIRT6]]-mediated transcriptional suppression of MALAT1 is a key mechanism for endothelial to mesenchymal transition.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31399301
|abstract=Vascular aging has profound effects on cardiovascular diseases. Endothelial to mesenchymal transition (EndMT) is defined as the acquisition of mesenchymal characteristics by endothelial cells (ECs) and has been found induced in a model of ECs aging. However, whether EndMT occurs during aging in vivo, the functional significance of EndMT on vascular biology and the underlying mechanisms remain unknown. In this study, we examined the vascular ECs from young (2 months old) and old (18 months old) mice, and demonstrated that aged ECs underwent EndMT. Moreover, the transwell assay showed that EndMT process was accompanied by increased endothelial permeability. It was found that sirtuin 6 ([[SIRT6]]), a nicotinamide adenine dinucleotide  (NAD )-dependent histone deacetylase, was down-regulated during ECs aging. Knockdown of [[SIRT6]] in young ECs could induce EndMT. Next, we identified five long non-coding RNAs that are enriched in ECs for downstream effector of [[SIRT6]]; only metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was significantly up-regulated in aged ECs. Knockdown of [[SIRT6]] could increase MALAT1 levels. Furthermore, the ChIP assay and luciferase reporter gene assay confirmed that [[SIRT6]] bound directly to the promoter region of MALAT1 and suppressed MALAT1 expression. Finally, we demonstrated that MALAT1 mediated aging-induced EndMT through increasing Snail expression. Our study provides in vivo evidence that ECs undergo EndMT during vascular aging, which increases endothelial permeability. [[SIRT6]]-mediated transcriptional suppression of MALAT1 is a key mechanism for EndMT. Manipulating EndMT may be considered as a new therapeutic strategy for retarding aging-associated vascular diseases.
|mesh-terms=* Aging
* Animals
* Cells, Cultured
* Disease Models, Animal
* Endothelium, Vascular
* Epithelial-Mesenchymal Transition
* Gene Expression Regulation
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* RNA, Long Noncoding
* Signal Transduction
* Sirtuins
* Vascular Diseases

|full-text-url=https://sci-hub.do/10.1016/j.ijcard.2019.07.082
}}
==AMH==

{{medline-entry
|title=Beyond premature ovarian insufficiency: Staging reproductive aging in adolescent and young adult cancer survivors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33141175
|abstract=While stages of reproductive aging for women in the general population are well described by STRAW+10 criteria, this is largely unknown for female adolescent and young adult cancer survivors (AYA survivors). To evaluate applying STRAW+10 criteria in AYA survivors using bleeding patterns with and without endocrine biomarkers, and assess how cancer treatment gonadotoxicity is related to reproductive aging stage. The sample (n=338) included AYA survivors from the Window Study cohort. Menstrual bleeding data and dried blood spots for [[AMH]] and FSH measurements (Ansh DBS ELISAs) were utilized for reproductive aging stage assessment. Cancer treatment data were abstracted from medical records. Among participants, mean age 34.0±4.5 and at a mean of 6.9±4.6 years since cancer treatment, the most common cancers were lymphomas(31%), breast(23%), and thyroid(17%). Twenty-nine percent was unclassifiable by STRAW+10 criteria, occuring more frequently in the first 2 years from treatment . Most unclassifiable survivors exhibited bleeding patterns consistent with the menopausal transition, but had reproductive phase [[AMH]] and/or FSH levels. For classifiable survivors (48% peak reproductive, 30% late reproductive, 12% early transition, 3% late transition, 7% post-menopause), endocrine biomarkers distinguished among peak, early and late stages within the reproductive and transition phases. Gonadotoxic treatments were associated with more advanced stages. We demonstrate a novel association between gonadotoxic treatments and advanced stages of reproductive aging. Without endocrine biomarkers, bleeding pattern alone can misclassify AYA survivors into either more or less advanced stages. Moreover, a large proportion of AYA survivors exhibited combinations of endocrine biomarkers and bleeding patterns that do not fit STRAW+10 criteria, suggesting the need for modified staging for this population.

|keywords=* STRAW
* adolescent and young adult cancer
* menopausal transition
* premature ovarian insufficiency
* reproductive aging
|full-text-url=https://sci-hub.do/10.1210/clinem/dgaa797
}}
{{medline-entry
|title=Correlates and Timing of Reproductive Aging Transitions in a Global Cohort of Midlife Women With Human Immunodeficiency Virus: Insights From the REPRIEVE Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32645159
|abstract=Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [[[AMH]])] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial. A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; [[AMH]] level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; [[AMH]] <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; [[AMH]] <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones ([[AMH]] <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model. Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy. Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed. NCT0234429.

|keywords=* Cardiometabolic Risk
* HIV
* Menopause
* Reproductive Aging
* Sex
* Women
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347076
}}
{{medline-entry
|title=Epigenetic clock measuring age acceleration via DNA methylation levels in blood is associated with decreased oocyte yield.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32285295
|abstract=To investigate how biologic age (phenotypic age at which your body functions) greater than chronologic age, (age acceleration (AgeAccel)), correlates with oocyte yield. Thirty-nine women undergoing ovarian stimulation, inclusive of all infertility diagnoses, were included in this pilot study. Methylome analysis of peripheral blood was utilized to determine biologic age. AgeAccel was defined as biologic age > 2 years older than chronologic age. A negative binomial model was used to obtain the crude association of AgeAccel with number of oocytes. A parsimonious adjusted model for the number of oocytes was obtained using backwards selection (p < 0.05). Measures of age were negatively correlated with number of oocytes (chronological age Pearson ρ = - 0.45, biologic age Pearson ρ = - 0.46) and [[AMH]] was positively correlated with number of oocytes (Pearson ρ = 0.91). Patients with AgeAccel were noted to have lower [[AMH]] values (1.29 ng/mL vs. 2.29, respectively (p = 0.049)) and lower oocyte yield (5.50 oocytes vs. 14.50 oocytes, respectively (p = 0.0030)). A crude association of a 7-oocyte reduction in the age-accelerated group was found (- 6.9 oocytes (CI - 11.6, - 2.4)). In a model with [[AMH]] and antral follicle count, AgeAccel was associated with a statistically significant 3.3 reduction in the number of oocytes (- 3.1; 95% CI - 6.5, - 0.1; p = 0.036). In this small pilot study, AgeAccel is associated with a lower [[AMH]] and lower oocyte yield providing preliminary evidence that biologic age, specifically AgeAccel, may serve as an epigenetic biomarker to improve the ability of predictive models to assess ovarian reserve.

|keywords=* Aging
* DNA methylation
* Epigenetic clock
* Epigenetics
* Infertility
* Methylome
* Ovarian aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244694
}}
{{medline-entry
|title=Modeling Variation in the Reproductive Lifespan of Female Adolescent and Young Adult Cancer Survivors Using [[AMH]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32270202
|abstract=Many female survivors of adolescent and young adult cancers (AYA survivors) have shortened reproductive lifespans. However, the timing and duration of ovarian function after cancer treatment are largely unknown. To model the trajectory of ovarian function over two decades following cancer treatment and evaluate how trajectories vary by treatment gonadotoxicity and age. In a prospective cohort, AYA survivors aged 18-39 at variable times since cancer treatment completion provided dried blood spots (DBS) every 6 months for up to 18 months. Anti-Müllerian hormone ([[AMH]]) levels were measured using the Ansh DBS [[AMH]] enzyme-linked immunosorbent assay. The mean [[AMH]] trajectory was modeled for the entire cohort and separately by treatment gonadotoxicity and age using functional principal components analysis. 763 participants, mean (standard deviation) enrollment age 33.3 (4.7) and age at cancer diagnosis 25.9 (5.7) years, contributed 1905 DBS samples. The most common cancers were breast (26.9%), lymphoma (24.8%), and thyroid (18.0%). [[AMH]] trajectories differed among survivors by treatment gonadotoxicity (low, moderate, or high) (P < 0.001). Following low or moderately gonadotoxic treatments, [[AMH]] levels increased over 2-3 years and plateaued over 10-15 years before declining. In contrast, following highly gonadotoxic treatment, [[AMH]] levels were lower overall and declined shortly after peak at 2-3 years. Younger age at treatment was associated with higher trajectories, but a protective effect of younger age was not observed in survivors exposed to highly gonadotoxic treatments (Pinteraction < 0.001). In this large AYA survivor cohort, timing and duration of ovarian function strongly depended on treatment gonadotoxicity and age at treatment. The findings provide novel, more precise information to guide reproductive decision-making.

|keywords=* AMH
* adolescent and young adult cancer
* functional principal components analysis
* ovarian reserve
* reproductive lifespan
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7329316
}}
{{medline-entry
|title=Improving Prediction of Age at Menopause Using Multiple Anti-Müllerian Hormone Measurements: the Tehran Lipid-Glucose Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32109280
|abstract=Several statistical models were introduced for the prediction of age at menopause using a single measurement of anti-müllerian hormone ([[AMH]]); however, individual prediction is challenging and needs to be improved. The objective of this study was to determine whether multiple [[AMH]] measurements can improve the prediction of age at menopause. All eligible reproductive-age women (n = 959) were selected from the Tehran Lipid and Glucose Study. The serum concentration of [[AMH]] was measured at the time of recruitment and twice after that at an average of 6-year intervals. An accelerated failure-time model with Weibull distribution was used to predict age at menopause, using a single [[AMH]] value vs a model that included the annual [[AMH]] decline rate. The adequacy of these models was assessed using C statistics. The median follow-up period was 14 years, and 529 women reached menopause. Adding the annual decline rate to the model that included single [[AMH]] improved the model's discrimination adequacy from 70% (95% CI: 67% to 71%) to 78% (95% CI: 75% to 80%) in terms of C statistics. The median of differences between actual and predicted age at menopause for the first model was -0.48 years and decreased to -0.21 in the model that included the decline rate. The predicted age at menopause for women with the same amount of age-specific [[AMH]] but an annual [[AMH]] decline rate of 95 percentiles was about one decade lower than in those with a decline rate of 5 percentiles. Prediction of age at menopause could be improved by multiple [[AMH]] measurements; it will be useful in identifying women at risk of early menopause.

|keywords=* Tehran Lipid and Glucose Study (TLGS)
* anti-müllerian hormone (AMH)
* menopause
* reproductive aging
|full-text-url=https://sci-hub.do/10.1210/clinem/dgaa083
}}
{{medline-entry
|title=Antimullerian Hormone and Impending Menopause in Late Reproductive Age: The Study of Women's Health Across the Nation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31965189
|abstract=A test that helps predict the time to the final menstrual period (FMP) has been sought for many years. To assess the ability of antimullerian hormone ([[AMH]]) measurements to predictions the time to FMP. Prospective longitudinal cohort study. The Study of Women's Health Across the Nation. [[AMH]] and FSH were measured in 1537 pre- or early perimenopausal women, mean age 47.5 ± 2.6 years at baseline, then serially until 12 months of amenorrhea occurred. [[AMH]] was measured using a 2-site ELISA with a detection limit of 1.85 pg/mL. Areas under the receiver operating curves (AUC) for [[AMH]]-based and FSH-based predictions of time to FMP, stratified by age. Probabilities that women would undergo their FMP in the next 12, 24, or 36 months across a range of [[AMH]] values were assessed. AUCs for predicting that the FMP will occur within the next 24 months were significantly greater for [[AMH]]-based than FSH-based models. The probability that a woman with an [[AMH]] <10 pg/mL would undergo her FMP within the next 12 months ranged from 51% at h<48 years of age to 79% at ≥51 years. The probability that a woman with an [[AMH]] >100 pg/mL would not undergo her FMP within the next 12 months ranged from 97% in women <48 years old to 90% in women ≥51 years old. [[AMH]] measurement helps estimate when a woman will undergo her FMP, and, in general, does so better than FSH.

|keywords=* aging
* female reproductive endocrinology
* gonadotropins
* inhibin/activin/follistatin/AMH
* menopause
* ovaries
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067546
}}
{{medline-entry
|title=Basal characterization and in vitro differentiation of putative stem cells derived from the adult mouse ovary.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31900800
|abstract=Lately, stem cell approaches have provided new information on reproductive organ function and additionally recommended novel treatment possibilities. The type(s) and differentiation potential of stem cells present in the mammalian ovary are largely unknown; while oogonial stem cells have been reported, we explored the possibility that multipotent stem cells may reside in the ovary and have wide differentiation potential. In this experimental study, homogenates of whole mouse ovaries were sorted using the stem cell surface markers stem cell antigen-1 and stage specific embryonic antigen-1/CD15. Viable double-positive cells 3-10 μm in diameter were evaluated immediately after sorting and after culture using differentiation conditions. Ovarian-derived stem cells were differentiated into the three main cell types: adipocytes, chondrocytes, or osteocytes. The subsequent culture was performed in media containing bone morphogenetic protein 4 (BMP-4) and/or retinoic acid (RA). RA, BMP-4 or the two agents in combination, consistently stimulated germ cell gene expression. RA treatment strongly stimulated germline gene expression and also the development of cells that were morphologically reminiscent of oocytes. The germ cell genes Dazl, Ddx4, Figla, Gdf-9, Nobox, Prdm9, and Sycp-1 were all detected at low levels. Remarkably, treatment with BMP-4 alone significantly increased protein expression of the granulosa cell product anti-Müllerian hormone ([[AMH]]). We have shown that an inclusive isolation protocol results in the consistent derivation of multipotent stem cells from the adult ovary; these cells can be differentiated towards the germ cell fate (RA alone), somatic ovarian cell fate as indicated by [[AMH]] production (BMP-4 alone), or classical mesenchymal cell types. Taken together, these data suggest the presence of multipotent mesenchymal stem cells in the murine ovary.
|mesh-terms=* Aging
* Animals
* Anti-Mullerian Hormone
* Antigens, Ly
* Cell Differentiation
* Cell Shape
* Female
* Lewis X Antigen
* Membrane Proteins
* Mice, Inbred C57BL
* Ovary
* Stem Cells
|keywords=* BMP-4
* Multipotent
* Ovary
* Retinoic acid
* Stem cells
|full-text-url=https://sci-hub.do/10.1007/s11626-019-00411-x
}}
{{medline-entry
|title=Serum anti-Müllerian hormone concentration and follicle density throughout reproductive life and in different diseases-implications in fertility preservation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31782794
|abstract=How do anti-Müllerian hormone ([[AMH]]) serum concentrations and follicle densities (FDs) change with age and disease and what are the implications for fertility preservation? [[AMH]] concentrations and FD do not correlate in young women, and [[AMH]] but not FD is reduced in some diseases, limiting the value of [[AMH]] as a predictive parameter of ovarian tissue transplantation. [[AMH]] is widely used as a parameter to estimate the ovarian reserve. However, the reliability of [[AMH]] to predict total number of follicles and the FD is questionable. Women with lymphoma and leukaemia have been shown to have reduced [[AMH]] concentrations, but it is unknown if the FD is also reduced. In fertility preservation it is essential to estimate the correct total number of follicles and the FD, as ovarian tissue should only be cryopreserved if ovarian reserve is high. Furthermore, the amount of tissue to be transplanted should be based on the estimation of the real FD. This retrospective observational study included 830 women (mean ± SD age, 28.2 ± 6.81 years; range, 4-43 years) with malignant (n = 806) and benign (n = 24) diseases who cryopreserved tissue in a single centre as part of a national fertility preservation programme. Females with ovarian surgery or known predispositions for a reduced ovarian reserve were excluded. [[AMH]] concentrations and FD were evaluated from March 2011 to September 2016. [[AMH]] concentrations were analysed before gonadotoxic therapies. Standardized biopsies, obtained from different areas of ovarian cortex, were collected. FD was analysed after tissue digestion and calcein staining and was expressed as average number of primordial and primary follicles count per 3 mm biopsy and per cubic millimeter tissue. [[AMH]] concentrations and FD were analysed in relation to age and diagnosis group. Both parameters were age adjusted, and associations between the different diagnosis groups and [[AMH]] versus FD were assessed. Mean ± SD [[AMH]] concentration was 3.1 ± 2.81 g/ml, mean FD per 3 mm biopsy was 137 ± 173.9 and 19.4 ± 24.60 per mm3. Maximum [[AMH]] concentrations were found in children and teenagers at the age of 6-10 years (5.71 ng/ml) and in adults at the age of 21-25 years (3.33 ng/ml). FD was highest in young children up to an age of 15 years and decreased with increasing age. [[AMH]] and FD were not correlated in women ≤20 years and weakly to moderately correlated in women 21-40 years (r = 0.24-0.39). Age-adjusted correlations between [[AMH]] and FD were demonstrated in several diagnosis groups such as breast cancer, leukaemia, sarcoma, gastrointestinal cancer and gynaecological cancer but not in the groups exhibiting Hodgkin's and non-Hodgkin's lymphoma, cerebral cancer, other types of malignancies and other types of benign diseases. Further statistical analysis supported the finding that, in some diagnosis groups such as Hodgkin's lymphoma and in gynaecological cancer, [[AMH]] concentrations but not FDs are reduced, questioning the prognostic accuracy of [[AMH]] for the FD in these diseases. Even though biopsies were taken from different sites, heterogenous distribution of follicles might have had some effect on the accuracy of the analysis. [[AMH]] should be used with care to estimate the total ovarian reserve and FD of cancer patients in young women in some diseases. Therefore, calculating the amount of ovarian tissue to be transplanted based solely on [[AMH]] might be inaccurate whereas FD might be a better parameter. The study did not receive any exterior funding.
|mesh-terms=* Adolescent
* Adult
* Aging
* Anti-Mullerian Hormone
* Child
* Child, Preschool
* Female
* Fertility Preservation
* Humans
* Ovarian Follicle
* Retrospective Studies
* Young Adult
|keywords=* anti-Müllerian hormone
* cancer
* fertility preservation
* ovarian reserve
* ovarian tissue
* primary follicle
* primordial follicle
|full-text-url=https://sci-hub.do/10.1093/humrep/dez215
}}
{{medline-entry
|title=Associations Between Anti-Mullerian Hormone and Cardiometabolic Health in Reproductive Age Women Are Explained by Body Mass Index.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31586179
|abstract=The relationship between reproductive and cardiometabolic aging is unclear. It is unknown if the relationship differs across different clinical populations. To determine whether markers of ovarian reserve are associated with cardiometabolic risk in reproductive aged women with unexplained infertility (UI), polycystic ovary syndrome (PCOS), and regularly cycling women (OVA). Cross-sectional data from 8 US-based academic centers. Women aged 25-40 from 3 clinical populations: 870 with UI, 640 with PCOS, and 921 community-based OVA. Multivariable linear regression models were used to relate anti-mullerian hormone ([[AMH]]) and antral follicle count with cardiometabolic parameters including body mass index (BMI), waist circumference (WC), fasting glucose and insulin, homeostasis model assessment-insulin resistance (HOMA-IR), lipids, and C-reactive protein. In age and study site-adjusted models, [[AMH]] inversely related to BMI in the UI and OVA groups (P = 0.02 and P < 0.001). Among women with PCOS, [[AMH]] inversely related to BMI (P < 0.001), and also to WC (P < 0.001), fasting insulin (P < 0.01), HOMA-IR (P < 0.01), triglycerides (P = 0.04), and C-reactive protein (P < 0.001) and directly related to higher total (P = 0.02), low-density lipoprotein (P < 0.01), and high-density lipoprotein cholesterol (P < 0.01). In OVA, [[AMH]] also varied inversely with WC (P < 0.001), fasting insulin (P = 0.02), and HOMA-IR (P = 0.02). Adjustment for BMI eliminated associations in the OVA group but in PCOS, the relationship of [[AMH]] to total (P = 0.03) and low-density lipoprotein cholesterol (P = 0.003) remained. Associations observed between [[AMH]] and cardiometabolic indices are largely explained by BMI in women with and without PCOS. (J Clin Endocrinol Metab XX: 0-0, 2019).
|mesh-terms=* Adult
* Anti-Mullerian Hormone
* Biomarkers
* Body Mass Index
* Cardiovascular Diseases
* Case-Control Studies
* Cross-Sectional Studies
* Female
* Follow-Up Studies
* Humans
* Incidence
* Infertility, Female
* Polycystic Ovary Syndrome
* Prognosis
* United States
|keywords=* anti-mullerian hormone (AMH)
* cardiometabolic health
* cardiovascular risk
* ovarian aging
* ovarian reserve markers
* reproductive aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024739
}}
{{medline-entry
|title=Relationships between antral follicle count, blood serum concentration of anti-Müllerian hormone and fertility in mares.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31586925
|abstract=The anti-Müllerian hormone ([[AMH]]) plays an inhibitory role during folliculogenesis by regulating the number of follicles entering the growing pool. Antral follicle counts (AFC) are highly correlated with serum [[AMH]] concentrations and both appear to be related to the ovarian reserve in several species. Few data on [[AMH]] and AFC in mares exist, especially with regard to fertility. Therefore, the objective of the current study was to investigate the interrelationship between antral follicle count, serum [[AMH]] concentrations and fertility outcome in mares. One hundred and twenty-seven mares were enrolled in the study and grouped according to their reproductive status. Around time of estrus, serum [[AMH]] concentrations and AFC before and after ovulation were determined. Mares were artificially inseminated and pregnancy diagnosis was performed 14 to 18 days later. A high inter-individual variability in AFC and [[AMH]] concentration and a positive relationship between [[AMH]] and AFC for follicles ≤ 30 mm in diameter were observed, with a stronger correlation in mares older than 18 years. A high correlation between AFC measurements before and after ovulation was identified. The AFC after ovulation was higher than AFC before ovulation. [[AMH]] concentrations were neither related to the mares' reproductive status nor to age, number of cycles needed for pregnancy and pregnancy outcome. Excepted for a higher AFC in the middle-aged mares (9-18 years) compared to the younger mares (< 9 years), no associations between AFC and age, reproductive status as well as fertility of mares were found. This study confirms the relationship between AFC and [[AMH]] and a high degree of reproducibility of AFC measurements. However, based on our findings, neither AFC nor [[AMH]] are useful predictors of fertility in mares.
|mesh-terms=* Aging
* Animals
* Anti-Mullerian Hormone
* Female
* Fertility
* Horses
* Ovarian Follicle
* Ovulation
|keywords=* AMH
* Anzahl Follikel
* Ovar
* Pferd
* Ultraschall
* compte folliculaire
* conta dei follicoli
* ecografia
* equine
* equini
* follicle count
* ovaia
* ovaire
* ovary
* reproductive status
* stato riproduttivo
* ultrasonography
* Reproduktionsstatus
* échographie
* équin
* état reproducteur
|full-text-url=https://sci-hub.do/10.17236/sat00225
}}
==ATR==

{{medline-entry
|title=Bloodstain age estimation through infrared spectroscopy and Chemometric models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33077037
|abstract=The chemical profiling of bloodstains is essential to link the suspect with the crime. The current study proposed a proof-of-concept methodology for the investigation of bloodstains by utilizing advanced [[ATR]]-FTIR spectroscopy coupled with new generation chemometric methods. Current study providesencouraging datato allow discrimination between human and animal blood though with small sample size. In this study, different models for the age estimation of human bloodstains are developed from the trained data sets of 1-175 days old bloodstains. The models such as curve estimation (CE), multiple linear regression (MLR), and partial least squares regressions (PLSR) are developed to determine the best prediction model for aged human bloodstains. The obtained results on the dating of bloodstains are very encouraging and also tested for unknown samples. The maximum dating errors are observed in the curve estimation models whereas, the other models MLR, PLSR show excellent age estimation of unknown bloodstains. These models represent an error of ~3 ± 1 days and ~4 ± 1 days in actual and estimated date, respectively, which is lowest ever reported so far. The present methodology is expected to provide a valuable insight into forensic society and hence, to the law enforcement community. The present methodology can further be explored for an ideal model by including all other external variables/factors and for more longer aging time.

|keywords=* Aging
* Bloodstains
* Chemometric
* Forensic chemistry
* MLR
* PLSR
|full-text-url=https://sci-hub.do/10.1016/j.scijus.2020.07.004
}}
{{medline-entry
|title=Artificial Intelligence and fourier-transform infrared spectroscopy for evaluating water-mediated degradation of lubricant oils.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32887052
|abstract=The presence of water in lubricant oils is a parameter related to the lubricant deterioration, which can be indicative of a serious loss of tribological efficiency and, therefore, an increase in maintenance costs. Likewise, controlling the aging of the lubricant oil is a keynote issue to prevent damage on the lubricated surfaces (e.g. engine pieces). The combination of Attenuated Total Reflectance ([[ATR]]) techniques with Fourier-Transform Infrared Spectrometry (FTIR) result in an easy, simple, fast and non-destructive way for obtaining accurate information about the actual situation of a lubricant oil. The analysis of this [[ATR]]-FTIR information using Artificial Neural Networks (ANN) as well as Linear Discriminant Analysis (LDA) results in the proper classification of lubricant oils regarding the presence/absence of water, age and viscosity. The methodology proposed in this work describes procedures for identifying the deterioration degree of oils with as high as 100% success (aging week) or 97.7% (for viscosity and water presence).

|keywords=* ANN
* Artificial neural networks
* FTIR
* LDA
* Linear discriminant analysis
* Lubricant oil aging
|full-text-url=https://sci-hub.do/10.1016/j.talanta.2020.121312
}}
{{medline-entry
|title=Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32883016
|abstract=DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 ([[ATR]]; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and [[ATR]] inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction.

|keywords=* ATM
* ATR
* DNA damage response inhibitor
* DNAPK
* HNSCC
* homologous recombination
* ionizing radiation
* kinase inhibitor
* radiosensitivity
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563880
}}
{{medline-entry
|title=Kinetics of thermal degradation and lifetime study of poly(vinylidene fluoride) (PVDF) subjected to bioethanol fuel accelerated aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32775731
|abstract=PVDF was prepared by compression molding, and its phase content/structure was assessed by WAXD, DSC, and FTIR-[[ATR]] spectroscopy. Next, PVDF samples were aged in bioethanol fuel at 60 °C or annealed in the same temperature by 30 ─ 180 days. Then, the influence of aging/annealing on thermal stability, thermal degradation kinetics, and lifetime of the PVDF was investigated by thermogravimetric analysis (TGA/DTG), as well as the structure was again examined. The crystallinity of ~41% (from WAXD) or ~49% (from DSC) were identified for unaged PVDF, without significant changes after aging or annealing. This PVDF presented not only one phase, but a mixture of [i]α[/i]-, [i]β[/i]- and [i]γ[/i]-phases, [i]α[/i]- and [i]β[/i]-phases with more highlighted vibrational bands. Thermal degradation kinetics was evaluated using the non-isothermal Ozawa-Flynn-Wall method. The activation energy ([i]E[/i]   ) of thermal degradation was calculated for conversion levels of [i]α[/i] = 5 ─ 50% at constant heating rates (5, 10, 20, and 40 °C min ), [i]α[/i] = 10% was fixed for lifetime estimation. The results indicated that temperature alone does not affect the material, but its combination with bioethanol reduced the onset temperature and [i]E[/i]   of primary thermal degradation. Additionally, the material lifetime decreased until about five decades ([i]T[/i]   = 25 °C and 90 days of exposition) due to the fluid effect after aging.

|keywords=* Activation energy
* Aging
* Bioethanol fuel
* Kinetics analysis
* Lifetime prediction
* Materials chemistry
* Materials science
* Poly(vinylidene fluoride)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398943
}}
{{medline-entry
|title=Supraphysiological protection from replication stress does not extend mammalian lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32253367
|abstract=Replication Stress (RS) is a type of DNA damage generated at the replication fork, characterized by single-stranded DNA (ssDNA) accumulation, and which can be caused by a variety of factors. Previous studies have reported elevated RS levels in aged cells. In addition, mouse models with a deficient RS response show accelerated aging. However, the relevance of endogenous or physiological RS, compared to other sources of genomic instability, for the normal onset of aging is unknown. We have performed long term survival studies of transgenic mice with extra copies of the [i]Chk1[/i] and/or [i]Rrm2[/i] genes, which we previously showed extend the lifespan of a progeroid [[ATR]]-hypomorphic model suffering from high levels of RS. In contrast to their effect in the context of progeria, the lifespan of [i]Chk1, Rrm2[/i] and [i]Chk1/Rrm2[/i] transgenic mice was similar to WT littermates in physiological settings. Most mice studied died due to tumors -mainly lymphomas- irrespective of their genetic background. Interestingly, a higher but not statistically significant percentage of transgenic mice developed tumors compared to WT mice. Our results indicate that supraphysiological protection from RS does not extend lifespan, indicating that RS may not be a relevant source of genomic instability on the onset of normal aging.

|keywords=* DNA damage
* aging
* cancer
* mouse models
* replication stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185120
}}
{{medline-entry
|title=Assessing the Retest Reliability of Prefrontal EEG Markers of Brain Rhythm Slowing in the Eyes-Closed Resting State.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32253926
|abstract=[i]Objective[/i]. We examined whether prefrontal lobe EEG markers of slower brain rhythms, which are correlated with functional brain aging, can reliably reflect those of other brain lobes, as measured by a multichannel device. [i]Methods[/i]. EEG measurements were taken of 112 healthy individuals aged 20 to 69 years in the eyes-closed resting state. A 5-minute measurement was taken at 8 regions (Fp1, Fp2, F3, F4, T3, T4, O1, O2). Indices (median frequency [MDF], peak frequency [PF]) that quantitatively reflect the characteristics of EEG slowing, and traditional commonly used spectral indices (absolute powers as delta, theta, alpha, beta, and relative power as alpha-to-theta ratio [[[ATR]]]), were extracted from the EEG signals. For these indices, the differences between the prefrontal lobe and other areas were analyzed and the test-retest reproducibility was investigated. [i]Results[/i]. The EEG slowing indicators showed high conformity over all brain lobes and stable reproducibility. On the other hand, the typical EEG spectral indicators delta, theta, alpha, beta, and [[ATR]] differed between brain regions. [i]Conclusion[/i]. It was found that EEG slowing markers, which were used for assessing the aging or degeneration of brain functions, could be reliably extracted from a prefrontal EEG alone. [i]Significance[/i]. These findings suggest that EEG prefrontal markers may reflect markers of other brain regions when a multi-channel device is used. Thus, this method may constitute a low-cost, wearable, wireless, easily accessible, and noninvasive tool for neurological assessment that could be used in the early detection of cognitive decline and in the prevention of dementia.

|keywords=* EEG
* EEG slowing
* brain aging
* dominant frequency
* prefrontal
|full-text-url=https://sci-hub.do/10.1177/1550059420914832
}}
{{medline-entry
|title=Effects of Hydrogen Peroxide and Sodium Hypochlorite Aging on Properties and Performance of Polyethersulfone Ultrafiltration Membrane.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31635217
|abstract=Chemical reaction of main polymer and additive with oxidative cleaning agents plays an important role in aging of polymeric membrane for water and wastewater treatment. As a green and powerful oxidant, hydrogen peroxide (H O ) can achieve good cleaning efficacy under alkaline condition, but its influence on membrane aging was poorly understood. In this study, degradation of polyethersulfone (PES) membrane due to H O  exposure under alkaline condition (pH 9 and 11) was holistically investigated by humic acid (HA) filtration experiments and multiple membrane characterization techniques, with sodium hypochlorite (NaClO) aging examined as a comparison. Membrane permeability and HA retention rate was hardly changed by H O  aging at an exposure dose of 500 g·h/L, whereas NaClO aging led to substantial increase of membrane permeability and significant decrease of retention ability. Meanwhile, H O  aging slightly increased fouling propensity with HA filtration, while NaClO aging resulted in more serious fouling. [[ATR]]-FTIR and XPS analysis revealed much less degradation of PES and hydrophilic additive by H O  than that by NaClO, and membrane morphology and surface properties were characterized to explain the variation of filtration performance. Overall, compared with cleaning with NaClO, membrane degradation can be minimized by cleaning with H O .
|mesh-terms=* Humic Substances
* Hydrogen Peroxide
* Hydrophobic and Hydrophilic Interactions
* Membranes, Artificial
* Polymers
* Sodium Hypochlorite
* Sulfones
* Ultrafiltration
|keywords=* chemical cleaning
* hydrogen peroxide (H2O2)
* membrane aging
* polyethersulfone (PES) ultrafiltration (UF) membrane
* sodium hypochlorite (NaClO)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843545
}}
{{medline-entry
|title=NF-κB signaling in skin aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31634486
|abstract=Skin is the largest organ of the body, and is prone to be affected by external environmental factors. Skin aging is caused by both genetic and environmental factors. Furthermore, aging skin tissue is known to create a permissive tissue microenvironment that promotes the initiation, progression and resistance of cancer cells by promoting the senescence-associated secretory phenotype (SASP). Therefore, more attention should be paid to skin aging. In this review, we highlight the common Rel proteins and two activation pathways: the canonical activation pathway and the non-canonical activation pathway. Furthermore, we summarize the role of NF-κB in skin aging. The effects of UV on the skin results from the production of ROS. Excessive free radicals activate the NF-κB signaling pathway and MAPK signaling pathway, contributing to the activation of AP-1 and NF-κB. Then it increased the level of TNF-α and the expression of MMPs, which induce the degradation of ECM and accelerated skin aging. We also summarize some reported natural antioxidants and synthetic antioxidants which are related to NF-κB signals. On the other hand, NF-κB plays a key role in SASP. Upon senescence-inducing signals, ATM and [[ATR]] block p62-dependent autophagic degradation of GATA4, contributing to NF-κB activation and SASP induction.
|mesh-terms=* Animals
* Cellular Senescence
* Humans
* NF-kappa B
* Phenotype
* Signal Transduction
* Skin Aging
* Skin Neoplasms
|keywords=* NF-κB
* Senescence-associated secretory phenotype
* Skin aging
|full-text-url=https://sci-hub.do/10.1016/j.mad.2019.111160
}}
{{medline-entry
|title=Development of a w/o emulsion using ionic liquid strategy for transdermal delivery of anti - aging component α - lipoic acid: Mechanism of different ionic liquids on skin retention and efficacy evaluation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31634554
|abstract=Skin aging affects personal image and health. α - lipoic acid (ALA), with excellent free radical scavenging capacity, was used in this research to prepare W/O emulsion. Considering the instability of ALA, ionic liquid strategy was adopted to heighten the solubility of ALA for dissolving in water phase. The mechanism of different ionic liquids (ILs) on skin retention of ALA was investigated by in vitro skin permeation experiment, emulsion quality characterization, rheological test, [[ATR]] - FTIR and molecular simulation. The results showed that ionic liquid strategy had a positive influence on the solubilization of ALA. Different ILs were different in skin retention and regulated by skin layers rather than drug release, in which ALA - triethanolamine (ALA - TEOA) presented the best affinity with both stratum corneum (SC) and viable epidermis and dermis (VED), while ALA - N - (2 - Hydroxyethyl) piperidine (ALA - HEPP) as well as ALA - N - (2 - hydroxyethyl) pyrrolidine (ALA - HEPR) showed affinity with either SC or VED respectively. Finally, the emulsion presented brilliant anti - aging efficacy. This study provided a new method of emulsion research and had great significance for the development of topical formulations.
|mesh-terms=* Administration, Cutaneous
* Animals
* Emulsions
* Hydroxyproline
* Ionic Liquids
* Male
* Rats, Wistar
* Skin
* Skin Absorption
* Skin Aging
* Thioctic Acid
* Ultraviolet Rays
|keywords=* Anti – aging efficacy
* Ionic liquids
* Skin retention
* Solubility
* Α – lipoic acid
|full-text-url=https://sci-hub.do/10.1016/j.ejps.2019.105042
}}
{{medline-entry
|title=Effect of Nitrogen-Doped Graphene Oxide on the Aging Behavior of Nitrile-Butadiene Rubber.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31658636
|abstract=Nitrogen-doped graphene oxide (GO), namely, NG, was prepared by o-phenylenediamine (OPD) grafting onto GO. The structure and morphology of NG were characterized by FITR, XRD, SEM, EDS, Raman spectroscopy, and TGA. OPD was linked to the GO surface by covalent bonds, and the absorption peak of the C=N bond in the phenazine structure was identified in the FITR spectra. The aging resistance properties of nitrile-butadiene rubber (NBR)-NG composites was investigated by mechanical testing, before and after aging. The resistance of the NBR/NG composites with the addition of 3 phr NG fillers was the highest. The aging mechanism was investigated by TGA-DSC, DMA, equilibrium swelling testing, and [[ATR]]-FTIR. The results showed that NG could effectively inhibit chain cross-linking in NBR.

|keywords=* aging resistance
* graphene oxide
* nitrile-butadiene rubber
* nitrogen-doped
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835680
}}
==PTEN==

{{medline-entry
|title=Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33186519
|abstract=Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by [[PTEN]] deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of [[PTEN]] and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.

|keywords=* FGF1
* GDF-15
* MMPs
* PTEN
* TIMP1
* docetaxel
* prostate cancer metastasis
* senescence
* senescence-associated secretory phenotype (SASP)
* senolytic therapy
|full-text-url=https://sci-hub.do/10.1016/j.ccell.2020.10.012
}}
{{medline-entry
|title=Alterations in Mitochondrial Dynamic-related Genes in the Peripheral Blood of Alzheimer's Disease Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33023448
|abstract=Mitochondrial dysfunction is a pathological feature that manifests early in the brains of patients with Alzheimer's Disease (AD). The disruption of mitochondrial dynamics contributes to mitochondrial morphological and functional impairments. Our previous study demonstrated that the expression of genes involved in amyloid beta generation was altered in the peripheral blood of AD patients. The aim of this study was to further investigate the relative levels of mitochondrial genes involved in mitochondrial dynamics, including mitochondrial fission and fusion, and mitophagy in peripheral blood samples from patients with AD compared to healthy controls. The mRNA levels were analyzed by real-time polymerase chain reaction. Gene expression profiles were assessed in relation to cognitive performance. Significant changes were observed in the mRNA expression levels of fission-related genes; Fission1 (FIS1) levels in AD subjects were significantly higher than those in healthy controls, whereas Dynamin- related protein 1 (DRP1) expression was significantly lower in AD subjects. The levels of the mitophagy-related genes, [[PTEN]]-induced kinase 1 (PINK1) and microtubule-associated protein 1 light chain 3 (LC3), were significantly increased in AD subjects and elderly controls compared to healthy young controls. The mRNA levels of Parkin (PARK2) were significantly decreased in AD. Correlations were found between the expression levels of FIS1, DRP1 and PARK2 and cognitive performance scores. Alterations in mitochondrial dynamics in the blood may reflect impairments in mitochondrial functions in the central and peripheral tissues of AD patients. Mitochondrial fission, together with mitophagy gene profiles, might be potential considerations for the future development of blood-based biomarkers for AD.

|keywords=* Alzheimer's disease
* DRP1
* FIS1
* aging
* mitochondrial dynamics
* mitophagy
|full-text-url=https://sci-hub.do/10.2174/1567205017666201006162538
}}
{{medline-entry
|title=Human ESC-sEVs alleviate age-related bone loss by rejuvenating senescent bone marrow-derived mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32944188
|abstract=Tissue-resident stem cell senescence leads to stem cell exhaustion, which is a major cause of physiological and pathological ageing. Stem cell-derived extracellular vesicles (SC-EVs) have been reported in preclinical studies to possess therapeutic potential for diverse diseases. However, whether SC-EVs can rejuvenate senescent tissue stem cells to prevent age-related disorders still remains unknown. Here, we show that chronic application of human embryonic stem cell-derived small extracellular vesicles (hESC-sEVs) rescues the function of senescent bone marrow mesenchymal stem cells (BM-MSCs) and prevents age-related bone loss in ageing mice. Transcriptome analysis revealed that hESC-sEVs treatment upregulated the expression of genes involved in antiaging, stem cell proliferation and osteogenic differentiation in BM-MSCs. Furthermore, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis identified 4122 proteins encapsulated in hESC-sEVs. Bioinformatics analysis predicted that the protein components in the hESCs-sEVs function in a synergistic way to induce the activation of several canonical signalling pathways, including Wnt, Sirtuin, AMPK, [[PTEN]] signalling, which results in the upregulation of antiaging genes in BM-MSCs and then the recovery of senescent BM-MSCs function. Collectively, our findings reveal the effect of hESC-sEVs in reversing BM-MSCs senescence and age-related osteogenic dysfunction, thereby preventing age-related bone loss. Because hESC-sEVs could alleviate senescence of tissue-resident stem cells, they might be promising therapeutic candidates for age-related diseases.

|keywords=* Extracellular vesicle
* bone loss
* bone marrow MSCs
* cellular senescence
* embryonic stem cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480439
}}
{{medline-entry
|title=The precursor of PI(3,4,5)P  alleviates aging by activating daf-18(Pten) and independent of daf-16.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32901024
|abstract=Aging is characterized by the loss of homeostasis and the general decline of physiological functions, accompanied by various degenerative diseases and increased rates of mortality. Aging targeting small molecule screens have been performed many times, however, few have focused on endogenous metabolic intermediates-metabolites. Here, using C. elegans lifespan assays, we conducted a worm metabolite screen and identified an eukaryotes conserved metabolite, myo-inositol (MI), to extend lifespan, increase mobility and reduce fat content. Genetic analysis of enzymes in MI metabolic pathway suggest that MI alleviates aging through its derivative PI(4,5)P . MI and PI(4,5)P  are precursors of PI(3,4,5)P , which is negatively related to longevity. The longevity effect of MI is dependent on the tumor suppressor gene, daf-18 (homologous to mouse Pten), independent of its classical pathway downstream genes, akt or daf-16. Furthermore, we found MI effects on aging and lifespan act through mitophagy regulator [[PTEN]] induced kinase-1 (pink-1) and mitophagy. MI's anti-aging effect is also conserved in mouse, indicating a conserved mechanism in mammals.
|mesh-terms=* Aging
* Animals
* Animals, Genetically Modified
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Cell Line, Tumor
* Female
* Forkhead Transcription Factors
* Inositol
* Locomotion
* Longevity
* Metabolic Networks and Pathways
* Metabolomics
* Mice
* Mitophagy
* Models, Animal
* PTEN Phosphohydrolase
* Phosphatidylinositol Phosphates
* Protein Kinases
* Protein-Serine-Threonine Kinases
* RNA Interference
* RNA-Seq

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479145
}}
{{medline-entry
|title=Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the SIRT1/PINK1/mitophagy axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32702447
|abstract=Emerging evidence implicates accelerated renal tubular epithelial cell (RTEC) senescence in renal fibrosis progression. Mitophagy protects against kidney injury. However, the mechanistic interplay between cell senescence and mitophagy in RTECs is not clearly defined. The purpose of this study was to evaluate the inhibition of RTEC senescence and renal fibrosis by quercetin and explore the underlying mechanisms. We found that quercetin attenuated RTEC senescence induced by angiotensin II (AngII) in vitro and unilateral ureteral obstruction in vivo. Moreover, we demonstrated that mitochondrial abnormalities such as elevated reactive oxygen species, decreased membrane potential, and fragmentation and accumulation of mitochondrial mass, occurred in AngII-treated RTECs. Quercetin treatment reversed these effects. Furthermore, quercetin enhanced mitophagy in AngII-treated RTECs, which was markedly reduced by treatment with mitophagy-specific inhibitors. Sirtuin-1 (SIRT1) was involved in quercetin-mediated [[PTEN]]-induced kinase 1 (PINK1)/Parkin-associated mitophagy activation. Pharmacological antagonism of SIRT1 in AngII-treated RTECs blocked the effects of quercetin on mitophagy and cellular senescence. Finally, quercetin alleviated kidney fibrosis by reducing RTEC senescence via mitophagy. Collectively, the antifibrotic effect of quercetin involved inhibition of RTEC senescence, possibly through activation of SIRT1/PINK1/Parkin-mediated mitophagy. These findings suggest that pharmacological elimination of senescent cells and stimulation of mitophagy represent effective therapeutic strategies to prevent kidney fibrosis.
|mesh-terms=* Animals
* Antioxidants
* Cell Line
* Cellular Senescence
* Epithelium
* Fibrosis
* Flow Cytometry
* Kidney
* Kidney Tubules, Proximal
* Mitophagy
* Protein Kinases
* Quercetin
* Rats
* Sirtuin 1
|keywords=* Fibrosis
* Mitochondria
* Mitophagy
* Quercetin
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.118116
}}
{{medline-entry
|title=Downregulation of [[PTEN]] mediates bleomycin-induced premature senescence in lung cancer cells by suppressing autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32436415
|abstract=Bleomycin is an important chemotherapeutic drug that activates premature senescence to decrease the tumorigenic process. We aimed to investigate the role of phosphatase and tensin homolog deleted on chromosome ten ([[PTEN]]) in bleomycin-induced premature senescence in lung cancer cells. Human lung cancer A549 cells were incubated in the presence of different concentrations of bleomycin for 5 days. A lentivirus vector was used to silence the [i][[PTEN]][/i] gene, followed by stimulation with bleomycin (1 µg/mL). Changes were evaluated by senescence-associated β-galactosidase staining, reverse transcription-polymerase chain reaction, and western blot. Treatment with bleomycin induced premature senescence. [[PTEN]] expression was decreased and key downstream molecules in the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway were gradually activated following bleomycin treatment. Silencing [i][[PTEN]][/i] reduced autophagy and accelerated senescence of A549 cells. Autophagy levels were also increased and senescence markers were reduced after inhibiting mTOR. Downregulation of [[PTEN]] mediates bleomycin-induced premature senescence in lung cancer cells by suppressing autophagy via the PI3K/Akt/mTOR pathway. These findings provide new insights into the potential role of [[PTEN]] as a molecular target for cancer chemotherapy.

|keywords=* PI3K/Akt/mTOR pathway
* PTEN
* autophagy
* bleomycin
* cancer cell
* premature senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287201
}}
{{medline-entry
|title=miR-155 inhibits mitophagy through suppression of BAG5, a partner protein of PINK1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31948758
|abstract=Removal of dysfunctional mitochondria is essential step to maintain normal cell physiology, and selective autophagy in mitochondria, called mitophagy, plays a critical role in quality control of mitochondria. While in several diseases and aging, disturbed mitophagy has been observed. In stem cells, accumulation of damaged mitochondria can lead to deterioration of stem cell properties. Here, we focused on miR-155-5p (miR-155), one of the most prominent miRNAs in inflammatory and aged tissues, and found that miR-155 disturbed mitophagy in mesenchymal stem cells (MSCs). As a molecular mechanism of miR-155-mediated mitophagy suppression, we found that BCL2 associated athanogene 5 (BAG5) is a direct target of miR-155. Reduction of BAG5 resulted in destabilization of [[PTEN]]-induced kinase (PINK1) and consequently disrupted mitophagy. Our study suggests a novel mechanism connecting aging and aging-associated inflammation with mitochondrial dysfunction in stem cells through a miRNA-mediated mechanism.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Aging
* Animals
* Cell Line
* Cells, Cultured
* Down-Regulation
* Humans
* Male
* Mesenchymal Stem Cells
* Mice, Inbred C57BL
* MicroRNAs
* Mitophagy
* Protein Interaction Maps
* Protein Kinases
* Up-Regulation
|keywords=* Aging
* Bone marrow MSCs
* Mitophagy
* miR-155
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2020.01.022
}}
{{medline-entry
|title=Environmental Exposures and Asthma Development: Autophagy, Mitophagy, and Cellular Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31849968
|abstract=Environmental pollutants and allergens induce oxidative stress and mitochondrial dysfunction, leading to key features of allergic asthma. Dysregulations in autophagy, mitophagy, and cellular senescence have been associated with environmental pollutant and allergen-induced oxidative stress, mitochondrial dysfunction, secretion of multiple inflammatory proteins, and subsequently development of asthma. Particularly, particulate matter 2.5 (PM ) has been reported to induce autophagy in the bronchial epithelial cells through activation of AMP-activated protein kinase (AMPK), drive mitophagy through activating [[PTEN]]-induced kinase 1(PINK1)/Parkin pathway, and induce cell cycle arrest and senescence. Intriguingly, allergens, including [i]ovalbumin[/i] (OVA), [i]Alternaria alternata[/i], and [i]cockroach allergen[/i], have also been shown to induce autophagy through activation of different signaling pathways. Additionally, mitochondrial dysfunction can induce cell senescence due to excessive ROS production, which affects airway diseases. Although autophagy and senescence share similar properties, recent studies suggest that autophagy can either accelerate the development of senescence or prevent senescence. Thus, in this review, we evaluated the literature regarding the basic cellular processes, including autophagy, mitophagy, and cellular senescence, explored their molecular mechanisms in the regulation of the initiation and downstream signaling. Especially, we highlighted their involvement in environmental pollutant/allergen-induced major phenotypic changes of asthma such as airway inflammation and remodeling and reviewed novel and critical research areas for future studies. Ultimately, understanding the regulatory mechanisms of autophagy, mitophagy, and cellular senescence may allow for the development of new therapeutic targets for asthma.
|mesh-terms=* Airway Remodeling
* Asthma
* Autophagy
* Cellular Senescence
* Disease Susceptibility
* Environmental Exposure
* Humans
* Mitophagy
* Oxidative Stress
* Respiratory Mucosa
|keywords=* asthma
* autophagy
* mitophagy
* oxidative stress
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896909
}}
{{medline-entry
|title=[[PTEN]] loss regulates alveolar epithelial cell senescence in pulmonary fibrosis depending on Akt activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31527305
|abstract=Idiopathic pulmonary fibrosis (IPF) is an aging-associated disease with poor prognosis. The mechanisms underlying the role of alveolar epithelial cell (AEC) senescence in IPF remain poorly understood. We aimed to investigate if [[PTEN]]/Akt activates AEC senescence to induce pulmonary fibrosis. We investigated the association between [[PTEN]]/Akt and cellular senescence in lung tissues from IPF patients. As a result, decreased [[PTEN]] and activated Akt pathway were found in AECs in fibrotic lung tissues detected by immunohistochemistry (IHC) and immunofluorescence (IF). Increased expression levels of aging-associated markers (P21  and SA-β-gal) in AECs treated with bleomycin were found. AEC senescence was accelerated by [[PTEN]] knockdown and attenuated by [[PTEN]] overexpression. Bleomycin induced AEC senescence was reversed by Akt2 knockdown and the pharmacological inhibitors (LY294002 and MK2206) of the Akt pathway. Reducing Akt activation dramatically improved lung fibrosis in a fibrotic mice model. In addition, a co-immunoprecipitation (co-IP) assay demonstrated that [[PTEN]] physically associated with Akt. These indicated that senescent AECs modulated by the [[PTEN]]/Akt pathway promote lung fibrosis. In conclusion, our study demonstrated that as a trigger indicator in IPF, the senescence process in AECs should be a potential therapeutic target and that the [[PTEN]]/Akt pathway may be a promising candidate for intervention.
|mesh-terms=* Aging
* Cellular Senescence
* Epithelial Cells
* Humans
* Idiopathic Pulmonary Fibrosis
* PTEN Phosphohydrolase
* Proto-Oncogene Proteins c-akt
* Pulmonary Alveoli
* Respiratory Mucosa
|keywords=* aging
* cellular senescence
* phosphatase and tension homolog deleted on chromosome ten
* protein kinase B
* pulmonary fibrosis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781970
}}
==CCK==

{{medline-entry
|title=Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33242601
|abstract=Intervertebral disc degeneration (IDD) represents major cause of low back pain. Quercetin (QUE) is one of the approved senolytic agents. In this study, we evaluated the protective effects of QUE on IDD development and its underlying mechanism. Effects of senolytic agent QUE on the viability of nucleus pulposus cells (NPCs) were measured by [[CCK]]-8 assays and EdU staining. The senescence associated secreted phenotype (SASP) factors expressions were measured by qPCR, western blot, and ELISA; and NF-κB pathway was detected by immunofluorescence and western blot. Molecular docking was applied to predict the interacting protein of QUE; while Nrf2 was knocked down by siRNAs to confirm its role in QUE regulated senescence phenotype. X-ray, MRI, Hematoxylin-Eosin and Safranin O-Fast green staining were performed to evaluate the therapeutic effects of QUE on IDD in the puncture-induced rat model. In in vitro experiments, QUE inhibited SASP factors expression and senescence phenotype in IL-1β-treated NPCs. Mechanistically, QUE suppressed IL-1β induced activation of the NF-κB pathway cascades; it was also demonstrated in molecular docking and knock down studies that QUE might bind to Keap1-Nrf2 complex to suppress NF-κB pathway. In vivo, QUE ameliorated the IDD process in the puncture-induced rat model. Together the present work suggests that QUE inhibits SASP factors expression and senescence phenotype in NPCs and ameliorates the progression of IDD via the Nrf2/NF-κB axis, which supports senolytic agent QUE as a potential therapeutic agent for the treatment of IDD.

|keywords=* Intervertebral disc degeneration
* NF-κB pathway
* Nrf2
* Quercetin
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.joca.2020.11.006
}}
{{medline-entry
|title=Astragalus improve aging bone marrow mesenchymal stem cells (BMSCs) vitality and osteogenesis through VD-FGF23-Klotho axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32355520
|abstract=To clarify the regulation of astragalus on the aging BMSCs model and the effect of astragalus on Vitamin D (VD)-FGF23-Klotho axis. siRNA was used to interfere the expression of VDR gene in aging BMSCs. Serum containing astragalus in different concentrations was added to the cultured cells. The expression of osteocalcin and alkaline phosphatase were detected by alizarin red staining and ELISA. Cell vitality was detected by flow cytometry, [[CCK]]-8 test, and [i]β[/i]-galactosidase staining. The expression of FGF23, Klotho, CYP27B1, and CYP24A1 was detected by qRT-PCR and western blot. The results showed that after reducing VDR gene expression, the aging BMSCs model showed decreased activity and osteogenic ability, increased expression of FGF23, Klotho and CYP24A1, and decreased expression of CYP27B1. After adding serum-containing astragalus, the activity of cells and the osteogenic ability was increased; the expression levels of FGF23, Klotho and CYP24A1 were decreased, the expression levels of CYP27B1 were increased, and the trend was more obvious with the increase of astragalus concentration. This study confirmed that astragalus could inhibit the aging of BMSCs and improve the osteogenesis ability by regulating the VD-FGF23-Klotho pathway. This study provided a certain research basis for the therapeutic of traditional Chinese medicine (TCM) on primary osteoporosis.

|keywords=* Astragalus
* BMSCs
* VD-FGF23-Klotho axis
* aging
* osteogenesis differentiation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191145
}}
{{medline-entry
|title=Effects of Age on Acute Appetite-Related Responses to Whey-Protein Drinks, Including Energy Intake, Gastric Emptying, Blood Glucose, and Plasma Gut Hormone Concentrations-A Randomized Controlled Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32268554
|abstract=Protein-rich supplements are used commonly to increase energy intake in undernourished older people. This study aimed to establish age effects on energy intake, appetite, gastric emptying, blood glucose, and gut hormones in response to protein-rich drinks. In a randomized double-blind, order, 13 older men (age: 75 ± 2 yrs, body mass index (BMI): 26 ± 1 kg/m ) and 13 younger (23 ± 1 yrs, 24 ± 1 kg/m ) men consumed (i) a control drink (~2 kcal) or drinks (450 mL) containing protein/fat/carbohydrate: (ii) 70 g/0 g/0 g (280 kcal/'P ), (iii) 14 g/12.4 g/28 g (280 kcal/'M ), (iv) 70 g/12.4 g/28 g (504 kcal/'M ), on four separate days. Appetite (visual analog scales), gastric emptying (3D ultrasonography), blood glucose, plasma insulin, ghrelin, cholecystokinin ([[CCK]]), glucagon-like peptide-1 (GLP-1) concentrations (0-180 min), and ad-libitum energy intake (180-210 min) were determined. Older men, compared to younger men, had higher fasting glucose and [[CCK]] concentrations and lower fasting GLP-1 concentrations (all [i]p[/i] < 0.05). Energy intake by P  compared to control was less suppressed in older men (increase: 49 ± 42 kcal) than it was in younger men (suppression: 100 ± 54 kcal, [i]p[/i] = 0.038). After the caloric drinks, the suppression of hunger and the desire to eat, and the stimulation of fullness was less ([i]p[/i] < 0.05), and the stimulation of plasma GLP-1 was higher ([i]p[/i] < 0.05) in older men compared to younger men. Gastric emptying, glucose, insulin, ghrelin, and [[CCK]] responses were similar between age groups. In conclusion, ageing reduces the responses of caloric drinks on hunger, the desire to eat, fullness, and energy intake, and protein-rich nutrition supplements may be an effective strategy to increase energy intake in undernourished older people.

|keywords=* aging
* appetite
* energy intake
* gastric emptying
* glucose
* gut hormones
* whey protein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231005
}}
{{medline-entry
|title=Lactose induced redox-dependent senescence and activated Nrf2 pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31934025
|abstract=Lactose is a disaccharide found in milk and thus a part of our daily food intake. Upon ingestion, it is hydrolyzed to glucose and galactose by the enzyme lactase and absorbed in the small intestine. People who suffer from lactose intolerance are unable to completely digest it due to deficiency of lactase, leading to intestinal problems such as diarrhoea, and bloating. Various studies have focused on treating these symptoms. However, the effects of lactose that diffuses passively into cells, on cellular senescence have largely remained unknown. Thus, the present study investigated the effects and mechanisms of lactose on senescence both [i]in vitro[/i] and [i]in vivo[/i]. The study was conducted in MRC-5 cells. The cellular senescence was estimated by determining the expression of SA-β-gal and p16 . The cell viability of MRC-5 cells was determined by the [[CCK]]-8 Assay. Activity of intracellular reactive oxygen species was estimated by measuring the levels of superoxide dismutase (SOD), glutathione (GHS), and reactive oxygen species (ROS). The mechanism of lactose on cellular senescence was explored by western blotting. We also studied the effect of lactose on the lifespan of [i]Caenorhabditis elegans[/i]. Increased activities of SA-β-gal and p16  revealed the ability of lactose to induce senescence in MRC-5 cells. The elevated intracellular ROS level and decreased GSH and SOD levels in these cells were indicative of cellular oxidative stress induced by lactose. Furthermore, western blotting analysis of Nrf2 and mRNA expression of its downstream genes suggested the Nrf2/ARE pathway was involved in the oxidative stress induced by lactose. These results were further validated by the shortened lifespan of C. elegans after lactose supplement. Moreover, the lactose-induced senescence could be alleviated by an antioxidant, N-Acetyl-L-cysteine (NAC), both [i]in vitro[/i] and [i]in vivo[/i]. The present study observed a positive correlation between lactose and cellular oxidative stress, suggesting the latter to be an underlying mechanism of lactose-induced senescence.

|keywords=* Lactose
* Nrf2
* ROS
* cellular senescence
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949649
}}
{{medline-entry
|title=Quercetin Suppresses the Progression of Atherosclerosis by Regulating MST1-Mediated Autophagy in ox-LDL-Induced RAW264.7 Macrophage Foam Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31816893
|abstract=To investigate the process by which quercetin suppresses atherosclerosis by upregulating MST1-mediated autophagy in RAW264.7 macrophages. An in vitro foam cell model was established by culturing RAW264.7 macrophages with oxidized low-density lipoprotein (ox-LDL). The cells were treated with quercetin alone or in combination with the autophagy inhibitor, 3-methyladenine, and autophagy agonist, rapamycin. Cell viability was detected with a [[CCK]]-8 kit. Lipid accumulation was detected by oil red O staining, senescence was detected by SA-β-gal (senescence-associated β-galactosidase) staining, reactive oxygen species were detected by ROS assay kit. Autophagosomes and mitochondria were detected by transmission electron microscope (TEM), and expression of MST1, LC3-II/I, Beclin1, Bcl-2, P21, and P16 were detected by immunofluorescence and Western blot. Ox-LDL induced RAW264.7 macrophage-derived foam cell formation, reduced survival, aggravated cell lipid accumulation, and induced a senescence phenotype. This was accompanied by decreased formation of autophagosome; increased expression of P53, P21, and P16; and decreased expression of LC3-II/I and Beclin1. After intervention with quercetin, the cell survival rate was increased, and lipid accumulation and senescence phenotype were reduced. Furthermore, the expression of LC3-II/I and Beclin1 were increased, which was consistent with the ability of quercetin to promote autophagy. Ox-LDL also increased the expression of MST1, and this increase was blocked by quercetin, which provided a potential mechanism by which quercetin may protect foam cells against age-related detrimental effects. Quercetin can inhibit the formation of foam cells induced by ox-LDL and delay senescence. The mechanism may be related to the regulation of MST1-mediated autophagy of RAW264.7 cells.
|mesh-terms=* Adenine
* Animals
* Atherosclerosis
* Autophagy
* Cell Survival
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p21
* Disease Progression
* Foam Cells
* Hepatocyte Growth Factor
* Lipid Metabolism
* Lipoproteins, LDL
* Mice
* Proto-Oncogene Proteins
* Quercetin
* RAW 264.7 Cells
* Sirolimus
* Up-Regulation
|keywords=* RAW264.7
* atherosclerosis
* autophagy
* quercetin
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928812
}}
{{medline-entry
|title=LncRNA AW112010 Promotes Mitochondrial Biogenesis and Hair Cell Survival: Implications for Age-Related Hearing Loss.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31781342
|abstract=Long noncoding RNA (lncRNA) disorder has been found in many kinds of age-associated diseases. However, the role of lncRNA in the development of age-related hearing loss (AHL) is still largely unknown. This study sought to uncover AHL-associated lncRNAs and the function. RNA-sequencing was conducted to profile lncRNA expression in the cochlea of an early-onset AHL mouse model. RT-qPCR assay was used to validate the expression pattern of lncRNAs. ATP assay, JC-1 assay, mitochondrial probe staining, [[CCK]]-8 assay, Western blot, and immunocytochemistry were performed to detect the effects of lncRNA AW112010 in HEI-OC1 cells and the mouse cochlea. We identified 88 significantly upregulated lncRNAs and 46 significantly downregulated lncRNAs in the cochlea of aged C57BL/6 mice. We focused on the significantly upregulated AW112010. Silencing of AW112010 decreased the ATP level, mitochondrial membrane potential, and cell viability and increased mitochondrial ROS generation under oxidative stress in HEI-OC1 cells. AW112010 overexpression promoted cell survival in HEI-OC1 cells. AW112010 knockdown reduced mitochondrial mass and impaired mitochondrial biogenesis in HEI-OC1 cells. Activation of mitochondrial biogenesis by resveratrol and STR1720 promoted cell survival. The mitochondrial biogenesis process was activated in the cochlea of aged mice. Moreover, AW112010 regulated AMPK signaling in HEI-OC1 cells. Transcription factor Arid5b elevated in the aged cochlea and induced AW112010 expression and mitochondrial biogenesis in HEI-OC1 cells. Taken together, lncRNAs are dysregulated with aging in the cochlea of C57BL/6 mice. The Arid5b/AW112010 signaling was induced in the aged mouse cochlea and positively modulated the mitochondrial biogenesis to maintain mitochondrial function.
|mesh-terms=* Adenosine Triphosphate
* Aging
* Animals
* Cell Survival
* DNA-Binding Proteins
* Gene Silencing
* Hair Cells, Auditory
* Hearing Loss
* Mice
* Mitochondria
* Organelle Biogenesis
* RNA, Long Noncoding
* Resveratrol
* Signal Transduction
* Transcription Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855056
}}
{{medline-entry
|title=Effects of age on feeding response: Focus on the rostral C1 neuron and its glucoregulatory proteins.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31705967
|abstract=Older people are likely to develop anorexia of aging. Rostral C1 (rC1) catecholaminergic neurons in rostral ventrolateral medulla (RVLM) are recently discovered its role in food intake control. It is well established that these neurons regulate cardiovascular function. This study aims to determine the effect of age on the function of rostral C1 (rC1) neurons in mediating feeding response. Male Sprague Dawley rats at 3-months (n = 22) and 24-months (n = 22) old were used and further divided into two subgroups; 1) treatment group with 2-deoxy-d-glucose (2DG) and 2) vehicle group. Feeding hormones such as cholecystokinin ([[CCK]]), ghrelin and leptin were analysed using enzyme-linked immunosorbent assay (ELISA). Rat brain was carefully dissected to obtain the brainstem RVLM region. Further analysis was carried out to determine the level of proteins and genes in RVLM that were associated with feeding pathway. Protein expression of tyrosine hydroxylase (TH), phosphorylated TH at Serine40 (pSer40TH), AMP-activated protein kinase (AMPK), phosphorylated AMPK (phospho AMPK) and neuropeptide Y Y5 receptor (NPY5R) were determined by western blot. Expression of TH, AMPK and NPY genes were determined by real-time PCR. This study showed that blood glucose level was elevated in young and old rats following 2DG administration. Plasma [[CCK]]-8 concentration was higher in the aged rats at basal and increased with 2DG administration in young rats, but the leptin and ghrelin showed no changes. Old rats showed higher TH and lower AMPK mRNA levels. Glucoprivation decreased AMPK mRNA level in young rats and decreased TH mRNA in old rats. Aged rC1 neurons showed higher NPY5R protein level. Following glucoprivation, rC1 neurons produced distinct molecular changes across age in which, in young rats, AMPK phosphorylation level was increased and in old rats, TH phosphorylation level was increased. These findings suggest that glucose-counterregulatory responses by rC1 neurons at least, contribute to the ability of young and old rats in coping glucoprivation. Age-induced molecular changes within rC1 neurons may attenuate the glucoprivic responses. This situation may explain the impairment of feeding response in the elderly.

|keywords=* Aging
* Catecholaminergic neurons
* Feeding response
* Glucoprivation
* Rostral ventrolateral medulla
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110779
}}
{{medline-entry
|title=Ser-Tyr and Asn-Ala, vasorelaxing dipeptides found by comprehensive screening, reduce blood pressure via different age-dependent mechanisms.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31685714
|abstract=To understand the changes in physiological responses due to aging, a number of bioactive probes based on different signal transduction pathways are necessary. In this study, we comprehensively and systematically investigated changes in blood vessel function with age using a 336-dipeptide library. In the early stage of hypertension, the most potent vasorelaxant dipeptide was Ser-Tyr (SY) in the mesenteric artery isolated from spontaneously hypertensive rats (SHR). SY-induced vasorelaxation and anti-hypertensive effects were blocked by L-NAME, an inhibitor of nitric oxide synthase (NOS), suggesting that SY activates the NO system. On the other hand, the patterns of dipeptides with vasorelaxation activity in early and advanced stages of hypertension were different. In the advanced stage, the most potent vasorelaxing dipeptide was Asn-Ala (NA). Orally administered NA (1.5 mg/kg) reduced the blood pressure in the advanced stage, at which drugs were sometimes less effective, and the anti-hypertensive effects lasted for 6 hr. The NA-induced vasorelaxation and anti-hypertensive activity was blocked by lorglumide, an antagonist of the cholecystokinin [[CCK]]  receptor, suggesting that NA activated the [[CCK]] system. Taken together, in the early and advanced stages of hypertension, SY and NA exhibited vasorelaxing and anti-hypertensive effects via the NO and [[CCK]] systems, respectively.
|mesh-terms=* Aging
* Amino Acid Sequence
* Animals
* Antihypertensive Agents
* Blood Pressure
* Cholecystokinin
* Dipeptides
* Drug Evaluation, Preclinical
* Hypertension
* Male
* Mesenteric Arteries
* Nitric Oxide
* Peptide Library
* Proglumide
* Rats
* Rats, Inbred SHR
* Receptors, Cholecystokinin
* Vasodilation
* Vasodilator Agents
|keywords=* aging
* dipeptide library
* nitric oxide
* structure-activity relationship
* vasorelaxation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874431
}}
{{medline-entry
|title=Fisetin, via CKIP-1/REGγ, limits oxidized LDL-induced lipid accumulation and senescence in RAW264.7 macrophage-derived foam cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31655030
|abstract=To test the hypothesis that the flavonoid compound, fisetin, protects macrophages from lipid accumulation and senescence through regulation of casein kinase 2-interacting protein-1 (CKIP-1)/REGγ (11S regulatory particles, 28 kDa proteasome activator, proteasome activator subunit 3) signaling. RAW264.7 macrophage cells were exposed to 100 μg/ml oxidized low-density lipoprotein (ox-LDL) with or without 20 μg/ml fisetin for 24 h. Cell viability was detected by [[CCK]]-8 after 1 h. Intracellular lipid accumulation was measured using Oil Red O staining. Total cholesterol (TC) and free cholesterol (FC) contents were measured using assay kits, and cell senescence was inferred by β-gal staining. Protein expression levels of CKIP-1, REGγ, organic cation transporter 1 (Oct-1), lectin-like oxidized LDL receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cell cycle regulatory protein p21 (p21), and multiple tumor suppressor-1 (p16) were detected by immunofluorescence and confirmed by Western blot. Stimulating RAW264.7 macrophage cells with 100 μg/ml ox-LDL for 24 h induced the formation of foam cells, increased intracellular lipid accumulation, increased TC and FC content, and promoted cell senescence. Furthermore, cells induced with 100 μg/ml ox-LDL for 24 h showed decreased CKIP-1 and REGγ protein, while the expressions of Oct-1, LOX-1, p53, p21 and p16 were increased. In contrast, treatment with 20 μg/ml fisetin reversed 100 μg/ml ox-LDL effects to increase cell viability, and decrease β-gal staining, intracellular lipid levels and TC and FC levels. These beneficial effects were associated with increased CKIP-1 and REGγ and decreased Oct-1, LOX-1, p53, p21, and p16 protein expression. Results indicated that fisetin limited ox-LDL-mediated lipid accumulation and senescence in RAW264.7 macrophage-derived foam cells. The mechanism underlying these effects may involve regulation of CKIP-1/REGγ signaling.
|mesh-terms=* Animals
* Autoantigens
* Carrier Proteins
* Cellular Senescence
* Flavonoids
* Foam Cells
* Lipid Metabolism
* Lipoproteins, LDL
* Mice
* Proteasome Endopeptidase Complex
* RAW 264.7 Cells
* Signal Transduction
|keywords=* CKIP-1/REGγ signaling
* Fisetin
* Lipid accumulation
* RAW264.7
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.ejphar.2019.172748
}}
==FGF21==

{{medline-entry
|title=Differential effects of sulfur amino acid-restricted and low-calorie diets on gut microbiome profile and bile acid composition in male C57BL6/J mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33106871
|abstract=Diet can affect health and longevity by altering the gut microbiome profile. Sulfur amino acid restriction (SAAR), like caloric restriction, extends lifespan. But, its effect on the gut microbiome profile and functional significance of such effects are understudied. We investigated whether SAAR alters the gut microbiome profile and bile acid composition, an index of microbial metabolism. We also compared these changes with those induced by a 12% low-calorie diet (LCD). Male 21-week-old C57BL6/J mice were fed CD (0.86% methionine), SAAR (0.12% methionine), and LCD diets (0.86% methionine). After ten weeks on the diet, plasma markers and fecal microbial profiles were determined. SAAR mice had lower body weights and IGF-1, and higher food intake and [[FGF21]] than CD mice. Compared to SAAR mice, LCD mice had higher body weights, lower FGF-21 and food intake, but similar IGF-1. β-Diversity indices were different between SAAR and LCD, LCD and CD, but not between CD and SAAR. In group-wise comparisons of individual taxa, differences were more discernable between SAAR and LCD than between other groups. Abundances of firmicutes, clostridiaceae, and turicibacteraceae were higher, but verrucomicrobia was lower in SAAR than in LCD. Secondary bile acids and the ratio of secondary to primary bile acids were lower in SAAR than in LCD. SAAR favored bile acid conjugation with glycine at the expense of taurine. Overall, SAAR and LCD diets induced distinct changes in the gut microbiome and bile acid profiles. Additional studies on the role of these changes in improving health and lifespan are warranted.

|keywords=* Clostridales
* firmicutes
* lifespan
* methionine restriction
* sulfur metabolism
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa270
}}
{{medline-entry
|title=Relationship between physical activity and circulating fibroblast growth factor 21 in middle-aged and older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32911033
|abstract=Circulating levels of fibroblast growth factor 21 ([[FGF21]]) increase with advancing age and may lead to the development of cardiometabolic diseases via impaired lipid and glucose metabolism. While physical activity can reduce these risks of cardiometabolic dysfunction, it remains obscure whether circulation [[FGF21]] levels are influenced by physical activity. The purpose of this study was to investigate the relations between daily physical activities and circulating [[FGF21]] levels in middle-aged and older adults. In this cross-sectional study with 110 middle-aged and 102 older adults, circulating (serum) [[FGF21]] levels were evaluated by enzyme-linked immunosorbent assay, and the time spent in light-intensity physical activity (LPA) and moderate-to-vigorous-intensity physical activity (MVPA) was assessed using a uniaxial accelerometer. Serum [[FGF21]] levels in the older group (158 pg/mL) were significantly higher than those in the middle-aged group (117 pg/mL). When we examined the joint association of age (middle-aged or older) and MVPA (lower or higher than the median) groups, serum [[FGF21]] levels in the older and higher MVPA group (116 pg/mL) were significantly lower than those in the older and lower MVPA group (176 pg/mL). However, there was no difference in serum [[FGF21]] levels between the lower and higher MVPA groups in the middle-aged group. In multivariable liner regression analysis, serum [[FGF21]] levels were independently determined by MVPA time after adjusting for potential covariates in older adults (β = -0.209). These cross-sectional study findings indicate that the time spent in MVPA is an independent determinant of circulating [[FGF21]] levels, and that an age-related increase in serum [[FGF21]] levels may be attenuated by habitually performing MVPA. (250/250 words).

|keywords=* Accelerometer
* Activity intensity
* Aging
* FGF21
* Physical activity
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111081
}}
{{medline-entry
|title=Exercise and dietary intervention ameliorate high-fat diet-induced NAFLD and liver aging by inducing lipophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32863214
|abstract=Exercise and dietary intervention are currently available strategies to treat nonalcoholic fatty liver disease (NAFLD), while the underlying mechanism remains controversial. Emerging evidence shows that lipophagy is involved in the inhibition of the lipid droplets accumulation. However, it is still unclear if exercise and dietary intervention improve NAFLD through regulating lipophagy, and how exercise of skeletal muscle can modulate lipid metabolism in liver. Moreover, NAFLD is associated with aging, and little is known about the effect of lipid accumulation on aging process. Here in vivo and in vitro models, we found that exercise and dietary intervention reduced lipid droplets formation, decreased hepatic triglyceride in the liver induced by high-fat diet. Exercise and dietary intervention enhanced the lipophagy by activating AMPK/ULK1 and inhibiting Akt/mTOR/ULK1 pathways respectively. Furthermore, exercise stimulated [[FGF21]] production in the muscle, followed by secretion to the circulation to promote the lipophagy in the liver via an AMPK-dependent pathway. Importantly, for the first time, we demonstrated that lipid accumulation exacerbated liver aging, which was ameliorated by exercise and dietary intervention through inducing lipophagy. Our findings suggested a new mechanism of exercise and dietary intervention to improve NAFLD through promoting lipophagy. The study also provided evidence to support that muscle exercise is beneficial to other metabolic organs such as liver. The [[FGF21]]-mediated AMPK dependent lipophagy might be a potential drug target for NAFLD and aging caused by lipid metabolic dysfunction.

|keywords=* Aging
* Exercise
* FGF21
* Lipophagy
* Nonalcoholic fatty liver disease (NAFLD)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365984
}}
{{medline-entry
|title=Mitochondria, immunosenescence and inflammaging: a role for mitokines?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32757036
|abstract=A global reshaping of the immune responses occurs with ageing, indicated as immunosenescence, where mitochondria and mitochondrial metabolism play an important role. However, much less is known about the role of mitochondrial stress response in this reshaping and in particular of the molecules induced by such response, collectively indicated as mitokines. In this review, we summarize the current knowledge on the role of mitokines in modulating immune response and inflammation focusing on GDF15, [[FGF21]] and humanin and their possible involvement in the chronic age-related low-grade inflammation dubbed inflammaging. Although many aspects of their biology are still controversial, available data suggest that these mitokines have an anti-inflammatory role and increase with age. Therefore, we hypothesize that they can be considered part of an adaptive and integrated immune-metabolic mechanism activated by mitochondrial dysfunction that acts within the framework of a larger anti-inflammatory network aimed at controlling both acute inflammation and inflammaging.

|keywords=* Human ageing
* Immunosenescence
* Inflammaging
* Mitochondrial metabolism
* Mitokines
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666292
}}
{{medline-entry
|title=Age-at-onset-dependent effects of sulfur amino acid restriction on markers of growth and stress in male F344 rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32573078
|abstract=Trade-offs in life-history traits are clinically and mechanistically important. Sulfur amino acid restriction (SAAR) extends lifespan. But whether this benefit comes at the cost of other traits including stress resistance and growth is unclear. We investigated the effects of SAAR on growth markers (body weight, IGF1, and IGFBP3) and physiological stresses. Male-F344 rats were fed control (0.86% Met) and SAAR (0.17% Met) diets starting at 2, 10, and 20 months. Rats were injected with keyhole-limpet-hemocyanin (KLH) to measure immune responses (anti-KLH-IgM, anti-KLH-IgG, and delayed-type-hypersensitivity [DTH]). Markers of ER stress ([[FGF21]] and adiponectin), detoxification capacity (glutathione [GSH] concentrations, GSH-S-transferase [GST], and cytochrome-P  -reductase [CPR] activities), and low-grade inflammation (C-reactive protein [CRP]) were also determined. SAAR decreased body weight, liver weight, food intake, plasma IGF1, and IGFBP3; the effect size diminished with increasing age-at-onset. SAAR increased [[FGF21]] and adiponectin, but stress damage markers GRP78 and Xbp1  were unchanged, suggesting that ER stress is hormetic. SAAR increased hepatic GST activity despite lower GSH, but CPR activity was unchanged, indicative of enhanced detoxification capacity. Other stress markers were either uncompromised (CRP, anti-KLH-IgM, and DTH) or slightly lower (anti-KLH-IgG). Increases in stress markers were similar across all ages-at-onset, except for adiponectin, which peaked at 2 months. Overall, SAAR did not compromise stress responses and resulted in maximal benefits with young-onset. In survival studies, median lifespan extension with initiation at 52 weeks was 7 weeks (p = .05); less than the 33.5-week extension observed in our previous study with 7-week initiation. Findings support SAAR translational studies and the need to optimize Met dose based on age-at-onset.

|keywords=* ER stress
* cysteine
* glutathione
* hormesis
* lifespan
* methionine
* trade-offs
* translational
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426777
}}
{{medline-entry
|title=Fibroblast growth factor 21 prolongs lifespan and improves stress tolerance in the silkworm, [i]Bombyx mori[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32309367
|abstract=Fibroblast growth factor 21 ([[FGF21]]), an FGF family member, is an atypical hormone and pro-longevity factor. To better understand of the effects of exogenous administration of [[FGF21]] on lifespan and stress tolerance, and the underlying molecular basis, we used the silkworm, [i]Bombyx mori[/i], as an experimental animal model to evaluate [[FGF21]]'s pharmaceutical effects. Lifespan was significantly prolonged in female silkworms with [[FGF21]] replenishment, whereas no effect was observed in the male silkworms. [[FGF21]] replenishment also significantly improved the activity of antioxidant systems such as glutathione-S-transferase (GST) and superoxide dismutase (SOD) and significantly decreased malondialdehyde (MDA) content. Moreover, [[FGF21]] was found to play a critical role in enhancing stress resistance, including ultraviolet (UV) irradiation tolerance and thermotolerance. Furthermore, [i]AMPK[/i], [i]FoxO[/i], and sirtuins were activated by [[FGF21]] and may be responsible for the prolonged lifespan and enhanced antioxidant activity observed in silkworms. Collectively, the results suggest the molecular pathways underlying of [[FGF21]]-induced longevity and stress tolerance, and support the use of silkworms as a promising experimental animal model for evaluating the pharmaceutical effects of small molecules.

|keywords=* Bombyx mori
* fibroblast growth factor 21 (FGF21)
* lifespan
* oxidation resistance
* stress tolerance
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154471
}}
{{medline-entry
|title=Neurogenesis and prolongevity signaling in young germ-free mice transplanted with the gut microbiota of old mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31723038
|abstract=The gut microbiota evolves as the host ages, yet the effects of these microbial changes on host physiology and energy homeostasis are poorly understood. To investigate these potential effects, we transplanted the gut microbiota of old or young mice into young germ-free recipient mice. Both groups showed similar weight gain and skeletal muscle mass, but germ-free mice receiving a gut microbiota transplant from old donor mice unexpectedly showed increased neurogenesis in the hippocampus of the brain and increased intestinal growth. Metagenomic analysis revealed age-sensitive enrichment in butyrate-producing microbes in young germ-free mice transplanted with the gut microbiota of old donor mice. The higher concentration of gut microbiota-derived butyrate in these young transplanted mice was associated with an increase in the pleiotropic and prolongevity hormone fibroblast growth factor 21 ([[FGF21]]). An increase in [[FGF21]] correlated with increased AMPK and SIRT-1 activation and reduced mTOR signaling. Young germ-free mice treated with exogenous sodium butyrate recapitulated the prolongevity phenotype observed in young germ-free mice receiving a gut microbiota transplant from old donor mice. These results suggest that gut microbiota transplants from aged hosts conferred beneficial effects in responsive young recipients.
|mesh-terms=* Animals
* Butyrates
* Fecal Microbiota Transplantation
* Fibroblast Growth Factors
* Gastrointestinal Microbiome
* Germ-Free Life
* Hippocampus
* Intestines
* Liver
* Longevity
* Male
* Metabolome
* Mice, Inbred C57BL
* Microtubule-Associated Proteins
* Neurogenesis
* Neurons
* Neuropeptides
* Phenotype
* Proton Magnetic Resonance Spectroscopy

|full-text-url=https://sci-hub.do/10.1126/scitranslmed.aau4760
}}
{{medline-entry
|title=Fibroblast Growth Factor 21 Mediates the Associations between Exercise, Aging, and Glucose Regulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31490857
|abstract=Aging increases the prevalence of glucose intolerance, but exercise improves glucose homeostasis. The fibroblast growth factor 21 ([[FGF21]])-adiponectin axis helps regulate glucose metabolism. However, the role of [[FGF21]] in mediating glucose metabolism with aging and exercise remains unknown. This study examined whether [[FGF21]] responses to a glucose challenge are associated with habitual exercise, aging and glucose regulation. Eighty age- and sex-matched healthy individuals were assigned to young sedentary and active (≤36 yr, n = 20 each group) and older sedentary and active (≥45 yr, n = 20 each group) groups. Fasted and postprandial blood glucose concentration and plasma concentration of insulin, [[FGF21]], and adiponectin were determined during an oral glucose tolerance test (OGTT). During the OGTT, glucose concentrations were 9% higher (P = 0.008) and [[FGF21]] concentrations were 58% higher (P = 0.014) in the older than the younger group, independent of activity status. Active participants had 40% lower insulin concentration and 53% lower [[FGF21]] concentration than sedentary participants, independent of age (all P < 0.001). Adiponectin concentration during the OGTT did not differ by age (P = 0.448) or activity status (P = 0.611). Within the younger group, postprandial glucose, insulin and [[FGF21]] concentrations during the OGTT were lower in active than in sedentary participants. In the older group, only postprandial insulin and [[FGF21]] concentrations were lower in active participants. [[FGF21]], but not adiponectin, response during the OGTT is higher in older than younger adults and lower in active than sedentary individuals. Exercise-associated reduction in OGTT glucose concentrations was observed in younger but not older adults.
|mesh-terms=* Adiponectin
* Adult
* Aging
* Blood Glucose
* Blood Pressure
* Body Mass Index
* Diabetes Mellitus, Type 2
* Exercise
* Female
* Fibroblast Growth Factors
* Glucose Tolerance Test
* Humans
* Insulin
* Lipids
* Male
* Middle Aged
* Risk Factors

|full-text-url=https://sci-hub.do/10.1249/MSS.0000000000002150
}}
{{medline-entry
|title=Effects of Moderate Chronic Food Restriction on the Development of Postprandial Dyslipidemia with Ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31405194
|abstract=Ageing is a major risk factor for the development of metabolic disorders linked to dyslipidemia, usually accompanied by increased adiposity. The goal of this work was to investigate whether avoiding an excessive increase in adiposity with ageing, via moderate chronic food restriction (FR), ameliorates postprandial dyslipidemia in a rat model of metabolic syndrome associated with ageing. Accordingly, we performed an oral lipid loading test (OLLT) in mature middle-aged (7 months) and middle-old-aged (24 months) Wistar rats fed ad libitum (AL) or under moderate FR for 3 months. Briefly, overnight fasted rats were orally administered a bolus of extra-virgin olive oil (1 mL/Kg of body weight) and blood samples were taken from the tail vein before fat load (t = 0) and 30, 60, 90, 120, 180, and 240 min after fat administration. Changes in serum lipids, glucose, insulin, and glucagon levels were measured at different time-points. Expression of liver and adipose tissue metabolic genes were also determined before (t = 0) and after the fat load (t = 240 min). Postprandial dyslipidemia progressively increased with ageing and this could be associated with hepatic ChREBP activity. Interestingly, moderate chronic FR reduced adiposity and avoided excessive postprandial hypertriglyceridemia in 7- and 24-month-old Wistar rats, strengthening the association between postprandial triglyceride levels and adiposity. The 24-month-old rats needed more insulin to maintain postprandial normoglycemia; nevertheless, hyperglycemia occurred at 240 min after fat administration. FR did not alter the fasted serum glucose levels but it markedly decreased glucagon excursion during the OLLT and the postprandial rise of glycemia in the 24-month-old rats, and [[FGF21]] in the 7-month-old Wistar rats. Hence, our results pointed to an important role of FR in postprandial energy metabolism and insulin resistance in ageing. Lastly, our data support the idea that the vWAT might function as an ectopic site for fat deposition in 7-month-old and in 24-month-old Wistar rats that could increase their browning capacity in response to an acute fat load.
|mesh-terms=* Adiposity
* Aging
* Animals
* Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
* Blood Glucose
* Diet, Fat-Restricted
* Dietary Fats
* Disease Models, Animal
* Dyslipidemias
* Glucagon
* Insulin
* Lipids
* Liver
* Metabolic Syndrome
* Postprandial Period
* Rats
* Rats, Wistar
* Triglycerides
|keywords=* ChREBP
* adipose tissue
* ageing
* oral lipid loading test
* postprandial hypertrigliceridemia
* postprandial thermogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723802
}}
==TG==

{{medline-entry
|title=Inhibition of the alternative lengthening of telomeres pathway by subtelomeric sequences in Saccharomyces cerevisiae.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33126043
|abstract=In the budding yeast Saccharomyces cerevisiae, telomerase is constitutively active and is essential for chromosome end protection and illimited proliferation of cell populations. However, upon inactivation of telomerase, alternative mechanims of telomere maintenance allow proliferation of only extremely rare survivors. S. cerevisiae type I and type II survivors differ by the nature of the donor sequences used for repair by homologous recombination of the uncapped terminal [[TG]]  telomeric sequences. Type I amplifies the subtelomeric Y' sequences and is more efficient than type II, which amplifies the terminal [[TG]]  repeats. However, type II survivors grow faster than type I survivors and can easily outgrow them in liquid cultures. The mechanistic interest of studying S. cerevisiae telomeric recombination is reinforced by the fact that type II recombination is the equivalent of the alternative lengthening of telomeres (ALT) pathway that is used by 5-15 % of cancer types as an alternative to telomerase reactivation. In budding yeast, only around half of the 32 telomeres harbor Y' subtelomeric elements. We report here that in strains harboring Y' elements on all telomeres, type II survivors are not observed, most likely due to an increase in the efficiency of type I recombination. However, in a temperature-sensitive cdc13-1 mutant grown at semi-permissive temperature, the increased amount of telomeric [[TG]]  repeats could overcome type II inhibition by the subtelomeric Y' sequences. Strikingly, in the 100 % Y' strain the replicative senescence crisis normally provoked by inactivation of telomerase completely disappeared and the severity of the crisis was proportional to the percentage of chromosome-ends lacking Y' subtelomeric sequences. The present study highlights the fact that the nature of subtelomeric elements can influence the selection of the pathway of telomere maintenance by recombination, as well as the response of the cell to telomeric damage caused by telomerase inactivation.

|keywords=* Budding yeast
* Rad52
* Replicative senescence
* Subtelomeric Y’ elements
* Telomerase-independent telomere maintenance
* Telomere recombination
|full-text-url=https://sci-hub.do/10.1016/j.dnarep.2020.102996
}}
{{medline-entry
|title=E4orf1, an Adeno-viral protein, attenuates renal lipid accumulation in high fat fed mice: A novel approach to reduce a key risk factor for chronic kidney disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33102865
|abstract=Obesity and hyperlipidemia are independent risk factors of chronic kidney disease (CKD). In mice, diet induced obesity accelerates lipogenesis, lipid accumulation, and injury in kidneys. Expression of adenoviral protein, E4orf1, improves glucose clearance and reduces endogenous insulin secretion to glucose challenge in mice. Therefore, in this pilot study, we examined, if enhanced glycemic control in HFD fed E4orf1 transgenic (E4orf1-Tg) mice, will reduce renal lipogenesis and lipid accumulation. In two separate experiments, E4orf1-Tg mice were fed 60% (kcal) high-fat diet (HFD) supplemented with doxycycline for 10-weeks or 20-weeks along with wild-type (C57BL6/J) or E4orf1-non-transgenic (E4orf1-non-Tg) control mice, respectively. Protein expression of Fatty Acid Synthase (FAS) and Acetyl-CoA Carboxylase (ACC), accumulation of triglyceride ([[TG]]) along with mRNA levels of lipid metabolism and injury markers were determined in kidneys. Renal expression of FAS and ACC, and [[TG]] content was significantly reduced in E4orf1-Tg mice compared to controls. E4orf1-Tg mice show significant increase in genes involved in mitochondrial fatty acid oxidation and oxidative stress compared to wild-type mice after 10-weeks of HFD. However, mice exposed to 20-weeks of HFD, show no difference in gene expression. E4orf1 expression reduces lipid synthesis and accumulation in kidneys despite HFD, which may be due to attenuation of hyperinsulinemia by E4orf1.

|keywords=* Aging
* CKD
* Diabetes
* Diet
* E4orf1
* FA synthesis
* Hyperinsulinemia
* Insulin
* Lipid metabolism
* Obesity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575883
}}
{{medline-entry
|title=Resistance exercise attenuates postprandial metabolic responses to a high-fat meal similarly in younger and older men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33032071
|abstract=This study examined whether an acute bout of resistance exercise (RE) attenuated postprandial responses to a high fat meal (HFM) similarly in younger versus older adult men, and probed relationships among skeletal muscle mass (SMM), age, the metabolic load index (MLI) response, and the improvement in the MLI elicited by RE versus CON. Eleven younger (24 ± 4y) and 9 older (61 ± 5y) men completed RE or control (CON) the night prior to a HFM. Before and 1, 3, and 5 hours after the HFM, blood triglycerides ([[TG]]), glucose (GLU), MLI, and cholesterol concentrations were quantified. Following a 7 ± 1-day washout period, participants returned and completed the opposite condition. Independent of age, [[TG]]s were 32.1 ± 27.1 mg/dL and 52.7 ± 26.8 mg/dL lower in RE than CON at 3 and 5 hours, respectively. MLI was also 24.3 to 56.9 mg/dL lower in RE than CON from 1 to 5 hours post-meal independent of age. The [[TG]] and MLI area under the curves (AUCs) were 15% to 31% lower in RE than CON. The GLU response was greater in the older than younger men at 1 to 5 hours post-meal. Moreover, the average GLU response was 5.6 ± 2.5 mg/dL lower in RE versus CON and was inversely related to SMM across the sample (r = -0.615). However, age, volume, or SMM were not related to the MLI , nor to the improvement elicited by RE. Therefore, although the older men displayed a greater postprandial glucose response than the younger men, RE attenuated the postprandial metabolic response to a HFM similarly in younger and older men.

|keywords=* Aging
* Cardiometabolic
* Lipemia
* Metabolism
* Nutrition
|full-text-url=https://sci-hub.do/10.1016/j.nutres.2020.08.012
}}
{{medline-entry
|title=Aging-induced aberrant RAGE/PPARα axis promotes hepatic steatosis via dysfunctional mitochondrial β oxidation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32936538
|abstract=Non-alcoholic fatty liver disease (NAFLD), characterized by an increase in hepatic triglyceride ([[TG]]) content, is the most common liver disease worldwide. Aging has been shown to increase susceptibility to NAFLD; however, the underlying molecular mechanism remains poorly understood. In the present study, we examined hepatic [[TG]] content and gene expression profiles in body weight-matched young (3 months old), middle-aged (10 months old), and old (20 months old) C57BL/6 mice and found that [[TG]]s were markedly accumulated while mitochondrial β-oxidation-related genes, including PPARα, were downregulated in the liver of old mice. In addition, advanced glycation end product receptor (RAGE), a key regulator of glucose metabolism, was upregulated in the old mice. Mechanistically, suppression of RAGE upregulated PPARα and its downstream target genes, which in turn led to reduced [[TG]] retention. Finally, we found that hepatic RAGE expression was increased in aging patients, a finding that correlated with decreased PPARα levels. Taken together, our findings demonstrate that the upregulation of RAGE may play a critical role in aging-associated liver steatosis.

|keywords=* PPARα
* RAGE
* aging
* hepatic steatosis
* mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576254
}}
{{medline-entry
|title=Fenofibrate impairs liver function and structure more pronounced in old than young rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32927318
|abstract=Since old animals are known to accumulate lipids in some organs, we compared effects of fenofibrate (FN) on systemic lipid metabolism, activity of liver marker enzymes and structure in young and old rats. Young and old rats were fed chow supplemented with 0.1 % or 0.5 % FN. After 30 days, intraperitoneal glucose tolerance test (IPGTT) was performed, and blood and liver samples were collected. In young rats, 0.1 % FN, but not 0.5 % FN, decreased serum Chol by 74 %, and did not affect [[TG]] levels at either doses. In old rats, 0.5 % FN, but not 0.1 % FN, decreased Chol and [[TG]] level by 56 % and 49 %, respectively. In young rats, 0.1 % and 0.5 % FN increased serum activity of ALP by 227 % and 260 %, respectively, and did not affect AST and ALT activities. In old rats, only 0.5 % FN increased serum ALP activity by 150 %, respectively. In old rats, neither dose of FN affected serum AST activity, and only 0.5 % FN increased serum ALT activity by 200 %. The histological examination of liver structure revealed that both doses of FN impaired lobular architecture, expansion of bile canaliculi, and degeneration of parenchymal cells with the presence of cells containing fat droplets; administration of FN increased area occupied by collagen fibers. Although 0.5 % FN decreased serum Chol concentration, it increased serum ALP activity and impaired liver structure in both in both age groups of rats. Thus, FN treatment should be under the control of liver function, especially in older patients.

|keywords=* Aging
* Fenofibrate
* Lipids
* Liver function and morphology
* Rat
* serum
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104244
}}
{{medline-entry
|title=Awareness of major cardiovascular risk factors and its relationship with markers of vascular aging: Data from the Brisighella Heart Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32249143
|abstract=General population awareness about cardiovascular risk factors is usually low. The aim of the present study was to evaluate the vascular aging of subjects aware and not aware to be hypertensive, hypercholesterolemic, hypertriglyceridemic or diabetics in a general population sample. We interviewed 1652 subjects without atherosclerotic cardiovascular diseases (M: 46.6%, F: 53.4%) about their awareness of hypertension, hypercholesterolemia, hypertriglyceridemia or type 2 diabetes. Then we compared the augmentation index and pulse wave velocity of subjects aware and not aware of the investigated cardiovascular risk factors. 1049 participants declared not to be hypertensive, while 32 were not sure. Among them, respectively, 23.5% and 50% were hypertensive. Subjects not aware of their hypertension had significantly higher aortic blood pressure than aware ones (p < 0.001). 841 participants declared not to be hypercholesterolemic, while 60 were not sure. Among them, respectively, 18.1% and 40% were hypercholesterolemic. Subjects not aware of their hypercholesterolemia had significantly higher augmentation index than the aware ones (p < 0.05). 1226 participants declared not to be hypertriglyceridemic, while 200 were not sure. Among them, respectively, 19.2% and 44% were hypertriglyceridemic. Subjects not aware of their hypertriglyceridemia had significantly higher [[TG]] levels aware ones (p < 0.05), although this seemed to not related to increased arterial stiffness. 1472 participants declared not to be diabetic, while 20 were not sure. Among them, respectively, 2.0% and 25.0% were diabetics. Subjects not aware of their diabetes had significantly higher augmentation index than the aware ones (p < 0.05). In conclusion, the lack of awareness of hypertension and hypercholesterolemia is relatively frequent in the general population and is associated to significantly higher arterial stiffness.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Blood Glucose
* Blood Pressure
* Cardiovascular Diseases
* Cholesterol
* Cross-Sectional Studies
* Diabetes Mellitus
* Female
* Humans
* Hypercholesterolemia
* Hypertension
* Hypertriglyceridemia
* Italy
* Male
* Middle Aged
* Risk Assessment
* Risk Factors
* Triglycerides
* Vascular Stiffness
* Young Adult
|keywords=* Arterial aging
* Awareness
* Epidemiology
* Pulse wave velocity
* Risk factors
|full-text-url=https://sci-hub.do/10.1016/j.numecd.2020.03.005
}}
{{medline-entry
|title=Characterisation of the dynamic nature of lipids throughout the lifespan of genetically identical female and male Daphnia magna.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32221338
|abstract=Lipids play a significant role in regulation of health and disease. To enhance our understanding of the role of lipids in regulation of lifespan and healthspan additional studies are required. Here, UHPLC-MS/MS lipidomics was used to measure dynamic changes in lipid composition as a function of age and gender in genetically identical male and female Daphnia magna with different average lifespans. We demonstrate statistically significant age-related changes in triglycerides ([[TG]]), diglycerides (DG), phosphatidylcholine, phosphatidylethanolamine, ceramide and sphingomyelin lipid groups, for example, in males, 17.04% of [[TG]] lipid species decline with age whilst 37.86% increase in relative intensity with age. In females, 23.16% decrease and 25.31% increase in relative intensity with age. Most interestingly, the rate and direction of change can differ between genetically identical female and male Daphnia magna, which could be the cause and/or the consequence of the different average lifespans between the two genetically identical genders. This study provides a benchmark dataset to understand how lipids alter as a function of age in genetically identical female and male species with different average lifespan and ageing rate.
|mesh-terms=* Aging
* Animals
* Daphnia
* Diglycerides
* Female
* Lipid Metabolism
* Longevity
* Male
* Phosphatidylcholines
* Sphingomyelins
* Triglycerides

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101400
}}
{{medline-entry
|title=Effects of laboratory biotic aging on the characteristics of biochar and its water-soluble organic products.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31472466
|abstract=Effects of biotic aging on the characteristics of biochar and its water-soluble organic products were determined through a one-year laboratory incubation study. Biochar had a positive influence on microbial population size. Without microbial addition, biochars showed little change, except for an obvious increase in oxygen content from 3.2% to 6.3% after one year. By contrast, the carbon (C) content of the biologically-aged biochars continually decreased throughout the incubation at two humidity levels, suggesting that microbes consumed biochar C or encouraged organic matter solubilization. Fourier Transform Infrared Spectroscopy (FTIR) analysis indicated that all aged biochar surfaces showed increases in oxygen-containing functional groups and [[TG]]-D[[TG]] analysis showed that biologically-aged biochars were less stable than the corresponding abiotically-aged one. The release of dissolved organic matters from biologically-aged biochar logarithmically increasing with time, corresponded with of the pattern of microbe production, suggesting microbial involvement in solubilizing biochar. Combined three-dimensional excitation-emission matrix (3DEEM) and parallel factor (PARAFAC) analyses revealed that fulvic and humic acid-like components were the main water-soluble products of biologically-aged biochar, and these became increasingly rich in O-containing functional groups, i.e. humified, over time. These results highlight the importance of microbes in chemically transforming biochar and the dissolved products of biochar during aging.
|mesh-terms=* Benzopyrans
* Charcoal
* Humic Substances
* Microbiota
* Soil Microbiology
* Solubility
* Triticum
* Water
|keywords=* Biochar
* Biotic incubation aging
* Dissolved organic matter (DOM)
* Excitation-emission matrix
* Humification
|full-text-url=https://sci-hub.do/10.1016/j.jhazmat.2019.121071
}}
{{medline-entry
|title=Using Caenorhabditis elegans for Studying Trans- and Multi-Generational Effects of Toxicants.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31403614
|abstract=Information about toxicities of chemicals are essential in their application and waste management. For chemicals at low concentrations, the long-term effects are very important in judging their consequences in the environment and on human health. In demonstrating long-term influences, effects of chemicals over generations in recent studies provide new insight. Here, we describe protocols for studying effects of chemicals over multiple generations using free-living nematode Caenorhabditis elegans. Two aspects are presented: (1) trans-generational ([[TG]]) and (2) multi-generational effect studies, the latter of which is separated to multi-generational exposure (MGE) and multi-generational residual (MGR) effect studies. The [[TG]] effect study is robust with a simple purpose to determine whether chemical exposure to parents can result in any residual consequences on offspring. After the effects are measured on parents, sodium hypochlorite solutions are used to kill the parents and keep the offspring so as to facilitate effect measurement on the offspring. The [[TG]] effect study is used to determine whether the offspring are affected when their parent is exposed to the pollutants. The MGE and MGR effect study is systematical used to determine whether continuous generational exposure can result in adaptive responses in offspring over generations. Careful pick-up and transfer are used to distinguish generations to facilitate effect measurement on each generation. We also combined protocols to measure locomotion behavior, reproduction, lifespan, biochemical and gene expression changes. Some example experiments are also presented to illustrate the trans- and multi-generational effect studies.
|mesh-terms=* Animals
* Caenorhabditis elegans
* Hazardous Substances
* Humans
* Longevity
* Reproduction
* Toxicity Tests

|full-text-url=https://sci-hub.do/10.3791/59367
}}
==CD34==

{{medline-entry
|title=Comparing the Effect of TGF-β Receptor Inhibition on Human Perivascular Mesenchymal Stromal Cells Derived from Endometrium, Bone Marrow and Adipose Tissues.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33271899
|abstract=Rare perivascular mesenchymal stromal cells (MSCs) with therapeutic properties have been identified in many tissues. Their rarity necessitates extensive in vitro expansion, resulting in spontaneous differentiation, cellular senescence and apoptosis, producing therapeutic products with variable quality and decreased potency. We previously demonstrated that A83-01, a transforming growth factor beta (TGF-β) receptor inhibitor, maintained clonogenicity and promoted the potency of culture-expanded premenopausal endometrial MSCs using functional assays and whole-transcriptome sequencing. Here, we compared the effects of A83-01 on MSCs derived from postmenopausal endometrium, menstrual blood, placenta decidua-basalis, bone marrow and adipose tissue. Sushi-domain-containing-2 (SUSD2 ) and [[CD34]] CD31 CD45  MSCs were isolated. Expanded MSCs were cultured with or without A83-01 for 7 days and assessed for MSC properties. SUSD2 identified perivascular cells in the placental decidua-basalis, and their maternal origin was validated. A83-01 promoted MSC proliferation from all sources except bone marrow and only increased SUSD2 expression and prevented apoptosis in MSCs from endometrial-derived tissues. A83-01 only improved the cloning efficiency of postmenopausal endometrial MSCs (eMSCs), and expanded adipose tissue MSCs (adMSCs) underwent significant senescence, which was mitigated by A83-01. MSCs derived from bone marrow (bmMSCs) were highly apoptotic, but A83-01 was without effect. A83-01 maintained the function and phenotype in MSCs cultured from endometrial, but not other, tissues. Our results also demonstrated that cellular SUSD2 expression directly correlates with the functional phenotype.

|keywords=* SUSD2
* adipose tissue
* apoptosis
* bone marrow
* clonogenicity
* endometrium
* menstrual fluid
* perivascular mesenchymal stromal cells
* placenta
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712261
}}
{{medline-entry
|title=ACE2/ACE imbalance and impaired vasoreparative functions of stem/progenitor cells in aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33247425
|abstract=Aging increases risk for ischemic vascular diseases. Bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) are known to stimulate vascular regeneration. Activation of either the Mas receptor (MasR) by angiotensin-(1-7) (Ang-(1-7)) or angiotensin-converting enzyme-2 (ACE2) stimulates vasoreparative functions in HSPCs. This study tested if aging is associated with decreased ACE2 expression in HSPCs and if Ang-(1-7) restores vasoreparative functions. Flow cytometric enumeration of Lin CD45 [[CD34]]  cells was carried out in peripheral blood of male or female individuals (22-83 years of age). Activity of ACE2 or the classical angiotensin-converting enzyme (ACE) was determined in lysates of HSPCs. Lin Sca-1 cKit  (LSK) cells were isolated from young (3-5 months) or old (20-22 months) mice, and migration and proliferation were evaluated. Old mice were treated with Ang-(1-7), and mobilization of HSPCs was determined following ischemia induced by femoral ligation. A laser Doppler blood flow meter was used to determine blood flow. Aging was associated with decreased number (Spearman r = - 0.598, P < 0.0001, n = 56), decreased ACE2 (r = - 0.677, P < 0.0004), and increased ACE activity (r = 0.872, P < 0.0001) (n = 23) in HSPCs. Migration or proliferation of LSK cells in basal or in response to stromal-derived factor-1α in old cells is attenuated compared to young, and these dysfunctions were reversed by Ang-(1-7). Ischemia increased the number of circulating LSK cells in young mice, and blood flow to ischemic areas was recovered. These responses were impaired in old mice but were restored by treatment with Ang-(1-7). These results suggest that activation of ACE2 or MasR would be a promising approach for enhancing ischemic vascular repair in aging.

|keywords=* ACE2
* Aging
* Angiotensin-(1-7)
* Hematopoietic stem/progenitor cells
* Ischemia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694587
}}
{{medline-entry
|title=Innovative Mind-Body Intervention Day Easy Exercise Increases Peripheral Blood [[CD34]]  Cells in Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32841054
|abstract=Mind-body interventions (MBIs) have many health benefits, such as reducing stress, modulating blood pressure, and improving sleep and life quality. The long-term practice of Tai chi, an MBI, also increases the number of [[CD34]]  cells, which are surface markers of hematopoietic stem cells, so prolonged Tai chi practice may have antiaging effects. We developed the day easy exercise (DEE), an innovative MBI, that is easy to learn and requires only a small exercise area and a short practice time. The aim of this study was to explore whether DEE, like Tai chi, has antiaging effects after short-term practice. Total 44 individuals (25 to 62 years old) with or without 3-month DEE practice were divided into young- and middle-aged groups (≤30 and >30 years old) and peripheral blood was collected at 0, 1, 2, and 3 months for analysis of [[CD34]]  cells. The number of [[CD34]]  cells in peripheral blood remained unchanged in control young- and middle-aged groups. After DEE, the number of [[CD34]]  cells in peripheral blood was increased over time in both young- and middle-aged groups. For young-aged adults, the cell number was markedly increased by threefold at 3 months after DEE, and for middle-aged adults, the increase was significant from the first month. DEE practice indeed increased the number of [[CD34]]  cells in peripheral blood and the increase was more significant for older people in a shorter time. This is the first study to provide evidence that the DEE may have antiaging effects and could be beneficial for older people.

|keywords=* CD34+ cells
* aging
* day easy exercise
* mind–body intervention
|full-text-url=https://sci-hub.do/10.1177/0963689720952352
}}
{{medline-entry
|title=Human Thymic Involution and Aging in Humanized Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32733465
|abstract=Thymic involution is an important factor leading to the aging of the immune system. Most of what we know regarding thymic aging comes from mouse models, and the nature of the thymic aging process in humans remains largely unexplored due to the lack of a model system that permits longitudinal studies of human thymic involution. In this study, we sought to explore the potential to examine human thymic involution in humanized mice, constructed by transplantation of fetal human thymus and [[CD34]]  hematopoietic stem/progenitor cells into immunodeficient mice. In these humanized mice, the human thymic graft first underwent acute recoverable involution caused presumably by transplantation stress, followed by an age-related chronic form of involution. Although both the early recoverable and later age-related thymic involution were associated with a decrease in thymic epithelial cells and recent thymic emigrants, only the latter was associated with an increase in adipose tissue mass in the thymus. Furthermore, human thymic grafts showed a dramatic reduction in [i]FOXN1[/i] and [i]AIRE[/i] expression by 10 weeks post-transplantation. This study indicates that human thymus retains its intrinsic mechanisms of aging and susceptibility to stress-induced involution when transplanted into immunodeficient mice, offering a potentially useful [i]in vivo[/i] model to study human thymic involution and to test therapeutic interventions.

|keywords=* aging
* human
* humanized mouse
* recent thymic emigrants
* thymus involution
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358581
}}
{{medline-entry
|title=Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood [[CD34]]  cells via inhibition of senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32602209
|abstract=The stemness of ex vivo expanded hematopoietic stem cells (HSCs) is usually compromised by current methods. To explore the failure mechanism of stemness maintenance of human HSCs, which were expanded from human umbilical cord blood (hUCB) [[CD34]]  cells, by differentiation inhibitor Stem Regenin 1 (SR1), an antagonist of aryl hydrocarbon receptor, we investigated the activity of p38 mitogen-activated protein kinase α (p38 MAPKα, p38α) and mammalian target of rapamycin complex 1 (mTORC1), and their effect on SR1-expanded hUCB [[CD34]]  cells. Our results showed that cellular senescence occurred in the SR1-expanded hUCB [[CD34]]  cells in which p38α and mTORC1 were successively activated. Furthermore, their coinhibition resulted in a further decrease in hUCB [[CD34]]  cell senescence without an effect on apoptosis, promoted the maintenance of expanded phenotypic HSCs without differentiation inhibition, increased the hematopoietic reconstitution ability of multiple lineages, and potentiated the long-term self-renewal capability of HSCs from SR1-expanded hUCB [[CD34]]  cells in NOD/Shi-scid/IL-2Rγ  mice. Our mechanistic study revealed that senescence inhibition by our strategy was mainly attributed to downregulation of the splicesome, proteasome formation, and pyrimidine metabolism signaling pathways. These results suggest that coinhibition of activated p38α and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded hUCB [[CD34]]  cells via senescence inhibition. Thus, we established a new strategy to maintain the stemness of ex vivo differentiation inhibitor-expanded human HSCs via coinhibition of multiple independent senescence initiating signal pathways. This senescence inhibition-induced stemness maintenance of ex vivo expanded HSCs could also have an important role in other HSC expansion systems.

|keywords=* HSC stemness maintenance
* Stem Regenin 1
* cellular senescence
* ex vivo expansion
* human cord blood CD34+ cells
* mammalian target of rapamycin complex 1
* p38 mitogen-activated protein kinase α
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695631
}}
{{medline-entry
|title=Bulk and single-cell gene expression analyses reveal aging human choriocapillaris has pro-inflammatory phenotype.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32531351
|abstract=The human choroidal vasculature is subject to age-related structural and gene expression changes implicated in age-related macular degeneration (AMD). In this study, we performed both bulk and single-cell RNA sequencing on infant (n = 4 for bulk experiments, n = 2 for single-cell experiments) and adult (n = 13 for bulk experiments, n = 6 for single-cell experiments) human donors to characterize how choroidal gene expression changes with age. Differential expression analysis revealed that aged choroidal samples were enriched in genes encoding pro-inflammatory transcription factors and leukocyte transendothelial cell migration adhesion proteins. Such genes were observed to be differentially expressed specifically within choroidal endothelial cells at the single-cell level. Immunohistochemistry experiments support transcriptional findings that [[CD34]] is elevated in infant choriocapillaris endothelial cells while ICAM-1 is enriched in adults. These results suggest several potential drivers of the pro-inflammatory vascular phenotype observed with advancing age.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Choroid
* Endothelial Cells
* Female
* Gene Expression Regulation
* Humans
* Infant
* Infant, Newborn
* Inflammation
* Inflammation Mediators
* Macular Degeneration
* Male
* Middle Aged
* Phenotype
* Sequence Analysis, RNA
* Single-Cell Analysis
|keywords=* Age-related macular degeneration
* Choriocapillaris
* Choroid
* Infant
* Pericytes
* Single-cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396301
}}
{{medline-entry
|title=Mesenchymal stem cells repair bone marrow damage of aging rats and regulate autophagy and aging genes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32432372
|abstract=The current study investigated the role of mesenchymal stem cells (MSCs) in repairing senile bone marrow injury and the underlying mechanism. Adenoviral vectors expressing green fluorescent protein (GFP) were used to label MSCs. The level of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) were detected by thiobarbituric acid (TBA) and xanthine oxidation (XTO) methods. The proportions of [[CD34]], CD3  cells, cell proliferation and apoptosis were determined by flow cytometry, Cell counting kit (CCK)-8 and comet assay. Tissues were stained by haematoxylin-eosin (HE) staining and their changes were observed under a transmission electron microscopy. Expression levels of age-related and autophagy-related genes were detected by RT-qPCR and Western Blot. MSCs were successfully implanted into the bone marrow of aging rats. We found that the SOD activity was increased and MDA content was reduced in MSCs group. The proportions of [[CD34]] cells were significantly more in the MSCs group than those in the Model group, and bone marrow cell colony formation and cell viability were both greatly increased in MSCs group. The proportions of CD3  cells and level of Vascular endothelial growth factor (VEGF) were increased significantly, while IL-6 level was reduced greatly in MSCs group. Moreover, the bone marrow tissues of the model group were severely damaged, but those of the MSCs group were significantly improved. In addition, MSCs were involved in regulation of aging-related genes and autophagy-related genes. In conclusion, our findings showed that MSCs can repair bone marrow damage in aging rats, and regulate aging- and autophagy-related genes and immune response. SIGNIFICANCE: This study investigated the role of MSCs in the repair of senile bone marrow injury and the underlying mechanism. The effects of MSCs on physiological and biochemical indicators, cell function, tissue structure differences and pathological changes in aging rats were studied. It was found that MSCs can repair bone marrow damage in aging rats. MSCs regulate aging and autophagy-related genes and its involvement in immune response. Our findings improve the understandings on the regulatory mechanism of MSCs and provide key evidence for the study of MSCs in bone marrow repair.

|keywords=* aging
* autophagy
* bone marrow injury
* mesenchymal stem cells
* repair
|full-text-url=https://sci-hub.do/10.1002/cbf.3548
}}
{{medline-entry
|title=Immune cell extracellular vesicles and their mitochondrial content decline with ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31911808
|abstract=Although the mechanisms of action are not fully understood, extracellular vesicles (EVs) have emerged as key indicators and effectors of immune function. Characterizing circulating EVs associated with stem and immune cells across the lifespan of healthy individuals could aid an understanding of immunosenescence, a process of age-related decline of cells in both adaptive and innate immune systems. Using high resolution multicolor flow cytometry, we identified three major subsets of EVs of varying sizes in healthy control (HC) plasma. Multiple plasma EVs associated with immune cells declined with ageing in HCs. In addition, we observed age-associated declines of respiring mitochondria cargo in EVs of several types of immune cells, suggesting that these parent cells may experience a decline in mitophagy or a mitochondrial dysfunction-induced immunosenescence. By contrast, the number of [[CD34]]  hematopoietic stem cell-associated EVs were high and carried respiring mitochondria, which did not decline with age. As demonstrated here, multicolor flow cytometry simultaneously measures plasma EV size, surface markers and cargo that reflect biological processes of specific cell types. The distinct surface markers and cytokine cargo of plasma EVs suggest that they may carry different bio-messages and originate by different biogenesis pathways.

|keywords=* Ageing
* Apoptotic bodies
* Exosomes
* Extracellular vesicles
* Immune cells
* Immunosenescence
* Inflammageing
* Microvesicles
* Mitochondria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942666
}}
{{medline-entry
|title=Young and elderly oral squamous cell carcinoma patients present similar angiogenic profile and predominance of M2 macrophages: Comparative immunohistochemical study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31497915
|abstract=M2 macrophages are often detected in oral squamous cell carcinoma (OSCC), which, influenced by hypoxic conditions, appear to have high angiogenesis-inducing capacity. However, the effects of immunosenescence on tumor-associated macrophages (TAMs) and angiogenesis in OSCC are unknown. Fifty-seven OSCCs were divided into 3 groups (I: <40 years [n = 17]; II: 40-65 years [n = 20]; III: >65 years [n = 20]). Immunohistochemistry for CD68 and CD163 (TAMs), and [[CD34]] and D2-40 for microvessel density (MVD), microvessel area (MVA), and total vascular area (TVA) were performed. All groups showed similar clinicopathological and immunohistochemical findings. Similar CD68 and CD163 expression, confirmed a M2 phenotype. MVD, MVA, and TVA were similar, however, with significant predominance of blood vessels. No significant correlation between macrophage and angiogenic markers was observed. A similar TAM and angiogenesis profile suggests the participation of other mechanisms, instead immunosenescence, in young and elderly OSCC patients.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Carcinoma, Squamous Cell
* Female
* Humans
* Immunohistochemistry
* Immunosenescence
* Macrophages
* Male
* Middle Aged
* Mouth Neoplasms
* Neovascularization, Pathologic
* Receptors, Cell Surface
* Tumor Microenvironment
|keywords=* M1 and M2 macrophages
* angiogenesis
* immunohistochemistry
* immunosenescence
* oral squamous cell carcinoma
|full-text-url=https://sci-hub.do/10.1002/hed.25954
}}
==ACE==

{{medline-entry
|title=Elite swimmers possess shorter telomeres than recreationally active controls.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33068677
|abstract=Elite athletes are reported to possess longer telomeres than their less active counterparts. [[ACE]] gene (Insertion/Deletion) polymorphism has been previously associated with elite athletic performance, with the deletion (D) variant appearing more frequently in short distance swimmers. Additionally, the D allele has been reported to have a negative effect on telomere length. The aim of this study was to investigate the telomere length of elite swimmers and its potential association with [[ACE]] genotype. Telomere length was measured by real-time quantitative PCR and [[ACE]] I/D genotypes analysed by standard PCR and electrophoresis in 51 young elite swimmers and 56 controls. Elite swimmers displayed shorter telomeres than controls (1.043 ± 0.127 vs 1.128 ± 0.177, p = 0.006). When split by sex, only elite female swimmers showed significantly shorter telomeres than their recreationally active counterparts (p = 0.019). [[ACE]] genotype distribution and allelic frequency did not differ between elite swimmers and controls, or by event distance among elite swimmers only. No association was observed between telomere length and [[ACE]] genotype in the whole cohort. Elite swimmers possessed shorter telomeres than recreationally active controls. Our findings suggesting a negative effect of high-level swimming competition and/or training on telomere length and subsequent biological aging, particularly in females. However, this significant difference in telomere length does not appear to be attributed to the D allele as we report a lack of association between telomere length and [[ACE]] genotype frequency in elite swimmers and controls.

|keywords=* Aging
* Athlete
* Exercise
* Genetics
|full-text-url=https://sci-hub.do/10.1016/j.gene.2020.145242
}}
{{medline-entry
|title=Coronavirus Disease-2019 Conundrum: RAS Blockade and Geriatric-Associated Neuropsychiatric Disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32850927
|abstract=Coronavirus Disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which primarily targets the human respiratory system and may lead to severe pneumonia and ultimately death. Mortality rate is particurlarly high among people beyond the sixth decade of life with cardiovascular and metabolic diseases. The discovery that the SARS-CoV-2 uses the renin-angiotensin system (RAS) component [[ACE]]2 as a receptor to invade host epithelial cells and cause organs damage resulted in a debate regarding the role of [[ACE]] inhibitors ([[ACE]]Is) and angiotensin receptor blockers (ARBs) therapies during COVID-19 pandemic. Some authors proposed the discontinuation of [[ACE]]Is and ARBs for cardiovascular, kidney, and metabolic diseases, while expert opinions have discouraged that due to limited empirical evidence of their negative effect on COVID-19 outcomes, and that withdrawing treatment may contribute to clinical decompensation in high-risk patients. Moreover, as cardiovascular and metabolic diseases are associated with neurodegenerative and psychiatric disorders, especially among older adults, a critical appraisal of the potential positive effects of [[ACE]]Is and ARBs is highly needed. Herein, we aim to discuss the conundrum of [[ACE]]Is and ARBs use in high-risk patients for COVID-19, and their potential protective role on the development and/or progression of geriatric neuropsychiatric disorders.

|keywords=* ACE2
* ACEIs
* ARBs
* COVID-19
* RAS
* SARS-CoV-2
* geriatrics
* neuropsychiatric disorders
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431869
}}
{{medline-entry
|title=Pregnancy Protects Hyperandrogenemic Female Rats From Postmenopausal Hypertension.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32755410
|abstract=Polycystic ovary syndrome, the most common endocrine disorder in women of reproductive age, is characterized by hyperandrogenemia, obesity, insulin resistance, and elevated blood pressure. However, few studies have focused on the consequences of pregnancy on postmenopausal cardiovascular disease and hypertension in polycystic ovary syndrome women. In hyperandrogenemic female (HAF) rats, the hypothesis was tested that previous pregnancy protects against age-related hypertension. Rats were implanted with dihydrotestosterone (7.5 mg/90 days, beginning at 4 weeks and continued throughout life) or placebo pellets (controls), became pregnant at 10 to 15 weeks, and pups were weaned at postnatal day 21. Dams and virgins were then aged to 10 months (still estrous cycling) or 16 months (postcycling). Although numbers of offspring per litter were similar for HAF and control dams, birth weights were lower in HAF offspring. At 10 months of age, there were no differences in blood pressure, proteinuria, nitrate/nitrite excretion, or body composition in previously pregnant HAF versus virgin HAF. However, by 16 months of age, despite no differences in dihydrotestosterone, fat mass/or lean mass/body weight, previously pregnant HAF had significantly lower blood pressure and proteinuria, higher nitrate/nitrite excretion, with increased intrarenal mRNA expression of endothelin B receptor and eNOS (endothelial nitric oxide synthase), and decreased [[ACE]] (angiotensin-converting enzyme), AT1aR (angiotensin 1a receptor), and endothelin A receptor than virgin HAF. Thus, pregnancy protects HAF rats against age-related hypertension, and the mechanism(s) may be due to differential regulation of the nitric oxide, endothelin, and renin-angiotensin systems. These data suggest that polycystic ovary syndrome women who have experienced uncomplicated pregnancy may be protected from postmenopausal hypertension.

|keywords=* aging
* endothelin
* menopause
* nitric oxide
* renin-angiotensin system
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429272
}}
{{medline-entry
|title=Heart failure is associated with accelerated age related metabolic bone disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32498656
|abstract= The heart failure (HF)-syndrome is associated with neuro-hormonal activation, chronic kidney disease (CKD), inflammation and alterations in the phosphorus-metabolism, all of which are involved in regulation of mineral bone density. However, the role of HF as an independent factor associated with metabolic bone disease (MBD) remains unclear.  HF-patients undergoing dual X-ray absorptiometry (DEXA) were matched in a 1:2 fashion against age and gender matched controls without HF, to determine the proportion of osteoporosis (T-score < -2.5). HF-status was tested against known predictors of MBD. Correlation analysis and Z-score analysis were used to assess the impact of HF on age-related bone demineralisation.  A total of 190 HF-patients (age = 80 ± 10 years, female = 61%) were age and gender matched to 380 controls. HF-patients had a higher proportion of osteoporosis (26 vs 17%; [i]p[/i] = .007). HF patients had a lower averaged mineral bone density expressed in g/cm  ([i]p[/i] = .030), T-scores ([i]p[/i] = .001) and Z-scores ([i]p[/i] < .001). After adjusting for the individual osteoporosis risk-factors of the FRAX-score, difference in baseline features, kidney function and phosphorus-metabolism alterations, heart failure remained independently associated with a lower averaged T-score (Adjusted [i]β[/i] = -0.189; [i]p[/i] = .017). Heart failure was associated with an accelerated age-related decline in mineral bone density ([i]p[/i] = .0418). Therapies with [[ACE]]-I or ARBs and beta-blockers associated with ameliorated bone demineralisation ([i]p[/i] = .023, respectively [i]p[/i] = .029), while loop diuretic associated with worsened bone demineralization ([i]p[/i] < .001).  Heart failure independently associates with MBD and higher prevalence of osteoporosis. Heart failure aggravates the aged related loss in mineral bone density while treatment with neuro-hormonal blockers seemed to ameliorate this finding.

|keywords=* Heart failure
* comorbidities
* geriatrics
* metabolic bone disease
* osteoporosis
|full-text-url=https://sci-hub.do/10.1080/00015385.2020.1771885
}}
{{medline-entry
|title=Management of heart failure: an Italian national survey on fellows/specialists in geriatrics.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32383033
|abstract=Heart failure (HF) is often managed by geriatricians. Few data are available on their knowledge and attitudes about this condition. To compare perceptions and knowledge on HF of specialists/fellows in geriatrics working in Italy. This nation-wide survey carried out by the Italian Society of Gerontology and Geriatrics in May-June 2019 enrolled 283 specialists/fellows in geriatrics in Italy. Results were stratified by qualification (specialist/fellow) and performance (lower/higher quartile of correct answers). About half (55.5%) of the participants worked in acute care wards, 190 were residents, and 93 specialists. The overall proportion of correct answers was 70.8%, with no differences between specialists and fellows. There was a poor knowledge, with no differences between groups, about the target doses of [[ACE]]-inhibitors (36% of correct answers), the pharmacological treatment of HF with preserved ejection fraction (HFpEF) (37% of correct answers), and the inotropes indicated in acute HF (35% of correct answers). Compared to specialists, fellows performed better on indication (88% vs 76%, P = 0.019) and mechanism of action (93% vs 84%, P = 0.023) of sacubitril/valsartan, and on therapeutic indications of patients with atrial fibrillation (92% vs 75%, P < 0.001). Globally, there was a good knowledge of the latest guidelines on the diagnosis and management of HF. However, for some important topics, such as HFpEF, that is the most common HF manifestation in older adults, the observed performance was relatively poor, indicating the need for focused educational campaigns.
|mesh-terms=* Aged
* Geriatrics
* Heart Failure
* Humans
* Italy
* Specialization
* Stroke Volume
* Surveys and Questionnaires
|keywords=* Aged, 65 years or over
* Care survey
* Health
* Heart failure
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01577-1
}}
{{medline-entry
|title=Angiotensin-Converting Enzyme ([[ACE]]) genetic variation and longevity in Peruvian older people: a cross-sectional study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32281429
|abstract= Some studies have suggested that the insertion(I)/deletion(D) polymorphism of the Angiotensin-Converting Enzyme ([[ACE]]) gene may be associated with human longevity, especially in centenarians. However, this association is still controversial. Besides, there have been no studies in Peruvians.  To describe the age distribution of the [[ACE]] polymorphism in a convenience sample of Peruvian older people.  This was a cross-sectional study in 104 Geriatric Day Hospital patients in Lima, Perú. The [[ACE]] polymorphism was determined in all patients. For the purpose of association with age, the sample was divided into four categories: young (< 65), youngest-old (65-74), middle-old (75-84) and oldest-old (85 or more).  The distribution of genotype frequencies was consistent with a population in Hardy-Weinberg equilibrium ([i]p[/i] = 0.62). The number (%) of D/D, I/D and I/I genotypes in the young was 2 (14.3%), 3 (21.4%) and 9 (64.3%), respectively; in youngest-old: 4 (11.4%), 15 (42.9%) and 16 (45.7%); in middle-old: 6 (12.2%), 20 (40.8%) and 23 (46.9%); and in oldest-old: 0 (0.0%), 4 (66.7%) and 2 (33.3%). A chi-square analysis showed no significant differences in genotype distribution between age groups ([i]p[/i] = 0.647).  No significant age differences were found in the distribution of the [[ACE]] polymorphism in this sample. Further studies with greater statistical power are recommended.
|mesh-terms=* Aged
* Aged, 80 and over
* Cross-Sectional Studies
* Female
* Genetic Variation
* Humans
* Longevity
* Male
* Middle Aged
* Peptidyl-Dipeptidase A
* Peru
* Polymorphism, Genetic
|keywords=* ACE gene
* Longevity
* Perú
* ageing
|full-text-url=https://sci-hub.do/10.1080/03014460.2020.1748227
}}
{{medline-entry
|title=COVID-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32229706
|abstract=COVID-19, also known as SARS-CoV-2, is a new emerging zoonotic corona virus of the SARS (Severe Acute Respiratory Syndrome) and the MERS (Middle East Respiratory Syndrome) family. COVID-19 originated in China and spread world-wide, resulting in the pandemic of 2020. For some reason, COVID-19 shows a considerably higher mortality rate in patients with advanced chronological age. This begs the question as to whether there is a functional association between COVID-19 infection and the process of chronological aging. Two host receptors have been proposed for COVID-19. One is CD26 and the other is [[ACE]]-2 (angiotensin-converting enzyme 2). Interestingly, both CD26 and the angiotensin system show associations with senescence. Similarly, two proposed therapeutics for the treatment of COVID-19 infection are Azithromycin and Quercetin, both drugs with significant senolytic activity. Also, Chloroquine-related compounds inhibit the induction of the well-known senescence marker, Beta-galactosidase. Other anti-aging drugs should also be considered, such as Rapamycin and Doxycycline, as they behave as inhibitors of protein synthesis, blocking both SASP and viral replication. Therefore, we wish to speculate that the fight against COVID-19 disease should involve testing the hypothesis that senolytics and other anti-aging drugs may have a prominent role in preventing the transmission of the virus, as well as aid in its treatment. Thus, we propose that new clinical trials may be warranted, as several senolytic and anti-aging therapeutics are existing FDA-approved drugs, with excellent safety profiles, and would be readily available for drug repurposing efforts. As Azithromycin and Doxycycline are both commonly used antibiotics that inhibit viral replication and IL-6 production, we may want to consider this general class of antibiotics that functionally inhibits cellular protein synthesis as a side-effect, for the treatment and prevention of COVID-19 disease.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Angiotensin-Converting Enzyme 2
* Antiviral Agents
* Azithromycin
* Betacoronavirus
* COVID-19
* Coronavirus Infections
* Dipeptidyl Peptidase 4
* Humans
* Hydroxychloroquine
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* Quercetin
* Receptors, Virus
* SARS-CoV-2
|keywords=* Azithromycin
* COVID-19
* Doxycycline
* Hydroxy-chloroquine
* Quercetin
* Rapamycin
* aging
* antibiotic
* corona virus
* drug repurposing
* prevention
* senescence
* senolytic drug therapy
* viral replication
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202514
}}
{{medline-entry
|title=[i]A[/i]ngiotensin Converting Enzyme Inhibitors [i]C[/i]ombined with [i]E[/i]xercise for Hypertensive [i]S[/i]eniors (The [[ACE]]S Trial): Study Protocol of a Randomized Controlled Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32039215
|abstract=Prior evidence suggests that the choice of antihypertensive medication may influence functional status among older adults with hypertension, particularly in conjunction with exercise. In particular, angiotensin converting enzyme ([[ACE]]) inhibitors have shown potential to positively influence function. However, randomized, controlled trials are needed to confirm this hypothesis. This paper outlines an RCT designed to determine if choice of first-line antihypertensive medication influences functional and cardiovascular risk factor responses to exercise among older adults with hypertension. Two hundred and thirteen inactive, community-dwelling adults ≥60 years of age with hypertension and functional limitations will be recruited to engage in a 32-week intervention study. Participants will be randomized to one of three first-line antihypertensive agents: (1) the [[ACE]] inhibitor perindopril, (2) the AT1 receptor antagonist losartan, or (3) the thiazide diuretic hydrochlorothiazide (HCTZ). Six weeks after randomization, participants will begin a 20-week structured aerobic exercise intervention. Participants will perform two 45-min center-based sessions coupled with 60 min of home-based walking per week. The primary aim is to determine if perindopril improves self-paced gait speed when compared with losartan and HCTZ. The secondary aim is to determine the relative effect of perindopril on secondary outcomes such as: (a) exercise capacity, (b) body mass and composition, and (c) circulating indices of cardiovascular risk. This RCT is expected to identify differential effects of first-line antihypertensive medications when combined with physical exercise thus have potential implications for antihypertensive prescription guidelines for older adults.   www.ClinicalTrials.gov, identifier: NCT03295734.

|keywords=* aging
* antihypertensive
* exercise
* functional status
* hypertension
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988302
}}
{{medline-entry
|title=Vascular age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32013519
|abstract=Age can be evaluated according to many criteria. Of course the objective measure is the calendar age which may differ from the biological age. The biological age more or less correlates with the vascular age. The concept of vascular age is based on the statement that &#8220;An individual is as old as his blood vessels&#8221;. The process of vascular aging already starts in childhood. Arterial aging may essentially be viewed from two standpoints. First, it involves stiffening of arteries and loss of their elasticity; second, degenerative changes and formation of atherosclerotic plaques occur, being the cause of ischemia, especially in case of the development of atherothrombosis. Both these processes can be monitored: The change of elasticity (arteriosclerosis) mainly by examination of pulse wave velocity (PWV), atherosclerosis then primarily with non-invasive methods, ultrasound or CT angiography examination. From the clinical point of view it is particularly important whether we can influence vascular age in some way. Evidence is available now that atherosclerosis can be affected by hypolipidemic treatment, arteriosclerosis then in particular by [[ACE]] inhibitors. The aforementioned possibility of influencing vascular age brings us to another problem, which is compliance of patients. With regard to that it is good that in a situation where we have two drugs affecting vascular age, we can use their fixed combination. It is available as a combination of atorvastatin and perindopril.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aging
* Angiotensin-Converting Enzyme Inhibitors
* Atherosclerosis
* Child
* Elasticity
* Humans
* Middle Aged
* Perindopril
* Pulse Wave Analysis
* Vascular Stiffness
* Young Adult
|keywords=* ACE inhibitors
* CT angiography
* atorvastatin
* dyslipidemia
* hypertension
* intima media thickness (IMT)
* perindopril
* pulse wave velocity (PWV)
* statins 
* vascular age

}}
==DBP==

{{medline-entry
|title=Do baseline blood pressure and type of exercise influence level of reduction induced by training in hypertensive older adults? A meta-analysis of controlled trials.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32795629
|abstract=Exercise recommendations for hypertensive individuals encourage the use of aerobic training (AT) for lowering blood pressure (BP). However, it is not clear whether equivalent BP-lowering effects are obtained with different exercise training types in older adults, among whom hypertension is more prevalent. We meta-analyzed previous literature testing different types of training [AT, resistance (RT) and combined (CT)] effects on casual systolic BP (SBP) and diastolic BP ([[DBP]]), taking into account age and baseline BP influences. Randomized controlled trials (RCTs), published up to August 2019 (PubMed), assessing exercise training effects on BP in hypertensive older adults (aged ≥50 years) were included (11, 8 and 3 RCTs tested the effects of AT, RT and CT, respectively). First, both AT and RT reduced SBP (-12.31 [-16.39; -8.24] and - 6.76 [-8.36; -5.17] mm Hg, respectively) and [[DBP]] (-4.31 [-5.96; -2.65] and - 3.53 [-4.22; -2.85] mm Hg, respectively) in older adults, while there was not enough evidence for the effects of CT on SBP, due to high variance among the small number of CT studies. Second, training-induced BP reductions were more prominent in patients <65 years compared to those >65 years. However, this difference was mostly driven by differences between AT and CT versus RT intervention on age subgroups. Third, baseline BP values, rather than type of exercise and age, were the main determinant of BP response to exercise (predicted 74% and 53% of SBP and [[DBP]] reduction, respectively), indicating this is a major confounding factor to be considered in studies evaluating the impact of exercise training on BP.

|keywords=* Aged
* Aging
* Exercise
* Exercise therapy
* High blood pressure
* Hypertension
* Resistance training
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111052
}}
{{medline-entry
|title=Attenuated aortic blood pressure responses to metaboreflex activation in older adults with dynapenia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32502600
|abstract=Low muscle strength (dynapenia) is a primary characteristic of sarcopenia, the age-related loss of muscle mass and strength or low walking speed. New evidence suggests that muscle strength positively affects blood pressure (BP) responses to exercise. As older adults with lowest handgrip strength also have lowest BP at rest, those with dynapenia may experience attenuated BP responses during physical activity. The purpose of this study was to test the hypothesis that dynapenic older adults would exhibit lower BP response to post-exercise muscle ischemia (PEMI). Brachial and aortic systolic BP (SBP), diastolic BP ([[DBP]]), and mean arterial pressure (MAP) were measured in older adults (age, 80 ± 5 y) with dynapenia (n = 16) and non-dynapenia (n = 9) at rest and during PEMI following 2 min of isometric handgrip exercise at 30% maximal voluntary contraction. Walking speed was assessed by an 8-foot (2.44 m) walk course. Increases in aortic SBP (11 ± 2 vs. 23 ± 6 mm Hg, p = .03), [[DBP]] (6 ± 2 vs.14 ± 4 mm Hg, p = .04), and MAP (8 ± 1 vs. 17 ± 5 mm Hg, p = .02) were lower in dynapenic compared to non-dynapenic adults. Aortic MAP (r = 0.52, p < .05) response to PEMI was correlated with MVC in dynapenic adults. Gait speed was correlated with aortic [[DBP]] response to PEMI (r = 0.698, p = .05) in non-dynapenic adults. Our findings indicate that aortic [[DBP]] response to muscle metaboreflex activation is attenuated in older adults with dynapenia. Normal aortic [[DBP]] response during metaboreflex activation may positively affect walking performance in non-dynapenic older adults.

|keywords=* Aging
* Diastolic pressure
* Handgrip strength
* Post-exercise muscle ischemia
* Walking performance
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110984
}}
{{medline-entry
|title=The Effect of Blood Pressure on Cognitive Performance. An 8-Year Follow-Up of the Tromsø Study, Comprising People Aged 45-74 Years.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32373010
|abstract=The relationship between blood pressure (BP) and cognition is complex were age appears to be an intervening variable. High and low BP have been associated with cognitive deficits as part of the aging process, but more studies are needed, especially in more recent birth cohorts. The study sample comprised 4,465 participants, with BP measured at baseline in the Tromsø Study, Wave 6 in 2007-2008 (T0), and cognition assessed at follow-up 8 years later, in 2015-2016 in Tromsø Study 7 (T1). Age at T0 was 45-74 years, and at T1 it was 53-82 years. Cognition was assessed with three tests: The Mini Mental State Examination (MMSE), the Digit Symbol Test, and the Twelve-word Test. The associations between BP and cognition were examined specifically for age and sex using linear regression analysis adjusted for baseline BP medication use, education and body mass index (kg/m ). BP was associated with cognition at the 8-year follow-up, but the association differed according to age and sex. In men, higher systolic blood pressure (SBP) and diastolic blood pressure ([[DBP]]) at a young age (45-55 years of age) was associated with poorer cognition; the association was reversed at older ages, especially for those above 65 years of age. In women, the associations were generally weaker than for men, and sometimes in the opposite direction: For women, a higher SBP was associated with better cognition at a younger age and higher SBP poorer cognition at older ages - perhaps due to an age delay in women compared to men. Digit Symbol Test results correlated best with BP in a three-way interaction: BP by age by sex was significant for both SBP ([i]p[/i] = 0.005) and [[DBP]] ([i]p[/i] = 0.005). Increased SBP and [[DBP]] at the younger age was clearly associated with poorer cognitive function in men 8 years later; in women the associations were weaker and sometimes in the opposite direction. Our findings clearly indicate that interactions between age and sex related to BP can predict cognitive performance over time. Men and women have different age trajectories regarding the influence of BP on cognition.

|keywords=* aging
* blood pressure
* cognitive performance
* dementia
* sex differences
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7186429
}}
{{medline-entry
|title=Low Diastolic Blood Pressure and Cognitive Decline in Korean Elderly People: The Korean Longitudinal Study on Cognitive Aging and Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31995969
|abstract=Cardiovascular diseases are representative risk factors for the onset of cognitive decline. The purpose of this study was to confirm the relationship between diastolic blood pressure and cognitive function in elderly people in Korea. Data from subjects who were enrolled in the prospective Korean Longitudinal Study on Cognitive Aging and Dementia were used in this study. Data from 701 subjects whose diastolic blood pressure range did not change (≤79 mm Hg or ≥80 mm Hg) over 2 years were analyzed. To analyze the differences in cognitive function between the groups at the 2-year follow-up, an analysis of covariance was performed with covariates, which were significantly different between the two groups, and the baseline cognitive function. Significant differences were observed between the two groups, and the mean scores on the constructional praxis (η2=0.010) and word list recall tests (η2=0.018) in the diastolic blood pressure ≥80 mm Hg group were higher than those in the diastolic blood pressure ≤79 mm Hg group at the 2-year follow-up. These results indicate that maintaining a [[DBP]] below 79 mm Hg presents a greater risk of cognitive decline in Korean elderly people.

|keywords=* Cognition
* Diastolic blood pressure
* Senility
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992855
}}
{{medline-entry
|title=Diastolic Blood Pressure Is Associated With Regional White Matter Lesion Load: The Northern Manhattan Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31910743
|abstract=Background and Purpose- Few studies have examined the separate contributions of systolic blood pressure and diastolic blood pressures ([[DBP]]) on subclinical cerebrovascular disease, especially using the 2017 American College of Cardiology/American Heart Association Blood Pressure Guidelines. Furthermore, associations with region-specific white matter hyperintensity volume (WMHV) are underexplored. Methods- Using data from the NOMAS (Northern Manhattan Study), a prospective cohort study of stroke risk and cognitive aging, we examined associations between systolic blood pressure and [[DBP]], defined by the 2017 American College of Cardiology/American Heart Association guidelines, with regional WMHV. We used a linear mixed model approach to account for the correlated nature of regional brain measures. Results- The analytic sample (N=1205; mean age 64±8 years) consisted of 61% women and 66% Hispanics/Latinos. [[DBP]] levels were significantly related to WMHV differentially across regions ([i]P[/i] for interaction<0.05). Relative to those with [[DBP]] 90+ mm Hg, participants with [[DBP]] <80 mm Hg had 13% lower WMHV in the frontal lobe (95% CI, -21% to -3%), 11% lower WMHV in the parietal lobe (95% CI, -19% to -1%), 22% lower WMHV in the anterior periventricular region (95% CI, -30% to -14%), and 16% lower WMHV in the posterior periventricular region (95% CI, -24% to -6%). Participants with [[DBP]] 80 to 89 mm Hg also exhibited about 12% (95% CI, -20% to -3%) lower WMHV in the anterior periventricular region and 9% (95% CI, -18% to -0.4%) lower WMHV in the posterior periventricular region, relative to participants with [[DBP]] 90≥ mm Hg. Post hoc pairwise [i]t[/i] tests showed that estimates for periventricular WMHV were significantly different from estimates for temporal WMHV (Holms stepdown-adjusted [i]P[/i]<0.05). Systolic blood pressure was not strongly related to regional WMHV. Conclusions- Lower [[DBP]] levels, defined by the 2017 American College of Cardiology/American Heart Association guidelines, were related to lower white matter lesion load, especially in the periventricular regions relative to the temporal region.
|mesh-terms=* Aged
* Arterial Pressure
* Blood Pressure
* Brain
* Cohort Studies
* Diastole
* Female
* Frontal Lobe
* Humans
* Hypertension
* Linear Models
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Organ Size
* Parietal Lobe
* Prospective Studies
* Systole
* Temporal Lobe
* White Matter
|keywords=* American Heart Association
* blood pressure
* cerebrovascular disease
* cognitive aging
* white matter
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7219602
}}
{{medline-entry
|title=Orthostatic Hypotension and Novel Blood Pressure Associated Gene Variants in Older Adults: Data From the TILDA Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31821404
|abstract=Orthostatic hypotension (OH) is associated with increased risk of trauma and cardiovascular events. Recent studies have identified new genetic variants that influence orthostatic blood pressure (BP). The aim of this study was to investigate the associations of candidate gene loci with orthostatic BP responses in older adults. A total of 3,430 participants aged ≥50 years from The Irish Longitudinal Study on Ageing (TILDA) with BP measures and genetic data from 12 single-nucleotide polymorphism (SNP) linked to BP responses were analyzed. Orthostatic BP responses were recorded at each 10 s interval and were defined as OH (SBP drop ≥20 mmHg or [[DBP]] drop ≥10 mmHg) at the time-points 40, 90, and 110 s. We defined sustained OH (SOH) as a drop that exceeded consensus BP thresholds for OH at 40, 90, and 110 s after standing. Logistic regression analyses modeled associations between the candidate SNP alleles and OH. We report no significant associations between OH and measured SNPs after correction for multiple comparisons apart from the SNP rs5068 where proportion of the minor allele was significantly different between cases and controls for SOH 40 (p = .002). After adjustment for covariates in a logistic regression, those with the minor G allele (compared to the A allele) had a decreased incidence rate ratio (IRR) for SOH 40 (IRR 0.45, p = .001, 95% CI 0.29-0.72). Only one SNP linked with increased natriuretic peptide concentrations was associated with OH. These results suggest that genetic variants may have a weak impact on OH but needs verification in other population studies.

|keywords=* Aging
* Blood pressure
* Cardiovascular
* Genetics
* Single-nucleotide polymorphism
|full-text-url=https://sci-hub.do/10.1093/gerona/glz286
}}
{{medline-entry
|title=Blood pressure and hypertension prevalence among oldest-old in China for 16 year: based on CLHLS.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31500574
|abstract=There were little national data on hypertension based on the oldest-old, and lack of information on chronological changes. This study aimed to describe trends of blood pressure (BP) levels and hypertension prevalence for the past 16 years among the oldest-old in China. All the oldest-old who had participated in the Chinese Longitudinal Healthy Longevity Survey (CLHLS) 1998 to 2014 with information about BP levels and hypertension were included in the analysis. There was fluctuation over the past 16 years for both SBP and [[DBP]] levels. The mean SBP level decreased from 148.4 ± 24.4 mmHg in 1998 to 130.8 ± 18.7 mmHg in 2005, and then increased to 139.7 ± 22.0 mmHg in 2014. The mean [[DBP]] level decreased from 84.3 ± 13.4 mmHg in 1998 to 78.9 ± 11.7 mmHg in 2008, and then increased to 79.7 ± 11.8 mmHg in 2014. The hypertension prevalence increased from 43.1 to 56.5% for the 16 years. The prevalence of isolated systolic hypertension was lowest in 2002-2005 (14.3%), and then increased to 30.7% in 2014. Multivariate logistic regression showed that older age, lower education and economic level, without health insurance were associated with higher hypertension prevalence. There was a significant increase in hypertension prevalence among the Chinese oldest-old from 1998 to 2014. Greater efforts are needed for hypertension prevention among this specific population.
|mesh-terms=* Aged, 80 and over
* Blood Pressure
* Blood Pressure Determination
* China
* Female
* Health Surveys
* Humans
* Hypertension
* Longevity
* Longitudinal Studies
* Male
* Prevalence
|keywords=* Blood pressure
* Epidemiology
* Hypertension
* Oldest-old
* Prevalence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734230
}}
{{medline-entry
|title=The age-related blood pressure trajectories from young-old adults to centenarians: A cohort study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31443986
|abstract=Blood pressure (BP) trajectories among older adults, especially among the oldest-old, are still poorly characterized. To investigate the longitudinal trajectories of four BP components with age and their potential influential factors. This population-based prospective cohort study included 3315 participants (age 60-105 years, 64.6% women) who were regularly examined from 2001 to 2004 through 2013-2016. The longitudinal trajectories of systolic BP (SBP), diastolic BP ([[DBP]]), pulse pressure (PP), and mean arterial pressure (MAP) with age were estimated using linear mixed-effects models. Overall, SBP and PP increased with age until ∼80 years and then declined, whereas [[DBP]] and MAP decreased constantly after 60 years of age. The age-related BP trajectories varied by survival time, birth cohort, use of antihypertensive drugs, and heart disease. Specifically, people who survived <2 years after the last visit showed higher levels of BP components before ∼80 years, followed by steeper declines in SBP and PP. At the same age, people who were born earlier showed higher BP than those who were born later. People who used antihypertensive drugs had higher BP than those who did not until ∼80-90 years old, thereafter BP showed no significant difference. After ∼80 years old, people with heart disease showed steeper declines in SBP and PP than those without. The late-life longitudinal BP trajectories with age vary with demographics, clinical conditions, and contextual factors. These findings may help better understand the age-dependent relationship of BP with health outcomes as well as help achieve optimal BP control in older people. Competency in medical knowledge: Understanding the age-related blood pressure trajectories and potential influential factors may help improve blood pressure management in older people. Translational outlook 1: Blood pressure trajectories with age in older adults vary by birth cohort, survival time, antihypertensive therapy, and heart disease. The age-related blood pressure trajectories by birth cohorts are featured with lower blood pressure levels at the same age in more recent birth cohorts, which may partially reflect the improvement of blood pressure control over time. Translational outlook 2: The age-related blood pressure trajectories in the oldest old (e.g., age ≥ 85 years) are characterized by steeper and faster blood pressure declines associated with heart disease and short survival (e.g., <2 years). This may have implications for the optimal management of blood pressure as well as for the interpretation of the relationships between blood pressure and health outcomes (e.g., death) among the oldest old.
|mesh-terms=* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Blood Pressure
* Cohort Studies
* Female
* Humans
* Male
* Middle Aged
|keywords=* Antihypertensive therapy
* Birth cohort effect
* Blood pressure
* Cohort study
* Heart disease
* Survival
|full-text-url=https://sci-hub.do/10.1016/j.ijcard.2019.08.011
}}
==CAT==

{{medline-entry
|title=Training improves the handling of inhaler devices and reduces the severity of symptoms in geriatric patients suffering from chronic-obstructive pulmonary disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33036566
|abstract=Elderly patients with impaired vision, cognitive decline or motor/sensory disturbances of their fingers suffering from chronic-obstructive pulmonary disease (COPD) encounter difficulties in handling inhaler devices used as the cornerstones of treatment of pulmonary obstruction. Many elderly patients make severe mistakes which impede adequate drug delivery to the bronchioles. This multimodal training program was designed to reduce the number of handling mistakes of inhaler devices. From October 1, 2016 to September 30, 2017, a prospective intervention study was conducted in 38 in-patients > 65 years (median age 79 years) with previously diagnosed COPD. The effect of an 8-day intervention comprising daily counselling and video demonstration according to the recommendations of the German Airway League on the frequency of mistakes during handling of inhaler devices, the forced expiratory volume in 1 s (FEV1), the forced vital capacity (FVC) and the perception of symptoms (COPD Assessment Test, [[CAT]]) were studied. Measurements on days 1 and 8 were compared by Wilcoxon signed rank test. The number of handling mistakes per patient decreased as a consequence of the intervention from 3.0 (0-7) to 0.5 (0-6) [median (minimum-maximum; p < 0.0001)]. The [[CAT]] Score decreased from 19.5 (14/24) to 14.5 (10.75/21) [median (25./75. percentile; p < 0.0001) indicating a substantial reduction of clinical symptoms. Conversely, FEV1 and FVC only slightly increased (difference statistically not significant). At study entry, the number of handling mistakes was inversely correlated with the Mini Mental Status Test (MMST) score (p = 0.01). The reduction of the number of handling mistakes during the intervention was not correlated with the MMST. In COPD, intensive training for 8 days improved the handling of inhalers and reduced clinical symptoms in geriatric patients. Patients with cognitive abnormalities also benefitted from this intervention. German Clinical Trials Registry DRKS00023196 , date of registration September 29, 2020 (retrospectively registered).

|keywords=* Chronic-obstructive pulmonary disease - Inhaler devices
* Compliance
* Geriatrics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547456
}}
{{medline-entry
|title=7-chloro-4-(phenylselanyl) quinoline co-treatment prevent oxidative stress in diabetic-like phenotype induced by hyperglycidic diet in Drosophila melanogaster.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32931926
|abstract=The goals of this work were to evaluate the effects produced by a hyperglycidic diet (HD) on Drosophila melanogaster and to verify the protective effect of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) on this model. Adult flies were divided into eight groups of 50 flies each: (1) RD, (regular diet) (2) RD + 4-PSQ (25 μM), (3) HD 5%, (4) HD 10%, (5) HD 30% (6) HD 5% + 4-PSQ (25 μM), (7) HD 10% + 4-PSQ (25 μM) and (8) HD 30% + 4-PSQ (25 μM). Flies were exposed to a diet containing sucrose and or 4-PSQ for ten days, according to each group. At the end of treatment survival rate, longevity, hatch rate, food intake, glucose and triglyceride levels, as well as, some markers of oxidative stress, such as thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD) and catalase ([[CAT]]) activities, protein thiol (PSH) and non-protein levels (NPSH) and cell viability assays (Resazurin and MTT) were evaluated. It was observed that HD's consumption was associated with lower survival of the flies, lower longevity, and increased levels of glucose, triglycerides, TBARS and increased SOD activities and [[CAT]] activities. Treatment with 25 μM 4-PSQ increased the satiety of flies, increased survival, reduced glucose, triglyceride and TBARS levels, increased hatching, and normalized SOD and [[CAT]] activities. These results suggest that 25 μM 4-PSQ had a potential antioxidant effect and provided greater satiety by attenuating the effects of high HD consumption on this model.

|keywords=* 4-PSQ
* 7-chloro-4-(phenylselanyl) quinolone
* Antioxidant effect
* Diabetic-like phenotype
* Hyperglycidic diet
* Longevity
* Oxidative stress
|full-text-url=https://sci-hub.do/10.1016/j.cbpc.2020.108892
}}
{{medline-entry
|title=Aging influences in the blood-brain barrier permeability and cerebral oxidative stress in sepsis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32827711
|abstract=Sepsis is a set of serious manifestations throughout the body produced by an infection, leading to changes that compromise cellular homeostasis and can result in dysfunction of the central nervous system. The elderly have a higher risk of developing sepsis than younger peoples. Under the influence of inflammatory mediators and oxidizing agents released in the periphery as a result of the infectious stimulus, changes occur in the blood-brain barrier (BBB) permeability, with neutrophil infiltration, the passage of toxic compounds, activation of microglia and production of reactive species that results in potentiation of neuroimmune response, with the progression of neuronal damage and neuroinflammation. The objective of this study is to compare BBB permeability and the development of oxidative stress in the hippocampus and prefrontal cortex of young and old rats submitted to polymicrobial sepsis induction. Male Wistar rats grouped into sham (60d), sham (210d), cecal ligation and perforation (CLP) (60d) and CLP (210d) with n = 16 per experimental group were evaluated using the CLP technique to induce sepsis. The brain regions were collected at 24 h after sepsis induction to determine BBB permeability, myeloperoxidase (MPO) activity as marker of neutrophil activation, nitrite/nitrate (N/N) levels as marker of reactive nitrogen species, thiobarbituric acid reactive substances as marker of lipid peroxidation, protein carbonylation as marker of protein oxidation, and activity of antioxidant enzyme catalase ([[CAT]]). There was an increase in the BBB permeability in the CLP groups, and this was enhanced with aging in both brain region. MPO activity in the brain regions increased in the CLP groups, along with a hippocampal increase in the CLP 210d group compared to the 60d group. The concentration of N/N in the brain region was increased in the CLP groups. The damage to lipids and proteins in the two structures was enhanced in the CLP groups, while only lipid peroxidation was higher in the prefrontal cortex of the CLP 210d group compared to the 60d. [[CAT]] activity in the hippocampus was decreased in both CLP groups, and this was also influenced by age, whereas in the prefrontal cortex there was only a decrease in [[CAT]] in the CLP 60d group compared to the sham 60d. These findings indicate that aging potentiated BBB permeability in sepsis, which possibly triggered an increase in neutrophil infiltration and, consequently, an increase in oxidative stress.

|keywords=* Aging
* Blood-brain barrier
* Brain
* Oxidative stress
* Sepsis
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111063
}}
{{medline-entry
|title=2 -Deoxy - d-glucose at chronic low dose acts as a caloric restriction mimetic through a mitohormetic induction of ROS in the brain of accelerated senescence model of rat.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32559563
|abstract=Aging induces significant molecular alteration in brain morphology. Glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) is considered to act as a caloric restriction mimetic (CRM) but it is correlated with elevated mortality risk in rats at persistent high dosage. In young and d-galactose induced accelerated senescent rat aging models, we tested a persistent low-dose dietary 2-DG administration and evaluated various aging biomarkers in brain tissue. A significant increase in reactive oxygen species (ROS) was observed in 2-DG treated (both young and accelerated senescent rat model). Increased Ferric reducing antioxidant potential (FRAP) value, Superoxide Dismutase (SOD), Catalase ([[CAT]]), and activity of mitochondrial complexes I and IV was observed. There was also significant improvements in the autophagy expression of genes (Beclin-1 and Atg-3) after 2- DG treatment. We propose that 2-DG induces a mitohormetic effect through elevation of ROS which reinforces defensive mechanism(s) through increased FRAP, SOD, [[CAT]] and autophagy gene expression. Our observations indicate that a consistently low dose 2-DG could be a valuable CRM.

|keywords=* 2-Deoxy- d-glucose
* Aging
* Brain
* CRM
* Mitohormosis
* ROS
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104133
}}
{{medline-entry
|title=Ceftriaxone improves senile neurocognition damages induced by D-galactose in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32440324
|abstract=Ceftriaxone (Cef), a beta-lactam antibiotic, is accompanied by antioxidant and anti-inflammatory properties. It has been shown that Cef has beneficial effects on Alzheimer's disease. In the current investigation, the effect of Cef in a mice model of aging was investigated. Forty male mice were equally aliquoted into four groups as follows: Control (as healthy normal animals), D-galactose (DG) group (treated with 500 mg/kg/day DG for 6 weeks), DG + Cef group (treated with DG plus Cef 200 mg/kg/day for 6 weeks), and Cef group (treated with Cef 200 mg/kg/day for 6 weeks). A battery of behavioral tests was done to evaluate age-related neurocognitive changes. The activities of catalase ([[CAT]]), glutathione peroxidase (GPx), and superoxide dismutase (SOD), as well as the level of malondialdehyde (MDA) in the brain, were measured by biochemical methods. Also, to determine the brain damage, histopathological alterations in the hippocampus were measured using hematoxylin and eosin (H&E) staining. Our results indicate that neurobehavioral dysfunctions of DG can be prevented by co-administration of Cef. We also found that Cef increases the activity of SOD, GPx, and [[CAT]] as well as decreasing the level of MDA in the brain of aged mice. Based on our findings, Cef declines neurocognitive dysfunctions in the DG-induced model of aging, possibly through its antioxidative properties.

|keywords=* Aging
* Ceftriaxone
* D-galactose
* Mice
* Oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229512
}}
{{medline-entry
|title=Ginsenoside Rg1 protects against d-galactose induced fatty liver disease in a mouse model via FOXO1 transcriptional factor.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32437790
|abstract=Rg1 is the most active component of traditional Chinese medicine ginseng, having anti-aging and anti-oxidative stress features in multiple organs. Cellular senescence of hepatocytes is involved in the progression of a wide spectrum of chronic liver diseases. In this study, we investigated the potential benefits and mechanism of action of Rg1 on aging-driven chronic liver diseases. A total of 40 male C57BL/6 mice were randomly divided into four groups: control group; Rg1 group; Rg1+d-gal group; and d-gal group. Blood and liver tissue samples were collected for determination of liver function, biochemical and molecular markers, as well as histopathological investigation. Rg1 played an anti-aging role in reversing d-galactose induced increase in senescence-associated SA-β-gal staining and p53, p21 protein in hepatocytes of mice and sustained mitochondria homeostasis. Meanwhile, Rg1 protected livers from d-galactose caused abnormal elevation of ALT and AST in serum, hepatic steatosis, reduction in hepatic glucose production, hydrogenic degeneration, inflammatory phenomena including senescence-associated secretory phenotype (SASP) IL-1β, IL-6, MCP-1 elevation and lymphocyte infiltration. Furthermore, Rg1 suppressed drastic elevation in FOXO1 phosphorylation resulting in maintaining FOXO1 protein level in the liver after d-galactose treatment, followed by FOXO1 targeted antioxidase SOD and [[CAT]] significant up-regulation concurrent with marked decrease in lipid peroxidation marker MDA. Rg1 exerts pharmaceutic effects of maintaining FOXO1 activity in liver, which enhances anti-oxidation potential of Rg1 to ameliorate SASP and to inhibit inflammation, also promotes metabolic homeostasis, and thus protects livers from senescence induced fatty liver disease. The study provides a potential therapeutic strategy for alleviating chronic liver pathology.
|mesh-terms=* Animals
* Antioxidants
* Cellular Senescence
* Disease Models, Animal
* Fatty Liver
* Forkhead Box Protein O1
* Galactose
* Ginsenosides
* Lipid Peroxidation
* Male
* Medicine, Chinese Traditional
* Mice
* Mice, Inbred C57BL
* Oxidative Stress
* Protective Agents
* Transcription Factors
|keywords=* D-galactose
* FOXO1
* Non-alcoholic fatty liver disease
* Rg1
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.117776
}}
{{medline-entry
|title=Effects of long-term intermittent versus chronic calorie restriction on oxidative stress in a mouse cancer model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31424629
|abstract=Calorie restriction (CR) is one of the most effective methods to prevent many diseases including cancer in preclinical models. However, the molecular mechanism of how CR prevents cancer is unclear. The aim of this study was to understand the role of oxidative stress (OS) in the preventive effects of different types of CR in aging mouse mammary tumor virus-transforming growth factor-alpha (MMTV-TGF-α) female mice. Mice were enrolled in ad libitum (AL), chronic CR (CCR, 15% CR) or intermittent CR [ICR, 3 weeks AL (ICR-Refeed, ICR-RF) and 1 week 60% CR (ICR-Restriction, ICR-R) in cyclic periods] groups started at the age of 10 weeks and continued until 81/82 weeks of age. Blood samples were collected to measure malondialdehyde (MDA), glutathione (GSH), catalase ([[CAT]]), and superoxide dismutase (SOD) levels. There was no significant difference for MDA levels among the dietary groups although the chronic calorie restriction (CCR) group had lower MDA levels compared to intermittent calorie restriction (ICR) and AL group at different time points. There was also no change in MDA levels of CCR group with aging. On the other hand, the CCR group had higher [[CAT]] and SOD activity compared to ICR-R, ICR-RF, and AL groups. Moreover, GSH level was higher in CCR compared to ICR group at week 49/50 (p < .05). [[CAT]] and SOD activities were also positively correlated (p < .05). Here, for the first time, the long-term (72 weeks) effects of different types of CR on OS parameters were reported. In conclusion, moderate that is, 15%, CCR is more likely to be protective compared to the same overall calorie deficit implemented by ICR against OS that may play role in the preventive effects of CR.
|mesh-terms=* Aging
* Animals
* Antioxidants
* Caloric Restriction
* Catalase
* Erythrocytes
* Female
* Glutathione
* Lipid Peroxidation
* Malondialdehyde
* Mammary Neoplasms, Experimental
* Mice, Inbred C57BL
* Oxidative Stress
* Superoxide Dismutase
|keywords=* MMTV-TGF-α mice
* breast cancer
* energy restriction
* intermittent calorie restriction
* mammary tumor
* oxidative stress
|full-text-url=https://sci-hub.do/10.1002/iub.2145
}}
{{medline-entry
|title=The Toxicity of Nonaged and Aged Coated Silver Nanoparticles to Freshwater Alga Raphidocelis subcapitata.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31403715
|abstract=The transformation of coated silver nanoparticles (AgNPs) and their impacts on aquatic organisms require further study. The present study investigated the role of aging on the transformation of differently coated AgNPs and their sublethal effects on the freshwater alga Raphidocelis subcapitata. The stability of AgNPs was evaluated over 32 d, and the results indicated that transformation of AgNPs occurred during the incubation; however, coating-specific effects were observed. Fresh AgNPs increased reactive oxygen species (ROS) formation, whereas aged AgNPs induced excessive ROS generation compared with their fresh counterparts. Increased ROS levels caused increased lipid peroxidation (LPO) in treatment groups exposed to both fresh and aged NPs, although LPO was comparatively higher in algae exposed to aged AgNPs. The observed increase in catalase ([[CAT]]) activity of algal cells was attributed to early stress responses induced by excessive intracellular ROS generation, and [[CAT]] levels were higher in the aged NP treatment groups. In conclusion, AgNPs increased ROS levels and LPO in algae and caused the activation of antioxidant enzymes such as [[CAT]]. Overall, the results suggest that aging and coating of AgNPs have major impacts on AgNP transformation in media and their effects on algae. Environ Toxicol Chem 2019;38:2371-2382. © 2019 SETAC.
|mesh-terms=* Aquatic Organisms
* Chlorophyta
* Fresh Water
* Hydrodynamics
* Lipid Peroxidation
* Metal Nanoparticles
* Particle Size
* Reactive Oxygen Species
* Silver
* Static Electricity
* Toxicity Tests
|keywords=* Aquatic toxicology
* Ecotoxicology
* Environmental fate
* Heavy metals
* Nanoparticle aging
* Nanotoxicology
|full-text-url=https://sci-hub.do/10.1002/etc.4549
}}
==AFM==

{{medline-entry
|title=Photocatalytic aging process of Nano-TiO  coated polypropylene microplastics: Combining atomic force microscopy and infrared spectroscopy ([[AFM]]-IR) for nanoscale chemical characterization.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33080556
|abstract=Microplastics (MPs) are considered to have greater environmental hazards than large plastics. Most MPs undergo different degrees of aging and aged MPs exhibit different physicochemical properties from pristine ones. This study successfully prepared a nano-TiO  coated polypropylene MPs, and explored the nanoscale infrared, thermal, and mechanical properties of MPs before and after photo-aging using a combined [[AFM]]-IR technique. Surface height range of MPs was ± 25 nm. The signal intensity of the absorption peak at 1654 cm  in terms of vinylidene end groups gradually increased as the irradiation time prolonged. The softening temperature of MPs decreased from 126.7 °C to 108.5 °C as the irradiation time increased from 0 h to 4 h. The MPs after photo-aging became stiffer, especially for the components surrounding the nano-TiO  particle, indicating that photocatalytic reaction accelerated the aging process of MPs. The resonance frequency of MPs surrounding the nano-TiO  particle was stronger after photo-aging and the stiffer components were uniformly distributed, confirming that the thermal and mechanical properties of MPs changed after photo-aging. These novel findings are essential to better understand the changes in the surface microstructures, physical properties, and chemical compositions of MPs during aging process.

|keywords=* AFM-IR
* Aging process
* Microplastics
* Nanoscale characterization
* Polypropylene
|full-text-url=https://sci-hub.do/10.1016/j.jhazmat.2020.124159
}}
{{medline-entry
|title=Nanoscale infrared, thermal and mechanical properties of aged microplastics revealed by an atomic force microscopy coupled with infrared spectroscopy ([[AFM]]-IR) technique.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32702545
|abstract=Microplastics (MPs) often undergo different degrees of aging, and the aged MPs exhibit different surface properties from pristine MPs. This study explored the nanoscale infrared, thermal and mechanical properties of TiO -pigmented MPs before and after aging by using an [[AFM]]-IR technique. Results showed that the surface of MPs was relatively smooth before aging, and was rough with more granular domains after aging. The stronger band at 1706 cm  (assigned to CO) and the weaker band at 1470 cm  (assigned to -CH ) were observed in aged MPs due to oxidation of CH bond in low-density polyethylene (LDPE). The softening temperature of MPs was about 209.50 ± 11.48 °C before aging, but after aging it dropped to 94.91 ± 4.40 °C. Aging process mainly reduced the glass transition temperature of the continuous phase (LDPE) rather than the discrete phase (TiO ) in MPs. Resonance deviations of the two characteristic peaks (i.e., 299/645 kHz and 311/670 kHz) between unaged and aged MPs were observed, and these characteristic peaks obviously appeared at higher frequencies in aged MPs, suggesting that the MPs after aging became stiffer. A stronger signal at a high frequency and the uniform signal distribution at this frequency confirmed that the mechanical properties of MPs changed after aging. These findings help to better understand the effects of aging process on the physicochemical properties of MPs.

|keywords=* AFM-IR
* Aging process
* Mechanical properties
* Microplastics (MPs)
* Thermal analysis
|full-text-url=https://sci-hub.do/10.1016/j.scitotenv.2020.140944
}}
{{medline-entry
|title=Detecting zeta potential of polydimethylsiloxane (PDMS) in electrolyte solutions with atomic force microscope.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32521351
|abstract=Zeta potential of PDMS-liquid interface is an important parameter for generating electroosmotic flow in a PDMS microchannel. In this paper, the zeta potentials of a PDMS slab in contacting with electrolyte solutions were evaluated with an atomic force microscope ([[AFM]]). As a colloidal probe of the [[AFM]] approaches to the surface of a PDMS slab in an electrolyte solution, a force curve is obtained and used to calculate the zeta potential of the PDMS. The effects of the plasma treating time and the aging of the electrolyte solutions on the zeta potential of PDMS surfaces were examined. The experimental results show that the air plasma treating time does not change the zeta potential of PDMS appreciably. Furthermore, the decreased zeta potential of a plasma-treated PDMS in an electrolyte solution is due to liquid aging, not the PDMS itself. Such characteristics probed by [[AFM]] provide new understanding of the surface charges of PDMS in electrolyte solutions.

|keywords=* AFM
* Air plasma treatment
* Liquid aging
* PDMS
* Zeta potential
|full-text-url=https://sci-hub.do/10.1016/j.jcis.2020.05.061
}}
{{medline-entry
|title=Recent Applications of Advanced Atomic Force Microscopy in Polymer Science: A Review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32429499
|abstract=Atomic force microscopy ([[AFM]]) has been extensively used for the nanoscale characterization of polymeric materials. The coupling of [[AFM]] with infrared spectroscope ([[AFM]]-IR) provides another advantage to the chemical analyses and thus helps to shed light upon the study of polymers. This paper reviews some recent progress in the application of [[AFM]] and [[AFM]]-IR in polymer science. We describe the principle of [[AFM]]-IR and the recent improvements to enhance its resolution. We also discuss the latest progress in the use of [[AFM]]-IR as a super-resolution correlated scanned-probe infrared spectroscopy for the chemical characterization of polymer materials dealing with polymer composites, polymer blends, multilayers, and biopolymers. To highlight the advantages of [[AFM]]-IR, we report several results in studying the crystallization of both miscible and immiscible blends as well as polymer aging. Finally, we demonstrate how this novel technique can be used to determine phase separation, spherulitic structure, and crystallization mechanisms at nanoscales, which has never been achieved before. The review also discusses future trends in the use of [[AFM]]-IR in polymer materials, especially in polymer thin film investigation.

|keywords=* AFM-IR
* blends
* nanoscale characterization
* polymer aging
* polymer composites
* polymers
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284686
}}
{{medline-entry
|title=Active fractions of mannoproteins derived from yeast cell wall stimulate innate and acquired immunity of adult and elderly dogs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32288071
|abstract=Nutritional intervention in older dogs aims to increase lifespan and improve life quality as well as delay the development of diseases related to ageing. It is believed that active fractions of mannoproteins ([[AFM]]s) obtained through extraction and fractionation of yeast cell walls ([i]Saccharomyces cerevisiae[/i]) may beneficially modulate the immune system. However, studies that have evaluated this component and the effects of ageing on the immune system of dogs are scarce. This study aimed to evaluate the immunological effects of [[AFM]]s in adult and elderly dogs. Three extruded iso-nutrient experimental diets were formulated: without addition of [[AFM]] (T0); with [[AFM]] at 400 mg/kg (T400); and with [[AFM]] at 800 mg/kg (T800). Thirty-six beagle dogs were used, and six experimental treatments, resulting in combinations of age (adult and elderly) and diet (T0, T400, and T800), were evaluated. On days zero, 14, and 28, blood samples were obtained for leucocyte phenotyping and phagocytosis assays. On days zero and 28, a lymphoproliferation test, quantification of reactive oxygen (H O ) and nitrogen (NO) intermediate production, evaluation of faecal immunoglobulin A (IgA) content, and a delayed cutaneous hypersensitivity test (DCHT) were performed. Statistical analyses were performed with SAS software. Repeated measure variance analyses were performed, and means were compared by the Tukey test. Values of P ≤ 0.05 were considered significant, and values of P ≤ 0.10 were considered tendencies. Dogs fed T400 tended to have higher neutrophilic phagocytic activity than dogs fed T800 (P = 0.073). Regarding reactive oxygen intermediates, bacterial lipopolysaccharide (LPS)-stimulated neutrophils from animals that were fed T400 had a tendency to produce more H O  than those from animals fed the control diet (P = 0.093). Elderly dogs, when compared to adult dogs, had lower absolute T and B lymphocyte counts, lower auxiliary T lymphocyte counts, and higher cytotoxic T lymphocyte counts (P < 0.05). A significant effect of diet, age, and time with saline inoculation was noted for the DCHT. There was no effect of diet or age on faecal IgA content in dogs. This study suggests beneficial effects of mannoproteins on the specific and nonspecific immune responses in adult and elderly dogs.

|keywords=* AFM, active fraction of mannoproteins
* ALP, alkaline phosphatase
* ALT, alanine aminotransferase
* Ageing
* CBC, complete blood count
* CD21+, B lymphocyte
* CD4+, auxiliary T lymphocyte
* CD5+, total T lymphocyte
* CD8+, cytotoxic lymphocyte
* CO, cells only
* Canine
* DCHT, delayed cutaneous hypersensitivity test
* FOSs, fructooligosaccharides
* GALT, gut-associated lymphoid tissue
* IL-12, interleukin 12
* IgA, immunoglobulin A
* Immunosenescence
* LPS, bacterial lipopolysaccharide
* MOSs, mannanoligosaccharides
* NADPH, reduced nicotinamide adenine dinucleotide phosphate
* NO, nitrogen monoxide
* NOS, nitric oxide synthase
* OD, optical density
* PMA, phorbol myristate acetate
* Saccharomyces cerevisiae
* Senescence
* TNF-α, tumour necrosis factor alpha
* Th1, helper T lymphocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126846
}}
{{medline-entry
|title=The Effect of Waste Engine Oil and Waste Polyethylene on UV Aging Resistance of Asphalt.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32155867
|abstract=Waste engine oil (WEO) and waste polyethylene (WPE) are two common wastes, which are easy to pollute the environment. As the primary material in road construction, natural asphalt is a non-renewable energy source and asphalt is vulnerable to ultraviolet (UV) radiation during the service life. It results in degradation of asphalt pavement performance. In this paper, 22 wt % to 82 wt % of WEO and WPE were used to modify asphalts and the UV aging simulation experiment was carried out. The physical parameters of asphalts before the UV aging experiment show that the asphalt containing 42 wt % WPE and 62 wt % WEO mixture (42 wt % WPE + 62 wt % WEO) has similar physical properties with that of the matrix asphalt. Besides, gel permeation chromatography (GPC) verifies that the molecular weight distribution of the asphalt containing 42 wt % WPE + 62 wt % WEO is close to that of the matrix asphalt. The storage stability test shows that 42 wt % WPE + 62 wt % WEO has good compatibility with the matrix asphalt. The functional groups and micro-morphology of asphalts before and after the UV aging experiment were investigated by Fourier transform infrared spectroscopy (FTIR) and atomic force microscopy ([[AFM]]). FTIR results display that 42 wt % WPE + 62 wt % WEO can effectively reduce the formation of carbonyl and sulfoxide functional groups. [[AFM]] shows that 42 wt % WPE + 62 wt % WEO can also retard the formation of a "bee-like" structure in asphalt after the UV aging experiment. Based on the above results, it can be concluded that WEO and WPE mixture can replace part of asphalt and improve the UV aging resistance of asphalt.

|keywords=* Fourier transform infrared spectroscopy
* atomic force microscopy
* gel permeation chromatography
* ultraviolet aging
* waste engine oil
* waste polyethylene
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7182932
}}
{{medline-entry
|title=Mechanical properties measured by atomic force microscopy define health biomarkers in ageing C. elegans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32098962
|abstract=Genetic and environmental factors are key drivers regulating organismal lifespan but how these impact healthspan is less well understood. Techniques capturing biomechanical properties of tissues on a nano-scale level are providing new insights into disease mechanisms. Here, we apply Atomic Force Microscopy ([[AFM]]) to quantitatively measure the change in biomechanical properties associated with ageing Caenorhabditis elegans in addition to capturing high-resolution topographical images of cuticle senescence. We show that distinct dietary restriction regimes and genetic pathways that increase lifespan lead to radically different healthspan outcomes. Hence, our data support the view that prolonged lifespan does not always coincide with extended healthspan. Importantly, we identify the insulin signalling pathway in C. elegans and interventions altering bacterial physiology as increasing both lifespan and healthspan. Overall, [[AFM]] provides a highly sensitive technique to measure organismal biomechanical fitness and delivers an approach to screen for health-improving conditions, an essential step towards healthy ageing.
|mesh-terms=* Aging
* Animal Feed
* Animals
* Bacillus subtilis
* Biomarkers
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Comamonas
* Escherichia coli
* Forkhead Transcription Factors
* Hot Temperature
* Insulin
* Microbiota
* Microscopy, Atomic Force
* Mutation
* Receptor, Insulin
* Signal Transduction
* Ultraviolet Rays

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042263
}}
{{medline-entry
|title=Nanomechanical insights: Amyloid beta oligomer-induced senescent brain endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31513781
|abstract=Senescent cells accumulate in various peripheral tissues during aging and have been shown to exacerbate age-related inflammatory responses. We recently showed that exposure to neurotoxic amyloid β (Aβ1-42) oligomers can readily induce a senescence phenotype in human brain microvascular endothelial cells (HBMECs). In the present work, we used atomic force microscopy ([[AFM]]) to further characterize the morphological properties such as cell membrane roughness and cell height and nanomechanical properties such as Young's modulus of the membrane (membrane stiffness) and adhesion resulting from the interaction between [[AFM]] tip and cell membrane in Aβ1-42 oligomer-induced senescent human brain microvascular endothelial cells. Morphological imaging studies showed a flatter and spread-out nucleus in the senescent HBMECs, both characteristic features of a senescent phenotype. Furthermore, the mean cell body roughness and mean cell height were lower in senescent HBMECs compared to untreated normal HBMECs. We also observed increased stiffness and alterations in the adhesion properties in Aβ1-42 oligomer-induced senescent endothelial cells compared to the untreated normal HBMECs suggesting dynamic reorganization of cell membrane. We then show that vascular endothelial growth factor receptor 1 (VEGFR-1) knockdown or overexpression of Rho GTPase Rac 1 in the endothelial cells inhibited senescence and reversed these nanomechanical alterations, confirming a direct role of these pathways in the senescent brain endothelial cells. These results illustrate that nanoindentation and topographic analysis of live senescent brain endothelial cells can provide insights into cerebrovascular dysfunction in neurodegenerative diseases such as Alzheimer's disease.
|mesh-terms=* Alzheimer Disease
* Amyloid beta-Peptides
* Biomechanical Phenomena
* Brain
* Cell Culture Techniques
* Cell Membrane
* Cellular Senescence
* Endothelial Cells
* Endothelium, Vascular
* Humans
* Microscopy, Atomic Force
* Vascular Endothelial Growth Factor A
|keywords=* Amyloid beta oligomer
* Atomic force microscopy
* Brain endothelial cells
* Nanoindentation
* Nanomechanical properties
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791778
}}
==SIRT3==

{{medline-entry
|title=[[SIRT3]] protects endothelial cells from high glucose-induced senescence and dysfunction via the p53 pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33160987
|abstract=Hyperglycemia induces endothelial cells (ECs) dysfunction and vascular complications by accelerating ECs senescence. It also induces downregulation of sirtuins (SIRTs). However, the molecular mechanism involved in the regulation of ECs senescence by [[SIRT3]] remains unclear. Here, we showed that high glucose (HG) decreased the expression level of [[SIRT3]] in human umbilical vein endothelial cells (HUVECs), increased the proportion of cells expressing senescence-associated galactosidase (SA-gal), and HG damaged the cell's ability to form tubule networks on Matrigel. However, transfection with adenoviral construct including [[SIRT3]] significantly inhibited HG-induced SA-gal activity, decreased p53 acetylation level at the site Lys 320 (k320), and overexpression of [[SIRT3]] antagonized high glucose-induced angiogenic dysfunction. Our results suggested a possible molecular mechanism involving HG-[[SIRT3]]-p53 in ECs senescence.

|keywords=* Endothelial senescence
* High glucose
* SIRT3
* p53
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.118724
}}
{{medline-entry
|title=Melatonin and Sirtuins in Buccal Epithelium: Potential Biomarkers of Aging and Age-Related Pathologies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33143333
|abstract=Melatonin (MT) and sirtuins (SIRT) are geroprotective molecules that hold back the aging process and the development of age-related diseases, including cardiovascular pathologies. Buccal epithelium (BE) sampling is a non-invasive procedure, yielding highly informative material for evaluating the expression of genes and proteins as well as the synthesis of molecules. Among these, MT and SIRTs are valuable markers of the aging process and age-related pathologies. The purpose of this study was to examine age-related expression patterns of these signaling molecules, in particular MT, SIRT1, [[SIRT3]], and SIRT6 in BE of subjects of different ages with and without arterial hypertension (AH). We used real-time polymerase chain reaction (RT-PCR) and immunofluorescence analysis by confocal microscopy. We found that MT immunofluorescence intensity in BE decreases with aging, more evidently in AH patients. [[SIRT3]] and SIRT6 genes expression and immunofluorescence intensity in BE was decreased in aging controls. In AH patients, SIRT1, [[SIRT3]], and SIRT6 gene expression and immunofluorescence intensity in BE was decreased in relation to age and in comparison with age-matched controls. In conclusion, the evaluation of MT and sirtuins in BE could provide a non-invasive method for appraising the aging process, also when accompanied by AH.

|keywords=* aging
* arterial hypertension
* buccal epithelium
* melatonin
* sirtuins
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662974
}}
{{medline-entry
|title=[i][[SIRT3]][/i] Transfection of Aged Human Bone Marrow-Derived Mesenchymal Stem Cells Improves Cell Therapy-Mediated Myocardial Repair.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32228121
|abstract=Sirtuin 3 ([[SIRT3]]) is a deacetylase important for antioxidant protection, cell longevity, and aging. We hypothesized that [[SIRT3]] improve oxidative resistance of aged cells and improve cell therapy in aged patients. [i]In vitro[/i], the proliferation and oxidative resistance of human mesenchymal stem cells (hMSCs) significantly declined with age. The expression and activity of antioxidant enzymes, including catalase (CAT) and manganese superoxide dismutase (MnSOD), increased after transfection of [i][[SIRT3]][/i] in hMSCs from older donors (O-hMSCs). The protein level of Forkhead box O3a (FOXO3a) in nucleus increased after [[SIRT3]] overexpression. The antioxidant capacity of O-hMSCs increased after [[SIRT3]] overexpression. 3-Amino-1,2,4-triazole (3-AT, CAT inhibitor) or diethyldithiocarbamate (DETC, SOD inhibitor) that was used to inhibit CAT or SOD activity significantly blocked the antioxidant function of [[SIRT3]]. When two inhibitors were used together, the antioxidant function of [[SIRT3]] almost disappeared. Following myocardial infarction and intramyocardial injections of O-hMSCs in rats [i]in vivo[/i], the survival rate of O-hMSCs increased by [i][[SIRT3]][/i] transfection. The cardiac function of rats was improved after [[SIRT3]]-overexpressed O-hMSC transplantation. The infarct size, collagen content, and expression levels of matrix metalloproteinase 2 (MMP2) and MMP9 decreased. Besides, the protein level of vascular endothelial growth factor A and vascular density increased after cell transplantation with [[SIRT3]]-modified O-hMSCs. These results indicate that damage resistance of hMSCs decline with age and [[SIRT3]] might protect O-hMSCs against oxidative damage by activating CAT and MnSOD through transferring FOXO3a into nucleus. Meanwhile, the therapeutic effect of aged hMSC transplantation can be improved by [[SIRT3]] overexpression.

|keywords=* O-hMSC transplantation
* SIRT3
* aging
* gene modification
* myocardial infarction
* myocardial repair
|full-text-url=https://sci-hub.do/10.1089/rej.2019.2260
}}
{{medline-entry
|title=17β-estradiol inhibits H O -induced senescence in HUVEC cells through upregulating [[SIRT3]] expression and promoting autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32172411
|abstract=17β-estradiol (17β-E ) has been implicated in inhibiting the senescence of vascular endothelial cells (VEC) and slowing down the process of atherosclerosis. However, the underlying molecular mechanisms are still unknown. In this study, we examined the roles of [[SIRT3]] in 17β-E -induced autophagy and 17β-E -mediated inhibition of hydrogen peroxide (H O )-induced senescence in Human umbilical vein endothelial cells (HUVEC). Cellular senescence was measured by immunoblot analysis with antibodies against phosphorylated Rb and senescence-associated β-galactosidase staining. Immunoblot analysis with antibodies against LC3 and p62 was performed to determine autophagy flux. Our findings show that 17β-E  activates [[SIRT3]] promoter and upregulates [[SIRT3]] gene expression in HUVEC cells. siRNA-mediated silencing of [[SIRT3]] gene expression inhibits 17β-E -induced processing of LC3-I to LC3-II and degradation of p62, two widely-used makers of autophagy. [[SIRT3]] knockdown also blocks 17β-E -induced inhibition of cellular senescence triggered by H O . Our data further reveal that [[SIRT3]] knockdown impairs 17β-E -induced co-localization of LC3 and VDAC1, a marker protein on mitochondria, when HUVEC cells were co-treated with H O . Together, our findings suggest that 17β-E  upregulates [[SIRT3]] gene expression by activating [[SIRT3]] promoter and then promotes autophagy, which in turn serves to remove dysfunctional mitochondria caused by H O  and consequently inhibit H O -induced senescence in HUVEC cells.

|keywords=* 17β-estradiol
* Autophagy
* SIRT3
* Senescence
|full-text-url=https://sci-hub.do/10.1007/s10522-020-09868-w
}}
{{medline-entry
|title=CR6 interacting factor 1 deficiency induces premature senescence via [[SIRT3]] inhibition in endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32109515
|abstract=Vascular endothelial cell senescence is an important cause of cardiac-related diseases. Mitochondrial reactive oxygen species (mtROS) have been implicated in cellular senescence and multiple cardiovascular disorders. CR6 interacting factor 1 (CRIF1) deficiency has been shown to increase mtROS via the inhibition of mitochondrial oxidative phosphorylation; however, the mechanisms by which mtROS regulates vascular endothelial senescence have not been thoroughly explored. The goal of this study was to investigate the effects of CRIF1 deficiency on endothelial senescence and to elucidate the underlying mechanisms. CRIF1 deficiency was shown to increase the activity of senescence-associated β-galactosidase along with increased expression of phosphorylated p53, p21, and p16 proteins. Cell cycle arrested in the G0/G1 phase were identified in CRIF1-deficient cells using the flow cytometry. Furthermore, CRIF1 deficiency was also shown to increase cellular senescence by reducing the expression of Sirtuin 3 ([[SIRT3]]) via ubiquitin-mediated degradation of transcription factors PGC1α and NRF2. Downregulation of CRIF1 also attenuated the function of mitochondrial antioxidant enzymes including manganese superoxide dismutase (MnSOD), Foxo3a, nicotinamide-adenine dinucleotide phosphate, and glutathione via the suppression of [[SIRT3]]. Interestingly, overexpression of [[SIRT3]] in CRIF1-deficient endothelial cells not only reduced mtROS levels by elevating expression of the antioxidant enzyme MnSOD but also decreased the expression of cell senescence markers. Taken together, these results suggest that CRIF1 deficiency induces vascular endothelial cell senescence via ubiquitin-mediated degradation of the transcription coactivators PGC1α and NRF2, resulting in decreased expression of [[SIRT3]].

|keywords=* Antioxidant system
* Mitochondria
* Oxidative stress
* Senescence
* Vascular endothelial cell
|full-text-url=https://sci-hub.do/10.1016/j.freeradbiomed.2020.02.017
}}
{{medline-entry
|title=Mitochondrial function in skeletal myofibers is controlled by a TRF2-[[SIRT3]] axis over lifetime.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31991048
|abstract=Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere-capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene ([[SIRT3]]) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2-compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the Terf2 gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2-compromised human myotubes. Altogether, these results reveal a TRF2-[[SIRT3]] axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism.

|keywords=* aging
* mitochondria
* postmitotic cells
* skeletal muscle
* telomeres
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059141
}}
{{medline-entry
|title=Context-Dependent Roles for SIRT2 and [[SIRT3]] in Tumor Development Upon Calorie Restriction or High Fat Diet.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31970087
|abstract=Calorie restriction (CR) is considered one of the most robust ways to extend life span and reduce the risk of age-related diseases, including cancer, as shown in many different organisms, whereas opposite effects have been associated with high fat diets (HFDs). Despite the proven contribution of sirtuins in mediating the effects of CR in longevity, the involvement of these nutrient sensors, specifically, in the diet-induced effects on tumorigenesis has yet to be elucidated. Previous studies focusing on SIRT1, do not support a critical role for this sirtuin family member in CR-mediated cancer prevention. However, the contribution of other family members which exhibit strong deacetylase activity is unexplored. To fill this gap, we aimed at investigating the role of SIRT2 and [[SIRT3]] in mediating the anti and pro-tumorigenic effect of CR and HFD, respectively. Our results provide strong evidence supporting distinct, context-dependent roles played by these two family members. SIRT2 is indispensable for the protective effect of CR against tumorigenesis. On the contrary, [[SIRT3]] exhibited oncogenic properties in the context of HFD-induced tumorigenesis, suggesting that [[SIRT3]] inhibition may mitigate the cancer-promoting effects of HFD. Given the different functions regulated by SIRT2 and [[SIRT3]], unraveling downstream targets/pathways involved may provide opportunities to develop new strategies for cancer prevention.

|keywords=* SIRT2
* SIRT3
* aging
* calorie restriction
* cancer
* high fat diet
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960403
}}
{{medline-entry
|title=The yin and yang faces of the mitochondrial deacetylase sirtuin 3 in age-related disorders.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31740222
|abstract=Aging, the most important risk factor for many of the chronic diseases affecting Western society, is associated with a decline in mitochondrial function and dynamics. Sirtuin 3 ([[SIRT3]]) is a mitochondrial deacetylase that has emerged as a key regulator of fundamental processes which are frequently dysregulated in aging and related disorders. This review highlights recent advances and controversies regarding the yin and yang functions of [[SIRT3]] in metabolic, cardiovascular and neurodegenerative diseases, as well as the use of [[SIRT3]] modulators as a therapeutic strategy against those disorders. Although most studies point to a protective role upon [[SIRT3]] activation, there are conflicting findings that need a better elucidation. The discovery of novel [[SIRT3]] modulators with higher selectivity together with the assessment of the relative importance of different [[SIRT3]] enzymatic activities and the relevance of crosstalk between distinct sirtuin isoforms will be pivotal to validate [[SIRT3]] as a useful drug target for the prevention and treatment of age-related diseases.
|mesh-terms=* Aging
* Animals
* Cardiovascular Diseases
* Humans
* Metabolic Diseases
* Mitochondria
* Neurodegenerative Diseases
* Protein Isoforms
* Sirtuin 3
|keywords=* Age-related diseases
* Deacetylation
* Genetic manipulations
* Mitochondria
* Pharmacological modulators
* Sirtuins
|full-text-url=https://sci-hub.do/10.1016/j.arr.2019.100983
}}
==PINK1==

{{medline-entry
|title=Spermidine inhibits neurodegeneration and delays aging via the [[PINK1]]-PDR1-dependent mitophagy pathway in [i]C. elegans[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32902411
|abstract=Aging is the primary driver of various diseases, including common neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Currently there is no cure for AD and PD, and the development of novel drug candidates is demanding. Spermidine is a small anti-aging molecule with elimination of damaged mitochondria via the process of mitophagy identified as a molecular mechanism of action. Here, we show that spermidine inhibits memory loss in AD worms and improves behavioral performance, e.g., locomotor capacity, in a PD worm model, both via the [[PINK1]]-PDR1-dependent mitophagy pathway. Additionally, spermidine delays accelerated aging and improves healthspan in the DNA repair-deficient premature aging Werner syndrome (WS) worm model. While possible intertwined interactions between mitophagy/autophagy induction and DNA repair by spermidine are to be determined, our data support further translation of spermidine as a possible therapeutic intervention for such diseases.

|keywords=* aging
* caenorhabditis elegans
* mitophagy
* neurodegenerative diseases
* spermidine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521492
}}
{{medline-entry
|title=Female mice are resilient to age-related decline of substantia nigra dopamine neuron firing parameters.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32846275
|abstract=Degeneration of substantia nigra pars compacta dopamine neurons is a central feature in the pathology of Parkinson's disease, which is characterized by progressive loss of motor and cognitive functions. The largest risk factors for Parkinson's disease are age and sex; most cases occur after age 60 and males have nearly twice the incidence as females. Preclinical work has scarcely considered the influence of these 2 factors to disease risk and presentation. Here, we observed a progressive decline in dopamine neuron firing activity in male C57BL/6 mice by 18 months of age, while dopamine neurons from females remained largely unaffected. This was accompanied by increased mRNA expression of [[PINK1]] in both males and females, and PARK2 primarily in males, both of which have been linked to Parkinson's. Since the declining cell properties were accompanied by only slight decreases in locomotion in both sexes, it is likely that these age-related impairments in males represent a vulnerability to further insults that could predispose the neurons to neurodegenerative processes such as in Parkinson's.

|keywords=* Aging
* Dopamine
* Electrophysiology
* Firing
* Mouse
* Substantia nigra
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606778
}}
{{medline-entry
|title=Attenuation of epigenetic regulator SMARCA4 and ERK-ETS signaling suppresses aging-related dopaminergic degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32749068
|abstract=How complex interactions of genetic, environmental factors and aging jointly contribute to dopaminergic degeneration in Parkinson's disease (PD) is largely unclear. Here, we applied frequent gene co-expression analysis on human patient substantia nigra-specific microarray datasets to identify potential novel disease-related genes. In vivo Drosophila studies validated two of 32 candidate genes, a chromatin-remodeling factor SMARCA4 and a biliverdin reductase BLVRA. Inhibition of SMARCA4 was able to prevent aging-dependent dopaminergic degeneration not only caused by overexpression of BLVRA but also in four most common Drosophila PD models. Furthermore, down-regulation of SMARCA4 specifically in the dopaminergic neurons prevented shortening of life span caused by α-synuclein and LRRK2. Mechanistically, aberrant SMARCA4 and BLVRA converged on elevated ERK-ETS activity, attenuation of which by either genetic or pharmacological manipulation effectively suppressed dopaminergic degeneration in Drosophila in vivo. Down-regulation of SMARCA4 or drug inhibition of MEK/ERK also mitigated mitochondrial defects in [[PINK1]] (a PD-associated gene)-deficient human cells. Our findings underscore the important role of epigenetic regulators and implicate a common signaling axis for therapeutic intervention in normal aging and a broad range of age-related disorders including PD.

|keywords=* 
Drosophila

* MAPK-ERK-ETS signaling
* Parkinson's disease
* SMARCA4/Brahma
* aging
* neurodegeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511865
}}
{{medline-entry
|title=SIRT1 alleviates high-magnitude compression-induced senescence in nucleus pulposus cells via [[PINK1]]-dependent mitophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32687063
|abstract=Mechanical overloading-induced nucleus pulposus (NP) cells senescence plays an important role in the pathogenesis of intervertebral disc degeneration (IVDD). The silent mating type information regulator 2 homolog-1 (SIRT1)-mediated pathway preserves the normal NP cell phenotype and mitochondrial homeostasis under multiple stresses. We aimed to investigate the role of SIRT1 in IVDD by assessing the effects of SIRT1 overexpression on high-magnitude compression-induced senescence in NP cells. High-magnitude compression induced cellular senescence and mitochondrial dysfunction in human NP cells. Moreover, SIRT1 overexpression tended to alleviate NP cell senescence and mitochondrial dysfunction under compressive stress. Given the mitophagy-inducing property of SIRT1, activity of mitophagy was evaluated in NP cells to further demonstrate the underlying mechanism. The results showed that SIRT1-overexpression attenuated senescence and mitochondrial injury in NP cells subjected to high-magnitude compression. However, depletion of [[PINK1]], a key mitophagic regulator, impaired mitophagy and blocked the protective role of SIRT1 against compression induced senescence in NP cells. In summary, these results suggest that SIRT1 plays a protective role in alleviating NP cell senescence and mitochondrial dysfunction under high-magnitude compression, the mechanism of which is associated with the regulation of [[PINK1]]-dependent mitophagy. Our findings may provide a potential therapeutic approach for IVDD treatment.

|keywords=* SIRT1
* compression
* mitophagy
* nucleus pulposus
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485741
}}
{{medline-entry
|title=Synergistic action of propolis with levodopa in the management of Parkinsonism in Drosophila melanogaster.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32386191
|abstract=Background The Phosphatase and tensin-induced putative kinase 1 ([[PINK1]]B9) mutant for Drosophila melanogaster is a key tool that has been used in assessing the pathology of Parkinsonism and its possible remedy. This research was targeted toward determining the effects of ethanolic extract of propolis, with levodopa therapy in the management of Parkinsonism. Method The [[PINK1]]B9 flies were divided into groups and fed with the different treatment doses of ethanoic extract of propolis. The treatment groups were subjected to 21 days of administration of propolis and the levodopa at different doses after which percentage climbing index, antioxidant activity and lifespan studies were done. Results Propolis alone improved motor activity, antioxidant and lifespan in Drosophila melanogaster than in [[PINK1]] flies. Propolis in combination with levodopa significantly (P<0.05) improved physiological parameters at higher than lower concentrations in Parkinsonism Drosophila melanogaster demonstrating its importance in managing side effects associated with levodopa. Conclusion Propolis is a novel candidate as an alternative and integrative medicinal option to use in the management of Parkinsonism in both animals and humans at higher concentrations.

|keywords=* Drosophila melanogaster
* Levodopa induced dyskinesia
* PINK1B9

* Parkinsonism
* Parkinson’s disease
* aging
* antioxidant activity
* catalase
* climbing index
* lifespan
* oxidative stress
* propolis
|full-text-url=https://sci-hub.do/10.1515/jcim-2019-0136
}}
{{medline-entry
|title=Compression-induced senescence of nucleus pulposus cells by promoting mitophagy activation via the [[PINK1]]/PARKIN pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32281308
|abstract=The current research aimed to explore the possible relationship between [[PINK1]]/PARKIN-mediated mitophagy and the compression-induced senescence of nucleus pulposus cells (NPCs). Therefore, the stages of senescence in NPCs were measured under compression lasting 0, 24 and 48 hours. The mitophagy-related markers, autophagosomes and mitochondrial membrane potential were tested to determine the levels of [[PINK1]]/PARKIN-mediated mitophagy under compression. The [[PINK1]] and PARKIN levels were also measured by immunohistochemistry of human and rat intervertebral disc (IVD) tissues taken at different degenerative stages. A specific mitophagy inhibitor, cyclosporine A (CSA) and a constructed [[PINK1]]-shRNA were used to explore the relationship between mitophagy and senescence by down-regulating the [[PINK1]]/PARKIN-mediated mitophagy levels. Our results indicated that compression significantly enhanced the senescence of NPCs in a time-dependent manner. Also, [[PINK1]]/PARKIN-mediated mitophagy was found to be activated by the extended duration of compression on NPCs as well as the increased degenerative stages of IVD tissues. After inhibition of [[PINK1]]/PARKIN-mediated mitophagy by CSA and [[PINK1]]-shRNA, the senescence of NPCs induced by compression was strongly rescued. Hence, the excessive degradation of mitochondria in NPCs by mitophagy under continuous compression may accelerate the senescence of NPCs. Regulating [[PINK1]]/PARKIN-mediated mitophagy might be a potential therapeutic treatment for IVD degeneration.

|keywords=* PARKIN pathway
* PINK1
* compression
* intervertebral disc
* mitophagy
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214186
}}
{{medline-entry
|title=Doxorubicin-induced normal breast epithelial cellular aging and its related breast cancer growth through mitochondrial autophagy and oxidative stress mitigated by ginsenoside Rh2.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32100342
|abstract=Clinical dose of doxorubicin (100 nM) induced cellular senescence and various secretory phenotypes in breast cancer and normal epithelial cells. Herein, we reported the detailed mechanism underlying ginsenoside Rh2-mediated NF-κB inhibition, and mitophagy promotion were evaluated by antibody array assay, western blotting analysis, and immunocytostaining. Ginsenoside Rh2 suppressed the protein levels of TRAF6, p62, phosphorylated IKK, and IκB, which consequently inactivated NF-κB activity. Rh2-mediated secretory phenotype was delineated by the suppressed IL-8 secretion. Senescent epithelial cells showed increased level of reactive oxygen species (ROS), which was significantly abrogated by Rh2, with upregulation on SIRT 3 and SIRT 5 and subsequent increase in SOD1 and SOD2. Rh2 remarkably favored mitophagy by the increased expressions of [[PINK1]] and Parkin and decreased level of PGC-1α. A decreased secretion of IL-8 challenged by mitophagy inhibitor Mdivi-1 with an NF-κB luciferase system was confirmed. Importantly, secretory senescent epithelial cells promoted the breast cancer (MCF-7) proliferation while decreased the survival of normal epithelial cells demonstrated by co-culture system, which was remarkably alleviated by ginsenoside Rh2 treatment. These data included ginsenoside Rh2 regulated ROS and mitochondrial autophagy, which were in large part attributed to secretory phenotype of senescent breast epithelial cells induced by doxorubicin. These findings also suggested that ginsenoside Rh2 is a potential treatment candidate for the attenuation of aging related disease.
|mesh-terms=* Autophagy
* Breast Neoplasms
* Cell Culture Techniques
* Cell Line, Tumor
* Doxorubicin
* Drugs, Chinese Herbal
* Female
* Ginsenosides
* Humans
* Mitochondria
* Oxidative Stress
|keywords=* ROS
* cancer growth
* cellular senescence
* chemotherapy
* ginsenoside Rh2
* mitophagy
|full-text-url=https://sci-hub.do/10.1002/ptr.6636
}}
{{medline-entry
|title=Mitochondrial DNA heteroplasmy rises in substantial nigra of aged [[PINK1]] KO mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31727366
|abstract=Mutations in [[PINK1]] and Parkin result in early-onset autosomal recessive Parkinson's disease (PD). [[PINK1]]/Parkin pathway maintain mitochondrial function by mediating the clearance of damaged mitochondria. However, the role of [[PINK1]]/Parkin in maintaining the balance of mtDNA heteroplasmy is still unknown. Here, we isolated mitochondrial DNA (mtDNA) from cortex, striatum and substantia nigra of wildtype (WT), [[PINK1]] knockout ([[PINK1]] KO) and Parkin knockout (Parkin KO) mice to analyze mtDNA heteroplasmy induced by [[PINK1]]/Parkin deficiency or aging. Our results showed that the Single Nucleotide Variants (SNVs) of late-onset somatic variants mainly increased with aging. Conversely, the early-onset somatic variants exhibited significant increase in the cortex and substantia nigra of [[PINK1]] KO mice than WT mice of the same age. Increased average variant allele frequency was observed in aged [[PINK1]] KO mice and in substantial nigra of aged Parkin KO mice than in WT mice. Cumulative variant allele frequency in the substantia nigra of [[PINK1]] KO mice was significantly higher than that in WT mice, further supporting the pivotal role of [[PINK1]] in mtDNA maintenance. This study presented a new evidence for [[PINK1]] and Parkin in participating in mitochondrial quality control and provided clues for further revealing the role of [[PINK1]] and Parkin in the pathogenesis of PD.
|mesh-terms=* Aging
* Animals
* Brain
* DNA Copy Number Variations
* DNA, Mitochondrial
* Gene Frequency
* Mice, Knockout
* Mutation Rate
* Protein Kinases
* Substantia Nigra
|keywords=* PINK1
* Parkin
* Parkinson’s disease
* mtDNA heteroplasmy
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2019.10.112
}}
==AR==

{{medline-entry
|title=Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32650419
|abstract=The androgen receptor ([[AR]]) plays a leading role in the control of prostate cancer (PCa) growth. Interestingly, structurally different [[AR]] antagonists with distinct mechanisms of antagonism induce cell senescence, a mechanism that inhibits cell cycle progression, and thus seems to be a key cellular response for the treatment of PCa. Surprisingly, while physiological levels of androgens promote growth, supraphysiological androgen levels (SAL) inhibit PCa growth in an [[AR]]-dependent manner by inducing cell senescence in cancer cells. Thus, oppositional acting ligands, [[AR]] antagonists, and agonists are able to induce cellular senescence in PCa cells, as shown in cell culture model as well as ex vivo in patient tumor samples. This suggests a dual [[AR]]-signaling dependent on androgen levels that leads to the paradox of the rational to keep the [[AR]] constantly inactivated in order to treat PCa. These observations however opened the option to treat PCa patients with [[AR]] antagonists and/or with androgens at supraphysiological levels. The latter is currently used in clinical trials in so-called bipolar androgen therapy (BAT). Notably, cellular senescence is induced by [[AR]] antagonists or agonist in both androgen-dependent and castration-resistant PCa (CRPC). Pathway analysis suggests a crosstalk between [[AR]] and the non-receptor tyrosine kinase Src-Akt/PKB and the PI3K-mTOR-autophagy signaling in mediating [[AR]]-induced cellular senescence in PCa. In this review, we summarize the current knowledge of therapeutic induction and intracellular pathways of [[AR]]-mediated cellular senescence.

|keywords=* PKB/Akt
* Src
* androgen receptor antagonist
* antiandrogen
* bipolar androgen therapy
* cellular senescence
* prostate cancer
* supraphysiological androgen levels
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408918
}}
{{medline-entry
|title=Interleukin-23 Represses the Level of Cell Senescence Induced by the Androgen Receptor Antagonists Enzalutamide and Darolutamide in Castration-Resistant Prostate Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32562083
|abstract=Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related deaths of men in Western countries. Androgen deprivation therapy is initially successful, however eventually fails, and tumors progress to the more aggressive castration-resistant PCa (CRPC). Yet, androgen receptor ([[AR]]) usually remains as a major regulator of tumor cell proliferation in CRPC. Interleukin-23 (IL-23) was recently shown to promote the development of CRPC by driving [[AR]] transcription. Here we used the androgen-sensitive LNCaP, castration-resistant C4-2, and 22Rv1 cells. Interestingly, cellular senescence is induced in these human cell lines by treatment with the [[AR]] antagonists enzalutamide (ENZ) or darolutamide (ODM), which might be one underlying mechanism for inhibition of PCa cell proliferation. Treatment with IL-23 alone did not change cellular senescence levels in these cell lines, whereas IL-23 inhibited significantly cellular senescence levels induced by ENZ or ODM in both CRPC cell lines C4-2 and 22Rv1 but not in LNCaP cells. This indicates a response of IL-23 specific in CRPC cells. Generating LNCaP and C4-2 three-dimensional (3D) spheroids and treatment with [[AR]] antagonists resulted in the reduced spheroid volume and thus growth inhibition. However, the combination of [[AR]] antagonists with IL-23 did not affect the antagonist-mediated reduction of spheroid volumes. This observation was confirmed with proliferation assays using adherent monolayer cell cultures. Taken together, the data indicate that IL-23 treatment reduces the [[AR]] antagonists-induced level of cellular senescence of CRPC cells, which could be one possible mechanism for promoting castration resistance.

|keywords=* Androgen receptor antagonists
* Cellular senescence
* Interleukin-23
* Prostate cancer spheroids
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335377
}}
{{medline-entry
|title=A Landscape of Murine Long Non-Coding RNAs Reveals the Leading Transcriptome Alterations in Adipose Tissue during Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32460027
|abstract=Aging is an inevitable process that involves profound physiological changes. Long non-coding RNAs (lncRNAs) are emerging as important regulators in various biological processes but are not systemically studied in aging. To provide an organism-wide lncRNA landscape during aging, we conduct comprehensive RNA sequencing (RNA-seq) analyses across the mouse lifespan. Of the 1,675 aging-regulated lncRNAs ([[AR]]-lncRNAs) identified, the majority are connected to inflammation-related biological pathways. [[AR]]-lncRNAs exhibit high tissue specificity; conversely, those with higher tissue specificity are preferentially regulated during aging. White adipose tissue (WAT) displays the highest number of [[AR]]-lncRNAs and develops the most dynamic crosstalk between [[AR]]-lncRNA and [[AR]]-mRNA during aging. An adipose-enriched [[AR]]-lncRNA, lnc-adipo[[AR]]1, is negatively correlated with aging, and knocking it down inhibits adipogenesis, phenocopying the compromised adipogenic capacity of aged fat. Our works together reveal [[AR]]-lncRNAs as essential components in aging and suggest that although each tissue ages in a distinct manner, WAT is a leading contributor to aging-related health decline.

|keywords=* adipocyte
* adipose tissue
* aging
* lncRNA
* long non-coding RNA
* non-coding RNA
* transcriptome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603645
}}
{{medline-entry
|title=Senolytic compounds control a distinct fate of androgen receptor agonist- and antagonist-induced cellular senescent LNCaP prostate cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32351687
|abstract=The benefit of inducing cellular senescence as a tumor suppressive strategy remains questionable due to the senescence-associated secretory phenotype. Hence, studies and development of senolytic compounds that induce cell death in senescent cells have recently emerged. Senescent cells are hypothesized to exhibit different upregulated pro-survival/anti-apoptotic networks depending on the senescent inducers. This might limit the effect of a particular senolytic compound that targets rather only a specific pathway. Interestingly, cellular senescence in prostate cancer (PCa) cells can be induced by either androgen receptor ([[AR]]) agonists at supraphysiological androgen level (SAL) used in bipolar androgen therapy or by [[AR]] antagonists. This challenges to define ligand-specific senolytic compounds. Here, we first induced cellular senescence by treating androgen-sensitive PCa LNCaP cells with either SAL or the [[AR]] antagonist Enzalutamide (ENZ). Subsequently, cells were incubated with the HSP90 inhibitor Ganetespib (GT), the Bcl-2 family inhibitor ABT263, or the Akt inhibitor MK2206 to analyze senolysis. GT and ABT263 are known senolytic compounds. We observed that GT exhibits senolytic activity specifically in SAL-pretreated PCa cells. Mechanistically, GT treatment results in reduction of [[AR]], Akt, and phospho-S6 (p-S6) protein levels. Surprisingly, ABT263 lacks senolytic effect in both [[AR]] agonist- and antagonist-pretreated cells. ABT263 treatment does not affect [[AR]], Akt, or S6 protein levels. Treatment with MK2206 does not reduce [[AR]] protein level and, as expected, potently inhibits Akt phosphorylation. However, ENZ-induced cellular senescent cells undergo apoptosis by MK2206, whereas SAL-treated cells are resistant. In line with this, we reveal that the pro-survival p-S6 level is higher in SAL-induced cellular senescent PCa cells compared to ENZ-treated cells. These data indicate a difference in the agonist- or antagonist-induced cellular senescence and suggest a novel role of MK2206 as a senolytic agent preferentially for [[AR]] antagonist-treated cells. Taken together, our data suggest that both [[AR]] agonist and antagonist induce cellular senescence but differentially upregulate a pro-survival signaling which preferentially sensitize androgen-sensitive PCa LNCaP cells to a specific senolytic compound.

|keywords=* Akt inhibitor
* Antiandrogen
* Bcl-2 family inhibitor
* Bipolar androgen therapy
* Cellular senescence
* HSP90 inhibitor
* Prostate cancer
* Senolytic compounds
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183592
}}
{{medline-entry
|title=Role of gut microbiota in sex- and diet-dependent metabolic disorders that lead to early mortality of androgen receptor-deficient male mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32017595
|abstract=The gut microbiota is involved in metabolic disorders induced by androgen deficiency after sexual maturation in males (late-onset hypogonadism). However, its role in the energy metabolism of congenital androgen deficiency (e.g., androgen-insensitive syndrome) remains elusive. Here, we examined the link between the gut microbiota and metabolic disease symptoms in androgen receptor knockout ([[AR]]KO) mouse by administering high-fat diet (HFD) and/or antibiotics. HFD-fed male, but not standard diet-fed male or HFD-fed female, [[AR]]KO mice exhibited increased feed efficiency, obesity with increased visceral adipocyte mass and hypertrophy, hepatic steatosis, glucose intolerance, insulin resistance, and loss of thigh muscle. In contrast, subcutaneous fat mass accumulated in [[AR]]KO mice irrespective of the diet and sex. Notably, all HFD-dependent metabolic disorders observed in [[AR]]KO males were abolished after antibiotics administration. The ratios of fecal weight-to-food weight and cecum weight-to-body weight were specifically reduced by [[AR]]KO in HFD-fed males. 16S rRNA sequencing of fecal microbiota from HFD-fed male mice revealed differences in microbiota composition between control and [[AR]]KO mice. Several genera or species (e.g., [i]Turicibacter[/i] and [i]Lactobacillus reuteri[/i], respectively) were enriched in [[AR]]KO mice, and antibiotics treatment spoiled the changes. Furthermore, the life span of HFD-fed [[AR]]KO males was shorter than that of control mice, indicating that androgen deficiency causes metabolic dysfunctions leading to early death. These findings also suggest that [[AR]] signaling plays a role in the prevention of metabolic dysfunctions, presumably by influencing the gut microbiome, and improve our understanding of health consequences in subjects with hypogonadism and androgen insensitivity.
|mesh-terms=* Adipocytes
* Adipose Tissue
* Animals
* Anti-Bacterial Agents
* Diet
* Diet, High-Fat
* Feces
* Female
* Gastrointestinal Microbiome
* Lipid Metabolism
* Longevity
* Male
* Metabolic Diseases
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Obesity
* Receptors, Androgen
* Sex Characteristics
|keywords=* androgen-insensitive syndrome
* longevity
* metabolic syndrome
* testosterone
* type 2 diabetes
|full-text-url=https://sci-hub.do/10.1152/ajpendo.00461.2019
}}
{{medline-entry
|title=A jaboticaba extract prevents prostatic damage associated with aging and high-fat diet intake.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32003372
|abstract=Aging and overweight are involved in prostatic lesion development, due to their association with cell proliferation, hormonal imbalance and angiogenesis. The jaboticaba fruit is rich in bioactive compounds, showing potential chemopreventive action such as the capacity to modulate hormones and angiogenesis hallmarks. This study aimed to evaluate the jaboticaba extract (PJE) effect on the prostate morphology and on molecules related to hormone signaling and angiogenesis, during aging and/or high-fat diet (HFD) intake. Seventy FVB mice were distributed into experimental groups: YG group (young: 3 month old mice), AG group (aged: 11 month old mice), HfAG group (aged + HFD), JAGI group (aged + 2.9 g kg-1 PJE), JAGII group (aged + 5.8 g kg-1 PJE), HfJAGI group (aged + HFD + 2.9 g kg-1 PJE) and HfJAGII group (aged + HFD + 5.8 g kg-1 PJE). The ventral prostate was collected for morphological, immunohistochemistry and western-blotting analysis after 60 days of treatment. All PJE treatments promoted hormonal signaling balance and inhibited angiogenesis in the prostates of aged or HFD-fed aged mice, leading to the maintenance of healthy prostate morphology. A high dose of the PJE (JAGII and HfJAGII groups) led to the best capacity to reduce [[AR]] (58.40% and 74.42%; p = 0.0240 and p = 0.0023), ERα (30.29% and 45.12%; p = 0.0004 and p < 0.0001), aromatase (39.54% and 55.94%; p = 0.0038 and p = 0.0020), and VEGF (50.81% and 67.68%; p < 0.0001) and increase endostatin immunoexpression. Moreover, HFD intake intensified the hormonal and angiogenic alterations in the aged mouse prostates, contributing to the increase in premalignant lesion incidence. The PJE exerted a dose-dependent positive effect on aged or HFD-fed aged mouse prostates, contributing to the gland microenvironment recovery, mainly due to the hormonal and angiogenic balance. Therefore, we suggest that the PJE can be a potential candidate for prostatic lesion prevention.
|mesh-terms=* Aging
* Animals
* Cell Proliferation
* Diet, High-Fat
* Male
* Mice
* Myrtaceae
* Plant Extracts
* Prostate

|full-text-url=https://sci-hub.do/10.1039/c9fo02621e
}}
{{medline-entry
|title=Identifying blood-specific age-related DNA methylation markers on the Illumina MethylationEPIC® BeadChip.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31546163
|abstract=The past decade has seen rapid development in DNA methylation (DNAm) microarrays, including the Illumina HumanMethylation27 and HumanMethylation450 (450K) chips, which have played an essential role in identifying and evaluating age-related ([[AR]]) DNAm markers in different tissues. Recently, a new array, the Illumina MethylationEPIC (EPIC) was introduced, with nearly double the number of probes as the 450K (∼850,000 probes). In this study, we test these newly added probes for age association using a large cohort of 754 DNAm profiles from blood samples assayed on the EPIC BeadChip, for individuals aged 0-88 years old. 52 [[AR]] CpG sites (Spearman's abs(rho) >0.6 and P-value <10 ) were identified, 21 of which were novel sites and mapped to 18 genes, nine of which (LHFPL4, SLC12A8, EGFEM1P, GPR158, TAL1, KIAA1755, LOC730668, DUSP16, and FAM65C) have never previously been reported to be associated with age. The data were subsequently split into a 527-sample training set and a 227-sample testing set to build and validate two age prediction models using elastic net regression and multivariate regression. Elastic net regression selected 425 CpG markers with a mean absolute deviation (MAD) of 2.6 years based on the testing set. To build a multivariate linear regression model, [[AR]] CpG sites with R  > 0.5 at FDR < 0.05 were input into stepwise regression to select the best subset for age prediction. The resulting six CpG markers were linearly modelled with age and explained 81% of age-correlated variation in DNAm levels. Age estimation accuracy using bootstrap analysis was 4.5 years, with 95% confidence intervals of 4.56 to 4.57 years based on the testing set. These results suggest that EPIC BeadChip probes for age estimation fall within the range of probes found on the previous Illumina HumanMethylation platforms in terms of their age-prediction ability.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Child
* Child, Preschool
* Cohort Studies
* CpG Islands
* DNA Methylation
* Forensic Genetics
* Genetic Markers
* Humans
* Infant
* Infant, Newborn
* Linear Models
* Middle Aged
* Oligonucleotide Array Sequence Analysis
* Young Adult
|keywords=* Age
* CpG sites
* DNA methylation
* Forensic age estimation
* Forensic epigenetics
* Illumina MethylationEPIC
|full-text-url=https://sci-hub.do/10.1016/j.forsciint.2019.109944
}}
==IL6==

{{medline-entry
|title=Basic immunology may lead to translational therapeutic rationale: SARS-CoV-2 and rheumatic diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32645207
|abstract=COVID-19 pandemia is a major concern for patients and healthcare systems. The fear of infection by patients with concomitant rheumatic diseases (either adult or children) and connective tissue diseases is arising worldwide, because of their immunological background and immunological therapies. Analysing the basic biology of single diseases, the data suggest that there is an "immunological umbrella" that seems to protect against the infection, through IFN type 1 and NK cell function. To date, reports from China, United States and Europe did not reveal an higher risk of infection, either for rheumatoid arthritis, juvenile idiopathic arthritis nor for lupus erythematosus. Antimalarials, anti-[[IL6]]-Anti-[[IL6]] receptor, anti-IL1, anti-GM-CSF receptor and JAK1/2/3 inhibitors, are under investigation in COVID-dedicated clinical trials to control the inflammation raised by SARS-CoV-2 infection. Initial reports on the occurrence of autoimmune phenomena in the convalescence phase of SARS-CoV-2 infection suggests that the immunological consequences of the infection need to be strictly understood. Reporting of the study conforms to broad EQUATOR guidelines (Simera et al January 2010 issue of EJCI).
|mesh-terms=* Adaptive Immunity
* Aged
* Antirheumatic Agents
* COVID-19
* Comorbidity
* Coronavirus Infections
* Disease Outbreaks
* Female
* Humans
* Hydroxychloroquine
* Immunity, Innate
* Immunologic Factors
* Immunosuppressive Agents
* Italy
* Male
* Middle Aged
* Pandemics
* Pneumonia, Viral
* Rheumatic Diseases
* Risk Assessment
* Severe Acute Respiratory Syndrome
|keywords=* COVID-19
* SARS-CoV-2
* geriatrics
* pathophysiology
* pediatrics
* rheumatology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404583
}}
{{medline-entry
|title=ATM-deficient neural precursors develop senescence phenotype with disturbances in autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32621937
|abstract=ATM is a kinase involved in DNA damage response (DDR), regulation of response to oxidative stress, autophagy and mitophagy. Mutations in the ATM gene in humans result in ataxi A-Telangiectasia disease (A-T) characterized by a variety of symptoms with neurodegeneration and premature ageing among them. Since brain is one of the most affected organs in A-T, we have focused on senescence of neural progenitor cells (NPCs) derived from A-T reprogrammed fibroblasts. Accordingly, A-T NPCs obtained through neural differentiation of iPSCs in 5% oxygen possessed some features of senescence including increased activity of SA-β-gal and secretion of [[IL6]] and IL8 in comparison to control NPCs. This phenotype of A-T NPC was accompanied by elevated oxidative stress. A-T NPCs exhibited symptoms of impaired autophagy and mitophagy with lack of response to chloroquine treatment. Additional sources of oxidative stress like increased oxygen concentration (20 %) and H O  respectively aggravated the phenotype of senescence and additionally disturbed the process of mitophagy. In both cases only A-T NPCs reacted to the treatment. We conclude that oxidative stress may be responsible for the phenotype of senescence and impairment of autophagy in A-T NPCs. Our results point to senescent A-T cells as a potential therapeutic target in this disease.

|keywords=* ATM
* Ataxia-telangiectasia
* Autophagy
* Mitophagy
* Neural progenitors
* Oxidative stress
* Senescence
* hiPSCs
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111296
}}
{{medline-entry
|title=The microRNA-34a-Induced Senescence-Associated Secretory Phenotype (SASP) Favors Vascular Smooth Muscle Cells Calcification.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32585876
|abstract=The senescence of vascular smooth muscle cells (VSMCs), characterized by the acquisition of senescence-associated secretory phenotype (SASP), is relevant for VSMCs osteoblastic differentiation and vascular calcification (VC). MicroRNA-34a (miR-34a) is a driver of such phenomena and could play a role in vascular inflammaging. Herein, we analyzed the relationship between miR-34a and the prototypical SASP component [[IL6]] in in vitro and in vivo models. miR-34a and [[IL6]] levels increased and positively correlated in aortas of 21 months-old male C57BL/6J mice and in human aortic smooth muscle cells (HASMCs) isolated from donors of different age and undergone senescence. Lentiviral overexpression of miR-34a in HASMCs enhanced [[IL6]] secretion. HASMCs senescence and calcification accelerated after exposure to conditioned medium of miR-34a-overexpressing cells. Analysis of miR-34a-induced secretome revealed enhancement of several pro-inflammatory cytokines and chemokines, including [[IL6]], pro-senescent growth factors and matrix-degrading molecules. Moreover, induction of aortas medial calcification and concomitant [[IL6]] expression, with an overdose of vitamin D, was reduced in male C57BL/6J [i]Mir34a [/i] mice. Finally, a positive correlation was observed between circulating miR-34a and [[IL6]] in healthy subjects of 20-90 years. Hence, the vascular age-associated miR-34a promotes VSMCs SASP activation and contributes to arterial inflammation and dysfunctions such as VC.

|keywords=* IL6
* SASP
* VSMCs
* inflammaging
* senescence
* vascular calcification
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352675
}}
{{medline-entry
|title=Impact of Influenza on Pneumococcal Vaccine Effectiveness during [i]Streptococcus pneumoniae[/i] Infection in Aged Murine Lung.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32545261
|abstract=Changes in innate and adaptive immune responses caused by viral imprinting can have a significant direct or indirect influence on secondary infections and vaccine responses. The purpose of our current study was to investigate the role of immune imprinting by influenza on pneumococcal vaccine effectiveness during [i]Streptococcus pneumoniae[/i] infection in the aged murine lung. Aged adult (18 months) mice were vaccinated with the pneumococcal polyvalent vaccine Pneumovax (5 mg/mouse). Fourteen days post vaccination, mice were instilled with PBS or influenza A/PR8/34 virus (3.5 × 10  PFU). Control and influenza-infected mice were instilled with PBS or [i]S. pneumoniae[/i] (1 × 10  CFU, ATCC 6303) on day 7 of infection and antibacterial immune responses were assessed in the lung. Our results illustrate that, in response to a primary influenza infection, there was diminished bacterial clearance and heightened production of pro-inflammatory cytokines, such as [[IL6]] and IL1β. Vaccination with Pneumovax decreased pro-inflammatory cytokine production by modulating NFҡB expression; however, these responses were significantly diminished after influenza infection. Taken together, the data in our current study illustrate that immune imprinting by influenza diminishes pneumococcal vaccine efficacy and, thereby, may contribute to increased susceptibility of older persons to a secondary infection with [i]S. pneumoniae[/i].

|keywords=* Streptococcus pneumoniae
* aging
* influenza
* vaccine effectiveness
* viral immune imprinting
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349919
}}
{{medline-entry
|title=Patterns of multi-domain cognitive aging in participants of the Long Life Family Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32514870
|abstract=Maintaining good cognitive function at older age is important, but our knowledge of patterns and predictors of cognitive aging is still limited. We used Bayesian model-based clustering to group 5064 participants of the Long Life Family Study (ages 49-110 years) into clusters characterized by distinct trajectories of cognitive change in the domains of episodic memory, attention, processing speed, and verbal fluency. For each domain, we identified 4 or 5 large clusters with representative patterns of change ranging from rapid decline to exceptionally slow change. We annotated the clusters by their correlation with genetic and molecular biomarkers, non-genetic risk factors, medical history, and other markers of aging to discover correlates of cognitive changes and neuroprotection. The annotation analysis discovered both predictors of multi-domain cognitive change such as gait speed and predictors of domain-specific cognitive change such as [[IL6]] and NTproBNP that correlate only with change of processing speed or APOE genotypes that correlate only with change of processing speed and logical memory. These patterns also suggest that cognitive decline starts at young age and that maintaining good physical function correlates with slower cognitive decline. To better understand the agreement of cognitive changes across multiple domains, we summarized the results of the cluster analysis into a score of cognitive function change. This score showed that extreme patterns of change affecting multiple cognitive domains simultaneously are rare in this study and that specific signatures of biomarkers of inflammation and metabolic disease predict severity of cognitive changes. The substantial heterogeneity of change patterns within and between cognitive domains and the net of correlations between patterns of cognitive aging and other aging traits emphasizes the importance of measuring a wide range of cognitive functions and the need for studying cognitive aging in concert with other aging traits.

|keywords=* Aging
* Biomarker
* Cognition
* Neuropsychology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525612
}}
{{medline-entry
|title=Cholest-4,6-Dien-3-One Promote Epithelial-To-Mesenchymal Transition (EMT) in Biliary Tree Stem/Progenitor Cell Cultures In Vitro.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31731674
|abstract=Human biliary tree stem/progenitor cells (hBTSCs), reside in peribiliary glands, are mainly stimulated by primary sclerosing cholangitis (PSC) and cholangiocarcinoma. In these pathologies, hBTSCs displayed epithelial-to-mesenchymal transition (EMT), senescence characteristics, and impaired differentiation. Here, we investigated the effects of cholest-4,6-dien-3-one, an oxysterol involved in cholangiopathies, on hBTSCs biology. hBTSCs were isolated from donor organs, cultured in self-renewal control conditions, differentiated in mature cholangiocytes by specifically tailored medium, or exposed for 10 days to concentration of cholest-4,6-dien-3-one (0.14 mM). Viability, proliferation, senescence, [i]EMT[/i] genes expression, telomerase activity, interleukin 6 ([[IL6]]) secretion, differentiation capacity, and [i]HDAC6[/i] gene expression were analyzed. Although the effect of cholest-4,6-dien-3-one was not detected on hBTSCs viability, we found a significant increase in cell proliferation, senescence, and [[IL6]] secretion. Interestingly, cholest-4.6-dien-3-one impaired differentiation in mature cholangiocytes and, simultaneously, induced the EMT markers, significantly reduced the telomerase activity, and induced [i]HDAC6[/i] gene expression. Moreover, cholest-4,6-dien-3-one enhanced bone morphogenic protein 4 (Bmp-4) and sonic hedgehog (Shh) pathways in hBTSCs. The same pathways activated by human recombinant proteins induced the expression of EMT markers in hBTSCs. In conclusion, we demonstrated that chronic exposition of cholest-4,6-dien-3-one induced cell proliferation, EMT markers, and senescence in hBTSC, and also impaired the differentiation in mature cholangiocytes.
|mesh-terms=* Biliary Tract
* Cell Differentiation
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Cholestenones
* Epithelial-Mesenchymal Transition
* Histone Deacetylase 6
* Humans
* Interleukin-6
* Signal Transduction
* Stem Cells
* Tissue Donors
|keywords=* BMP pathway
* SHH pathway
* biliary tree stem/progenitor cells (BTSCs)
* epithelial-to-mesenchymal transition (EMT)
* primary sclerosing cholangitis (PSC)
* senescence
* telomerase
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912632
}}
{{medline-entry
|title=Single xenotransplant of rat brown adipose tissue prolonged the ovarian lifespan of aging mice by improving follicle survival.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31389140
|abstract=Prolonging the ovarian lifespan is attractive and challenging. An optimal clinical strategy must be safe, long-acting, simple, and economical. Allotransplantation of brown adipose tissue (BAT), which is most abundant and robust in infants, has been utilized to treat various mouse models of human disease. Could we use BAT to prolong the ovarian lifespan of aging mice? Could we try BAT xenotransplantation to alleviate the clinical need for allogeneic BAT due to the lack of voluntary infant donors? In the current study, we found that a single rat-to-mouse (RTM) BAT xenotransplantation did not cause systemic immune rejection but did significantly increase the fertility of mice and was effective for more than 5 months (equivalent to 10 years in humans). Next, we did a series of analysis including follicle counting; AMH level; estrous cycle; mTOR activity; GDF9, BMP15, LHR, Sirt1, and Cyp19a level; ROS and annexin V level; [[IL6]] and adiponectin level; biochemical blood indices; body temperature; transcriptome; and DNA methylation studies. From these, we proposed that rat BAT xenotransplantation rescued multiple indices indicative of follicle and oocyte quality; rat BAT also improved the metabolism and general health of the aging mice; and transcriptional and epigenetic (DNA methylation) improvement in F0 mice could benefit F1 mice; and multiple KEGG pathways and GO classified biological processes the differentially expressed genes (DEGs) or differentially methylated regions (DMRs) involved were identical between F0 and F1. This study could be a helpful reference for clinical BAT xenotransplantation from close human relatives to the woman.
|mesh-terms=* Adipose Tissue, Brown
* Animals
* Cellular Senescence
* Female
* Longevity
* Male
* Mice
* Ovarian Follicle
* Ovary
* Rats
* Rats, Sprague-Dawley
* Transplantation, Heterologous
|keywords=* aging
* brown adipose tissue (BAT)
* lifespan
* mice
* ovary
* rat
* xenotransplant
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826128
}}
==NHS==

{{medline-entry
|title=Telomerase Activation to Reverse Immunosenescence in Elderly Patients With Acute Coronary Syndrome: Protocol for a Randomized Pilot Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32965237
|abstract=Inflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation, acute coronary syndrome (ACS). Aging is associated with a decline of the immune system, a process known as immunosenescence. This is characterized by an increase in highly proinflammatory T cells that are involved in CHD progression, plaque destabilization, and myocardial ischemia-reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilation in microvasculature. The TACTIC (Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome) trial will investigate whether a telomerase activator, TA-65MD, can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD on decreasing telomere shortening, reducing oxidative stress, and improving endothelial function. The study was designed as a single-center, randomized, double-blind, parallel-group, placebo-controlled phase II trial. Recruitment started in January 2019. A total of 90 patients, aged 65 years or older, with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomized to one of two groups: TA-65MD oral therapy (8 mg twice daily) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA (T effector memory cells re-expressing CD45RA [CD45 expressing exon A]) cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP (N-terminal fragment of the prohormone brain-type natriuretic peptide), systemic inflammation, oxidative stress, and telomerase activity. The study received National Health Service ([[NHS]]) ethics approval on August 9, 2018; Medicines and Healthcare products Regulatory Agency approval on October 19, 2018; and [[NHS]] Health Research Authority approval on October 22, 2018. The trial began recruiting participants in January 2019 and completed recruitment in March 2020; the trial is due to report results in 2021. This pilot trial in older patients with CHD will explore outcomes not previously investigated outside in vitro or preclinical models. The robust design ensures that bias has been minimized. Should the results indicate reduced frequency of immunosenescent CD8+ T cells as well as improvements in telomere length and endothelial function, we will plan a larger, multicenter trial in patients to determine if TA-65MD is beneficial in the treatment of CHD in elderly patients. ISRCTN Registry ISRCTN16613292; http://www.isrctn.com/ISRCTN16613292 and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), European Union Clinical Trials Register 2017-002876-26; https://tinyurl.com/y4m2so8g. DERR1-10.2196/19456.

|keywords=* acute coronary syndrome
* coronary heart disease
* immunosenescence
* telomerase activator
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542409
}}
{{medline-entry
|title=Factors associated with COVID-19-related death using OpenSAFELY.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32640463
|abstract=Coronavirus disease 2019 (COVID-19) has rapidly affected mortality worldwide . There is unprecedented urgency to understand who is most at risk of severe outcomes, and this requires new approaches for the timely analysis of large datasets. Working on behalf of [[NHS]] England, we created OpenSAFELY-a secure health analytics platform that covers 40% of all patients in England and holds patient data within the existing data centre of a major vendor of primary care electronic health records. Here we used OpenSAFELY to examine factors associated with COVID-19-related death. Primary care records of 17,278,392 adults were pseudonymously linked to 10,926 COVID-19-related deaths. COVID-19-related death was associated with: being male (hazard ratio (HR) 1.59 (95% confidence interval 1.53-1.65)); greater age and deprivation (both with a strong gradient); diabetes; severe asthma; and various other medical conditions. Compared with people of white ethnicity, Black and South Asian people were at higher risk, even after adjustment for other factors (HR 1.48 (1.29-1.69) and 1.45 (1.32-1.58), respectively). We have quantified a range of clinical factors associated with COVID-19-related death in one of the largest cohort studies on this topic so far. More patient records are rapidly being added to OpenSAFELY, we will update and extend our results regularly.
|mesh-terms=* Adolescent
* Adult
* African Continental Ancestry Group
* Age Distribution
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Asian Continental Ancestry Group
* Asthma
* Betacoronavirus
* COVID-19
* Cohort Studies
* Coronavirus Infections
* Diabetes Mellitus
* Female
* Humans
* Hypertension
* Male
* Middle Aged
* Pandemics
* Pneumonia, Viral
* Proportional Hazards Models
* Risk Assessment
* SARS-CoV-2
* Sex Characteristics
* Smoking
* State Medicine
* Young Adult

|full-text-url=https://sci-hub.do/10.1038/s41586-020-2521-4
}}
{{medline-entry
|title=Advanced ophthalmic nurse practitioners: the potential to improve outcomes for older people with cataracts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32548985
|abstract=An ageing population has led to a substantial increase in the prevalence of visual impairments, which can compromise lifestyle, health and general physical and psychological well-being. Age-related cataracts can have a negative effect on older people's quality of life but can be corrected by surgery. It is imperative that older people have access to cataract surgery and, given government objectives of [[NHS]] efficiency gains, advanced level nurse practitioners have the potential to increase capacity for and access to cataract surgery. This article outlines the aetiology of cataracts, developments in ophthalmic nursing and the broadened scope of practice of advanced ophthalmic nurse practitioners (AONPs). It explores how the AONP is well-placed to provide high quality care to the older person who requires cataract surgery. Professional drivers for role development are explored in relation to older people.

|keywords=* advanced practice
* gerontology
* older people
* patient outcomes
* patients
* practice development
* professional
* professional issues
* quality of life
|full-text-url=https://sci-hub.do/10.7748/nop.2020.e1229
}}
{{medline-entry
|title=Patient Satisfaction in the Spanish National Health Service: Partial Least Squares Structural Equation Modeling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31817147
|abstract=The aim of this article was to determine which key indicators influence patient satisfaction with the Spanish [[NHS]] to provide useful information for policy decision-making. A total of 33 variables for each of the 17 Spanish autonomous communities were collected from the statistical portal of the Spanish Ministry of Health, Social Services, and Equality between 2005 and 2016. A cross-sectional study was applied using Partial Least Squares to a Structural Equation Model (PLS-SEM). The influence of expenditures, resource allocation, and safety were hypothesized about patient satisfaction. Gross Domestic Product (GDP) and life expectancy were used as control variables. Moreover, the influence of resource allocation on use was tested. The model explained 57.1% of patient satisfaction with the Spanish [[NHS]]. It was positively influenced mainly by resource allocation and expenditures, followed by safety and life expectancy. Additionally, resources directly influenced the level of use. The number of hospital beds, hemodialysis equipment, rate of adverse drug reactions, and expenditure positively influenced patient satisfaction. In contrast, the number of posts in day hospitals, the hospital infection rate, and the percentage of pharmacy spending negatively influenced patient satisfaction.
|mesh-terms=* Cross-Sectional Studies
* Gross Domestic Product
* Health Care Rationing
* Health Expenditures
* Humans
* Latent Class Analysis
* Least-Squares Analysis
* Life Expectancy
* Patient Safety
* Patient Satisfaction
* Spain
* State Medicine
|keywords=* National Health Service
* health policy
* partial least squares structural equation modeling (PLS-SEM)
* patient satisfaction
* quality of healthcare
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6950388
}}
{{medline-entry
|title=Heart failure with preserved ejection fraction (HFpEF) pathophysiology study (IDENTIFY-HF): does increased arterial stiffness associate with HFpEF, in addition to ageing and vascular effects of comorbidities? Rationale and design.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31748285
|abstract=There has been a paradigm shift proposing that comorbidities are a major contributor towards the heart failure with preserved ejection fraction (HFpEF) syndrome. Furthermore, HFpEF patients have abnormal macrovascular and microvascular function, which may significantly contribute towards altered ventricular-vascular coupling in these patients. The IDENTIFY-HF study will investigate whether gradually increased arterial stiffness (in addition to ageing) as a result of increasing common comorbidities, such as hypertension and diabetes, is associated with HFpEF. In our observational study, arterial compliance and microvascular function will be assessed in five groups (Groups A to E) of age, sex and body mass index matched subjects (age ≥70 years in all groups):Group A; normal healthy volunteers without major comorbidities such as hypertension and diabetes mellitus (control). Group B; patients with hypertension without diabetes mellitus or heart failure (HF). Group C; patients with hypertension and diabetes mellitus without HF. Group D; patients with HFpEF. Group E; patients with heart failure and reduced ejection fraction (parallel group). Vascular function and arterial compliance will be assessed using pulse wave velocity, as the primary outcome measure. Further outcome measures include cutaneous laser Doppler flowmetry as a measure of endothelial function, transthoracic echocardiography and exercise tolerance measures. Biomarkers include NT-proBNP, high-sensitivity troponin T, as well as serum galectin-3 as a marker of fibrosis. The study was approved by the regional research ethics committee (REC), West Midland and Black Country 17/WM/0039, UK, and permission to conduct the study in the hospital was also obtained from the RDI, UHCW [[NHS]] Trust. The results will be published in peer-reviewed journals and presented in local, national and international medical society meetings. NCT03186833.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Comorbidity
* Diabetes Mellitus
* Echocardiography
* Exercise Tolerance
* Female
* Heart Failure
* Heart Ventricles
* Humans
* Hypertension
* Male
* Observational Studies as Topic
* Prospective Studies
* Pulse Wave Analysis
* Research Design
* Stroke Volume
* Vascular Stiffness
|keywords=* arterial stiffness
* comorbidities
* heart failure with preserved ejection fraction
* pathophysiology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886989
}}
{{medline-entry
|title=Challenges to concordance: theories that explain variations in patient responses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31604052
|abstract=To meet the challenges of an increasingly ageing and multimorbid population, patients must be fully engaged to work in partnership with their health professional (HP) in the management of their condition(s). The [[NHS]] Long Term Plan (2019) outlines goals to manage the increasing demands on the health service-hospital admission avoidance, shorter length of hospital stays through enhanced recovery pathways, increased management of patients within primary care and ensuring a person-centred approach to care provision. Meeting these goals is predicated on HPs being equipped to activate patients using the skills of motivational interviewing, person-centred care and a willingness to share decision making. This article presents a range of psychological theories that could explain the everyday challenges faced in care delivery. Awareness of these theories may help HPs target their approach to care delivery more effectively, to understand patient responses and, therefore, optimise the provision of person-centred care.
|mesh-terms=* Aging
* Benchmarking
* Communication Barriers
* Community Health Nursing
* Humans
* Nurse-Patient Relations
* State Medicine
* United Kingdom
|keywords=* Concordance
* Decision making
* Person-centred care
* Psychological theories
* Self-management
|full-text-url=https://sci-hub.do/10.12968/bjcn.2019.24.10.466
}}
{{medline-entry
|title=Optimism is associated with exceptional longevity in 2 epidemiologic cohorts of men and women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31451635
|abstract=Most research on exceptional longevity has investigated biomedical factors associated with survival, but recent work suggests nonbiological factors are also important. Thus, we tested whether higher optimism was associated with longer life span and greater likelihood of exceptional longevity. Data are from 2 cohorts, women from the Nurses' Health Study ([[NHS]]) and men from the Veterans Affairs Normative Aging Study (NAS), with follow-up of 10 y (2004 to 2014) and 30 y (1986 to 2016), respectively. Optimism was assessed using the Life Orientation Test-Revised in [[NHS]] and the Revised Optimism-Pessimism Scale from the Minnesota Multiphasic Personality Inventory-2 in NAS. Exceptional longevity was defined as survival to age 85 or older. Primary analyses used accelerated failure time models to assess differences in life span associated with optimism; models adjusted for demographic confounders and health conditions, and subsequently considered the role of health behaviors. Further analyses used logistic regression to evaluate the likelihood of exceptional longevity. In both sexes, we found a dose-dependent association of higher optimism levels at baseline with increased longevity ([i]P[/i] trend < 0.01). For example, adjusting for demographics and health conditions, women in the highest versus lowest optimism quartile had 14.9% (95% confidence interval, 11.9 to 18.0) longer life span. Findings were similar in men. Participants with highest versus lowest optimism levels had 1.5 (women) and 1.7 (men) greater odds of surviving to age 85; these relationships were maintained after adjusting for health behaviors. Given work indicating optimism is modifiable, these findings suggest optimism may provide a valuable target to test for strategies to promote longevity.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Female
* Health Behavior
* Humans
* Logistic Models
* Longevity
* Longitudinal Studies
* Male
* Middle Aged
* Odds Ratio
|keywords=* aging
* longevity
* longitudinal study
* optimism
* psychological well-being
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744861
}}
==CAD==

{{medline-entry
|title=Serum soluble Klotho is inversely related to coronary artery calcification assessed by intravascular ultrasound in patients with stable coronary artery disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33303310
|abstract=Although the Klotho gene is recognized as an aging-suppressor gene, the clinical significance of its soluble product, soluble Klotho, in coronary artery disease ([[CAD]]) has not been completely determined. The relationship between soluble Klotho and coronary artery calcification (CAC) was investigated in patients with stable [[CAD]]. CAC in culprit lesions was analyzed in 75 non-dialysis patients with stable [[CAD]] who were scheduled for percutaneous coronary intervention (PCI) following intravascular ultrasound (IVUS). The main outcome measure was the calcium index (CalcIndex), a volumetric IVUS-derived measure of total calcification per culprit lesion. A low CalcIndex was defined as a first-quartile calcium index (<0.042). Patients were divided into two groups according to the median serum Klotho value: low Klotho (n = 37, ≤460 pg/mL) and high Klotho (n = 38, >460 pg/mL). The CalcIndex was significantly lower in patients with high than with low Klotho. Patients with high Klotho had a significantly higher prevalence of a low CalcIndex than those with low Klotho. The number of angiographic moderate-severe CACs in whole coronary arteries was significantly decreased in patients with high Klotho compared to low Klotho. Serum Klotho levels correlated significantly and inversely with the CalcIndex. This relationship was pronounced in patients with estimated glomerular filtration rate <60 mL/min/1.73 m . Logistic regression analysis showed that high Klotho was associated with a low CalcIndex independent of classical coronary risk factors and markers of mineral metabolism. High serum soluble Klotho levels are associated with a low degree of CAC in non-dialysis, stable [[CAD]] patients treated by PCI.

|keywords=* Aging
* Coronary artery calcification
* Intravascular ultrasound
* Klotho
|full-text-url=https://sci-hub.do/10.1016/j.jjcc.2020.11.014
}}
{{medline-entry
|title=Shear bond strengths of aged and non-aged [[CAD]]/CAM materials after different surface treatments.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33149848
|abstract=To assess shear bond strengths (SBS) of resin composites on aged and non-aged prosthetic materials with various surface treatments. Cerasmart (CE), Vita Enamic (VE), Vita Mark II (VM), and IPS e.max [[CAD]] (EC) blocks were sliced, and rectangular-shaped specimens (14 × 12 × 1.5 mm; N = 352) were obtained. Half of the specimens were aged (5000 thermal cycles) for each material. Non-aged and aged specimens were divided into 4 groups according to the surface treatments (control, air abrasion, etching, and laser irradiation; n = 11) and processed for scanning electron microscopy (SEM). The repair procedure was performed after the surface treatments. SBS values and failure types were determined. Obtained data were statistically analyzed ([i]P[/i]≤.05). The material type, surface treatment type, and their interactions were found significant with regard to SBS ([i]P[/i]<.001). Aging also had a significant effect on prosthetic material-resin composite bonding ([i]P[/i]<.001). SBS values of non-aged specimens ranged from 12.16 to 17.91 MPa, while SBS values of aged specimens ranged from 9.46 to 15.61 MPa. Non-aged VM in combination with acid etching presented the highest score while the control group of aged CE showed the lowest. Etching was more effective in achieving durable SBS for VM and EC. Laser irradiation could be considered as an alternative surface treatment method to air abrasion for all tested materials. Aging had significant effect on SBS values generated between tested materials and resin composite.

|keywords=* Bond strength
* Computer-aided design and computer-aided manufacturing (CAD/CAM)
* Laser
* Repair
* Surface treatment
* Thermal aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604239
}}
{{medline-entry
|title=Prediction of Early Postoperative Major Cardiac Events and In-Hospital Mortality in Elderly Hip Fracture Patients: The Role of Different Types of Preoperative Cardiac Abnormalities on Echocardiography Report.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32546993
|abstract=Transthoracic echocardiography (TTE) is a common cardiac screening test before hip fracture surgery. However, the general TTE test delays surgery, so it would be meaningful if we could simplify the TTE by only assessing cardiac abnormality specifically. Therefore, we aimed to establish the most clinically relevant abnormality by comparing the predictive value of each major cardiac abnormality in postoperative cardiac complications and mortality in elderly hip fracture patients. From January 2014 to January 2019, the medical records of all surgically treated elderly patients (>65 years) with hip fracture were analyzed. The major TTE abnormalities were defined as left ventricular hypertrophy, systolic pulmonary arterial pressure >25 mm Hg, moderate-severe valve abnormality, left ventricular ejection fraction (LVEF) <50%, and pericardial effusion. The outcomes were postoperative cardiac complications and in-hospital mortality. There were 354 patients involved finally. Postoperative cardiac complications were encountered in 7.6% (n=27) of patients. The mortality rate was 2.8% (n=10). History of coronary artery disease ([[CAD]]) (OR: 3.281, 95% CI: 1.332-8.079, p=0.010) and presence of aortic stenosis (AS) (OR:5.656, 95% CI: 1.869-17.117, p=0.002) were independent predictors of postoperative cardiac complications. In addition, age (OR: 1.264, 95% CI: 1.047-1.527, p=0.015), history of [[CAD]] (OR: 19.290, 95% CI: 2.002-185.885, p=0.010), presence of AS (OR:7.164, 95% CI: 1.988-51.413, p=0.040) and LVEF <50% (OR:8.803, 95% CI: 1.115-69.472, p=0.039) were independent predictors of mortality. However, the rest of preoperative TTE abnormalities were not associated with postoperative cardiac complications or mortality. Among the TTE abnormalities presented by elderly patients with hip fracture, moderate-severe AS was the predictor of postoperative cardiac complications. Moreover, moderate-severe AS and LVEF <50% were the predictors of in-hospital mortality. Therefore, we could simplify the TTE process by assessing aortic valve and LVEF specifically on focused echocardiography, which could avoid surgery delay.
|mesh-terms=* Aged
* Aortic Valve Stenosis
* Cardiovascular Diseases
* Comorbidity
* Echocardiography
* Female
* Fracture Fixation
* Hip Fractures
* Hospital Mortality
* Humans
* Male
* Postoperative Complications
* Prognosis
* Risk Factors
|keywords=* aging
* echocardiographic abnormality
* hip fracture surgery
* mortality
* postoperative cardiac complications
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266334
}}
{{medline-entry
|title=[Polymorbidity in elderly patients needing myocardial revascularization (a review article).]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31800187
|abstract=In the present review, the main attention is focused on the problem of polymorbidity and age-related conditions in elderly patients with [[CAD]] who need myocardial revascularization. In addition to a high risk of mortality, elderly patients with polymorbidity are characterized reduced functional activity, cognitive impairment, low quality of life and frequent seeking medical help. There is evidence of the presence of common mechanisms that affect the aging process and the development of a number of associated diseases associated with age. Accordingly, the study of polymorbidity will allow us to develop strategies for the prevention it and understand the aging process and significantly reduce the risks of surgical intervention. In this regard, there is a necessity for research aimed at studying the causal relationship between coronary artery disease and polymorbidity in elderly patients with an additional assessment of functional and cognitive status for the development of specific prognostic tools and treatment strategies.
|mesh-terms=* Aged
* Cognitive Dysfunction
* Coronary Artery Disease
* Humans
* Myocardial Revascularization
* Quality of Life
* Risk
|keywords=* aging
* elderly
* ischemic heart disease
* myocardial revascularization
* polymorbidity

}}
{{medline-entry
|title=Fracture force of [[CAD]]/CAM resin composite crowns after in vitro aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31712983
|abstract=The aim of this in vitro study was to investigate the influence of material, preparation, and pre-treatment on the aging and fracture force of [[CAD]]/CAM resin composite molar crowns. [[CAD]]/CAM molar crowns (n = 80) were milled from four resin composites (Block HC, Shofu; Lava Ultimate, 3 M; Grandio Blocs, Voco; and Tetric [[CAD]], Ivoclar Vivadent, with/without sandblasting). Extracted human teeth were prepared with optimal preparation (height 6-8 mm, angle 6-8°) or worst-case preparation (height 3.5-4 mm, angle 10-15°). Both groups were prepared with a 1-mm deep cervical circular shoulder. Crowns were adhesively bonded after corresponding tooth treatment required for the individual adhesive systems (Table 1). Specimens were aged for 90 days in water storage (37 °C) and subsequently subjected to thermal cycling and mechanical loading (TCML 3000 × 5 °C/3000 × 55 °C, 2 min each cycle, H20 distilled; 1.2 × 10  cycles à 50 N, 1.6 Hz). De-bonding and fracture force was determined. one-way-ANOVA; post hoc Bonferroni, α = 0.05. Four crowns of Lava Ultimate with worst-case preparation de-bonded during TCML. Individual crowns without sandblasting treatment (3x Tetric [[CAD]] with optimal preparation; 1x Tetric [[CAD]] with worst-case preparation) de-bonded during water storage. One crown of Grandio Blocs with optimal preparation showed a small chipping during TCML. All other crowns survived TCML and water storage without failure. Fracture forces differed between 1272 ± 211 N (Lava Ultimate) and 3061 ± 521 N (Tetric [[CAD]]). All Grandio Blocs and Tetric [[CAD]] crowns revealed significantly (p ≤ 0.023) higher fracture forces than Block HC or Lava Ultimate crowns. No significantly different (p > 0.05) fracture forces were found between optimal or worst-case preparation/fit groups. De-bonding during water storage and TCML was dependent on material and crown pre-treatment. Therefore, surface roughening seems strongly required. Fracture forces were not influenced by preparation but by the type of material. Clinical success and de-bonding of [[CAD]]/CAM resin composite crowns is strongly influenced by the type of material and its pre-treatment.
|mesh-terms=* Ceramics
* Composite Resins
* Computer-Aided Design
* Crowns
* Dental Porcelain
* Dental Restoration Failure
* Dental Stress Analysis
* Humans
* Materials Testing
|keywords=* Aging
* CAD/CAM
* CAD/CAM bloc
* Dental material
* Fit
* Preparation
* Resin composite
* Resin-based material
* Storage
* TCML
|full-text-url=https://sci-hub.do/10.1007/s00784-019-03099-1
}}
{{medline-entry
|title=Clinical performance of chairside monolithic lithium disilicate glass-ceramic [[CAD]]-CAM crowns.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31565848
|abstract=To evaluate the clinical performance and the effect of various patient and provider-related factors on the longevity of chairside monolithic posterior lithium disilicate glass-ceramic (LDGC) computer-aided design ([[CAD]])-computer-aided manufacturing (CAM) crowns provided by predoctoral students. A sample of posterior LDGC [[CAD]]-CAM crowns was evaluated. Crown preparations were milled chairside using the CEREC Omnicam system and cemented with Rely-X Unicem or Calibra Universal resin cements. Clinical assessment of the crowns and supporting periodontal structures was performed using the modified California Dental Association (CDA) criteria. Intraoral photographs as well as radiographs were taken for further assessment by two evaluators. Kaplan-Meier survival analysis was performed. A total of 40 crowns were inserted in 32 patients and evaluated for 4 years. Three complications were observed (two-technical and one-biological). No chipping or fracture of crowns was observed. No significant association was found between age, sex, periodontal condition, tooth type, tooth vitality, cement type, and longevity. The 4-year cumulative survival and success rates were 95.0 and 92.3%, respectively. Chairside LDGC [[CAD]]-CAM crowns exhibited a high survival rate after 4 years in function and were shown to be a viable and reliable treatment option for posterior teeth. The high survival rate of chairside [[CAD]]-CAM crowns observed in this study suggests the likelihood of predictable performance in the predoctoral setup.
|mesh-terms=* Ceramics
* Computer-Aided Design
* Crowns
* Dental Porcelain
* Dental Prosthesis Design
* Humans
* Materials Testing
|keywords=* CAD-CAM
* chairside
* dental crowns
* lithium disilicate
* longevity
* survival
|full-text-url=https://sci-hub.do/10.1111/jerd.12531
}}
{{medline-entry
|title=Acute resveratrol supplementation in coronary artery disease: towards patient stratification.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31429599
|abstract=[i]Objective:[/i] Resveratrol (RV) is a polyphenol with antioxidant, anti-inflammatory and cardio-protective properties. Our objective was to investigate whether acute supplementation with high doses of RV would improve flow-mediated dilation (FMD) and oxygen consumption (VO ) kinetics in older coronary artery disease ([[CAD]]) patients. [i]Design:[/i] We employed a placebo-controlled, single-blind, crossover design in which ten participants (aged 66.6 ± 7.8 years) received either RV or placebo (330 mg, 3× day ) during three consecutive days plus additional 330 mg in the morning of the fourth day with a seven-day wash-out period in-between. On the fourth day, FMD of the brachial artery and VO  on-kinetics were determined. [i]Results:[/i] RV improved FMD in patients who had undergone coronary artery bypass grafting (CABG; -1.4 [i]vs[/i]. 5.0%; [i]p =[/i] .004), but not in those who had undergone percutaneous coronary intervention (PCI; 4.2 [i]vs[/i]. -0.2%; NS). [i]Conclusion:[/i] Acute high dose supplementation with RV improved FMD in patients after CABG surgery but impaired FMD in patients who underwent PCI. The revascularization method-related differential effects of RV may be due to its direct effects on endothelial-dependent dilator responses. Our findings have important implications for personalized treatment and stratification of older [[CAD]] patients.
|mesh-terms=* Aged
* Biomarkers
* Brachial Artery
* Cardiac Rehabilitation
* Coronary Artery Bypass
* Coronary Artery Disease
* Cross-Over Studies
* Exercise Therapy
* Female
* Humans
* Kinetics
* Male
* Middle Aged
* Oxygen
* Oxygen Consumption
* Percutaneous Coronary Intervention
* Resveratrol
* Single-Blind Method
* Treatment Outcome
* Vasodilation
|keywords=* Antioxidant
* aging
* endothelial dysfunction
* oxygen uptake
|full-text-url=https://sci-hub.do/10.1080/14017431.2019.1657584
}}
==SI==

{{medline-entry
|title=Microarray Profiling Reveals Distinct Circulating miRNAs in Aged Male and Female Mice Subjected to Post-stroke Social Isolation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33074466
|abstract=Social isolation ([[SI]]) increases ischemic injury and significantly delays recovery after experimental stroke. Changes in circulating microRNAs (miRNAs) have been implicated in several neurological disorders, including stroke. However, potential biomarkers to elucidate the mechanisms that underlie the detrimental effects of post-stroke isolation are unknown. Aged C57BL/6 male and female mice (18-20 months) were subjected to a 60-min middle cerebral artery occlusion followed by reperfusion and were assigned to either isolation ([[SI]]) or continued pair housing (PH) immediately after stroke. On day 15, mice were sacrificed, and plasma samples were collected for miRNAome analysis. Top candidate miRNAs and their biological functions were identified using integrated bioinformatics. The miRNAome analysis revealed a total of 21 differentially expressed miRNAs across both sexes with fold change of 3 or higher. Within the female cohort, miR-206-3p, -376a-3p, -34b-5p, -133a-5p, -466f, and -671-3p were highly altered relative to the PH housing condition. Similarly in males, miR-376c-3p, -181d-5p, -712-5p, -186-5p, -21a-3p, -30d-3p, -495-3p, -669c-5p, -335-5p, -429-3p, -31-3p, and -217-5p were identified. Following Kyoto Encyclopedia of Genes and Genomes analysis, the identified miRNAs effected distinct subset of pathways within sexes. Interactional network analysis revealed miR-495-3p (male) and miR-34b-5p (female) as pivotal nodes that targeted the largest subset of genes. We identified several sex-specific miRNAs as candidate biomarkers for post-stroke [[SI]] in aged male and female mice. Additionally, these results suggest that there is potential to use plasma-based circulating miRNAs as a source of novel biomarkers to identify biological pathways involved in post-stroke [[SI]].

|keywords=* Aging
* Biomarkers
* Sex differences
* Social isolation
* Stroke
* miRNAs
|full-text-url=https://sci-hub.do/10.1007/s12017-020-08622-2
}}
{{medline-entry
|title=Is Heart Rate a Confounding Factor for Photoplethysmography Markers? A Systematic Review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32290168
|abstract=Finger photoplethysmography (PPG) waveform is blood volume change of finger microcirculation that reflects vascular function. Reflection index (RI), stiffness index ([[SI]]) and second derivative of photoplethysmogram (SDPPG) are derived from PPG waveforms proposed as cardiovascular disease (CVD) markers. Heart rate (HR) is a known factor that affects vascular function. Individual resting HR variation may affect RI, [[SI]] and SDPPG. This review aims to identify studies about the relationship between HR with RI, [[SI]] and SDPPG among humans. A literature search was conducted in Medline via the Ebscohost and Scopus databases to find relevant articles published within 11 years. The main inclusion criteria were articles in the English language that discuss the relationship between HR with RI, [[SI]] and SDPPG using PPG among humans. The search found 1960 relevant articles but only six articles that met the inclusion criteria. [[SI]] and RI showed an association with HR. SDPPG (SDPPG-b/SDPPG-a ratio, SDPPG-d/SDPPG-a ratio, aging index (AGI) and revised aging index (RAGI)) also had an association with HR. Only RI had a considerable association with HR, the association between [[SI]] and HR was non-considerable and the association between HR and SDPPG was inconclusive. Further interventional studies should be conducted to investigate this issue, as a variation in resting HR may challenge the validity of PPG-based CVD markers.
|mesh-terms=* Aging
* Cardiovascular Diseases
* Diabetes Mellitus, Type 2
* Female
* Fingers
* Heart Rate
* Humans
* Male
* Microcirculation
* Photoplethysmography
* Vascular Stiffness
|keywords=* cardiovascular disease
* heart rate
* photoplethysmography
* reflection index
* second derivative of photoplethysmography
* stiffness index
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177218
}}
{{medline-entry
|title=Survival time after marked reduction in oral intake in terminally ill noncancer patients: A retrospective study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32161695
|abstract=The prediction of short-term survival is important for noncancer patients and their families. Although a markedly reduced oral intake by cancer patients suggests a poor prognosis, the survival times of noncancer patients after its onset remain unclear. We herein investigated the time from a marked reduction in oral intake to death in noncancer patients as well as factors associated with their subsequent survival. We conducted a retrospective medical record review of noncancer patients who died in our hospital between April 2017 and April 2018. We recorded the day when oral intake markedly decreased and the date of death. We extracted data on age, gender, the Charlson Comorbidities Index, mean daily fluid volume, laboratory test results, and vital signs converted to the Shock Index ([[SI]]). We used Cox's proportional hazards models to assess relationships between these factors and survival times after the onset of a markedly reduced oral intake. We analyzed data from 44 noncancer patients. The median time from the onset of a markedly reduced oral intake to death was 16.5 days. Based on Cox's proportional hazards models, only [[SI]] ≧ 1.0 at the onset of a markedly reduced oral intake correlated with survival times (hazard ratio: 5.89, 95% confidence interval (CI): 1.71-20.1, [i]P[/i] = .005). Noncancer patients died a median of 16.5 days after the onset of a markedly reduced oral intake, and [[SI]] ≧1.0 correlated with subsequent survival times. These results will provide novel insights into the prognosis of noncancer patients at the end of life.

|keywords=* elderly
* geriatrics
* palliative medicine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060293
}}
{{medline-entry
|title=Adherence to Mediterranean diet moderates the association between multimorbidity and depressive symptoms in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32109694
|abstract=Adherence to Mediterranean Diet (Med-Diet) has been associated with a lower incidence of chronic diseases and may be associated with lower risk for depression. The aim of the present study was to investigate (i) the association of adherence to Med-Diet with depressive symptoms and multimorbidity in a cohort of geriatric medical outpatients, and (ii) the role of Med-Diet in mediating the association between depressive symptoms and multimorbidity. A total of 143 geriatric patients (mean age: 73.1 ± 8.35) were included. Adherence to Med-Diet was evaluated using a validated 14-item questionnaire; depressive and cognitive symptoms were assessed through the 15-item Geriatric Depression Scale (GDS) and Mini Mental State Examination (MMSE) respectively; multimorbidity was evaluated using the Cumulative Illness Rating Scale for Geriatrics (CIRSG-[[SI]]). Significant associations were found between MDQ score, GDS and CIRSG-[[SI]] (MDQ score and GDS: r= -0.206, p = 0.014; MDQ score and CIRSG-[[SI]]: r= -0.247, p = 0.003; GDS and CIRSG-[[SI]]: r = 0.251; p = 0.003). These associations remained significant after adjusting for potential confounding factors. A mediational model analysis showed that the direct effect of CIRSG-[[SI]] on GDS was significant (b = 1.330; se = 0.59; p = 0.028) with this effect being counterbalanced by higher MDQ scores (indirect effect of CIRS-G on GDS through MDQ: b = 0.382; se = 0.19; p = 0.048). These findings (i) add to the accumulating evidence that Med-Diet may have a positive impact on mental health in the elderly, and (ii) suggest that Med-Diet may contribute, at least in part, to protect geriatric patients with multimorbidity from the development of depressive symptoms, ultimately promoting healthy aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Cohort Studies
* Depression
* Diet, Mediterranean
* Healthy Aging
* Humans
* Multimorbidity
* Surveys and Questionnaires
|keywords=* Aging
* Depressive symptoms
* Mediterranean diet
* Mental health
* Multimorbidity
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104022
}}
{{medline-entry
|title=Loneliness, Social Isolation, and Objectively Measured Physical Activity in Rural-Living Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31860831
|abstract=This cross-sectional, observational study examined whether objectively measured physical activity (PA) and specific activities are associated with loneliness and social isolation ([[SI]]) in rural-living older adults. A total of 112 participants (Mage = 72.8 [SD = 6.6], 51.8% female) from 23 villages in Wiltshire, United Kingdom, completed questionnaires, 7-day accelerometry, and activity diaries. Regression analysis was used to test associations between objectively measured light PA, moderate to vigorous PA, and total PA; loneliness; and [[SI]] from family, neighbors, or friends and to explore these associations using specific activities. Daily mean light, moderate to vigorous, and total PA were not associated with loneliness or [[SI]]. Volunteering, accompanying others, and sports/exercise were associated with lower [[SI]] from neighbors (odds ratio = 0.23, 95% CI [0.06, 0.91]), family (odds ratio = 0.39, 95% CI [0.22, 0.68]), and friends (odds ratio = 0.56, 95% CI [0.33, 0.97]), respectively. There were no associations between loneliness, [[SI]], and objectively measured PA. The contribution of PA to loneliness and [[SI]] needs to be further investigated with larger and diverse samples of rural-living older adults.

|keywords=* accelerometry
* aging
* health
* social well-being
* volunteering
|full-text-url=https://sci-hub.do/10.1123/japa.2019-0027
}}
{{medline-entry
|title=The associations between social support and negative social interaction with suicidal ideation in US Chinese older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31650846
|abstract=To examine associations between social support and negative social interaction with past suicidal ideation ([[SI]]) at multiple time intervals. The study used cross-sectional data collected from 3157 US Chinese older adults in Chicago to assess past 2-week, 1-month, 1-year, and lifetime [[SI]]. Self-perceived social support and negative social interaction were measured. Multiple logistic regression analyses were used to examine the associations. People perceived more social support and less negative social interaction were 17-19% less likely to have [[SI]]. People perceived more social support were 14-20% less likely to have [[SI]]. Meanwhile, people perceived more negative social interaction were 28-37% more likely to have [[SI]]. The independent associations between different social interaction and [[SI]] are significant regardless of the time intervals. Research should pay attention not only to bolstering perceptions of social support, but also to strategies that help individuals cope with the influence of negative social interactions.

|keywords=* Chinese American
* Social support
* aging
* negative social interaction
* suicidal ideation
|full-text-url=https://sci-hub.do/10.1080/13607863.2019.1680953
}}
{{medline-entry
|title=Cell Senescence and Cerebral Small Vessel Disease in the Brains of People Aged 80 Years and Older.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31553444
|abstract=Cerebral small vessel disease (cSVD) in penetrating arteries is a major cause of age-related morbidity. Cellular senescence is a molecular process targeted by novel senolytic drugs. We quantified senescence in penetrating arteries and tested whether myocyte senescence was associated with cSVD. We immunolabeled subcortical white matter of older persons (age 80-96 years, n = 60) with minimal AD, using antibodies to 2 established senescence markers (H3K9me3, γH2AX) and a myocyte marker (hSMM). Within the walls of penetrating arteries (20-300 µm), we quantified senescence-associated heterochromatic foci (SAHF)-positive nuclei, cell density (nuclei/µm2), and sclerotic index ([[SI]]). Senescent-appearing mural cells were present in small arteries of all cases. cSVD cases exhibited a lower proportion of senescent-appearing cells and lower area fraction (AF%) of SAHF-positive nuclei compared to controls (p = 0.014, 0.016, respectively). cSVD severity and [[SI]] both correlated negatively with AF% (p = 0.013, 0.002, respectively). Mural cell density was lower (p < 0.001) and [[SI]] higher (p < 0.001) in cSVD, relative to controls. In conclusion, senescent myocyte-like cells were universal in penetrating arteries of an AD-free cohort aged 80 years and older. Senescent-appearing nuclei were more common in persons aged 80 years and older without cSVD compared to cSVD cases, indicating caution in senolytic drug prescribing. Myocyte senescence and cSVD may represent alternative vessel fates in the aging human brain.
|mesh-terms=* Aged, 80 and over
* Aging
* Brain
* Cellular Senescence
* Cerebral Arteries
* Cerebral Small Vessel Diseases
* Female
* Humans
* Male
* White Matter
|keywords=* Brain aging
* Cerebrovascular disease
* Senescence
* Small vessel disease
|full-text-url=https://sci-hub.do/10.1093/jnen/nlz088
}}
==TF==

{{medline-entry
|title=A preliminary investigation of the contribution of different tenderness factors to beef loin, tri-tip and heel tenderness.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32736289
|abstract=The objective of this study was to identify the relative contribution of tenderness factors for three beef muscles with similar tenderness ratings. Longissimus lumborum (LL), tensor fascia latae ([[TF]]) and gastrocnemius (GC) were collected from 10 USDA low Choice beef carcasses and assigned to a 5 or 21 days aging period (n = 60). Sarcomere length, troponin-T degradation, collagen content, mature collagen crosslink density, intramuscular lipid content and trained panel analysis were measured. Correlation and multivariate regression analysis indicated each muscle has a specific tenderness factor that contributed to the overall tenderness evaluated by trained panelists. The equations indicated LL tenderness was driven by lipid content (P < .05); [[TF]] tenderness was driven by collagen content (P < .05). GC tenderness was driven by proteolysis (P < .01), and only collagen content can be casually used as an overall tenderness predictor for all three cuts.

|keywords=* Aging
* Beef
* Collagen
* Tenderness
* Trained panel
|full-text-url=https://sci-hub.do/10.1016/j.meatsci.2020.108247
}}
{{medline-entry
|title=The transcription factor ZmNAC126 accelerates leaf senescence downstream of the ethylene signalling pathway in maize.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32430911
|abstract=Leaf senescence is an integral part of plant development, during which, nutrients are remobilized from senescent leaves to fast-growing organs. The initiation and progression dynamics of leaf senescence is therefore vital not only to the maximal accumulation of assimilates but also to the efficient remobilization of nutrients. Senescence is a finely tuned process that involves the action of a large number of transcription factors ([[TF]]s). The NAC [[TF]]s play critical roles in regulating leaf senescence in Arabidopsis, wheat, rice and tomato. Here, we identified a NAC [[TF]], ZmNAC126 that is responsive to leaf senescence in maize. Ectopic overexpression of ZmNAC126 in Arabidopsis and maize enhanced chlorophyll degradation and promoted leaf senescence. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed that ZmNAC126 could directly bind to the promoters of major chlorophyll catabolic genes in maize. Dual-luciferase assay in maize protoplasts indicated that ZmNAC126 positively regulates these chlorophyll catabolic genes in maize. Moreover, ZmNAC126 could be induced by ethylene, and ZmEIN3, a major [[TF]] of ethylene signalling, could bind to its promoter to transactivate its expression. Taken together, ZmNAC126 may play a pivotal role in regulating natural and ethylene-triggered leaf senescence in maize.

|keywords=* ZmNAC
* chlorophyll catabolic genes
* ethylene
* leaf senescence
* maize
|full-text-url=https://sci-hub.do/10.1111/pce.13803
}}
{{medline-entry
|title=Extensive transcriptome changes during seasonal leaf senescence in field-grown black cottonwood (Populus trichocarpa Nisqually-1).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32313054
|abstract=To better understand the molecular control of leaf senescence, we examined transcriptome changes during seasonal leaf senescence in Populus trichocarpa Nisqually-1, the Populus reference genome, growing in its natural habitat. Using monthly (from May to October) transcriptomes for three years (2009, 2015, and 2016), we identified 17,974 differentially expressed genes (DEGs; false discovery rate <0.05; log-fold change cutoff = 0) from 36,007 expressed Populus gene models. A total of 14,415 DEGs were directly related to transitions between four major developmental phases - growth, senescence initiation, reorganization, and senescence termination. These DEGs were significantly (p < 0.05) enriched in 279 gene ontology (GO) terms, including those related to photosynthesis, metabolic process, catalytic activity, protein phosphorylation, kinase activity, pollination, and transport. Also, there were 881 differentially expressed transcription factor ([[TF]]) genes from 54 [[TF]] families, notably bHLH, MYB, ERF, MYB-related, NAC, and WRKY. We also examined 28 DEGs known as alternative splicing (AS) factors that regulate AS process, and found evidence for a reduced level of AS activity during leaf senescence. Furthermore, we were able to identify a number of promoter sequence motifs associated with leaf senescence. This work provides a comprehensive resource for identification of genes involved in seasonal leaf senescence in trees, and informs efforts to explore the conservation and divergence of molecular mechanisms underlying leaf senescence between annual and perennial species.
|mesh-terms=* Aging
* Gene Expression Profiling
* Gene Expression Regulation, Plant
* Genome, Plant
* Photosynthesis
* Plant Leaves
* Populus
* Seasons
* Transcription Factors
* Transcriptome

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170949
}}
{{medline-entry
|title=Expression of Transferrin and Albumin in the Sperm-Storage Tubules of Japanese Quail and their Possible Involvement in Long-Term Sperm Storage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32174770
|abstract=Because of the presence of sperm storage tubules (SSTs) in the utero-vaginal junction (UVJ) in the oviduct, once ejaculated sperm enter the female reproductive tract, they can survive for a prolonged period in domestic birds; however, the specific mechanisms involved in sperm maintenance within the SST remain to be elucidated. In this study, we showed that transferrin ([[TF]]) and albumin (ALB) are expressed in SSTs. When UVJ extracts were subjected to size-exclusion column chromatography, we obtained fractions that extend sperm longevity [i]in vitro[/i]. LC-MS/MS analysis of the two major proteins in the fractions identified these proteins as [[TF]] and ALB. Immunohistochemical analysis using specific antisera against [[TF]] and ALB indicated that both proteins were localized not only in the SSTs, but also in the surface epithelium of the UVJ. When the ejaculated sperm were incubated with either purified [[TF]] or ALB, sperm viability increased after 24 h. These results indicated that oviductal [[TF]] and ALB are involved in the process of sperm storage in SSTs and may open a new approach for technological improvement to prolong sperm longevity [i]in vitro[/i].

|keywords=* Japanese quail
* albumin
* sperm longevity
* sperm storage tubules
* transferrin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063080
}}
{{medline-entry
|title=OsWRKY5 Promotes Rice Leaf Senescence via Senescence-Associated NAC and Abscisic Acid Biosynthesis Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31505875
|abstract=he onset of leaf senescence is triggered by external cues and internal factors such as phytohormones and signaling pathways involving transcription factors ([[TF]]s). Abscisic acid (ABA) strongly induces senescence and endogenous ABA levels are finely tuned by many senescence-associated [[TF]]s. Here, we report on the regulatory function of the senescence-induced [[TF]] OsWRKY5 [[TF]] in rice ([i]Oryza[/i] [i]sativa[/i]). [i]OsWRKY5[/i] expression was rapidly upregulated in senescing leaves, especially in yellowing sectors initiated by aging or dark treatment. A T-DNA insertion activation-tagged [i]OsWRKY5[/i]-overexpressing mutant (termed [i]oswrky5-D[/i]) promoted leaf senescence under natural and dark-induced senescence (DIS) conditions. By contrast, a T-DNA insertion [i]oswrky5[/i]-knockdown mutant (termed [i]oswrky5[/i]) retained leaf greenness during DIS. Reverse-transcription quantitative PCR (RT-qPCR) showed that [i]OsWRKY5[/i] upregulates the expression of genes controlling chlorophyll degradation and leaf senescence. Furthermore, RT-qPCR and yeast one-hybrid analysis demonstrated that OsWRKY5 indirectly upregulates the expression of senescence-associated [i]NAM/ATAF1/2/CUC2[/i] ([i]NAC[/i]) genes including [i]OsNAP[/i] and [i]OsNAC2[/i]. Precocious leaf yellowing in the [i]oswrky5-D[/i] mutant might be caused by elevated endogenous ABA concentrations resulting from upregulated expression of ABA biosynthesis genes [i]OsNCED3[/i], [i]OsNCED4[/i], and [i]OsNCED5[/i], indicating that OsWRKY is a positive regulator of ABA biosynthesis during leaf senescence. Furthermore, [i]OsWRKY5[/i] expression was suppressed by ABA treatment. Taken together, [i]OsWRKY5[/i] is a positive regulator of leaf senescence that upregulates senescence-induced [i]NAC[/i], ABA biosynthesis, and chlorophyll degradation genes.
|mesh-terms=* Abscisic Acid
* Chlorophyll
* Gene Expression Regulation, Plant
* Gene Knockdown Techniques
* Oryza
* Plant Leaves
* Plant Proteins
* Transcription Factors
|keywords=* NAC
* OsWRKY
* abscisic acid (ABA)
* leaf senescence
* rice
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770167
}}
{{medline-entry
|title=BrTCP7 Transcription Factor Is Associated with MeJA-Promoted Leaf Senescence by Activating the Expression of [i]BrOPR3[/i] and [i]BrRCCR[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31416297
|abstract=The plant hormone jasmonic acid (JA) has been recognized as an important promoter of leaf senescence in plants. However, upstream transcription factors ([[TF]]s) that control JA biosynthesis during JA-promoted leaf senescence remain unknown. In this study, we report the possible involvement of a TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) [[TF]] BrTCP7 in methyl jasmonate (MeJA)-promoted leaf senescence in Chinese flowering cabbage. Exogenous MeJA treatment reduced maximum quantum yield (Fv/Fm) and total chlorophyll content, accompanied by the increased expression of senescence marker and chlorophyll catabolic genes, and accelerated leaf senescence. To further understand the transcriptional regulation of MeJA-promoted leaf senescence, a class I member of TCP [[TF]]s BrTCP7 was examined. BrTCP7 is a nuclear protein and possesses trans-activation ability through subcellular localization and transcriptional activity assays. A higher level of [i]BrTCP7[/i] transcript was detected in senescing leaves, and its expression was up-regulated by MeJA. The electrophoretic mobility shift assay and transient expression assay showed that BrTCP7 binds to the promoter regions of a JA biosynthetic gene [i]BrOPR3[/i] encoding OPDA reductase3 (OPR3) and a chlorophyll catabolic gene [i]BrRCCR[/i] encoding red chlorophyll catabolite reductase (RCCR), activating their transcriptions. Taken together, these findings reveal that BrTCP7 is associated with MeJA-promoted leaf senescence at least partly by activating JA biosynthesis and chlorophyll catabolism, thus expanding our knowledge of the transcriptional mechanism of JA-mediated leaf senescence.
|mesh-terms=* Amino Acid Sequence
* Brassica
* Cellular Senescence
* Cyclopentanes
* Gene Expression Regulation, Plant
* Oxylipins
* Phenotype
* Phylogeny
* Plant Growth Regulators
* Plant Leaves
* Plant Proteins
* Promoter Regions, Genetic
* Protein Binding
* Transcription Factors
|keywords=* Chinese flowering cabbage
* JA
* leaf senescence
* transcriptional activation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719003
}}
{{medline-entry
|title=Activation of the Transcription of [i]BrGA20ox3[/i] by a BrTCP21 Transcription Factor Is Associated with Gibberellin-Delayed Leaf Senescence in Chinese Flowering Cabbage during Storage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31398806
|abstract=Several lines of evidence have implicated the involvement of the phytohormone gibberellin (GA) in modulating leaf senescence in plants. However, upstream transcription factors ([[TF]]s) that regulate GA biosynthesis in association with GA-mediated leaf senescence remain elusive. In the current study, we report the possible involvement of a TEOSINTE BRANCHED1/CYCLOIDEA/PCF (TCP) [[TF]] BrTCP21 in GA-delayed leaf senescence in Chinese flowering cabbage. Exogenous GA  treatment maintained a higher value of maximum PSII quantum yield (Fv/Fm) and total chlorophyll content, accompanied by the repression of the expression of senescence-associated genes and chlorophyll catabolic genes, which led to the delay of leaf senescence. A class I member of TCP [[TF]]s BrTCP21, was further isolated and characterized. The transcript level of [i]BrTCP21[/i] was low in senescing leaves, and decreased following leaf senescence, while GA  could keep a higher expression level of [i]BrTCP21[/i]. BrTCP21 was further found to be a nuclear protein and exhibit trans-activation ability through transient-expression analysis in tobacco leaves. Intriguingly, the electrophoretic mobility shift assay (EMSA) and transient expression assay illustrated that BrTCP21 bound to the promoter region of a GA biosynthetic gene [i]BrGA20ox3[/i], and activated its transcription. Collectively, these observations reveal that BrTCP21 is associated with GA-delayed leaf senescence, at least partly through the activation of the GA biosynthetic pathway. These findings expand our knowledge on the transcriptional mechanism of GA-mediated leaf senescence.
|mesh-terms=* Aging
* Base Sequence
* Brassica
* Food Preservation
* Gene Expression Regulation, Plant
* Gibberellins
* Phenotype
* Phylogeny
* Plant Leaves
* Plant Proteins
* Promoter Regions, Genetic
* Protein Binding
* Transcription Factors
|keywords=* Chinese flowering cabbage
* GA
* leaf senescence
* transcriptional activation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720506
}}
==GDF11==

{{medline-entry
|title=Growth differentiation factor-11 supplementation improves survival and promotes recovery after ischemic stroke in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32365331
|abstract=Growth differentiation factor (GDF) 11 levels decline with aging. The age-related loss of GDF 11 has been implicated in the pathogenesis of a variety of age-related diseases. [[GDF11]] supplementation reversed cardiac hypertrophy, bone loss, and pulmonary dysfunction in old mice, suggesting that [[GDF11]] has a rejuvenating effect. Less is known about the potential of [[GDF11]] to improve recovery after an acute injury, such as stroke, in aged mice. [[GDF11]]/8 levels were assessed in young and aged male mice and in postmortem human brain samples. Aged mice were subjected to a transient middle cerebral artery occlusion (MCAo). Five days after MCAo, mice received and bromodeoxyuridine / 5-Bromo-2'-deoxyuridine (BrdU) and either recombinant [[GDF11]] or vehicle for five days and were assessed for recovery for one month following stroke. MRI was used to determine cerebrospinal fluid (CSF) volume, corpus callosum (CC) area, and brain atrophy at 30 days post-stroke. Immunohistochemistry was used to assess gliosis, neurogenesis, angiogenesis and synaptic density. Lower [[GDF11]]/8 levels were found with age in both mice and humans (p<0.05). [[GDF11]] supplementation reduced mortality and improved sensorimotor deficits after stroke. Treatment also reduced brain atrophy and gliosis, increased angiogenesis, improved white matter integrity, and reduced inflammation after stroke. [[GDF11]] may have a role in brain repair after ischemic injury.

|keywords=* GDF11
* White matter integrity
* aging
* gliosis
* stroke
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244081
}}
{{medline-entry
|title=Anti-Aging Effects of [[GDF11]] on Skin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32283613
|abstract=Human skin is composed of three layers: the epidermis, the dermis, and the hypodermis. The epidermis has four major cell layers made up of keratinocytes in varying stages of progressive differentiation. Skin aging is a multi-factorial process that affects every phase of its biology and function. The expression profiles of inflammation-related genes analyzed in resident immune cells demonstrated that these cells have a strong ability to regenerate adult skin stem cells and to produce endogenous substances such as growth differentiation factor 11 ([[GDF11]]). [[GDF11]] appears to be the key to progenitor proliferation and/or differentiation. The preservation of youthful phenotypes has been tied to the presence of [[GDF11]] in different human tissues, and, in the skin, this factor inhibits inflammatory responses. The protective role of [[GDF11]] depends on a multi-factorial process implicating various types of skin cells such as keratinocytes, fibroblasts and inflammatory cells. [[GDF11]] should be further studied for the purpose of developing novel therapies for the treatment of skin diseases.

|keywords=* disease
* growth factors
* regeneration
* skin aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177281
}}
{{medline-entry
|title=Targeted Approach to Distinguish and Determine Absolute Levels of GDF8 and [[GDF11]] in Mouse Serum.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32104967
|abstract=Growth differentiation factor 11 ([[GDF11]]) is a TGF-β superfamily circulating factor that regulates cardiomyocyte size in rodents, sharing 90% amino acid sequence identity in the active domains with myostatin (GDF8)-the major determinant of skeletal muscle mass. Conflicting data on age-related changes in circulating levels have been reported mainly due to the lack of specific detection methods. More recently, liquid chromatography tandem mass spectrometry (LC-MS/MS) based assay showed that the circulating levels of [[GDF11]] do not change significantly throughout human lifespan, but GDF8 levels decrease with aging in men. Here a novel detection method is demonstrated based on parallel reaction monitoring LC-MS/MS assay combined with immunoprecipitation to reliably distinguish [[GDF11]] and GDF8 as well as determine their endogenous levels in mouse serum. The data indicate that both [[GDF11]] and GDF8 circulating levels significantly decline with aging in female mice.

|keywords=* GDF11
* aging
* immunoprecipitation
* myostatin/GDF8
* serum
* targeted-quantitative proteomics
|full-text-url=https://sci-hub.do/10.1002/pmic.201900104
}}
{{medline-entry
|title=Growth differentiation factor 11 impairs titanium implant healing in the femur and leads to mandibular bone loss.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31983062
|abstract=Growth differentiation factor 11 ([[GDF11]]), a secreted member of the transforming growth factor-β superfamily, has recently been suggested as an anti-aging factor that declines with age in the bloodstream, and restoration of the youthful level by administration of its recombinant protein could reverse age-related dysfunctions. However, its effects on titanium implant osseointegration and mandibular bone during aging remain unknown. Two-month-old and 18-month-old C57BL male mice were given daily intraperitoneal injections of recombinant [[GDF11]] (r[[GDF11]]) or vehicle for 6 weeks. Experimental titanium implants were inserted into femurs on the fourth week. Inhibition of [[GDF11]] function was achieved by [[GDF11]] antibody. Implant-bearing femurs were subjected to histomorphometric analysis and biomechanical evaluation. Mandibles were scanned with micro-CT and decalcified for histological measurements. In both young adult and aged mice, supraphysiologic [[GDF11]] leads to a significantly decreased bone-to-implant contact ratio (BIC) and peri-implant bone volume/total volume (BV/TV) at the histologic level and reduced resistance at the biomechanical level, indicating weakened implant fixation. Moreover, r[[GDF11]] administration resulted in less trabecular bone volume and thinner cortical thickness in the mandible, which was further compromised in the old animals. In contrast, inhibition of [[GDF11]] improved peri-implant bone healing in old mice. Rather than functioning as a rejuvenating factor, exogenous [[GDF11]] negatively affects not only titanium implant healing but also mandibular bone in both young and old mice. In contrast, neutralization of endogenous [[GDF11]] has positive effects on implant fixation in aged mice.

|keywords=* aging
* alveolar bone loss
* dental implants
* osseointegration
* transforming growth factors
|full-text-url=https://sci-hub.do/10.1002/JPER.19-0247
}}
{{medline-entry
|title=Systemic [[GDF11]] stimulates the secretion of adiponectin and induces a calorie restriction-like phenotype in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31637864
|abstract=Aging is a negative regulator of general homeostasis, tissue function, and regeneration. Changes in organismal energy levels and physiology, through systemic manipulations such as calorie restriction and young blood infusion, can regenerate tissue activity and increase lifespan in aged mice. However, whether these two systemic manipulations could be linked has never been investigated. Here, we report that systemic [[GDF11]] triggers a calorie restriction-like phenotype without affecting appetite or GDF15 levels in the blood, restores the insulin/IGF-1 signaling pathway, and stimulates adiponectin secretion from white adipose tissue by direct action on adipocytes, while repairing neurogenesis in the aged brain. These findings suggest that [[GDF11]] has a pleiotropic effect on an organismal level and that it could be a linking mechanism of rejuvenation between heterochronic parabiosis and calorie restriction. As such, [[GDF11]] could be considered as an important therapeutic candidate for age-related neurodegenerative and metabolic disorders.

|keywords=* GDF11
* adiponectin
* aging
* calorie restriction
* heterochronic parabiosis
* rejuvenation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974718
}}
{{medline-entry
|title=Circulating factors in young blood as potential therapeutic agents for age-related neurodegenerative and neurovascular diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31400495
|abstract=Recent animal studies on heterochronic parabiosis (a technique combining the blood circulation of two animals) have revealed that young blood has a powerful rejuvenating effect on brain aging. Circulating factors, especially growth differentiation factor 11 ([[GDF11]]) and C-C motif chemokine 11 (CCL11), may play a key role in this effect, which inspires hope for novel approaches to treating age-related cerebral diseases in humans, such as neurodegenerative and neurovascular diseases. Recently, attempts have begun to translate these astonishing and exciting findings from mice to humans and from bench to bedside. However, increasing reports have shown contradictory data, questioning the capacity of these circulating factors to reverse age-related brain dysfunction. In this review, we summarize the current research on the role of young blood, as well as the circulating factors [[GDF11]] and CCL11, in the aging brain and age-related cerebral diseases. We highlight recent controversies, discuss related challenges and provide a future outlook.
|mesh-terms=* Age Factors
* Aging
* Animals
* Blood
* Bone Morphogenetic Proteins
* Chemokine CCL11
* Enzyme Therapy
* Enzymes
* Growth Differentiation Factors
* Mice
* Neurodegenerative Diseases
* Parabiosis
* Vascular Diseases
|keywords=* C-C motif chemokine 11
* Circulating factor
* Growth differentiation factor 11
* Neurodegenerative diseases
* Neurovascular diseases
* Young blood
|full-text-url=https://sci-hub.do/10.1016/j.brainresbull.2019.08.004
}}
{{medline-entry
|title=Effects of Exercise Training on Growth and Differentiation Factor 11 Expression in Aged Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31417428
|abstract=Exercise training is considered an effective way to prevent age-related skeletal muscle loss. However, the molecular mechanism has not been clarified. Growth and differentiation factor 11 ([[GDF11]]) has been controversially considered a regulator of skeletal muscle aging. In this study, we examined whether [[GDF11]] is associated with skeletal muscle aging and the effects of exercise training on age-related skeletal muscle loss. First, we observed that [i]Gdf11[/i] mRNA and protein expression levels in young (5-month-old, [i]n[/i] = 6) and aged (22-to 26-month-old, [i]n[/i] = 5) mice were not significantly different. Aged mice were then divided into sedentary ([i]n[/i] = 5) and exercise ([i]n[/i] = 6) groups. The exercise group performed moderate-intensity treadmill running for 6 weeks. Treadmill exercise training increased [i]Gdf11[/i] mRNA expression in the soleus muscle, but its protein expression was not altered. In contrast, the [[GDF11]] level in the plantaris muscle was not changed at either the mRNA or protein level. Collectively, our data demonstrate that [[GDF11]] levels do not change during aging, and that treadmill exercise training increased [i]Gdf11[/i] mRNA expression in a predominantly slow-twitch muscle.

|keywords=* aging
* exercise
* growth and differentiation factor 11
* sarcopenia
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684741
}}
==SDS==

{{medline-entry
|title=Semiautomatic morphometric analysis of skeletal muscle obtained by needle biopsy in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32946050
|abstract=Analysis of skeletal muscle mass and composition is essential for studying the biology of age-related sarcopenia, loss of muscle mass, and function. Muscle immunohistochemistry (IHC) allows for simultaneous visualization of morphological characteristics and determination of fiber type composition. The information gleaned from myosin heavy chain (MHC) isoform, and morphological measurements offer a more complete assessment of muscle health and properties than classical techniques such as [[SDS]]-PAGE and ATPase immunostaining; however, IHC quantification is a time-consuming and tedious method. We developed a semiautomatic method to account for issues frequently encountered in aging tissue. We analyzed needle-biopsied vastus lateralis (VL) of the quadriceps from a cohort of 14 volunteers aged 74.9 ± 2.2 years. We found a high correlation between manual quantification and semiautomatic analyses for the total number of fibers detected (r  = 0.989) and total fiber cross-sectional area (r  = 0.836). The analysis of the VL fiber subtype composition and the cross-sectional area also did not show statistically significant differences. The semiautomatic approach was completed in 10-15% of the time required for manual quantification. The results from these analyses highlight some of the specific issues which commonly occur in aged muscle. Our methods which address these issues underscore the importance of developing efficient, accurate, and reliable methods for quantitatively analyzing the skeletal muscle and the standardization of collection protocols to maximize the likelihood of preserving tissue quality in older adults. Utilizing IHC as a means of exploring the progression of disease, aging, and injury in the skeletal muscle allows for the practical study of muscle tissue down to the fiber level. By adding editing modules to our semiautomatic approach, we accurately quantified the aging muscle and addressed common technical issues.

|keywords=* Aging skeletal muscle
* Morphometric analysis
* Myosin heavy chain
* Semiautomatic muscle analysis
* Skeletal muscle
|full-text-url=https://sci-hub.do/10.1007/s11357-020-00266-1
}}
{{medline-entry
|title=Effects of late-onset dietary intake of salidroside on insulin/insulin-like growth factor-1 (IGF-1) signaling pathway of the annual fish Nothobranchius guentheri.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32858432
|abstract=Salidroside ([[SDS]]) is the main active ingredient of Rhodiola which has many biological functions including anti-fatigue, anti-tumor, and immune regulation activities. Our last paper demonstrated that [[SDS]] prolonged longevity of the annual fish Nothobranchius guentheri, a promising vertebrate model for anti-aging research. However, little is known about its effect on insulin/insulin-like growth factor-1 (IGF-1) signaling pathway (IIS pathway). In this study, we show that [[SDS]] is able to decrease accumulation of SA-β-Gal. We also show that [[SDS]] administraton could reduce the expression levels of Igf-1 and Igf-1R, downregulate the expressions of p-PI3K and p-Akt and upregulate the expression levels of Sirt1 and Foxo3a, both of which are the downstream regulators of the IIS pathway. We also find that [[SDS]] could alleviate DNA damage, which could result in increased expression of transcription factor Foxo3a. Collectively, these data indicate that [[SDS]] may take part in the IIS pathway.

|keywords=* Aging
* Annual fish
* Lifespan
* Nothobranchius
* Salidroside
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104233
}}
{{medline-entry
|title=Quantification of Insoluble Protein Aggregation in Caenorhabditis elegans during Aging with a Novel Data-Independent Acquisition Workflow.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32831297
|abstract=We and others have shown that the aging process results in a proteome-wide accumulation of insoluble proteins. Knocking down genes encoding the insoluble proteins over 40% of the time results in an extension of the lifespan in C. elegans, suggesting that many of these proteins are key determinants of the aging process. Isolation and quantitative identification of these insoluble proteins are crucial to understand key biological processes that occur during aging. Here, we present a modified and improved protocol that details how to extract and isolate the [[SDS]]-insoluble proteins (insolublome) from C. elegans more efficiently to streamline mass spectrometric workflows via a novel label-free quantitative proteomics analysis. This improved protocol utilizes a highly efficient sonicator for worm lysis that greatly increases efficiency for protein extraction and allows us to use significantly less starting material (approximately 3,000 worms) than in previous protocols (typically using at least 40,000 worms). Subsequent quantitative proteomic analysis of the insolublome was performed using data-dependent acquisition (DDA) for protein discovery and identification and data-independent acquisition (DIA) for comprehensive and more accurate protein quantification. Bioinformatic analysis of quantified proteins provides potential candidates that can be easily followed up with other molecular methods in C. elegans. With this workflow, we routinely identify more than 1000 proteins and quantify more than 500 proteins. This new protocol enables efficient compound screening with C. elegans. Here, we validated and applied this improved protocol to wild-type C. elegans N2-Bristol strain and confirmed that aged day-10 N2 worms showed greater accumulation of the insolublome than day-2 young worms.
|mesh-terms=* Aging
* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Longevity
* Protein Aggregates
* Proteome
* Proteomics
* Workflow

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519758
}}
{{medline-entry
|title=Skeletal Muscle Myofibrillar Protein Abundance Is Higher in Resistance-Trained Men, and Aging in the Absence of Training May Have an Opposite Effect.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31936810
|abstract=Resistance training generally increases skeletal muscle hypertrophy, whereas aging is associated with a loss in muscle mass. Interestingly, select studies suggest that aging, as well as resistance training, may lead to a reduction in the abundance of skeletal muscle myofibrillar (or contractile) protein (per mg tissue). Proteomic interrogations have also demonstrated that aging, as well as weeks to months of resistance training, lead to appreciable alterations in the muscle proteome. Given this evidence, the purpose of this small pilot study was to examine total myofibrillar as well as total sarcoplasmic protein concentrations (per mg wet muscle) from the vastus lateralis muscle of males who were younger and resistance-trained (denoted as YT, n = 6, 25 ± 4 years old, 10 ± 3 self-reported years of training), younger and untrained (denoted as YU, n = 6, 21 ± 1 years old), and older and untrained (denoted as OU, n = 6, 62 ± 8 years old). The relative abundances of actin and myosin heavy chain (per mg tissue) were also examined using [[SDS]]-PAGE and Coomassie staining, and shotgun proteomics was used to interrogate the abundances of individual sarcoplasmic and myofibrillar proteins between cohorts. Whole-body fat-free mass (YT > YU = OU), VL thickness (YT > YU = OU), and leg extensor peak torque (YT > YU = OU) differed between groups ([i]p[/i] < 0.05). Total myofibrillar protein concentrations were greater in YT versus OU ([i]p[/i] = 0.005), but were not different between YT versus YU ([i]p[/i] = 0.325). The abundances of actin and myosin heavy chain were greater in YT versus YU ([i]p[/i] < 0.05) and OU ([i]p[/i] < 0.001). Total sarcoplasmic protein concentrations were not different between groups. While proteomics indicated that marginal differences existed for individual myofibrillar and sarcoplasmic proteins between YT versus other groups, age-related differences were more prominent for myofibrillar proteins (YT = YU > OU, [i]p[/i] < 0.05: 7 proteins; OU > YT = YU, [i]p[/i] < 0.05: 11 proteins) and sarcoplasmic proteins (YT = YU > OU, [i]p[/i] < 0.05: 8 proteins; OU > YT&YU, [i]p[/i] < 0.05: 29 proteins). In summary, our data suggest that modest (~9%) myofibrillar protein packing (on a per mg muscle basis) was evident in the YT group. This study also provides further evidence to suggest that notable skeletal muscle proteome differences exist between younger and older humans. However, given that our n-sizes are low, these results only provide a preliminary phenotyping of the reported protein and proteomic variables.

|keywords=* aging
* myofibrillar protein
* proteomics
* resistance training
* sarcoplasmic protein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022975
}}
{{medline-entry
|title=Characterization, evaluation of nutritional parameters of Radix isatidis protein and its antioxidant activity in D-galactose induced ageing mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31694618
|abstract=Radix isatidis (Isatis indigotica Fort.) is an ancient medicinal herb, which has been applied to the prevention and treatment of influenza virus since ancient times. In recent years, the antioxidant activity of Radix isatidis has been widely concerned by researchers. Our previous studies have shown that Radix isatidis protein (RIP) has good antioxidant activity in vitro. In this study, the composition of the protein was characterized and its antioxidant activity in vivo was evaluated. The model of oxidative damage in mice was established by subcutaneous injection of D-galactose for 7 weeks. Commercially available kits were used to determine the content of protein and several oxidation indexes in different tissues of mice. The tissue samples were stained with hematoxylin and eosin (H&E) and the pathological changes were observed by optical microscope. The molecular weight of RIP was analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis ([[SDS]]-PAGE). The amino acid composition of RIP was determined by a non-derivative method developed by our research group. RIP significantly increased the activities of antioxidant enzymes such as SOD, CAT, GSH-Px and total antioxidant capability (TAOC) but decreased the MDA level in the serum, kidney and liver. H&E stained sections of liver and kidney revealed D-galactose could cause serious injury and RIP could substantially attenuate the injury. The analysis of [[SDS]]-PAGE showed that four bands with molecular weights of 19.2 kDa, 21.5 kDa, 24.8 kDa and 40.0 kDa were the main protein components of RIP. The results suggested that RIP had excellent antioxidant activity, which could be explored as a health-care product to retard aging and a good source of protein nutrition for human consumption.
|mesh-terms=* Aging
* Animals
* Antioxidants
* Catalase
* Drugs, Chinese Herbal
* Galactose
* Humans
* Kidney
* Liver
* Male
* Malondialdehyde
* Mice
* Mice, Inbred ICR
* Molecular Weight
* Oxidative Stress
* Plant Proteins
* Plant Roots
* Superoxide Dismutase
|keywords=* Antioxidant activity
* D-galactose
* Oxidative damage
* Protein composition
* Radix isatidis protein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836523
}}
{{medline-entry
|title=[Effects of silver nanoparticles on pupation, eclosion, life span, apoptosis and protein expression in Drosophila melanogaster].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31621246
|abstract=Silver nanoparticle is widely used in the field of medicine because of its strong and effective antibacterial action. However, it has potential biological toxicity. In this study, the classical model organism, Drosophila melanogaster, was used to explore underlying mechanism for the toxic effects of silver nanoparticle. The pupation rate, eclosion time, eclosion rate and lifespan of Oregon R, w1118, and MTF mutants under different concentrations of silver nanoparticle were measured. The lacZ activity of rpr-lacZ strain was used to determine apoptosis of imaginal disc after treated with different concentrations of silver nanoparticle. The difference of intestinal protein expression in MTF mutants treated with different concentrations of silver nanoparticle was studied by [[SDS]]-PAGE. The amino acid sequence of differential proteins was further analyzed by mass spectrometry. The results showed that pupation rate and eclosion rate of MTF mutants significantly decreased when the concentration of silver nanoparticle increased to 200 μg·mL  and above. When the concentration of silver nanoparticle increased to 800 μg·mL , the rate of pupation and eclosion was significantly reduced, with the time of pupation and eclosion being not correlated to the concentration of silver nanoparticle. The concentrations of silver nanoparticle had no effect on the lifespan of Oregon R and w1118, while 200 μg·mL  silver nanoparticle significantly reduced the average lifespan of MTF mutant. Apoptosis increased with increasing concentration of silver nanoparticle. Results from [[SDS]]-PAGE and mass spectrometry analysis showed that the expression levels of proteins such as ATP kinase, heat shock protein and glucose metabolism related enzymes increased with increasing concentration of silver nanoparticle. Our results showed that high concentration of silver nanoparticle would reduce the survival rate of Drosophila, promote apoptosis and the expression of some proteins, which provided a theoretical basis for further understanding of the toxic mechanism of silver nanoparticle.
|mesh-terms=* Animals
* Apoptosis
* Drosophila melanogaster
* Longevity
* Metal Nanoparticles
* Oregon
* Silver
|keywords=* Drosophila melanogaster
* apoptosis
* protein expression
* silver nanoparticles
|full-text-url=https://sci-hub.do/10.13287/j.1001-9332.201910.036
}}
{{medline-entry
|title=Does an Age-Specific Treatment Program Augment the Efficacy of a Cognitive-Behavioral Weight Loss Program in Adolescence and Young Adulthood? Results from a Controlled Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31480678
|abstract=Research on weight-loss interventions in emerging adulthood is warranted. Therefore, a cognitive-behavioral group treatment (CBT), including development-specific topics for adolescents and young adults with obesity (YOUTH), was developed. In a controlled study, we compared the efficacy of this age-specific CBT group intervention to an age-unspecific CBT group delivered across ages in an inpatient setting. The primary outcome was body mass index standard deviation score (BMI-[[SDS]]) over the course of one year; secondary outcomes were health-related and disease-specific quality of life (QoL). 266 participants aged 16 to 21 years (65% females) were randomized. Intention-to-treat (ITT) and per-protocol analyses (PPA) were performed. For both group interventions, we observed significant and clinically relevant improvements in BMI-[[SDS]] and QoL over the course of time with small to large effect sizes. Contrary to our hypothesis, the age-specific intervention was not superior to the age-unspecific CBT-approach.
|mesh-terms=* Adolescent
* Aging
* Behavior Therapy
* Cognitive Behavioral Therapy
* Female
* Humans
* Male
* Weight Loss
* Weight Reduction Programs
* Young Adult
|keywords=* adolescents
* behavioral weight loss
* controlled trial
* emerging adults
* obesity
* quality of life
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769959
}}
==DDT==

{{medline-entry
|title=Prognostic Value of a Test of Central Auditory Function in Conversion from Mild Cognitive Impairment to Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32388503
|abstract=It has been suggested that central auditory processing dysfunction might precede the development of cognitive decline and Alzheimer's disease (AD). The Dichotic Digits Test ([[DDT]]) has been proposed as a test of central auditory function. Our objective was to evaluate the predictive capacity of the [[DDT]] in conversion from mild cognitive impairment (MCI) to dementia. A total of 57 participants (26 females) with MCI were tested at baseline with pure tone audiometry, speech in quiet and in noise, and the [[DDT]]. The cognitive outcome was retrieved from medical files after 5 years. Groupwise comparisons of the baseline [[DDT]] scores were performed and the relative risk was calculated. Altogether 22 subjects developed any kind of dementia. Of the original 57 individuals within the MCI group, 15 developed AD and 7 developed other types of dementia. There was no significant difference in baseline [[DDT]] scores between the participants who converted to AD and those who did not. However, the group who developed other types of dementia (especially frontotemporal dementia) had lower [[DDT]] scores in the left ear than those participants who did not develop dementia. With a baseline [[DDT]] score below 50% correct responses, the participants diagnosed with MCI had a 2.49-times-higher risk of developing dementia than those with scores of 50% or better. The [[DDT]] as a central auditory test may be suitable when evaluating cognitive decline.

|keywords=* Aging
* Alzheimer’s disease
* Auditory processing
* Cognition
* Dichotic Digits Test
|full-text-url=https://sci-hub.do/10.1159/000506621
}}
{{medline-entry
|title=Uptake kinetics of four hydrophobic organic pollutants in the earthworm Eisenia andrei in aged laboratory-contaminated natural soils.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32061977
|abstract=Laboratory studies of pollutant uptake kinetics commonly start shortly after experimental soil contamination when it is not clear if the processes between soil and chemicals are equilibrated and stabilized. For instance, when the concentration in soil quickly decreases due to initial biodegradation, bioaccumulation may show a peak-shape accumulation curve instead of conventional first order kinetics with a plateau at the end. The results of such experiments with soil freshly contaminated in the laboratory are then hardly comparable to bioaccumulation observed in soils from historically contaminated sites. Therefore, our study focused on the uptake kinetics of four hydrophobic organic compounds (pyrene, lindane, p,p'-[[DDT]] and PCB 153) in two laboratory-contaminated natural soils with different soil properties (e.g. total organic carbon content of 1.6 and 9.3%) aged for 203 days to mimic long-term contamination. For pyrene, the results surprisingly showed peak-shape accumulation curves despite long aging. It seems compound biodegradation might be significant in aged soils when the conditions change (e.g. by distribution to the experimental vessels) and this should be also considered when testing historically contaminated soils. For lindane, longer aging seems to guarantee stability of the soil-compound-earthworm system and the steady state was reached after 5 days of exposure. Furthermore, although concentrations of p,p'-[[DDT]] and PCB 153 in earthworms after 11-15-day exposure did not statistically differ, which is a commonly-used indicator that a steady state was reached, they continuously increased until the end of the exposure. Therefore, despite the aging, longer exposure was probably needed to reach the true equilibrium between concentrations in earthworms and soil. In summary, aging does not warranty the conventional first order kinetic curve with the equilibrium at the end of the exposure but may have diverse effects for compounds with different environmental properties and should be taken into account in the bioaccumulation factor calculation and the risk assessment.
|mesh-terms=* Animals
* DDT
* Hexachlorocyclohexane
* Hydrophobic and Hydrophilic Interactions
* Kinetics
* Oligochaeta
* Polychlorinated Biphenyls
* Pyrenes
* Soil Pollutants
|keywords=* Aging
* BAFs
* Bioaccumulation
* HOCs
* Laboratory-contaminated soils
|full-text-url=https://sci-hub.do/10.1016/j.ecoenv.2020.110317
}}
{{medline-entry
|title=Adult exposure to insecticides causes persistent behavioral and neurochemical alterations in zebrafish.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31911208
|abstract=Farmers are often chronically exposed to insecticides, which may present health risks including increased risk of neurobehavioral impairment during adulthood and across aging. Experimental animal studies complement epidemiological studies to help determine the cause-and-effect relationship between chronic adult insecticide exposure and behavioral dysfunction. With the zebrafish model, we examined short and long-term neurobehavioral effects of exposure to either an organochlorine insecticide, dichlorodiphenyltrichloroethane ([[DDT]]) or an organophosphate insecticide chlorpyrifos (CPF). Adult fish were exposed continuously for either two or 5 weeks (10-30 nM [[DDT]], 0.3-3 μM CPF), with short- and long-term effects assessed at 1-week post-exposure and at 14 months of age respectively. The behavioral test battery included tests of locomotor activity, tap startle, social behavior, anxiety, predator avoidance and learning. Long-term effects on neurochemical indices of cholinergic function were also assessed. Two weeks of [[DDT]] exposure had only slight effects on locomotor activity, while a longer five-week exposure led to hypoactivity and increased anxiety-like diving responses and predator avoidance at 1-week post-exposure. When tested at 14 months of age, these fish showed hypoactivity and increased startle responses. Cholinergic function was not found to be significantly altered by [[DDT]]. The two-week CPF exposure led to reductions in anxiety-like diving and increases in shoaling responses at the 1-week time point, but these effects did not persist through 14 months of age. Nevertheless, there were persistent decrements in cholinergic presynaptic activity. A five-week CPF exposure led to long-term effects including locomotor hyperactivity and impaired predator avoidance at 14 months of age, although no effects were apparent at the 1-week time point. These studies documented neurobehavioral effects of adult exposure to chronic doses of either organochlorine or organophosphate pesticides that can be characterized in zebrafish. Zebrafish provide a low-cost model that has a variety of advantages for mechanistic studies and may be used to expand our understanding of neurobehavioral toxicity in adulthood, including the potential for such toxicity to influence behavior and development during aging.

|keywords=* Aging
* Anxiety-related behavior
* DDT
* Neurobehavioral toxicology
* Zebrafish
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061078
}}
{{medline-entry
|title=Second generation effects of larval metal pollutant exposure on reproduction, longevity and insecticide tolerance in the major malaria vector Anopheles arabiensis (Diptera: Culicidae).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31910892
|abstract=Members of the Anopheles gambiae complex breed in clean, sunlit temporary bodies of water. Anthropogenic pollution is, however, altering the breeding sites of the vectors with numerous biological effects. Although the effects of larval metal pollution have previously been examined, this study aims to assess the transgenerational effects of larval metal pollution on the major malaria vector An. arabiensis. Two laboratory strains of An. arabiensis, SENN (insecticide-susceptible) and SENN-[[DDT]] (insecticide-resistant), were used in this study. After being bred in water polluted with either cadmium chloride, copper nitrate or lead nitrate, several life history characteristics that can have epidemiological implications (fertility, apoptotic damage to reproductive structures, adult longevity and insecticide tolerance) were examined in the adults and compared to those of adults bred in clean water. All metal treatments reduced fecundity in SENN, but only lead treatment reduced fertility in SENN-[[DDT]]. Cadmium chloride exposure resulted in apoptosis and deformation of the testes in both strains. After breeding generation F0 in polluted water, F1 larvae bred in clean water showed an increase in longevity in SENN-[[DDT]] adult females. In contrast, after breeding the F0 generation in polluted water, longevity was reduced after cadmium and copper exposure in the F1 generation. Larval metal exposure resulted in an increase in insecticide tolerance in adults of the SENN strain, with SENN-[[DDT]] adults gaining the greatest fold increase in insecticide tolerance. This study demonstrates that a single exposure to metal pollution can have transgenerational effects that are not negated by subsequent breeding in clean water.
|mesh-terms=* Animals
* Anopheles
* Drug Resistance
* Female
* Fertility
* Insecticides
* Larva
* Male
* Metals
* Reproduction
* Water Pollutants
|keywords=* Anopheles arabiensis
* Insecticide resistance
* Longevity
* Transgenerational effects
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6947826
}}
{{medline-entry
|title=Protective effect of Pedro-Ximénez must against p,p'-DDE-induced liver damages in aged Mus spretus mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31765701
|abstract=Aging is characterized by deterioration of biomolecules and impaired stress responses that make the elderly especially vulnerable to environmental pollutants. The pesticide p,p'-DDE is a [[DDT]] derivative that generates great concern because of its wide distribution and its harmful effects on both human health and the environment. We analyzed here the biological responses elicited by p,p'-DDE exposure in the liver of aged Mus spretus mice. Data demonstrate that the elderly constitute a population especially sensitive to this noxious environmental pollutant. We also demonstrated here that the daily consumption of sun-dried Pedro Ximénez (PX) white-grape must (PXM) protects the liver of aged mice from both the age and the damages caused by p,p'-DDE exposure. The PXM activity was exerted through the restoration of the hepatic metabolisms of lipids and carbohydrates and, probably, is a consequence of the ability of this polyphenol-rich mixture to avoid oxidative stress. Nutritional interventions including PXM, which ameliorates the effects of unavoidable exposure to pesticides in our food, are helpful tools that can help elderly populations to enjoy a healthy and expanded lifetime.
|mesh-terms=* Aging
* Animals
* Antioxidants
* Chemical and Drug Induced Liver Injury
* Dichlorodiphenyl Dichloroethylene
* Down-Regulation
* Liver
* Male
* Mice
* Oxidative Stress
* Pesticides
* Plant Extracts
* Polyphenols
* Transcriptome
* Up-Regulation
* Vitis
|keywords=* Aging
* Hepatoprotection
* Mus spretus
* Organochlorine
* Oxidative damage
* Pedro-ximénez grape must
* Transcriptional analysis
* p,p'-DDE
|full-text-url=https://sci-hub.do/10.1016/j.fct.2019.110984
}}
{{medline-entry
|title=Low-dose endosulfan inhibits proliferation and induces senescence and pro-inflammatory cytokine production in human lymphocytes, preferentially impacting cytotoxic cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31589084
|abstract=Endosulfan is a [[DDT]]-era organochlorine pesticide. Due to past and current environmental contamination, investigation of endosulfan exposure is of current importance. Acute high dose exposure precipitates neural/endocrine system damage, but the effects on the immune system and of lower doses are not well-characterized. Two relatively low concentrations of endosulfan (i.e. 0.1 and 17 µM ENDO) were investigated in an [i]in vitro[/i] study using human peripheral blood mononuclear cells (PBMC) to understand effects of relatively low doses (0.1-25.0 µM [≈0.04-10 ppm/40-10,000 ppb]) of ENDO upon normal human T- and B-lymphocytes and NK cells. The study here found that 17 µM ENDO inhibited phytohemagglutinin-M (PHA)-induced human PBMC proliferation. It was also seen that senescence and apoptosis among non-stimulated cells was increased, specifically within CD8 and NK populations, and that CD4:CD8 ratios also were increased. Treatment of non-stimulated PBMC with ENDO led to overall increases in production of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-2, -4, and -6, and decreased production of anti-inflammatory IL-10, suggesting an immunosenescence secretory phenotype. Interestingly, when the cells were pre-stimulated with mitogen (PHA), ENDO became inhibitory against the mitogen-induced proliferation and cytokine formation - with the exception of that of TNFα and IL-6, suggesting differential effects of ENDO on activated cells. Thus, at the organismal level, ENDO might also display differential effects during states of autoimmune disease or chronic viral infection in the exposed host.
|mesh-terms=* Adult
* B-Lymphocytes
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Cytokines
* Dose-Response Relationship, Drug
* Endosulfan
* Female
* Healthy Volunteers
* Humans
* Inflammation Mediators
* Insecticides
* Killer Cells, Natural
* Male
* Primary Cell Culture
* T-Lymphocytes, Cytotoxic
* Young Adult
|keywords=* Endosulfan
* Immunosenescence
* NK cells
* PBMC
* cytotoxic cells
* interferon
* organochlorine pesticide
* senescence
|full-text-url=https://sci-hub.do/10.1080/1547691X.2019.1668513
}}
==GDF15==

{{medline-entry
|title=Disease-specific plasma levels of mitokines FGF21, [[GDF15]], and Humanin in type II diabetes and Alzheimer's disease in comparison with healthy aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33131010
|abstract=Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 ([[GDF15]]), and Humanin (HN) are mitochondrial stress-related mitokines, whose role in health and disease is still debated. In this study, we confirmed that their plasma levels are positively correlated with age in healthy subjects. However, when looking at patients with type 2 diabetes (T2D) or Alzheimer's disease (AD), two age-related diseases sharing a mitochondrial impairment, we found that [[GDF15]] is elevated in T2D but not in AD and represents a risk factor for T2D complications, while FGF21 and HN are lower in AD but not in T2D. Moreover, FGF21 reaches the highest levels in centenarian' offspring, a model of successful aging. As a whole, these data indicate that (i) the adaptive mitokine response observed in healthy aging is lost in age-related diseases, (ii) a common expression pattern of mitokines does not emerge in T2D and AD, suggesting an unpredicted complexity and disease-specificity, and (iii) FGF21 emerges as a candidate marker of healthy aging.

|keywords=* AD
* Aging
* FGF21
* GDF15
* Humanin
* T2D
|full-text-url=https://sci-hub.do/10.1007/s11357-020-00287-w
}}
{{medline-entry
|title=Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32691494
|abstract=Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 ([[GDF15]]) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of [[GDF15]] to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced [[GDF15]] production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of [[GDF15]] as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of [[GDF15]]. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced [[GDF15]] expression in human blood to increased body weight and inflammation. [[GDF15]] deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although [[GDF15]] is not required for Th17 cell differentiation and IL-17 production in Th17 cells, [[GDF15]] contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that [[GDF15]] is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.

|keywords=* T cell
* aging
* inflammation
* mitochondria
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431835
}}
{{medline-entry
|title=Analysis of Epigenetic Age Predictors in Pain-Related Conditions.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32582603
|abstract=Chronic pain prevalence is high worldwide and increases at older ages. Signs of premature aging have been associated with chronic pain, but few studies have investigated aging biomarkers in pain-related conditions. A set of DNA methylation (DNAm)-based estimates of age, called "epigenetic clocks," has been proposed as biological measures of age-related adverse processes, morbidity, and mortality. The aim of this study is to assess if different pain-related phenotypes show alterations in DNAm age. In our analysis, we considered three cohorts for which whole-blood DNAm data were available: heat pain sensitivity (HPS), including 20 monozygotic twin pairs discordant for heat pain temperature threshold; fibromyalgia (FM), including 24 cases and 20 controls; and headache, including 22 chronic migraine and medication overuse headache patients (MOH), 18 episodic migraineurs (EM), and 13 healthy subjects. We used the Horvath's epigenetic age calculator to obtain DNAm-based estimates of epigenetic age, telomere length, levels of 7 proteins in plasma, number of smoked packs of cigarettes per year, and blood cell counts. We did not find differences in epigenetic age acceleration, calculated using five different epigenetic clocks, between subjects discordant for pain-related phenotypes. Twins with high HPS had increased CD8+ T cell counts (nominal [i]p[/i] = 0.028). HPS thresholds were negatively associated with estimated levels of [[GDF15]] (nominal [i]p[/i] = 0.008). FM patients showed decreased naive CD4+ T cell counts compared with controls (nominal [i]p[/i] = 0.015). The severity of FM manifestations expressed through various evaluation tests was associated with decreased levels of leptin, shorter length of telomeres, and reduced CD8+ T and natural killer cell counts (nominal [i]p[/i] < 0.05), while the duration of painful symptoms was positively associated with telomere length (nominal [i]p[/i] = 0.034). No differences in DNAm-based estimates were detected for MOH or EM compared with controls. In summary, our study suggests that HPS, FM, and MOH/EM do not show signs of epigenetic age acceleration in whole blood, while HPS and FM are associated with DNAm-based estimates of immunological parameters, plasma proteins, and telomere length. Future studies should extend these observations in larger cohorts.

|keywords=* DNA methylation
* aging biomarker
* chronic pain
* epigenetic aging
* epigenetic clock
* fibromyalgia
* headache
* pain sensitivity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296181
}}
{{medline-entry
|title=[[GDF15]] Plasma Level Is Inversely Associated With Level of Physical Activity and Correlates With Markers of Inflammation and Muscle Weakness.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32477368
|abstract=Growth differentiation factor 15 ([[GDF15]]) is a stress molecule produced in response to mitochondrial, metabolic and inflammatory stress with a number of beneficial effects on metabolism. However, at the level of skeletal muscle it is still unclear whether [[GDF15]] is beneficial or detrimental. The aim of the study was to analyse the levels of circulating [[GDF15]] in people of different age, characterized by different level of physical activity and to seek for correlation with hematological parameters related to inflammation. The plasma concentration of [[GDF15]] was determined in a total of 228 subjects in the age range from 18 to 83 years. These subjects were recruited and divided into three different groups based on the level of physical activity: inactive patients with lower limb mobility impairment, active subjects represented by amateur endurance cyclists, and healthy controls taken from the general population. Cyclists were sampled before and after a strenuous physical bout (long distance cycling race). The plasma levels of [[GDF15]] increase with age and are inversely associated with active lifestyle. In particular, at any age, circulating [[GDF15]] is significantly higher in inactive patients and significantly lower in active people, such as cyclists before the race, with respect to control subjects. However, the strenuous physical exercise causes in cyclists a dramatic increase of [[GDF15]] plasma levels, that after the race are similar to that of patients. Moreover, [[GDF15]] plasma levels significantly correlate with quadriceps torque in patients and with the number of total leukocytes, neutrophils and lymphocytes in both cyclists (before and after race) and patients. Taken together, our data indicate that [[GDF15]] is associated with decreased muscle performance and increased inflammation.

|keywords=* GDF15
* healthy aging
* inflammation
* physical activity
* sedentarity
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235447
}}
{{medline-entry
|title=[[GDF15]] is an epithelial-derived biomarker of idiopathic pulmonary fibrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31432710
|abstract=Idiopathic pulmonary fibrosis (IPF) is the most common and devastating of the interstitial lung diseases. Epithelial dysfunction is thought to play a prominent role in disease pathology, and we sought to characterize secreted signals that may contribute to disease pathology. Transcriptional profiling of senescent type II alveolar epithelial cells from mice with epithelial-specific telomere dysfunction identified the transforming growth factor-β family member, growth and differentiation factor 15 ([i]Gdf15[/i]), as the most significantly upregulated secreted protein. [i]Gdf15[/i] expression is induced in response to telomere dysfunction and bleomycin challenge in mice. [i]Gdf15[/i] mRNA is expressed by lung epithelial cells, and protein can be detected in peripheral blood and bronchoalveolar lavage following bleomycin challenge in mice. In patients with IPF, [i][[GDF15]][/i] mRNA expression in lung tissue is significantly increased and correlates with pulmonary function. Single-cell RNA sequencing of human lungs identifies epithelial cells as the primary source of [i][[GDF15]][/i], and circulating concentrations of [[GDF15]] are markedly elevated and correlate with disease severity and survival in multiple independent cohorts. Our findings suggest that [[GDF15]] is an epithelial-derived secreted protein that may be a useful biomarker of epithelial stress and identifies IPF patients with poor outcomes.
|mesh-terms=* Aged
* Alveolar Epithelial Cells
* Animals
* Bleomycin
* Bronchoalveolar Lavage Fluid
* Case-Control Studies
* Disease Models, Animal
* Female
* Gene Expression Profiling
* Growth Differentiation Factor 15
* Humans
* Idiopathic Pulmonary Fibrosis
* Lung
* Male
* Mice
* Middle Aged
* Respiratory Function Tests
* Severity of Illness Index
* Survival Analysis
* Telomere
* Transcriptome
|keywords=* MIC-1
* NAG-1
* SASP
* aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842909
}}
{{medline-entry
|title=Senescence-associated tissue microenvironment promotes colon cancer formation through the secretory factor [[GDF15]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31389184
|abstract=The risk of colorectal cancer (CRC) varies between people, and the cellular mechanisms mediating the differences in risk are largely unknown. Senescence has been implicated as a causative cellular mechanism for many diseases, including cancer, and may affect the risk for CRC. Senescent fibroblasts that accumulate in tissues secondary to aging and oxidative stress have been shown to promote cancer formation via a senescence-associated secretory phenotype (SASP). In this study, we assessed the role of senescence and the SASP in CRC formation. Using primary human colon tissue, we found an accumulation of senescent fibroblasts in normal tissues from individuals with advanced adenomas or carcinomas in comparison with individuals with no polyps or CRC. In in vitro and ex vivo model systems, we induced senescence using oxidative stress in colon fibroblasts and demonstrated that the senescent fibroblasts secrete [[GDF15]] as an essential SASP factor that promotes cell proliferation, migration, and invasion in colon adenoma and CRC cell lines as well as primary colon organoids via the MAPK and PI3K signaling pathways. In addition, we observed increased mRNA expression of [[GDF15]] in primary normal colon tissue from people at increased risk for CRC in comparison with average risk individuals. These findings implicate the importance of a senescence-associated tissue microenvironment and the secretory factor [[GDF15]] in promoting CRC formation.
|mesh-terms=* Aging
* Cells, Cultured
* Cellular Senescence
* Colonic Neoplasms
* Fibroblasts
* Growth Differentiation Factor 15
* HEK293 Cells
* Humans
* Phenotype
* RNA, Messenger
* Tumor Microenvironment
|keywords=* GDF15
* colon organoids
* colorectal cancer
* microenvironment
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826139
}}
==CD44==

{{medline-entry
|title=Hyaluronan goes to great length.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32908962
|abstract=Hyaluronan is a major non-protein component of extracellular matrix that affects biomechanical properties of tissues and interacts with cell receptors. Hyaluronan is a linear glycosaminoglycan composed of repeating disaccharides of (β, 1-4)-glucuronic acid (GlcUA) and (β, 1-3)-N-acetyl glucosamine (GlcNAc). The length of hyaluronan can range from an oligomer to an extremely long form up to millions of daltons. The concept that emerged in the field is that high (HMW-HA) and low (LMW-HA) molecular weight hyaluronans have different biological properties and trigger different signaling cascades within the cells. LMW-HA is associated with inflammation, tissue injury and metastasis, while HMW-HA improves tissue homeostasis and has anti-inflammatory and antimetastatic properties. HMW-HA is used in the clinic to treat arthritis, and as a filler in surgery and in the form of rinses to treat local inflammation. However, HMW-HA products used in the clinic come in a range of sizes between 0.5-6 mDa that are used interchangeably. Remarkably, the tissues of a long-lived and cancer-resistant rodent, the naked mole rat, contain abundant HA of very high molecular weight. While human fibroblasts secrete HA up to 2 MDa, naked mole rat fibroblasts produce HA of 6-12 MDa. Does this very high HMW-HA (vHMW-HA) differ functionally from HMW-HA? We found that vHMW-HA has superior cytoprotective properties compared to HMW-HA, and interacts differently with the [[CD44]] receptor leading to distinct transcriptional changes (Takasugi [i]et al.[/i] (2020), Nat Commun). These results indicate that vHMW-HA has greater therapeutic benefits than the standard HMW-HA.

|keywords=* aging
* hyaluronan
* longevity
* naked mole rat
* very high molecular weight hyaluronan
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453635
}}
{{medline-entry
|title=Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32398747
|abstract=Naked mole-rat (NMR), the longest-living rodent, produces very-high-molecular-mass hyaluronan (vHMM-HA), compared to other mammalian species. However, it is unclear if exceptional polymer length of vHMM-HA is important for longevity. Here, we show that vHMM-HA (>6.1 MDa) has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner. The cytoprotective effect is dependent on the major HA-receptor, [[CD44]]. We find that vHMM-HA suppresses [[CD44]] protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of [[CD44]]-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.
|mesh-terms=* Animals
* Apoptosis
* Cell Cycle Checkpoints
* Cell Line
* Cytoprotection
* Gene Expression Regulation
* Gene Knockout Techniques
* Humans
* Hyaluronan Receptors
* Hyaluronic Acid
* Longevity
* Mice
* Mole Rats
* Molecular Weight
* Primary Cell Culture
* Protein Interaction Maps
* RNA-Seq
* Signal Transduction
* Species Specificity
* Stress, Physiological
* Tumor Suppressor Protein p53

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217962
}}
{{medline-entry
|title=Maturity-dependent cartilage cell plasticity and sensitivity to external perturbation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32321631
|abstract=Articular cartilage undergoes biological and morphological changes throughout maturation. The prevalence of osteoarthritis in the aged population suggests that maturation predisposes cartilage to degradation and/or impaired regeneration, but this process is not fully understood. Therefore, the objective of this study was to characterize the cellular and genetic profile of cartilage, as well as biological plasticity in response to mechanical and culture time stimuli, as a function of animal maturity. Porcine articular cartilage explants were harvested from stifle joints of immature (2-4 weeks), adolescent (5-6 months), and mature (1-5 years) animals. Half of all samples were subjected to a single compressive mechanical load. Loaded samples were paired with unloaded controls for downstream analyses. Expression of cartilage progenitor cell markers CD105, [[CD44]], and CD29 were determined via flow cytometry. Expression of matrix synthesis genes Col1, Col2, Col10, ACAN, and SOX9 were determined via qPCR. Tissue morphology and matrix content were examined histologically. Post-loading assays were performed immediately and following 7 days in culture. CD105 and CD29 expression decreased with maturity, while [[CD44]] expression was upregulated in cartilage from mature animals. Expression of matrix synthesis genes were generally upregulated in cartilage from mature animals, and adolescent animals showed the lowest expression of several matrix synthesizing genes. Culture time and mechanical loading analyses revealed greater plasticity to mechanical loading and culture time in cartilage from younger animals. Histology confirmed distinct structural and biochemical profiles across maturity. This study demonstrates differential, nonlinear expression of chondroprogenitor markers and matrix synthesis genes as a function of cartilage maturity, as well as loss of biological plasticity in aged tissue. These findings have likely implications for age-related loss of regeneration and osteoarthritis progression.

|keywords=* Aging
* Articular cartilage
* Osteoarthritis
* Plasticity
* Progenitor cells
|full-text-url=https://sci-hub.do/10.1016/j.jmbbm.2020.103732
}}
{{medline-entry
|title=Aged Mice Exhibit Severe Exacerbations of Dry Eye Disease with an Amplified Memory Th17 Cell Response.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32289288
|abstract=The prevalence as well as the severity of dry eye disease increase with age. Memory T helper 17 (Th17) cells (CD4 IL-17A [[CD44]] ) drive the chronic and relapsing course of dry eye disease. Here, we investigated the contribution of memory Th17 cells to age-related dry eye disease, and evaluated memory Th17 cell depletion with anti-IL-15 antibody as a strategy to abrogate the severe exacerbations of dry eye disease observed in aged mice. After initial exposure to desiccating stress, aged mice maintained higher frequencies of memory Th17 cells in the draining lymph nodes relative to young mice. Upon secondary exposure to desiccating stress, aged mice developed more severe corneal epitheliopathy than young mice, which is associated with increased local frequencies of Th17 cells (CD4 IL-17A ). Treatment with anti-IL-15 antibody decreased the enlarged memory Th17 pool in aged mice to frequencies comparable with young mice. Furthermore, anti-IL-15-treated mice showed significantly reduced conjunctival infiltration of Th17 cells and lower corneal fluorescein staining scores compared with saline-treated control mice. Our data suggest that age-related increases in the memory Th17 compartment predispose aged mice toward the development of severe corneal epithelial disease after exposure to a dry environment. Selectively targeting memory Th17 cells may be a viable therapeutic approach in the treatment of age-related dry eye disease.
|mesh-terms=* Aging
* Animals
* Dry Eye Syndromes
* Female
* Immunologic Memory
* Mice
* Mice, Inbred C57BL
* Th17 Cells

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369573
}}
{{medline-entry
|title=Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32054990
|abstract=Modern society characterized by a 24/7 lifestyle leads to misalignment between environmental cycles and endogenous circadian rhythms. Persisting circadian misalignment leads to deleterious effects on health and healthspan. However, the underlying mechanism remains not fully understood. Here, we subjected adult, wild-type mice to distinct chronic jet-lag paradigms, which showed that long-term circadian misalignment induced significant early mortality. Non-biased RNA sequencing analysis using liver and kidney showed marked activation of gene regulatory pathways associated with the immune system and immune disease in both organs. In accordance, we observed enhanced steatohepatitis with infiltration of inflammatory cells. The investigation of senescence-associated immune cell subsets from the spleens and mesenteric lymph nodes revealed an increase in PD-1 [[CD44]]  CD4 T cells as well as CD95 GL7  germinal center B cells, indicating that the long-term circadian misalignment exacerbates immune senescence and consequent chronic inflammation. Our results underscore immune homeostasis as a pivotal interventional target against clock-related disorders.
|mesh-terms=* Animals
* B-Lymphocytes
* Cellular Senescence
* Circadian Rhythm
* Disease Models, Animal
* Humans
* Hyaluronan Receptors
* Inflammation
* Jet Lag Syndrome
* Longevity
* Mice
* Programmed Cell Death 1 Receptor
* Sequence Analysis, RNA
* T-Lymphocytes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018741
}}
{{medline-entry
|title=Defective induction of the proteasome associated with T-cell receptor signaling underlies T-cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31621149
|abstract=The proteasome degradation machinery is essential for a variety of cellular processes including senescence and T-cell immunity. Decreased proteasome activity is associated with the aging process; however, the regulation of the proteasome in CD4  T cells in relation to aging is unclear. Here, we show that defects in the induction of the proteasome in CD4  T cells upon T-cell receptor (TCR) stimulation underlie T-cell senescence. Proteasome dysfunction promotes senescence-associated phenotypes, including defective proliferation, cytokine production and increased levels of PD-1  [[CD44]]  CD4  T cells. Proteasome induction by TCR signaling via MEK-, IKK- and calcineurin-dependent pathways is attenuated with age and decreased in PD-1  [[CD44]]  CD4  T cells, the proportion of which increases with age. Our results indicate that defective induction of the proteasome is a hallmark of CD4  T-cell senescence.
|mesh-terms=* Animals
* CD4-Positive T-Lymphocytes
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Cytokines
* Hyaluronan Receptors
* Mice
* Mice, Inbred C57BL
* Phenotype
* Programmed Cell Death 1 Receptor
* Proteasome Endopeptidase Complex
* Receptors, Antigen, T-Cell
* Signal Transduction
|keywords=* T cell receptor signal
* T cell senescence
* aging
* proteasome
|full-text-url=https://sci-hub.do/10.1111/gtc.12728
}}
==APC==

{{medline-entry
|title=Differences between blacks and whites in well-being, beliefs, emotional states, behaviors and survival, 1978-2014.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32925952
|abstract=Material well-being, beliefs, and emotional states are believed to influence one's health and longevity. In this paper, we explore racial differences in self-rated health, happiness, trust in others, feeling that society is fair, believing in God, frequency of sexual intercourse, educational attainment, and percent in poverty and their association with mortality. Age-period-cohort ([[APC]]) study. Using data from the 1978-2014 General Social Survey-National Death Index (GSS-NDI), we conducted [[APC]] analyses using generalized linear models to quantify the temporal trends of racial differences in our selected measures of well-being, beliefs, and emotional states. We then conducted [[APC]] survival analysis using mixed-effects Cox proportional hazard models to quantify the temporal trends of racial differences in survival after removing the effects of racial differences in our selected measures. For whites, the decline in happiness was steeper than for blacks despite an increase in high school graduation rates among whites relative to blacks over the entire period, 1978-2010. Self-rated health increased in whites relative to blacks from 1978 through 1989 but underwent a relative decline thereafter. After adjusting for age, sex, period effects, and birth cohort effects, whites, overall, had higher rates of self-rated health (odds ratio [OR] = 1.88; 95% confidence interval [CI] = 1.63, 2.16), happiness (OR = 2.05; 1.77, 2.36), and high school graduation (OR = 2.88; 2.34, 3.53) compared with blacks. Self-rated health, happiness, and high school graduation also mediated racial differences in survival over time. We showed that some racial differences in survival could be partly mitigated by eliminating racial differences in health, happiness, and educational attainment. Future research is needed to analyze longitudinal clusters and identify causal mechanisms by which social, behavioral, and economic interventions can reduce survival differences.
|mesh-terms=* Adult
* African Americans
* Aged
* Behavior
* Cohort Studies
* Emotions
* European Continental Ancestry Group
* Female
* Hispanic Americans
* Humans
* Longevity
* Male
* Middle Aged
* Socioeconomic Factors
* Survival Analysis
* United States

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489510
}}
{{medline-entry
|title=Wnt-induced, TRP53-mediated Cell Cycle Arrest of Precursors Underlies Interstitial Cell of Cajal Depletion During Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32771388
|abstract=Gastric dysfunction in the elderly may cause reduced food intake, frailty, and increased mortality. The pacemaker and neuromodulator cells interstitial cells of Cajal (ICC) decline with age in humans, and their loss contributes to gastric dysfunction in progeric klotho mice hypomorphic for the anti-aging Klotho protein. The mechanisms of ICC depletion remain unclear. Klotho attenuates Wnt (wingless-type MMTV integration site) signaling. Here, we examined whether unopposed Wnt signaling could underlie aging-associated ICC loss by up-regulating transformation related protein TRP53 in ICC stem cells (ICC-SC). Mice aged 1-107 weeks, klotho mice, [[APC]]  mice with overactive Wnt signaling, mouse ICC-SC, and human gastric smooth muscles were studied by RNA sequencing, reverse transcription-polymerase chain reaction, immunoblots, immunofluorescence, histochemistry, flow cytometry, and methyltetrazolium, ethynyl/bromodeoxyuridine incorporation, and ex-vivo gastric compliance assays. Cells were manipulated pharmacologically and by gene overexpression and RNA interference. The klotho and aged mice showed similar ICC loss and impaired gastric compliance. ICC-SC decline preceded ICC depletion. Canonical Wnt signaling and TRP53 increased in gastric muscles of klotho and aged mice and middle-aged humans. Overstimulated canonical Wnt signaling increased DNA damage response and TRP53 and reduced ICC-SC self-renewal and gastric ICC. TRP53 induction persistently inhibited G /S and G /M cell cycle phase transitions without activating apoptosis, autophagy, cellular quiescence, or canonical markers/mediators of senescence. G /S block reflected increased cyclin-dependent kinase inhibitor 1B and reduced cyclin D1 from reduced extracellular signal-regulated kinase activity. Increased Wnt signaling causes age-related ICC loss by up-regulating TRP53, which induces persistent ICC-SC cell cycle arrest without up-regulating canonical senescence markers.

|keywords=* Compliance
* Senescence
* Stem Cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672319
}}
{{medline-entry
|title=Burden of musculoskeletal disorders in Iran during 1990-2017: estimates from the Global Burden of Disease Study 2017.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32651719
|abstract=Musculoskeletal diseases (MSDs) are the leading cause of disability and facing them demands updated reports on their burden for efficient policymaking. We showed Iran had the highest female-to-male ratio and highest increase in the burden of musculoskeletal diseases, in the past three decades, worldwide. We further confirmed the role of population aging as the main cause. MSDs comprise most of the top causes of years lived with disability (YLDs) worldwide and are rapidly increasing in lower- and middle-income countries. Here, we present disability and mortality due to MSDs in Iran at the national level from 1990 to 2017. We used Global Burden of Disease (GBD) 2017 Study data and standard methodology and presented the burden of MSDs in rates of years of life lost (YLLs), YLDs, and disability-adjusted life years (DALYs) during 1990-2017, for population aged ≥ 5 years old. We further explored attributable risk factors and decomposed the changing trend in DALYs to assess underlying causes. In Iran, MSDs were responsible for 1.82 million (95%uncertainty interval [UI] 1.3-2.4) DALYs, in 2017. During the past 28 years, with 1.75% annualized percentage change ([[APC]]), Iran had the highest percentage increase in the all-ages MSD DALYs rate worldwide, while the age-standardized DALYs [[APC]] was negligible. Low back pain was the greatest contributor to DALYs and caused 4.5% of total DALYs. The female population is experiencing considerably higher burden of MSDs, with 115% and 48% higher all-ages YLLs and YLDs rates per 100,000, respectively (YLLs 28.7; YLDs 2629.1), than males (YLLs 13.2; YLDs 1766.1). However, due to wide UIs, difference was not significant. Only 17.6% of MSD YLDs are attributable to assessed risk factors. Despite that MSDs are rising as an important cause of disability in Iran, these conditions are not sufficiently addressed in health policies. There is urgent need for cross-sectoral engagement, especially addressing the MSDs in females.
|mesh-terms=* Female
* Global Burden of Disease
* Global Health
* Humans
* Iran
* Life Expectancy
* Male
* Musculoskeletal Diseases
* Quality-Adjusted Life Years
|keywords=* Burden
* DALY
* Decomposition
* Global burden of diseases
* Iran
* Musculoskeletal diseases
|full-text-url=https://sci-hub.do/10.1007/s11657-020-00767-8
}}
{{medline-entry
|title=Fall-related mortality trends in older Japanese adults aged ≥65 years: a nationwide observational study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31831549
|abstract=Fall-related mortality among older adults is a major public health issue, especially for ageing societies. This study aimed to investigate current trends in fall-related mortality in Japan using nationwide population-based data covering 1997-2016. We analysed fall-related deaths among older persons aged ≥65 years using the data provided by the Japanese Ministry of Health, Labour and Welfare. The crude and age-standardised mortality rates were calculated per 100 000 persons by stratifying by age (65-74, 75-84 and ≥85 years) and sex. To identify trend changes, a joinpoint regression model was applied by estimating change points and annual percentage change ([[APC]]). The total number of fall-related deaths in Japan increased from 5872 in 1997 to 8030 in 2016, of which 78.8% involved persons aged ≥65 years. The younger population (65-74 years) showed continuous and faster-decreasing trends for both men and women. Average [[APC]] among men aged ≥75 years did not decrease. Among middle-aged and older women (75-84 and ≥85 years) decreasing trends were observed. Furthermore, the age-adjusted mortality rate of men was approximately twice that of women, and it showed a faster decrease for women. Although Japanese healthcare has shown improvement in preventing fall-related deaths over the last two decades, the crude mortality for those aged over 85 years remains high, indicating difficulty in reducing fall-related deaths in the super-aged population. Further investigations to uncover causal factors for falls in older populations are required.
|mesh-terms=* Accidental Falls
* Aged
* Aged, 80 and over
* Female
* Geriatrics
* Health Policy
* Health Services Needs and Demand
* Humans
* Japan
* Male
* Mortality
* Public Health
|keywords=* adult intensive & critical care
* epidemiology
* geriatric medicine
* health & safety
* health policy
* public health
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924807
}}
{{medline-entry
|title=Stroke Mortality Rates and Trends in Romania, 1994-2017.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31624036
|abstract=Romanian national level stroke mortality data is relatively scarce. The current study investigated stroke mortality rates and trends in Romania. All individual deaths registered in Romania during 1994-2017 were analyzed using an anonymized database, based on death certificates. Stroke crude mortality rates (CMR) and age-standardized mortality rates (ASMR) were calculated and expressed per 100,000 persons-year. Between 1994 and 2017, 6,281,873 persons died in Romania, stroke being registered as the underlying cause of death in 959,319 cases. The overall stroke CMR was 188.2 (199.3 for women and 176.5 for men). The CMR for hemorrhagic stroke (HEMS) was 32.4 and for ischemic stroke (ISCS) 10.9. There was a significant decrease in stroke ASMR from 344.4 (95% confidence interval [CI] 343.4-345.4) in 1994 to 192.1 (95% CI 191.5-192.7) in 2017, with an annual percent change ([[APC]]) of 2.53% per year (95% CI 2.50-2.55, P < .001). Although compared with men, women had higher CMRs, when those rates were age-standardized men had higher ASMR as compared with women. The decline in HEMS ASMR had an [[APC]] of 4.65% per year (95% CI 4.59-4.70, P < .001). ISCS ASMR showed an initial increase in ASMR during 1994-2005, with [[APC]] 6.39% per year (95% CI 6.09-6.70, P < .001), followed by a significant decrease until 2017, with [[APC]] 2.83% per year (95% CI 2.59-3.07, P < .001). There was a significant reduction in stroke ASMR during 1994-2017. The decline was slow until 2002 and became steeper after that, with significant differences in gender analysis.
|mesh-terms=* Adult
* Age Distribution
* Aged
* Aged, 80 and over
* Cause of Death
* Female
* Humans
* Life Expectancy
* Male
* Middle Aged
* Prognosis
* Registries
* Risk Assessment
* Risk Factors
* Romania
* Sex Distribution
* Stroke
* Time Factors
|keywords=* Mortality
* age-standardized mortality rates
* life expectancy
* stroke
|full-text-url=https://sci-hub.do/10.1016/j.jstrokecerebrovasdis.2019.104431
}}
{{medline-entry
|title=A new approach to quantifying the EEG during walking: Initial evidence of gait related potentials and their changes with aging and dual tasking.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31449852
|abstract=The electroencephalogram (EEG) can be a useful tool to investigate the neurophysiology of gait during walking. Our aims were to develop an approach that identify and quantify event related potentials (ERPs) during a gait cycle and to examine the effects of aging and dual tasking on these gait related potentials (GRPs). 10 young and 10 older adults walked on a treadmill while wearing a wireless 20-channels EEG and accelerometers on the ankles. Each heel strike extracted from the accelerometers was used as an event to which the electrical brain activity pattern was locked. The subjects performed usual and dual task walking that included an auditory oddball task. GRPs amplitude and latency were computed, and a new measure referred to as Amplitude Pattern Consistency ([[APC]]) was developed to quantify the consistency of these GRP amplitudes within a gait cycle. The results were compared between and within groups using linear mixed model analysis. The electrical pattern during a gait cycle consisted of two main positive GRPs. Differences in these GRPs between young and older adults were observed in Pz and Cz. In Pz, older adults had higher GRPs amplitude (p = 0.006, p = 0.010), and in Cz lower [[APC]] (p = 0.025). Alterations were also observed between the walking tasks. Both groups showed shorter latency during oddball walking compared to usual walking in Cz (p = 0.040). In addition, the [[APC]] in Cz was correlated with gait speed (r = 0.599, p = 0.011) in all subjects and with stride time variability in the older adults (r = -0.703, p = 0.023). This study is the first to define specific gait related potentials within a gait cycle using novel methods for quantifying waveforms. Our findings show the potential of this approach to be applied broadly to study the EEG during gait in a variety of contexts. The observed changes in GRPs with aging and walking task and the relationship between GRPs and gait may suggest the neurophysiologic foundation for studying walking and for developing new approaches for improving gait.
|mesh-terms=* Accelerometry
* Adult
* Aged
* Aging
* Electroencephalography
* Evoked Potentials
* Exercise Test
* Female
* Gait
* Humans
* Male
* Middle Aged
* Multitasking Behavior
* Reaction Time
* Walking
|keywords=* Dual task
* EEG
* Gait cycle
* Gait related potentials (GRP)
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110709
}}
==CCR2==

{{medline-entry
|title=Hip Fracture Leads to Transitory Immune Imprint in Older Patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33072114
|abstract= Hip fracture (HF) is common in the geriatric population and is associated with a poor vital and functional prognosis which could be impacted by immunological changes. The objective here is to decipher immune changes occurring in the 1st days following HF and determine how phenotype, function, and regulation of innate and adaptive compartments adapt during acute stress event.   We included HF patients, aged over 75 years. For each patient, blood samples were taken at five different timepoints: four in the perioperative period (day 0 to hospital discharge) and one at long term (6-12 months). Phenotypical and functional analysis were performed longitudinally on fresh blood or cryopreserved PBMCs. Clinical data were prospectively collected.   One-hundred HF patients and 60 age-matched controls were included. Innate compartment exhibits pro-inflammatory phenotypes (hyperleukocytosis, increase of CD14+ CD16+ proportion and [[CCR2]] expression), maintaining its ability to produce pro-inflammatory cytokines. Adaptive compartment extends toward a transitory immunosuppressive profile (leucopenia) associated with an active T-cell proliferation. Furthermore, increases of LAG-3 and PD-1 and a decrease of 2-B4 expression are observed on T-cells, reinforcing their transitory suppressive status. Of note, these immune changes are transitory and sequential but may participate to a regulation loop necessary for homeostatic immune control at long term.   HF is associated with several transitory immunological changes including pro-inflammatory phenotype in innate compartment and immunosuppressive profile in adaptive compartment. A comprehensive assessment of immune mechanisms implicated in the patient's prognosis after HF could pave the way to develop new immune therapeutics strategies.

|keywords=* acute stress
* aging
* immune response
* inflammation
* regulation loop
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7533556
}}
{{medline-entry
|title=The CC-chemokine receptor 2 is involved in the control of ovarian folliculogenesis and fertility lifespan in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32615332
|abstract=The chemokine receptor 2 ([[CCR2]]) was first described as a chemotactic factor involved in immune responses, but it also plays an essential function in several biological processes. The chemokine (C-C motif) ligand 2 (CCL2) binds to [[CCR2]] triggering G protein-coupled receptor (GPCR) signaling in leukocytes, including activation of PI3K/Akt/mTOR, a key pathway that is also related to follicular activation and survival. However, the potential role of [[CCR2]] in ovarian follicular physiology remain unexplored. Thus, we investigated the role of [[CCR2]] on follicular growth during adult life and aging. Ovaries and oocytes were collected from wild type (WT) mice at 1.5 months old (mo), and [[CCR2]] expression was observed predominantly in oocytes included in growing follicles, as well as after ovulation. Follicle populations were assessed in WT and [[CCR2]]-/- mice at 1.5 mo, and [[CCR2]]-/- mice had more primordial and less primary and secondary follicles, while there were no differences in antral follicle numbers. Pro-apoptotic genes Bax and Casp3 were downregulated, while anti-apoptotic Bcl2 was upregulated in [[CCR2]]-/- mice. To further characterize the role of [[CCR2]] in ovarian aging, follicle populations were assessed in WT and [[CCR2]]-/- mice at 1.5, 2.5, 6, 10, and 12 mo. A larger ovarian follicular reserve at 1.5-6 mo was observed in [[CCR2]]-/- mice. Finally, [[CCR2]]-/- aged mice (6-12 mo) ovulated more oocytes than WT mice. Altogether, these data suggest that [[CCR2]] plays an important role in the regulation of murine folliculogenesis, potentially affecting the reproductive lifespan.

|keywords=* Aging
* CCR2
* Fertility
* Follicle
* Ovary
|full-text-url=https://sci-hub.do/10.1016/j.jri.2020.103174
}}
{{medline-entry
|title=Deficit of resolution receptor magnifies inflammatory leukocyte directed cardiorenal and endothelial dysfunction with signs of cardiomyopathy of obesity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32543720
|abstract=Chronic unresolved inflammation is the primary determinant of cardiovascular disease. Precise mechanisms that define the genesis of unresolved inflammation in heart failure with preserved ejection fraction (HFpEF) are of interest due to the obesity epidemic. To examine the obesity phenotype and its direct/indirect consequences, multiple approaches were employed using the lipoxin receptor (abbreviated as ALX) dysfunction mouse model. Indirect calorimetry analyses revealed that the deletion of ALX dysregulated energy metabolism driving toward age-related obesity. Heart function data suggest that obesity-prone ALX deficient mice had impaired myocardium strain. Comprehensive measurement of chemokines, extracellular matrix, and arrhythmogenic arrays confirmed the dysregulation of multiple ion channels gene expression with amplified inflammatory chemokines and cytokines response at the age of 4 months compared with WT counterparts. Quantitative analyses of leukocytes demonstrated an increase of proinflammatory Ly6C  [[CCR2]]  macrophages in the spleen and heart at a steady-state resulting in an inflamed splenocardiac axis. Signs of subtle inflammation were marked with cardiorenal, endothelial defects with decreased CD31 and eNOS and an increased iNOS and COX2 expression. Thus, ALX receptor deficiency serves as an experimental model that defines multiple cellular and molecular mechanisms in HFpEF that could be a target for the development of HFpEF therapy in cardiovascular medicine.

|keywords=* inflammatory macrophage
* kidney function
* non-resolving inflammation
* obesogenic aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704037
}}
{{medline-entry
|title=Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32154790
|abstract=Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We developed a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived [[CCR2]]+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived [[CCR2]]- cardiac-resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2-mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

|keywords=* Aging
* Bone marrow transplantation
* Cardiology
* Hematopoietic stem cells
* Macrophages
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213793
}}
{{medline-entry
|title=Inflammation and Ectopic Fat Deposition in the Aging Murine Liver Is Influenced by [[CCR2]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31843499
|abstract=Aging is associated with inflammation and metabolic syndrome, which manifests in the liver as nonalcoholic fatty liver disease (NAFLD). NAFLD can range in severity from steatosis to fibrotic steatohepatitis and is a major cause of hepatic morbidity. However, the pathogenesis of NAFLD in naturally aged animals is unclear. Herein, we performed a comprehensive study of lipid content and inflammatory signature of livers in 19-month-old aged female mice. These animals exhibited increased body and liver weight, hepatic triglycerides, and inflammatory gene expression compared with 3-month-old young controls. The aged mice also had a significant increase in F4/80  hepatic macrophages, which coexpressed CD11b, suggesting a circulating monocyte origin. A global knockout of the receptor for monocyte chemoattractant protein ([[CCR2]]) prevented excess steatosis and inflammation in aging livers but did not reduce the number of CD11b  macrophages, suggesting changes in macrophage accumulation precede or are independent from chemokine (C-C motif) ligand-[[CCR2]] signaling in the development of age-related NAFLD. RNA sequencing further elucidated complex changes in inflammatory and metabolic gene expression in the aging liver. In conclusion, we report a previously unknown accumulation of CD11b  macrophages in aged livers with robust inflammatory and metabolic transcriptomic changes. A better understanding of the hallmarks of aging in the liver will be crucial in the development of preventive measures and treatments for end-stage liver disease in elderly patients.
|mesh-terms=* Aging
* Animals
* Body Weight
* Chemokine CCL2
* Disease Models, Animal
* Female
* Gene Expression Profiling
* Inflammation
* Macrophages
* Male
* Mice
* Mice, Inbred C57BL
* Non-alcoholic Fatty Liver Disease
* Organ Size
* Receptors, CCR2

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013280
}}
{{medline-entry
|title=Klotho-mediated targeting of CCL2 suppresses the induction of colorectal cancer progression by stromal cell senescent microenvironments.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31545552
|abstract=Senescent microenvironments play an important role in tumor progression. Here, we report that doxorubicin (DOX)-pretreated or replicative senescent stromal cells (WI-38 and HUVEC) promote colorectal cancer (CRC) cell growth and invasion in vitro and in vivo. These pro-tumorigenic effects were attenuated by exogenous administration of Klotho, an anti-aging factor. We subsequently identified several senescence-associated secretory phenotype (SASP)-associated genes, including CCL2, which were significantly upregulated in both types of senescent stromal cells during replication and DNA damage-induced senescence. Importantly, we found that the secretion of CCL2 by senescent stromal cells was significantly higher than that seen in nonsenescent cells or in senescent cells pretreated with Klotho. Notably, CCL2 was found to accelerate CRC cell proliferation and invasion, while this effect could be blocked by administration of a specific [[CCR2]] antagonist. We further show that Klotho can suppress NF-κB activation during DOX-induced senescence and thus block CCL2 transcription. Low expression of Klotho, or high expression of CCL2 in patient tumor tissues, correlated with poor overall survival of CRC patients. Collectively, our findings suggest that senescent stromal cells are linked to progression of CRC. Klotho can suppress the senescent stromal cell-associated triggering of CRC progression by inhibiting the expression of SASP factors including CCL2. The identification of key SASP factors such as CCL2 may provide potential therapeutic targets for improving CRC therapy.
|mesh-terms=* Aged
* Cell Line, Tumor
* Cell Movement
* Cell Proliferation
* Cellular Microenvironment
* Cellular Senescence
* Chemokine CCL2
* Colorectal Neoplasms
* Disease Progression
* Down-Regulation
* Doxorubicin
* Female
* Glucuronidase
* Human Umbilical Vein Endothelial Cells
* Humans
* Male
* Middle Aged
* NF-kappa B
* Neoplasm Invasiveness
* Proportional Hazards Models
* Signal Transduction
* Stromal Cells
|keywords=* CCL2
* Klotho
* colorectal cancer
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822285
}}
==PCNA==

{{medline-entry
|title=Impairment of Pol β-related DNA Base-excision Repair Leads to Ovarian Aging in Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33223510
|abstract=The mechanism underlying the association between age and depletion of the human ovarian follicle reserves remains uncertain. Many identified that impaired DNA polymerase β (Pol β)-mediated DNA base-excision repair (BER) drives to mouse oocyte aging. With aging, DNA lesions accumulate in primordial follicles. However, the expression of most DNA BER genes, including APE1, OGG1, XRCC1, Ligase I, Ligase α, [[PCNA]] and FEN1, remains unchanged during aging in mouse oocytes. Also, the reproductive capacity of Pol β+/- heterozygote mice was impaired, and the primordial follicle counts were lower than that of wild type (wt) mice. The DNA lesions of heterozygous mice increased. Moreover, the Pol β knockdown leads to increased DNA damage in oocytes and decreased survival rate of oocytes. Oocytes over-expressing Pol β showed that the vitality of senescent cells enhancesis significantly. Furthermore, serum concentrations of anti-Müllerian hormone (AMH) indicated that the ovarian reserves of young mice with Pol β germline mutations were lower than those in wt. These data show that Pol β-related DNA BER efficiency is a major factor governing oocyte aging in mice.

|keywords=* BER
* Pol β
* menopause
* oocytes
* ovarian aging
|full-text-url=https://sci-hub.do/10.18632/aging.104123
}}
{{medline-entry
|title=[Heat shock protein 90 (HSP90) in age-dependent changes in the number of fibroblasts in human skin.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32362082
|abstract=The aim of this work was to examine the content of heat shock protein 90 (HSP90) in fibroblasts of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of HSP90 in age-dependent changes in the number of fibroblasts in the dermis. HSP90, proliferating cells nuclear antigen ([[PCNA]]) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for HSP90 in the dermis is not changed from 20 weeks of development to 20 years old. Percent of HSP90 positive fibroblasts in dermis is decreased from 21 to 60 years old. From 61 year, the number of HSP90 positive fibroblasts in dermis is increased. Age-related changes in the number of HSP90 positive fibroblasts is not statistically associated with an age-related decrease in a total number and percent of [[PCNA]] positive fibroblasts the dermis.
|mesh-terms=* Adolescent
* Adult
* Aging
* Child
* Child, Preschool
* Dermis
* Female
* Fibroblasts
* HSP90 Heat-Shock Proteins
* Humans
* Infant
* Infant, Newborn
* Middle Aged
* Pregnancy
* Young Adult
|keywords=* HSP90
* PCNA
* aging
* fibroblasts
* skin

}}
{{medline-entry
|title=A Higher Frequency Administration of the Nontoxic Cycloartane-Type Triterpene Argentatin A Improved Its Anti-Tumor Activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32295227
|abstract=[i]Parthenium argentatum[/i] (Gray), commonly known as guayule, has been used to obtain natural rubber since the beginning of the 20th century. Additionally, the so called "resin" is a waste product derived from the industrial process. The cycloartane-type triterpene Argentatin A (AA) is one of the main constituents of the industrial waste resin. In this study we evaluated the AA anticancer activity both in vitro and in vivo in the HCT116 colon cancer cells. The apoptosis promotion of AA was assessed by the annexin V/propidium iodide (PI) assay. The senescence was evaluated for SA-β-galactosidase, and [[PCNA]] was used as a marker of proliferation. Its antitumor activity was evaluated using a xenograft mouse model. The results indicated that AA-induced apoptosis in HCT-116 cells and was positively stained for SA-β-galactosidase. In the xenografted mice test, the administration of AA at the dose of 250 mg/kg three times a week for 21 days reduced tumor growth by 78.1%. A comparable tumor reduction was achieved with cisplatin at the dose of 2 mg/kg administered three times a week for 21 days. However, nude mice treated with AA did not lose weight, as they did remarkably when treated with cisplatin. Furthermore, the animals treated with AA showed similar blood profiles as the healthy control group. These data indicate the low toxicity of AA compared to that shown by cisplatin.

|keywords=* Argentatin A
* PCNA
* antiproliferative
* antitumor
* apoptosis
* cell senescence
* colon cancer
* xenografts
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221627
}}
{{medline-entry
|title=[Mechanosensitive protein of Hippo regulatory pathway - transcription coactivator with PZD-binding motif (TAZ) in human skin during aging.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32145162
|abstract=The aim of this work was to examine the content of transcription coactivator with PZD-binding motif (TAZ) in fibroblasts and blood vessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of TAZ in age-dependent changes in the number of fibroblasts and blood vessels in the dermis. TAZ, proliferating cells nuclear antigen ([[PCNA]]), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that portion of fibroblasts with positive staining for TAZ in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of TAZ positive fibroblasts in dermis is increased since 41 years old until 60-85 years old group. The content of TAZ in blood vessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old followed by an increase from 41 years old. From 61 to 85 years of life, content of TAZ in dermal vessels was not differ from those in 41-60 age group. Age-related changes in the content of TAZ in fibroblasts and blood vessels is not associated with an age-related decrease in total number and percent of [[PCNA]] positive fibroblasts, the number of blood vessels in the dermis.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Child
* Child, Preschool
* Dermis
* Female
* Fibroblasts
* Humans
* Infant
* Infant, Newborn
* Middle Aged
* Pregnancy
* Protein-Serine-Threonine Kinases
* Skin Aging
* Trans-Activators
* Young Adult
|keywords=* CD31
* PCNA
* TAZ
* aging
* blood vessels
* fibroblasts
* skin

}}
{{medline-entry
|title=[Mechanosensitive Yes-associated protein in human skin during aging.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31800177
|abstract=The aim of this work was to examine the content of Yes-associated protein (YAP) in fibroblasts and blood microvessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of YAP in age-dependent changes in the number of fibroblasts and blood microvessels in the dermis. YAP, proliferating cells nuclear antigen ([[PCNA]]), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that portion of fibroblasts with positive staining for YAP in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of YAP positive fibroblasts in dermis is increased sufficiently since 41 years old until 60-85 years old group. The content of YAP in blood microvessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old. Age-related changes in the content of YAP in fibroblasts and blood microvessels is not statistically associated with an age-related decrease in total number and percent of [[PCNA]] positive fibroblasts, the number of blood vessels in the dermis.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Adult
* Aged
* Aged, 80 and over
* Aging
* Dermis
* Endothelial Cells
* Female
* Fibroblasts
* Humans
* Middle Aged
* Pregnancy
* Skin Aging
* Transcription Factors
|keywords=* CD31
* PCNA
* YAP
* aging
* blood vessels
* fibroblasts
* skin

}}
{{medline-entry
|title=[Role of mechanosensitive protein Piezo1 in human age-dependent changes in the number of fibroblasts and blood vessels in human skin.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31512421
|abstract=The aim of this work was to examine the content of Piezo1 in fibroblasts and blood vessels of human dermis from the development until deep aging (from 20 weeks of pregnancy until 85 years old), and defining of a role of Piezo1 in age-dependent changes in the number of fibroblasts and blood vessels in the dermis. Piezo1, proliferating cells nuclear antigen ([[PCNA]]), endothelial cells marker CD31 were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for Piezo1 in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of Piezo1 positive fibroblasts in dermis is increased sufficiently since 41 years old until 60-85 years old group. The content of Piezo1 in blood vessels in the human dermis is decreased sufficiently from 20 weeks of pregnancy until 40 years old. Age-related changes in the content of Piezo1 in fibroblasts and blood vessels is not associated with an age-related decrease in total number and percent of [[PCNA]] positive fibroblasts, the number of blood vessels in the dermis.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Blood Vessels
* Child
* Child, Preschool
* Dermis
* Female
* Fibroblasts
* Humans
* Infant
* Ion Channels
* Male
* Middle Aged
* Platelet Endothelial Cell Adhesion Molecule-1
* Pregnancy
* Proliferating Cell Nuclear Antigen
* Skin Aging
|keywords=* CD31
* PCNA
* Piezo1
* aging
* blood vessels
* fibroblasts
* skin

}}
==EGF==

{{medline-entry
|title=Acute, exercise-induced alterations in cytokines and chemokines in the blood distinguish physically active and sedentary aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33289019
|abstract=Aging results in a chronic, pro-inflammatory state which can promote and exacerbate age-associated diseases. In contrast, physical activity in older adults improves whole body health, protects against disease, and reduces inflammation, but the elderly are less active making it difficult to disentangle the effects of aging from a sedentary lifestyle. To interrogate this interaction, we analyzed peripheral blood collected at rest and post-exercise from 68 healthy younger and older donors that were either physically active aerobic exercisers or chronically sedentary. Subjects were profiled for 44 low-abundance cytokines, chemokines and growth factors in peripheral blood. At rest, we found that regular physical activity had no impact on the age-related elevation in circulating IL-18, eotaxin, GRO, IL-8, IP-10, PDGF-AA or RANTES. Similarly, there was no impact of physical activity on the age-related reduction in V[[EGF]], [[EGF]] or IL-12 (p70). However, older exercisers had lower resting plasma fractalkine, IL-3, IL-6 and TNF-α compared to sedentary older adults. In contrast to our resting characterization, blood responses following acute exercise produced more striking difference between groups. Physically active younger and older subjects increased over 50% of the analyzed factors in their blood which resulted in both unique and overlapping exercise signatures. However, sedentary individuals, particularly the elderly, had few detectable changes in response to exercise. Overall, we show that long term physical activity has a limited effect on age-associated changes in basal cytokines and chemokines in the healthy elderly, yet physically active individuals exhibit a broader induction of factors post-exercise irrespective of age.

|keywords=* growth factors
* human aging
* inflammation
* physical activity
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa310
}}
{{medline-entry
|title=Proinflammation, profibrosis, and arterial aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33103036
|abstract=Aging is a major risk factor for quintessential cardiovascular diseases, which are closely related to arterial proinflammation. The age-related alterations of the amount, distribution, and properties of the collagen fibers, such as cross-links and degradation in the arterial wall, are the major sequelae of proinflammation. In the aging arterial wall, collagen types I, II, and III are predominant,  and are mainly produced by stiffened vascular smooth muscle cells (VSMCs) governed by proinflammatory signaling, leading to profibrosis. Profibrosis is regulated by an increase in the proinflammatory molecules angiotensin II, milk fat globule-[[EGF]]-VIII, and transforming growth factor-beta 1 (TGF-β1) signaling and a decrease in the vasorin signaling cascade. The release of these proinflammatory factors triggers the activation of matrix metalloproteinase type II (MMP-2) and activates profibrogenic TGF-β1 signaling, contributing to profibrosis. The age-associated increase in activated MMP-2 cleaves latent TGF-β and subsequently increases TGF-β1 activity leading to collagen deposition in the arterial wall. Furthermore, a blockade of the proinflammatory signaling pathway alleviates the fibrogenic signaling, reduces profibrosis, and prevents arterial stiffening with aging. Thus, age-associated proinflammatory-profibrosis coupling is the underlying molecular mechanism of arterial stiffening with advancing age.

|keywords=* aging
* artery
* collagen
* profibrosis
* proinflammation
* stiffening
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574637
}}
{{medline-entry
|title=Hinokitiol induces cell death and inhibits epidermal growth factor-induced cell migration and signaling pathways in human cervical adenocarcinoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32917321
|abstract=The aim of this study was to examine the antitumor activity of hinokitiol for its clinical application in the treatment of human cervical carcinoma. Cervical carcinoma HeLa cells were treated by different concentrations of hinokitiol. Flow cytometry was used to analyze cell cycle. Senescence-associated β-galactosidase (SA-β-gal) assay was used to identify senescent cells. The effects of hinokitiol on [[EGF]]-induced cell migration were determined by wound healing and transwell migration assays. Western blot was used to detect proteins involved in cell cycle progression, apoptosis, autophagy, and [[EGF]]-induced signaling pathways. Hinokitiol suppressed cell viability in a dose-dependent manner. Flow cytometric analysis indicated that hinokitiol treatment resulted in cell cycle arrest at G1 phase, with reduced number of cells in the G2/M phase. Western blot analysis further demonstrated that hinokitiol treatment increased the levels of p53 and p21, and concomitantly reduced the expression of cell cycle regulatory proteins, including cyclin D and cyclin E. SA-β-gal assay showed that hinokitiol treatment significantly induced β-galactosidase activity. In addition, treatment with hinokitiol increased the accumulation of the autophagy regulators, beclin 1 and microtubule-associated protein 1 light chain 3 (LC3-II), in a dose-dependent manner; however, it did not induce caspase-3 activation and poly ADP ribose polymerase (PARP) cleavage. In addition, epidermal growth factor-induced cell migration and c-Jun N-terminal kinase (JNK) and focal adhesion kinase (FAK) phosphorylation were significantly inhibited by hinokitiol. Our findings revealed that hinokitiol might serve as a potential therapeutic agent for cervical carcinoma therapy.

|keywords=* Autophagy
* Epidermal growth factor
* Hinokitiol
* Senescence
* c-Jun N-Terminal kinase
|full-text-url=https://sci-hub.do/10.1016/j.tjog.2020.07.013
}}
{{medline-entry
|title=Activation of epidermal growth factor receptor signaling mediates cellular senescence induced by certain pro-inflammatory cytokines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32323422
|abstract=It is well established that inflammation in the body promotes organism aging, and recent studies have attributed a similar effect to senescent cells. Considering that certain pro-inflammatory cytokines can induce cellular senescence, systematically evaluating the effects of pro-inflammatory cytokines in cellular senescence is an important and urgent scientific problem, especially given the ongoing surge in aging human populations. Treating IMR90 cells and HUVECs with pro-inflammatory cytokines identified six factors able to efficiently induce cellular senescence. Of these senescence-inducing cytokines, the activity of five (namely IL-1β, IL-13, MCP-2, MIP-3α, and SDF-1α) was significantly inhibited by treatment with cetuximab (an antibody targeting epidermal growth factor receptor [[[EGF]]R]), gefitinib (a small molecule inhibitor of [[EGF]]R), and [[EGF]]R knockdown. In addition, treatment with one of the senescence-inducing cytokines, SDF-1α, significantly increased the phosphorylation levels of [[EGF]]R, as well as Erk1/2. These results suggested that pro-inflammatory cytokines induce cellular senescence by activating [[EGF]]R signaling. Next, we found that [[EGF]] treatment could also induce cellular senescence of IMR90 cells and HUVECs. Mechanically, [[EGF]] induced cellular senescence via excessive activation of Ras and the Ras-BRaf-Erk1/2 signaling axis. Moreover, [[EGF]]R activation induced IMR90 cells to secrete certain senescence-associated secretory phenotype factors (IL-8 and MMP-3). In summary, we report that certain pro-inflammatory cytokines induce cellular senescence through activation of the [[EGF]]R-Ras signaling pathway. Our study thus offers new insight into a long-ignored mechanism by which [[EGF]]R could regulate cellular senescence and suggests that growth signals themselves may catalyze aging under certain conditions.

|keywords=* EGFR
* HUVEC
* IMR90
* Ras signaling
* pro-inflammatory cytokine
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253070
}}
{{medline-entry
|title=Insulin Signaling in Intestinal Stem and Progenitor Cells as an Important Determinant of Physiological and Metabolic Traits in [i]Drosophila[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32225024
|abstract=The insulin-IGF-1 signaling (IIS) pathway is conserved throughout multicellular organisms and regulates many traits, including aging, reproduction, feeding, metabolism, stress resistance, and growth. Here, we present evidence of a survival-sustaining role for IIS in a subset of gut cells in [i]Drosophila melanogaster[/i], namely the intestinal stem cells (ISCs) and progenitor cells. Using RNAi to knockdown the insulin receptor, we found that inhibition of IIS in ISCs statistically shortened the lifespan of experimental flies compared with non-knockdown controls, and also shortened their survival under starvation or malnutrition conditions. These flies also showed decreased reproduction and feeding, and had lower amounts of glycogen and glucose in the body. In addition, increased expression was observed for the [i]Drosophila[/i] transcripts for the insulin-like peptides [i]dilp2[/i], [i]dilp5[/i], and [i]dilp6.[/i] This may reflect increased insulin signaling in peripheral tissues supported by up-regulation of the target of the brain insulin gene ([i]tobi[/i]). In contrast, activation of IIS (via knockdown of the insulin pathway inhibitor PTEN) in intestinal stem and progenitor cells decreased fly resistance to malnutrition, potentially by affecting adipokinetic hormone signaling. Finally, [i]Pten[/i] knockdown to enhance IIS also activated JAK-STAT signaling in gut tissue by up-regulation of [i]upd2[/i], [i]upd3[/i], and [i]soc36[/i] genes, as well as genes encoding the [[EGF]] receptor ligands [i]spitz[/i] and [i]vein[/i]. These results clearly demonstrate that manipulating insulin levels may be used to modulate various fly traits, which are important determinants of organismal survival.

|keywords=* ISC
* fruit fly
* insulin signaling pathway
* lifespan
* metabolism
* midgut
* progenitor cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226132
}}
{{medline-entry
|title=Different cellular properties and loss of nuclear signalling of porcine epidermal growth factor receptor with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32001323
|abstract=Epidermal growth factor ([[EGF]]) has important physiological functions that are mediated by the epidermal growth factor receptor ([[EGF]]R); however, to date, the changes in cellular behaviours and signalling properties of [[EGF]]/[[EGF]]R with aging remain unclear in the pig tissue models. Hence, the present study used porcine hepatocytes as a model to explore this issue. The study revealed the following results: 1) [[EGF]] could activate the intra-cellular signalling pathways in a time- and dose-dependent manner both in the young- and aged-pig hepatocytes, [[EGF]] induced tyrosine phosphorylation of [[EGF]]R, signal transducers and activators of transcription 3 (STAT3), protein kinase B (AKT) and extra-cellular signal-regulated kinase 1/2 (ERK1/2). Nevertheless, the [[EGF]]'s signalling ability in the aged-pig hepatocytes was significantly reduced compared with that of the young-pig hepatocytes; 2) although [[EGF]]/[[EGF]]R can still be internalised into cells in a time-dependent manner with aging, the endocytic pathway differs between the young- and aged-pig hepatocytes. Furthermore, the results of the present study indicated that caveolin may play a pivotal role in the endocytosis of [[EGF]]/[[EGF]]R in the aged-pig hepatocytes, which is different from that of [[EGF]]/[[EGF]]R's endocytosis in young-pig hepatocytes; 3) It is well-known that [[EGF]]R carried out its biological effects via two signalling pathways, cytoplasmic pathway (traditional) and nuclear pathway; however, we found that the nuclear localisation of [[EGF]]R was significantly reduced in the aged-pig hepatocytes, which indicated that [[EGF]]R may lose its nuclear pathway with aging. Collectively, the present study lays the foundation for further study regarding the biological functional changes occurring in [[EGF]]/[[EGF]]R with aging.
|mesh-terms=* Animals
* ErbB Receptors
* Signal Transduction
* Swine
|keywords=* Aging
* Cell behaviour
* EGF
* EGFR
* Signalling pathway
|full-text-url=https://sci-hub.do/10.1016/j.ygcen.2020.113415
}}
==FOXO3==

{{medline-entry
|title=The DNA methylation of [[FOXO3]] and TP53 as a blood biomarker of late-onset asthma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33298101
|abstract=Late-onset asthma (LOA) is beginning to account for an increasing proportion of asthma patients, which is often underdiagnosed in the elderly. Studies on the possible relations between aging-related genes and LOA contribute to the diagnosis and treatment of LOA. Forkhead Box O3 ([[FOXO3]]) and TP53 are two classic aging-related genes. DNA methylation varies greatly with age which may play an important role in the pathogenesis of LOA. We supposed that the differentially methylated sites of [[FOXO3]] and TP53 associated with clinical phenotypes of LOA may be useful biomarkers for the early screening of LOA. The mRNA expression and DNA methylation of [[FOXO3]] and TP53 in peripheral blood of 43 LOA patients (15 mild LOA, 15 moderate LOA and 13 severe LOA) and 60 healthy controls (HCs) were determined. The association of methylated sites with age was assessed by Cox regression to control the potential confounders. Then, the correlation between differentially methylated sites (DMSs; p-value < 0.05) and clinical lung function in LOA patients was evaluated. Next, candidate DMSs combining with age were evaluated to predict LOA by receiver operating characteristic (ROC) analysis and principal components analysis (PCA). Finally, HDM-stressed asthma model was constructed, and DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-AZA) were used to determine the regulation of DNA methylation on the expression of [[FOXO3]] and TP53. Compared with HCs, the mRNA expression and DNA methylation of [[FOXO3]] and TP53 vary significantly in LOA patients. Besides, 8 DMSs from LOA patients were identified. Two of the DMSs, chr6:108882977 ([[FOXO3]]) and chr17:7591672 (TP53), were associated with the severity of LOA. The combination of the two DMSs and age could predict LOA with high accuracy (AUC values = 0.924). In HDM-stressed asthma model, DNA demethylation increased the expression of [[FOXO3]] and P53. The mRNA expression of [[FOXO3]] and TP53 varies significantly in peripheral blood of LOA patients, which may be due to the regulation of DNA methylation. [[FOXO3]] and TP53 methylation is a suitable blood biomarker to predict LOA, which may be useful targets for the risk diagnosis and clinical management of LOA.

|keywords=* Aging
* DNA methylation
* FOXO3
* Late-onset asthma
* TP53
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726856
}}
{{medline-entry
|title=[[FOXO3]] targets are reprogrammed as Huntington's disease neural cells and striatal neurons face senescence with p16  increase.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33156570
|abstract=Neurodegenerative diseases (ND) have been linked to the critical process in aging-cellular senescence. However, the temporal dynamics of cellular senescence in ND conditions is unresolved. Here, we show senescence features develop in human Huntington's disease (HD) neural stem cells (NSCs) and medium spiny neurons (MSNs), including the increase of p16  , a key inducer of cellular senescence. We found that HD NSCs reprogram the transcriptional targets of [[FOXO3]], a major cell survival factor able to repress cell senescence, antagonizing p16  expression via the [[FOXO3]] repression of the transcriptional modulator ETS2. Additionally, p16  promotes cellular senescence features in human HD NSCs and MSNs. These findings suggest that cellular senescence may develop during neuronal differentiation in HD and that the [[FOXO3]]-ETS2-p16  axis may be part of molecular responses aimed at mitigating this phenomenon. Our studies identify neuronal differentiation with accelerated aging of neural progenitors and neurons as an alteration that could be linked to NDs.

|keywords=* neurodegenerative disease
* neuronal differentiation
* neuronal senescence
* response mechanisms
* temporal dynamics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681055
}}
{{medline-entry
|title=Astaxanthin as a Putative Geroprotector: Molecular Basis and Focus on Brain Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32635607
|abstract=In recent years, the scientific interest in natural compounds with geroprotective activities has grown exponentially. Among the various naturally derived molecules, astaxanthin (ASX) represents a highly promising candidate geroprotector. By virtue of the central polyene chain, ASX acts as a scavenger of free radicals in the internal membrane layer and simultaneously controls oxidation on the membrane surface. Moreover, several studies have highlighted ASX's ability to modulate numerous biological mechanisms at the cellular level, including the modulation of transcription factors and genes directly linked to longevity-related pathways. One of the main relevant evolutionarily-conserved transcription factors modulated by astaxanthin is the forkhead box O3 gene ([[FOXO3]]), which has been recognized as a critical controller of cell fate and function. Moreover, [[FOXO3]] is one of only two genes shown to robustly affect human longevity. Due to its tropism in the brain, ASX has recently been studied as a putative neuroprotective molecule capable of delaying or preventing brain aging in different experimental models of brain damage or neurodegenerative diseases. Astaxanthin has been observed to slow down brain aging by increasing brain-derived neurotrophic factor (BDNF) levels in the brain, attenuating oxidative damage to lipids, protein, and DNA and protecting mitochondrial functions. Emerging data now suggest that ASX can modulate Nrf2, [[FOXO3]], Sirt1, and Klotho proteins that are linked to longevity. Together, these mechanisms provide support for a role of ASX as a potential geroneuroprotector.

|keywords=* FOXO3
* NRF2
* SIRT1
* astaxanthin
* geroprotector
* longevity
* neuroprotection
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401246
}}
{{medline-entry
|title=Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32340146
|abstract=Ageing is associated with disrupted redox signalling and increased circulating inflammatory cytokines. Skeletal muscle homeostasis depends on the balance between muscle hypertrophy, atrophy and regeneration, however during ageing this balance is disrupted. The molecular pathways underlying the age-related decline in muscle regenerative potential remain elusive. microRNAs are conserved robust gene expression regulators in all tissues including skeletal muscle. Here, we studied satellite cells from adult and old mice to demonstrate that inhibition of miR-21 in satellite cells from old mice improves myogenesis. We determined that increased levels of proinflammatory cytokines, TNFα and IL6, as well as H O , increased miR-21 expression in primary myoblasts, which in turn resulted in their decreased viability and myogenic potential. Inhibition of miR-21 function rescued the decreased size of myotubes following TNFα or IL6 treatment. Moreover, we demonstrated that miR-21 could inhibit myogenesis in vitro via regulating IL6R, PTEN and [[FOXO3]] signalling. In summary, upregulation of miR-21 in satellite cells and muscle during ageing may occur in response to elevated levels of TNFα and IL6, within satellite cells or myofibrillar environment contributing to skeletal muscle ageing and potentially a disease-related decline in potential for muscle regeneration.

|keywords=* IL6
* IL6R
* aging
* cachexia
* miR-21
* microRNA
* muscle
* regeneration
* sarcopenia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222422
}}
{{medline-entry
|title=Variable DNA methylation of aging-related genes is associated with male COPD.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31684967
|abstract=Chronic obstructive pulmonary disease (COPD) is a chronic lung inflammatory disease which has a close relationship with aging. Genome-wide analysis reveals that DNA methylation markers vary obviously with age. DNA methylation variations in peripheral blood have the potential to be biomarkers for COPD. However, the specific DNA methylation of aging-related genes in the peripheral blood of COPD patients remains largely unknown. Firstly, 9 aging-related differentially expressed genes (DEGs) in COPD patients were screened out from the 25 aging-related genes profile through a comprehensive screening strategy. Secondly, qPCR and multiple targeted bisulfite enrichment sequencing (MethTarget) were used to detect the mRNA level and DNA methylation level of the 9 differentially expressed genes in the peripheral blood of 60 control subjects and 45 COPD patients. The candidate functional CpG sites were selected on the basis of the regulation ability of the target gene expression. Thirdly, the correlation was evaluated between the DNA methylation level of the key CpG sites and the clinical parameters of COPD patients, including forced expiratory volume in one second (FEV1), forced expiratory volume in one second as percentage of predicted volume (FEV1%), forced expiratory volume/ forced vital capacity (FEV/FVC), modified British medical research council (mMRC) score, acute exacerbation frequency and the situation of frequent of acute aggravation (CAT) score. Lastly, differentially methylated CpG sites unrelated to smoking were also determined in COPD patients. Of the 9 differentially expressed aging-related genes, the mRNA expression of 8 genes were detected to be significantly down-regulated in COPD group, compared with control group. Meanwhile, the methylated level of all aging-related genes was changed in COPD group containing 219 COPD-related CpG sites in total. Notably, 27 CpG sites of [[FOXO3]] gene showed a lower False Discovery Rate (FDR) and higher methylation difference values. Also, some variable DNA methylation is associated with the severity of COPD. Additionally, of the 219 COPD-related CpG sites, 147 CpG sites were not related to smoking. These results identified that the mRNA expression and DNA methylation level of aging-related genes were changed in male COPD patients, which provides a molecular link between aging and COPD. The identified CpG markers are associated with the severity of COPD and provide new insights into the prediction and identification of COPD.
|mesh-terms=* Adolescent
* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Case-Control Studies
* CpG Islands
* DNA Methylation
* Databases, Genetic
* Female
* Forced Expiratory Volume
* Forkhead Transcription Factors
* Genetic Predisposition to Disease
* Humans
* Lung
* Male
* Middle Aged
* Pulmonary Disease, Chronic Obstructive
* Risk Assessment
* Risk Factors
* Severity of Illness Index
* Sex Factors
* Transcriptome
* Vital Capacity
* Young Adult
|keywords=* Aging
* Aging-related genes
* COPD
* DNA methylation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829949
}}
{{medline-entry
|title=A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31415568
|abstract=Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and [[FOXO3]] being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.
|mesh-terms=* Animals
* Animals, Genetically Modified
* Cohort Studies
* Disease Models, Animal
* Drosophila melanogaster
* Feeding Behavior
* Female
* Gene Knockdown Techniques
* Gout
* Humans
* Insulin
* Kidney Calculi
* Longevity
* Male
* Metabolic Networks and Pathways
* Middle Aged
* NADPH Oxidases
* Polymorphism, Single Nucleotide
* Purines
* Signal Transduction
* Urate Oxidase
* Uric Acid

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695094
}}
==ABR==

{{medline-entry
|title=[Hidden hearing loss and early identification].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32791650
|abstract=b  The symptoms of hidden hearing loss（HHL） are concealed, mainly manifested as defects in the threshold upper auditory function, which are related to noise exposure, aging and drug damage. There is no definite evidence to prove that whether the three factors participate in mechanism of synaptic damage in the cochlea. The clinical audiological characteristics of HHL are mostly as follows: the normal threshold of PTA and the wave response of [[ABR]]; the amplitude of the CAP of [[ABR]] wave Ⅰ or ECochG is lower at medium and high stimulation intensity; the lower speech recognition rate under noise, etc. Ultra-high frequency pure tone audiometry, a series of objective audiological examinations, such as [[ABR]], ECochG and frequency-following response, speech audiometry under noise, noise exposure questionnaire evaluation were applied to detect HHL at early stage.
|mesh-terms=* Acoustic Stimulation
* Audiometry, Pure-Tone
* Auditory Threshold
* Evoked Potentials, Auditory, Brain Stem
* Hearing Loss, Noise-Induced
* Humans
* Noise
|keywords=* aging
* drug damage
* hidden hearing loss
* noise exposure
|full-text-url=https://sci-hub.do/10.13201/j.issn.2096-7993.2020.07.023
}}
{{medline-entry
|title=Aging But Not Age-Related Hearing Loss Dominates the Decrease of Parvalbumin Immunoreactivity in the Primary Auditory Cortex of Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32327469
|abstract=Alterations in inhibitory circuits of the primary auditory cortex (pAC) have been shown to be an aspect of aging and age-related hearing loss (AHL). Several studies reported a decline in parvalbumin (PV) immunoreactivity in aged rodent pAC of animals displaying AHL and conclude a relationship between reduced sensitivity and declined PV immunoreactivity. However, it remains elusive whether AHL or a general molecular aging is causative for decreased PV immunoreactivity. In this study, we aimed to disentangle the effects of AHL and general aging on PV immunoreactivity patterns in inhibitory interneurons of mouse pAC. We compared young and old animals of a mouse line with AHL (C57BL/6) and a mutant (C57B6.CAST-[i]Cdh23 [/i] ) that is not vulnerable to AHL according to their hearing status by measuring auditory brainstem responses ([[ABR]]s) and by an immunohistochemical evaluation of the PV immunoreactivity patterns in two dimensions (rostro-caudal and layer) in the pAC. Although AHL could be confirmed by [[ABR]] measurements for the C57BL/6 mice, both aged strains showed a similar reduction of PV  positive interneurons in both, number and density. The pattern of reduction across the rostro-caudal axis and across cortical layers was similar for both aged lines. Our results demonstrate that a reduced PV immunoreactivity is a sign of general, molecular aging and not related to AHL.

|keywords=* age-related hearing loss
* aging
* mouse primary auditoy cortex
* parvalbumin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210488
}}
{{medline-entry
|title=Hearing loss through apoptosis of the spiral ganglion neurons in apolipoprotein E knockout mice fed with a western diet.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31948760
|abstract=Age-related hearing loss (ARHL) is a neurodegenerative disease associated with an aged population. ARHL is influenced by biological factors such as aging, sex difference, and atherosclerosis. The mechanisms of ARHL caused by atherosclerosis have not been previously determined in apolipoprotein E knockout (ApoE KO) male mice. To investigate the onset and cause of the hearing loss, ApoE KO male mice were treated with a western diet (ApoE KO-WD) for 16 weeks. The lipid profile, atherosclerotic plaques throughout the aorta, and auditory brainstem response ([[ABR]]) thresholds were measured in the ApoE KO-WD male mice. The expression of S100 calcium-binding protein B (S100B), a neuronal damage biomarker, was also observed. Reactive oxygen species (ROS) and apoptosis rates were detected in the cochlea of the ApoE KO male mice. Atherosclerotic plaques on the aorta and [[ABR]] thresholds were significantly increased in the ApoE KO-WD male mice at 24 weeks of age. [[ABR]] thresholds had a statistically significant positive correlation with the area of atherosclerotic plaques (r = 0.783, p = 0.013) in male mice at 24 weeks of age. S100B protein expression and the dihydroethidium (DHE) reaction to ROS in the cochlear spiral ganglion neurons (SGNs) were significantly increased in the ApoE KO and ApoE KO-WD male mice. Cells positive for active caspase-3 and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) in the SGNs were significantly increased in ApoE KO-WD male mice indicating an increased rate of cellular apoptosis. In conclusion, ROS in the SGNs were activated by increased S100B expression in ApoE KO-WD male mice, and this resulted in an increased apoptosis rate. Thus, hearing loss began at 16 weeks in ApoE KO-WD male mice. Our results suggest that the ApoE KO-WD male mice are a suitable animal model for studying ARHL associated with exacerbated atherosclerosis.
|mesh-terms=* Aging
* Animals
* Apolipoproteins E
* Apoptosis
* Diet, Western
* Disease Models, Animal
* Hearing Loss
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Neurons
* Spiral Ganglion
|keywords=* Apoptosis
* Atherosclerosis
* Hearing loss
* Reactive oxygen specie
* Spiral ganglion neurons
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2019.12.100
}}
{{medline-entry
|title=Effects of enriched endogenous omega-3 fatty acids on age-related hearing loss in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31771637
|abstract=Dietary intervention is a practical prevention strategy for age-related hearing loss (AHL). Omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may be effective in prevention of AHL due to their anti-inflammatory and tissue-protective functions. Age-related changes in the hearing function of wild-type and Fat-1 transgenic mice derived from the C57BL/6N strain, which can convert omega-6 PUFAs to n-3 PUFAs and consequently produce enriched endogenous n-3 PUFAs, were investigated to test the efficacy of n-3 PUFAs for AHL prevention. At 2 months, the baseline auditory brainstem response ([[ABR]]) thresholds were the same in Fat-1 and wild-type mice at 8-16 kHz but were significantly higher in Fat-1 mice at 4 and 32 kHz. In contrast, the [[ABR]] thresholds of Fat-1 mice were significantly lower at 10 months. Moreover, the [[ABR]] thresholds of Fat-1 mice at low-middle frequencies were significantly lower at 13 months (12 kHz). Body weights were significantly reduced in Fat-1 mice at 13 months, but not at 2, 10, and 16-17 months. In conclusion, enriched endogenous n-3 PUFAs produced due to the expression of the Fat-1 transgene partially alleviated AHL in male C57BL/6N mice.
|mesh-terms=* Aging
* Animals
* Body Weight
* Caenorhabditis elegans Proteins
* Cochlea
* Evoked Potentials, Auditory, Brain Stem
* Fatty Acid Desaturases
* Fatty Acids, Omega-3
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Neurons
* Presbycusis
* Spiral Ganglion
|keywords=* Age-related hearing loss
* C57BL/6 mouse
* Cochlea
* Omega-3 (n-3) fatty acids
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878677
}}
{{medline-entry
|title=Hearing impairment and associated morphological changes in pituitary adenylate cyclase activating polypeptide (PACAP)-deficient mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31601840
|abstract=Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system having antiapoptotic effects. Expression of Ca -binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response ([[ABR]]) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced [[ABR]] wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.
|mesh-terms=* Aging
* Animals
* Cochlea
* Evoked Potentials, Auditory, Brain Stem
* Genotype
* Hearing
* Hearing Loss
* Inflammation
* Male
* Mice
* Mice, Knockout
* Models, Animal
* Neovascularization, Pathologic
* Neurons
* Pituitary Adenylate Cyclase-Activating Polypeptide
* Proteome
* Proto-Oncogene Proteins c-fos

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787024
}}
{{medline-entry
|title=Global nurse/midwife workforce and reproductive health through social ecology lens.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31402489
|abstract=To explore how community social ecology factors may be associated with country registered nurse/registered midwife (RN/RM) workforce supply and reproductive health globally. A cross-sectional design using a social ecology framework was employed. Data were retrieved from publicly available websites for 107 countries. Dependent variables included RN/RM density, maternal mortality ratios (MMR), and adolescent birth rates ([[ABR]]). Independent variables included gender inequality, region, country income classification, education, gross domestic product per capita, government expenditure of spending on education and health, life expectancy, percent of female seats in legislature, and labor force participation factors. The best fit multivariable model of RN/RM density showed that after adjustment for region, country income and the GII, the percent of females with some secondary education explained most of variation in RN/RM density. The best fit models of MMR and [[ABR]] showed that gender inequality explained most of the variation. Other factors in the models were the percent of female seats in legislatures, region, country income class, and mean years of schooling. Employing a social ecology model can useful in RN/RM workforce planning and development as countries seek multisectoral strategies for increasing the RN/RM supply and improving reproductive health outcomes.
|mesh-terms=* Adolescent
* Cross-Sectional Studies
* Employment
* Female
* Global Health
* Health Education
* Humans
* Income
* Life Expectancy
* Male
* Midwifery
* Pregnancy
* Reproductive Health
* Social Environment
* Socioeconomic Factors
* Workforce
|keywords=* global health
* nurse/midwife workforce
* reproductive health
* social ecology
|full-text-url=https://sci-hub.do/10.1111/phn.12648
}}
==NGF==

{{medline-entry
|title=Dietary fish hydrolysate supplementation containing n-3 LC-PUFAs and peptides prevents short-term memory and stress response deficits in aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32976934
|abstract=Brain aging is characterized by a decline in cognitive functions, which can lead to the development of neurodegenerative pathologies. Age-related spatial learning and memory deficits are associated with a chronic low-grade inflammation. Anxiety disorders and stress response alterations, occurring for a part of the elderly, have also been linked to an increased neuroinflammation and thus, an accelerated cognitive decline. Nutrition is an innovative strategy to prevent age-related cognitive impairments. Among the nutrients, n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides from proteins, especially those from marine resources, are good candidates for their immunomodulatory, anxiolytic and neuroprotective properties. The aim of this study is to determine the combined effect of n-3 LC-PUFAs and low molecular weight peptides on cognitive functions, and their mechanism of action. We are the first to show that a dietary supplementation with a fish hydrolysate containing n-3 LC-PUFAs and low molecular weight peptides prevented the age-related spatial short-term memory deficits and modulated navigation strategies adopted during spatial learning. In addition, the fish hydrolysate displayed anxiolytic activities with the reduction of anxiety-like behaviour in aged mice, restored the plasmatic corticosterone levels similar to adult animals following an acute stress and modulated the hypothalamic stress response. These effects on behaviour can be explained by the immunomodulatory and neuroprotective properties of the fish hydrolysate that limited microgliosis in vivo, decreased LPS-induced expression of pro-inflammatory cytokines and increased the expression of growth factors such as BDNF and [[NGF]] in vitro. Thus, n-3 LC-PUFAs and low molecular weight peptides contained in the fish hydrolysate can play an important role in the limitation of neuroinflammation and stress response alterations during aging and represent a potential strategy for the prevention of age-related cognitive decline.

|keywords=* Aging
* Anxiety-like behaviour
* Cognitive decline
* Hydrolysate
* Low molecular weight peptides
* Marine by-products
* Memory
* Navigation strategies
* Neuroinflammation
* Stress response
* n-3 Long chain polyunsaturated fatty acids (n-3 LC-PUFAs)
|full-text-url=https://sci-hub.do/10.1016/j.bbi.2020.09.022
}}
{{medline-entry
|title=Imbalance of nerve growth factor metabolism in aging women with overactive bladder syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32870355
|abstract=Given the disputable link between nerve growth factor ([[NGF]]) and overactive bladder syndrome (OAB) and the lack of studies on its precursor (pro[[NGF]]) in OAB, the aim of the study was to identify changes in the urinary levels of [[NGF]] and its proteolytic enzymes in aging women with OAB. We examined the urinary pro[[NGF]]/[[NGF]] ratio and its processing enzymes in aging women (50-80 years), comparing 20 controls and 20 subjects with OAB. In contrast to previous reports correlating [[NGF]] to OAB symptoms, we found that pro[[NGF]]/[[NGF]] ratio in the OAB group was twice as high compared to controls (p = 0.009) with a lower [[NGF]] levels in women with OAB without statistical significance [1.36 (Q1, Q3: 0.668, 2.39) vs. 1.7 (Q1, Q3: 1.27, 3.045) pg/mg creatinine in control group, p = 0.05]. Enzymatic activity of MMP-7, the main enzyme for extracellular pro[[NGF]] maturation, was significantly increased in the OAB group and correlated positively with scores of OAB symptoms questionnaires. However, this was counteracted by several-folds increase in the MMP-9 enzyme responsible for [[NGF]] proteolysis. While these findings highlight the importance of changes in the proteolytic enzymes to maintain pro[[NGF]]/[[NGF]] balance in OAB, analysis of covariates showed that these changes were attributed to age, insulin resistance and renal function. [[NGF]] proteolysis imbalance can be clinically meaningful in OAB related to aging, rendering it as a potential therapeutic target. However, other age-related factors such as insulin resistance and renal function may contribute to the relationship between [[NGF]] and aging-related OAB phenotype.

|keywords=* Aging female
* MMP-7
* MMP-9
* Nerve growth factor
* Overactive bladder
* proNGF
|full-text-url=https://sci-hub.do/10.1007/s00345-020-03422-6
}}
{{medline-entry
|title=Parity Attenuates Intraepithelial Corneal Sensory Nerve Loss in Female Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32708332
|abstract=Aging impacts the ocular surface and reduces intraepithelial corneal nerve (ICN) density in male and female mice. Many researchers use retired breeders to study naturally aged female mice. Yet, the impact of parity and the length of time since breeders were retired on age-related changes in the intraepithelial corneal nerves is not known. Here we study 2 month (M) nulliparous (NP) females as well as 9M, 10M, and 11M NP and multiparous (MP) female mice to determine whether parity impacts the age-related decline seen in corneal axon density; 9M male mice are also included in these assessments. After showing that parity attenuates age-related loss in axon density, we also assess the impact of parity on corneal epithelial cell proliferation and find that it impacts cell proliferation and axon density normalized by cell proliferation. Stromal nerve arborization is also impacted by aging with parity enhancing stromal nerves in older mice. qPCR was performed on 20 genes implicated in ICN density using corneal epithelial RNA isolated from 10M NP and MP mice and showed that [[NGF]] expression was significantly elevated in MP corneal epithelium. Corneal sensitivity was significantly higher in 9M MP mice compared to NP mice and increased sensitivity in MP mice was accompanied by increased nerve terminals in the apical and middle cell layers. Together, these data show that parity in mice attenuates several aspects of the age-related decline seen on the ocular surface by retaining sensory axons and corneal sensitivity as mice age.

|keywords=* aging
* corneal epithelial cell proliferation
* corneal sensitivity
* corneal sensory nerves
* mouse
* parity
* pregnancy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404034
}}
{{medline-entry
|title=Cholinergic System and [[NGF]] Receptors: Insights from the Brain of the Short-Lived Fish [i]Nothobranchius furzeri[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32575701
|abstract=Nerve growth factor ([[NGF]]) receptors are evolutionary conserved molecules, and in mammals are considered necessary for ensuring the survival of cholinergic neurons. The age-dependent regulation of NTRK1/NTRKA and p75/[[NGF]]R in mammalian brain results in a reduced response of the cholinergic neurons to neurotrophic factors and is thought to play a role in the pathogenesis of neurodegenerative diseases. Here, we study the age-dependent expression of [[NGF]] receptors ([i]NTRK1/NTRKA[/i] and p75/[i][[NGF]]R[/i]) in the brain of the short-lived teleost fish [i]Nothobranchius furzeri[/i]. We observed that [i]NTRK1/NTRKA[/i] is more expressed than p75/[[NGF]]R in young and old animals, although both receptors do not show a significant age-dependent change. We then study the neuroanatomical organization of the cholinergic system, observing that cholinergic fibers project over the entire neuroaxis while cholinergic neurons appear restricted to few nuclei situated in the equivalent of mammalian subpallium, preoptic area and rostral reticular formation. Finally, our experiments do not confirm that [i]NTRK1/NTRKA[/i] and [i]p75/[[NGF]]R[/i] are expressed in cholinergic neuronal populations in the adult brain of [i]N. furzeri[/i]. To our knowledge, this is the first study where [[NGF]] receptors have been analyzed in relation to the cholinergic system in a fish species along with their age-dependent modulation. We observed differences between mammals and fish, which make the African turquoise killifish an attractive model to further investigate the fish specific [[NGF]] receptors regulation.

|keywords=* NTRK1/NTRKA
* aging
* cholinergic system
* fish
* p75/NGFR
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348706
}}
{{medline-entry
|title=Retrograde axonal transport of BDNF and pro[[NGF]] diminishes with age in basal forebrain cholinergic neurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31574357
|abstract=Basal forebrain cholinergic neurons (BFCNs) are critical for learning and memory and degenerate early in Alzheimer's disease (AD). BFCNs depend for their survival and function on nerve growth factor ([[NGF]]) and brain-derived neurotrophic factor (BDNF), which are retrogradely transported from BFCN targets. Age is the greatest risk factor for developing AD, yet the influence of age on BFCN axonal transport is poorly understood. To model aging, embryonic rat basal forebrain or cortical neurons were cultured in microfluidic chambers. Senescence-associated beta-galactosidase staining indicated an aging phenotype only in BFCNs cultured for 18+ days in vitro. BDNF axonal transport impairments were observed exclusivley in aged BFCNs. BFCNs displayed robust pro[[NGF]] transport, which also diminished with in vitro age. The expression of [[NGF]] receptor tropomyosin-related kinase-A and BDNF receptor tropomyosin-related kinase-B also decreased significantly with in vitro age in BFCNs only. These results suggest a unique vulnerability of BFCNs to age-induced transport deficits. These deficits, coupled with the reliance of BFCNs on neurotrophin transport, may explain their vulnerability to age-related neurodegenerative disorders like AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Axonal Transport
* Brain-Derived Neurotrophic Factor
* Cholinergic Neurons
* Humans
* Nerve Growth Factor
* Prosencephalon
|keywords=* Alzheimer's disease
* Axonal transport
* Basal forebrain
* Neurodegeneration
* Neurotrophins
* Trk receptors
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2019.07.018
}}
{{medline-entry
|title=C-SH2 point mutation converts p85β regulatory subunit of phosphoinositide 3-kinase to an anti-aging gene.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31481652
|abstract=Insulin interacts with the insulin receptor, and the activated receptor promotes activity of the phosphoinositide-3 kinase (PI3K) enzyme. A decrease in insulin or insulin-like growth factor 1 (IGF-1) signaling increases the lifespan in mammalian species. We found that a point mutation in the C-SH2 domain of the p85β regulatory subunit of PI3K results in a prolonged lifespan. In p85β mutant cells, nerve growth factor ([[NGF]]) activates the longevity protein FOXO, and the mutant p85β gene produces strong resistance to oxidative stress, which contributes to aging. The p85β gene mutation causes increased serum insulin and low blood glucose in p85β mutant transgenic mice. Our results indicate that the p85β mutant allele alters the activity of downstream targets of PI3K by [[NGF]] and platelet-derived growth factor (PDGF) but not by insulin. We report that a point mutation in the C-SH2 domain of p85β transforms p85β into a novel anti-aging gene by abnormally regulating PI3K.
|mesh-terms=* Aging
* Animals
* Blood Glucose
* Class I Phosphatidylinositol 3-Kinases
* Class Ia Phosphatidylinositol 3-Kinase
* Female
* Forkhead Transcription Factors
* Insulin
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Nerve Growth Factor
* Oxidative Stress
* PC12 Cells
* Platelet-Derived Growth Factor
* Point Mutation
* Proto-Oncogene Proteins c-akt
* Rats
* src Homology Domains

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722097
}}
==CD38==

{{medline-entry
|title=Re-equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32935380
|abstract=Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated [[CD38]] NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and [[CD38]] inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.

|keywords=* CD38 NADase
* NAD metabolism
* mitochondrial impairment
* replicative senescence
* telomere biology disorders
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604620
}}
{{medline-entry
|title=TNFRSF12A and [[CD38]] Contribute to a Vicious Circle for Chronic Obstructive Pulmonary Disease by Engaging Senescence Pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32537452
|abstract=Pathogenesis of chronic obstructive pulmonary disease (COPD) is dependent on chronic inflammation and is hypothesized to represent organ-specific senescence phenotype. Identification of senescence-associated gene drivers for the development of COPD is warranted. By employing automated pipeline, we have compiled lists of the genes implicated in COPD ([i]N[/i] = 918) and of the genes changing their activity along with cell senescence ([i]N[/i] = 262), with a significant ([i]p[/i] < 7.06e ) overlap between these datasets ([i]N[/i] = 89). A mega-analysis and a partial mega-analysis were conducted for gene sets linked to senescence but not yet to COPD, in nine independent mRNA expression datasets comprised of tissue samples of COPD cases ([i]N[/i] = 171) and controls ([i]N[/i] = 256). Mega-analysis of expression has identified [i][[CD38]][/i] and [i]TNFRSF12A[/i] ([i]p[/i] < 2.12e ) as genes not yet explored in a context of senescence-COPD connection. Functional pathway enrichment analysis allowed to generate a model, which explains accelerated aging phenotypes previously observed in COPD patients. Presented results call for investigation of the role of TNFRSF12A/[[CD38]] balance in establishing a vicious cycle of unresolvable tissue remodeling in COPD lungs.

|keywords=* aging
* chronic inflammation
* lung
* network analysis
* senescence
* tissue remodeling
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268922
}}
{{medline-entry
|title=Aging alters acetylation status in skeletal and cardiac muscles.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32300965
|abstract=During aging, organs such as skeletal muscle and heart require sufficient NAD  both as a coenzyme for oxidative-reductive electron transfer and as a substrate for multiple signaling pathways. Sirtuins (SIRTs), a family of NAD -dependent deacetylase, play an important role in regulating mitochondrial homeostasis and antioxidant defense by deacetylating transcription factors and enzymes such as PGC-1α, p65, GCN5, and SOD2. However, age-related DNA damage and increased SASP activate PARP-1 and [[CD38]], the enzymes competing with SIRTs for NAD . Thus, it is important to know how aging alters intracellular NAD  status and NAD -depending enzyme expression in muscles. In this study, we report that the acetylation level of muscle protein pool, as well as major SIRTs target proteins (PGC-1α, GCN5, p65, and SOD2), was significantly increased in hindlimb and cardiac muscles of 24-month old mice compared with their 6-month old counterparts, despite the fact that most members of the SIRT family were upregulated with aging. Aging increased the protein content of PARP-1 and [[CD38]], whereas decreased NAD  levels in both skeletal and heart muscles. Aged muscles demonstrated clear signs of mitochondrial dysfunction, oxidative stress, and inflammation. Taken together, our data suggest that despite the upregulation of SIRTs, aged muscles suffered from NAD  deficit partly due to the competition of elevated [[CD38]] and PARP-1. The enhanced acetylation of several key proteins involved in broad cellular functions may contribute to the age-related muscle deterioration.

|keywords=* Aging
* CD38
* Deacetylation
* NAD+
* PARP
* SIRT
* Skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286993
}}
{{medline-entry
|title=[[CD38]] in Neurodegeneration and Neuroinflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32085567
|abstract=Neurodegenerative diseases are characterized by neuronal degeneration as well as neuroinflammation. While [[CD38]] is strongly expressed in brain cells including neurons, astrocytes as well as microglial cells, the role played by [[CD38]] in neurodegeneration and neuroinflammation remains elusive. Yet, [[CD38]] expression increases as a consequence of aging which is otherwise the primary risk associated with neurodegenerative diseases, and several experimental data demonstrated that [[CD38]] knockout mice are protected from neurodegenerative and neuroinflammatory insults. Moreover, nicotinamide adenine dinucleotide, whose levels are tightly controlled by [[CD38]], is a recognized and potent neuroprotective agent, and NAD supplementation was found to be beneficial against neurodegenerative diseases. The aims of this review are to summarize the physiological role played by [[CD38]] in the brain, present the arguments indicating the involvement of [[CD38]] in neurodegeneration and neuroinflammation, and to discuss these observations in light of [[CD38]] complex biology.

|keywords=* ALS.
* Alzheimer’s disease
* CD38
* NAD
* Parkinson’s disease
* aging
* neurodegeneration
* neuroinflammation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072759
}}
{{medline-entry
|title=[[CD38]], a Receptor with Multifunctional Activities: From Modulatory Functions on Regulatory Cell Subsets and Extracellular Vesicles, to a Target for Therapeutic Strategies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31783629
|abstract=[[CD38]] is a multifunctional cell surface protein endowed with receptor/enzymatic functions. The protein is generally expressed at low/intermediate levels on hematological tissues and some solid tumors, scoring the highest levels on plasma cells (PC) and PC-derived neoplasia. [[CD38]] was originally described as a receptor expressed by activated cells, mainly T lymphocytes, wherein it also regulates cell adhesion and cooperates in signal transduction mediated by major receptor complexes. Furthermore, [[CD38]] metabolizes extracellular NAD , generating ADPR and cyclic ADPR. This ecto-enzyme controls extra-cellular nucleotide homeostasis and intra-cellular calcium fluxes, stressing its relevance in multiple physiopathological conditions (infection, tumorigenesis and aging). In clinics, [[CD38]] was adopted as a cell activation marker and in the diagnostic/staging of leukemias. Quantitative surface [[CD38]] expression by multiple myeloma (MM) cells was the basic criterion used for therapeutic application of anti-[[CD38]] monoclonal antibodies (mAbs). Anti-[[CD38]] mAbs-mediated PC depletion in autoimmunity and organ transplants is currently under investigation. This review analyzes different aspects of [[CD38]]'s role in regulatory cell populations and how these effects are obtained. Characterizing [[CD38]] functional properties may widen the extension of therapeutic applications for anti-[[CD38]] mAbs. The availability of therapeutic mAbs with different effects on [[CD38]] enzymatic functions may be rapidly translated to immunotherapeutic strategies of cell immune defense.
|mesh-terms=* ADP-ribosyl Cyclase 1
* Aging
* Animals
* Antibodies, Monoclonal
* B-Lymphocytes, Regulatory
* Cell Line
* Extracellular Vesicles
* Humans
* Infections
* Membrane Glycoproteins
* Mice
* Neoplasms
* T-Lymphocytes, Regulatory
|keywords=* CD38
* adenosine
* immune-modulation
* regulatory cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953043
}}
{{medline-entry
|title=[[CD38]] Deficiency Alleviates D-Galactose-Induced Myocardial Cell Senescence Through NAD /Sirt1 Signaling Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31551807
|abstract=Our previous research showed that [[CD38]] played vital roles in Ang-II induced hypertrophy and high fat diet induced heart injury. However, the role of [[CD38]] in heart aging is still unknown. In the present study, we reported that [[CD38]] knockdown significantly protected cardiomyocytes from D-galactose (D-gal)-induced cellular senescence. Cellular senescence was evaluated by [i]β[/i]-galactosidase staining, the expressions of genes closely related to aging including p16 and p21, and the ROS production, MDA content and the expressions of oxidant stress related genes were examined by biochemical analysis, Western blot and QPCR. Our results showed that the expression of [[CD38]] was increased in H9c2 cells after D-gal treatment and the expressions of NAMPT and Sirt1 were downregulated in heart tissue from old mice. [[CD38]] knockdown significantly reduced the number of SA-[i]β[/i]-gal-positive cells and the expressions of p16 and p21 in H9c2 cells with or without D-gal treatment. The acetylation level of total protein was decreased in [[CD38]] knockdown group, but the expression of Sirt3 was increased in [[CD38]] knockdown group treated with D-gal. In addition, knockdown of [[CD38]] significantly attenuated D-gal induced ROS production, MDA content and NOX4 expression in the cells. Inhibition Sirt1 partially reversed the effects of [[CD38]] knockdown on D-gal induced senescence and oxidative stress. Furthermore, NAD  supplementation reduced D-gal induced cellular senescence, ROS production and MDA content. The expression of SOD2 was increased and the NOX4 expression was decreased in H9c2 cells after NAD  supplementation. Taken together, our results demonstrated that [[CD38]] knockdown alleviated D-gal induced cell senescence and oxidative stress via NAD /Sirt1 signaling pathway.

|keywords=* CD38
* D-galactose
* NAD+
* heart senescence
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735286
}}
==LMNA==

{{medline-entry
|title=Metformin alters peripheral blood mononuclear cells (PBMC) senescence biomarkers gene expression in type 2 diabetic patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33187870
|abstract=Although there is increasing evidence showing that cell senescence is increased in circulating PBMC in type 2 diabetes mellitus (T2DM), the data are contradictory. This study examined several senescence biomarkers, including [[LMNA]]/C transcript variants, p16 , p53, and p21 , in PBMC of T2DM patients and the effect of Metformin on these senescence markers. Blood samples were obtained from 30 lean, 30 obese, 20 newly diagnosed type 2 diabetes mellitus (T2DM), and 30 T2DM on Metformin. PBMC were isolated and mRNA expression of the senescence biomarkers were quantified by RT-qPCR. The effect of ectopic expression of [[LMNA]] and LMNC in human monocytic cells lines (THP-1 and U937) on several inflammatory mediators were also examined. [[LMNA]] expression was significantly higher in PBMC of obese and T2DM patients. LMNC expression was significantly inhibited in T2DM patients. [[LMNA]]Δ10 and Progerin mRNA expression was not detected in PBMC of all groups. Expression of p16 , p21  and p53 were inhibited significantly in T2DM. Metformin treatment reverted [[LMNA]], LMNC, and p53 expression levels to normal levels. Upregulation of [[LMNA]] in monocytic THP-1 and U937 cell lines induced CD68, TNFα, CCL2, IL-6 and NOS2. These data support the notion that [[LMNA]] may mediate senescence in PBMCs of T2DM by upregulating inflammatory pathways. Metformin may exert its anti-inflammatory property by modulation of senescence mediator [[LMNA]].

|keywords=* Inflammation and cellular senescence
* Insulin resistance
* LMNA/C transcript variants
* Mononuclear cells
* Type 2 diabetes mellitus
|full-text-url=https://sci-hub.do/10.1016/j.jdiacomp.2020.107758
}}
{{medline-entry
|title=Protein structural and mechanistic basis of progeroid laminopathies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32799420
|abstract=Progeroid laminopathies are characterized by the premature appearance of certain signs of physiological aging in a subset of tissues. They are caused by mutations in genes coding for A-type lamins or lamin-binding proteins. Here, we review how different mutations causing progeroid laminopathies alter protein structure or protein-protein interactions and how these impact on mechanisms that protect cell viability and function. One group of progeroid laminopathies, which includes Hutchinson-Gilford progeria syndrome, is characterized by accumulation of unprocessed prelamin A or variants. These are caused by mutations in the A-type lamin gene ([[LMNA]]), altering prelamin A itself, or in ZMPSTE24, encoding an endoprotease involved in its processing. The abnormally expressed farnesylated proteins impact on various cellular processes that may contribute to progeroid phenotypes. Other [[LMNA]] mutations lead to the production of nonfarnesylated A-type lamin variants with amino acid substitutions in solvent-exposed hot spots located mainly in coil 1B and the immunoglobulin fold domain. Dominant missense mutations might reinforce interactions between lamin domains, thus giving rise to excessively stabilized filament networks. Recessive missense mutations in A-type lamins and barrier-to-autointegration factor (BAF) causing progeroid disorders are found at the interface between these interacting proteins. The amino acid changes decrease the binding affinity of A-type lamins for BAF, which may contribute to lamina disorganization, as well as defective repair of mechanically induced nuclear envelope rupture. Targeting these molecular alterations in A-type lamins and associated proteins identified through structural biology studies could facilitate the design of therapeutic strategies to treat patients with rare but severe progeroid laminopathies.

|keywords=* 3D structure
* aging disorders
* contact sites
* lamin
* nuclear structure
|full-text-url=https://sci-hub.do/10.1111/febs.15526
}}
{{medline-entry
|title=Progerin Expression Induces Inflammation, Oxidative Stress and Senescence in Human Coronary Endothelial Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32408587
|abstract=Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disorder notably characterized by precocious and deadly atherosclerosis. Almost 90% of HGPS patients carry a [[LMNA]] p.G608G splice variant that leads to the expression of a permanently farnesylated abnormal form of prelamin-A, referred to as progerin. Endothelial dysfunction is a key determinant of atherosclerosis, notably during aging. Previous studies have shown that progerin accumulates in HGPS patients' endothelial cells but also during vascular physiological aging. However, whether progerin expression in human endothelial cells can recapitulate features of endothelial dysfunction is currently unknown. Herein, we evaluated the direct impact of exogenously expressed progerin and wild-type lamin-A on human endothelial cell function and senescence. Our data demonstrate that progerin, but not wild-type lamin-A, overexpression induces endothelial cell dysfunction, characterized by increased inflammation and oxidative stress together with persistent DNA damage, increased cell cycle arrest protein expression and cellular senescence. Inhibition of progerin prenylation using a pravastatin-zoledronate combination partly prevents these defects. Our data suggest a direct proatherogenic role of progerin in human endothelial cells, which could contribute to HGPS-associated early atherosclerosis and also potentially be involved in physiological endothelial aging participating to age-related cardiometabolic diseases.

|keywords=* Hutchinson–Gilford progeria syndrome
* LMNA
* aging
* atherosclerosis
* endothelial dysfunction
* inflammation
* lamin A
* prenylation
* progerin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290406
}}
{{medline-entry
|title=The JAK1/2 inhibitor ruxolitinib delays premature aging phenotypes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32196928
|abstract=Hutchinson-Gilford progeria syndrome (HGPS) is caused by an [[LMNA]] mutation that results in the production of the abnormal progerin protein. Children with HGPS display phenotypes of premature aging and have an average lifespan of 13 years. We found earlier that the targeting of the transmembrane protein PLA2R1 overcomes senescence and improves phenotypes in a mouse model of progeria. PLA2R1 is regulating the JAK/STAT signaling, but we do not yet know whether targeting this pathway directly would influence cellular and in vivo progeria phenotypes. Here, we show that JAK1/2 inhibition with ruxolitinib rescues progerin-induced cell cycle arrest, cellular senescence, and misshapen nuclei in human normal fibroblasts expressing progerin. Moreover, ruxolitinib administration reduces several premature aging phenotypes: bone fractures, bone mineral content, grip strength, and a trend to increase survival in a mouse model of progeria. Thus, we propose that ruxolitinib, an FDA-approved drug, should be further evaluated as a drug candidate in HGPS therapy.

|keywords=* JAK/STAT pathway
* cellular senescence
* progeria
* ruxolitinib
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189991
}}
{{medline-entry
|title=Pharmacotherapy to gene editing: potential therapeutic approaches for Hutchinson-Gilford progeria syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32048129
|abstract=Hutchinson-Gilford progeria syndrome (HGPS), commonly called progeria, is an extremely rare disorder that affects only one child per four million births. It is characterized by accelerated aging in affected individuals leading to premature death at an average age of 14.5 years due to cardiovascular complications. The main cause of HGPS is a sporadic autosomal dominant point mutation in [[LMNA]] gene resulting in differently spliced lamin A protein known as progerin. Accumulation of progerin under nuclear lamina and activation of its downstream effectors cause perturbation in cellular morphology and physiology which leads to a systemic disorder that mainly impairs the cardiovascular system, bones, skin, and overall growth. Till now, no cure has been found for this catastrophic disorder; however, several therapeutic strategies are under development. The current review focuses on the overall progress in the field of therapeutic approaches for the management/cure of HGPS. We have also discussed the new disease models that have been developed for the study of this rare disorder. Moreover, we have highlighted the therapeutic application of extracellular vesicles derived from stem cells against aging and aging-related disorders and, therefore, suggest the same for the treatment of HGPS.

|keywords=* Aging
* Extracellular vesicles
* Hutchinson–Gilford progeria syndrome
* Progerin
* Stem cells
* Therapeutics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205988
}}
{{medline-entry
|title=Long term breeding of the Lmna G609G progeric mouse: Characterization of homozygous and heterozygous models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31794853
|abstract=The transgenic Lmna  progeric mouse represents an outstanding animal model for studying the human Hutchinson-Gilford Progeria Syndrome (HGPS) caused by a mutation in the [[LMNA]] gene, coding for the nuclear envelope protein Lamin A/C, and, as an important, more general scope, for studying the complex process governing physiological aging in humans. Here we give a comprehensive description of the peculiarities related to the breeding of Lmna  mice over a prolonged period of time, and of many features observed in a large colony for a 2-years period. We describe the breeding and housing conditions underlining the possible interference of the genetic background on the phenotype expression. This information represents a useful tool when planning and interpreting studies on the Lmna  mouse model, complementing any specific data already reported in the literature about this model since its production. It is also particularly relevant for the heterozygous mouse, which mirrors the genotype of the human pathology however requires an extended time to manifest symptoms and to be carefully studied.

|keywords=* Aging
* Animal model breeding
* Bone strength
* Hutchinson-Gilford Progeria Syndrome (HGPS)
* Kyphosis
* Quality of life
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110784
}}
==IVD==

{{medline-entry
|title=MicroRNAs in Intervertebral Disc Degeneration, Apoptosis, Inflammation, and Mechanobiology.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32443722
|abstract=Intervertebral disc ([[IVD]]) degeneration is a multifactorial pathological process associated with low back pain, the leading cause of years lived in disability worldwide. Key characteristics of the pathological changes connected with degenerative disc disease (DDD) are the degradation of the extracellular matrix (ECM), apoptosis and senescence, as well as inflammation. The impact of nonphysiological mechanical stresses on [[IVD]] degeneration and inflammation, the mechanisms of mechanotransduction, and the role of mechanosensitive miRNAs are of increasing interest. As post-transcriptional regulators, miRNAs are known to affect the expression of 30% of proteincoding genes and numerous intracellular processes. The dysregulation of miRNAs is therefore associated with various pathologies, including degenerative diseases such as DDD. This review aims to give an overview of the current status of miRNA research in degenerative disc pathology, with a special focus on the involvement of miRNAs in ECM degradation, apoptosis, and inflammation, as well as mechanobiology.

|keywords=* ECM
* MMP
* annulus fibrosus
* cartilaginous endplate
* degenerative disc disease
* miRNA
* nucleus pulposus
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279351
}}
{{medline-entry
|title=A step-by-step protocol for isolation of murine nucleus pulposus cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31891122
|abstract=The intervertebral disc ([[IVD]]) is composed of three separate tissues with distinct origins and properties. Elucidating changes occurring in these tissues in response to injury or age is paramount to identify new therapies to better manage disc and spine degenerative conditions, including low back pain. Despite their small size and different mechanical load pattern compared to higher species, the use of mouse models represents a cost-effective and powerful approach to better understand the formation, maintenance, and degeneration of the [[IVD]]. However, the isolation of the different compartments of the [[IVD]] is complicated by their diminutive size. Here, we describe a simple, step-by-step protocol for the isolation of the nucleus pulposus (NP) tissues that can then be processed for further analyses. Analysis from mouse NP tissues shows sufficient quantities of RNAs, purity of the NP fraction, and overall RNA quality for gene expression studies, and reveals no increase in expression of disc degeneration markers, including [i]TNFa[/i], [i]IL1b[/i], and [i]Mmp1[/i] up to 15 months of age in C57BL6 wildtype mice.

|keywords=* aging
* gene expression
* intervertebral disc degeneration
* nucleus pulposus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920701
}}
{{medline-entry
|title=Caspase-3 knockout inhibits intervertebral disc degeneration related to injury but accelerates degeneration related to aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31852919
|abstract=Approximately 40% of people under 30 and over 90% of people 55 or older suffer from moderate-to-severe levels of degenerative intervertebral disc ([[IVD]]) disease in their lumbar spines. Surgical treatments are sometimes effective; however, the treatment of back pain related to [[IVD]] degeneration is still a challenge; therefore, new treatments are necessary. Apoptosis may be important in [[IVD]] degeneration because suppressing cell apoptosis inside the [[IVD]] inhibits degeneration. Caspase-3, the primary effector of apoptosis, may be a key treatment target. We analyzed caspase-3's role in two different types of [[IVD]] degeneration using caspase-3 knockout (Casp-3 KO) mice. Casp-3 KO delayed [[IVD]] degeneration in the injury-induced model but accelerated it in the age-induced model. Our results suggest that this is due to different pathological mechanisms of these two types of [[IVD]] degeneration. Apoptosis was suppressed in the [[IVD]] cells of Casp-3 KO mice, but cellular senescence was enhanced. This would explain why the Casp-3 KO was effective against injury-induced, but not age-related, [[IVD]] degeneration. Our results suggest that short-term caspase-3 inhibition could be used to treat injury-induced [[IVD]] degeneration.
|mesh-terms=* Aging
* Animals
* Annulus Fibrosus
* Apoptosis
* Biomarkers
* Carcinogenesis
* Caspase 3
* Cell Count
* Extracellular Matrix
* Intervertebral Disc
* Intervertebral Disc Degeneration
* Mice, Inbred C57BL
* Mice, Knockout
* Nucleus Pulposus
* Up-Regulation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6920379
}}
{{medline-entry
|title=Finite element and deformation analyses predict pattern of bone failure in loaded zebrafish spines.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31690186
|abstract=The spine is the central skeletal support structure in vertebrates consisting of repeated units of bone, the vertebrae, separated by intervertebral discs ([[IVD]]s) that enable the movement of the spine. Spinal pathologies such as idiopathic back pain, vertebral compression fractures and [[IVD]] failure affect millions of people worldwide. Animal models can help us to understand the disease process, and zebrafish are increasingly used as they are highly genetically tractable, their spines are axially loaded like humans, and they show similar pathologies to humans during ageing. However, biomechanical models for the zebrafish are largely lacking. Here, we describe the results of loading intact zebrafish spinal motion segments on a material testing stage within a micro-computed tomography machine. We show that vertebrae and their arches show predictable patterns of deformation prior to their ultimate failure, in a pattern dependent on their position within the segment. We further show using geometric morphometrics which regions of the vertebra deform the most during loading, and that finite-element models of the trunk subjected reflect the real patterns of deformation and strain seen during loading and can therefore be used as a predictive model for biomechanical performance.
|mesh-terms=* Aging
* Animals
* Back Pain
* Disease Models, Animal
* Finite Element Analysis
* Humans
* Intervertebral Disc
* Movement
* Weight-Bearing
* Zebrafish
|keywords=* deformation
* finite element
* geometric morphometrics
* mechanics
* spine
* zebrafish
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6893493
}}
{{medline-entry
|title=Improvement in determining the risk of damage to the human lumbar functional spinal unit considering age, height, weight and sex using a combination of FEM and RSM.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31473842
|abstract=Human functional spinal unit (FSU) is comprised of two adjacent vertebrae, the intervertebral disc ([[IVD]]), the cartilage endplates and the connecting ligamentous tissues. As humans age, trabecular, cortical bone and [[IVD]] change in mechanical properties. These changes influence the movement of the FSU (displacements, rotations and disc bulges). This paper proposes a method to determine the influence of sex, age, weight and height on the movements of the FSU using a combination of the FEM and RSM. The work concentrates on the medium-sized human FSU (L3-L4 lumbar level with standard dimensions of [[IVD]]: width = 50 mm, depth = 35 mm and height = 11 mm). Also, the proposed method could be an improvement to the determination of risk of damage based on body mass index (BMI), as well as an alternative method of searching for a healthy weight. The method was developed as follows: First, a three-dimensional parameterized human healthy FSU FE model was generated based on the standard test (for compression, flexion, extension, lateral bending, torsion and shear). The movements of the FSU FE model based on the aforementioned standardized test when the sex, age, weight and height varies in a range for each individual (30-80 years; 70-120 kg; 160-190 cm) were simulated. Quadratic regression models were generated for each standardized test using RSM. An ANOVA test showed that all of the tests have a significant influence on weight and age, whereas height influences only those tests that involve rotation of the FSU (flexion, extension and lateral bending). Normal weight, overweight and obesity BMI classifications were considered in determining the healthy weight with the following constraints: the limit angles of flexion and lateral bending, as well as the maximum posterior bulge limit of the [[IVD]], could not exceed of one-third of the spinal canal. The proposed method concluded that: (1) normal BMI values do not cause damage to the FSU, (2) some overweight BMI values may cause damage to the FSU for a certain range of ages and heights and (3) for BMI obesity values, the risk of damage to the FSU may be imminent.
|mesh-terms=* Adult
* Age Factors
* Aging
* Analysis of Variance
* Biomechanical Phenomena
* Body Height
* Body Mass Index
* Body Weight
* Cortical Bone
* Female
* Finite Element Analysis
* Humans
* Imaging, Three-Dimensional
* Intervertebral Disc
* Lumbar Vertebrae
* Male
* Models, Biological
* Range of Motion, Articular
* Risk Factors
* Sex Characteristics
|keywords=* Age
* Biomechanics
* Body mass index (BMI)
* Finite element method (FEM)
* Functional spinal unit (FSU)
* Height
* Response surface method (RSM)
* Sex
* Weight
|full-text-url=https://sci-hub.do/10.1007/s10237-019-01215-4
}}
{{medline-entry
|title=In vivo contrast-enhanced microCT for the monitoring of mouse thoracic, lumbar, and coccygeal intervertebral discs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31463468
|abstract=Mouse models are often used for studies of intervertebral disc ([[IVD]]) homeostasis and degeneration, yet the relatively small size of the [[IVD]] poses challenges for noninvasive, longitudinal imaging modalities. The recently developed contrast-enhanced microCT (CEμCT) using Ioversol has been successful in detecting degenerative changes in the murine [[IVD]] ex vivo at the micrometer scale. Further leveraging the superior biocompatibility of Ioversol as a contrast agent, we demonstrate the in vivo use of this CEμCT technique to examine [[IVD]]s at multiple spinal sites. Ioversol was administered via tail vein injection (TVI) in growing and adult male FVB/NJ mice (n = 5 /group). The animals were anesthetized and underwent in vivo micro-computed tomographic (microCT) at the coccygeal (CC5/CC6), lumbar (L5/6), and thoracic (T12/T13) [[IVD]]s. TVI of Ioversol was well-tolerated by all animals. As Ioversol filtered through the kidneys and accumulated in the bladder, the attenuations of the mouse bladder and kidneys increased due to the high molecular weight of Ioversol, confirming that the Ioversol is biological available. Average [[IVD]] attenuations increased 3%-15% following TVI (ANOVA; [i]P[/i] < .01). The presence of Ioversol in the [[IVD]] combined with high-resolution microCT allow for nondestructive visualization of structural features of the [[IVD]]. These results demonstrate CEμCT with Ioversol as a viable strategy for the in vivo monitoring of multiple mouse [[IVD]]s during degeneration, disease, and injury.

|keywords=* Contrast‐enhanced microCT
* aging
* intervertebral disc
* mouse model
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686789
}}
==H2AX==

{{medline-entry
|title=Evaluation of Gamma[[H2AX]] in Buccal Cells as a Molecular Biomarker of DNA Damage in Alzheimer's Disease in the AIBL Study of Ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32781776
|abstract=In response to double-stranded breaks (DSBs) in chromosomal DNA, [[H2AX]] (a member of histone H2A family) becomes phosphorylated to form γ[[H2AX]]. Although increased levels of γ[[H2AX]] have been reported in the neuronal nuclei of Alzheimer's disease (AD) patients, the understanding of γ[[H2AX]] responses in buccal nuclei of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In the current study, endogenous γ[[H2AX]] was measured in buccal cell nuclei from MCI (n = 18) or AD (n = 16) patients and in healthy controls (n = 17) using laser scanning cytometry (LSC). The γ[[H2AX]] level was significantly elevated in nuclei of the AD group compared to the MCI and control group, and there was a concomitant increase in [i]P[/i]-trend for γ[[H2AX]] from the control group through MCI to the AD group. Receiver-operating characteristic curves were carried out for different γ[[H2AX]] parameters; γ[[H2AX]] in nuclei resulted in the greatest area under the curve value of 0.7794 ([i]p[/i] = 0.0062) with 75% sensitivity and 70% specificity for the identification of AD patients from control. In addition, nuclear circularity (a measure of irregular nuclear shape) was significantly higher in the buccal cell nuclei from the AD group compared with the MCI and control groups. Additionally, there was a positive correlation between the nuclear circularity and γ[[H2AX]] signals. The results indicated that increased DNA damage is associated with AD.

|keywords=* Alzheimer’s disease
* DNA damage
* mild cognitive impairment
* senescence
* γH2AX
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459751
}}
{{medline-entry
|title=Cisplatin-induced peripheral neuropathy is associated to neuronal senescence-like response.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32597980
|abstract=Cisplatin-Induced Peripheral Neuropathy (CIPN) is a frequent serious dose-dependent adverse event that can determine dosage limitations for cancer treatment. CIPN severity correlates with the amount of platinum detected in sensory neurons of the dorsal root ganglia (DRG). However, the exact pathophysiology of CIPN is poorly understood, so the chance of developing neuroprotective treatment is reduced. The aim of this study was to determine the exact mechanisms involved in CIPN development. By single-cell RNA-sequencing (scRNAseq), we have studied the transcriptomic profile of DRG sensory neurons from a well characterized neurophysiological mice model of CIPN. Gene Ontology analysis of the scRNAseq data indicated that cisplatin treatment induces the up regulation of biological pathways related with DNA damage response (DDR) in the DRG neuronal population. Moreover, DRG neurons also upregulated the Cdkn1a gene, confirmed later by the measurement of its protein product p21. While apoptosis activation pathways were not observed in DRG sensory neurons of cisplatin-treated mice, these neurons did express several senescence hallmarks, including senescence-associated β-galactosidase, phospho-[[H2AX]] and nuclear Nfkb-p65 proteins. In this study, we determined that after cisplatin-induced DNA damage, p21 appears as the most relevant downstream factor of the DDR in DRG sensory neurons in vivo, which survive in a non-functional senescence-like state.

|keywords=* cisplatin
* neuropathy
* neurotoxicity
* p21
* senescence
|full-text-url=https://sci-hub.do/10.1093/neuonc/noaa151
}}
{{medline-entry
|title=Guanine Deaminase Stimulates Ultraviolet-induced Keratinocyte Senescence in Seborrhoeic Keratosis via Guanine Metabolites.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32215662
|abstract=DNA damage and oxidative stress play a critical role in photoageing. Seborrhoeic keratosis (SK) affects sunlight-exposed sites in aged individuals. This study examined the mechanism of photoageing in SK. The guanine deaminase gene, which is involved in purine metabolism, was upregulated with uric acid levels and p21 in SK. Guanine deaminase was detectable in keratinocytes. Repeated exposure to ultraviolet (UV) increased levels of guanine deaminase, together with DNA damage, such as γ-[[H2AX]] and cyclobutane pyrimidine dimer formation, generation of reactive oxygen species, and keratinocyte senescence, which were reversed by guanine deaminase knockdown. However, guanine deaminase overexpression and H2O2 formed γ-[[H2AX]], but not cyclobutane pyrimidine dimer. Loss-of-function guanine deaminase mutants reduced the metabolic end-product uric acid, which was increased by exposure to exogenous xanthine. Repeated exposure to UV increased levels of uric acid. Exogenous uric acid increased cellular senescence, reactive oxygen species, and γ-[[H2AX]], similar to guanine deaminase. Overall, guanine deaminase upregulation increased UV-induced keratinocyte senescence in SK, via uric acid mediated by reactive oxygen species followed by DNA damage.

|keywords=*  DNA damage
*  UV-induced keratinocyte senescence
*  guanine deaminase
*  reactive oxygen species
*  uric acid
* seborrhoeic keratosis
|full-text-url=https://sci-hub.do/10.2340/00015555-3473
}}
{{medline-entry
|title=Do BRCA1 and BRCA2 gene mutation carriers have a reduced ovarian reserve? Protocol for a prospective observational study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31772111
|abstract=BRCA1/2 gene mutations increase risk of breast and/or ovarian cancer and may have implications for reproductive health. Indirect biomarkers of the ovarian primordial follicle pool (anti-Müllerian hormone (AMH)) and one small study in female cadavers suggest that ovarian reserve may be reduced in BRCA mutation carriers, but findings are conflicting and association between circulating AMH and primordial follicle number is not established. The aim of this study is to measure primordial follicle density in premenopausal ovarian tissue samples from women with BRCA1/2 gene mutations versus age-matched comparison group. Prospective observational study measuring associations between BRCA gene mutation status, premenopausal ovarian primordial follicle density and serum AMH concentrations versus age-matched premenopausal women from the general population. Primordial follicle density will be measured in cortical sections from ovarian tissue collected at the time of risk-reducing bilateral salpingo-oophorectomy (RRBSO) in 88 BRCA1 gene mutation carriers, 65 BRCA2 gene mutation carriers and 157 non-mutation carriers. Primordial follicle density will be determined by counting follicles in a known volume of ovarian cortical tissue using light microscopy. Follicles will be identified by immunohistochemical staining for oocyte marker mouse vasa homologue. To inform the mechanisms underlying reduced ovarian reserve, the proportion of follicles containing oocytes with DNA damage will be determined by immunohistochemical staining for phosphorylated histone [[H2AX]] and terminal deoxynucleotidyl transferase dUTP nick end labelling assay to identify apoptotic cells. Follicle density will be correlated with circulating AMH concentrations quantified in the same cohort, using an electrochemiluminescence immunoassay on an automated platform. Ethics approval has been granted by Peter MacCallum Cancer Centre to access biobanks, including; The Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab-HREC#97_27) and the What Happens after Menopause? (HREC12PMCC24-12/90) and Melbourne IVF.
|mesh-terms=* Adolescent
* Adult
* Aging
* BRCA1 Protein
* BRCA2 Protein
* Female
* Germ-Line Mutation
* Heterozygote
* Humans
* Immunohistochemistry
* Middle Aged
* Observational Studies as Topic
* Ovarian Follicle
* Ovarian Reserve
* Prospective Studies
* Research Design
* Young Adult
|keywords=* BRCA
* DNA repair
* fertility
* follicle
* germline mutation
* oocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887091
}}
{{medline-entry
|title=Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31730540
|abstract=Although there is previous evidence showing an increase in various types of DNA damage with aging in mice and humans, a comparative study determining accumulation rates of DNA double strand breaks, as determined by presence of phosphorylated histone [[H2AX]] (γ[[H2AX]]), in leukocytes of individuals of different ages from phylogenetically distinct species from birds to mammals was lacking. Here, we demonstrate that the rate of accumulation of DNA damage as measured by the DNA damage marker γ[[H2AX]] correlates with species longevity in dolphins, goats, reindeer, American flamingos, and griffon vultures. In particular, we find that species that show slower rates of accumulation of the DNA damage marker γ[[H2AX]] also live longer.
|mesh-terms=* Animals
* Birds
* Bottle-Nosed Dolphin
* Cross-Sectional Studies
* DNA Damage
* Goats
* Leukocytes
* Longevity
* Reindeer
* Turtles
* Vertebrates
|keywords=* DNA damage
* lifespan
* short telomeres
* species
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874430
}}
{{medline-entry
|title=Phosphoproteomic analysis reveals plant DNA damage signalling pathways with a functional role for histone [[H2AX]] phosphorylation in plant growth under genotoxic stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31410901
|abstract=DNA damage responses are crucial for plant growth under genotoxic stress. Accumulating evidence indicates that DNA damage responses differ between plant cell types. Here, quantitative shotgun phosphoproteomics provided high-throughput analysis of the DNA damage response network in callus cells. MS analysis revealed a wide network of highly dynamic changes in the phosphoprotein profile of genotoxin-treated cells, largely mediated by the ATAXIA TELANGIECTASIA MUTATED (ATM) protein kinase, representing candidate factors that modulate plant growth, development and DNA repair. A C-terminal dual serine target motif unique to [[H2AX]] in the plant lineage showed 171-fold phosphorylation that was absent in atm mutant lines. The physiological significance of post-translational DNA damage signalling to plant growth and survival was demonstrated using reverse genetics and complementation studies of h2ax mutants, establishing the functional role of ATM-mediated histone modification in plant growth under genotoxic stress. Our findings demonstrate the complexity and functional significance of post-translational DNA damage signalling responses in plants and establish the requirement of [[H2AX]] phosphorylation for plant survival under genotoxic stress.
|mesh-terms=* ATP-Binding Cassette Transporters
* Aging
* Arabidopsis
* Arabidopsis Proteins
* Cells, Cultured
* DNA Damage
* DNA Repair
* Gene Expression Regulation, Plant
* Gene Ontology
* Germination
* Histones
* Mass Spectrometry
* Phosphorylation
* Proteome
* Seeds
* Serine
* Signal Transduction
* Stress, Physiological
* X-Rays
|keywords=* ATAXIA TELANGIECTASIA MUTATED (ATM)
* DNA damage response
* DNA repair
* phosphorylation
* seed
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900162
}}
==MAPT==

{{medline-entry
|title=Association of relative brain age with tobacco smoking, alcohol consumption, and genetic variants.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32001736
|abstract=Brain age is a metric that quantifies the degree of aging of a brain based on whole-brain anatomical characteristics. While associations between individual human brain regions and environmental or genetic factors have been investigated, how brain age is associated with those factors remains unclear. We investigated these associations using UK Biobank data. We first trained a statistical model for obtaining relative brain age (RBA), a metric describing a subject's brain age relative to peers, based on whole-brain anatomical measurements, from training set subjects (n = 5,193). We then applied this model to evaluation set subjects (n = 12,115) and tested the association of RBA with tobacco smoking, alcohol consumption, and genetic variants. We found that daily or almost daily consumption of tobacco and alcohol were both significantly associated with increased RBA (P < 0.001). We also found SNPs significantly associated with RBA (p-value < 5E-8). The SNP most significantly associated with RBA is located in [[MAPT]] gene. Our results suggest that both environmental and genetic factors are associated with structural brain aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alcohol Drinking
* Biological Specimen Banks
* Brain
* Cognition
* Female
* Humans
* Magnetic Resonance Imaging
* Male
* Middle Aged
* Neuroimaging
* Polymorphism, Single Nucleotide
* Smoking
* United Kingdom
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992742
}}
{{medline-entry
|title=A blood-based nutritional risk index explains cognitive enhancement and decline in the multidomain Alzheimer prevention trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31921969
|abstract=Multinutrient approaches may produce more robust effects on brain health through interactive qualities. We hypothesized that a blood-based nutritional risk index (NRI) including three biomarkers of diet quality can explain cognitive trajectories in the multidomain Alzheimer prevention trial ([[MAPT]]) over 3-years. The NRI included erythrocyte n-3 polyunsaturated fatty acids (n-3 PUFA 22:6n-3 and 20:5n-3), serum 25-hydroxyvitamin D, and plasma homocysteine. The NRI scores reflect the number of nutritional risk factors (0-3). The primary outcome in [[MAPT]] was a cognitive composite [i]Z[/i] score within each participant that was fit with linear mixed-effects models. Eighty percent had at lease one nutritional risk factor for cognitive decline (NRI ≥1: 573 of 712). Participants presenting without nutritional risk factors (NRI=0) exhibited cognitive enhancement ([i]β[/i] = 0.03 standard units [SU]/y), whereas each NRI point increase corresponded to an incremental acceleration in rates of cognitive decline (NRI-1: [i]β[/i] = -0.04 SU/y, [i]P[/i] = .03; NRI-2: [i]β[/i] = -0.08 SU/y, [i]P[/i] < .0001; and NRI-3: [i]β[/i] = -0.11 SU/y, [i]P[/i] = .0008). Identifying and addressing these well-established nutritional risk factors may reduce age-related cognitive decline in older adults; an observation that warrants further study.

|keywords=* Aging
* Biomarkers of diet quality
* Cognitive decline
* DHA
* EPA
* Elderly
* Homocysteine
* Metabolomics
* Nutrient biomarkers
* Omega-3 fatty acids
* Vitamin D
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944714
}}
{{medline-entry
|title=Longitudinal associations of physical activity levels with morphological and functional changes related with aging: The [[MAPT]] study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31669813
|abstract=The biological process of aging is characterized by molecular and physiological processes that lead to alterations in the organism. There is still a lack of a consensus about the measurement of biological aging, but physical activity (PA) could be a potential marker of an aging phenotype. Measurements of body composition, muscle quality (MQ), blood biochemistry, and neurodegeneration were assessed over three years. Physical activity levels were measured using a self-reported questionnaire. Three-year progression of PA levels showed that those who maintained low levels of PA was significantly associated with the evolution of brain and hippocampal volume, compared to inactive individuals. Similar results were found always active individuals, but also had better cognition. PA levels are associated with some elements of biological aging, but more studies with objective-based PA measurements could provide a more in-depth knowledge on biological aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Body Composition
* Brain
* Cognition
* Exercise
* Female
* Humans
* Longitudinal Studies
* Male
|keywords=* Aging
* Biomarkers
* Phenotype
* Physical activity
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110758
}}
{{medline-entry
|title=Ageing and amyloidosis underlie the molecular and pathological alterations of tau in a mouse model of familial Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31673052
|abstract=Despite compelling evidence that the accumulation of amyloid-beta (Aβ) promotes neocortical [[MAPT]] (tau) aggregation in familial and idiopathic Alzheimer's disease (AD), murine models of cerebral amyloidosis are not considered to develop tau-associated pathology. In the present study, we show that tau can accumulate spontaneously in aged transgenic APP /PS1  mice. Tau pathology is abundant around Aβ deposits, and further characterized by accumulation of Gallyas and thioflavin-S-positive inclusions, which were detected in the APP /PS1  brain at 18 months of age. Age-dependent increases in argyrophilia correlated positively with binding levels of the paired helical filament (PHF) tracer [ F]Flortaucipir, in all brain areas examined. Sarkosyl-insoluble PHFs were visualized by electron microscopy. Quantitative proteomics identified sequences of hyperphosphorylated and three-repeat tau in transgenic mice, along with signs of RNA missplicing, ribosomal dysregulation and disturbed energy metabolism. Tissue from the frontal gyrus of human subjects was used to validate these findings, revealing primarily quantitative differences between the tau pathology observed in AD patient vs. transgenic mouse tissue. As physiological levels of endogenous, 'wild-type' tau aggregate secondarily to Aβ in APP /PS1  mice, this study suggests that amyloidosis is both necessary and sufficient to drive tauopathy in experimental models of familial AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloidosis
* Animals
* Disease Models, Animal
* Mice
* Mice, Transgenic
* tau Proteins

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823454
}}
{{medline-entry
|title=Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer's disease from a ferroptosis perspective.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31604111
|abstract=The complexity of Alzheimer's disease (AD) complicates the search for effective treatments. While the key roles of pathologically modified proteins has occupied a central role in hypotheses of the pathophysiology, less attention has been paid to the potential role for transition metals overload, subsequent oxidative stress, and tissue injury. The association of transition metals, the major focus heretofore iron and amyloid, the same can now be said for the likely pathogenic microtubular associated tau ([[MAPT]]). This review discusses the interplay between iron, pathologically modified tau and oxidative stress, and connects many related discoveries. Basic principles of the transition to pathological [[MAPT]] are discussed. Iron, its homeostatic mechanisms, the recently described phenomenon of ferroptosis and purported, although still controversial roles in AD are reviewed as well as considerations to overcome existing hurdles of iron-targeted therapeutic avenues that have been attempted in AD. We summarize the involvement of multiple pathological pathways at different disease stages of disease progression that supports the potential for a combinatorial treatment strategy targeting multiple factors.

|keywords=* Alzheimer’s disease
* Ferroptosis
* Iron
* Reactive oxygen species
* Senescence
* Tau
|full-text-url=https://sci-hub.do/10.1016/j.pneurobio.2019.101716
}}
==WRN==

{{medline-entry
|title=The Impact of Vitamin C on Different System Models of Werner Syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33202145
|abstract= Werner syndrome (WS) is a rare autosomal recessive malady typified by a pro-oxidant/proinflammatory status, genetic instability, and by the early onset of numerous age-associated illnesses. The protein malfunctioning in WS individuals ([[WRN]]) is a helicase/exonuclease implicated in transcription, DNA replication/repair, and telomere maintenance.   In the last two decades, a series of important biological systems were created to comprehend at the molecular level the effect of a defective [[WRN]] protein. Such biological tools include mouse and worm ([i]Caenorhabditis elegans[/i]) with a mutation in the Wrn helicase ortholog as well as human WS-induced pluripotent stem cells that can ultimately be differentiated into most cell lineages. Such WS models have identified anomalies related to the hallmarks of aging. Most importantly, vitamin C counteracts these age-related cellular phenotypes in these systems.   Vitamin C is the only antioxidant agent capable of reversing the cellular aging-related phenotypes in those biological systems. Since vitamin C is a cofactor for many hydroxylases and mono- or dioxygenase, it adds another level of complexity in deciphering the exact molecular pathways affected by this vitamin. Moreover, it is still unclear whether a short- or long-term vitamin C supplementation in human WS patients who already display aging-related phenotypes will have a beneficial impact.   The discovery of new molecular markers specific to the modified biological pathways in WS that can be used for novel imaging techniques or as blood markers will be necessary to assess the favorable effect of vitamin C supplementation in WS.

|keywords=* Werner syndrome
* aging
* mouse
* stem cells
* vitamin C
* worm
|full-text-url=https://sci-hub.do/10.1089/ars.2020.8147
}}
{{medline-entry
|title=[[WRN]] modulates translation by influencing nuclear mRNA export in HeLa cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33054770
|abstract=The Werner syndrome protein ([[WRN]]) belongs to the RecQ family of helicases and its loss of function results in the premature aging disease Werner syndrome (WS). We previously demonstrated that an early cellular change induced by [[WRN]] depletion is a posttranscriptional decrease in the levels of enzymes involved in metabolic pathways that control macromolecular synthesis and protect from oxidative stress. This metabolic shift is tolerated by normal cells but causes mitochondria dysfunction and acute oxidative stress in rapidly growing cancer cells, thereby suppressing their proliferation. To identify the mechanism underlying this metabolic shift, we examined global protein synthesis and mRNA nucleocytoplasmic distribution after [[WRN]] knockdown. We determined that [[WRN]] depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. We further observed that [[WRN]] depletion affects the nuclear export of mRNAs and demonstrated that [[WRN]] interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1). Our findings suggest that [[WRN]] influences the export of mRNAs from the nucleus through its interaction with the NXF1 export receptor thereby affecting cellular proteostasis. In summary, we identified a new partner and a novel function of [[WRN]], which is especially important for the proliferation of cancer cells.

|keywords=* Cancer
* NXF1 export receptor
* Senescence
* Translation
* Werner syndrome protein
* mRNA export
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557079
}}
{{medline-entry
|title=MIB1-mediated degradation of [[WRN]] promotes cellular senescence in response to camptothecin treatment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32652764
|abstract=Werner syndrome protein ([[WRN]]) plays critical roles in DNA replication, recombination, and repair, as well as transcription and cellular senescence. Ubiquitination and degradation of [[WRN]] have been reported, however, the E3 ubiquitin ligase of [[WRN]] is little known. Here, we identify mindbomb E3 ubiquitin protein ligase 1 (MIB1) as a novel E3 ubiquitin ligase for [[WRN]] protein. MIB1 physically interacts with [[WRN]] in vitro and in vivo and induces ubiquitination and degradation of [[WRN]] in the ubiquitin-proteasome pathway. Camptothecin (CPT) enhances the interaction between MIB1 and [[WRN]], and promotes [[WRN]] degradation in a MIB1-dependent manner. In addition, CPT-induced cellular senescence is facilitated by the expression of MIB1 and attenuated by [[WRN]] expression. Our results show that MIB1-mediated degradation of [[WRN]] promotes cellular senescence and reveal a novel model executed by MIB1 and [[WRN]] to regulate cellular senescence.

|keywords=* CPT
* Mind bomb 1
* Werner syndrome protein
* aging
* protein stability
|full-text-url=https://sci-hub.do/10.1096/fj.202000268RRR
}}
{{medline-entry
|title=A Case Report of Werner's Syndrome With a Novel Mutation From India.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32528764
|abstract=Werner's syndrome (WS) or progeria adultorum is a heritable autosomal recessive disease in which the aging process is accelerated, just after puberty. It is caused by mutations in the [[WRN]] gene, which encodes a member of the RECQ family of DNA helicases and has a role in DNA repair. WS is being more appropriately recognized as a condition in which the lack of [[WRN]] protein results in an overall decline in the normal physiological functions of various organs rather than premature aging. Here, we describe a rare case of WS with a novel mutation from India. Our patient was an adult male with a history of growth arrest since puberty and other clinical features such as sclerodermatous skin changes, premature graying and thinning of hair, bilateral cataract, a single non-healing ulcer, hypothyroidism, underdeveloped secondary sexual characters with hypogonadism, infertility, squeaky voice, and early signs of arteriosclerosis. On genetic analysis, he was found to have a homozygous pathogenic variant c.3190C>T in exon 26 of the [[WRN]] gene, which has never been reported in WS.

|keywords=* aging
* novel mutation
* progeria
* werner syndrome
* wrn gene
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282380
}}
{{medline-entry
|title=Evidence for premature aging in a Drosophila model of Werner syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31518666
|abstract=Werner syndrome (WS) is an autosomal recessive progeroid disease characterized by patients' early onset of aging, increased risk of cancer and other age-related pathologies. WS is caused by mutations in [[WRN]], a RecQ helicase that has essential roles responding to DNA damage and preventing genomic instability. While human [[WRN]] has both an exonuclease and helicase domain, Drosophila [[WRN]]exo has high genetic and functional homology to only the exonuclease domain of [[WRN]]. Like [[WRN]]-deficient human cells, Drosophila [[WRN]]exo null mutants ([[WRN]]exo ) are sensitive to replication stress, demonstrating mechanistic similarities between these two models. Compared to age-matched wild-type controls, [[WRN]]exo  flies exhibit increased physiological signs of aging, such as shorter lifespans, higher tumor incidence, muscle degeneration, reduced climbing ability, altered behavior, and reduced locomotor activity. Interestingly, these effects are more pronounced in females suggesting sex-specific differences in the role of [[WRN]]exo in aging. This and future mechanistic studies will contribute to our knowledge in linking faulty DNA repair mechanisms with the process of aging.
|mesh-terms=* Aging, Premature
* Animals
* Behavior, Animal
* Body Composition
* Body Weight
* DNA Repair
* Drosophila
* Drosophila Proteins
* Exonucleases
* Female
* Gastrointestinal Neoplasms
* Male
* Motor Activity
* Muscle Weakness
* Mutation
* Phenotype
* Werner Syndrome
|keywords=* Aging
* DNA repair
* Locomotor function
* Tumor
* Werner syndrome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935377
}}
==TFEB==

{{medline-entry
|title=A Novel Lipofuscin-detecting Marker of Senescence Relates With Hypoxia, Dysregulated Autophagy and With Poor Prognosis in Non-small-cell-lung Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33144423
|abstract=The role of senescence in defining tumor aggressiveness at a clinical level remains obscure. A novel mixed histochemical/immunohistochemical method (SenTraGor™, STG) detecting lipofuscin accumulation allows the assessment of senescent cells in paraffin-embedded tissue material. STG expression was quantified in 98 surgically resected primary non-small-cell-lung carcinomas (NSCLC). Data were analyzed in parallel with other immunohistochemical markers related to hypoxia and autophagy. Strong STG staining was noted in 36/98 cases (36.7%). High STG expression was significantly associated with high HIF1α expression and high expression of glucose (GLUT1) and monocarboxylate (MCT2) transporters, pointing to a link between senescence, hypoxia and glycolysis. High STG expression was also linked with high cytoplasmic accumulation of MAP1-LC3B, [[TFEB]] and LAMP2a, suggestive of a blockage of autophagy flux in tumors with intense senescence. Survival analysis showed a direct association with poor survival, independently of stage. SenTraGor™ provides a reliable methodology to detect lipofuscin accumulation in cancer cells in paraffin-embedded tissues, opening a new field for translational studies focused on senescence.

|keywords=* Senescence
* autophagy
* glycolysis
* hypoxia
* lipofuscin
* lung cancer
|full-text-url=https://sci-hub.do/10.21873/invivo.12154
}}
{{medline-entry
|title=ESC-sEVs Rejuvenate Senescent Hippocampal NSCs by Activating Lysosomes to Improve Cognitive Dysfunction in Vascular Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32440476
|abstract=Vascular dementia (VD) is one of the most common types of dementia, however, the intrinsic mechanism is unclear and there is still lack of effective medications. In this study, the VD rats exhibit a progressive cognitive impairment, as well as a time-related increasing in hippocampal neural stem cells (H-NSCs) senescence, lost and neurogenesis decline. Then, embryonic stem cell-derived small extracellular vesicles (ESC-sEVs) are intravenously injected into VD rats. ESC-sEVs treatment significantly alleviates H-NSCs senescence, recovers compromised proliferation and neuron differentiation capacity, and reverses cognitive impairment. By microarray analysis and RT-qPCR it is identified that several miRNAs including miR-17-5p, miR-18a-5p, miR-21-5p, miR-29a-3p, and let-7a-5p, that can inhibit mTORC1 activation, exist in ESC-sEVs. ESC-sEVs rejuvenate H-NSCs senescence partly by transferring these miRNAs to inhibit mTORC1 activation, promote transcription factor EB ([[TFEB]]) nuclear translocation and lysosome resumption. Taken together, these data indicate that H-NSCs senescence cause cell depletion, neurogenesis reduction, and cognitive impairment in VD. ESC-sEVs treatment ameliorates H-NSCs senescence by inhibiting mTORC1 activation, and promoting [[TFEB]] nuclear translocation and lysosome resumption, thereby reversing senescence-related neurogenesis dysfunction and cognitive impairment in VD. The application of ESC-sEVs may be a novel cell-free therapeutic tool for patients with VD, as well as other aging-related diseases.

|keywords=* embryonic stem cells derived small extracellular vesicles (ESC‐sEVs)
* hippocampal neural stem cells (HNSCs)
* lysosomes
* senescence
* vascular dementia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237844
}}
{{medline-entry
|title=Nitrative Stress-Related Autophagic Insufficiency Participates in Hyperhomocysteinemia-Induced Renal Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32047576
|abstract=The kidneys are important organs that are susceptible to aging. Hyperhomocysteinemia (HHcy) is a risk factor for nephropathy and is associated with chronic nephritis, purpuric nephritis, and nephrotic syndrome. Numerous studies have shown that elevated serum homocysteine levels can damage the kidneys; however, the underlying mechanism of HHcy on kidney damage remains unclear. In this study, we make use of a diet-induced HHcy rat model and in vitro cell culture to explore the role of autophagy in HHcy-induced renal aging and further explored the underlying mechanism. We demonstrated that HHcy led to the development of renal aging. Promoted kidney aging and autophagic insufficiency were involved in HHcy-induced renal aging. HHcy decreased the expression of transcription factor EB ([[TFEB]]), the key transcription factor of autophagy-related genes in renal tissue. Further experiments showed that nitrative stress levels were increased in the kidney of HHcy rats. Interestingly, pretreatment with the peroxynitrite (ONOO ) scavenger FeTMPyP not only reduced the Hcy-induced nitrative stress in vitro but also partially attenuated the decrease in [[TFEB]] in both protein and mRNA levels. Moreover, our results indicated that HHcy reduced [[TFEB]] expression and inhibited [[TFEB]]-mediated autophagy activation by elevating nitrative stress. In conclusion, this study showed an important role of autophagic insufficiency in HHcy-induced renal aging, in which downregulation of [[TFEB]] plays a major role. Furthermore, downexpression of [[TFEB]] was associated with increased nitrative stress in HHcy. This study provides a novel insight into the mechanism and therapeutic strategy for renal aging.
|mesh-terms=* Aging
* Animals
* Autophagy
* Cells, Cultured
* Homocysteine
* Humans
* Hyperhomocysteinemia
* Kidney
* Kidney Diseases
* Male
* Metalloporphyrins
* Peroxynitrous Acid
* Rats
* Rats, Sprague-Dawley

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007752
}}
{{medline-entry
|title=Polyamines reverse immune senescence via the translational control of autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31679458
|abstract=Organismal aging is associated with compromised cellular function, which can be partially attributed to accumulation of cellular damage. Being the major, if not only, cellular bulk-degradation mechanism, macroautophagy (hereafter autophagy) declines with age in multiple tissues and organisms. Spermidine is an endogenous polyamine metabolite that also declines with age. It prolongs lifespan and improves tissue functions of model organisms in an autophagy-dependent manner. We report that autophagic flux is significantly reduced in B cells from old mice. Spermidine induces autophagy and improves the function of both old mouse and old human B cells. Mechanistically, spermidine post-translationally modifies (hypusinates) the translation factor EIF5A. Hypusinated EIF5A specifically regulates the synthesis of the master autophagy and lysosome transcription factor, [[TFEB]] (transcription factor EB). This pathway declines with age in both mice and humans, which may eventually lead to declining autophagy and impaired tissue functions in old individuals.
|mesh-terms=* Aging
* Animals
* Autophagy
* Humans
* Lysosomes
* Polyamines
* Protein Processing, Post-Translational
* Spermidine
|keywords=* Aging
* B cells
* EIF5A
* TFEB
* autophagy
* hypusine
* spermidine
* translation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984486
}}
{{medline-entry
|title=Polyamines Control eIF5A Hypusination, [[TFEB]] Translation, and Autophagy to Reverse B Cell Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31474573
|abstract=Failure to make adaptive immune responses is a hallmark of aging. Reduced B cell function leads to poor vaccination efficacy and a high prevalence of infections in the elderly. Here we show that reduced autophagy is a central molecular mechanism underlying immune senescence. Autophagy levels are specifically reduced in mature lymphocytes, leading to compromised memory B cell responses in old individuals. Spermidine, an endogenous polyamine metabolite, induces autophagy in vivo and rejuvenates memory B cell responses. Mechanistically, spermidine post-translationally modifies the translation factor eIF5A, which is essential for the synthesis of the autophagy transcription factor [[TFEB]]. Spermidine is depleted in the elderly, leading to reduced [[TFEB]] expression and autophagy. Spermidine supplementation restored this pathway and improved the responses of old human B cells. Taken together, our results reveal an unexpected autophagy regulatory mechanism mediated by eIF5A at the translational level, which can be harnessed to reverse immune senescence in humans.
|mesh-terms=* Adaptive Immunity
* Age Factors
* Aging
* Animals
* Autophagy
* B-Lymphocytes
* Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
* Cellular Senescence
* HEK293 Cells
* Humans
* Immunologic Memory
* Immunosenescence
* Jurkat Cells
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* NIH 3T3 Cells
* Peptide Initiation Factors
* Protein Processing, Post-Translational
* RNA-Binding Proteins
* Signal Transduction
* Spermidine
|keywords=* B cell
* TFEB
* aging
* autophagy
* eIF5A
* spermidine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863385
}}
==LBP==

{{medline-entry
|title=Lipopolysaccharide binding protein is associated with CVD risk in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32895891
|abstract=Intestinal (i.e., "gut") permeability may be related to cardiovascular disease (CVD) risk, but biomarkers for gut permeability are limited and associations with CVD risk are unknown-particularly among older adults. This cross-sectional study aimed to determine if serum biomarkers related to gut permeability [intestinal fatty acid-binding protein (iFABP)] and bacterial toxin clearing [cluster of differentiation 14 (CD14), lipopolysaccharide binding protein ([[LBP]])] are associated with CVD risk among older adults. Older adults (n = 74, 69.6 ± 6.5-years-old) were stratified by CVD risk category. One-way ANOVAs determined differences in each biomarker by risk category, and associations with risk score were evaluated with Pearson correlations. [[LBP]] (p = 0.007), but not iFABP and CD14, was significantly different between CVD risk categories. Post-hoc tests indicated [[LBP]] was higher in moderate risk and high-moderate risk compared to the high risk category (p < 0.005). Evaluation of [[LBP]] and individual components in the risk score demonstrated a moderate, negative correlation of [[LBP]] with age and systolic blood pressure (r = - 0.335 and r = - 0.297) and a small positive correlation between [[LBP]] and total cholesterol and LDL cholesterol (r = 0.204 and r = 0.220). Lower risk for CVD was associated with higher circulating concentrations of [[LBP]], lower iFABP, and lower systemic inflammation in older adults. Further, there were small positive relationships between total and LDL cholesterol and circulating levels of [[LBP]]. These data suggest [[LBP]] may be a key component in reducing CVD risk in older adults.

|keywords=* Aging
* Cardiovascular disease risk
* Intestinal permeability
* Lipopolysaccharide binding protein
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01684-z
}}
{{medline-entry
|title=Aging-related liver degeneration is associated with increased bacterial endotoxin and lipopolysaccharide binding protein levels.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32090603
|abstract=Aging is a risk factor in the development of many diseases, including liver-related diseases. The two aims of the present study were [i]1[/i]) to determine how aging affects liver health in mice in the absence of any interventions and [i]2[/i]) if degenerations observed in relation to blood endotoxin levels are critical in aging-associated liver degeneration. Endotoxin levels and markers of liver damage, mitochondrial dysfunction, insulin resistance, and apoptosis as well as the Toll-like receptor 4 (Tlr-4) signaling cascade were studied in liver tissue and blood, respectively, of 3- and 24-mo-old male C57BL/6J mice. In a second set of experiments, 3- to 4-mo-old and 14-mo-old female lipopolysaccharide-binding protein ([[LBP]])  mice and littermates fed standard chow, markers of liver damage, insulin resistance, and mitochondrial dysfunction were assessed. Plasma activity of aspartate aminotransferase and histological signs of hepatic inflammation and fibrosis were significantly higher in old C57BL/6J mice than in young animals. The number of neutrophils, CD8α-positive cells, and mRNA expression of markers of apoptosis were also significantly higher in livers of old C57BL/6J mice compared with young animals, being also associated with a significant induction of hepatic Tlr-4 and [[LBP]] expression as well as higher endotoxin levels in peripheral blood. Compared with age-matched littermates, [[LBP]]  mice display less signs of senescence in liver. Taken together, our data suggest that, despite being fed standard chow, old mice developed liver inflammation and beginning fibrosis and that bacterial endotoxin may play a critical role herein.  Old age in mice is associated with marked signs of liver degeneration, hepatic inflammation, and fibrosis. Aging-associated liver degeneration is associated with elevated bacterial endotoxin levels and an induction of lipopolysaccharide-binding protein ([[LBP]]) and Toll-like receptor 4-dependent signaling cascades in liver tissue. Furthermore, in old aged [[LBP]]  mice, markers of senescence seem to be lessened, supporting the hypothesis that bacterial endotoxin levels might be critical in aging-associated decline of liver.
|mesh-terms=* Acute-Phase Proteins
* Aging
* Animals
* Apoptosis
* Biomarkers
* Carrier Proteins
* Endotoxins
* Female
* Gene Expression Regulation
* Glucose
* Inflammation
* Insulin Receptor Substrate Proteins
* Liver
* Liver Cirrhosis
* Malate Dehydrogenase
* Male
* Membrane Glycoproteins
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* RNA, Messenger
* Receptor, Insulin
* Toll-Like Receptor 4
|keywords=* Tlr-4 signaling
* aging
* bacterial endotoxin
* lipopolysaccharide binding protein
* liver degeneration
|full-text-url=https://sci-hub.do/10.1152/ajpgi.00345.2018
}}
{{medline-entry
|title=Biomarkers of leaky gut are related to inflammation and reduced physical function in older adults with cardiometabolic disease and mobility limitations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31654268
|abstract=Intestinal barrier dysfunction is hypothesized to be a contributing determinant of two prominent characteristics of aging: inflammation and decline in physical function. A relationship between microbial translocation (MT), or their biomarkers (lipopolysaccharide binding protein-1 [[[LBP]]-1], soluble cluster of differentiation [sCD]-14), and physical function has been reported in healthy older adults, rats, and invertebrates. However, it is not known whether the existence of comorbidities, or clinical interventions intended to reduce comorbidities through weight loss or exercise, alters this connection. We measured inflammation, MT, and physical function in 288 overweight/obese older patients with cardiometabolic disease and self-reported mobility limitations who were enrolled in a weight loss and lifestyle intervention study. At baseline, inflammatory cytokines and [[LBP]]-1 were positively correlated after adjustment for age, gender, and body mass index. A higher [[LBP]]-1 was significantly associated with poorer physical functional after covariate adjustment. Further, even when IL-6 levels were included in the models, 400-m walk time (p = 0.003), short physical performance battery (p = 0.07), and IL-8 (p < 0.001) remained positively associated with [[LBP]]-1. Lifestyle interventions improved body mass and some functional measures; however, MT and inflammation were unchanged. MT is reliably related to inflammation, and to poorer physical function in older adults with comorbid conditions. Intestinal barrier function did not appear to improve as a result of intervention assignment, suggesting alternative strategies are needed to target this pro-inflammatory pathway in aging.
|mesh-terms=* Aged
* Aging
* Biomarkers
* Exercise Therapy
* Female
* Follow-Up Studies
* Humans
* Inflammation
* Male
* Metabolic Syndrome
* Middle Aged
* Mobility Limitation
* Motor Activity
* Obesity
* Retrospective Studies
* Weight Loss
|keywords=* Ageing
* Lipopolysaccharide-binding protein
* Microbial translocation
* Physical function
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925090
}}
{{medline-entry
|title=Needle-shaped amyloid deposition in rat mammary gland: evidence of a novel amyloid fibril protein.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31615282
|abstract=Amyloidosis is an extremely rare event in rats. In this study, we report that lipopolysaccharide binding protein ([[LBP]]) is the most likely amyloidogenic protein in rat mammary amyloidosis. Histologically, corpora amylacea (CA) and stromal amyloid (SA) were observed in rat mammary glands, and needle-shaped amyloid (NA) was also observed on the surface or gap of CA and SA. Following surveillance in aged rats, NA was observed in 62% of mammary tumours, 25% of male mammary glands and 83% of female mammary glands. Proteomic analysis showed that lactadherin was a major constitutive protein of CA and SA, and both were positive following immunohistochemistry with anti-lactadherin antibodies. In the same analysis, [[LBP]] was detected as a prime candidate protein in NA, and NA was positive following immunohistochemistry and immunoelectron microscopy with anti-[[LBP]] antibody. Furthermore, synthetic peptides derived from rat [[LBP]] formed amyloid fibrils [i]in vitro[/i]. Overall, these results provide evidence that [[LBP]] is an amyloid precursor protein of NA in rat mammary glands.
|mesh-terms=* Aging
* Amyloidogenic Proteins
* Amyloidosis
* Animals
* Antigens, Surface
* Female
* Mammary Glands, Animal
* Milk Proteins
* Plaque, Amyloid
* Rats
* Rats, Sprague-Dawley
|keywords=* Amyloidosis
* lipopolysaccharide binding protein
* mammary gland
* pathology
* rat
|full-text-url=https://sci-hub.do/10.1080/13506129.2019.1675623
}}
{{medline-entry
|title=Effects of Lycium barbarum Polysaccharides on Health and Aging of [i]C. elegans[/i] Depend on [i]daf-12/daf-16[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31583041
|abstract=As the global population ages, searching for drugs and functional foods which can slow down the aging process has attracted a number of researchers. In this paper, the Lycium barbarum polysaccharides ([[LBP]]) extracted from Lycium barbarum was characterized and the effects of [[LBP]] on the aging and health of [i]C. elegans[/i] were studied. Results showed that [[LBP]] can prolong the lifespan, improve the abilities to withstand environmental stress, enhance reproductive potentials, and maintain muscle integrity of [i]C. elegans[/i]. By using genetically mutated [i]C. elegans[/i] strains, RNAi gene silencing, and measuring the mRNA expression level, it was demonstrated that the lifespan of [i]C. elegans[/i] was extended by [[LBP]] mainly through [i]sir-2.1[/i], [i]daf-12[/i], and [i]daf-16[/i]. The present study might provide a basis for further study of [[LBP]] as a food or drug to interfere with aging and reduce the incidence of age-related diseases.
|mesh-terms=* Aging
* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Drugs, Chinese Herbal
* Receptors, Cytoplasmic and Nuclear

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754959
}}
==FES==

{{medline-entry
|title=An outpatient Tai Chi program: Effects on veterans' functional outcomes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33241873
|abstract=To evaluate the effectiveness of an evidence-based 12-week Tai Chi course designed to improve balance and physical function in a population of older veterans. Community dwelling veterans of all ages with gait and balance problems were invited to participate in the Tai Chi program. Participants completed the Berg Balance Scale (BBS), the Timed Up and Go (TUG) test, and the Falls Efficacy Scale-International ([[FES]]-I) at baseline and again at the end of the program. Descriptive statistics were used to summarize study participants' characteristics. The change from baseline to the end of the 12-week program was calculated for each of the three primary outcome variables (BBS, TUG, [[FES]]-I). Twenty-two veterans, aged 58 years and above, with perceived gait and/or balance issues were enrolled in the program with completion by 11 veterans. Veterans who completed their final assessments showed the BBS, improved significantly (p = 0.004) from baseline to the 12-week assessment. The TUG scores improved by a median of 1.3 s (p = 0.022). There was not a significant change in the [[FES]]-I. Preliminary findings provide evidence of the effectiveness of a 12-week Tai Chi program to improve functional outcomes for older veterans with mild to moderate gait and balance problems.

|keywords=* Tai Chi
* balance
* exercise
* gait
* geriatrics
|full-text-url=https://sci-hub.do/10.1111/nuf.12532
}}
{{medline-entry
|title=Gait Function in Adults Aged 50 Years and Older With Spina Bifida.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33166524
|abstract=To study gait function among individuals with spina bifida (SB) aged 50 years or older. A cross-sectional study conducted in 2017. Home-dwelling participants from all regions in Norway. Individuals between the ages of 51 and 76 years (N=26; 16 women) categorized as independent walkers (n=9), walkers with aids (n=10) and nonwalkers (n=7). Not applicable. Questionnaire, pain assessment, anthropometry, Falls Efficacy Scale International ([[FES]]-I), objective gait analysis, 6-minute walk test (6MWT), and timed Up and Go (TUG). Walking speed correlated with SB severity (ρ=-.59; P=.008). Individuals who walked slower than 0.81 m/s had a higher body mass index (BMI) than those who walked faster (P=.008). Independent walkers walked slower than healthy age-matched walkers (P=.046); spatiotemporal variables showed that this was owing to shorter steps rather than cadence. The mean TUG was 10.6±2.6 seconds in independent walkers and 20.2±6.5 in walkers with aids (P<.01). The mean 6MWT was 504±126 meters in independent walkers and 316±88 in walkers with aids (P<.01). The mean pain intensity (numeric rating scale) was 4.9±2.2 in independent walkers and 4.2±1.6 in walkers with aids, but the difference was not statistically significant. [[FES]]-I was significantly lower among independent walkers (mean, 23.6±3.9) than walkers with aids (mean, 31.4±10.0) (P=.042). Participants commonly experienced an early onset deterioration in gait function, and walking speed was influenced by SB severity and BMI. This highlights the importance of early monitoring and weight management during follow-up for SB.

|keywords=* Adult
* Aging
* Gait analysis
* Myelomeningocele
* Rehabilitation
|full-text-url=https://sci-hub.do/10.1016/j.apmr.2020.10.118
}}
{{medline-entry
|title=A Single Question as a Screening Tool to Assess Fear of Falling in Young-Old Community-Dwelling Persons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32165062
|abstract=Fear of falling (FOF) is common in older persons and related to negative outcomes. This study aimed to investigate the relationship between 2 FOF measures: the Falls Efficacy Scale-International ([[FES]]-I) and the single question on FOF and activity restriction (SQ-FAR). Factors associated with disagreement between the 2 measures were further examined. Cross-sectional study. Participants (N = 1359) were community-dwelling persons aged 65 to 70 years who were enrolled in the Lausanne cohort 65+. Data included demographic, functional, cognitive, affective, and health status. FOF was measured with [[FES]]-I and the 3-level SQ-FAR (no FOF, FOF without activity restriction (AR, FOF with AR). [[FES]]-I concern about falling was categorized as low (score 16-19), moderate (score 20-27), and high (score 28-64). Weighted agreement between the [[FES]]-I and the SQ-FAR was 87.8% (Kappa = 0.57). Using the [[FES]]-I as gold standard, the performance of SQ-FAR was good (specificity 86%; sensitivity 74%, negative predicting value 89%, positive predicting value 69%). Among participants with moderate/high FOF according to [[FES]]-I, male sex (P = .011) and the absence of previous falls (P < .001) were associated with disagreement between the 2 tools. Among participants with low FOF, female sex (P = .005), falls history (P < .001), and pre-frailty/frailty status (P = .050) were associated with disagreement. The SQ-FAR has a moderate agreement with [[FES]]-I and might be used as a screening tool. The results also may help design a step-by-step strategy to evaluate and address FOF in the clinical setting.

|keywords=* FES-I
* elderly
* fear of falling
* healthy aging
* older adults
|full-text-url=https://sci-hub.do/10.1016/j.jamda.2020.01.101
}}
{{medline-entry
|title=Fall-related efficacy is a useful and independent index to detect fall risk in Japanese community-dwelling older people: a 1-year longitudinal study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31664911
|abstract=Fall-related efficacy has been found to be associated with both falls and fall risk factors such as physical performance. The aim of the present study was to clarify whether fall-related efficacy is, independent of physical performance and other potential risk factors, associated with future falls in community-dwelling older people. The study participants were 237 Japanese older people aged 65 years and over who were living independently in their community. Fall-related efficacy and physical performance were assessed at baseline using the short version of the Falls Efficacy Scale-International (short [[FES]]-I) and 5-m walking time, the Timed Up and Go Test, the 5 Times Sit to Stand Test, and grip strength. Physical performance was then again assessed at 1-year follow-up. The number of falls was obtained every 6 months for 1 year after the baseline survey. Instrumental activities of daily living (IADL), depression, fall history, current medications, medical history, and pain were also investigated as potential confounding factors that have possible associations with falls. The associations between the short [[FES]]-I, physical performance, and number of falls were analyzed using Poisson regression analysis adjusted for physical performance and potential confounding factors. The mean age of the participants (75.9% women) was 71.1 ± 4.6 years, and 92.8% could perform IADL independently. The total numbers of falls and fallers during the 1-year follow-up period were 70 and 42, respectively. On Poisson regression analysis adjusted for walking time and potential confounding factors, independent of physical performance, the short [[FES]]-I was found to be significantly associated with number of falls (relative risk = 1.09, p < 0.05). On the other hand, physical performance was not significantly associated with the number of falls. The findings of the present study suggest that the short [[FES]]-I, independent of physical performance and other potential risk factors, is a useful index to detect fall risk in community-dwelling older people, and that fall-related efficacy is an important factor in terms of fall prevention.
|mesh-terms=* Accidental Falls
* Activities of Daily Living
* Aged
* Aging
* Female
* Geriatric Assessment
* Humans
* Independent Living
* Japan
* Longitudinal Studies
* Male
* Physical Functional Performance
* Postural Balance
* Risk Factors
* Walking Speed
|keywords=* Accidental falls
* Aged
* Fall-related efficacy
* Japanese
* Physical performance
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820944
}}
{{medline-entry
|title=Investigating Changes in Real-time Conscious Postural Processing by Older Adults during Different Stance Positions Using Electroencephalography Coherence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31514583
|abstract=: Adjustments of posture in response to balance challenges may lead to subsequent increases in conscious posture processing. If cognitive resources are stretched by conscious processing of postural responses fewer resources will be available to attend to environmental trip or fall hazards. The objective of the study was to explore brain activity related to conscious processing of posture as a function of movement specific reinvestment and fear of falling.  : Forty-three older adults ([i]M[/i] = 71.4, [i]SD[/i] = 4.1) stood with a wide or narrow stance on a force-plate while neural coherence between verbal-analytical (T3) and motor planning (Fz) regions of the brain was assessed using electroencephalography. The propensity for movement specific reinvestment was assessed using the Chinese version Movement Specific Reinvestment Scale (MSRS-C) and fear of falling was assessed using the Chinese version Fall Efficacy Scale International ([[FES]]-I[CH]).  : Scores from the MSRS-C were negatively correlated with changes in T3-Fz coherence that occurred when participants shifted from wide to narrow stance. Together, MSRS-C and [[FES]]-I(CH) uniquely predicted the percentage change in T3-Fz coherence between the two stance conditions.  : Presented with two postural tasks of different complexities, participants with a lower propensity for conscious control of their movements (movement specific reinvestment) exhibited larger changes in real-time brain activity (neural coherence) associated with conscious postural processing.
|mesh-terms=* Accidental Falls
* Aged
* Aging
* Brain
* Electroencephalography
* Fear
* Female
* Humans
* Male
* Movement
* Postural Balance
* Posture

|full-text-url=https://sci-hub.do/10.1080/0361073X.2019.1664450
}}
==CORT==

{{medline-entry
|title=Sex differences in body composition, metabolism-related hormones, and energy homeostasis during aging in Wistar rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33075214
|abstract=Aging affects the body composition and balance of energy metabolism. Here, we collected in a single work several physiological parameters to show how aging and sex differences can influence energy homeostasis. Body mass index (BMI), Lee index, glucose tolerance, glycemia, and lipidogram in fasting were measured in male and female Wistar rats at the ages of 2, 6, 9, 12, and 18 months. We also measured the lipid profile, free fatty acids, glycerol, glycemia, leptin, adiponectin, insulin, corticosterone ([[CORT]]), prolactin (PRL), thyroid stimulated hormone, and triiodothyronine (T3) in 3- and 18-month-old rats of both sexes, fed ad libitum. Animals were classified as obese beginning at 2 months in males and 6 months in females. Aged male rats showed hyperglycemia and glucose intolerance compared to young males and old females. In the ad libitum condition, the 18-month males presented higher serum levels of triglycerides, total cholesterol, and free fatty acids than females. The 18-month-old females had higher PRL and [[CORT]] concentration than males, but insulin and T3 were higher in 18-month-old males than females. Our work demonstrated that aging processes on energy metabolism in rats is sex specific, with a better lipid profile and glucose tolerance in aged females.

|keywords=* aging
* body composition
* energy metabolism
* metabolism-related hormone
* sex differences
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571994
}}
{{medline-entry
|title=Effects of age and social isolation on murine hippocampal biochemistry and behavior.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32866520
|abstract=Social isolation (SI) is a major health risk in older people leading to cognitive decline. This study examined how SI and age influence performance in the novel object recognition (NOR) and elevated plus maze (EPM) tasks in C57BL/6 mice aged 3 or 24 months. Mice were group-housed (groups of 2-3) or isolated for 2 weeks prior to experimentation. Following NOR and EPM testing hippocampal norepinephrine (NE), 5, hydroxytryptamine (5-HT), 5, hydroxyindole acetic acid (5-HIAA), corticosterone ([[CORT]]) and interleukin-6 (IL-6) were determined and serum collected for basal [[CORT]] analysis. A separate set of mice were exposed to the forced swim test (FST), sacrificed immediately and serum [[CORT]] determined. SI impaired performance in the NOR and the FST, reduced hippocampal 5-HT, increased hippocampal IL-6 and increased serum [[CORT]] post-FST in young mice. Aged mice either failed to respond significantly to SI (NOR, FST, hippocampal 5-HT, serum [[CORT]] post FST) or SI had synergistic effects with age (hippocampal NE, 5-HIAA:5-HT). In conclusion, the lack of response to SI in the aged mice may affect health by preventing them adapting to new stressors, while the synergistic effects of SI with age would increase allostatic load and enhance the deleterious effects of the ageing process.

|keywords=* Aging
* Hippocampus
* Inflammation
* Memory
* Serotonin
* Social isolation
* Stress
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111337
}}
{{medline-entry
|title=Interleukin 6 reduces allopregnanolone synthesis in the brain and contributes to age-related cognitive decline in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32669383
|abstract=Cognitive decline with age is a harmful process that can reduce quality of life. Multiple factors have been established to contribute to cognitive decline, but the overall etiology remains unknown. Here, we hypothesized that cognitive dysfunction is mediated, in part, by increased levels of inflammatory cytokines that alter allopregnanolone (AlloP) levels, an important neurosteroid in the brain. We assessed the levels and regulation of AlloP and the effects of AlloP supplementation on cognitive function in 4-month-old and 24-month-old male C57BL/6 mice. With age, the expression of enzymes involved in the AlloP synthetic pathway was decreased and corticosterone ([[CORT]]) synthesis increased. Supplementation of AlloP improved cognitive function. Interestingly, interleukin 6 (IL-6) infusion in young animals significantly reduced the production of AlloP compared with controls. It is notable that inhibition of IL-6 with its natural inhibitor, soluble membrane glycoprotein 130, significantly improved spatial memory in aged mice. These findings were supported by in vitro experiments in primary murine astrocyte cultures, indicating that IL-6 decreases production of AlloP and increases [[CORT]] levels. Our results indicate that age-related increases in IL-6 levels reduce progesterone substrate availability, resulting in a decline in AlloP levels and an increase in [[CORT]]. Furthermore, our results indicate that AlloP is a critical link between inflammatory cytokines and the age-related decline in cognitive function.

|keywords=* Alzheimer’s disease
* aging
* cognitive function
* enzyme regulation
* inflammation
* neurosteroid
* progesterone
* steroid hormones
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529050
}}
{{medline-entry
|title=Sex- and age-dependent differences in the hormone and drinking responses to water deprivation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31967852
|abstract=Maintenance of the volume and osmolality of body fluids is important, and the adaptive responses recruited to protect against osmotic stress are crucial for survival. The objective of this work was to compare the responses that occur in aging male and female rats during water deprivation. For this purpose, groups of male and female Wistar rats aged 3 mo (adults) or 18 mo (old) were submitted to water deprivation (WD) for 48 h. The water and sodium (0.15 M NaCl) intake, plasma concentrations of oxytocin (OT), arginine vasopressin (AVP), corticosterone ([[CORT]]), atrial natriuretic peptide (ANP), and angiotensin II (ANG II) were determined in hydrated and water-deprived animals. In response to WD, old male and female rats drank less water and saline than adults, and both adult and old females drank more water and saline than respective males. Dehydrated old animals displayed lower ANG II plasma concentration and [[CORT]] response compared with the respective normohydrated rats. Dehydrated adult males had higher plasma ANP and AVP as well as lower [[CORT]] concentrations than dehydrated adult females. Moreover, plasma OT and [[CORT]] levels of old female rats were higher than those in the dehydrated old male rats. Relative expression of ANG II type 1 receptor mRNA was decreased in the subfornical organ of adult and old male rats as well as adult female rats in response to WD. In conclusion, the study elucidated the effect of sex and age on responses induced by WD, altering the degree of dehydration induced by 48 h of WD.
|mesh-terms=* Age Factors
* Animals
* Arginine Vasopressin
* Behavior, Animal
* Dehydration
* Drinking
* Female
* Male
* Rats, Wistar
* Sex Factors
* Sodium Chloride
* Subfornical Organ
* Water Deprivation
|keywords=* aging
* hormonal response
* sex differences
* sodium appetite
* thirst
|full-text-url=https://sci-hub.do/10.1152/ajpregu.00303.2019
}}
{{medline-entry
|title=Ontogeny of the adrenocortical response in an extremely altricial bird.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31545013
|abstract=Life history theory predicts that physiological and behavioral responsiveness to stress should be delayed in development until the benefits of heightened reactivity outweigh the costs of potentially chronic glucocorticoid levels. Birds often acquire stress-responsiveness at locomotor independence, however, both stress-responsiveness and locomotor ability are delayed in birds with altricial developmental strategies. Parrots (Psittacidae) are extremely altricial, but it is not known whether they also postpone physiological responsiveness to stress until locomotor independence. We quantified individual variation in baseline and stress-induced plasma corticosterone ([[CORT]]) concentrations, the main avian glucocorticoid, in wild green-rumped parrotlets (Forpus passerinus) of Venezuela at four stages of nestling development. Parrotlet neonates are very underdeveloped and compete for parental care among extreme sibling size hierarchies, a competitive scenario that might benefit from early hypothalamic-pituitary-adrenal (HPA) functionality. Nestlings that underwent a standardized restraint stress-treatment showed higher average [[CORT]] concentrations compared to baseline in all age groups sampled, and exhibited no evidence of age-related changes in the stress response. This is 2 weeks before locomotor independence and earlier than previously documented for altricial species. Results suggest that precocity of HPA function may be advantageous to growth and survivorship in extremely altricial birds.
|mesh-terms=* Adrenal Glands
* Aging
* Animals
* Corticosterone
* Female
* Hypothalamo-Hypophyseal System
* Male
* Parrots
* Restraint, Physical
* Stress, Physiological
|keywords=* Venezuela
* adrenocortical
* altricial
* birds
* corticosterone
* glucocorticoid
* hypothalamic-pituitary-adrenal axis
* ontogeny
* parrots
* stress
|full-text-url=https://sci-hub.do/10.1002/jez.2317
}}
==CCS==

{{medline-entry
|title=Frailty Significantly Associated with a Risk for Mid-term Outcomes in Elderly Chronic Coronary Syndrome Patients: a Prospective Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33306315
|abstract=Frailty is a condition of elderly characterized by increased vulnerability to stressful events. Frail patients are more likely to have adverse events. The purposes of this study were to define frailty in patients aged ≥ 70 years with chronic coronary syndrome ([[CCS]]) and to evaluate mortality and prognostic significance of frailty in these patients. We included 99 patients, ≥ 70 years old (mean age 74±5.3 years), with diagnosis of [[CCS]]. They were followed-up for up to 12 months. The frailty score was evaluated according to the Canadian Study of Health and Aging (CSHA). All patients were divided as frail or non-frail. The groups were compared for their characteristics and clinical outcomes. Fifty patients were classified as frail, and 49 patients as non-frail. The 12-month Major Adverse Cardiac Events (MACE) rate was 69.4% in frail patients and 20% in non-frail patients. Frailty increases the risk for MACE as much as 3.48 times. Two patients died in the non-frail group and 11 patients died in the frail group. Frailty increases the risk for death as much as 6.05 times. When we compared the aforementioned risk factors by multivariate analysis, higher CSHA frailty score was associated with increased MACE and death (relative risk [RR] = 22.94, 95% confidence interval [CI] 3.33-158.19, P=0.001, for MACE; RR = 7.41, 95% CI 1.44-38.03, P=0.016, for death). Being a frail elderly [[CCS]] patient is associated with worse outcomes. Therefore, frailty score should be evaluated for elderly [[CCS]] patients as a prognostic marker.

|keywords=* Aging
* Canada
* Confidence Intervals
* Death
* Frail Elderly
* Frailty
* Heart
* Multivariate Analysis
* Prognosis
* Risk Factors
|full-text-url=https://sci-hub.do/10.21470/1678-9741-2019-0484
}}
{{medline-entry
|title=Microbleeds and Medial Temporal Atrophy Determine Cognitive Trajectories in Normal Aging: A Longitudinal PET-MRI Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32925053
|abstract=The cognitive trajectories in normal aging may be affected by medial temporal atrophy (MTA) and amyloid burden, as well as vascular pathologies such as cortical microbleeds (CMB) and white matter hyperintensities (WMH). We addressed here the role of imaging markers in their prediction in a real-world situation. We performed a 4.5-year longitudinal study in 90 older community-dwellers coupling two neuropsychological assessments, MTA estimated with the Schelten's scale, number of CMB, and WMH evaluated with the Fazekas score at inclusion and follow-up, visual rating of amyloid PET and glucose hypometabolism at follow-up, and APOE genotyping. Regression models were built to explore the association between the continuous cognitive score ([[CCS]]) and imaging parameters. The number of strictly lobar CMB at baseline (4 or more) was related to a 5.5-fold increase of the risk of cognitive decrement. This association persisted in multivariable models explaining 10.6% of the [[CCS]] decrease variance. MTA, and Fazekas score at baseline and amyloid positivity or abnormal FDG PET, were not related to the cognitive outcome. The increase of right MTA at follow-up was the only correlate of [[CCS]] decrease both in univariate and multivariable models explaining 9.2% of its variance. The present data show that the accumulation of more than four CMB is associated with significant cognitive decrement over time in highly educated elderly persons. They also reveal that the progressive deterioration of cognitive performance within the age-adjusted norms is also related to the increase of visually assessed MTA.

|keywords=* Atrophy
* cognition
* imaging markers
* medial temporal lobe
* microbleeds
* normal aging
|full-text-url=https://sci-hub.do/10.3233/JAD-200559
}}
{{medline-entry
|title=Hippocampal Volume Loss, Brain Amyloid Accumulation, and APOE Status in Cognitively Intact Elderly Subjects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31846965
|abstract=Hippocampal volume loss (HVL), PET-documented brain amyloid accumulation, and APOE-ε4 status are predictive biomarkers of the transition from mild cognitive impairment to Alzheimer disease (AD). In asymptomatic cases, the role of these biomarkers remains ambiguous. In contrast to the idea that HVL occurs in late phases of neurodegeneration, recent contributions indicate that it might occur before abnormal amyloid PET occurrence in elderly subjects and that its severity could be only marginally related to APOE variants. Using a longitudinal design, we examined the determinants of HVL in our sample, i.e., brain amyloid burden and the presence of APOE-ε4, and made a longitudinal assessment of cognitive functions. We performed a 4.5-year longitudinal study on 81 elderly community dwellers (all right-handed;, 48 (59.3%) women; mean age 73.7 ± 3.7 years) including MRI at baseline and follow-up, PET amyloid during follow-up, neuropsychological assessment at 18 and 54 months, and APOE genotyping. All cases were assessed using a continuous cognitive score ([[CCS]]) that took into account the global evolution of neuropsychological performance. Linear regression models were used to identify predictors of HVL. There was a negative association between the [[CCS]] and HVL bilaterally. In multivariate models adjusting for demographic variables, the presence of APOE-ε4 was related to increased HVL bilaterally. A trend of significance was observed with respect to the impact of amyloid positivity on HVL in the left hemisphere. No significant interaction was found between amyloid positivity and the APOE-ε4 allele. The progressive decrement of neuropsychological performance is associated with HVL long before the emergence of clinically overt symptoms. In this cohort of healthy individuals, the presence of the APOE-ε4 allele was shown to be an independent predictor of worst hippocampal integrity in asymptomatic cases independently of amyloid positivity.
|mesh-terms=* Aged
* Aged, 80 and over
* Amyloid beta-Peptides
* Apolipoprotein E4
* Brain
* Cognitive Aging
* Female
* Hippocampus
* Humans
* Longitudinal Studies
* Magnetic Resonance Imaging
* Male
* Positron-Emission Tomography
|keywords=* APOE
* Aging
* Amyloid
* Hippocampus
|full-text-url=https://sci-hub.do/10.1159/000504302
}}
{{medline-entry
|title=Amyloid Load, Hippocampal Volume Loss, and Diffusion Tensor Imaging Changes in Early Phases of Brain Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31803008
|abstract=Amyloid imaging, gray matter (GM) morphometry and diffusion tensor imaging (DTI) have all been used as predictive biomarkers in dementia. Our objective was to define the imaging profile of healthy elderly controls as a function of their cognitive trajectories and explore whether amyloid burden and white matter (WM) microstructure changes are associated with subtle decrement of neuropsychological performances in old age. We performed a 4.5-year longitudinal study in 133 elderly individuals who underwent cognitive testing at inclusion and follow-up, amyloid PET, MRI including DTI sequences at inclusion, and APOE epsilon 4 genotyping. All cases were assessed using a continuous cognitive score ([[CCS]]) taking into account the global evolution of neuropsychological performances. Data processing included region of interest analysis of amyloid PET analysis, GM densities and tract-based spatial statistics (TBSS)-DTI. Regression models were built to explore the association between the [[CCS]] and imaging parameters controlling for significant demographic and clinical covariates. Amyloid uptake was not related to the cognitive outcome. In contrast, GM densities in bilateral hippocampus were associated with worst [[CCS]] at follow-up. In addition, radial and axial diffusivities in left hippocampus were negatively associated with [[CCS]]. Amyloid load was associated with decreased VBM and increased radial and axial diffusivity in the same area. These associations persisted when adjusting for gender and APOE4 genotype. Importantly, they were absent in amygdala and neocortical areas studied. The progressive decrement of neuropsychological performances in normal aging is associated with volume loss and WM microstructure changes in hippocampus long before the emergence of clinically overt symptoms. Higher amyloid load in hippocampus is compatible with cognitive preservation in cases with better preservation of GM densities and WM microstructure in this area.

|keywords=* APOE genotyping
* amyloid deposition
* magnetic resonance imaging
* normal aging
* positron emission tomography
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872975
}}
{{medline-entry
|title=Lower bone mass is associated with subclinical atherosclerosis, endothelial dysfunction and carotid thickness in the very elderly.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31783200
|abstract=Osteoporosis and coronary heart disease (CHD) are very common conditions among elderly people, and both represent a public health concern due to their prognostic consequences. Osteoporosis and CHD share many risk factors and pathophysiological mechanisms, such as calcification pathways. Clinical evidence associates lower bone mass with cardiovascular diseases and endothelial dysfunction. Hence, this study aims to investigate whether bone mass density is associated with subclinical atherosclerosis and/or endothelial dysfunction in the very elderly. We performed a cross-sectional study of cohort enrolled individuals, ages 80 years or older (n = 208), who had never manifested cardiovascular diseases. Medical evaluation, blood tests, flow-mediated dilation (FMD), carotid intimal-media thickness (IMT), Dual Energy X-ray Absorptiometry (DEXA) and Coronary Calcium Score ([[CCS]]) were obtained. Odds Ratio (OR) was calculated by multivariate logistic regression models using [[CCS]], FMD and IMT categories. Adjustments for covariates were done. Overall bone mass was independently and inversely associated with [[CCS]] categories [OR:1.68(1.16-8.85); p = 0.024] and IMT categories [OR:2.97(1.11-7.90); p = 0.030]. Conversely, overall bone mass was independent and directly associated with FMD categories [OR:2.73(1.36-70.39); p = 0.023]. This study indicates that overall bone mass is independently and inversely associated with subclinical atherosclerosis, endothelial dysfunction and thickness of carotid in the very elderly.

|keywords=* Aging
* Endothelial dysfunction
* Osteoporosis
* Subclinical atherosclerosis
|full-text-url=https://sci-hub.do/10.1016/j.atherosclerosis.2019.11.007
}}
==FGF23==

{{medline-entry
|title=Phosphate as a Pathogen of Arteriosclerosis and Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33028781
|abstract=During the evolution of skeletons, terrestrial vertebrates acquired strong bones made of calcium-phosphate. By keeping the extracellular fluid in a supersaturated condition regarding calcium and phosphate ions, they created the bone when and where they wanted simply by providing a cue for precipitation. To secure this strategy, they acquired a novel endocrine system to strictly control the extracellular phosphate concentration. In response to phosphate intake, fibroblast growth factor-23 ([[FGF23]]) is secreted from the bone and acts on the kidney through binding to its receptor Klotho to increase urinary phosphate excretion, thereby maintaining phosphate homeostasis. The [[FGF23]]-Klotho endocrine system, when disrupted in mice, results in hyperphosphatemia and vascular calcification. Besides, mice lacking Klotho or [[FGF23]] suffer from complex aging-like phenotypes, which are alleviated by placing them on a low-phosphate diet, indicating that phosphate is primarily responsible for the accelerated aging. Phosphate acquires the ability to induce cell damage and inflammation when precipitated with calcium. In the blood, calcium-phosphate crystals are adsorbed by serum protein fetuin-A and prevented from growing into large precipitates. Consequently, nanoparticles that comprised calcium-phosphate crystals and fetuin-A, termed calciprotein particles (CPPs), are generated and dispersed as colloids. CPPs increase in the blood with an increase in serum phosphate and age. Circulating CPP levels correlate positively with vascular stiffness and chronic non-infectious inflammation, raising the possibility that CPPs may be an endogenous pro-aging factor. Terrestrial vertebrates with the bone made of calcium-phosphate may be destined to age due to calcium-phosphate in the blood.

|keywords=* Aging
* Calciprotein particles (CPPs)
* Fibroblast growth factor-23 (FGF23)
* Inflammation
* Klotho
* Phosphate
* Vascular calcification
|full-text-url=https://sci-hub.do/10.5551/jat.RV17045
}}
{{medline-entry
|title=Plasma Soluble αKlotho, Serum Fibroblast Growth Factor 23, and Mobility Disability in Community-Dwelling Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32405607
|abstract=αKlotho is a hormone and co-receptor for fibroblast growth factor 23 ([[FGF23]]), a hormone that downregulates active vitamin D synthesis and promotes phosphate excretion. Low αKlotho and high [[FGF23]] occur in chronic kidney disease (CKD). We aimed to assess the relationships of αKlotho and [[FGF23]] with mobility disability in community-dwelling older adults. We estimated associations of plasma-soluble αKlotho and serum [[FGF23]] concentrations with mobility disability over 6 years. Additional analyses was stratified by CKD. Participants included 2751 adults (25.0% with CKD), aged 71 to 80 years, from the 1998 to 1999 Health, Aging, and Body Composition Study visit. Walking disability and stair climb disability were defined as self-reported "a lot of difficulty" or an inability to walk a quarter mile and climb 10 stairs, respectively. Median (interquartile range [IQR]) serum [[FGF23]] and plasma soluble αKlotho concentrations were 46.6 (36.7, 60.2) pg/mL and 630.4 (478.4, 816.0) pg/mL, respectively. After adjustment, higher αKlotho concentrations were associated with lower walking disability rates (Rate Ratio [RR] highest vs. lowest tertile = 0.74; 95% confidence interval l [CI] = 0.62, 0.89; [i]P[/i] = 0.003). Higher [[FGF23]] concentrations were associated with higher walking disability rates (RR highest vs. lowest tertile = 1.24; 95%CI = 1.03, 1.50; [i]P[/i] = 0.005). Overall, higher αKlotho combined with lower [[FGF23]] was associated with the lowest walking disability rates ([i]P[/i] for interaction = 0.023). Stair climb disability findings were inconsistent. No interactions with CKD were statistically significant ([i]P[/i] for interaction > 0.10). Higher plasma soluble αKlotho and lower serum [[FGF23]] concentrations were associated with lower walking disability rates in community-dwelling older adults, particularly those without CKD.

|keywords=* aging
* chronic kidney disease
* fibroblast growth factor 23
* mobility disability
* αKlotho
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209777
}}
{{medline-entry
|title=Protective effect of Polygonatum sibiricum Polysaccharide on D-galactose-induced aging rats model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32042011
|abstract=The polysaccharide of Polygonatum sibiricum (PSP)is one of the main active ingredients of Polygonatum Polygonatum in Liliaceae. It has anti-tumor, anti-aging, immune regulation, and anti-oxidative effects. Recent studies have shown that the Klotho gene and fibroblast growth factor-23 (FGF-23) have a common receptor, which is closely related to aging and highly expressed in kidney and meninges. Our study aimed to investigate the anti-aging effect of PSP on D-galactose-induced rats and its mechanism. D-galactose (120 mg Kg ) and PSP (100 mg Kg ) was used to intervene in rats, respectively. Then The changes of indexes of the natural aging-like model rats before and after PSP intervention were observed. We found that PSP could significantly improve the learning and memory abilities of rats and reverse the pathological changes of kidney tissues in rats. At the same time, PSP up-regulated the expression of Klotho mRNA and Klotho protein in the renal cortex, down-regulated the expression of FOXO3a mRNA and p-FOXO3a protein in renal tissue, and inhibited the expression of FGF-23 protein in the femur. Our studies suggest that PSP may play a role by regulating the Klotho-[[FGF23]] endocrine axis, alleviating oxidative stress, and balancing calcium and phosphorus metabolism.
|mesh-terms=* Aging
* Animals
* Calcium
* Dietary Carbohydrates
* Fibroblast Growth Factors
* Galactose
* Glucuronidase
* Male
* Oxidative Stress
* Phosphorus
* Phytochemicals
* Polygonatum
* Polysaccharides
* Protective Agents
* Rats
* Rats, Sprague-Dawley

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010663
}}
{{medline-entry
|title=[[FGF23]] expression is stimulated in transgenic α-Klotho longevity mouse model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31801907
|abstract=Observations in transgenic α-Klotho (Kl) mice (KlTg) defined the antiaging role of soluble Klotho (sKL130). A genetic translocation that elevates sKL levels in humans is paradoxically associated with increased circulating fibroblast growth factor 23 ([[FGF23]]) levels and the potential of both membrane KL (mKL135) and sKL130 to act as coreceptors for [[FGF23]] activation of fibroblast growth factor receptors (FGFRs). Neither [[FGF23]] expression nor the contributions of [[FGF23]], mKL135, and sKL130 codependent and independent functions have been investigated in KlTg mice. In the current study, we examined the effects of Kl overexpression on [[FGF23]] levels and functions in KlTg mice. We found that mKL135 but not sKL130 stimulated [[FGF23]] expression in osteoblasts, leading to elevated Fgf23 bone expression and circulating levels in KlTg mice. Elevated [[FGF23]] suppressed 1,25(OH)2D and parathyroid hormone levels but did not cause hypophosphatemic rickets in KlTg mice. KlTg mice developed low aldosterone-associated hypertension but not left ventricular hypertrophy. Mechanistically, we found that mKL135 and sKL130 are essential cofactors for [[FGF23]]-mediated ERK activation but that they inhibited [[FGF23]] stimulation of PLC-γ and PI3K/AKT signaling. Thus, increased longevity in KlTg mice occurs in the presence of excess [[FGF23]] that interacts with mKL and sKL to bias FGFR pathways.
|mesh-terms=* Aldosterone
* Animals
* Bone and Bones
* Cardiovascular Diseases
* Disease Models, Animal
* Female
* Fibroblast Growth Factors
* Gene Knockout Techniques
* Glucuronidase
* Kidney
* Longevity
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Osteoblasts
* Protein Isoforms
* Transcriptome
|keywords=* Bone Biology
* Cardiovascular disease
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962016
}}
{{medline-entry
|title=Fibroblast growth factor 23 and symmetric dimethylarginine concentrations in geriatric cats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31568615
|abstract=Fibroblast growth factor 23 ([[FGF23]]) is a phosphaturic hormone that is increased in azotemic cats with chronic kidney disease (CKD) and predictive of the onset of azotemia in older cats. The introduction of symmetric dimethylarginine (SDMA) as a biomarker of glomerular filtration rate has led to the identification of cats in which SDMA is increased, but plasma creatinine concentrations remains within reference range. There is currently little understanding of the metabolic changes present in such cats. To examine the relationship between plasma [[FGF23]] and SDMA concentrations in non-azotemic geriatric cats. Records of a cross section of client-owned cats (n = 143) without azotemic CKD. Clinicopathological information was obtained from cats (≥ 9 years) from records of 2 first opinion practices. The relationship between plasma SDMA and [[FGF23]] concentrations was examined using Spearman's correlation and variables compared using the Mann-Whitney U test. Cats with increased SDMA concentrations had significantly higher plasma [[FGF23]] (P < .001) and creatinine (P < .001) concentrations compared to cats with SDMA concentrations within reference range. A weak positive relationship was demonstrated between plasma [[FGF23]] and SDMA concentrations (r = .35, P < .001) and between plasma [[FGF23]] and creatinine (r = .23, P = .005) concentrations. More cats with increased SDMA concentrations had higher [[FGF23]] concentrations than those with SDMA concentrations within the reference range, suggesting the presence of an alteration in phosphate homeostasis. Further studies are warranted to identify influencing factors and to explore the utility of [[FGF23]] concentration to inform management of cats with early stage CKD.
|mesh-terms=* Aging
* Animals
* Arginine
* Biomarkers
* Cats
* Cross-Sectional Studies
* Female
* Fibroblast Growth Factors
* Male
* Reference Values
* Retrospective Moral Judgment
|keywords=* azotemia
* feline
* phosphate
* renal
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872607
}}
==CFI==

{{medline-entry
|title=Psychosocial Resources for Hedonic Balance, Life Satisfaction and Happiness in the Elderly: A Path Analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32781590
|abstract=We explored possible paths from physical and mental health-related quality of life, self-efficacy, optimism, and social support to happiness in older adults, considering hedonic balance and life satisfaction as mediators. A total of 154 Spanish male and female (50%) older adults (65-96 years old, M = 77.44, SD = 8.03; 64% noninstitutionalized elderly) voluntarily participated in this correlational, cross-sectional study. The participants completed self-reports on their perceived health status, self-efficacy, social support, optimism, and global subjective well-being (SWB) as well as its dimensions. Path analysis was used to examine direct and indirect relationships. The final model had an excellent fit with the data (χ2(10) = 11.837, [i]p[/i] = 0.296, χ2/df = 1.184; SRMR = 0.050, [[CFI]] = 0.994, RMSEA = 0.035), revealing the unique causal effects of all the included predictors on happiness. With the exception of self-efficacy, the psychosocial resources predicted older adults' current happiness, and this relationship was fully mediated by hedonic balance and life satisfaction, which were found to be putative intermediary factors for SWB. Self-efficacy in turn predicted the remaining psychosocial resources. Our findings extend the existing evidence on the influences of health-related quality of life, self-efficacy, optimism, and social support on SWB. Furthermore, they support the proposal of hedonic balance and life satisfaction as dimensions of SWB, thus supporting the tripartite hierarchical model of happiness. These results may inform future interventions seeking to improve happiness in late adulthood.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Cross-Sectional Studies
* Female
* Happiness
* Health Status
* Humans
* Male
* Personal Satisfaction
* Quality of Life
|keywords=* happiness
* older adults
* path analysis
* psychosocial resources
* subjective well-being
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459462
}}
{{medline-entry
|title=Validity and Reliability of the Flourishing Scale in a Sample of Older Adults in Iran.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32546985
|abstract=Flourishing is related to positive outcomes for physical and mental health, as well as overall wellbeing. The aim of the present study was to determine the validity and reliability of the Flourishing Scale (FS) among a sample of older participants in Iran. In this validation study, 300 older people were selected by cluster sampling method. Data were collected using a checklist for demographic characteristics, the FS, and the Oxford happiness questionnaire. The validity (face, content, convergent, and construct) and reliability (Cronbach's alpha, test-retest) of the FS was evaluated in this cross-sectional study. The exploratory factor analysis demonstrated a one-dimensional structure consisting of 8 items with an eigenvalue of 3.583. The model had a good fit [χ  = 52.983, p < 0.001, χ /df = 2.944, GFI = 0.958, [[CFI]] = 0.915, IFI = 0.949, TLI = 0.919, AGFI = 0.948, and RMSEA = 0.081, SRMR = 0.086] with all factor loadings greater than 0.5 and statistically significant. A test of concurrent validity showed a direct and significant association between the FS and the Oxford happiness questionnaire ([i]r[/i] = 0.647, [i]p[/i] < 0.001). The results of the reliability tests confirmed that the values of Cronbach's alpha coefficient (0.819) and test-retest (0.821) were acceptable. The Persian version of the FS demonstrated suitable validity and reliability among a sample of older participants.
|mesh-terms=* Aged
* Aging
* Cross-Sectional Studies
* Female
* Geriatric Assessment
* Health Status Disparities
* Humans
* Iran
* Male
* Mental Health
* Psychometrics
* Reproducibility of Results
* Surveys and Questionnaires
|keywords=* aging
* factor analysis
* flourishing
* reliability
* validity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7244746
}}
{{medline-entry
|title=The decision about retirement: A scale to describe representations and practices of medical doctors and nurses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32258559
|abstract=New reliable and valid instrument to describe health professionals representations about retirement.A valid instrument that can be used to compare different health professionals.Job satisfaction is the major factor associated with positions about general policies about retirement. To test the psychometric properties of a newly designed instrument to describe the REpresentations and Practices About REtirement (the PREPARE instrument). Participants were nurses and doctors working in the two public hospitals of Porto, aged 55-65 years, in 2011. Among the 367 eligible participants, 231 (65.9%) participated in the study. The PREPARE instrument consists of four sections: 9, 5 and 12, respectively. A principal component analysis was performed to evaluate the scale's dimensionality, followed by a confirmatory factor analysis to test the fit using different indexes (TLI - Tucker-Lewis Index and [[CFI]] - Confirmatory fit index). Principal confirmatory analysis and confirmatory factor analysis identified 3, 1 and 2 factors for section 1, 2 and 3. All confirmatory factor analysis models had a value of [[CFI]] and TLI higher than 0.9. Section 1 showed a first factor related with items about the importance of personal competences, a second factor related with items about the importance of relationships with patients, and third factor related with items about the importance of following ethical and directive rules; section 2 showed a general factor about the features you valued most in the other health professional group; and, finally, in section 3, the first factor was related with items about satisfaction with the work environment and the second factor with items about satisfaction with professional career. The PREPARE instrument has the basic requirements of a valid and reliable measurement of a scale to describe medical doctors and nurses representations and practices about the decision regarding retirement.

|keywords=* Aging
* Job satisfaction
* Retirement
* Scale
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806742
}}
{{medline-entry
|title=Family versus intimate partners: Estimating who matters more for health in a 20-year longitudinal study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31697103
|abstract=This study tested the extent to which the emotional climate (positive and negative relationship quality) in family relationships and intimate partnerships are each uniquely linked to specific domains of aging health outcomes, over and above the impact of earlier health. Data included partnered participants who completed all three waves of the Midlife Development in the United States (MIDUS). We used measures of family and intimate partner strain and support, at MIDUS 1, 2, and 3, and estimated the effects of each on subsequent morbidity and health appraisal (i.e., 10 and 20 years later). Autoregressive cross-lagged paths were modeled using maximum likelihood estimation with robust standard errors. Family strain was associated with later health in both the morbidity, χ²(35) = 411.01, [i]p[/i] < .001; root mean square error of approximation (RMSEA) = .062, comparative fit index ([[CFI]]) = .952; standardized root-mean-square residual (SRMR) = .034 and health appraisal, χ²(35) = 376.80, [i]p[/i] < .001; RMSEA = .058, [[CFI]] = .956; SRMR = .032 models. Morbidity and health appraisal also predicted later family emotional climate, reciprocally. Intimate partner emotional climate-health pathways were nonsignificant at each wave, in both models. Results are novel and may be the first to indicate the quality of family relationships are a more powerful predictor of aging health than the quality of intimate partnerships. Findings implicate the health of adults should be considered in the systemic context of families. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
|mesh-terms=* Adult
* Aged
* Aging
* Emotions
* Family Relations
* Female
* Health Status
* Humans
* Interpersonal Relations
* Longitudinal Studies
* Male
* Middle Aged
* Sexual Partners
* United States

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012715
}}
{{medline-entry
|title=Adapting and validating the Rosenberg Self-Esteem Scale for elderly Spanish population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31524131
|abstract=This study aims to adapt and validate the most common measure of self-esteem, the Rosenberg Self-Esteem Scale (RSES), in the elderly Spanish population based on the initial one-factor model proposed by the author of the scale. The factorial validity of the scale was tested using confirmatory factor analysis. The study was carried out in the city of Valencia (Spain). A total of 231 elderly people with a mean age 72.68 (SD=8.55). The participants completed the questionnaire RSES for the validation process, sociodemographic data and Mini-Mental State Examination. Confirmatory factor analysis with a five-item structure for the one-factor structure showed good fit indexes (Chi square [5] = 217.20, p < .05; [[CFI]] = .965; GFI = .980; RMSEA = .070 [90% confidence interval of RMSEA, .022-.087]), and reliability, as internal consistency, measure with Cronbach's alpha was .732. The adaptation of the RSES showed a unifactorial structure with good internal consistency. This reduced adaptation/version of the scale may facilitate clinical practice and be useful in research in older people.

|keywords=* aging
* life span
* self-esteem
* structural equation model
* validity
|full-text-url=https://sci-hub.do/10.1017/S1041610219001170
}}
==TEC==

{{medline-entry
|title=Vestibular function and cortical and sub-cortical alterations in an aging population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32904672
|abstract=While it is well known that the vestibular system is responsible for maintaining balance, posture and coordination, there is increasing evidence that it also plays an important role in cognition. Moreover, a growing number of epidemiological studies are demonstrating a link between vestibular dysfunction and cognitive deficits in older adults; however, the exact pathways through which vestibular loss may affect cognition are unknown. In this cross-sectional study, we sought to identify relationships between vestibular function and variation in morphometry in brain structures from structural neuroimaging. We used a subset of 80 participants from the Baltimore Longitudinal Study of Aging, who had both brain MRI and vestibular physiological data acquired during the same visit. Vestibular function was evaluated through the cervical vestibular-evoked myogenic potential (cVEMP). The brain structures of interest that we analyzed were the hippocampus, amygdala, thalamus, caudate nucleus, putamen, insula, entorhinal cortex (ERC), trans-entorhinal cortex ([[TEC]]) and perirhinal cortex, as these structures comprise or are connected with the putative "vestibular cortex." We modeled the volume and shape of these structures as a function of the presence/absence of cVEMP and the cVEMP amplitude, adjusting for age and sex. We observed reduced overall volumes of the hippocampus and the ERC associated with poorer vestibular function. In addition, we also found significant relationships between the shape of the hippocampus (p = 0.0008), amygdala (p = 0.01), thalamus (p = 0.008), caudate nucleus (p = 0.002), putamen (p = 0.02), and ERC-[[TEC]] complex (p = 0.008) and vestibular function. These findings provide novel insight into the multiple pathways through which vestibular loss may impact brain structures that are critically involved in spatial memory, navigation and orientation.

|keywords=* Aging
* Cognition
* Diffeomorphometry
* Epidemiology
* Eye-ear-nose-throat
* MRI
* Medical imaging
* Shape
* Vestibular
* Volume
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457317
}}
{{medline-entry
|title=Metabolic Flexibility and Innate Immunity in Renal Ischemia Reperfusion Injury: The Fine Balance Between Adaptive Repair and Tissue Degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32733450
|abstract=Renal ischemia reperfusion injury (IRI), a common event after renal transplantation, causes acute kidney injury (AKI), increases the risk of delayed graft function (DGF), primes the donor kidney for rejection, and contributes to the long-term risk of graft loss. In the last decade, epidemiological studies have linked even mild episodes of AKI to chronic kidney disease (CKD) progression, and innate immunity seems to play a crucial role. The ischemic insult triggers an acute inflammatory reaction that is elicited by Pattern Recognition Receptors (PRRs), expressed on both infiltrating immune cells as well as tubular epithelial cells ([[TEC]]s). Among the PRRs, Toll-like receptors (TLRs), their synergistic receptors, Nod-like receptors (NLRs), and the inflammasomes, play a pivotal role in shaping inflammation and [[TEC]] repair, in response to renal IRI. These receptors represent promising targets to modulate the extent of inflammation, but also function as gatekeepers of tissue repair, protecting against AKI-to-CKD progression. Despite the important considerations on timely use of therapeutics, in the context of IRI, treatment options are limited by a lack of understanding of the intra- and intercellular mechanisms associated with the activation of innate immune receptors and their impact on adaptive tubular repair. Accumulating evidence suggests that [[TEC]]-associated innate immunity shapes the tubular response to stress through the regulation of immunometabolism. Engagement of innate immune receptors provides [[TEC]]s with the metabolic flexibility necessary for their plasticity during injury and repair. This could significantly affect pathogenic processes within [[TEC]]s, such as cell death, mitochondrial damage, senescence, and pro-fibrotic cytokine secretion, well-known to exacerbate inflammation and fibrosis. This article provides an overview of the past 5 years of research on the role of innate immunity in experimental and human IRI, with a focus on the cascade of events activated by hypoxic damage in [[TEC]]s: from programmed cell death (PCD) and mitochondrial dysfunction-mediated metabolic rewiring of [[TEC]]s to maladaptive repair and progression to fibrosis. Finally, we will discuss the important crosstalk between metabolism and innate immunity observed in [[TEC]]s and their therapeutic potential in both experimental and clinical research.

|keywords=* cell death
* innate immunity
* kidney transplantation
* mitochondria
* senescence
* tubular repair
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7358591
}}
{{medline-entry
|title=Postnatal Involution and Counter-Involution of the Thymus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32477366
|abstract=Thymus involution occurs in all vertebrates. It is thought to impact on immune responses in the aged, and in other clinical circumstances such as bone marrow transplantation. Determinants of thymus growth and size are beginning to be identified. Ectopic expression of factors like cyclin D1 and Myc in thymic epithelial cells ([[TEC]])s results in considerable increase in thymus size. These models provide useful experimental tools that allow thymus function to be understood. In future, understanding [[TEC]]-specific controllers of growth will provide new approaches to thymus regeneration.

|keywords=* Myc
* aging
* cyclin D1
* growth
* involution
* thymus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235445
}}
{{medline-entry
|title=Gender Disparity Impacts on Thymus Aging and LHRH Receptor Antagonist-Induced Thymic Reconstitution Following Chemotherapeutic Damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32194555
|abstract=One of the main consequences of thymus aging is the decrease in naïve T cell output. This condition accelerates at the onset of puberty, and presents as a major clinical complication for cancer patients who require cytoablative therapy. Specifically, the extensive use of chemotherapeutics, such as cyclophosphamide, in such treatments damage thymic structure and eliminate the existing naïve T cell repertoire. The resulting immunodeficiency can lead to increased incidence of opportunistic infections, tumor growth relapse and/or autoimmune diseases, particularly in older patients. Thus, strategies aimed at rejuvenating the aged thymus following chemotherapeutic damage are required. Previous studies have revealed that sex hormone deprivation in male mice is capable of regenerating the thymic microenvironment following chemotherapy treatment, however, further investigation is crucial to identify gender-based differences, and the molecular mechanisms involved during thymus regeneration. Through phenotypic analyzes, we identified gender-specific alterations in thymocytes and thymic epithelial cell ([[TEC]]) subsets from the onset of puberty. By middle-age, females presented with a higher number of thymocytes in comparison to males, yet a decrease in their Aire  medullary [[TEC]]/thymocyte ratio was observed. This reduction could be associated with an increased risk of autoimmune disease in middle-aged women. Given the concurrent increase in female Aire  c[[TEC]]/thymocyte ratio, we proposed that there may be an impediment in Aire  m[[TEC]]  differentiation, and Aire  c[[TEC]]  as its upstream precursor. The regenerative effects of LHRH receptor antagonist, degarelix, on [[TEC]] subsets was also less pronounced in middle-aged females compared to males, possibly due to slower progression of thymic involution in the former, which presented with greater [[TEC]]  proportions. Furthermore, following cyclophosphamide treatment, degarelix enhanced thymocyte and mature [[TEC]] subset recovery, with faster recovery kinetics observed in females. These events were found to involve both reactivation and proliferation of thymic epithelial progenitor cells. Taken together, the findings from this study portray a relationship between gender disparity and thymus aging, and highlight the potential benefits of LHRH receptor antagonist treatment for thymic regeneration. Further research is required, however, to determine how gender may impact on the mechanisms underpinning these events.

|keywords=* aging
* chemotherapy
* gender
* luteinizing hormone-releasing hormone
* regeneration
* sex hormone deprivation
* thymic epithelial cell
* thymus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062683
}}
{{medline-entry
|title=Clonogenic Culture of Mouse Thymic Epithelial Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31396938
|abstract=The thymus plays an essential role in the development and selection of T cells by providing a unique microenvironment that is mainly composed of thymic epithelial cells ([[TEC]]s). We previously identified stem cells of medullary [[TEC]]s (m[[TEC]]s) that are crucial for central tolerance induction using a novel clonogenic culture system. We also found that medullary thymic epithelial stem cells (mTESCs) maintain life-long m[[TEC]]s regeneration and central T cell self-tolerance in mouse models. The clonogenic efficiency of [[TEC]]s in vitro is highly correlated to the [[TEC]] reconstitution activity in vivo. Here, we describe the clonogenic culture system to evaluate the self-renewing activity of TESCs. The colonies are derived from TESCs, are visualized and quantified by rhodamine-B staining on a feeder layer, and can be passaged in vitro. Thus, our system enables quantitative evaluation of TESC activity and is useful for dissecting the mechanisms that regulate TESC activity in physiological aging as well as in various clinical settings.
|mesh-terms=* Aging
* Animals
* Cell Differentiation
* Cell Line
* Coculture Techniques
* Colony-Forming Units Assay
* DNA-Binding Proteins
* Epithelial Cells
* Flow Cytometry
* Fluorescent Antibody Technique, Direct
* Fluorescent Dyes
* Immunomagnetic Separation
* Mice
* Mice, Knockout
* Primary Cell Culture
* Rhodamines
* Self Tolerance
* Staining and Labeling
* Stem Cells
* Thymus Gland
|keywords=* Clonogenic assay
* Thymic epithelial cells
* Thymic epithelial stem cells
* Thymus
|full-text-url=https://sci-hub.do/10.1007/978-1-4939-9728-2_15
}}
==EGFR==

{{medline-entry
|title=Type I Collagen Aging Increases Expression and Activation of [[EGFR]] and Induces Resistance to Erlotinib in Lung Carcinoma in 3D Matrix Model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33014812
|abstract=Type I collagen is the major structural component of lung stroma. Because of its long half-life, type I collagen undergoes post-translational modifications such as glycation during aging process. These modifications have been shown to impact the structural organization of type I collagen fibers. In the present work we evaluated the impact of collagen aging on lung carcinoma cells response to erlotinib-induced cytotoxicity and apoptosis, and on Epidermal Growth Factor Receptor ([[EGFR]]) expression and phosphorylation. To this end, experiments were performed in 2D and 3D matrix models established from type I collagen extracted from adult (10 weeks-old) and old (100 weeks-old) rat's tail tendons. Our results show that old collagen induces a significant increase in [[EGFR]] expression and phosphorylation when compared to adult collagen in 3D matrix but not in 2D coating. Such modification was associated to an increase in the IC  of erlotinib in the presence of old collagen and a lower sensitivity to drug-induced apoptosis. These data suggest that collagen aging confers resistance to the cytotoxic and apoptotic effects of therapies targeting [[EGFR]] kinase function in lung carcinoma. Moreover, our data underline the importance of the 3D matrix environment in this process.

|keywords=* EGFR
* Erlotinib
* Type I collagen
* aging
* resistance
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511549
}}
{{medline-entry
|title=Comparative effectiveness and cost-effectiveness of three first-line [[EGFR]]-tyrosine kinase inhibitors: Analysis of real-world data in a tertiary hospital in Taiwan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32267879
|abstract=Comparison of the effectiveness and cost-effectiveness of three first-line [[EGFR]]-tyrosine kinase inhibitors (TKIs) would improve patients' clinical benefits and save costs. Using real-world data, this study attempted to directly compare the effectiveness and cost-effectiveness of first-line afatinib, erlotinib, and gefitinib. During May 2011-December 2017, all patients with non-small cell lung cancer (NSCLC) visiting a tertiary center were invited to fill out the EuroQol five-dimension (EQ-5D) questionnaires and World Health Organization Quality of Life, brief version (WHOQOL-BREF), and received follow-ups for survival and direct medical costs. A total of 379 patients with [[EGFR]] mutation-positive advanced NSCLC under first-line TKIs were enrolled for analysis. After propensity score matching for the patients receiving afatinib (n = 48), erlotinib (n = 48), and gefitinib (n = 96), we conducted the study from the payers' perspective with a lifelong time horizon. Patients receiving afatinib had the worst lifetime psychometric scores, whereas the differences in quality-adjusted life expectancy (QALE) were modest. Considering 3 treatments together, afatinib was dominated by erlotinib. Erlotinib had an incremental cost-effectiveness of US$17,960/life year and US$12,782/QALY compared with gefitinib. Acceptability curves showed that erlotinib had 58.6% and 78.9% probabilities of being cost-effective given a threshold of 1 Taiwanese per capita GDP per life year and QALY, respectively. Erlotinib appeared to be cost-effective. Lifetime psychometric scores may provide additional information for effectiveness evaluation.
|mesh-terms=* Afatinib
* Aged
* Carcinoma, Non-Small-Cell Lung
* Cost-Benefit Analysis
* Erlotinib Hydrochloride
* Female
* Gefitinib
* Humans
* Life Expectancy
* Lung Neoplasms
* Male
* Propensity Score
* Protein Kinase Inhibitors
* Quality of Life
* Survival Rate
* Taiwan
* Tertiary Care Centers

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141611
}}
{{medline-entry
|title=An Optogenetic Method to Study Signal Transduction in Intestinal Stem Cell Homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32201167
|abstract=Homeostasis in adult organs involves replacement of cells from a stem cell pool maintained in specialized niches regulated by extracellular signals. This cell-to-cell communication employs signal transduction pathways allowing cells to respond with a variety of behaviors. To study these cellular behaviors, signaling must be perturbed within tissues in precise patterns, a technique recently made possible by the development of optogenetic tools. We developed tools to study signal transduction in vivo in an adult fly midgut stem cell model where signaling was regulated by the application of light. Activation was achieved by clustering of membrane receptors [[EGFR]] and Toll, while inactivation was achieved by clustering the downstream activators ERK/Rolled and NFκB/Dorsal in the cytoplasm, preventing nuclear translocation and transcriptional activation. We show that both pathways contribute to stem and transit amplifying cell numbers and affect the lifespan of adult flies. We further present new approaches to overcome overexpression phenotypes and novel methods for the integration of optogenetics into the already-established genetic toolkit of Drosophila.
|mesh-terms=* Animals
* Cell Communication
* Cell Proliferation
* Cells, Cultured
* Drosophila Proteins
* Drosophila melanogaster
* Gene Expression Regulation
* Gene Regulatory Networks
* Homeostasis
* Intestinal Mucosa
* Light
* Longevity
* Optogenetics
* Signal Transduction
* Stem Cells
|keywords=* Drosophila
* EGFR
* Toll
* optogenetics
* stem cells
|full-text-url=https://sci-hub.do/10.1016/j.jmb.2020.03.019
}}
{{medline-entry
|title=Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31935369
|abstract=Eradicating tumor dormancy that develops following epidermal growth factor receptor ([[EGFR]]) tyrosine kinase inhibitor (TKI) treatment of [[EGFR]]-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following [[EGFR]] TKI treatment by combined [[EGFR]]/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing [[EGFR]]/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.
|mesh-terms=* Adaptor Proteins, Signal Transducing
* Animals
* Apoptosis
* Cell Cycle Proteins
* Cell Line, Tumor
* Cell Proliferation
* Cell Survival
* Cellular Senescence
* Drug Resistance, Neoplasm
* ErbB Receptors
* Female
* Gene Deletion
* Gene Expression Regulation, Neoplastic
* Humans
* Lung Neoplasms
* MAP Kinase Kinase 1
* Male
* Mice
* Mice, Knockout
* Mutation
* Signal Transduction
* Transcription Factors
* Transcription, Genetic
|keywords=* YAP
* dormancy
* drug resistance
* drug tolerance
* epidermal growth factor receptor
* lung cancer
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146079
}}
{{medline-entry
|title=Association between [[EGFR]] mutation and ageing, history of pneumonia and gastroesophageal reflux disease among patients with advanced lung cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31634646
|abstract=Epidermal growth factor receptor ([[EGFR]]) mutation is the most frequently encountered oncogenic driver in lung cancer. Risk factors for [[EGFR]] mutation may help prevention, surveillance and diagnosis strategies of [[EGFR]]-mutated lung cancer. A nationwide, retrospective, longitudinal, cohort study was performed between January 2002 and December 2015. Patient data were collected from the Korean National Health Insurance Database. The lung cancer group included [[EGFR]] tyrosine kinase inhibitor (TKI)-treated patients. Controls were randomly selected from people without a history of lung cancer and determined to be four times the number of patients with [[EGFR]]-mutated advanced lung cancer. The risk model of developing [[EGFR]]-mutated lung cancer was constructed by multiple logistic regression analysis. Among the 2010 new cases of lung cancer treated in 2010-2015, 214 cases were classified as [[EGFR]]-mutated advanced lung cancer. The risk of developing [[EGFR]]-mutated advanced lung cancer was higher in patients in their 50s (odds ratio [OR]: 3.42; 95% confidence interval [CI]: 1.68-6.93), 60s (OR: 7.04; 95% CI: 3.35-14.77) and 70s (OR: 10.27; 95% CI: 4.73-22.30) and in those aged >80 years (OR: 5.98; 95% CI: 2.25-15.92) than those in their 40s. The risk of developing [[EGFR]]-mutated lung cancer was also higher in hospitalised patients with a history of pneumonia (OR: 5.22; 95% CI: 1.88-14.46) and those with gastroesophageal reflux disease (OR: 2.02; 95% CI: 1.32-3.07). Patients with [[EGFR]]-mutated advanced lung cancer were associated with ageing, history of being hospitalised for pneumonia and gastroesophageal reflux disease.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Case-Control Studies
* ErbB Receptors
* Female
* Gastroesophageal Reflux
* Humans
* Lung Neoplasms
* Male
* Middle Aged
* Mutation
* Pneumonia
* Republic of Korea
* Retrospective Studies
* Risk Factors
* Young Adult
|keywords=* Ageing
* EGFR mutation
* GERD
* Lung cancer
* Pneumonia
* Risk factors
|full-text-url=https://sci-hub.do/10.1016/j.ejca.2019.09.010
}}
==F3==

{{medline-entry
|title=A Comprehensive Analysis of Age and Gender Effects in European Portuguese Oral Vowels.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33293174
|abstract=The knowledge about the age effects in speech acoustics is still disperse and incomplete. This study extends the analyses of the effects of age and gender on acoustics of European Portuguese (EP) oral vowels, in order to complement initial studies with limited sets of acoustic parameters, and to further investigate unclear or inconsistent results. A database of EP vowels produced by a group of 113 adults, aged between 35 and 97, was used. Duration, fundamental frequency (f0), formant frequencies (F1 to [[F3]]), and a selection of vowel space metrics (F1 and F2 range ratios, vowel articulation index [VAI] and formant centralization ratio [FCR]) were analyzed. To avoid the arguable division into age groups, the analyses considered age as a continuous variable. The most relevant age-related results included: vowel duration increase in both genders; a general tendency to formant frequencies decrease for females; changes that were consistent with vowel centralization for males, confirmed by the vowel space acoustic indexes; and no evidence of [[F3]] decrease with age, in both genders. This study has contributed to knowledge on aging speech, providing new information for an additional language. The results corroborated that acoustic characteristics of speech change with age and present different patterns between genders.

|keywords=* Acoustic
* Aging voice
* European Portuguese
* Oral vowel
|full-text-url=https://sci-hub.do/10.1016/j.jvoice.2020.10.021
}}
{{medline-entry
|title=Prenatal exposure to an environmentally relevant phthalate mixture accelerates biomarkers of reproductive aging in a multiple and transgenerational manner in female mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33129917
|abstract=Phthalates are known endocrine-disrupting chemicals that are found in many consumer products. Our laboratory previously developed a relevant phthalate mixture consisting of six phthalates and found that it disrupted female fertility in mice. However, it is unknown if prenatal exposure to phthalate mixtures can accelerate reproductive aging and if this occurs in multiple generations. Thus, we tested the hypothesis that prenatal exposure to a mixture of phthalates accelerates biomarkers of reproductive aging in multiple generations of female mice. Pregnant CD-1 mice were orally dosed with vehicle control or a phthalate mixture (20 μg/kg/day-500 mg/kg/day) daily from gestational day 10 to birth. Adult F1 females born to these dams were used to create the F2 and [[F3]] generations by mating them with unexposed males. At 13 months, estrous cyclicity was monitored and ovaries and sera were collected for analysis. In the F1 generation, the mixture decreased testosterone and inhibin B levels, but increased follicle-stimulating hormone and luteinizing hormone levels compared to control. In the F2 generation, the phthalate mixture decreased the percent of antral follicles and testosterone hormone levels compared to control. In the [[F3]] generation, prenatal exposure to the phthalate mixture increased ovarian weight, increased the time in metestrus/diestrus, altered follicle numbers, and decreased the levels of luteinizing hormone compared to control. Collectively, these data suggest that prenatal exposure to a phthalate mixture may accelerate several biomarkers of reproductive aging in a multi- and transgenerational manner in female mice.

|keywords=* cyclicity
* hormone
* mixture
* ovary
* phthalates
* reproductive aging
* transgenerational
|full-text-url=https://sci-hub.do/10.1016/j.reprotox.2020.10.009
}}
{{medline-entry
|title=Combining Frontal Transcranial Direct Current Stimulation With Walking Rehabilitation to Enhance Mobility and Executive Function: A Pilot Clinical Trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32808403
|abstract=This pilot study assessed whether frontal lobe transcranial direct current stimulation (tDCS) combined with complex walking rehabilitation is feasible, safe, and shows preliminary efficacy for improving walking and executive function. Participants were randomized to one of the following 18-session interventions: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking (Sham/Typical). Active tDCS was delivered over [[F3]] (cathode) and F4 (anode) scalp locations for 20 min at 2 mA intensity. Outcome measures included tests of walking function, executive function, and prefrontal activity measured by functional near infrared spectroscopy. Ninety percent of participants completed the intervention protocol successfully. tDCS side effects of tingling or burning sensations were low (average rating less than two out of 10). All groups demonstrated gains in walking performance based on within-group effect sizes (d ≥ 0.50) for one or more assessments. The Sham/Typical group showed the greatest gains for walking based on between-group effect sizes. For executive function, the Active/Complex group showed the greatest gains based on moderate to large between-group effect sizes (d = 0.52-1.11). Functional near-infrared spectroscopy (fNIRS) findings suggest improved prefrontal cortical activity during walking. Eighteen sessions of walking rehabilitation combined with tDCS is a feasible and safe intervention for older adults. Preliminary effects size data indicate a potential improvement in executive function by adding frontal tDCS to walking rehabilitation. This study justifies future larger clinical trials to better understand the benefits of combining tDCS with walking rehabilitation.

|keywords=* Aging
* cognition
* rehabilitation
* transcranial direct current stimulation
* walking
|full-text-url=https://sci-hub.do/10.1111/ner.13250
}}
{{medline-entry
|title=Multigenerational exposure to TiO  nanoparticles in soil stimulates stress resistance and longevity of survived C. elegans via activating insulin/IGF-like signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32203849
|abstract=With increasing release of nanoparticles (NPs) into the environment, soil organisms likely suffer from high dose and long duration of NPs contamination, while the effect of NPs across multiple generations in soil is rarely studied. Herein, we investigated how multigenerational exposure to different crystal forms (anatase, rutile, and their mixture) of TiO  NPs (nTiO ) affected the survival, behavior, physiological and biochemical traits, and lifespan of nematodes (C. elegans) in a paddy soil. The soil property changed very slightly after being spiked with nTiO , and the toxicities of three nTiO  forms were largely comparable. The nTiO  exposure adversely influenced the survival and locomotion of nematodes, and increased intracellular reactive oxygen species (ROS) generation. Interestingly, the toxic effect gradually attenuated and the lifespan of survived nematodes increased from the P0 to [[F3]] generation, which was ascribed to the survivor selection and stimulatory effect. The lethal effect and the increased oxidative stress may continuously screen out offspring possessing stronger anti-stress capabilities. Moreover, key genes (daf-2, age-1, and skn-1) in the insulin/IGF-like signaling (IIS) pathway actively responded to the nTiO  exposure, which further optimized the selective expression of downstream genes, increased the antioxidant enzyme activities and antioxidant contents, and thereby increased the stress resistance and longevity of survived nematodes across successive generations. Our findings highlight the crucial role of bio-responses in the progressively decreased toxicity of nTiO , and add new knowledge on the long-term impact of soil nTiO  contamination.
|mesh-terms=* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Insulin
* Longevity
* Nanoparticles
* Oxidative Stress
* Soil
* Titanium
|keywords=* Insulin/IGF-like signaling
* Longevity
* Multigenerational toxicity
* Nanomaterial
* Soil nematode
|full-text-url=https://sci-hub.do/10.1016/j.envpol.2020.114376
}}
{{medline-entry
|title=Co-expression network analysis identified hub genes critical to triglyceride and free fatty acid metabolism as key regulators of age-related vascular dysfunction in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31514170
|abstract= Aging has often been linked to age-related vascular disorders. The elucidation of the putative genes and pathways underlying vascular aging likely provides useful insights into vascular diseases at advanced ages. Transcriptional regulatory network analysis is the key to describing genetic interactions between molecular regulators and their target gene transcriptionally changed during vascular aging.  A total of 469 differentially expressed genes were parsed into 6 modules. Among the incorporated sample traits, the most significant module related to vascular aging was associated with triglyceride and enriched with biological terms like proteolysis, blood circulation, and circulatory system process. The module associated with triglyceride was preserved in an independent microarray dataset, indicating the robustness of the identified vascular aging-related subnetwork. Additionally, Enpp5, Fez1, Kif1a, [[F3]], H2-Q7, and their interacting miRNAs mmu-miR-449a, mmu-miR-449c, mmu-miR-34c, mmu-miR-34b-5p, mmu-miR-15a, and mmu-let-7, exhibited the most connectivity with external lipid-related traits. Transcriptional alterations of the hub genes Enpp5, Fez1, Kif1a, and [[F3]], and the interacting microRNAs mmu-miR-34c, mmu-miR-34b-5p, mmu-let-7, mmu-miR-449a, and mmu-miR-449c were confirmed.  Our findings demonstrate that triglyceride and free fatty acid-related genes are key regulators of age-related vascular dysfunction in mice and show that the hub genes for Enpp5, Fez1, Kif1a, and [[F3]] as well as their interacting miRNAs mmu-miR-34c, mmu-miR-34b-5p, mmu-let-7, mmu-miR-449a, and mmu-miR-449c, could serve as potential biomarkers in vascular aging.  The microarray gene expression profiles of aorta samples from 6-month old mice (n=6) and 20-month old mice (n=6) were processed to identify nominal differentially expressed genes. These nominal differentially expressed genes were subjected to a weighted gene co-expression network analysis. A network-driven integrative analysis with microRNAs and transcription factors was performed to define significant modules and underlying regulatory pathways associated with vascular aging, and module preservation test was conducted to validate the age-related modules based on an independent microarray gene expression dataset in mice aorta samples including three 32-week old wild-type mice (around 6-month old) and three 78-week old wild-type mice (around 20-month old). Gene ontology and protein-protein interaction analyses were conducted to determine the hub genes as potential biomarkers in the progress of vascular aging. The hub genes were further validated with quantitative real-time polymerase chain reaction in aorta samples from 20 young (6-month old) mice and 20 old (20-month old) mice.
|mesh-terms=* Aging
* Animals
* Fatty Acids, Nonesterified
* Gene Expression Profiling
* Gene Expression Regulation
* Gene Regulatory Networks
* Lipid Metabolism
* Mice
* Microarray Analysis
* Signal Transduction
* Triglycerides
* Vascular Diseases
|keywords=* aging
* co-expression network
* hub gene
* module
* mouse
* vascular dysfunction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781998
}}
==ATG7==

{{medline-entry
|title=Age-related impairment of autophagy in cervical motor neurons.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33290859
|abstract=Neuromuscular dysfunction is common in old age. Damaged cytoplasmic structures aggregate with aging, especially in post-mitotic cells like motor neurons. Autophagy is a ubiquitous cell process that aids in the clearance of damaged aggregates. Accordingly, we hypothesized that autophagy is impaired in old age, contributing to neuromuscular dysfunction via an effect in motor neurons. Autophagy flux may be impaired as a result of deficits in the initiation, elongation or degradation phases. Changes in the expression levels of core proteins necessary for each of the autophagy phases were evaluated by Western blotting in the cervical spinal cord (segments C2-C6 corresponding to the phrenic motor pool) of adult male and female mice at 6-, 18-, and 24-months of age (reflecting 100%, 90% and 75% survival, respectively). There was no evidence of an effect of age on the expression of the autophagy markers Beclin-1 (Becn-1; initiation), [[ATG7]] and ATG5/12 complex (elongation) or LC3 (elongation/degradation). Reduced p62 expression (a marker of degradation) was evident in the cervical spinal cord of adult mice at 18-months compared to 24-months. Accordingly, expression of LC3 and p62 in motor neurons was analyzed using immunofluorescence and confocal microscopy in separate animals. LC3 and p62 immunoreactivity was evident in the gray matter with minimal expression in the white matter across all age groups. A mixed linear model with animal as a random effect was used to compare relative LC3 and p62 expression in motor neurons to gray matter across age groups. Expression of both LC3 and p62 was higher in choline acetyl transferase (ChAT)-positive motor neurons (~2-3 fold vs. gray matter). Across age groups, there were differences in the relative expression of LC3 (F  = 7.59, p < 0.01) and p62 (F  = 8.00, p < 0.01) in cervical motor neurons. LC3 expression in motor neurons increased ~20% by 24-months of age in both male and female mice. p62 expression in motor neurons increased ~70% by 18-months compared to 6-months with no further changes by 24-months of age in male mice. p62 expression did not change across age groups in female mice, and was ~20% higher than in males. Our findings highlight important changes in autophagy pathways that likely contribute to the development of aging-related neuromuscular dysfunction in mice. At 18-months of age, increased autophagosome clearance (reduced p62 expression) appears to be a global effect not restricted to motor neurons. By 24-months of age, increased expression of LC3 and p62 indicates impaired autophagy with autophagosome accumulation in cervical motor neurons.

|keywords=* Aging
* Autophagy
* Motor neuron
* Neuromuscular dysfunction
* Spinal cord
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111193
}}
{{medline-entry
|title=Comprehensive Bioinformatics Identifies Key microRNA Players in [[ATG7]]-Deficient Lung Fibroblasts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32527064
|abstract=Deficient autophagy has been recently implicated as a driver of pulmonary fibrosis, yet bioinformatics approaches to study this cellular process are lacking. Autophagy-related 5 and 7 (ATG5/[[ATG7]]) are critical elements of macro-autophagy. However, an alternative ATG5/[[ATG7]]-independent macro-autophagy pathway was recently discovered, its regulation being unknown. Using a bioinformatics proteome profiling analysis of [[ATG7]]-deficient human fibroblasts, we aimed to identify key microRNA (miR) regulators in autophagy. We have generated [[ATG7]]-knockout MRC-5 fibroblasts and performed mass spectrometry to generate a large-scale proteomics dataset. We further quantified the interactions between various proteins combining bioinformatics molecular network reconstruction and functional enrichment analysis. The predicted key regulatory miRs were validated via quantitative polymerase chain reaction. The functional enrichment analysis of the 26 deregulated proteins showed decreased cellular trafficking, increased mitophagy and senescence as the major overarching processes in [[ATG7]]-deficient lung fibroblasts. The 26 proteins reconstitute a protein interactome of 46 nodes and miR-regulated interactome of 834 nodes. The miR network shows three functional cluster modules around miR-16-5p, miR-17-5p and let-7a related to multiple deregulated proteins. Confirming these results in a biological setting, serially passaged wild-type and autophagy-deficient fibroblasts displayed senescence-dependent expression profiles of miR-16-5p and miR-17-5p. We have developed a bioinformatics proteome profiling approach that successfully identifies biologically relevant miR regulators from a proteomics dataset of the ATG-7-deficient milieu in lung fibroblasts, and thus may be used to elucidate key molecular players in complex fibrotic pathological processes  The approach is not limited to a specific cell-type and disease, thus highlighting its high relevance in proteome and non-coding RNA research.

|keywords=* autophagy
* bioinformatics
* functional network analysis
* lung fibrosis
* miR
* proteomics
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312768
}}
{{medline-entry
|title=Regulation of autophagy by DNA G-quadruplexes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32420812
|abstract=Guanine-rich DNA strands can form secondary structures known as G-quadruplexes (G4-DNA). G4-DNA is important for the regulation of replication and transcription. We recently showed that the expression of [i]Atg7[/i], a gene that is critical for macroautophagy/autophagy, is controlled by G4-DNA in neurons. We demonstrated that the transcription factor SUB1/PC4 and the G4-DNA-specific antibody HF2 bind to a putative G4-DNA motif located in the [i]Atg7[/i] gene. Stabilizing G4-DNA with the G4-ligand pyridostatin (PDS) downregulates [i]Atg7[/i] expression in neurons. Here, we further investigated how G4-DNA in the [i]Atg7[/i] gene is stabilized by PDS. We show that PDS can form 1:1 and 2:1 complexes with the [i]Atg7[/i]'s G4. We also demonstrate that PDS downregulates the [[ATG7]] protein and the expression of [i]Atg7[/i] in astrocytes as well as in neurons. Together with our previous findings, these data establish a novel G4-DNA-associated mechanism of autophagy regulation at a transcriptional level in neurons and astrocytes.

|keywords=* G-quadruplex
* aging
* astrocytes
* autophagy
* neurodegeneration
* neurons
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1769991
}}
{{medline-entry
|title=[[ATG7]] is essential for secretion of iron from ameloblasts and normal growth of murine incisors during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31880208
|abstract=The incisors of rodents comprise an iron-rich enamel and grow throughout adult life, making them unique models of iron metabolism and tissue homeostasis during aging. Here, we deleted [i]Atg7[/i] (autophagy related 7) in murine ameloblasts, i.e. the epithelial cells that produce enamel. The absence of [[ATG7]] blocked the transport of iron from ameloblasts into the maturing enamel, leading to a white instead of yellow surface of maxillary incisors. In aging mice, lack of [[ATG7]] was associated with the growth of ectopic incisors inside severely deformed primordial incisors. These results suggest that 2 characteristic features of rodent incisors, i.e. deposition of iron on the enamel surface and stable growth during aging, depend on autophagic activity in ameloblasts.  : ATG5: autophagy related 5; [[ATG7]]: autophagy related 7; CMV: cytomegalovirus; Cre: Cre recombinase; CT: computed tomography; FTH1: ferritin heavy polypeptide 1; GFP: green fluorescent protein; KRT5: keratin 5; KRT14: keratin 14; LGALS3: lectin, galactose binding, soluble 3; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NCOA4: nuclear receptor coactivator 4; NRF2: nuclear factor, erythroid 2 like 2; SQSTM1: sequestosome 1.

|keywords=* ATG7
* Aging
* ameloblast
* autophagy
* epithelium
* ferritin
* hyperplasia
* iron
* secretion
* tooth
|full-text-url=https://sci-hub.do/10.1080/15548627.2019.1709764
}}
{{medline-entry
|title=Enhancing Autophagy Diminishes Aberrant Ca  Homeostasis and Arrhythmogenesis in Aging Rabbit Hearts.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31636573
|abstract=Aging in humans is associated with a 10-40-fold greater incidence of sudden cardiac death from malignant tachyarrhythmia. We have reported that thiol oxidation of ryanodine receptors (RyR2s) by mitochondria-derived reactive oxygen species (mito-ROS) contributes to defective Ca  homeostasis in cardiomyocytes (CMs) from aging rabbit hearts. However, mechanisms responsible for the increase in mito-ROS in the aging heart remain poorly understood. Here we test the hypothesis that age-associated decrease in autophagy is a major contributor to enhanced mito-ROS production and thereby pro-arrhythmic disturbances in Ca  homeostasis. Ventricular tissues from aged rabbits displayed significant downregulation of proteins involved in mitochondrial autophagy compared with tissues from young controls. Blocking autophagy with chloroquine increased total ROS production in primary rabbit CMs and mito-ROS production in HL-1 CMs. Furthermore, chloroquine treatment of HL-1 cells depolarized mitochondrial membrane potential (Δψm) to 50% that of controls. Blocking autophagy significantly increased oxidation of RyR2, resulting in enhanced propensity to pro-arrhythmic spontaneous Ca  release under β-adrenergic stimulation. Aberrant Ca  release was abolished by treatment with the mito-ROS scavenger mito-TEMPO. Importantly, the autophagy enhancer Torin1 and [[ATG7]] overexpression reduced the rate of mito-ROS production and restored both Δψm and defective Ca  handling in CMs derived from aged rabbit hearts. Decreased autophagy is a major cause of increased mito-ROS production in the aging heart. Our data suggest that promoting autophagy may reduce pathologic mito-ROS during normal aging and reduce pro-arrhythmic spontaneous Ca  release via oxidized RyR2s.

|keywords=* aging
* autophagy
* calcium
* cardiac physiology
* ryanodine receptor
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787934
}}
==F2==

{{medline-entry
|title=Environmental risk assessment of glufosinate-resistant soybean by pollen-mediated gene flow under field conditions in the region of the genetic origin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33189381
|abstract=Pollen-mediated gene flow of genetically modified crops to their wild relatives can facilitate the spread of transgenes into the ecosystem and alter the fitness of the consequential progeny. A two-year field study was conducted to quantify the gene flow from glufosinate-ammonium resistant (GR) soybean (Glycinemax) to its wild relative, wild soybean (G. soja), and assess the potential weed risk of hybrids resulting from the gene flow during their entire life cycle under field conditions in Korea, where wild soybean is the natural inhabitant. Pollen-mediated gene flow from GR soybeans to wild soybeans ranged from 0.292% (mixed planting) to 0.027% at 8 m distance. The log-logistic model described the gene flow rate with increasing distance from GR soybean to wild soybean; the estimated effective isolation distance for 0.01% gene flow between GR and wild soybeans was 37.7 m. The F1 and [[F2]] hybrids exhibited the intermediate characteristics of their parental soybeans in their vegetative and reproductive stages. Canopy height and stem length of hybrids were close to those of wild soybean, which shows an indeterminate growth; the numbers of flowers, pods, and seeds per hybrid plant were close to those of wild soybean and significantly higher than those of GR soybean. Seed longevity of [[F2]] hybrid plants was also intermediate but significantly greater than that of GR soybean due to high seed dormancy. Our results suggest that transgenes of the GR soybean might disperse into wild populations and persist in the agroecosystem of the genetic origin regions due to the pollen-mediated gene flow and the relatively high fitness of the hybrid progeny.

|keywords=* Glufosinate resistance
* Relative fitness
* Seed longevity
* Transgene flow
* Weed risk
|full-text-url=https://sci-hub.do/10.1016/j.scitotenv.2020.143073
}}
{{medline-entry
|title=Gestational arsenite exposure augments hepatic tumors of C3H mice by promoting senescence in F1 and [[F2]] offspring via different pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33010264
|abstract=Previous studies showed that gestational arsenite exposure increases incidence of hepatic tumors in the F1 and [[F2]] male offspring in C3H mice. However, the mechanisms are largely unknown. In this study, we focused on whether cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to tumor formation in C3H mice, and whether gestational arsenite exposure augments hepatic tumors through enhancement of cellular senescence. Three senescence markers (p16, p21 and p15) and two SASP factors (Cxcl1 and Mmp14) were increased in hepatic tumor tissues of 74- or 100-weeks-old C3H mice without arsenite exposure, and treatment with a senolytic drug (ABT-263) diminished hepatic tumor formation. Gestational arsenite exposure enhanced the expression of p16, p21 and Mmp14 in F1 and p15 and Cxcl1 in [[F2]], respectively. Exploring the mechanisms by which arsenite exposure promotes cellular senescence, we found that the expression of antioxidant enzymes (Sod1 and Cat) were reduced in the tumors of F1 in the arsenite group, and Tgf-β and the receptors of Tgf-β were increased in the tumors of [[F2]] in the arsenite group. Furthermore, the analysis of the Cancer Genome Atlas database showed that gene expression levels of the senescence markers and SASP factors were increased and associated with poor prognosis in human hepatocellular carcinoma (HCC). These results suggest that cellular senescence and SASP have important roles in hepatic tumorigenesis in C3H mice as well as HCC in humans, and gestational arsenite exposure of C3H mice enhances senescence in F1 and [[F2]] via oxidative stress and Tgf-β activation, respectively.

|keywords=* Arsenic
* Liver
* Multigenerational Effect
* SASP
* Senescence
* Tumor
|full-text-url=https://sci-hub.do/10.1016/j.taap.2020.115259
}}
{{medline-entry
|title=Familial Longevity is Associated with an Attenuated Thyroidal Response to Recombinant Human Thyroid Stimulating Hormone.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32303766
|abstract=Longevity is associated with higher circulating levels of TSH in the absence of differences in circulating thyroid hormones (TH), as previously observed in [[F2]] members of long-lived families ([[F2]]-LLS) and their partners ([[F2]]-Con). The mechanism underlying this observed difference remains unknown. We hypothesized that the thyroid gland of members from long-lived families are less responsive to TSH stimulation, thereby requiring higher circulating TSH levels to maintain adequate TH levels. We performed a case-control intervention study with a single intramuscular (gluteal) injection with 0.1 mg recombinant human TSH in a subgroup of 14 [[F2]]-LLS and 15 similarly aged [[F2]]-Con. They were followed for 4 days. No serious adverse events were reported. For analyses, we compared time trajectories of TSH and TH, and the ratio of TH to TSH using area under the curve (AUC) calculations. The AUC free T4/AUC TSH ratio was significantly lower in [[F2]]-LLS than in [[F2]]-Con (estimated mean [95% confidence interval] 1.6 [1.2-1.9] and 2.2 [1.9-2.6], respectively, P = 0.01). The AUC thyroglobulin/AUC TSH ratio was also lower in [[F2]]-LLS than in [[F2]]-Con (median [interquartile range] 2.1 [1.4-3.6] and 3.2 [2.7-7.4], respectively, P = 0.04). We observed the same trend with the AUC free T3/AUC TSH ratio, although the difference was not statistically significant (estimated mean [95% confidence interval] 0.6 [0.4-0.7] and 0.7 [0.6-0.8], respectively, P = 0.07). The present findings show that members of long-living families have a lower thyroid responsivity to TSH compared with their partners.

|keywords=* Thyroid
* longevity
* recombinant human TSH
* responsivity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239378
}}
{{medline-entry
|title=Conclusions from a behavioral aging study on male and female [[F2]] hybrid mice on age-related behavior, buoyancy in water-based tests, and an ethical method to assess lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31509518
|abstract=Due to strain-specific behavioral idiosyncrasies, inbred mouse strains are suboptimal research models for behavioral aging studies. The aim of this study is to determine age-related behavioral changes of [[F2]] hybrid C57BL/6NxBALB/c male and female mice. Lifespan was followed (n =48, n =51) and cohorts of mature adult (7 months), middle-aged (15 months), and old mice (22 months of age; n=7-12 per group) were assessed regarding open-field activity, exploration, passive avoidance learning/memory, and depressive-like behavior. We found that both males and females demonstrated decreased exploratory behavior with age, while memory and depressive-like behavior were maintained. Females exhibited enhanced depressive-like behavior compared to males; however, a correlation between fat mass and swimming activity in the test directly accounted for 30-46% of this behavioral sex difference. In addition, we suggest a method to qualitatively estimate natural lifespan from survival analyses in which animals with signs of pain or severe disease are euthanized. This is, to our knowledge, the first behavioral study to consider both sex and aging in hybrid mice. We here define decreased exploratory behavior as a conserved hallmark of aging independent of sex, highlight the effect of buoyancy in water tests, and provide a method to assay lifespan with reduced animal suffering.
|mesh-terms=* Adiposity
* Aging
* Animals
* Exploratory Behavior
* Female
* Male
* Memory
* Mice, Inbred BALB C
* Mice, Inbred C57BL
* Swimming
|keywords=* F2 hybrid mice
* aging
* exploratory activity
* sex comparison
* water-based behavioral tests
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756906
}}
{{medline-entry
|title=In utero exposure to acetaminophen and ibuprofen leads to intergenerational accelerated reproductive aging in female mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31428698
|abstract=Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesic drugs, such as acetaminophen (APAP), are frequently taken during pregnancy, even in combination. However, they can favour genital malformations in newborn boys and reproductive disorders in adults. Conversely, the consequences on postnatal ovarian development and female reproductive health after in utero exposure are unknown. Here, we found that in mice, in utero exposure to therapeutic doses of the APAP-ibuprofen combination during sex determination led to delayed meiosis entry and progression in female F1 embryonic germ cells. Consequently, follicular activation was reduced in postnatal ovaries through the AKT/FOXO3 pathway, leading in [[F2]] animals to subfertility, accelerated ovarian aging with abnormal corpus luteum persistence, due to decreased apoptosis and increased AKT-mediated luteal cell survival. Our study suggests that administration of these drugs during the critical period of sex determination could lead in humans to adverse effects that might be passed to the offspring.
|mesh-terms=* Acetaminophen
* Aging
* Animals
* Animals, Newborn
* Cell Proliferation
* Female
* Fertility
* Forkhead Box Protein O3
* Germ Cells
* Ibuprofen
* Luteolysis
* Mice
* Ovary
* Pregnancy
* Prenatal Exposure Delayed Effects
* Proto-Oncogene Proteins c-akt
* Reproduction
* Signal Transduction
|keywords=* Infertility
* Oogenesis
* Risk factors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692356
}}
==UCP1==

{{medline-entry
|title=Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32464603
|abstract=Altered adipose tissue may contribute to the longevity of Snell dwarf and growth hormone receptor (GHR) knock-out mice. We report here that white (WAT) and brown (BAT) fat have elevated [[UCP1]] in both kinds of mice, and that adipocytes in WAT depots turn beige/brown. These imply increased thermogenesis and are expected to lead to improved glucose control. Both kinds of long-lived mice show lower levels of inflammatory M1 macrophages and higher levels of anti-inflammatory M2 macrophages in BAT and WAT, with correspondingly lower levels of TNFα, IL-6, and MCP1. Experiments with mice with tissue-specific disruption of GHR showed that these adipocyte and macrophage changes were not due to hepatic IGF1 production nor to direct GH effects on adipocytes, but instead reflect GH effects on muscle. Muscles deprived of GH signals, either globally (GKO) or in muscle only (MKO), produce higher levels of circulating irisin and its precursor FNDC5. The data thus suggest that the changes in adipose tissue differentiation and inflammatory status seen in long-lived mutant mice reflect interruption of GH-dependent irisin inhibition, with consequential effects on metabolism and thermogenesis.

|keywords=* adipose tissue
* aging
* growth hormone
* inflammation
* uncoupling protein 1 (UCP1)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288969
}}
{{medline-entry
|title=Lack of [[UCP1]] stimulates fatty liver but mediates [[UCP1]]-independent action of beige fat to improve hyperlipidemia in Apoe knockout mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32179129
|abstract=Brown adipose tissue (BAT) plays a critical role in lipid metabolism and may protect from hyperlipidemia; however, its beneficial effect appears to depend on the ambient temperature of the environment. In this study, we investigated the effects of uncoupling protein 1 ([[UCP1]]) deficiency on lipid metabolism, including the pathophysiology of hyperlipidemia, in apolipoprotein E knockout (APOE-KO) mice at a normal (23 °C) and thermoneutral (30 °C) temperature. Unexpectedly, [[UCP1]] deficiency caused improvements in hyperlipidemia, atherosclerosis, and glucose metabolism, regardless of an increase in hepatic lipid deposition, in Ucp1/Apoe double-knockout (DKO) mice fed a high-fat diet at 23 °C, with BAT hyperplasia and robust browning of inguinal white adipose tissue (IWAT) observed. Proteomics and gene expression analyses revealed significant increases in many proteins involved in energy metabolism and strong upregulation of brown/beige adipocyte-related genes and fatty acid metabolism-related genes in browned IWAT, suggesting an induction of beige fat formation and stimulation of lipid metabolism in DKO mice at 23 °C. Conversely, mRNA levels of fatty acid oxidation-related genes decreased in the liver of DKO mice. The favorable phenotypic changes were lost at 30 °C, with BAT whitening and disappearance of IWAT browning, while fatty liver further deteriorated in DKO mice compared with that in APOE-KO mice. Finally, longevity analysis revealed a significant lifespan extension of DKO mice compared with that of APOE-KO mice at 23 °C. Irrespective of the fundamental role of [[UCP1]] thermogenesis, our results highlight the importance of beige fat for the improvement of hyperlipidemia and longevity under the atherogenic status at normal room temperature.

|keywords=* Apoe knockout mice
* Beige fat
* Gene expression
* Hyperlipidemia
* Longevity
* Uncoupling protein 1
|full-text-url=https://sci-hub.do/10.1016/j.bbadis.2020.165762
}}
{{medline-entry
|title=Postnatal leptin surge is critical for the transient induction of the developmental beige adipocytes in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31961706
|abstract=Beige adipocytes have become a promising therapeutic target to combat obesity. Our senior author Dr. B. Xue previously discovered a transient but significant induction of beige adipocytes in mice during early postnatal development, which peaked at postnatal day (P) 20 and then disappeared thereafter. However, the physiological mechanism underlying the transient induction of the developmental beige cells remains mystery. Interestingly, there exists a postnatal surge of leptin in mice at P10 before the appearance of the developmental beige adipocytes. Given the neurotropic effect of leptin during neuronal development and its role in activating the sympathetic nervous system (SNS), we tested the hypothesis that postnatal leptin surge is required for the transient induction of developmental beige adipocytes through sympathetic innervation. Unlike wild-type (WT) mice that were able to acquire the developmentally induced beige adipocytes at P20, [i]ob/ob[/i] mice had much less uncoupling protein 1 ([[UCP1]])-positive multilocular cells in inguinal white adipose tissue at the same age. This was consistent with reduced expression of [[UCP1]] mRNA and protein levels in white fat of [i]ob/ob[/i] mice. In contrast, daily injection of [i]ob/ob[/i] mice with leptin between P8 and P16, mimicking the postnatal leptin surge, largely rescued the ability of these mice to acquire the developmentally induced beige adipocytes at P20, which was associated with enhanced sympathetic nerve innervation assessed by whole mount adipose tissue immunostaining of tyrosine hydroxylase. Our data demonstrate that the postnatal leptin surge is essential for the developmentally induced beige adipocyte formation in mice, possibly through increasing sympathetic nerve innervation.
|mesh-terms=* Adipocytes, Beige
* Adipocytes, White
* Adipose Tissue
* Aging
* Animals
* Dose-Response Relationship, Drug
* Female
* Leptin
* Male
* Mice
* Mice, Obese
* Sympathetic Nervous System
* Tyrosine 3-Monooxygenase
* Uncoupling Protein 1
|keywords=* beige adipocytes
* leptin
* sympathetic nerve system
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191411
}}
{{medline-entry
|title=Age-related sex differences in the expression of important disease-linked mitochondrial proteins in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31806023
|abstract=The prevalence and progression of many illnesses, such as neurodegenerative and cardiovascular diseases, obesity, and cancer, vary between women and men, often in an age-dependent manner. A joint hallmark of these diseases is some type of mitochondrial dysfunction. While several mitochondrial proteins are known to be regulated by sex hormones, the levels of those proteins have not been systematically analyzed with regard to sex and age, and studies that consider sex and/or age differences in the protein expression are very rare. In this study, we compared the expression patterns of physiologically important mitochondrial proteins in female and male C57BL/6N mice of age cohorts frequently used in experiments. We found that sex-related differences in the expression of uncoupling proteins 1 and 3 ([[UCP1]] and UCP3) occur in an age-dependent manner. The sex-specific expression of [[UCP1]] and UCP3 in brown adipose tissue (BAT) was inversely correlated with differences in body weight. Expression of UCP4 in the brain, Complex I in the spleen, and Complex II in the brain and BAT was least affected by the sex of the mouse. We further demonstrated that there are serious limitations in using VDAC1 and actin as markers in western blot analyses, due to their sex- and age-specific fluctuations. Our results confirm that sex and age are important parameters and should be taken into account by researchers who examine the mechanistic aspects of diseases. HIGHLIGHTS: I.The levels of [[UCP1]] and UCP3 protein expression differ between females and males in an age-dependent manner.II.Pre-pubertal expression of almost all proteins tested in this study does not depend on the sex of the mouse.III.Expression of VDAC1 and actin, which are often used as loading control proteins in western blot analysis, is tissue-specifically influenced by sex and age.
|mesh-terms=* Adipose Tissue, Brown
* Aging
* Animals
* Brain
* Female
* Male
* Mice, Inbred C57BL
* Mitochondrial Proteins
* Muscle, Skeletal
* Sex Characteristics
* Spleen

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896328
}}
{{medline-entry
|title=An anti-inflammatory phenotype in visceral adipose tissue of old lean mice, augmented by exercise.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31427677
|abstract=Visceral adipose tissue is an immunogenic tissue, which turns detrimental during obesity by activation of proinflammatory macrophages. During aging, chronic inflammation increases proportional to visceral adipose tissue (VAT) mass and associates with escalating morbidity and mortality. Here, we utilize a mouse model to investigate the inflammatory status of visceral adipose tissue in lean aging mice and assess the effects of exercise training interventions. We randomized adult (11 months; n = 21) and old (23 months; n = 27) mice to resistance training (RT) or endurance training (ET), or to a sedentary control group (S). Strikingly, we observed an anti-inflammatory phenotype in the old mice, consisting of higher accumulation of M2 macrophages and IL-10 expression, compared to the adult mice. In concordance, old mice also had less VAT mass and smaller adipocytes compared to adult mice. In both age groups, exercise training enhanced the anti-inflammatory phenotype and increased PGC1-α mRNA expression. Intriguingly, the brown adipose tissue marker [[UCP1]] was modestly higher in old mice, while remained unchanged by the intervention. In conclusion, in the absence of obesity, visceral adipose tissue possesses a pronounced anti-inflammatory phenotype during aging which is further enhanced by exercise.
|mesh-terms=* Adipocytes
* Aging
* Animals
* Humans
* Inflammation
* Intra-Abdominal Fat
* Macrophages
* Mice
* Obesity
* Phenotype
* Physical Conditioning, Animal
* Resistance Training

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700172
}}
==CD68==

{{medline-entry
|title=Insulin activates microglia and increases COX-2/IL-1β expression in young but not in aged hippocampus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32422127
|abstract=Brain insulin resistance and neuroinflammation are known to increase with age. Insulin exerts metabolic roles on neurons and astrocytes, but its effects on microglia is unclear. In this study we investigated whether insulin affected microglia in the hippocampus of young and aged rats. We injected intracerebroventricular (i.c.v.) insulin (20 mU) or vehicle for five days and evaluated microglial inflammatory markers in the hippocampus of young (3 months) Wistar rats. Increased microglial activation (Iba-1 [[CD68]] cells) and COX-2/IL-1β levels in the hippocampus were found. Since the aged brain is an experimental model for brain insulin resistance and chronic neuroinflammation we submitted aged rats (22 months) to i.c.v. insulin/vehicle administration and found no significant increase in Iba-1 [[CD68]]  microglia or COX-2/IL-1β levels. To further investigate whether insulin triggered transient or persistent proinflammatory responses, young rats were evaluated eight-days after the last insulin injection. Microglia were persistently activated, and COX-2 levels remained elevated in the hippocampus, which paralleled increased spatial memory performance in the Morris Water Maze behavioral task. To determine if microglia were directly responsive to insulin, primary microglia were challenged with insulin and increased Akt Ser473 phosphorylation, a protein activated by the insulin receptor, was detected. These data suggest that microglia in the hippocampus integrate insulin signaling and neuroinflammatory responses and that this signal is disrupted during chronic inflammation. In our concept, the disruption between microglia activation by insulin signaling is a new pathological mechanism behind insulin resistance in the aging brain.

|keywords=* Aging
* Hippocampus
* Insulin
* Memory
* Microglia
* Neuroinflammation
|full-text-url=https://sci-hub.do/10.1016/j.brainres.2020.146884
}}
{{medline-entry
|title=Epigenetic modulation of macrophage polarization prevents lumbar disc degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32310825
|abstract=Inflammation plays an essential role in the development of lumbar disc degeneration (LDD), although the exact effects of macrophage subtypes on LDD remain unclear. Based on previous studies, we hypothesized that M2-polarization of local macrophages and simultaneous suppression of their production of fibrotic transforming growth factor beta 1 (TGFβ1) could inhibit progression of LDD. Thus, we applied an orthotopic injection of adeno-associated virus (AAV) carrying shRNA for DNA Methyltransferase 1 (DNMT1) and/or shRNA for TGFβ1 under a macrophage-specific [[CD68]] promoter to specifically target local macrophages in a mouse model for LDD. We found that shDNMT1 significantly reduced levels of the pro-inflammatory cytokines TNFα, IL-1β and IL-6, significantly increased levels of the anti-inflammatory cytokines IL-4 and IL-10, significantly increased M2 macrophage polarization, significantly reduced cell apoptosis in the disc degeneration zone and significantly reduced LDD-associated pain. The anti-apoptotic and anti-pain effects were further strengthened by co-application of shTGFβ1. Together, these data suggest that M2 polarization of macrophages induced by both epigenetic modulation and suppressed production and release of TGFβ1 from polarized M2 macrophages, may have a demonstrable therapeutic effect on LDD.

|keywords=* DNA methyltransferase 1 (DNMT1)
* aging
* lumbar disc degeneration (LDD)
* macrophage polarization
* transforming growth factor beta 1 (TGFβ1)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202517
}}
{{medline-entry
|title=Cellular senescence in recurrent tonsillitis and tonsillar hypertrophy in children.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32200310
|abstract=To observe the difference in cellular senescence patterns between recurrent tonsillitis and tonsillar hypertrophy. Forty-three patients diagnosed with recurrent tonsillitis or tonsillar hypertrophy, based on medical history and symptoms, underwent tonsillectomy. The specimens were collected and examined using senescence β-galactosidase staining for cellular senescence. Macrophages were detected by immunochemistry. Cellular senescence was found in both recurrent tonsillitis and tonsillar hypertrophy groups. The comparison of cellular senescence in microcompartments of tonsil tissue (germinal centre, mantle zone, subepithelial and intraepithelial) revealed a significant increase of senescent cells in germinal centres in tonsillar hypertrophy compared with that in tonsillar hypertrophy. The majority of senescent cells in both groups were [[CD68]]-positive. Different cellular senescence patterns were found between the two studied paediatric tonsillar diseases. Macrophage senescence may play a role in the pathogenesis of these diseases.
|mesh-terms=* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Cellular Senescence
* Child
* Germinal Center
* Humans
* Hypertrophy
* Macrophages
* Palatine Tonsil
* Recurrence
* Tonsillectomy
* Tonsillitis
|keywords=* Cellular senescence
* Recurrent tonsillitis
* Tonsillar hypertrophy
|full-text-url=https://sci-hub.do/10.1016/j.ijporl.2020.110004
}}
{{medline-entry
|title=Ginsenoside Rg1 supplementation clears senescence-associated β-galactosidase in exercising human skeletal muscle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31695564
|abstract=Ginsenoside Rg1 has been shown to clear senescence-associated beta-galactosidase (SA-β-gal) in cultured cells. It remains unknown whether Rg1 can influence SA-β-gal in exercising human skeletal muscle. To examine SA-β-gal change, 12 young men (age 21 ± 0.2 years) were enrolled in a randomized double-blind placebo controlled crossover study, under two occasions: placebo (PLA) and Rg1 (5 mg) supplementations 1 h prior to a high-intensity cycling (70% VO ). Muscle samples were collected by multiple biopsies before and after cycling exercise (0 h and 3 h). To avoid potential effect of muscle biopsy on performance assessment, cycling time to exhaustion test (80% VO ) was conducted on another 12 participants (age 23 ± 0.5 years) with the same experimental design. No changes of SA-β-gal were observed after cycling in the PLA trial. On the contrary, nine of the 12 participants showed complete elimination of SA-β-gal in exercised muscle after cycling in the Rg1 trial ([i]p[/i] < 0.05). Increases in apoptotic DNA fragmentation (PLA: +87% vs. Rg1: +133%, [i]p[/i] < 0.05) and [[CD68]]  (PLA: +78% vs. Rg1: +121%, [i]p[/i] = 0.17) occurred immediately after cycling in both trials. During the 3-h recovery, reverses in apoptotic nuclei content (PLA: +5% vs. Rg1: -32%, [i]p[/i] < 0.01) and increases in inducible nitrate oxide synthase and interleukin 6 mRNA levels of exercised muscle were observed only in the Rg1 trial ([i]p[/i] < 0.01). Rg1 supplementation effectively eliminates senescent cells in exercising human skeletal muscle and improves high-intensity endurance performance.

|keywords=* Cellular senescence
* Endurance
* Ergogenic aid
* Inflammation
* Macrophage
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823780
}}
{{medline-entry
|title=Histopathological, immunohistochemical, and molecular studies for determination of wound age and vitality in rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31448552
|abstract=In forensic medicine, it is vital to verify with the best attainable accuracy once injuries occurred during vital or post-mortem conditions. An immunohistochemical study was carried out to examine the time-dependent expression of macrophage-specific gene [[CD68]] (cluster of differentiation 68), alpha-smooth muscle actin (α-SMA), and vascular endothelial growth factor (VEGF) in different skin wound timings (0, 1, 3, 5, 7, and 14 days) in rats. Histopathological studies were performed to assess the wound age and vitality. Eighteen male albino Wister rats (weighing 170-200 g) were used for wound induction. Rats (n = 3) were euthanised at 0, 1, 3, 5, 7, and 14 days from the starting point of wound induction. Histopathological examination showed that the epidermal re-epithelialisation was completed 14 days after skin incision. The inflammatory phase was recorded during the first 3 days of healing and reached the maximum levels at 5 days, then declined after 7 days, and completely removed at 14 days. The beginning of the proliferative phase was dated to day 3 and the peak at days 5 and 7. The initiation of the granulation tissue formation and remodelling phase of the healing process was observed 5 days after wounding. By immunohistochemical staining, negative VEGF gene expressions at early stages (0-3 days) were observed, as well as neither [[CD68]]+ macrophages nor α-SMA+ myofibroblast cells were detected. By increasing the wound ages (5-7 days), granulation tissue and angiogenesis were observed, with the migration of macrophages and fibroblast, which expressed VEGF, [[CD68]], and α-SMA positive reaction. Time-dependent expression of the above markers suggested that they would be useful indicators for the determination of wound age. Both VEGF and transforming growth factor-beta 1 (TGFb1) mRNA levels were determined in different skin wound ages. The transcription of TGFb1 and VEGF increased shortly after wounding, until post-wounding day 7. It then declined constantly, reaching minimal values on day 14.
|mesh-terms=* Actins
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Cell Movement
* Fibroblasts
* Granulation Tissue
* Immunohistochemistry
* Macrophages
* Models, Animal
* Neovascularization, Physiologic
* RNA, Messenger
* Rats, Wistar
* Re-Epithelialization
* Skin
* Time Factors
* Transforming Growth Factor beta1
* Vascular Endothelial Growth Factor A
* Wound Healing
* Wounds and Injuries
|keywords=* TGFb1
* VEGF
* gene expression
* immunohistochemistry
* wound aging
|full-text-url=https://sci-hub.do/10.1111/iwj.13206
}}
==DBI==

{{medline-entry
|title=Quantifying cumulative anticholinergic and sedative drug load among US Medicare Beneficiaries.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33000867
|abstract=Medications with anticholinergic and sedative properties are widely used among older adults despite strong evidence of harm. The drug burden index ([[DBI]]), a pharmacological screening tool, measures these properties across drug classes, and higher [[DBI]] drug exposure ([[DBI]] > 1) has been associated with certain physical function-related adverse events. Our aim was to quantify mean daily [[DBI]] drug exposure among older adults in the United States (US). We screened medications for [[DBI]] properties and operationalized the [[DBI]] for US Medicare claims. We then conducted a retrospective cohort study of a 20% random, nationwide sample of 4 137 384 fee-for-service Medicare beneficiaries aged 66+ years (134 757 039 person-months) from January 2013 to December 2016. We measured the monthly distribution based on mean daily [[DBI]], categorized as (a) >0 vs 0 (any use) and (b) 0, 0 < [[DBI]] ≤ 1, 1 < [[DBI]] ≤ 2, and [[DBI]] > 2, and examined temporal trends. We described patient-level factors (eg, demographics, healthcare use) associated with high (>2) vs low (0 < [[DBI]]≤1) [[DBI]] drug exposure. The distribution of the mean daily [[DBI]], aggregated at the month-level, was: 58.1% [[DBI]] = 0, 29.0% 0 < [[DBI]]≤1, 9.3% 1 < [[DBI]]≤2, and 3.7% [[DBI]] > 2. Predictors of high monthly [[DBI]] drug exposure ([[DBI]] > 2) included certain indicators of increased healthcare use (eg, high number of drug claims), white race, younger age, frailty, and a psychosis diagnosis code. The predictors of high [[DBI]] drug exposure can inform discussions between patients and providers about medication appropriateness and potential de-prescribing. Future Medicare-based studies should assess the association between the [[DBI]] and adverse events.

|keywords=* aging
* cholinergic antagonists
* drug burden index
* drug utilization
* hypnotics and sedatives
* inappropriate prescribing
* pharmacoepidemiology
|full-text-url=https://sci-hub.do/10.1002/pds.5144
}}
{{medline-entry
|title=Drug Burden Index and Cognitive and Physical Function in Aged Care Residents: A Longitudinal Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32736845
|abstract=Anticholinergic/antimuscarinic and sedative medications (eg, benzodiazepines) have been found to be associated with poorer cognitive and physical function and mobility impairment in older age. However, previous studies were mostly conducted among community-dwelling older individuals and had often a cross-sectional design. Accordingly, our aim was to examine longitudinal associations between cumulative exposure to anticholinergic and sedative medications and cognitive and physical function among residents from aged care homes. Longitudinal study. A total of 4624 residents of Dutch aged care homes of whom data were collected between June 2005 and April 2014. Outcome measures were collected with the Long-Term Care Facilities assessment from the international Residential Assessment Instrument (interRAI-LTCF) and included the Cognitive Performance Scale, the Activities of Daily Living (ADL) Hierarchy scale, a timed 4-meter walk test, distance walked, hours of physical activity, and days being outside. Cumulative exposure to anticholinergic and sedative medications was calculated with the Drug Burden Index ([[DBI]]), a linear additive pharmacological dose-response model. Associations were examined with linear mixed models to take the potential dependence of observations into account (ie, data were collected at repeated assessment occasions of residents who were clustered in aged care homes). Analyses were adjusted for sex, age, dementia, comorbidity (neurological, psychiatric, cardiovascular, oncological, and pulmonary), fractures, depressive symptoms, and medications excluded from the [[DBI]]. We observed significant longitudinal associations between a higher [[DBI]] and poorer ADLs, fewer hours of physical activity, and fewer days being outside. We found no significant longitudinal association between a higher [[DBI]] and poorer cognitive function. Over time, cumulative exposure to anticholinergic and sedative medications is associated with poorer physical but not cognitive function in aged care residents. Careful monitoring of aged care residents with high cumulative anticholinergic and sedative medication exposure is needed.

|keywords=* Cognitive function
* anti-muscarinics
* benzodiazepines
* geriatrics
* longitudinal
* mobility impairment
* physical function
* polypharmacy
|full-text-url=https://sci-hub.do/10.1016/j.jamda.2020.05.037
}}
{{medline-entry
|title=Using the Drug Burden Index to identify older adults at highest risk for medication-related falls.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32532276
|abstract=The Drug Burden Index ([[DBI]]) was developed to assess patient exposure to medications associated with an increased risk of falling. The objective of this study was to examine the association between the [[DBI]] and medication-related fall risk. The study used a retrospective cohort design, with a 1-year observation period. Participants (n = 1562) were identified from 31 community pharmacies. We examined the association between [[DBI]] scores and four outcomes. Our primary outcome, which was limited to participants who received a medication review, indexed whether the review resulted in at least one medication-related recommendation (e.g., discontinue medication) being communicated to the participant's health care provider. Secondary outcomes indexed whether participants in the full sample: (1) screened positive for fall risk, (2) reported 1+ falls in the past year, and (3) reported 1+ injurious falls in the past year. All outcome variables were dichotomous (yes/no). Among those who received a medication review (n = 387), the percentage of patients receiving at least one medication-related recommendation ranged from 10.2% among those with [[DBI]] scores of 0 compared to 60.2% among those with [[DBI]] scores ≥1.0 (Chi-square (4)=42.4, p < 0.0001). Among those screened for fall risk (n = 1058), [[DBI]] scores were higher among those who screened positive compared to those who did not (Means = 0.98 (SD = 1.00) versus 0.59 (SD = 0.74), respectively, p < 0.0001). Our findings suggest that the [[DBI]] is a useful tool that could be used to improve future research and practice by focusing limited resources on those individuals at greatest risk of medication-related falls.

|keywords=* Accidental falls
* Aging
* Health services
* Medication
* Medication therapy management
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7291506
}}
{{medline-entry
|title=Impact of STEADI-Rx: A Community Pharmacy-Based Fall Prevention Intervention.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32315461
|abstract=To evaluate the effects of a community pharmacy-based fall prevention intervention (STEADI-Rx) on the risk of falling and use of medications associated with an increased risk of falling. Randomized controlled trial. A total of 65 community pharmacies in North Carolina (NC). Adults (age ≥65 years) using either four or more chronic medications or one or more medications associated with an increased risk of falling (n = 10,565). Pharmacy staff screened patients for fall risk using questions from the Stopping Elderly Accidents, Deaths, and Injuries (STEADI) algorithm. Patients who screened positive were eligible to receive a pharmacist-conducted medication review, with recommendations sent to patients' healthcare providers following the review. At intervention pharmacies, pharmacy staff used standardized forms to record participant responses to screening questions and information concerning the medication reviews. For participants with continuous Medicare Part D/NC Medicaid coverage (n = 3,212), the Drug Burden Index ([[DBI]]) was used to assess exposure to high-risk medications, and insurance claims records for emergency department visits and hospitalizations were used to assess falls. Among intervention group participants (n = 4,719), 73% (n = 3,437) were screened for fall risk. Among those who screened positive (n = 1,901), 72% (n = 1,373) received a medication review; and 27% (n = 521) had at least one medication-related recommendation communicated to their healthcare provider(s) following the review. A total of 716 specific medication recommendations were made. [[DBI]] scores decreased from the pre- to postintervention period in both the control and the intervention group. However, the amount of change over time did not differ between these two groups (P = .66). Risk of falling did not change between the pre- to postintervention period or differ between groups (P = .58). We successfully implemented STEADI-Rx in the community pharmacy setting. However, we found no differences in fall risk or the use of medications associated with increased risk of falling between the intervention and control groups. J Am Geriatr Soc 68:1778-1786, 2020.

|keywords=* aging
* community pharmacy
* falls
* health services
* medication
|full-text-url=https://sci-hub.do/10.1111/jgs.16459
}}
==MOS==

{{medline-entry
|title=Effect of mannan oligosaccharides on the microbiota and productivity parameters of Litopenaeus vannamei shrimp under intensive cultivation in Ecuador.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32066764
|abstract=The white leg Litopenaeus vannamei shrimp is of importance to the eastern Pacific fisheries and aquaculture industry but suffer from diseases such as the recently emerged early mortality syndrome. Many bacterial pathogens have been identified but the L. vannamei microbiota is still poorly known. Using a next-generation sequencing (NGS) approach, this work evaluated the impact of the inclusion in the diet of mannan oligosaccharide, ([[MOS]], 0.5% w/w), over the L. vannamei microbiota and production behavior of L. vannamei under intensive cultivation in Ecuador. The [[MOS]] supplementation lasted for 60 days, after which the shrimp in the ponds were harvested, and the production data were collected. [[MOS]] improved productivity outcomes by increasing shrimp survival by 30%. NGS revealed quantitative differences in the shrimp microbiota between [[MOS]] and control conditions. In the treatment with inclusion of dietary [[MOS]], the predominant phylum was Actinobacteria (28%); while the control group was dominated by the phylum Proteobacteria (30%). [[MOS]] has also been linked to an increased prevalence of Lactococcus- and Verrucomicrobiaceae-like bacteria. Furthermore, under the treatment of [[MOS]], the prevalence of potential opportunistic pathogens, like Vibrio, Aeromonas, Bergeyella and Shewanella, was negligible. This may be attributable to [[MOS]] blocking the adhesion of pathogens to the surfaces of the host tissues. Together, these findings point to the fact that the performance (survival) improvements of the dietary [[MOS]] may be linked to the impact on the microbiota, since bacterial lines with pathogenic potential towards shrimps were excluded in the gut.
|mesh-terms=* Actinobacteria
* Aeromonas
* Animal Feed
* Animals
* Aquaculture
* Bacterial Adhesion
* Ecuador
* Flavobacteriaceae
* Lactococcus
* Longevity
* Mannans
* Microbiota
* Oligosaccharides
* Penaeidae
* Proteobacteria
* Seafood
* Shewanella
* Verrucomicrobia
* Vibrio

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026423
}}
{{medline-entry
|title=Predictors of health-related quality of life among older adults living with HIV in Thailand: results from the baseline and follow-up surveys.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31870166
|abstract=The current longitudinal study consisted of baseline and follow-up surveys among older adults living with HIV (OALHIV) in Thailand. The health-related quality of life (HRQoL) was assessed using the Medical Outcomes Study HIV ([[MOS]]-HIV) questionnaire. We performed multiple linear regression analysis to document correlates of HRQoL at baseline and the predictors of the changes in HRQoL at follow-up. Of the 364 participants recruited at baseline; 327 (89.9%) completed the follow-up survey. The mean (SD) Physical Health Summary (PHS) and Mental Health Summary (MHS) scores were respectively 49.8 (7.3) and 53.2 (6.4). There was a significant increase in the mean score of most of the [[MOS]]-HIV domains, ranging between 1.3 for the PHS and 26.9 for the energy/fatigue dimension. In contrast, the mean score significantly decreased by 4.1 and 10.3 points, respectively for the cognitive and social functioning. Female gender was a predictor of the decline in social ([i]β [/i]=[i] [/i]-11.37; [i]P [/i]= 0.031) and cognitive ([i]β [/i]=[i] [/i]-8.05; [i]P [/i]= 0.002) functioning at follow-up, while being married was related to an increase of in the score of energy/fatigue (vitality) ([i]β[/i] = 5.98; [i]P [/i]= 0.011) at follow-up. Physical exercise was associated with an increase in social functioning ([i]β[/i] = 9.38; [i]p [/i]= 0.042). Overall the HRQoL of OALHIV improved or was maintained over time.

|keywords=* Chiang Mai
* HIV and aging
* Older adults living with HIV
* Thailand
* health-related quality of life
* quality of life
|full-text-url=https://sci-hub.do/10.1080/09540121.2019.1707472
}}
{{medline-entry
|title=Comparison of health-related quality of life between the Han and Yi ethnicity elderly in the Yi autonomous areas of Yunnan Province.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31766992
|abstract=The purpose of this research was to assess the health-related quality of life (HRQOL) and functional abilities of Yi and Han elderly who resided in Yi Autonomous prefecture or Counties in Yunnan Province, as well as to compare their differences in HRQOL, functional abilities and other factors. A total of 1636 older subjects, which included 863 Han and 773 Yi, were recruited from 10 Yi Autonomous regions. Their HRQOL and functional capabilities were assessed by the [[MOS]] 36-Item Short Form Health Survey (SF-36), activities of daily living (ADL), and instrumental activities of daily living (IADL) scales. The Han elderly performed better in every domain of SF-36 than the Yi elderly. Both of the two ethnic groups could perform their ADL independently but the Yi elderly showed greater dependency in IADL abilities. The HRQOL was positively associated with their ADL, IADL, and education levels. Moreover, age, health insurance status, and living arrangement were negatively correlated with HRQOL. The HRQOL and IADL capabilities of the Han elderly were higher than that of the Yi counterparts in the Yi Autonomous regions. The HRQOL of both the two ethnic groups was positively connected with ADL, IADL abilities as well as education levels, whereas it was negatively correlated with age and health insurance. The elderly-care policy on the Yi autonomous areas should focus more on the HRQOL, ADL improvement, education background, age needs, and health insurance, etc.
|mesh-terms=* Activities of Daily Living
* Aged
* Aged, 80 and over
* Aging
* China
* Cross-Sectional Studies
* Ethnic Groups
* Female
* Humans
* Male
* Middle Aged
* Quality of Life
|keywords=* ADL
* Elderly
* Health-related quality of life
* IADL
* Yi ethnic minority
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878633
}}
{{medline-entry
|title=Mannan oligosaccharide increases the growth performance, immunity and resistance capability against Vibro Parahemolyticus in juvenile abalone Haliotis discus hannai Ino.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31561025
|abstract=This trial was conducted to investigate the effect of mannose oligosaccharides ([[MOS]]) on the growth performance, antioxidation, immunity and disease resistance of Vibro Parahemolyticus in juvenile abalone Haliotis discus hannai Ino. Four formulated diets were produced to contain 0.00 g/kg, 0.40 g/kg, 0.80 g/kg and 1.60 g/kg Actigen®, with functional ingredients of [[MOS]], respectively. Accordingly, the experimental diets were named as A0, A4, A8 and A16. After 120-days feeding trial, the best growth performance was observed in A8 group (P < 0.05) and there was no significant difference in A0, A4 and A16 groups. With the increase of dietary [[MOS]], the activity of the total antioxidant capacity in hepatopancreas is increasingly elevated (P < 0.05) while no significant difference was observed on activity of glutathione S-transferase (P > 0.05). The activities of superoxide dismutase and glutathione peroxidase were firstly increased and then decreased, with the highest values in A8 group (P < 0.05). Immune-related parameters were significantly affected by dietary [[MOS]] inclusion. Specifically, the activities of alkaline phosphatase and acid phosphatase in hepatopancreas and serum of abalone fed diets containing [[MOS]] were significantly higher than those of control A0 group (P < 0.05). Moreover, the highest values of both enzymes were observed in hepatopancreas of A8 group but in serum of A16 group, respectively. The lysozyme activities in hepatopancreas and serum of A4 group were significantly higher than those of other groups (P < 0.05) and there was no significant difference in A0, A8 and A16 groups (P > 0.05). The activities of cytophagy and respiratory burst in serum of abalone were not significantly affected by dietary [[MOS]] content (P > 0.05). The mRNA levels of focal adhesion kinase and integrin-linked kinase were gradually elevated with the increase of dietary [[MOS]], with the highest value recorded in A16 group (P < 0.05). The gene expression of caspse-3 in A8 group was dramatically higher than those of other groups (P < 0.05) and there was no significant difference in A0, A4 and A16 groups (P > 0.05). The mRNA level of nuclear factor-κB was not significantly affected by dietary [[MOS]] (P > 0.05). During 56 h of V. Parahemolyticus challenge period, the accumulated mortality rate of abalone fed diets containing [[MOS]] were significantly lower than that of control A0 group in each time point (P < 0.05). Overall, the lowest rate was happened in A8 group (P < 0.05). In conclusion, [[MOS]] inclusion in diet has obviously positive effect on growth, immunity and disease resistance capability of abalone, with the optimal level of Actigen® at 0.80 g/kg in diet.
|mesh-terms=* Animal Feed
* Animals
* Antioxidants
* Diet
* Dietary Supplements
* Dose-Response Relationship, Drug
* Gastropoda
* Immunity, Innate
* Longevity
* Mannans
* Oligosaccharides
* Vibrio parahaemolyticus
|keywords=* Abalone
* Antioxidation
* Bacterial challenge
* Disease resistance
* Growth
* Immunity
* Mannan oligosaccharide
|full-text-url=https://sci-hub.do/10.1016/j.fsi.2019.09.058
}}
==RET==

{{medline-entry
|title=Effects of resistance exercise training on redox homeostasis in older adults. A systematic review and meta-analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32615210
|abstract=Resistance exercise training ([[RET]]) has proven effective at reducing the risk of chronic disease in older populations, and it appears to regulate redox homeostasis. To determine the effects of [[RET]] on redox homeostasis in older people. A systematic review and meta-analysis of randomized clinical trials identified by searching MEDLINE, Web of Science, EMBASE, Sportdiscus, LILACS, CENTRAL and CINAHL. We included studies of subjects aged 65 years or older, with or without pathologies, and including [[RET]] metrics with quantified molecular oxidation and antioxidant capacity outcomes. Fifteen studies were included in this review. Agreement between reviewers reached a kappa value of 0.725. There were a total of 614 participants, with an average age of 68.1 years. Five (for molecular oxidation markers) and three (for antioxidant capacity markers) studies included data that quantified the effects of [[RET]] on homeostasis redox. The results of the meta-analysis showed that there were no differences in the molecular oxidation markers (SMD = -0.26; 95% CI = -0.57 to 0.05; P = 0.10; I2 = 0%) and antioxidant capacity markers (SMD = 0.53; 95% CI = -0.20 to 1.26; P = 0.16; I2 = 71.5%) in healthy older people after a [[RET]] of 8-24 weeks compared to non-intervention. Based on a small number of studies of low methodological quality, this systematic review with meta-analysis suggests that [[RET]] is not effective at reducing molecular oxidation markers in healthy older people. More research is needed on the effects of [[RET]] on redox homeostasis in older people. CRD42019121529.

|keywords=* Aging
* Antioxidants
* Exercise
* Oxidative stress
* Resistance exercise training
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111012
}}
{{medline-entry
|title=Effects of an 8-week resistance training intervention on plantar flexor muscle quality and functional capacity in older women: A randomised controlled trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32562747
|abstract=The present study examined 8 weeks of resistance training and its effects on muscle quality measures, plantar flexor muscle strength, muscle thickness and functional capacity in older women. Moreover, we tested if changes in muscle quality were associated with functional capacity. Twenty-four older women (66.3 ± 5.8 years; 69.0 ± 3.0 kg; 25.3 ± 1.4 kg·m ) were recruited to the study. After completion of the baseline assessment, participants were randomly assigned to either the resistance training ([[RET]], n = 12) or an active control group (CTR, n = 12). Muscle quality was evaluated through muscle echo intensity (MQ ) and specific tension (MQ ). Muscle thickness, unilateral plantar flexor muscle strength and functional tests were evaluated at baseline and after the training period. After 8 weeks, both MQ  and MQ  did not respond to the intervention. Furthermore, significant changes in stair climb performance (P < 0.05) were not associated with plantar flexor-derived muscle quality (P > 0.05). Finally, significant gains in muscle hypertrophy were observed in the [[RET]] group (P < 0.01), while muscle strength failed to change significantly (P > 0.05). In conclusion, a resistance training program provided significant benefits in the stair climb test, unrelated to plantar flexor-derived muscle quality measures as previously demonstrated in quadriceps femoris.

|keywords=* Aging
* Muscle echo intensity
* Muscle quality
* Physical function
* Resistance training
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111003
}}
{{medline-entry
|title=Resistance exercise training promotes fiber type-specific myonuclear adaptations in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32134710
|abstract=Aging induces physiological decline in human skeletal muscle function and morphology, including type II fiber atrophy and an increase in type I fiber frequency. Resistance exercise training ([[RET]]) is an effective strategy to overcome muscle mass loss and improve strength, with a stronger effect on type II fibers. In the present study, we sought to determine the effect of a 12-wk progressive [[RET]] program on the fiber type-specific skeletal muscle hypertrophic response in older adults. Nineteen subjects [10 men and 9 women (71.1 ± 4.3 yr)] were studied before and after the 12-wk program. Immunohistochemical analysis was used to quantify myosin heavy chain (MyHC) isoform expression, cross-sectional area (CSA), satellite cell abundance, myonuclear content, and lipid droplet density. [[RET]] induced an increase in MyHC type II fiber frequency and a concomitant decrease in MyHC type I fiber frequency. Mean CSA increased significantly only in MyHC type II fibers (+23.3%, [i]P[/i] < 0.05), but myonuclear content increased only in MyHC type I fibers ([i]P[/i] < 0.05), with no change in MyHC type II fibers. Satellite cell content increased ~40% in both fiber types ([i]P[/i] > 0.05). [[RET]] induced adaptations to the capillary supply to satellite cells, with the distance between satellite cells and the nearest capillary increasing in type I fibers and decreasing in type II fibers. Both fiber types showed similar decrements in intramuscular lipid density with training ([i]P[/i] < 0.05). Our data provide intriguing evidence for a fiber type-specific response to [[RET]] in older adults and suggest flexibility in the myonuclear domain of type II fibers during a hypertrophic stimulus.  In older adults, progressive resistance exercise training ([[RET]]) increased skeletal muscle fiber volume and cross-sectional area independently of myonuclear accretion, leading to an expansion of the myonuclear domain. Fiber type-specific analyses illuminated differential adaptation; type II fibers underwent hypertrophy and exhibited myonuclear domain plasticity, whereas myonuclear accretion occurred in type I fibers in the absence of a robust hypertrophic response. [[RET]] also augmented satellite cell-capillary interaction and reduced intramyocellular lipid density to improve muscle quality.

|keywords=* aging
* hypertrophy
* myonuclear domain
* skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191507
}}
{{medline-entry
|title=Low skeletal muscle capillarization limits muscle adaptation to resistance exercise training in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31518665
|abstract=Adequate muscle perfusion supports the transport of nutrients, oxygen and hormones into muscle fibers. Aging is associated with a substantial decrease in skeletal muscle capillarization, fiber size and oxidative capacity, which may be improved with regular physical activity. The aim of this study was to investigate the relationship between muscle capillarization and indices of muscle hypertrophy (i.e. lean mass; fiber cross sectional area (CSA)) in older adults before and after 12 weeks of progressive resistance exercise training ([[RET]]). Interventional study SETTING AND PARTICIPANTS: 19 subjects (10 male and 9 female; 71.1 ± 4.3 years; 27.6 ± 3.2 BMI) were enrolled in the study and performed a whole body [[RET]] program for 12 weeks. Subjects where then retrospectively divided into a LOW or HIGH group, based on their pre-[[RET]] capillary-to-fiber perimeter exchange index (CFPE). Physical activity level, indices of capillarization (capillaries-to-fiber ratio, C:Fi; CFPE index and capillary-to-fiber interface, LC-PF index), muscle hypertrophy, muscle protein turnover and mitochondrial function were assessed before and after [[RET]]. Basal capillarization (C:Fi; CFPE and LP-CF index) correlates with daily physical activity level (C:Fi, r = 0.57, p = 0.019; CFPE index, r = 0.55, p = 0.024; LC-PF index, r = 0.56, p = 0.022) and CFPE and LC-PF indices were also positively associated with oxidative capacity (respectively r = 0.45, p = 0.06; r = 0.67, p = 0.004). Following [[RET]], subjects in the HIGH group underwent hypertrophy with significant improvements in muscle protein synthesis and muscle fiber CSA (p < 0.05). However, [[RET]] did not promote muscle hypertrophy in the LOW group, but [[RET]] significantly increased muscle capillary density (p < 0.05). Muscle fiber capillarization before starting an exercise training program may be predictive of the muscle hypertrophic response to [[RET]] in older adults. Increases in muscle fiber size following [[RET]] appear to be blunted when muscle capillarization is low, suggesting that an adequate initial capillarization is critical to achieve a meaningful degree of muscle adaptation to [[RET]].
|mesh-terms=* Adaptation, Physiological
* Aged
* Capillaries
* Citrate (si)-Synthase
* Exercise
* Female
* Humans
* Hypertrophy
* Male
* Muscle Fibers, Skeletal
* Muscle Proteins
* Muscle, Skeletal
* Resistance Training
* Sarcopenia
* Ubiquitin-Protein Ligases
|keywords=* Aging
* Capillary
* Fiber cross-sectional area
* Muscle hypertrophy
* Muscle protein synthesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904952
}}
==MET==

{{medline-entry
|title=Self-rated health in relation to fruit and vegetable consumption and physical activity among older cancer survivors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32979089
|abstract=We aimed to investigate associations of self-rated health with fruit and vegetable consumption (FVC) and physical activity (PA) among older cancer survivors. We used the 2017 Behavioral Risk Factor Surveillance System to identify cancer survivors ≥ 65 years (N = 2663). Self-reported FVC and PA were categorized as ordinal variables to approximate quartiles. Low general health (LGH) was defined as fair or poor self-rated health. A multivariable logistic regression treating LGH as the outcome was used to calculate adjusted odd ratios (aORs) and 95% confidence intervals (CIs) for FVC and PA. Restricted cubic spline depicted non-linear dose-response curves for FVC and PA. In comparative analysis, we used the same logistic regression and dose-response model to calculate ORs of FVC and PA in 73,134 people ≥ 65 years without cancer history. Overall, 470 (17.7%) survivors had LGH. Survivors' mean age was 73.3 years (SD = 5.2), 55.1% of them were female, and 95.4% self-reported as white. In cancer survivors, FVC was not associated with LGH (≥ 28 vs. < 14 times/week: aOR = 1.02, 95% CI = 0.75-1.39, p-trend = 0.50), whereas PA was inversely associated with LGH (≥ 30 vs. < 7 [[MET]]-hours/week: aOR = 0.55, 95% CI = 0.41-0.75, p-trend < 0.01). Dose-response curves demonstrated consistent association patterns. In comparative analysis, ORs of PA did not change substantially but we observed inverse association for FVC. An inverse association between PA and LGH was observed among older cancer survivors, but no significant association was obtained for FVC among them. Regular PA may maintain or indicate a favorable health in older cancer survivors, whereas impacts of FVC deserve further investigations.

|keywords=* Cancer survivorship
* Epidemiology
* Fruit and vegetable
* Gerontology
* Physical activity
|full-text-url=https://sci-hub.do/10.1007/s00520-020-05782-6
}}
{{medline-entry
|title=Leisure-time physical activity volume, intensity, and duration from mid- to late-life in U.S. subpopulations by race and sex. The Atherosclerosis Risk In Communities (ARIC) Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32170049
|abstract=Mitigating age-related disease and disability presents challenges. Physical activity (PA) may be influential for prolonging health and functioning, warranting characterization of its patterns over the life course in population-based data. With the availability of up to three self-reported assessments of past year leisure-time PA (LTPA) over multiple decades in 15,036 participants (26% African American; 55% women; mean baseline age=54; median follow-up=23 years) from the Atherosclerosis Risk in Communities (ARIC) Study sampled from four U.S. communities, race-sex-stratified trajectories of average weekly intensity (metabolic equivalent of task ([[MET]])), duration (hours), and energy expenditure or volume ([[MET]]-h) of LTPA were developed from age 45 to 90 using joint models to accommodate expected non-ignorable attrition. Declines in weekly LTPA intensity, duration, and volume from age 70 to 90 were observed in white women (2.9 to 1.2 [[MET]]; 2.5 to 0.6 h; 11.1 to 2.6 [[MET]]-h), white men (2.5 to 1.0 [[MET]]; 3.5 to 1.8 h; 15.5 to 6.4 [[MET]]-h), African American women (2.5 to 2.4 [[MET]]; 0.8 to 0.1 h; 6.7 to 6.0 [[MET]]-h), and African American men (2.3 to 1.4 [[MET]]; 1.5 to 0.6 h; 8.0 to 2.3 [[MET]]-h). These data reveal population-wide shifts towards less active lifestyles in older adulthood.

|keywords=* exercise
* healthy aging
* physical activity
* retirement
* successful aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093185
}}
{{medline-entry
|title=Repressive H3K9me2 protects lifespan against the transgenerational burden of COMPASS activity in [i]C. elegans[/i].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31815663
|abstract=In [i]Caenorhabditis elegans[/i], mutations in WDR-5 and other components of the COMPASS H3K4 methyltransferase complex extend lifespan and enable its inheritance. Here, we show that [i]wdr-5[/i] mutant longevity is itself a transgenerational trait that corresponds with a global enrichment of the heterochromatin factor H3K9me2 over twenty generations. In addition, we find that the transgenerational aspects of [i]wdr-5[/i] mutant longevity require the H3K9me2 methyltransferase [[MET]]-2, and can be recapitulated by removal of the putative H3K9me2 demethylase JHDM-1. Finally, we show that the transgenerational acquisition of longevity in [i]jhdm-1[/i] mutants is associated with accumulating genomic H3K9me2 that is inherited by their long-lived wild-type descendants at a subset of loci. These results suggest that heterochromatin facilitates the transgenerational establishment and inheritance of a complex trait. Based on these results, we propose that transcription-coupled H3K4me via COMPASS limits lifespan by encroaching upon domains of heterochromatin in the genome.
|mesh-terms=* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Heterochromatin
* Histone-Lysine N-Methyltransferase
* Histones
* Inheritance Patterns
* Jumonji Domain-Containing Histone Demethylases
* Longevity
* Lysine
* Methylation
* Mutation
|keywords=* C. elegans
* COMPASS
* aging
* chromatin
* chromosomes
* epigenetics
* gene expression
* genetics
* genomics
* heterochromatin
* transgenerational inheritance
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299346
}}
{{medline-entry
|title=Influence of Anthropometrics on Step-Rate Thresholds for Moderate and Vigorous Physical Activity in Older Adults: Scientific Modeling Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31518246
|abstract=Adults and older adults are recommended to engage in 150 minutes of moderate (MPA) to vigorous (VPA) aerobic physical activity (MVPA) per week, with the heuristic message of 3000 steps in 30 minutes (100 steps per minute [spm]). However, this message is based on adult populations, with a paucity of research on step-rate thresholds that correspond to absolute MVPA (moderate=3 metabolic equivalents [[[MET]]s], vigorous=6 [[MET]]s) and relative MVPA (moderate=40% estimated [[MET]] , vigorous=60% estimated [[MET]] ) in older persons, who have lower stride lengths and a lower exercise capacity. Also, there is a need to consider the influence of anthropometric differences when quantifying the relationship between step rate and intensity-related physical activity. This study assessed absolute and relative MVPA step-rate thresholds and anthropometric factors (ie, height, leg length, and body mass index [BMI]) in older adults. Nineteen older adults (7 females; age 69 years, SD 2, BMI 26 kg/m , SD 4) completed a staged treadmill walking protocol: six minutes at 2.4, 3.2, 4.0, 5.6, and 6.4 km/h. Steps were manually counted and volume rate of oxygen consumed (VO ) was measured via indirect calorimetry. Aerobic fitness was estimated via the submaximal single-stage treadmill protocol. When BMI was considered, mixed effects modeling revealed absolute and relative MPA step-rate thresholds of 108 spm and 117 spm, respectively. Absolute and relative VPA corresponded to step rates of 135 spm and 132 spm, respectively. Neither height nor leg length improved the ability of the model to predict stepping cadence from [[MET]]s. In general, older adults need to walk faster than 100 spm (ie, approximately 110 spm) to reach MPA and in excess of approximately 130 spm to achieve VPA, depending on BMI status. Health care professionals and researchers should adjust cadence-based recommendations for differences in BMI in their older patients and consider using relative intensity to most appropriately tailor their physical activity recommendations.

|keywords=* aging
* cadence
* physical activity intensity
* public health
* walking
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715008
}}
==SFN==

{{medline-entry
|title=The phytoprotective agent sulforaphane prevents inflammatory degenerative diseases and age-related pathologies via Nrf2-mediated hormesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33160067
|abstract=In numerous experimental models, sulforaphane ([[SFN]]) is shown herein to induce hormetic dose responses that are not only common but display endpoints of biomedical and clinical relevance. These hormetic responses are mediated via the activation of nuclear factor erythroid- derived 2 (Nrf2) antioxidant response elements (AREs) and, as such, are characteristically biphasic, well integrated, concentration/dose dependent, and specific with regard to the targeted cell type and the temporal profile of response. In experimental disease models, the [[SFN]]-induced hormetic activation of Nrf2 was shown to effectively reduce the occurrence and severity of a wide range of human-related pathologies, including Parkinson's disease, Alzheimer's disease, stroke, age-related ocular damage, chemically induced brain damage, and renal nephropathy, amongst others, while also enhancing stem cell proliferation. Although [[SFN]] was broadly chemoprotective within an hormetic dose-response context, it also enhanced cell proliferation/cell viability at low concentrations in multiple tumor cell lines. Although the implications of the findings in tumor cells are largely uncertain at this time and warrant further consideration, the potential utility of [[SFN]] in cancer treatment has not been precluded. This assessment of [[SFN]] complements recent reports of similar hormesis-based chemoprotections by other widely used dietary supplements, such as curcumin, ginkgo biloba, ginseng, green tea, and resveratrol. Interestingly, the mechanistic profile of [[SFN]] is similar to that of numerous other hormetic agents, indicating that activation of the Nrf2/ARE pathway is probably a central, integrative, and underlying mechanism of hormesis itself. The Nrf2/ARE pathway provides an explanation for how large numbers of agents that both display hormetic dose responses and activate Nrf2 can function to limit age-related damage, the progression of numerous disease processes, and chemical- and radiation- induced toxicities. These findings extend the generality of the hormetic dose response to include [[SFN]] and many other chemical activators of Nrf2 that are cited in the biomedical literature and therefore have potentially important public health and clinical implications.

|keywords=* Aging
* Hormesis
* Inflammation
* Neuroprotection
* Nrf2
* Sulforaphane
|full-text-url=https://sci-hub.do/10.1016/j.phrs.2020.105283
}}
{{medline-entry
|title=Multi-Omic Analysis Reveals Different Effects of Sulforaphane on the Microbiome and Metabolome in Old Compared to Young Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33003447
|abstract=Dietary factors modulate interactions between the microbiome, metabolome, and immune system. Sulforaphane ([[SFN]]) exerts effects on aging, cancer prevention and reducing insulin resistance. This study investigated effects of [[SFN]] on the gut microbiome and metabolome in old mouse model compared with young mice. Young (6-8 weeks) and old (21-22 months) male C57BL/6J mice were provided regular rodent chow ± [[SFN]] for 2 months. We collected fecal samples before and after [[SFN]] administration and profiled the microbiome and metabolome. Multi-omics datasets were analyzed individually and integrated to investigate the relationship between [[SFN]] diet, the gut microbiome, and metabolome. The [[SFN]] diet restored the gut microbiome in old mice to mimic that in young mice, enriching bacteria known to be associated with an improved intestinal barrier function and the production of anti-inflammatory compounds. The tricarboxylic acid cycle decreased and amino acid metabolism-related pathways increased. Integration of multi-omic datasets revealed [[SFN]] diet-induced metabolite biomarkers in old mice associated principally with the genera, [i]Oscillospira[/i], [i]Ruminococcus[/i], and [i]Allobaculum[/i]. Collectively, our results support a hypothesis that [[SFN]] diet exerts anti-aging effects in part by influencing the gut microbiome and metabolome. Modulating the gut microbiome by [[SFN]] may have the potential to promote healthier aging.

|keywords=* aging
* biomarkers
* gut microbiome
* metabolome
* sulforaphane
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599699
}}
{{medline-entry
|title=Sulforaphane controls the release of paracrine factors by keratinocytes and thus mitigates particulate matter-induced premature skin aging by suppressing melanogenesis and maintaining collagen homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32659677
|abstract=Skin aging, potentially caused by exposure to particulate matter (PM) , is characterized by wrinkling, abnormal pigmentation, and skin dryness triggered by several keratinocyte-derived paracrine factors. Sulforaphane (4-methylsulfinylbutyl isothiocyanate, [[SFN]]), commonly found in cruciferous vegetables, has diverse biological effects on skin tissue. In the present study, we have investigated whether [[SFN]] may alleviate PM -induced premature skin aging. We used keratinocyte/melanocyte or keratinocyte/fibroblast coculture models of skin cells and measured the parameters of melanogenesis, collagen homeostasis and inflammation. [[SFN]] inhibited the development of reactive oxygen species in keratinocytes exposed to PM . In keratinocyte/melanocyte cocultures, it significantly inhibited the upregulation of melanogenic paracrine mediators (including endothelin-1 and prostaglandin E2) in keratinocytes exposed to PM ; the synthesis of melanogenic proteins including microphthalmia-associated transcription factor, tyrosinase-related protein 1, and tyrosinase; and the levels of melanin in melanocytes. [[SFN]] treatment of keratinocyte/fibroblast cocultures significantly reduced the PM -induced expression of NF-κB-mediated cytokines including interleukin-1β, interleukin-6, tumor necrosis factor α, and cyclooxygenase-2. In fibroblasts of the keratinocyte/fibroblast coculture system, the expression levels of phospho-NF-κB, cysteine-rich protein 61, and matrix metalloproteinase-1 were significantly decreased whereas procollagen type I synthesis was significantly increased. Collectively, our results suggest that [[SFN]] mitigates PM -induced premature skin aging by suppressing melanogenesis and maintaining collagen homeostasis. It acts by regulating the release of paracrine factors from keratinocytes.

|keywords=* Coculture system
* Collagen homeostasis
* Melanogenesis
* Particulate matter 2.5
* Premature skin aging
* Sulforaphane
|full-text-url=https://sci-hub.do/10.1016/j.phymed.2020.153276
}}
{{medline-entry
|title=Sulforaphane Inhibits Autophagy and Induces Exosome-Mediated Paracrine Senescence via Regulating mTOR/TFE3.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32476238
|abstract=The development of novel compounds that trigger non-apoptotic cell death may represent alternative therapeutic strategies for esophageal squamous cell carcinoma (ESCC) treatment. Cellular senescence suppresses tumorigenesis by halting the proliferation of tumor cells, implying the induction of senescence as a promising anticancer strategy, especially when combined with senolytic agents that specially kill senescent cells. This study is designed to screen novel anti-ESCC compounds from a natural product resource and identify its mechanism-of-action. Identified are the significant anti-cancer effect and underlying mechanism of [[SFN]], an isothiocyanate derived from cruciferous vegetables, through RNA sequencing, western blot, and immunofluorescent assays. It is found that [[SFN]] inhibits proliferation of ESCC cells through inducing senescence. Mechanistically, [[SFN]] induces reactive oxygen species (ROS) via disrupting the balance between glutathione and oxidized glutathione, leading to DNA damage. In addition, ROS deregulates autophagy and promotes lysosome abnormal biogenesis through regulating mTOR/TFE3 axis. Finally, the inhibited autophagic flux facilitates exosome production, resulting in exosome-mediated paracrine senescence. This study suggests the important roles of autophagy and exosome-mediated paracrine senescence in cancer therapy and highlights [[SFN]] as a potent anti-ESCC drug candidate.

|keywords=* ROS
* autophagy
* exosome
* senescence
* sulforaphane
|full-text-url=https://sci-hub.do/10.1002/mnfr.201901231
}}
==MFI==

{{medline-entry
|title=The Influence of the Accelerated Aging Conditions on the Properties of Polyolefin Geogrids Used for Landfill Slope Reinforcement.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32825284
|abstract=Polyolefin geosynthetics are susceptible to oxidative degradation, which in turn leads to diminished mechanical properties in geotechnical constructions. When using these materials, it is extremely important to determine their durability over time in particularly aggressive conditions. In order to prolong the life of a geosynthetic material, antioxidants are added during the manufacturing process. The function of antioxidants is to prevent polymer oxidation reaction in time. As the antioxidant content is depleted, the polymer becomes less protected towards oxidative attacks. This article describes the aging process of uniaxial (high density polyethylene) HDPE geogrids under the influence of chemical and environmental factors. Evaluations of accelerated aging test of the uniaxial HDPE geogrids were incubated in simulated landfill conditions for a period of 12 months. Three temperatures (25 °C, 45 °C, and 75 °C) were selected for carrying out the aging experiments in aqueous solutions mimicking landfill conditions. The changes observed by differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and melt flow index ([[MFI]]) correlate with the mechanical properties of the aged geogrid. No significant changes in the FTIR and [[MFI]] were observed over the 12 months of accelerated aging tests at none of the three different temperatures. The oxidation induction time (OIT) test showed no antioxidant remaining in the geogrid following eight months of aging test at 75 °C. No significant changes in the influence of accelerated aging tests on the average relative elongation at 25 °C and 45 °C of the tested material were observed. Accelerated aging tests at 75 °C showed that the mean elongation of 12.12% for the sample not subjected to accelerated aging tests (new sample) increased to 19.32% (after 12 months of incubation).

|keywords=* HDPE
* accelerated aging tests
* decrease mechanical properties
* degradation
* geosynthetics
* landfill
* polyolefin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564637
}}
{{medline-entry
|title=Changes in Physical Meat Traits, Protein Solubility, and the Microstructure of Different Beef Muscles during Post-Mortem Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32575353
|abstract=This study was performed to compare the differences in pH, myofibril fragmentation index ([[MFI]]), total protein solubility (TPS), sarcoplasmic protein solubility (SPS), myofibrillar protein solubility (MPS), and the microstructure of seven beef muscles during aging. From the six beef carcasses of Xinjiang brown cattle, a total of 252 samples from [i]semitendinosus[/i] (ST), [i]longissimus thoracis[/i] (LT), [i]rhomboideus[/i] (RH), [i]gastrocnemius[/i] (GN), [i]infraspinatus[/i] (IN), [i]psoas major[/i] (PM), and [i]biceps femoris[/i] (BF) muscles were collected, portioned, and assigned to six aging periods (1, 3, 7, 9, 11, and 14 day/s) and 42 samples were used per storage period. IN muscle showed the highest pH ([i]p[/i] < 0.05) from 1 to 14 days and the lowest TPS ([i]p[/i] < 0.01) from 9 to 14 days with respect to the other muscles. Moreover, the changes in IN were further supported by transmission electron microscopy due to the destruction of the myofibril structure. The highest value of [[MFI]] was tested in ST muscle from 7 to 14 days. The total protein solubility in PM, RH, and GN muscles were not affected ([i]p[/i] > 0.05) as the aging period increased. The lowest TPS was found in the RH muscle on day 1, 3, and 7 and in the IN muscle on day 9, 11, and 14. The pH showed negative correlations with the [[MFI]], TPS, and MPS ([i]p[/i] < 0.01). The results suggest that changes in protein solubility and muscle fiber structure are related to muscle location in the carcass during aging. These results provide new insights to optimize the processing and storage of different beef muscles and enhance our understanding of the biological characteristics of Xinjiang brown cattle muscles.

|keywords=* aging
* beef muscle
* microstructure
* myofibril fragmentation
* protein solubility
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353465
}}
{{medline-entry
|title=Effect of a low-voltage electrical stimulation on yak meat tenderness during postmortem aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32583539
|abstract=This study evaluates the effect of a low-voltage electrical stimulation (ES) on the tenderness of yak longissimus muscle (LM). Samples from 16 yak bulls were divided into four treatment groups: normal chilling (NC), ES and chilling (ES & C) for 72 s (ES &C 72 s), ES & C for 90 s (ES & C 90 s), and ES & C for 108 s (ES & C 108 s). The temperature, the pH, the glycogen content, the Warner-Bratzler shear force (WBSF), the myofibril fragmentation index ([[MFI]]), and the muscle ultrastructure were determined during the course of postmortem aging. ES caused a rapid decrease in the pH to form a high-temperature and low-pH environment. The glycogen content gradually decreased with aging. The WBSF value of the ES & C groups was significantly lower than for the NC group (p < .05). The [[MFI]] values of ES & C groups after 24 hr postmortem aging were significantly higher than for the NC group. We concluded that ES improved yak meat tenderness during postmortem aging and that the different duration time by ES indicated different effects, and its affect was remarkable in the ES & C 90 s.
|mesh-terms=* Animals
* Cattle
* Cold Temperature
* Electric Stimulation
* Food Handling
* Food Quality
* Food Storage
* Hydrogen-Ion Concentration
* Male
* Meat
* Muscle, Skeletal
* Polysaccharides
* Postmortem Changes
* Time Factors
|keywords=* Yak
* electrical stimulation
* postmortem aging
* tenderness
|full-text-url=https://sci-hub.do/10.1111/asj.13410
}}
{{medline-entry
|title=Comparative effects of dry-aging and wet-aging on physicochemical properties and digestibility of Hanwoo beef.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31480178
|abstract=The purpose of this study was to investigate the effects of aging methods (AM) i.e. dry-aging (DA) and wet-aging (WA) on the physicochemical properties and in vitro digestibility of proteins in beef short loin. Short loins (M. longissmus lumborum), were trimmed and boned-out on the fifth day postmortem, from a total of 18 Hanwoo, which were purchased from a commercial slaughterhouse. Short loins were separated randomly grouped into one of the three treatments: control, WA (1°C, 7 days), and DA (1°C, 0.5 m/s, 85% relative humidity [RH], 30 days). Dry-aged beef (DAB) exhibited higher pH, water holding capacity (WHC), myofibrillar fragmentation index ([[MFI]]), and digestibility, however lower lightness, redness, and yellowness values, cooking loss, and shear force (SF), than those of wet-aged beef (WAB) (p<0.05). The myosin light chain band intensity of DAB was higher than that of control and WAB in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The in vitro digestibility of aged beef was highly (p<0.001) correlated to physicochemical properties except WHC. The correlation coefficient between AMs and WHC was higher than that between AM and SF (p<0.05) or [[MFI]] (p<0.001). A high correlation was observed between SF and [[MFI]] (p<0.001). Thus, we believe that DAB is more advantageous than WAB owing to its high digestibility and WHC and low SF.

|keywords=* Beef Loin
* Digestibility
* Dry Aging
* Shear Force
* Wet Aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054618
}}
==CD27==

{{medline-entry
|title=The Interplay between [[CD27]]  and [[CD27]]  B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32130900
|abstract=Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, [[CD27]]  and [[CD27]]  MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that [[CD27]]  and [[CD27]]  MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects [[CD27]]  into the [[CD27]]  MBC pool. Dynamics of human MBCs are exploited in pregnancy, when 50% of maternal MBCs are lost and [[CD27]]  MBCs transit to the more differentiated [[CD27]]  stage. In the postpartum period, the maternal MBC pool is replenished by the expansion of persistent [[CD27]]  clones. Thus, the stability and flexibility of human B cell memory is ensured by [[CD27]]  MBCs that expand and differentiate in response to change.

|keywords=* CD27
* VH repertoire
* aging
* germinal center
* immunodeficiency
* immunological memory
* memory B cells
* pregnancy
* spleen
* vaccine
|full-text-url=https://sci-hub.do/10.1016/j.celrep.2020.02.022
}}
{{medline-entry
|title=CMV-independent increase in [[CD27]]-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31993214
|abstract=Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of [[CD27]]-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, [[CD27]]-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.

|keywords=* Biomarkers
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972903
}}
{{medline-entry
|title=Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8  T cells in human cutaneous leishmaniasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31925782
|abstract=Cytotoxic activity mediated by CD8  T cells is the main signature of the immunopathogenesis of cutaneous leishmaniasis (CL). Here, we performed a broad evaluation of natural killer (NK) cell phenotypic and functional features during cutaneous leishmaniasis. We demonstrate for the first time that CL patients present the accumulation of circulating NK cells with multiple features of replicative senescence including low proliferative capacity and shorter telomeres, elevated expression of CD57, KLRG1 but diminished [[CD27]] stimulatory receptor expression. Moreover, they exhibited higher cytotoxic and inflammatory potential than age-matched controls. The accumulation of circulating senescent NK cells (CD56   CD57  ) correlated positively with skin lesion size in the same patients, suggesting that they, like circulating senescent CD8  T cells, may contribute to the immunopathology of CL. However, this senescent population had lower cutaneous lymphocyte antigen expression and so had diminished skin-homing potential compared with total or senescent CD8  T cells. This was confirmed in CL skin lesions where we found a predominance of CD8  T cells (both senescent and non-senescent) that correlated with the severity of the disease. Although there was also a correlation between the proportions of senescent NK cells (CD56   CD57  ) in the skin and lesion size, this was less evident. Collectively our results demonstrate first-hand that senescent cytotoxic cells may mediate skin pathology during human cutaneous leishmaniasis. However, as senescent cytotoxic CD8  T cells predominate in the skin lesions, they may have a greater role than NK cells in mediating the non-specific skin damage in CL.
|mesh-terms=* CD56 Antigen
* CD57 Antigens
* Case-Control Studies
* Cellular Senescence
* Cytotoxicity, Immunologic
* Female
* Gene Expression Regulation
* Host-Parasite Interactions
* Humans
* Interferon-gamma
* Killer Cells, Natural
* Lectins, C-Type
* Leishmania braziliensis
* Leishmaniasis, Cutaneous
* Male
* Oligosaccharides
* Receptors, Immunologic
* Severity of Illness Index
* Sialyl Lewis X Antigen
* Signal Transduction
* Skin
* T-Lymphocytes, Cytotoxic
|keywords=* 
Leishmania braziliensis

* CD8+ T cells
* cellular senescence
* cutaneous leishmaniasis
* immunopathology
* natural killer cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078002
}}
{{medline-entry
|title=[[CD27]]- IgD- B cell memory subset associates with inflammation and frailty in elderly individuals but only in males.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31423147
|abstract=Immunosenescence, i.e. the aging-associated decline of the capacity of the immune system, is characterized by several distinct changes in the number and functions of the immune cells. In the case of B cells, the total number of CD19+ B cells is lower in the blood of elderly individuals than in the younger ones. CD19+ B cell population contains several subsets, which are commonly characterized by the presence of [[CD27]] and IgD molecules, i.e. naïve B cells ([[CD27]]- IgD+), IgM memory ([[CD27]]+ IgD+), switched memory ([[CD27]]+ IgD-) and late memory ([[CD27]]- IgD-). This late memory, double negative, population represents cells which are nondividing, but are still able to produce inflammatory mediators and in this way maybe contributing to the aging-associated inflammation, inflammaging. Here we have focused on the role of these B cell subsets in elderly individuals, nonagenarians, in the regulation of inflammation and inflammation-associated decline of bodily functions. As the biological aging process demonstrates gender-specific characteristics, the analyses were performed separately in males and female. A subcohort of The Vitality 90+ study (67 nonagenarians, 22/45 males/females and 40 young controls, 13/27 males/females) was used. Flow cytometric analysis indicated that the total percentage of the CD19+ cells was ca. 50% lower in the nonagenarians than in the controls in both genders. The proportions of these four B cell subsets within the CD19+ populations were very similar in young and old individuals. Thus, it seems that the aging-associated decline of the total CD19+ cells affects similarly all these B cell subsets. To analyze the role of these subsets in the regulation of inflammation, the correlation with IL-6 levels was calculated. A significant correlation was observed only with the percentage of [[CD27]]- IgD- cells and only in males. As inflammation is associated with aging-associated functional performance and frailty, the correlations with the Barthel index and frailty score was analyzed. Again, only the [[CD27]]- IgD- population demonstrated a strong male-specific correlation. These data show that the [[CD27]]- IgD- B cell subset demonstrates a strong pro-inflammatory effect in nonagenarians, which significantly associates with the decline of the bodily functions. However, this phenomenon is only observed in males.

|keywords=* Aging
* B cell
* Frailty
* Immunosenescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693136
}}
==TP53==

{{medline-entry
|title=p53 inhibits the osteogenic differentiation but does not induce senescence in human dental follicle cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32473528
|abstract=Replicative senescence causes a reduced osteogenic differentiation potential of senescent dental follicle cells (DFCs). The transcription factor p53 is often involved in the induction of cellular senescence, but little is known about its role in DFCs. This study examined for the first time the role of p53 compared to its pro-proliferative antagonist E2F-1 in terms of osteogenic differentiation potential and induction of senescence. Protein expression of E2F-1 decreased during cell aging, while p53 was expressed constitutively. Gene silencing of E2F1 (E2F-1) inhibited the proliferation rate of DFCs and increased the induction of cellular senescence. The induction of cellular senescence is regulated independently of the gene expression of [[TP53]] (p53), since its gene expression depends on the expression of E2F1. Moreover, gene silencing of [[TP53]] induced E2F1 gene expression and increased cell proliferation, but did not affect the rate of induction of cellular senescence. [[TP53]] knockdown further induced the alkaline phosphatase and mineralization in DFCs. However, the simultaneous silencing of [[TP53]] and E2F1 did not inhibit the inductive effect of [[TP53]] knockdown on osteogenic differentiation, indicating that this effect is independent of E2F-1. In summary, our results suggest that p53 inhibits osteogenic differentiation and cell proliferation in senescent DFCs, but is not significantly involved in senescence induction.

|keywords=* Cellular senescence
* Dental follicle cells
* E2F-1
* Osteogenic differentiation
* p53
|full-text-url=https://sci-hub.do/10.1016/j.diff.2020.05.003
}}
{{medline-entry
|title=Mutational spectrum and dynamics of clonal hematopoiesis in anemia of older individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32243522
|abstract=Anemia is a major and currently poorly understood clinical manifestation of hematopoietic aging. Upon aging, hematopoietic clones harboring acquired leukemia-associated mutations expand and become detectable, now referred to as clonal hematopoiesis (CH). To investigate the relationship between CH and anemia of the elderly, we explored the landscape and dynamics of CH in older individuals with anemia. From the prospective, population-based Lifelines cohort (n = 167 729), we selected all individuals at least 60 years old who have anemia according to World Health Organization criteria (n = 676) and 1:1 matched control participants. Peripheral blood of 1298 individuals was analyzed for acquired mutations at a variant allele frequency (VAF) of 1% or higher in 27 driver genes. To track clonal evolution over time, we included all available follow-up samples (n = 943). CH was more frequently detected in individuals with anemia (46.6%) compared with control individuals (39.1%; P = .007). Although no differences were observed regarding commonly detected DTA mutations (DNMT3A, TET2, ASXL1) in individuals with anemia compared with control individuals, other mutations were enriched in the anemia cohort, including [[TP53]] and SF3B1. Unlike individuals with nutrient deficiency (P = .84), individuals with anemia of chronic inflammation and unexplained anemia revealed a higher prevalence of CH (P = .035 and P = .017, respectively) compared with their matched control individuals. Follow-up analyses revealed that clones may expand and decline, generally showing only a subtle increase in VAF (mean, 0.56%) over the course of 44 months, irrespective of the presence of anemia. Specific mutations were associated with different growth rates and propensities to acquire an additional hit. In contrast to smaller clones (<5% VAF), which did not affect overall survival, larger clones were associated with increased risk for death.
|mesh-terms=* Age Factors
* Aged
* Aging
* Anemia
* Female
* Hematopoiesis
* Humans
* Kaplan-Meier Estimate
* Male
* Middle Aged
* Mutation
* Prospective Studies

|full-text-url=https://sci-hub.do/10.1182/blood.2019004362
}}
{{medline-entry
|title=[[TP53]]/miR-34a-associated signaling targets [i]SERPINE1[/i] expression in human pancreatic cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31986125
|abstract=Pancreatic ductal adenocarcinoma (PDAC) is a disease of aging. The [i][[TP53]][/i] gene product regulates cell growth, aging, and cancer. To determine the important targets of [[TP53]] in PDAC, we examined the expression of 440 proteins on a reverse phase protein array (RPPA) in PDAC-derived MIA-PaCa-2 cells which either had WT-[i][[TP53]][/i] or lacked WT-[i][[TP53]][/i]. MIA-PaCa-2 cells have a [i][[TP53]][/i] mutation as well as mutant [i]KRAS[/i] and represent a good [i]in vitro[/i] model to study PDAC. RPPA analysis demonstrated expression of tumor promoting proteins in cells that lacked WT-[i][[TP53]][/i]; and this feature could be reversed significantly when the cells were transfected with vector encoding WT-[i][[TP53]][/i] or treated with berberine or a modified berberine (BBR). Expression of miR-34a-associated signaling was elevated in cells expressing WT-[i][[TP53]][/i] compared to cells expressing [i]m[[TP53]][/i]. Results from [i]in vivo[/i] studies using human PDAC specimens confirmed the [i]in vitro[/i] results as the expression of miR-34a and associated signaling was significantly decreased in PDAC specimens compared to non-cancerous tissues. This study determined [i]SERPINE1[/i] as a miR-34a target with relevance to the biology of PDAC. Thus, we have identified a key target ([i]SERPINE1[/i]) of the [[TP53]]/miR-34a axis that may serve as a potential biomarker for early detection of pancreatic cancer.

|keywords=* Aging
* PDAC
* SERPINE1
* TP53
* cancer
* miR-34a
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041729
}}
{{medline-entry
|title=Expression of p16 in nodular fasciitis: an implication for self-limited and inflammatory nature of the lesion.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31933915
|abstract=Nodular fasciitis (NF) is a self-limited tumorous lesion occurring in the upper as well as lower extremities. NF is composed of a proliferation of "primary culture"-like myofibroblastic cells with nuclear atypia and large nucleoli, thus mimicking sarcoma. NF harbors a promoter-swapping fusion gene containing the entire coding region of [i]USP6[/i] gene. Therefore, NF is a tumor with a fusion oncogene but self-limited. In order to explore why NF is self-limited, we examined whether myofibroblastic cells in NF express p16 protein, a gene product of [i]CDKN2A[/i] gene and an inhibitor of cyclin-dependent kinase 4 (CDK4) as well as one of the hallmarks of cellular senescence. We immunohistochemically demonstrated strong and diffuse expression of p16 in myofibroblastic cells in 11 out of 15 cases of NF, and strong but partial expression in the remaining 4 of the cases. We also showed that 15 out of 15 cases of NF were immunohistochemically negative or only showed focal and faint immunopositivity for CDK4, murine double minute 2 (MDM2), and [[TP53]] proteins. Furthermore, there were no significant changes in the copy number of [i]CDKN2A, CDK4[/i] and [i]MDM2[/i] genes, and no significant mutations in [i][[TP53]], RB1,[/i] and [i]CDKN2A[/i] genes in 1 case of NF selected. These data suggest a possible involvement in cell cycle arrest and presumed cellular senescence by p16 in myofibroblastic cells in NF. This may explain the self-limited as well as inflammatory nature of NF as a senescence-associated secretory phenotype.

|keywords=* CDK4
* MDM2
* TP53
* nodular fasciitis
* p16
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6945175
}}
==EZH2==

{{medline-entry
|title=Linking gene expression and phenotypic changes in the developmental and evolutionary origins of osteosclerosis in the ribs of bowhead whales (Balaena mysticetus).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32729176
|abstract=Bowhead whales are among the longest-lived mammals with an extreme lifespan of about 211 years. During the first 25 years of their lives, rib bones increase in mineral density and the medulla transitions from compact to trabecular bone. Molecular drivers associated with these phenotypic changes in bone remain unknown. This study assessed expression levels of osteogenic genes from samples of rib bones of bowheads. Samples were harvested from prenatal to 86-year-old whales, representing the first third of the bowhead lifespan. Fetal to 2-year-old bowheads showed expression levels consistent with the rapid deposition of the bone extracellular matrix. Sexually mature animals showed expression levels associated with low rates of osteogenesis and increased osteoclastogenesis. After the first 25 years of life, declines in osteogenesis corresponded with increased expression of [[EZH2]], an epigenetic regulator of osteogenesis. These findings suggest [[EZH2]] may be at least one epigenetic modifier that contributes to the age-related changes in the rib bone phenotype along with the transition from compact to trabecular bone. Ancient cetaceans and their fossil relatives also display these phenotypes, suggesting [[EZH2]] may have shaped the skeleton of whales in evolutionary history.

|keywords=* Cetacea
* aging
* bone
* hyperostosis
* osteoblasts
* whales
|full-text-url=https://sci-hub.do/10.1002/jez.b.22990
}}
{{medline-entry
|title=[[EZH2]] is involved in vulnerability to neuroinflammation and depression-like behaviors induced by chronic stress in different aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32553389
|abstract=Microglial activation and pro-inflammatory cytokines expression is closely related to pathogenesis of depression. Aging is a known risk factor for neuroinflammation in the central nervous system and subsequent behavioral impairment. Enhancer of zeste homolog 2 ([[EZH2]]), a methyltransferase of histone H3 lysine 27 which regulates microglial activation, plays a crucial role in proinflammatory cytokines expression. However, whether the [[EZH2]] is involved in susceptibility to depression in different ages remains elusive. Young and aged C57BL/6 mice were exposed to chronic unpredictable mild stress for three weeks. Depression- and anxiety-like behaviors, spatial memory impairment, and the expression of pro-inflammatory cytokines, P-p65, [[EZH2]], H3K27me3 and SOCS3 in the prefrontal cortex and hippocampus were measured using an established behavioral battery, ELISA, immunohistochemistry and western blotting techniques. Moreover, EPZ-6438, an inhibitor of [[EZH2]], was utilized to detect the role of [[EZH2]] in neuroinflammation and behavioral abnormalities. CUMS induced depression-like behaviors and spatial memory impairment, elevated levels of proinflammatory cytokines and P-p65, enhanced M1 microglia activation, and increased levels of [[EZH2]], H3K27me3 and SOCS3 in the prefrontal cortex and hippocampus in young and aged mice. Both unstressed and stressed aged mice displayed attention-deficit behavioral outcomes, alteration of protein levels compared with young mice. However, inhibition of [[EZH2]] could relieve most of behavioral and molecular alterations. A relative small sample size is a limitation. [[EZH2]] might be involved in susceptibility to neuroinflammation and depression-like behaviors in different aged mice.

|keywords=* Aging
* CUMS
* Cytokines
* Depresion
* EZH2
* Microglia
|full-text-url=https://sci-hub.do/10.1016/j.jad.2020.03.154
}}
{{medline-entry
|title=A positive feedback loop between [[EZH2]] and NOX4 regulates nucleus pulposus cell senescence in age-related intervertebral disc degeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32025238
|abstract=The senescence of nucleus pulposus (NP) cells plays a vital role in the pathogenesis of intervertebral disc (IVD) degeneration (IDD). NADPH oxidase 4 (NOX4)-associated oxidative stress has been shown to induce premature NP cell senescence. Enhancer of zeste homolog 2 ([[EZH2]]) is a crucial gene regulating cell senescence. The aim of this study was to investigate the roles of [[EZH2]] in NOX4-induced NP cell senescence and a feedback loop between [[EZH2]] and NOX4. The down-regulation of [[EZH2]] and the up-regulation of NOX4 and p16 were observed in the degenerative discs of aging rats. [[EZH2]] regulated NP cell senescence via the H3K27me3-p16 pathway. Also, [[EZH2]] regulated the expression of NOX4 in NP cells through the histone H3 lysine 27 trimethylation (H3K27me3) in the promoter of NOX4 gene. Furthermore, NOX4 down-regulated [[EZH2]] expression in NP cells via the canonical Wnt/β-catenin pathway. A positive feedback loop between [[EZH2]] and NOX4 is involved in regulating NP cell senescence, which provides a novel insight into the mechanism of IDD and a potential therapeutic target for IDD.

|keywords=* Epigenetic histone modification
* Intervertebral disc degeneration
* Nucleus pulposus cell senescence
* Wnt/β-catenin signaling pathway
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995653
}}
{{medline-entry
|title=Perinatal exposure to bisphenol A impacts in the mammary gland morphology of adult Mongolian gerbils.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31917966
|abstract=The endocrine disruptive effects caused by bisphenol A (BPA) are well known. Despite this, to date, evaluation of its long term effects is limited, meaning that there is still much to be unveiled in terms of alterations caused by perinatal exposure to BPA. Our aim was to determine if perinatal exposure to two different doses of BPA causes long term morphological and molecular alteration effects in the mammary gland (MG). We evaluated MG from Mongolian gerbil offspring exposed perinatally (during gestation and lactation) to 50 or 5000 μg/kg/day BPA. At 90 days of age the animals were subjected to a single dose of N-nitroso-N-methylurea in order to mimic a carcinogenic environment. At 6 months of age, animals in estrous were euthanized for morphological evaluation of the MGs. The MG architecture presented considerable changes in terms of detached epithelial cells, inflammation, glandular hyperplasia, and collagen fiber deposition. Furthermore, a higher index of epithelial cell proliferation was detected in comparison to the intact control group. In addition, we verified a higher molecular expression of [[EZH2]] in the vehicle treated group, indicating that corn oil applied alone can alter the expression of this epigenetic biomarker. In conclusion, BPA perinatal exposure promotes significant changes in glandular cytoarchitecture and increases glandular epithelium proliferation rate, leading to the retention of stem-like properties. This event could compromise the fate and differentiation potential of mammary epithelium.
|mesh-terms=* Actins
* Aging
* Animals
* Benzhydryl Compounds
* Cell Proliferation
* Collagen
* Enhancer of Zeste Homolog 2 Protein
* Female
* Gerbillinae
* Histones
* Mammary Glands, Animal
* Phenols
* Pregnancy
* Prenatal Exposure Delayed Effects
|keywords=* BPA
* EZH2
* Environment pollutant
* Estrogen
* Morphologic alterations
* Phospho-histone-h3
|full-text-url=https://sci-hub.do/10.1016/j.yexmp.2020.104374
}}
==TET2==

{{medline-entry
|title=Non-coding and Loss-of-Function Coding Variants in [[TET2]] are Associated with Multiple Neurodegenerative Diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32330418
|abstract=We conducted genome sequencing to search for rare variation contributing to early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD). Discovery analysis was conducted on 435 cases and 671 controls of European ancestry. Burden testing for rare variation associated with disease was conducted using filters based on variant rarity (less than one in 10,000 or private), computational prediction of deleteriousness (CADD) (10 or 15 thresholds), and molecular function (protein loss-of-function [LoF] only, coding alteration only, or coding plus non-coding variants in experimentally predicted regulatory regions). Replication analysis was conducted on 16,434 independent cases and 15,587 independent controls. Rare variants in [[TET2]] were enriched in the discovery combined EOAD and FTD cohort (p = 4.6 × 10 , genome-wide corrected p = 0.0026). Most of these variants were canonical LoF or non-coding in predicted regulatory regions. This enrichment replicated across several cohorts of Alzheimer's disease (AD) and FTD (replication only p = 0.0029). The combined analysis odds ratio was 2.3 (95% confidence interval [CI] 1.6-3.4) for AD and FTD. The odds ratio for qualifying non-coding variants considered independently from coding variants was 3.7 (95% CI 1.7-9.4). For LoF variants, the combined odds ratio (for AD, FTD, and amyotrophic lateral sclerosis, which shares clinicopathological overlap with FTD) was 3.1 (95% CI 1.9-5.2). [[TET2]] catalyzes DNA demethylation. Given well-defined changes in DNA methylation that occur during aging, rare variation in [[TET2]] may confer risk for neurodegeneration by altering the homeostasis of key aging-related processes. Additionally, our study emphasizes the relevance of non-coding variation in genetic studies of complex disease.
|mesh-terms=* Aged
* Aged, 80 and over
* Alzheimer Disease
* Animals
* Cognition
* DNA-Binding Proteins
* Female
* Frontotemporal Dementia
* Humans
* Loss of Function Mutation
* Male
* Mice
* Neurodegenerative Diseases
* Proto-Oncogene Proteins
|keywords=* AD
* ALS
* Alzheimer
* FTD
* TET2
* aging
* amyotrophic lateral sclerosis
* frontotemporal dementia
* genome sequencing
* non-coding
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212268
}}
{{medline-entry
|title=60 Years of clonal hematopoiesis research: From X-chromosome inactivation studies to the identification of driver mutations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32001340
|abstract=The history of clonal hematopoiesis (CH) research is punctuated by several seminal discoveries that have forged our understanding of cancer development. The clever application of the principle of random X-chromosome inactivation (XCI) in females led to the development of the first test to identify clonal derivation of cells. Initially limited by a low level of informativeness, the applicability of these assays expanded with differential methylation-based assays at highly polymorphic genes such as the human androgen receptor (HUMARA). Twenty years ago, the observation that skewing of XCI ratios increases as women age was the first clue that led to the identification of mutations in the [[TET2]] gene in hematologically normal aging individuals. In 2014, large-scale genomic approaches of three cohorts allowed definition of CH, which was reported to increase the risk of developing hematologic cancers and cardiovascular diseases. These observations created a fertile field of investigation aimed at investigating the etiology and consequences of CH. The most frequently mutated genes in CH are DNMT3A, [[TET2]], and ASXL1, which have a role in hematopoietic stem cell (HSC) development and self-renewal. These mutations confer a competitive advantage to the CH clones. However, the penetrance of CH is age dependent but incomplete, suggesting the influence of extrinsic factors. Recent data attribute a modest role to genetic predisposition, but several observations point to the impact of a pro-inflammatory milieu that advantages the mutated clones. CH may be a barometer of nonhealthy aging, and interventions devised at curbing its initiation or progression should be a research priority.
|mesh-terms=* Adult
* Aging
* Biomedical Research
* Chromosomes, Human, X
* DNA-Binding Proteins
* Female
* Hematopoiesis
* Hematopoietic Stem Cells
* History, 20th Century
* History, 21st Century
* Humans
* Male
* Mutation
* Proto-Oncogene Proteins
* Receptors, Androgen
* Repressor Proteins
* X Chromosome Inactivation

|full-text-url=https://sci-hub.do/10.1016/j.exphem.2020.01.008
}}
{{medline-entry
|title=DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31842975
|abstract=Aberrations in DNA methylation are widespread in colon cancer (CC). Understanding origin and progression of DNA methylation aberrations is essential to develop effective preventive and therapeutic strategies. Here, we aimed to dissect CC subtype-specific methylation instability to understand underlying mechanisms and functions. We have assessed genome-wide DNA methylation in the healthy normal colon mucosa (HNM), precursor lesions and CCs in a first comprehensive study to delineate epigenetic change along the process of colon carcinogenesis. Mechanistically, we used stable cell lines, genetically engineered mouse model of mutant BRAF  and molecular biology analysis to establish the role of BRAF -mediated-TET inhibition in CpG-island methylator phenotype (CIMP) inititation. We identified two distinct patterns of CpG methylation instability, determined either by age-lifestyle (CC-neutral CpGs) or genetically (CIMP-CpGs). CC-neutral-CpGs showed age-dependent hypermethylation in HNM, all precursors, and CCs, while CIMP-CpGs showed hypermethylation specifically in sessile serrated adenomas/polyps (SSA/Ps) and CIMP-CCs. BRAF -mutated CCs and precursors showed a significant downregulation of TET1 and [[TET2]] DNA demethylases. Stable expression of BRAF  in nonCIMP CC cells and in a genetic mouse model was sufficient to repress TET1/[[TET2]] and initiate hypermethylation at CIMP-CpGs, reversible by BRAF  inhibition. BRAF -driven CIMP-CpG hypermethylation occurred at genes associated with established CC pathways, effecting functional changes otherwise achieved by genetic mutation in carcinogenesis. Hence, while age-lifestyle-driven hypermethylation occurs generally in colon carcinogenesis, BRAF -driven hypermethylation is specific for the "serrated" pathway. This knowledge will advance the use of epigenetic biomarkers to assess subgroup-specific CC risk and disease progression.
|mesh-terms=* Animals
* Caco-2 Cells
* Cell Line, Tumor
* Colonic Neoplasms
* DNA Methylation
* DNA-Binding Proteins
* Down-Regulation
* Epigenesis, Genetic
* Female
* Gene Regulatory Networks
* HT29 Cells
* Humans
* Male
* Mice
* Mixed Function Oxygenases
* Mutation
* Neoplasms, Experimental
* Proto-Oncogene Proteins
* Proto-Oncogene Proteins B-raf
|keywords=* Aging
* BRAF V600E
* CIMP
* Colon cancer
* DNA methylation
* TET
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916434
}}
{{medline-entry
|title=Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31406340
|abstract=Ageing and inflammation strongly drive the risk of cardiovascular disease. Work over the past decade has uncovered a common condition characterized by the positive selection of certain somatic mutations in haematopoietic stem cells in ageing humans. This phenomenon, known as clonal haematopoiesis of indeterminate potential (CHIP), occurs most commonly as a result of mutations in the transcriptional regulators DNMT3A, [[TET2]] and ASXL1. CHIP is associated with a variety of adverse outcomes, including haematological cancer and death. Surprisingly, CHIP is also associated with a doubling of the risk of atherosclerotic cardiovascular disease. Studies in mice support the causality of this relationship. Mutations in [[TET2]], which are among the most commonly found mutations in CHIP, lead to increased expression of inflammatory genes in innate immune cells, potentially explaining the link between mutations and increased cardiovascular risk. Therapies targeting the mutant clones or the increased inflammatory mediators might be useful for ameliorating the risk of cardiovascular disease. We propose that the mutations leading to clonal haematopoiesis contribute to the increased inflammation seen in ageing and thereby explain some of the age-related risk of cardiovascular disease.
|mesh-terms=* Adult
* Age Factors
* Aged
* Aged, 80 and over
* Aging
* Animals
* Cardiovascular Diseases
* DNA (Cytosine-5-)-Methyltransferases
* DNA-Binding Proteins
* Genetic Predisposition to Disease
* Hematopoiesis
* Hematopoietic Stem Cells
* Humans
* Inflammation
* Middle Aged
* Mutation
* Phenotype
* Proto-Oncogene Proteins
* Repressor Proteins
* Risk Assessment
* Risk Factors

|full-text-url=https://sci-hub.do/10.1038/s41569-019-0247-5
}}
==JAK2==

{{medline-entry
|title=Senescence in Monocytes Facilitates Dengue Virus Infection by Increasing Infectivity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32850477
|abstract=Aging and chronic condition increase the incidence of dengue virus (DENV) infection, generally through a mechanism involving immunosenescence; however, the alternative effects of cellular senescence, which alters cell susceptibility to viral infection, remain unknown. Human monocytic THP-1 cells (ATCC TIB-202) treated with D-galactose to induce cellular senescence were susceptible to DENV infection. These senescent cells showed increased viral entry/binding, gene/protein expression, and dsRNA replication. The use of a replicon system showed that pharmacologically induced senescence did not enhance the effects on viral protein translation. By examining viral receptor expression, we found increased expression of CD209 (DC-SIGN) in the senescent cells. Interleukin (IL)-10 was aberrantly produced at high levels by the senescent cells, and the expression of the DENV receptor DC-SIGN was increased in these senescent cells, partially via IL-10-mediated regulation of the [[JAK2]]-STAT3 signaling pathway. The results demonstrate that a senescent phenotype facilitates DENV infection, probably by increasing DC-SIGN expression.

|keywords=* DC-SIGN
* IL-10
* dengue virus
* monocytes
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399640
}}
{{medline-entry
|title=Quercetin Directly Targets [[JAK2]] and PKCδ and Prevents UV-Induced Photoaging in Human Skin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31652815
|abstract=Quercetin is a naturally occurring polyphenol present in various fruits and vegetables. The bioactive properties of quercetin include anti-oxidative, anti-cancer, anti-inflammatory, and anti-diabetic effects. However, the effect of quercetin on skin aging and the direct molecular targets responsible have remained largely unknown. Herein, we investigated the protective effect of quercetin against UV-mediated skin aging and the molecular mechanisms responsible. Treatment with quercetin suppressed UV-induced matrix metalloproteinase-1 (MMP-1) and cyclooxygenase-2 (COX-2) expression and prevented UV-mediated collagen degradation in human skin tissues. Quercetin exerted potent inhibitory effects towards UV-induced activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB) activity. Further examination of the upstream signaling pathways revealed that quercetin can attenuate UV-mediated phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N terminal kinases (JNK), protein kinase B (Akt), and signal transducer and activator of transcription 3 (STAT3). Kinase assays using purified protein demonstrated that quercetin can directly inhibit protein kinase C delta (PKCδ) and Janus kinase 2 ([[JAK2]]) kinase activity. Quercetin was observed to bind to PKCδ and [[JAK2]] in pull-down assays. These findings suggest that quercetin can directly target PKCδ and [[JAK2]] in the skin to elicit protective effects against UV-mediated skin aging and inflammation. Our results highlight the potential use of quercetin as a natural agent for anti-skin aging applications.
|mesh-terms=* Antioxidants
* Cell Line
* Cells, Cultured
* Cyclooxygenase 2
* Humans
* Janus Kinase 2
* MAP Kinase Signaling System
* Matrix Metalloproteinase 1
* NF-kappa B
* Protein Kinase C-delta
* Quercetin
* STAT3 Transcription Factor
* Skin
* Skin Aging
* Transcription Factor AP-1
* Ultraviolet Rays
|keywords=* JAK2
* PKC-delta
* quercetin
* skin aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862686
}}
{{medline-entry
|title=[Red blood cell lifespan detected by endogenous carbon monoxide breath test in patients with polycythemia vera].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31594177
|abstract= To detect the red blood cell lifespan in patients with polycythemia vera (PV), and explore the influencing factors.   From February 2017 to December 2018, 27 patients with PV at Blood Diseases Hospital, Chinese Academy of Medical Science and 18 normal controls were recruited. Red blood cell lifespan was detected by endogenous carbon monoxide (CO) breath test. The related factors were analyzed.   The average red blood cell lifespan of 27 PV patients was 80 (range, 35-120) days (d), which was significantly shorter than that of the normal controls [110.5(69-166) d, [i]P<[/i]0.05], namely 35.3 d shorter. The red blood cell lifespan of ten newly diagnosed patients and 17 patients who were treated with hydroxyurea and/or interferon were 98 (35-117) d and 69 (45-120) d, respectively, which were both shorter than that of the normal control ([i]P=[/i]0.010, 0.000). Correlation analysis showed that red blood cell lifespan of patients with newly diagnosed PV was associated with [[JAK2]] mutation allele burden ([i]r=[/i]0.900, [i]P=[/i]0.037), peripheral blood lymphocyte count ([i]r=[/i]-0.742, [i]P=[/i]0.014) and the level of serum vitamin B(12) ([i]r=[/i]-0.821, [i]P=[/i]0.023).   The lifespan of red blood cells in patients with PV is about one-third shorter than normal, and is related to [[JAK2]] mutation allele burden, absolute lymphocyte count, and serum vitamin B(12) level.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Breath Tests
* Carbon Monoxide
* Case-Control Studies
* Erythrocyte Count
* Erythrocytes
* Female
* Humans
* Janus Kinase 2
* Longevity
* Male
* Middle Aged
* Polycythemia Vera
|keywords=* Carbon monoxide breath test
* Polycythemia vera
* Red blood cell lifespan
|full-text-url=https://sci-hub.do/10.3760/cma.j.issn.0578-1426.2019.10.010
}}
{{medline-entry
|title=Roles of [[JAK2]] in Aging, Inflammation, Hematopoiesis and Malignant Transformation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31398915
|abstract=Clonal alterations in hematopoietic cells occur during aging and are often associated with the establishment of a subclinical inflammatory environment. Several age-related conditions and diseases may be initiated or promoted by these alterations. [[JAK2]] mutations are among the most frequently mutated genes in blood cells during aging. The most common mutation within the [[JAK2]] gene is [[JAK2]]-V617F that leads to constitutive activation of the kinase and thereby aberrant engagement of downstream signaling pathways. [[JAK2]] mutations can act as central drivers of myeloproliferative neoplasia, a pre-leukemic and age-related malignancy. Likewise, hyperactive JAK-signaling is a hallmark of immune diseases and critically influences inflammation, coagulation and thrombosis. In this review we aim to summarize the current knowledge on [[JAK2]] in clonal hematopoiesis during aging, the role of JAK-signaling in inflammation and lymphocyte biology and [[JAK2]] function in age-related diseases and malignant transformation.
|mesh-terms=* Aging
* Animals
* Hematopoiesis
* Humans
* Inflammation
* Janus Kinase 2
* Mice
* Myeloproliferative Disorders
* Neoplasms
|keywords=* JAK2
* Janus-kinase
* aging
* clonal hematopoiesis (CHIP), myeloproliferative neoplasia (MPN)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721738
}}
==CD14==

{{medline-entry
|title=Human innate immune cell crosstalk induces melanoma cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32939325
|abstract=Mononuclear phagocytes and NK cells constitute the first line of innate immune defense. How these cells interact and join forces against cancer is incompletely understood. Here, we observed an early accumulation of slan  (6-sulfo LacNAc) non-classical monocytes (slanMo) in stage I melanoma, which was followed by an increase in NK cell numbers in stage III. Accordingly, culture supernatants of slanMo induced migration of primary human NK cells [i]in vitro[/i] via the chemotactic cytokine IL-8 (CXCL8), suggesting a role for slanMo in NK cell recruitment into cancer tissues. High levels of TNF-α and IFN-γ were produced in co-cultures of TLR-ligand stimulated slanMo and NK cells, whereas much lower levels were contained in cultures of slanMo and NK cells alone. Moreover, TNF-α and IFN-γ concentrations in slanMo/NK cell co-cultures exceeded those in [[CD14]]  monocyte/NK cell and slanMo/T cell co-cultures. Importantly, TNF-α and IFN-γ that was produced in TLR-ligand stimulated slanMo/NK cell co-cultures induced senescence in different melanoma cell lines, as indicated by reduced melanoma cell proliferation, increased senescence-associated β-galactosidase expression, p21 upregulation, and induction of a senescence-associated secretory phenotype (SASP). Taken together, we identified a role for slanMo and NK cells in a collaborative innate immune defense against melanoma by generating a tumor senescence-inducing microenvironment. We conclude that enhancing the synergistic innate immune crosstalk of slanMo and NK cells could improve current immunotherapeutic approaches in melanoma.

|keywords=* NK cell
* cytokines
* melanoma
* senescence
* slanMo
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470184
}}
{{medline-entry
|title=Fusion Potential of Human Osteoclasts In Vitro Reflects Age, Menopause, and In Vivo Bone Resorption Levels of Their Donors-A Possible Involvement of DC-STAMP.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32887359
|abstract=It is well established that multinucleation is central for osteoclastic bone resorption. However, our knowledge on the mechanisms regulating how many nuclei an osteoclast will have is limited. The objective of this study was to investigate donor-related variations in the fusion potential of in vitro-generated osteoclasts. Therefore, [[CD14]]  monocytes were isolated from 49 healthy female donors. Donor demographics were compared to the in vivo bone biomarker levels and their monocytes' ability to differentiate into osteoclasts, showing that: (1) C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (PINP) levels increase with age, (2) the number of nuclei per osteoclast in vitro increases with age, and (3) there is a positive correlation between the number of nuclei per osteoclast in vitro and CTX levels in vivo. Furthermore, the expression levels of the gene encoding dendritic cell-specific transmembrane protein ([i]DCSTAMP[/i]) of osteoclasts in vitro correlated positively with the number of nuclei per osteoclast, CTX levels in vivo, and donor age. Our results furthermore suggest that these changes in gene expression may be mediated through age-related changes in DNA methylation levels. We conclude that both intrinsic factors and age-induced increase in fusion potential of osteoclasts could be contributing factors for the enhanced bone resorption in vivo, possibly caused by increased expression levels of [i]DCSTAMP[/i].

|keywords=* CTX
* DC-STAMP
* DNA methylation
* aging
* cell fusion
* epigenetics
* menopause
* multinucleation
* osteoclast
* osteoclastogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504560
}}
{{medline-entry
|title=Association of [[CD14]] with incident dementia and markers of brain aging and injury.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31818907
|abstract=To test the hypothesis that the inflammatory marker plasma soluble [[CD14]] (s[[CD14]]) associates with incident dementia and related endophenotypes in 2 community-based cohorts. Our samples included the prospective community-based Framingham Heart Study (FHS) and Cardiovascular Health Study (CHS) cohorts. Plasma s[[CD14]] was measured at baseline and related to the incidence of dementia, domains of cognitive function, and MRI-defined brain volumes. Follow-up for dementia occurred over a mean of 10 years (SD 4) in the FHS and a mean of 6 years (SD 3) in the CHS. We studied 1,588 participants from the FHS (mean age 69 ± 6 years, 47% male, 131 incident events) and 3,129 participants from the CHS (mean age 72 ± 5 years, 41% male, 724 incident events) for the risk of incident dementia. Meta-analysis across the 2 cohorts showed that each SD unit increase in s[[CD14]] was associated with a 12% increase in the risk of incident dementia (95% confidence interval 1.03-1.23; [i]p[/i] = 0.01) following adjustments for age, sex, [i]APOE[/i] ε4 status, and vascular risk factors. Higher levels of s[[CD14]] were associated with various cognitive and MRI markers of accelerated brain aging in both cohorts and with a greater progression of brain atrophy and a decline in executive function in the FHS. s[[CD14]] is an inflammatory marker related to brain atrophy, cognitive decline, and incident dementia.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Atrophy
* Biomarkers
* Brain
* Cognitive Dysfunction
* Dementia
* Female
* Humans
* Incidence
* Lipopolysaccharide Receptors
* Longitudinal Studies
* Male
* Middle Aged

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108812
}}
{{medline-entry
|title=Compromised Bone Healing in Aged Rats Is Associated With Impaired M2 Macrophage Function.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31681320
|abstract=Fracture repair is initiated by a multitude of immune cells and induction of an inflammatory cascade. Alterations in the early healing response due to an aged adaptive immune system leads to impaired bone repair, delayed healing or even formation of non-union. However, immuno-senescence is not limited to the adaptive immunity, but is also described for macrophages, main effector cells from the innate immune system. Beside regulation of pro- and anti-inflammatory signaling, macrophages contribute to angiogenesis and granulation tissue maturation. Thus, it seems likely that an altered macrophage function due to aging may affect bone repair at various stages and contribute to age related deficiencies in bone regeneration. To prove this hypothesis, we analyzed the expression of macrophage markers and angiogenic factors in the early bone hematoma derived from young and aged osteotomized Spraque Dawley rats. We detected an overall reduced expression of the monocyte/pan-macrophage markers [[CD14]] and CD68 in aged rats. Furthermore, the analysis revealed an impaired expression of anti-inflammatory M2 macrophage markers in hematoma from aged animals that was connected to a diminished revascularization of the bone callus. To verify that the age related disturbed bone regeneration was due to a compromised macrophage function, [[CD14]]+ macrophage precursors were transplanted locally into the osteotomy gap of aged rats. Transplantation rescued bone regeneration partially after 6 weeks, demonstrated by a significantly induced deposition of new bone tissue, reduced fibrosis and significantly improved callus vascularization.
|mesh-terms=* Age Factors
* Aging
* Animals
* Antigens, CD
* Antigens, Differentiation, Myelomonocytic
* Biomarkers
* Bone Regeneration
* Bone and Bones
* Female
* Fractures, Bone
* Gene Expression
* Lipopolysaccharide Receptors
* Macrophages
* Osteotomy
* Rats, Sprague-Dawley
* Wound Healing
|keywords=* CD14+ cells
* aging
* angiogenesis
* bone regeneration
* compromised healing
* macrophage
* monocyte
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6813416
}}
==SHBG==

{{medline-entry
|title=Endogenous Testosterone Levels and the Risk of Incident Cardiovascular Events in Elderly Men: The MrOS Prospective Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32337470
|abstract=Observational studies show discordant links between endogenous testosterone levels and cardiovascular diseases (CVD). We assessed whether sex hormones and sex hormone-binding globulin ([[SHBG]]) are associated with CVD in community-dwelling elderly men. Prospective study of incident CVD among 552 men ≥ 65 years in the MrOS Sleep Study without prevalent CVD and no testosterone therapy at baseline. Fasting serum levels of total testosterone and estradiol were measured using liquid chromatography-mass spectrometry, and [[SHBG]] by chemiluminescent substrate. The association of sex hormones and [[SHBG]] with incident coronary heart disease (CHD), cerebrovascular (stroke and transient ischemic attack) and peripheral arterial disease (PAD) events were assessed by quartile and per SD increase in proportional hazards models. After 7.4 years, 137 men (24.8%) had at least 1 CVD event: 90 CHD, 45 cerebrovascular and 26 PAD. The risk of incident CVD events was not associated with quartiles of baseline sex hormones or [[SHBG]] (all [i]P[/i] ≥ 0.16). For +1 SD in total testosterone, the multivariate-adjusted hazard ratio was 1.04 (95% CI, 0.80-1.34) for CHD, 0.86 (0.60-1.25) for cerebrovascular, and 0.81 (0.52-1.26) for PAD events. When analyzed as continuous variables or comparing highest to low quartile, levels of bioavailable testosterone, total estradiol, testosterone/estradiol ratio and [[SHBG]] were not associated with CVD events. In community-dwelling elderly men, endogenous levels of testosterone, estradiol, and [[SHBG]] were not associated with increased risk of CHD, cerebrovascular, or PAD events. These results are limited by the small number of events and should be explored in future studies.

|keywords=* aging
* cardiovascular events
* men
* testosterone
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173399
}}
{{medline-entry
|title=Associations of Endogenous Sex Hormones with Carotid Plaque Burden and Characteristics in Midlife Women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31900485
|abstract=Endogenous sex hormones may be involved in the pathogenesis of cardiovascular disease (CVD) in women. Carotid plaque characteristics, such as echogenicity, an ultrasound measure that reflects plaque composition, may identify unstable plaques that are more likely to rupture, precipitating a CVD event. However, few studies have considered sex steroids in relation to carotid plaque and its characteristics. To evaluate estrone (E1), estradiol (E2), testosterone (T), sex hormone binding globulin ([[SHBG]]), and free T (FT) in relation to carotid plaque in women. In MsHeart, a cross-sectional study of 304 women aged 40 to 60 years, participants underwent a carotid artery ultrasound assessment. The current analysis included MsHeart participants with carotid plaque (n = 141, 46%). E1, E2, and T were assayed using liquid chromatography-tandem mass spectrometry; FT was estimated using ensemble allostery models. Regression models were adjusted for sociodemographic characteristics and CVD risk factors. Carotid plaque burden (number of plaques, total plaque area [TPA]) and characteristics (calcification, echogenicity) were determined using semi-automated software. [[SHBG]] was inversely related to TPA (odds ratio [OR] 0.39; 95% confidence interval [CI] 0.21, 0.74; multivariable) and higher FTs were associated with greater TPA (OR 2.89; 95% CI 1.31, 6.37; multivariable). Higher E1 was related to echogenicity (OR 2.31; 95% CI 1.26, 4.33; multivariable), characteristic of more stable plaque. [[SHBG]] and FT are related to TPA while E1 is related to plaque echogenicity, suggesting these hormones have different roles in the development of carotid plaque. Our findings highlight the importance of sex hormones in the development of carotid plaque in midlife women.

|keywords=* aging
* atherosclerosis
* carotid artery
* hormones
* women
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077951
}}
{{medline-entry
|title=Analysis of the Relationship between the Levels of Androgens and Biochemical Bone Markers in Men Aged 60-75 Years.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31877849
|abstract=[i]Introduction[/i]: The purpose of this study was to analyze the relationship between the parameters of bone turnover and the levels of hormonal parameters, such as total testosterone (TT), bioavailable and free testosterone (FT), and estradiol (E2) in men. [i]Material and methods[/i]: The study group included 63 men with testosterone deficiency syndrome (TDS). The control group consisted of 112 patients without TDS. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of osteocalcin (OC), parathyroid hormone (PTH), E2, sex hormone binding globulin ([[SHBG]]), dehydroepiandrosterone sulphate (DHEAS), insulin (I), Serum CrossLaps (CtX-I), human procollagen I N-terminal peptide (PINP), and TT. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. [i]Results[/i]: The groups with TSD and without TDS differed in terms of the following parameters: body weight ([i]p[/i] = 0.001), BMI ([i]p[/i] = 0.003), TT ([i]p[/i] = 0.001), FT ([i]p[/i] = 0.004), bioavailable testosterone ([i]p[/i] = 0.001), E2 ([i]p[/i] = 0.003), [[SHBG]] ([i]p[/i] = 0.003), and PINP ([i]p[/i] = 0.004). In the group without TDS, higher PINP levels were accompanied by higher levels of E2 (beta = 0.360, [i]p[/i] = 0.002) and TT (beta = 0.389, [i]p[/i] = 0.001). In the group without TDS, PINP was positively correlated with E2 (beta = 0.726, [i]p[/i] <0.001). Patients with TDS had significantly lower PINP levels ([i]p[/i] < 0.004). [i]Conclusions[/i]: Analysis of sex hormones and biochemical bone markers in reflecting the quality of the bone tissue in men may suggest a relationship between these parameters. Nevertheless, further research based on a larger sample size is necessary to better describe this relationship.
|mesh-terms=* Absorptiometry, Photon
* Aged
* Aging
* Androgens
* Biomarkers
* Bone Density
* Bone Remodeling
* Bone and Bones
* Collagen Type I
* Dehydroepiandrosterone Sulfate
* Estradiol
* Humans
* Male
* Middle Aged
* Parathyroid Hormone
* Peptide Fragments
* Peptides
* Procollagen
* Sex Hormone-Binding Globulin
* Testosterone
|keywords=* aging men
* biochemical bone markers
* levels of androgens
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6982106
}}
{{medline-entry
|title=Testosterone and Estrone Increase From the Age of 70 Years: Findings From the Sex Hormones in Older Women Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31408149
|abstract=There is a lack of understanding of what is normal in terms of sex steroid levels in older women. To determine whether sex steroid levels vary with age in and establish reference ranges for women >70 years of age. Cross-sectional, community-based study. Included 6392 women ≥70 years of age. Sex steroids measured by liquid chromatography-tandem mass spectrometry. A reference group, to establish sex steroid age-specific reference ranges, excluded women using systemic or topical sex steroid, antiandrogen or glucocorticoid therapy, or an antiglycemic agent. The reference group of 5326 women had a mean age of 75.1 (±4.2) years, range of 70 to 94.7 years. Median values (range) were 181.2 pmol/L (3.7 to 5768.9) for estrone (E1), 0.38 nmol/L (0.035 to 8.56) for testosterone (T), 2.60 nmol/L (0.07 to 46.85) for dehydroepiandrosterone (DHEA), and 41.6 nmol/L (2.4 to 176.6) for [[SHBG]]. Estradiol and DHT were below method sensitivity in 66.1% and 72.7% of the samples, respectively. Compared with women aged 70 to 74 years, women aged ≥85 years had higher median levels of E1 (11.7%, P = 0.01), T (11.3%, P = 0.02), and [[SHBG]] (22.7%, P < 0.001) and lower DHEA (30% less, P < 0.001). Women with overweight and obesity had higher E1 (P < 0.001) and T (P < 0.03) and lower [[SHBG]] (P < 0.001) than did women with normal body mass index. Smokers had 17.2% higher median T levels (P = 0.005). From the age of 70 years, T and E1 increase with age, despite a steady decline in DHEA. Whether E1 and T are biomarkers for longevity or contribute to healthy aging merits investigation.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Biomarkers
* Community-Based Participatory Research
* Cross-Sectional Studies
* Dehydroepiandrosterone
* Estrone
* Female
* Follow-Up Studies
* Humans
* Obesity
* Overweight
* Prognosis
* Testosterone

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830527
}}
==TST==

{{medline-entry
|title=H S Donors Reverse Age-Related Gastric Malfunction Impaired Due to Fructose-Induced Injury [i]via[/i] CBS, CSE, and [[TST]] Expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32848752
|abstract=Excess of fructose consumption is related to life-treating conditions that affected more than a third of the global population. Therefore, to identify a newer therapeutic strategy for the impact prevention of high fructose injury in age-related malfunctions of the gastric mucosa (GM) in the animal model is important. Adult and aged male rats were divided into control groups (standard diet, SD) and high fructose diet (HFD) groups; acute water immersion restraint stress (WIRS) was induced for evaluation of GM adaptive response and effects of testing the therapeutic potential of H S-releasing compounds (H S donors). Histological examination of gastric damage was done on hematoxylin-eosin stained slides. Cystathionine beta-synthase (CBS), Cystathionine gamma-lyase (CSE), and Thiosulfate-dithiol sulfurtransferase ([[TST]]) activities and oxidative index were assessed during exogenous administration of H S donors: sodium hydrosulfide (NaHS) and the novel hybrid H S-releasing aspirin (ATB-340). The results showed that HFD increased gastric damage in adult and aged rats. HFD-associated malfunction characterized by low activities of H S key enzymes, inducing increased oxidation. Pretreatment with NaHS, ATB-340 of aged rats in the models of HFD, and WIRS attenuated gastric damage in contrast to vehicle-treated group (p < 0.05). The effect of ATB-340 was characterized by reverse oxidative index and increased CBS, CSE, and [[TST]] activities. In conclusion, H S donors prevent GM age-related malfunctions by enhancement of CBS, CSE, and [[TST]] expression against fructose excess injury though reduction of oxidative damage.

|keywords=* aging
* donor
* fructose
* gastric mucosa
* hydrogen sulfide
* oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396573
}}
{{medline-entry
|title=Adaptations in mechanical muscle function, muscle morphology, and aerobic power to high-intensity endurance training combined with either traditional or power strength training in older adults: a randomized clinical trial.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32239311
|abstract=There is a lack of information on the effects of power training (PT) as an alternative to traditional strength training ([[TST]]) during concurrent training (CT) in older individuals. This study aimed to verify the neuromuscular adaptations that occurred following 16-week interventions with two CT models in older men: high-intensity interval training (HIIT) combined with either [[TST]] or PT. Thirty-five older men (65.8 ± 3.9 years) were randomly assigned into one of two training groups CTS: [[TST]] + HIIT (n = 18) or CTP: PT + HIIT (n = 17). CTS performed resistance training at intensities ranging from 65 to 80% of 1 RM at slow controlled speed, whereas CTP trained at intensities ranging from 40 to 60% of 1 RM at maximal intentional speed. Lower body one-repetition maximum (1 RM), isometric rate of force development (RFD), countermovement jump (CMJ) muscle power output, quadriceps femoris muscles thickness (QF MT), and peak oxygen uptake (VO ) were assessed before training and after 8 and 16 weeks of CT. Groups improved similarly in all primary outcomes (P < 0.05), with mean increases ranging: 1 RM (from 39.4 to 75.8%); RFD (from 9.9 to 64.8%); and CMJ muscle power (from 1.8 to 5.2%). Significant increases (P < 0.05) were observed in all secondary outcomes (QF MT, specific tension and VO ) with no differences between groups. CT models were effective for improving maximal and explosive force (1 RM, RFD, and CMJ power), QF MT, and VO . Moreover, despite that using lower loading intensities, PT induced similar adaptations to those of [[TST]].

|keywords=* Aging
* Concurrent training
* Explosive force
* Functional capacity
* HIIT
|full-text-url=https://sci-hub.do/10.1007/s00421-020-04355-z
}}
{{medline-entry
|title=Digital phenotyping by consumer wearables identifies sleep-associated markers of cardiovascular disease risk and biological aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31602410
|abstract=Sleep is associated with various health outcomes. Despite their growing adoption, the potential for consumer wearables to contribute sleep metrics to sleep-related biomedical research remains largely uncharacterized. Here we analyzed sleep tracking data, along with questionnaire responses and multi-modal phenotypic data generated from 482 normal volunteers. First, we compared wearable-derived and self-reported sleep metrics, particularly total sleep time ([[TST]]) and sleep efficiency (SE). We then identified demographic, socioeconomic and lifestyle factors associated with wearable-derived [[TST]]; they included age, gender, occupation and alcohol consumption. Multi-modal phenotypic data analysis showed that wearable-derived [[TST]] and SE were associated with cardiovascular disease risk markers such as body mass index and waist circumference, whereas self-reported measures were not. Using wearable-derived [[TST]], we showed that insufficient sleep was associated with premature telomere attrition. Our study highlights the potential for sleep metrics from consumer wearables to provide novel insights into data generated from population cohort studies.
|mesh-terms=* Adult
* Aged
* Aging
* Body Mass Index
* Cardiovascular Diseases
* Cohort Studies
* Female
* Humans
* Male
* Middle Aged
* Risk Factors
* Self Report
* Sleep
* Telomere
* Waist Circumference
* Wearable Electronic Devices
* Young Adult
|keywords=* Data integration
* Predictive markers
* Risk factors
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778117
}}
{{medline-entry
|title=Objective Sleep Duration in Older Adults: Results From The Irish Longitudinal Study on Ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31579942
|abstract=This study assessed the distribution and correlates of objective sleep duration in the older population in Ireland. Cross-sectional study using population-derived data from wave 3 of The Irish Longitudinal Study on Ageing. Community-dwelling adults. Adults, aged 50 years and older, who wore an accelerometer for at least 4 days (N = 1533). Sleep was measured for at least 4 days in 1533 participants using a GENEActiv wrist-worn accelerometer device. Sleep parameters included total sleep time ([[TST]]) and self-reported sleep problems. [[TST]] was categorized as short and long sleep duration using US National Sleep Foundation guidelines. Linear and multinomial logistic regression models assessed sociodemographic, health, and behavioral correlates of sleep duration. Mean [[TST]] for the sample was 463 minutes (SD = 72.6 minutes). Of participants, 13.9% and 16.5% measured short and long sleep duration, respectively. [[TST]] decreased as sleep problems increased, as did durations recorded in summer compared to winter recordings. Advancing age was associated with longer sleep, as was antidepressant use. Retired/unemployed participants recorded longer [[TST]] and were more likely to record long sleep compared to employed participants. Fair/poor self-rated health and separated/divorced participants were more likely to record short sleep. Those reporting moderate or high physical activity were less likely to record short or long sleep, respectively, compared to those reporting low physical activity. Participants reporting a limiting disability were less likely to record long sleep. Average [[TST]] was within recommended guidelines; however, a significant subset of older adults recorded sleep duration outside of the guidelines. Independent demographic and health correlates of suboptimal sleep were identified, many of which are modifiable. Patients and clinicians should be aware of factors potentially influencing sleep patterns. Longitudinal analyses to confirm directionality of relationships with potential risk factors are warranted. J Am Geriatr Soc 68:120-128, 2019.
|mesh-terms=* Accelerometry
* Aged
* Aging
* Cross-Sectional Studies
* Exercise
* Female
* Health Status
* Humans
* Independent Living
* Ireland
* Longitudinal Studies
* Male
* Polysomnography
* Self Report
* Sleep
* Time Factors
|keywords=* GENEActiv
* accelerometer
* actigraphy
* older population
* sleep duration
|full-text-url=https://sci-hub.do/10.1111/jgs.16177
}}
==MIP==

{{medline-entry
|title=Inspiratory muscle training improves cerebrovascular and postural control responses during orthostatic stress in older women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32705393
|abstract=We aimed to investigate the effect of inspiratory muscle training (IMT) on, hemodynamic, cerebrovascular and postural balance responses during orthostatic stress, in older women. Fourteen elderly women were assigned to perform IMT at 50% of maximal inspiratory pressure ([[MIP]]) (IMT group, n = 8) or placebo training at 5% [[MIP]] (Sham group, n = 6), in a counter-balanced order, using an inspiratory threshold device for 4 weeks. During the protocol, [[MIP]] was tested weekly once. In a second visit, blood pressure, heart rate, stroke volume, cardiac output, middle cerebral artery blood flow velocity (MCAv), and ventilation parameters were recorded continuously at rest and during orthostatic stress testing, which was conducted on a force plate to measure center-of-pressure (COP) oscillations (postural balance) and the electromyographic activity of the right medial gastrocnemius and tibialis anterior. IMT increased [[MIP]] from second to 4th week. The drops in MCAv, stroke volume, and cardiac output, as well as COP displacements during initial orthostasis decreased post-IMT. IMT improves the interplay of the respiratory pump, hemodynamic, cerebrovascular and postural balance responses during orthostatic stress in older women.

|keywords=* Aging
* Cardiac output
* Center-of-pressure
* Middle cerebral artery blood flow velocity
* Respiratory muscles
|full-text-url=https://sci-hub.do/10.1007/s00421-020-04441-2
}}
{{medline-entry
|title=A novel multi-marker discovery approach identifies new serum biomarkers for Parkinson's disease in older people: an EXosomes in PArkiNson Disease (EXPAND) ancillary study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32458283
|abstract=Dopaminergic nigrostriatal denervation and widespread intracellular α-synuclein accumulation are neuropathologic hallmarks of Parkinson's disease (PD). A constellation of peripheral processes, including metabolic and inflammatory changes, are thought to contribute to neurodegeneration. In the present study, we sought to obtain insight into the multifaceted pathophysiology of PD through the application of a multi-marker discovery approach. Fifty older adults aged 70+, 20 with PD and 30 age-matched controls were enrolled as part of the EXosomes in PArkiNson Disease (EXPAND) study. A panel of 68 circulating mediators of inflammation, neurogenesis and neural plasticity, and amino acid metabolism was assayed. Biomarker selection was accomplished through sequential and orthogonalized covariance selection (SO-CovSel), a multi-platform regression method developed to handle highly correlated variables organized in multi-block datasets. The SO-CovSel model with the best prediction ability using the smallest number of variables was built with seven biomolecules. The model allowed correct classification of 94.2 ± 3.1% participants with PD and 100% controls. The biomarker profile of older adults with PD was defined by higher circulating levels of interleukin (IL) 8, macrophage inflammatory protein ([[MIP]])-1β, phosphoethanolamine, and proline, and by lower concentrations of citrulline, IL9, and [[MIP]]-1α. Our innovative approach allowed identifying and evaluating the classification performance of a set of potential biomarkers for PD in older adults. Future studies are warranted to establish whether these biomolecules could serve as biomarkers for PD as well as unveil new targets for interventions.

|keywords=* Aging
* Amino acids
* Cytokines
* Metabolomics
* Neurodegeneration
* Personalized medicine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525911
}}
{{medline-entry
|title=Sexual dimorphism of physical activity on cognitive aging: Role of immune functioning.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32387511
|abstract=Exercise is one of the most potent strategies available to support cognitive health with age, yet substantial variability exists. Sexual dimorphism is evident for brain and immune functioning, the latter being implicated as important pathway for exercise. We examined the moderating role of sex on the relationship between physical activity and systemic inflammatory and brain health outcomes in support of more personalized approaches to behavioral interventions. Our discovery cohort included 45 typically aging women matched on age (±5y) and education (±2y) to 45 men (mean age = 72.5; Clinical Dementia Rating = 0) who completed self-reported current physical activity (Physical Activity Scale for Elderly), blood draw, neuropsychological evaluation, and brain MRI. An independent sample of 45 typically aging women and 36 men who completed the same measures comprised a replication cohort. Plasma was analyzed for 11 proinflammatory cytokine and chemokine markers via MesoScale Discovery. Discovery cohort: Reported physical activity did not differ between sexes (150 vs. 157, p = 0.72). There was a significant interaction between sex and physical activity on chemokine markers MDC, [[MIP]]-1b, MCP-4, and eotaxin-3 (ps < 0.03), with a similar trend for MCP-1 and INFγ (ps < 0.09). Men who reported greater activity demonstrated lower inflammatory markers, an effect attenuated-to-absent in women. An interaction between sex and physical activity was also observed for parahippocampal volumes (p = 0.02) and cognition (processing speed and visual memory; ps < 0.04). Again, the beneficial effect of physical activity on outcomes was present in men, but not women. Replication cohort analyses conferred a consistent effect of sex on the relationship between physical activity and immune markers; models examining neurobehavioral outcomes did not strongly replicate. Across cohorts, post-hoc models demonstrated an interaction between sex and activity-related inflammatory markers on total gray matter volume and visual memory. Men with higher inflammatory markers demonstrated poorer brain structure and function, whereas inflammatory markers did not strongly relate to neurobehavioral outcomes in women. Greater physical activity was associated with lower markers of inflammation in clinically normal older men, but not women - an effect consistently replicated across cohorts. Additionally, men appeared disproportionately vulnerable to the adverse effects of peripheral inflammatory markers on brain structure and function compared to women. Immune activation may be a male-specific pathway through which exercise confers neurobehavioral benefit.

|keywords=* Brain aging
* Chemokines
* Cognitive aging
* Exercise
* Gender
* Inflammation
* Lifestyle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416443
}}
{{medline-entry
|title=Comparison of balance changes after inspiratory muscle or Otago exercise training.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31978126
|abstract=The inspiratory muscles contribute to balance via diaphragmatic contraction and by increasing intra-abdominal pressure. We have shown inspiratory muscle training (IMT) improves dynamic balance significantly with healthy community-dwellers. However, it is not known how the magnitude of balance improvements following IMT compares to that of an established balance program. This study compared the effects of 8-week of IMT for community-dwellers, to 8-week of the Otago exercise program (OEP) for care-residents, on balance and physical performance outcomes. Nineteen healthy community-dwellers (74 ± 4 years) were assigned to self-administered IMT. Eighteen, healthy care-residents (82 ± 4 years) were assigned to instructor-led OEP. The IMT involved 30 breaths twice-daily at ~50% of maximal inspiratory pressure ([[MIP]]). The OEP group undertook resistance and mobility exercises for ~60 minutes, twice-weekly. Balance and physical performance were assessed using the mini Balance Evaluation System Test (mini-BEST) and time up and go (TUG). After 8-week, both groups improved balance ability significantly (mini-BEST: IMT by 24 ± 34%; OEP by 34 ± 28%), with no between-group difference. Dynamic balance sub-tasks improved significantly more for the IMT group (P < 0.01), than the OEP group and vice versa for static balance sub-tasks (P = 0.01). The IMT group also improved [[MIP]] (by 66 ± 97%), peak inspiratory power (by 31 ± 12%) and TUG (by -11 ± 27%); whereas the OEP did not. IMT and OEP improved balance ability similarly, with IMT eliciting greater improvement in dynamic balance, whilst OEP improved static balance more than IMT. Unlike IMT, the OEP did not provide additional benefits in inspiratory muscle function and TUG performance. Our findings suggest that IMT offers a novel method of improving dynamic balance in older adults, which may be more relevant to function than static balance and potentially a useful adjunct to the OEP in frailty prevention.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Breathing Exercises
* Exercise
* Exercise Therapy
* Female
* Humans
* Male
* Maximal Respiratory Pressures
* Muscle Strength
* Physical Endurance
* Postural Balance
* Respiratory Muscles
* Respiratory Therapy

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6980667
}}
==ATF6==

{{medline-entry
|title=Cellular proteostasis decline in human senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33257563
|abstract=Proteostasis collapse, the diminished ability to maintain protein homeostasis, has been established as a hallmark of nematode aging. However, whether proteostasis collapse occurs in humans has remained unclear. Here, we demonstrate that proteostasis decline is intrinsic to human senescence. Using transcriptome-wide characterization of gene expression, splicing, and translation, we found a significant deterioration in the transcriptional activation of the heat shock response in stressed senescent cells. Furthermore, phosphorylated HSF1 nuclear localization and distribution were impaired in senescence. Interestingly, alternative splicing regulation was also dampened. Surprisingly, we found a decoupling between different unfolded protein response (UPR) branches in stressed senescent cells. While young cells initiated UPR-related translational and transcriptional regulatory responses, senescent cells showed enhanced translational regulation and endoplasmic reticulum (ER) stress sensing; however, they were unable to trigger UPR-related transcriptional responses. This was accompanied by diminished [[ATF6]] nuclear localization in stressed senescent cells. Finally, we found that proteasome function was impaired following heat stress in senescent cells, and did not recover upon return to normal temperature. Together, our data unraveled a deterioration in the ability to mount dynamic stress transcriptional programs upon human senescence with broad implications on proteostasis control and connected proteostasis decline to human aging.

|keywords=* UPR
* chaperones
* heat shock response
* protein homeostasis
* senescence
|full-text-url=https://sci-hub.do/10.1073/pnas.2018138117
}}
{{medline-entry
|title=Impact of endoplasmic reticulum stress on oocyte aging mechanisms.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32514562
|abstract=Endoplasmic reticulum (ER) stress is associated with several aging-related diseases; however, the mechanism underlying age-related deterioration of oocyte quality is unclear. Here, we used post-ovulatory, in vivo aged mouse oocytes as a model. Super-ovulated oocytes harvested from the oviduct at 14 h and 20 h post-hCG injection were designated as 'fresh' and 'aged', respectively. Embryo development following IVF was compared between fresh, aged and ER stress-induced oocytes. Expression of the ER stress marker GRP78 was examined at each stage. To evaluate the effect of salubrinal, an ER stress suppressor, on embryo development following IVF, expression levels of GRP78 and phospho-eukaryotic initiation factor 2 alpha were compared between aged and salubrinal-treated aged oocytes. Embryo transfer of salubrinal-treated aged oocytes was performed to examine the safety of salubrinal. Similar to aged oocytes, ER stress-induced oocytes showed lower fertilization rates and poor embryo development. Following IVF, expression of GRP78 decreased with embryo development. GRP78 expression was significantly higher in aged oocytes than in fresh oocytes. Salubrinal lowered GRP78 levels and improved embryo development. No adverse effect of salubrinal treatment was found on the birth weight of pups or on organogenesis in mice. The limitation of this study was that protein kinase-like ER kinase was the only ER stress pathway examined; the role of IRE1 and [[ATF6]] pathways was not considered. Nevertheless, salubrinal can significantly improve embryo development in in vivo aged oocytes undergoing ER stress. Hence, regulation of ER stress might represent a promising therapeutic strategy to overcome poor oocyte quality.

|keywords=* ER stress
* GRP78
* PERK
* eIF2α
* endoplasmic reticulum
* mouse oocyte
* oocyte aging
* salubrinal
|full-text-url=https://sci-hub.do/10.1093/molehr/gaaa040
}}
{{medline-entry
|title=ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32279085
|abstract=The endoplasmic reticulum (ER) contains stress sensors which recognize the accumulation of unfolded proteins within the lumen of ER, and subsequently these transducers stimulate the unfolded protein response (UPR). The ER sensors include the IRE1, PERK, and [[ATF6]] transducers which activate the UPR in an attempt to restore the quality of protein folding and thus maintain cellular homeostasis. If there is excessive stress, UPR signaling generates alarmins, e.g., chemokines and cytokines, which activate not only tissue-resident immune cells but also recruit myeloid and lymphoid cells into the affected tissues. ER stress is a crucial inducer of inflammation in many pathological conditions. A chronic low-grade inflammation and cellular senescence have been associated with the aging process and many age-related diseases, such as Alzheimer's disease. Currently, it is known that immune cells can exhibit great plasticity, i.e., they are able to display both pro-inflammatory and anti-inflammatory phenotypes in a context-dependent manner. The microenvironment encountered in chronic inflammatory conditions triggers a compensatory immunosuppression which defends tissues from excessive inflammation. Recent studies have revealed that chronic ER stress augments the suppressive phenotypes of immune cells, e.g., in tumors and other inflammatory disorders. The activation of immunosuppressive network, including myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), has been involved in the aging process and Alzheimer's disease. We will examine in detail whether the ER stress-related changes found in aging tissues and Alzheimer's disease are associated with the activation of immunosuppressive network, as has been observed in tumors and many chronic inflammatory diseases.

|keywords=* Ageing
* Immunometabolism
* Immunosenescence
* Immunosuppression
* Inflammaging
* Neurodegeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220864
}}
{{medline-entry
|title=Towards Age-Related Anti-Inflammatory Therapy: Klotho Suppresses Activation of ER and Golgi Stress Response in Senescent Monocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31972978
|abstract=Immunosenescence in monocytes has been shown to be associated with several biochemical and functional changes, including development of senescence-associated secretory phenotype (SASP), which may be inhibited by klotho protein. To date, it was believed that SASP activation is associated with accumulating DNA damage. However, some literature data suggest that endoplasmic reticulum and Golgi stress pathways may be involved in SASP development. Thus, the aim of this study was to investigate the role of klotho protein in the regulation of immunosenescence-associated Golgi apparatus and ER stress response induced by bacterial antigens in monocytes. We provide evidence that initiation of immunosenescent-like phenotype in monocytes is accompanied by activation of CREB34L and TFE3 Golgi stress response and [[ATF6]] and IRE1 endoplasmic reticulum stress response, while klotho overexpression prevents these changes. Further, these changes are followed by upregulated secretion of proinflammatory cytokines, which final modification takes place exclusively in the Golgi apparatus. In conclusion, we provide for the first time evidence of klotho involvement in the crosstalk on the line ER-Golgi, which may, in turn, affect activation of SASP. This data may be useful for a novel potential target for therapy in age-related and chronic inflammatory conditions.

|keywords=* ER stress response
* Golgi apparatus/complex stress response
* SASP
* immunosenescence
* klotho
* monocytes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072557
}}
==S100A9==

{{medline-entry
|title=Cigarette smoke induction of [[S100A9]] contributes to chronic obstructive pulmonary disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32964723
|abstract=S100 calcium-binding protein A9 ([[S100A9]]), is elevated in plasma and bronchoalveolar lavage fluid (BALF) of COPD patients and aging enhances [[S100A9]] expression in several tissues. Currently, the direct impact of [[S100A9]]-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated [[S100A9]] levels in human BALF correlated with age. Elevated lung levels of [[S100A9]] were higher in older mice compared to young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced [[S100A9]] levels in age-matched mice. To examine the direct role of [[S100A9]] on the development of COPD, S100a9  mice or inhibited activity with paquinimod, and exposed the models to chronic cigarette smoke [[S100A9]] depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and FEV /FVC, compared to age-matched wild type or vehicle administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK, and c-RAF phosphorylation, MMP-3, MMP-9, MCP-1, IL-6, and KC release into the airways. Paquinimod administered to non-smoked aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor, LY3214996, or the c-RAF inhibitor, GW5074, resulting in less [[S100A9]]-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing TLR4, RAGE or EMMPRIN prevented [[S100A9]]-induced phosphorylation of ERK and c-RAF. Our data suggest that [[S100A9]] signaling contributes to the progression of smoke and age-related COPD.

|keywords=* Cigarette smoke
* S100A9
* aging
* kinase
* pulmonary function
|full-text-url=https://sci-hub.do/10.1152/ajplung.00207.2020
}}
{{medline-entry
|title=Modulation of KDM1A with vafidemstat rescues memory deficit and behavioral alterations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32469975
|abstract=Transcription disequilibria are characteristic of many neurodegenerative diseases. The activity-evoked transcription of immediate early genes (IEGs), important for neuronal plasticity, memory and behavior, is altered in CNS diseases and governed by epigenetic modulation. KDM1A, a histone 3 lysine 4 demethylase that forms part of transcription regulation complexes, has been implicated in the control of IEG transcription. Here we report the development of vafidemstat (ORY-2001), a brain penetrant inhibitor of KDM1A and MAOB. ORY-2001 efficiently inhibits brain KDM1A at doses suitable for long term treatment, and corrects memory deficit as assessed in the novel object recognition testing in the Senescence Accelerated Mouse Prone 8 (SAMP8) model for accelerated aging and Alzheimer's disease. Comparison with a selective KDM1A or MAOB inhibitor reveals that KDM1A inhibition is key for efficacy. ORY-2001 further corrects behavior alterations including aggression and social interaction deficits in SAMP8 mice and social avoidance in the rat rearing isolation model. ORY-2001 increases the responsiveness of IEGs, induces genes required for cognitive function and reduces a neuroinflammatory signature in SAMP8 mice. Multiple genes modulated by ORY-2001 are differentially expressed in Late Onset Alzheimer's Disease. Most strikingly, the amplifier of inflammation [[S100A9]] is highly expressed in LOAD and in the hippocampus of SAMP8 mice, and down-regulated by ORY-2001. ORY-2001 is currently in multiple Phase IIa studies.
|mesh-terms=* Aging
* Alzheimer Disease
* Animals
* Behavior, Animal
* Brain
* Disease Models, Animal
* Enzyme Inhibitors
* Epigenesis, Genetic
* Female
* Gene Expression
* Hippocampus
* Histone Demethylases
* Humans
* Male
* Memory Disorders
* Mice
* Mice, Inbred C57BL
* Mice, Mutant Strains
* Monoamine Oxidase Inhibitors
* Oxadiazoles
* Rats
* Rats, Sprague-Dawley

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259601
}}
{{medline-entry
|title=Cellular senescence induced by [[S100A9]] in mesenchymal stromal cells through NLRP3 inflammasome activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31727865
|abstract=Bone marrow stromal cells from patients with myelodysplastic syndrome (MDS) display a senescence phenotype, but the underlying mechanism has not been elucidated. Pro-inflammatory signaling within the malignant clone and the bone marrow microenvironment has been identified as a key pathogenetic driver of MDS. Our study revealed that [[S100A9]] is highly-expressed in lower-risk MDS. Moreover, normal primary mesenchymal stromal cells (MSCs) and the human stromal cell line HS-27a co-cultured with lower-risk MDS bone marrow mononuclear cells acquired a senescence phenotype. Exogenous supplemented [[S100A9]] also induced cellular senescence in MSCs and HS-27a cells. Importantly, Toll-like receptor 4 (TLR4) inhibition or knockdown attenuated the cellular senescence induced by [[S100A9]]. Furthermore, we showed that [[S100A9]] induces NLRP3 inflammasome formation, and IL-1β secretion; findings in samples from MDS patients further confirmed these thoughts. Moreover, ROS and IL-1β inhibition suppressed the cellular senescence induced by [[S100A9]], whereas NLRP3 overexpression and exogenous IL-1β supplementation induces cellular senescence. Our study demonstrated that [[S100A9]] promotes cellular senescence of bone marrow stromal cells via TLR4, NLRP3 inflammasome formation, and IL-1β secretion for its effects. Our findings deepen the understanding of the molecular mechanisms involved in MDS reprogramming of MSCs and indicated the essential role of [[S100A9]] in tumor-environment interactions in bone marrow.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Calgranulin B
* Case-Control Studies
* Cell Line
* Cells, Cultured
* Cellular Reprogramming
* Cellular Senescence
* Female
* Humans
* Inflammasomes
* Interleukin-1beta
* Male
* Mesenchymal Stem Cells
* Middle Aged
* Myelodysplastic Syndromes
* NLR Family, Pyrin Domain-Containing 3 Protein
* Reactive Oxygen Species
* Signal Transduction
* Stem Cell Niche
* Toll-Like Receptor 4
* Up-Regulation
* Young Adult
|keywords=* NLRP3
* S100A9
* cellular senescence
* mesenchymal stromal cells
* myelodysplastic syndromes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6874461
}}
{{medline-entry
|title=[[S100A9]] extends lifespan in insulin deficiency.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31391467
|abstract=Tens of millions suffer from insulin deficiency (ID); a defect leading to severe metabolic imbalance and death. The only means for management of ID is insulin therapy; yet, this approach is sub-optimal and causes life-threatening hypoglycemia. Hence, ID represents a great medical and societal challenge. Here we report that [[S100A9]], also known as Calgranulin B or Myeloid-Related Protein 14 (MRP14), is a leptin-induced circulating cue exerting beneficial anti-diabetic action. In murine models of ID, enhanced expression of [[S100A9]] alone (i.e. without administered insulin and/or leptin) slightly improves hyperglycemia, and normalizes key metabolic defects (e.g. hyperketonemia, hypertriglyceridemia, and increased hepatic fatty acid oxidation; FAO), and extends lifespan by at least a factor of two. Mechanistically, we report that Toll-Like Receptor 4 (TLR4) is required, at least in part, for the metabolic-improving and pro-survival effects of [[S100A9]]. Thus, our data identify the [[S100A9]]/TLR4 axis as a putative target for ID care.
|mesh-terms=* Animals
* Calgranulin B
* Diabetes Mellitus, Experimental
* Diphtheria Toxin
* Fatty Acids
* Humans
* Hyperglycemia
* Insulin
* Leptin
* Liver
* Longevity
* Male
* Mice
* Mice, Knockout
* Oxidation-Reduction
* Signal Transduction
* Streptozocin
* Toll-Like Receptor 4

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686003
}}
==TXNIP==

{{medline-entry
|title=Panax notoginseng saponins attenuate neuroinflammation through [[TXNIP]]-mediated NLRP3 inflammasome activation in aging rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33176641
|abstract=Microglia-mediated inflammatory responses play a crucial role in aging-related neurodegenerative diseases. The [[TXNIP]]/NLRP3 pathway is a key pathway leading to microglial activation. Panax notoginseng saponins (PNS) have been widely used for the treatment of stroke in China. This study evaluates the anti-neuroinflammatory effect of PNS and investigates the mechanism via [[TXNIP]]mediated NLRP3 inflammasome activation in aging rats. Eighteen-month-old Sprague-Dawley rats were randomly divided into the aging control group and PNS treated groups (n=15 each group). For PNS-treated groups, rats were administrated food with PNS at the doses of 10 mg/kg and 30 mg/kg for consecutive 6 months until they were 24-month old. Rats from the aging control group were given the same food without PNS. Two-month-old rats were purchased and given the same food until 6-month old as the adult control group (n = 15). Then, the cortex and hippocampus were rapidly harvested and deposited. H&E staining was used to assess histo-morphological changes. Western blotting was carried out to detect the protein expression. Immunofluorescence was employed to measure the co-localization of NLRP3, [[TXNIP]] and Iba-1. In vitro model was established by LPS+ATP coincubation in the BV2 microglia cell line. Aging rats exhibited increased activation of microglia, accompanied by a high level of IL-1β expression. Meanwhile, aging rats showed enhanced protein expression of [[TXNIP]] and NLRP3 related molecules, which co-localized with microglia. PNS treatment effectively reduced the number of degenerated neurons and reversed the activation of the [[TXNIP]]/NLRP3 inflammatory pathway. In vitro results showed that PNS up to 100 μg / ml had no significant toxicity on BV2 microglia. PNS (25, 50 μg/ml) effectively reduced the inflammatory response induced by LPS and ATP co-stimulation, thus inhibiting the expression of [[TXNIP]]/NLRP3 pathway-related proteins. PNS treatment improved aging-related neuronal damage through inhibiting [[TXNIP]] mediated NLRP3 inflammasome activation, which provided a potential target for the treatment of inflammatory-related neurodegenerative diseases.

|keywords=* Aging
* Microglia
* NLRP3 inflammasome
* Saponins from Panax notoginseng.
* TXNIP
* neuroinflammation
|full-text-url=https://sci-hub.do/10.2174/1389201021999201110204735
}}
{{medline-entry
|title=Redox homeostasis and cell cycle activation mediate beta-cell mass expansion in aged, diabetes-prone mice under metabolic stress conditions: Role of thioredoxin-interacting protein ([[TXNIP]]).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33128997
|abstract=Overnutrition contributes to insulin resistance, obesity and metabolic stress, initiating a loss of functional beta-cells and diabetes development. Whether these damaging effects are amplified in advanced age is barely investigated. Therefore, New Zealand Obese (NZO) mice, a well-established model for the investigation of human obesity-associated type 2 diabetes, were fed a metabolically challenging diet with a high-fat, carbohydrate restricted period followed by a carbohydrate intervention in young as well as advanced age. Interestingly, while young NZO mice developed massive hyperglycemia in response to carbohydrate feeding, leading to beta-cell dysfunction and cell death, aged counterparts compensated the increased insulin demand by persistent beta-cell function and beta-cell mass expansion. Beta-cell loss in young NZO islets was linked to increased expression of thioredoxin-interacting protein ([[TXNIP]]), presumably initiating an apoptosis-signaling cascade via caspase-3 activation. In contrast, islets of aged NZOs exhibited a sustained redox balance without changes in [[TXNIP]] expression, associated with higher proliferative potential by cell cycle activation. These findings support the relevance of a maintained proliferative potential and redox homeostasis for preserving islet functionality under metabolic stress, with the peculiarity that this adaptive response emerged with advanced age in diabetes-prone NZO mice.

|keywords=* Aging
* Beta-cells
* Cell cycle
* Metabolic stress
* Redox homeostasis
* Thioredoxin-interacting protein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589534
}}
{{medline-entry
|title=[Effect of diabetic induced thioredoxin interacting protein ([[TXNIP]]) on islet cell senescence].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32744003
|abstract= To investigate whether the increased expression of thioredoxin interacting protein ([[TXNIP]]) in diabetes affects the senescence of islet β cells.   Six normal mice (db/m) and six diabetic mice (db/db) were randomly selected. Fasting blood glucose was measured by blood sugar meter, the expression levels of [[TXNIP]] protein, p16, p21 and Rb in pancreatic tissues were detected by Western blot, senescence-associated beta-galactosidase activity in pancreatic tissue was determined by immunochemical staining. INS-1 islet beta cells were randomly divided into 7 groups ([i]n[/i]=6), and transfected with lentiviruses (30 μl) for 4 to 6 hours, then was screened with puromycin (PM, 3 μg/m) for 7 days to construct normal group, scramble ShRNA group (interference with airborne poison group), [[TXNIP]]-ShRNA-1 group ([[TXNIP]] silence group-1), [[TXNIP]]-ShRNA-2 group ([[TXNIP]] silence group 2), [[TXNIP]]-ShRNA-3 group ([[TXNIP]] silence group 3), Ad-GFP group (overexpression of the air virus group), Ad-[[TXNIP]]-GFP group ([[TXNIP]] overexpression group) stably transferred INS-1 islet beta cell line. [[TXNIP]] protein expression was detected by Western blot, aging-related beta-galactosidase activity was detected by immunochemical staining, the changes of expression of p16, p21 and Rb was determined by Western blot.   Compared with normal mice, the fasting blood glucose of db/db group was increased significantly ([i]P[/i]＜0. 01), the expression of [[TXNIP]] protein was increased significantly in pancreatic tissues([i]P[/i]＜0. 05), positive staining rate of β- galactosidase was increased significantly in pancreatic tissues, p16/p21/Rb protein expression levels were increased significantly ([i]P[/i]＜0. 05). Compared with Ad-GFP group, the positive staining rate of β- galactosidase in Ad-[[TXNIP]]-GFP group was increased significantly, p16/p21/Rb protein expression levels were increased significantly ([i]P[/i]＜0. 01). Compared to the scramble ShRNA group, the positive staining rate of β- galactosidase in [[TXNIP]]-ShRNA group was decreased, p16/p21/Rb protein expression levels were decreased significantly ([i]P[/i]＜0. 05).   Diabetes can induce islet β-cell senescence by up-regulating [[TXNIP]] expression.
|mesh-terms=* Animals
* Carrier Proteins
* Cellular Senescence
* Diabetes Mellitus, Experimental
* Islets of Langerhans
* Mice
* Thioredoxins
|keywords=* INS-1 cell
* cell senescence
* diabetes
* thioredoxin interacting protein
|full-text-url=https://sci-hub.do/10.12047/j.cjap.5878.2020.027
}}
{{medline-entry
|title=PRMT5-TRIM21 interaction regulates the senescence of osteosarcoma cells by targeting the [[TXNIP]]/p21 axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32023548
|abstract=Osteosarcoma (OS) is the most common bone malignancy in adolescents and has poor clinical outcomes. Protein arginine methyltransferase 5 (PRMT5) has recently been shown to be aberrantly expressed in various cancers, yet its role in OS remains elusive. Here, we found that PRMT5 was overexpressed in OS and its overexpression predicted poor clinical outcomes. PRMT5 knockdown significantly triggered pronounced senescence in OS cells, as evidenced by the increase in senescence-associated β-galactosidase (SA-β-gal)-stained cells, induction of p21 expression, and upregulation of senescence-associated secretory phenotype (SASP) gene expression. In addition, we found that PRMT5 plays a key role in regulating DNA damaging agents-induced OS cell senescence, possibly, via affecting the repair of DNA damage. Furthermore, we found that [[TXNIP]] acts as a key factor mediating PRMT5 depletion-induced DNA damage and cellular senescence. Mechanistically, TRIM21, which interacts with PRMT5, was essential for the regulation of [[TXNIP]]/p21 expression. In summary, we propose a model in which PRMT5, by interaction with TRIM21, plays a key role in regulating the [[TXNIP]]/p21 axis during senescence in OS cells. The present findings suggest that PRMT5 overexpression in OS cells might confer resistance to chemotherapy and that targeting the PRMT5/TRIM21/[[TXNIP]] signaling may enhance the therapeutic efficacy in OS.

|keywords=* PRMT5
* TRIM21
* TXNIP
* p21
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041745
}}
==LBR==

{{medline-entry
|title=Lamin B receptor: role on chromatin structure, cellular senescence and possibly aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32726434
|abstract=The nuclear envelope is composed by an outer nuclear membrane and an inner nuclear membrane, which is underlain by the nuclear lamina that provides the nucleus with mechanical strength for maintaining structure and regulates chromatin organization for modulating gene expression and silencing. A layer of heterochromatin is beneath the nuclear lamina, attached by inner nuclear membrane integral proteins such as Lamin B receptor ([[LBR]]). [[LBR]] is a chimeric protein, having also a sterol reductase activity with which it contributes to cholesterol synthesis. Lukasova et al. showed that when DNA is damaged by ɣ-radiation in cancer cells, [[LBR]] is lost causing chromatin structure changes and promoting cellular senescence. Cellular senescence is characterized by terminal cell cycle arrest and the expression and secretion of various growth factors, cytokines, metalloproteinases, etc., collectively known as senescence-associated secretory phenotype (SASP) that cause chronic inflammation and tumor progression when they persist in the tissue. Therefore, it is fundamental to understand the molecular basis for senescence establishment, maintenance and the regulation of SASP. The work of Lukasova et al. contributed to our understanding of cellular senescence establishment and provided the basis that lead to the further discovery that chromatin changes caused by [[LBR]] reduction induce an up-regulated expression of SASP factors. [[LBR]] dysfunction has relevance in several diseases and possibly in physiological aging. The potential bifunctional role of [[LBR]] on cellular senescence establishment, namely its role in chromatin structure together with its enzymatic activity contributing to cholesterol synthesis, provide a new target to develop potential anti-aging therapies.

|keywords=* Aging
* cancer
* cellular senescence
* chromatine structure
* nuclear envelop
|full-text-url=https://sci-hub.do/10.1042/BCJ20200165
}}
{{medline-entry
|title=The impact of age beyond ploidy: outcome data from 8175 euploid single embryo transfers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32173784
|abstract=The rate of embryonic aneuploidy increases with increasing female age and is the primary cause of lower pregnancy and live birth rates ([[LBR]]) in older reproductive age women. This retrospective cohort study evaluates single euploid embryo transfers to determine whether an age-related decline in reproductive efficiency persists. A total of 8175 non-donor single embryo transfers (SET) after pre-implantation testing for aneuploidy (PGT-A) and cryopreservation were included. These were divided into five groups by patient age: < 35 years old (n = 3789 embryos transferred), 35-37 (n = 2200), 38-40 (n = 1624), 41-42 (n = 319), and > 42 (n = 243). Implantation rate (IR), clinical pregnancy rate (CPR), and [[LBR]] were calculated for each group as a percentage of embryos transferred and compared. CPR was also analyzed as a percentage of implanted pregnancies, and [[LBR]] as a percentage of clinical pregnancies, to determine when age has the greatest impact. These results were then adjusted for confounding variables via a multivariate logistic regression model. Implantation rates negatively correlated with age. After adjusting for confounders, women 38 years or older had a significantly lower IR than those under 35 (OR 0.85, 95%CI 0.73-0.99 for 38-40 years old; 0.69, 0.53-0.91 for 41-42, and 0.69, 0.51-0.94 for > 42). These differences are also apparent in CPR and [[LBR]]. The rates of progression to clinical pregnancy and live birth did not differ significantly by age group. Other factors observed to affect IR independently were anti-Müllerian hormone (AMH), day of embryo transfer, and embryo morphology. While selection of euploid embryos may be effective in overcoming a significant proportion of the age-related decline in reproductive efficiency, a decrease in IR, CPR, and [[LBR]] persists even when analyzing only euploid embryo transfers. The observed impact of aging is, therefore, independent of ploidy, as well as of other variables that affect reproductive efficiency. These results indicate that factors other than aneuploidy contribute to reproductive senescence.

|keywords=* Aneuploidy
* Pregestational genetic testing
* Reproductive aging
* Single embryo transfer
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125286
}}
{{medline-entry
|title=The role of lamin B receptor in the regulation of senescence-associated secretory phenotype (SASP).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32126237
|abstract=Cellular senescence is a phenomenon of irreversible growth arrest of mammalian somatic cells. Senescent cells increase the production of secretory proteins such as inflammatory cytokines, a phenomenon termed senescence-associated secretory phenotype (SASP). SASP is known to have profound effects on organismal health and aging; however, the molecular mechanisms of SASP are not precisely understood. In our previous studies, we have shown that senescent cells show decreased function of lamin B receptor ([[LBR]]), a nuclear membrane protein that regulates heterochromatin organization. Here we examined the implication of [[LBR]] in the regulation of SASP because senescent cells show altered heterochromatin organization, which would affect gene expression. We found that knock-down of [[LBR]] up-regulated the expression of the SASP factors such as IL-6, IL-8, and MMP1 in HeLa cells, even though cellular senescence was not induced by [[LBR]] knock-down. Conversely, enforced expression of [[LBR]] suppressed their up-regulated expression in senescent cells induced by excess thymidine. Further, our gene expression profile analysis also showed that many secretory proteins were up-regulated by [[LBR]] knock-down. We then analyzed the regulatory mechanisms of the expression of SASP factors by [[LBR]], and found that the promoters of these SASP factors associated with [[LBR]] in normally growing cells, but dissociated from it in senescent cells. Additionally, we found that enforced expression of [[LBR]] decreased the generation of cytoplasmic DNA, which could be involved in SASP, in senescent cells. These findings suggested that [[LBR]] would play crucial roles in the regulation of SASP.

|keywords=* Gene expression
* LBR
* SAHF
* SASP
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.yexcr.2020.111927
}}
{{medline-entry
|title=Lamin B receptor plays a key role in cellular senescence induced by inhibition of the proteasome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31825172
|abstract=Cellular senescence is a terminal growth arrest phenomenon in mammalian cells. Coordinated regulation of protein synthesis and degradation is required to maintain protein homeostasis in cells; however, senescent cells exhibit decreased activity of the proteasome, a major cellular proteolytic machinery, with an accumulation of proteins. Indeed, we showed that MG132, a proteasome inhibitor, induced cellular senescence through an accumulation of proteins in human cells. We then investigated the mechanisms of cellular senescence induced by protein accumulation by treating cells with MG132. We found that lamin B receptor ([[LBR]]), a nuclear membrane protein that regulates heterochromatin organization, was mislocalized and down-regulated in cells on treatment with MG132. Importantly, enforced expression of [[LBR]] suppressed cellular senescence induced by MG132. We also showed that [[LBR]] was involved in the regulation of chromatin organization in senescent cells, and that endoplasmic reticulum stress and autophagy were likely to be involved in the mislocalization and down-regulation of [[LBR]]. These findings indicate that decreased [[LBR]] function was responsible for the induction of cellular senescence by MG132, and thus suggest that protein accumulation caused by inhibition of the proteasome induced cellular senescence probably through chromatin dysregulation in human cells.

|keywords=* LBR
* autophagy
* proteasome
* protein accumulation
* senescence
* unbalanced growth
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996348
}}
==C3==

{{medline-entry
|title=Inverse association between periumbilical fat and longevity mediated by complement [[C3]] and cardiac structure.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33221761
|abstract=Although abdominal obesity plays a fundamental role in the onset of immune and inflammatory reactions leading to cardiac abnormalities and premature mortality, the potential association between periumbilical fat and longevity mediated by the antibody-complement system and/or cardiac structure and function remains unclear. To address this issue, we collected biochemical and morphological data from 419 centenarians and 491 non-centenarian oldest-old individuals from the China Hainan Centenarian Cohort Study. Centenarians had lower waist circumference (WC), periumbilical fat thickness (PFT), serum complement [[C3]] level, right atrium end-systolic diameter (RAESD), left atrium end-systolic diameter (LAESD), and left ventricular end-diastolic diameter (LVEDD) than non-centenarians (P<0.05 for all comparisons). WC, PFT, complement [[C3]] levels, RAESD, LAESD, and LVEDD were inversely associated with centenarians (P<0.05 for all variables). Complement [[C3]] level, LAESD, and LVEDD were positively associated with PFT and WC (P<0.05 for all variables). RAESD was positively associated with WC and complement [[C3]] level (P<0.05 for both variables). Centenarians had less periumbilical fat, a weaker complement system, and smaller cardiac structure than non-centenarians. Importantly, periumbilical fat was inversely associated with longevity mediated by complement [[C3]] and cardiac structure. This study suggests that successful aging can be promoted by increased efforts to prevent abdominal obesity.

|keywords=* abdominal obesity
* cardiac structure
* complement C3
* longevity
* periumbilical fat
|full-text-url=https://sci-hub.do/10.18632/aging.104113
}}
{{medline-entry
|title=Complement [[C3]] deficiency ameliorates aging related changes in the kidney.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32882264
|abstract=Complement [[C3]] ([[C3]]) has been shown to be involved in the aging process. However, the role of [[C3]] in kidney aging has not been fully elucidated. This study aimed to investigate the effect of [[C3]] on senescence related kidney disorders in mice. Two-, 8-, and 16-month-old [[C3]]-deficient male mice (KO) (n = 6) and age-, gender-, and strain- matched wild type (WT) C57BL/6 mice (n = 6) were selected to represent young, middle-aged and aging mice. Renal, blood and urine samples were collected. Hematoxylin-eosin (HE), Masson, and immunohistochemistry (IHC) staining as well as ELISA and Western blotting were used to explore the mechanisms involved in renal aging. The level of [[C3]] was upregulated during aging in WT mice. The glomerular sclerosis index and tubulointerstitial fibrosis index were increased significantly in WT mice during aging. Renal function was not significantly different between the young and aged groups. Compared with those in WT mice, the levels of inflammation and fibrosis were decreased, while the expression of CD31 was significantly increased in the KO group. Our data demonstrated that age-related changes in renal structure occur earlier than functional changes and that complement [[C3]] is involved in aging-related kidney disorder.
|mesh-terms=* Aging
* Animals
* Complement C3
* Inflammation
* Kidney
* Kidney Diseases
* Male
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
|keywords=* Complement component 3
* Kidney disorder
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.lfs.2020.118370
}}
{{medline-entry
|title=Reduced sialylation triggers homeostatic synapse and neuronal loss in middle-aged mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32087947
|abstract=Sialic acid-binding Ig-like lectin (Siglec) receptors are linked to neurodegenerative processes, but the role of sialic acids in physiological aging is still not fully understood. We investigated the impact of reduced sialylation in the brain of mice heterozygous for the enzyme glucosamine-2-epimerase/N-acetylmannosamine kinase (GNE+/-) that is essential for sialic acid biosynthesis. We demonstrate that GNE+/- mice have hyposialylation in different brain regions, less synapses in the hippocampus and reduced microglial arborization already at 6 months followed by increased loss of neurons at 12 months. A transcriptomic analysis revealed no pro-inflammatory changes indicating an innate homeostatic immune process leading to the removal of synapses and neurons in GNE+/- mice during aging. Crossbreeding with complement [[C3]]-deficient mice rescued the earlier onset of neuronal and synaptic loss as well as the changes in microglial arborization. Thus, sialic acids of the glycocalyx contribute to brain homeostasis and act as a recognition system for the innate immune system in the brain.
|mesh-terms=* Aging
* Animals
* Brain
* Homeostasis
* Immunity, Innate
* Mice, Transgenic
* Neurons
* Racemases and Epimerases
* Sialic Acid Binding Immunoglobulin-like Lectins
* Sialic Acids
* Synapses
|keywords=* Aging
* GNE
* Glycocalyx
* Microglia
* Neurodegeneration
* Neuroinflammation
* Sialic acid
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.01.008
}}
{{medline-entry
|title=[Comparative analysis of experimental data about the effects of various polyphenols on lifespan and aging.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31512417
|abstract=To analyze experimental data on the effect of various polyphenolic compounds on lifespan of mice, we approximated survival curves with the Gompertz model in its minimal form, which does not account for the heterogeneity of samples and the age-independent mortality. The plots of regressions of log0 (logarithm of the initial mortality) on  (the rate of aging) in series of control samples were used to assess the deviations of vectors directed from control to experimental data from the slopes of the control regressions. The analysis of published data suggests that resveratrol, polyphenol-containing grape skin extract, metformin, tocopherol, and the antioxidant SkQ1 do not produce changes beyond those possible upon comparing of different samples of a control population. The effect of the polyphenolic composition BP-[[C3]] on female SHR mice is unique in being associated with a significant decrease in the rate of aging. The effect may be partly contributed to by the antioxidant properties of BP-[[C3]]. Its antioxidant capacity determined in vitro is comparable with that of established antioxidants, such as dihydroquercetin. Its effects in vivo include the ability to ameliorate reduction in the peroxide-decomposing activity of RBC lysates from male BALB/c mice treated with 5-fluorouracil.
|mesh-terms=* Animals
* Antioxidants
* Female
* Longevity
* Male
* Mice
* Mice, Inbred BALB C
* Polyphenols
* Survival Analysis
|keywords=* BP-C3
* Gompertz model
* SkQ1
* aging
* herbal extracts
* lifespan
* metformin
* polyphenols
* resveratrol
* tocopherol

}}
==LRRK2==

{{medline-entry
|title=Accelerated telomere shortening independent of [[LRRK2]] variants in Chinese patients with Parkinson's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33122450
|abstract=Oxidative stress and inflammation play vital roles in Parkinson's disease (PD) development. Thus, telomere length is expected to be shortened in this disease, but current data are inconclusive. We performed a case-control study of 261 patients with PD and 270 sex and age-matched healthy controls treated at the Peking Union Medical College Hospital. We found leucocyte telomere length (LTL) was significantly shortened in PD as compared with controls [1.02 (0.84-1.39) [i]vs[/i]. 1.48 (1.08-1.94), P<0.001] and shorter LTL was associated with a dramatically increased risk of PD (lowest [i]vs[/i]. highest quartile odds ratio (OR) =9.54, 95% CI: 5.33-17.06, P<0.001). We also investigated the roles of six [[LRRK2]] variants in the susceptibility to PD. R1441C/G/H, G2019S, and I2020T variations were not detected in our study. No significant differences were found in the presence of variants R1398H (15.4% [i]vs[/i]. 17.0%, P=0.619) and R1628P (2.3% [i]vs[/i]. 0.7%, P=0.159) in PD and controls, while the G2385R variant was found to be a risk factor associated with increased PD susceptibility (OR=2.14, 95% CI: 1.12-4.10, P=0.021). No significant association was found between different [[LRRK2]] variants and telomere length. These findings suggest that shorter LTL might be associated with PD in a manner independent of [[LRRK2]] variants.

|keywords=* LRRK2 variants
* Parkinson’s disease
* aging
* telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655166
}}
{{medline-entry
|title=The effect of [[LRRK2]] loss-of-function variants in humans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32461697
|abstract=Human genetic variants predicted to cause loss-of-function of protein-coding genes (pLoF variants) provide natural in vivo models of human gene inactivation and can be valuable indicators of gene function and the potential toxicity of therapeutic inhibitors targeting these genes . Gain-of-kinase-function variants in [[LRRK2]] are known to significantly increase the risk of Parkinson's disease , suggesting that inhibition of [[LRRK2]] kinase activity is a promising therapeutic strategy. While preclinical studies in model organisms have raised some on-target toxicity concerns , the biological consequences of [[LRRK2]] inhibition have not been well characterized in humans. Here, we systematically analyze pLoF variants in [[LRRK2]] observed across 141,456 individuals sequenced in the Genome Aggregation Database (gnomAD) , 49,960 exome-sequenced individuals from the UK Biobank and over 4 million participants in the 23andMe genotyped dataset. After stringent variant curation, we identify 1,455 individuals with high-confidence pLoF variants in [[LRRK2]]. Experimental validation of three variants, combined with previous work , confirmed reduced protein levels in 82.5% of our cohort. We show that heterozygous pLoF variants in [[LRRK2]] reduce [[LRRK2]] protein levels but that these are not strongly associated with any specific phenotype or disease state. Our results demonstrate the value of large-scale genomic databases and phenotyping of human loss-of-function carriers for target validation in drug discovery.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Biological Specimen Banks
* Cell Line
* Embryonic Stem Cells
* Female
* Gain of Function Mutation
* Heterozygote
* Humans
* Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
* Longevity
* Loss of Function Mutation
* Lymphocytes
* Male
* Middle Aged
* Myocytes, Cardiac
* Parkinson Disease
* Phenotype

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303015
}}
{{medline-entry
|title=Parkinson's disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32075681
|abstract=Multiple missense mutations in Leucine-rich repeat kinase 2 ([[LRRK2]]) are associated with familial forms of late onset Parkinson's disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to PD-related motor symptoms. Interestingly, [[LRRK2]] is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether [[LRRK2]] modulates the aging of SPNs remains to be determined. We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2 ) and control (Lrrk2 ) mice at 2 and 12 months of age. We examined SPN nuclear DNA damage and epigenetic modifications; SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of Lrrk2  and Lrrk2  mice from 2 to 24 months of age. Considering the strength of cell cultures for future mechanistic studies, we also performed preliminary studies in primary cultured SPNs derived from the Lrrk2  and Lrrk2  mice as well as the PD-related Lrrk2 G2019S and R1441C mutant mice. Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in aged Lrrk2  striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PD-related Lrrk2 G2019S mutant and [[LRRK2]] kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and γ-Aminobutyric acid type A receptor (GABA-AR) inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2  and R1441C SPNs. Our findings support an important physiological function of [[LRRK2]] in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that PD-related [[LRRK2]] mutations may cause the deterioration of neuronal structures through accelerating the aging process.

|keywords=* And aging
* Dendritic hypotrophy
* Excitability
* G2019S
* GABAA
* LRRK2
* Nuclear DNA damage
* Nuclear hypertrophy
* Nuclear invagination
* Parkinson’s disease
* R1441C
* Striatal spiny projection neuron
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031993
}}
{{medline-entry
|title=Autophagy and [[LRRK2]] in the Aging Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31920513
|abstract=Autophagy is a highly conserved process by which long-lived macromolecules, protein aggregates and dysfunctional/damaged organelles are delivered to lysosomes for degradation. Autophagy plays a crucial role in regulating protein quality control and cell homeostasis in response to energetic needs and environmental challenges. Indeed, activation of autophagy increases the life-span of living organisms, and impairment of autophagy is associated with several human disorders, among which neurodegenerative disorders of aging, such as Parkinson's disease. These disorders are characterized by the accumulation of aggregates of aberrant or misfolded proteins that are toxic for neurons. Since aging is associated with impaired autophagy, autophagy inducers have been viewed as a strategy to counteract the age-related physiological decline in brain functions and emergence of neurodegenerative disorders. Parkinson's disease is a hypokinetic, multisystemic disorder characterized by age-related, progressive degeneration of central and peripheral neuronal populations, associated with intraneuronal accumulation of proteinaceous aggregates mainly composed by the presynaptic protein α-synuclein. α-synuclein is a substrate of macroautophagy and chaperone-mediated autophagy (two major forms of autophagy), thus impairment of its clearance might favor the process of α-synuclein seeding and spreading that trigger and sustain the progression of this disorder. Genetic factors causing Parkinson's disease have been identified, among which mutations in the [[LRRK2]] gene, which encodes for a multidomain protein encompassing central GTPase and kinase domains, surrounded by protein-protein interaction domains. Six [[LRRK2]] mutations have been pathogenically linked to Parkinson's disease, the most frequent being the G2019S in the kinase domain. [[LRRK2]]-associated Parkinson's disease is clinically and neuropathologically similar to idiopathic Parkinson's disease, also showing age-dependency and incomplete penetrance. Several mechanisms have been proposed through which [[LRRK2]] mutations can lead to Parkinson's disease. The present article will focus on the evidence that [[LRRK2]] and its mutants are associated with autophagy dysregulation. Studies in cell lines and neurons [i]in vitro[/i] and in [[LRRK2]] knock-out, knock-in, kinase-dead and transgenic animals [i]in vivo[/i] will be reviewed. The role of aging in [[LRRK2]]-induced synucleinopathy will be discussed. Possible mechanisms underlying the [[LRRK2]]-mediated control over autophagy will be analyzed, and the contribution of autophagy dysregulation to the neurotoxic actions of [[LRRK2]] will be examined.

|keywords=* LAMP2A
* LC3
* LRRK2
* Parkinson’s disease
* aging
* autophagy
* lysosomes
* α-synuclein
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928047
}}
==HGF==

{{medline-entry
|title=Age-related changes in the immunomodulatory effects of human dental pulp derived mesenchymal stem cells on the CD4  T cell subsets.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33223447
|abstract=Mesenchymal stem cells (MSCs) are powerful immunomodulatory cells. The effects of the aging on these abilities of MSCs have not been adequately clarified. In this study, alterations in immunomodulatory abilities of MSCs caused by aging were investigated. For this, dental pulp (DP) MSCs and peripheral blood mononuclear cells (PBMCs) of elderly and young donors were co-cultured age-matched and cross. We detected that the effects of DP-MSCs on Th1 and Th2 cells and their specific cytokines IFN-γ and IL-4 are not affected by aging. However, we observed that young and elderly DP-MSCs have different effects on Th17 and Treg cells. Th17 frequencies of young and elderly PBMCs were significantly increased only by young DP-MSCs, in contrast, Treg frequencies were significantly increased by elderly DP-MSCs. IL-6, IL-17a and [[HGF]] levels of both young and elderly PBMCs showed a significant increase only by young DP-MSCs, but TGF-β levels were significantly increased only by elderly DP-MSCs. The oral cavity is home to a rich microflora. The interactions of dental tissues with this microflora can lead them to acquire different epigenetic modifications. Aging can affect the microflora composition of the oral cavity and change this process in different directions. According to our findings, DP-MSCs are effective cells in the regulation of CD4  T cells, and their effects on Th1 and Th2 cells were not affected by aging. However, pleiotropic molecules IL-6 and [[HGF]] expressions, which are important in dental and bone tissue regeneration, decreased significantly in elderly DP-MSCs. This situation may have indirectly made a difference in the modulation effects of young and elderly DP-MSCs on the Th17 and Treg cells.

|keywords=* Aging
* CD4 T cell
* Dental pulp
* Immunomodulation
* Mesenchymal stem cell
|full-text-url=https://sci-hub.do/10.1016/j.cyto.2020.155367
}}
{{medline-entry
|title=Hepatocyte growth factor ([[HGF]]) and stem cell factor (SCF) maintained the stemness of human bone marrow mesenchymal stem cells (hBMSCs) during long-term expansion by preserving mitochondrial function via the PI3K/AKT, ERK1/2, and STAT3 signaling pathways.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32736659
|abstract=Mesenchymal stem cells (MSCs) have a limited self-renewal ability, impaired multi-differentiation potential, and undetermined cell senescence during in vitro series expansion. To address this concern, we investigated the effects of the microenvironment provided by stem cells from human exfoliated deciduous teeth (SHED) in maintaining the stemness of human bone marrow mesenchymal stem cells (hBMSCs) and identified the key factors and possible mechanisms responsible for maintaining the stemness of MSCs during long-term expansion in vitro. The passage 3 (P3) to passage 8 (P8) hBMSCs were cultured in the conditioned medium from SHED (SHED-CM). The percentage of senescent cells was evaluated by β-galactosidase staining. In addition, the osteogenic differentiation potential was analyzed by reverse transcription quantitative PCR (RT-qPCR), Western blot, alizarin red, and alkaline phosphatase (ALP) staining. Furthermore, RT-qPCR results identified hepatocyte growth factor ([[HGF]]) and stem cell factor (SCF) as key factors. Thus, the effects of [[HGF]] and SCF on mitochondrial function were assessed by measuring the ROS and mitochondrial membrane potential levels. Finally, selected mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways were investigated to determine the effects of [[HGF]] and SCF in preserving the mitochondrial function of hBMSCs during long-term expansion. SHED-CM had significantly enhanced the cell proliferation, reduced the senescent cells, and maintained the osteogenesis and pro-angiogenic capacity in P8 hBMSCs during long-term expansion. In addition, hBMSCs treated with 100 ng/ml [[HGF]] and 10 ng/ml SCF had reduced ROS levels and preserved mitochondrial membrane potential compared with P8 hBMSCs during long-term expansion. Furthermore, [[HGF]] and SCF upregulated the expression of mitochondrial-related proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways, possibly contributing to the maintenance of hBMSCs stemness by preserving mitochondrial function. Both [[HGF]] and SCF are key factors in maintaining the stemness of hBMSCs by preserving mitochondrial function through the expression of proteins associated with the PI3K/AKT, ERK1/2, and STAT3 signaling pathways. This study provides new insights into the anti-senescence capability of [[HGF]] and SCF, as well as new evidence for their potential application in optimizing the long-term culture of MSCs.

|keywords=* Hepatocyte growth factor
* Mitochondrial function
* Osteogenic differentiation
* Senescence
* Stem cell factor
* Stem cells from human exfoliated deciduous teeth
* Stemness
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393921
}}
{{medline-entry
|title=Phenytoin sodium-ameliorated gingival fibroblast aging is associated with autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32281104
|abstract=Human gingival fibrolasts aging is an important cause of periodontal disease. Phenytoin sodium (phenytoin) has a side effect of gingival hyperplasia and an effect on the autophagy progress. This study investigated whether the effect of phenytoin on aging gingival fibroblast is related to the autophagy pathway. The aging model of gingival fibroblast cell line [[HGF]]-1 was induced by hydrogen peroxide (H  O  ), and the treatment of phenytoin and 3-methyladenine (3-MA) was performed simultaneously. Cell viability, cell cycle, and intracellular calcium ion were measured by flow cytometry. Changes in expression of basic fibroblast growth factor (bFGF), P16  , P21  , and bFGF, P16  , P21  , LC3II, p62, and Beclin were tested by using reverse transcription polymerase chain reaction, western blot, and immunofluorescence staining. The results showed that aging [[HGF]]-1 proliferation was inhibited by H  O  , gene, protein expression of bFGF, P16  , and P21  were decreased, autophagy-related proteins LC3II, p62, and Becline were decreased, and the proportion of G0/G1 phase and intracellular calcium ion of cell cycle was increased. Phenytoin treatment could recovery above changes, but the effect of phenytoin could be blocked by 3-MA. We propose that phenytoin alleviates the aging of gingival fibroblasts induced by H  O  . This condition is related to the enhancement of autophagy pathway.

|keywords=* aging
* autophagy
* gingival fibroblast
* phenytoin sodium
|full-text-url=https://sci-hub.do/10.1111/jre.12750
}}
{{medline-entry
|title=Impaired integrin α  /β  -mediated hepatocyte growth factor release by stellate cells of the aged liver.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32157808
|abstract=Hepatic blood flow and sinusoidal endothelial fenestration decrease during aging. Consequently, fluid mechanical forces are reduced in the space of Disse where hepatic stellate cells (HSC) have their niche. We provide evidence that integrin α  /β  is an important mechanosensor in HSC involved in shear stress-induced release of hepatocyte growth factor ([[HGF]]), an essential inductor of liver regeneration which is impaired during aging. The expression of the integrin subunits α  and β  decreases in liver and HSC from aged rats. CRISPR/Cas9-mediated integrin α  and β  knockouts in isolated HSC lead to lowered [[HGF]] release and impaired cellular adhesion. Fluid mechanical forces increase integrin α  and laminin gene expression whereas integrin β  remains unaffected. In the aged liver, laminin β2 and γ1 protein chains as components of laminin-521 are lowered. The integrin α  knockout in HSC reduces laminin expression via mechanosensory mechanisms. Culture of HSC on nanostructured surfaces functionalized with laminin-521 enhances Hgf expression in HSC, demonstrating that these ECM proteins are critically involved in HSC function. During aging, HSC acquire a senescence-associated secretory phenotype and lower their growth factor expression essential for tissue repair. Our findings suggest that impaired mechanosensing via integrin α  /β  in HSC contributes to age-related reduction of ECM and [[HGF]] release that could affect liver regeneration.

|keywords=* aging
* hepatic stellate cells
* integrins
* laminins
* mechanobiology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189994
}}
==STS==

{{medline-entry
|title=Delayed Impairment of Postural, Physical, and Muscular Functions Following Downhill Compared to Level Walking in Older People.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33192547
|abstract=Transient symptoms of muscle damage emanating from unaccustomed eccentric exercise can adversely affect muscle function and potentially increase the risk of falling for several days. Therefore, the aims of the present study were to investigate the shorter- and longer-lasting temporal characteristics of muscle fatigue and damage induced by level (i.e., concentrically biased contractions) or downhill (i.e., eccentrically biased contractions) walking on postural, physical, and muscular functions in older people. Nineteen participants were matched in pairs for sex, age and self-selected walking speed and allocated to a level ([i]n[/i] = 10, age = 72.3 ± 2.9 years) or downhill ([i]n[/i] = 9, age = 72.1 ± 2.2 years) walking group. Postural sway, muscle torque and power, physical function (5× and 60 s sit-to-stand; [[STS]]), and mobility (Timed-Up-and-Go; TUG) were evaluated at baseline (pre-exercise), 1 min, 15 min, 30 min, 24 h, and 48 h after 30 min of level (0% gradient) or downhill (-10% gradient) walking on a treadmill. Following downhill walking, postural sway (+66 to 256%), TUG (+29%), 60 s [[STS]] (+29%), five times [[STS]] (-25%) and concentric power (-33%) did not change at 1-30 min post exercise, but were significantly different ([i]p[/i] < 0.05) at 24 and48 h post-exercise when compared to baseline ([i]p[/i] < 0.05). Muscle torque decreased immediately after downhill walking and remained impaired at 48 h post-exercise (-27 to -38%). Immediately following level walking there was an increase in postural sway (+52 to +98%), slower TUG performance (+29%), fewer [[STS]] cycles in 60 s (-23%), slower time to reach five [[STS]] cycles (+20%) and impaired muscle torque (-23%) and power (-19%) which returned to baseline 30-min after exercise cessation ([i]p[/i] > 0.05). These findings have established for the first time distinct impairment profiles between concentric and eccentric exercise. Muscle damage emanating from eccentrically biased exercise can lead to muscle weakness, postural instability and impaired physical function persisting for several days, possibly endangering older adult's safety during activities of daily living by increasing the risk of falls.

|keywords=* aging
* balance
* falls
* fatigue
* functional performance
* muscle damage
* walking
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609421
}}
{{medline-entry
|title=Autophagy displays divergent roles during intermittent amino acid starvation and toxic stress-induced senescence in cultured skeletal muscle cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33022071
|abstract=Due to the ever-expanding functions attributed to autophagy, there is widespread interest in understanding its contribution to human physiology; however, its specific cellular role as a stress-response mechanism is still poorly defined. To investigate autophagy's role in this regard, we repeatedly subjected cultured mouse myoblasts to two stresses with diverse impacts on autophagic flux: amino acid and serum withdrawal (Hank's balanced salt solution [HBSS]), which robustly induces autophagy, or low-level toxic stress (staurosporine, [[STS]]). We found that intermittent [[STS]] (int-[[STS]]) administration caused cell cycle arrest, development of enlarged and misshapen cells/nuclei, increased senescence-associated heterochromatic foci and senescence-associated β-galactosidase activity, and prevented myogenic differentiation. These features were not observed in cells intermittently incubated in HBSS (int-HB). While int-[[STS]] cells displayed less DNA damage (phosphorylated H2A histone family, member X content) and caspase activity when administered cisplatin, int-HB cells were protected from [[STS]]-induced cell death. Interestingly, [[STS]]-induced senescence was attenuated in autophagy related 7-deficient cells. Therefore, while repeated nutrient withdrawal did not cause senescence, autophagy was required for senescence caused by toxic stress. These results illustrate the context-dependent effects of different stressors, potentially highlighting autophagy as a distinguishing factor.

|keywords=* autophagy
* caspase
* cell death
* remodeling
* senescence
|full-text-url=https://sci-hub.do/10.1002/jcp.30079
}}
{{medline-entry
|title=The WRKY53 transcription factor enhances stilbene synthesis and disease resistance by interacting with MYB14 and MYB15 in Chinese wild grape.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32080737
|abstract=Resveratrol is notable not only for its functions in disease resistance in plants but also for its health benefits when it forms part of the human diet. Identification of new transcription factors helps to reveal the regulatory mechanisms of stilbene synthesis. Here, the WRKY53 transcription factor was isolated from the Chinese wild grape, Vitis quinquangularis. Vqwrky53 was expressed in a variety of tissues and responded to powdery mildew infection and to exogenous hormone application. VqWRKY53 was located in the nucleus and had transcriptional activation activity in yeast. A yeast two-hybrid assay and a bimolecular fluorescence complementation assay confirmed that VqWRKY53 interacted physically with VqMYB14 and VqMYB15, which have previously been reported to regulate stilbene synthesis. When Vqwrky53 was overexpressed in grape leaves, the expression of Vq[[STS]]32 and Vq[[STS]]41 and the content of stilbenes were increased. A yeast one-hybrid assay demonstrated that VqWRKY53 could bind directly to the promoters of [[STS]] genes. Overexpression of Vqwrky53 activated β-glucuronidase expression, driven by [[STS]] promoters, and co-expressing Vqwrky53 with VqMYB14 and VqMYB15 showed stronger regulatory functions. Heterologous overexpression of Vqwrky53 in Arabidopsis accelerated leaf senescence and disease resistance to PstDC3000.

|keywords=* Chinese wild grape (Vitis quinquangularis)
* WRKY transcription factor
* disease resistance
* leaf senescence
* stilbene
* transcriptional regulation
|full-text-url=https://sci-hub.do/10.1093/jxb/eraa097
}}
{{medline-entry
|title=On the role of ageing and musculoskeletal pain on dynamic balance in manual workers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31733466
|abstract=The purpose of this study was to explore the interacting effects of age and musculoskeletal pain on balance in manual workers. Ninety male manual workers aged 51-72 yr were recruited and stratified according to lower extremity musculoskeletal pain intensity (pain/no pain) and work status (working/retired). The five-repetition sit-to-stand ([[STS]]) test was used to assess lower extremity function including completion time, stand time, sit time and dynamic rate of force development both in the upwards (RFD ) and downwards moving phase (RFD ). Dynamic balance was expressed as the range, velocity, standard deviation (SD), maximum Lyapunov Exponent and sample entropy of centre of pressure displacement in the anterior-posterior and medial-lateral direction, as well as free moment during the [[STS]] test. Except for higher age, no marked differences were seen between working and retired participants. Both age and musculoskeletal pain were negatively associated with motor function. Age × pain interactions showed that completion time, stand time, RFD  and RFD  were negatively associated with age for participants without pain, but positively for those with pain. Similar findings were seen for dynamic balance. These findings indicate that the effects of lower extremity musculoskeletal pain on lower extremity function and dynamic balance are age dependent.
|mesh-terms=* Aged
* Aging
* Female
* Humans
* Male
* Middle Aged
* Muscle, Skeletal
* Musculoskeletal Pain
* Occupational Diseases
* Postural Balance
|keywords=* Discomfort
* Lower extremity function
* Posturography
* Sit-to-stand
|full-text-url=https://sci-hub.do/10.1016/j.jelekin.2019.102374
}}
==CDK6==

{{medline-entry
|title=Saturated Fatty Acids Promote Hepatocytic Senecence through Regulation of miR-34a/Cyclin-Dependent Kinase 6.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32970940
|abstract=Obesity increases intracellular lipid accumulation in hepatocytes, which can induce non-alcoholic fatty liver disease (NAFLD). With progression of NAFLD, a sizable fraction of patients develop non-alcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The mechanism involved in obesity-induced NAFLD remains unclear. Free fatty acids and high-fat diets, which induce hepatocyte senescence, are major risk factors for NAFLD. Therefore in this study, the mechanism of lipotoxicity-induced hepatocyte senescence is investigated. The mice are fed a high-fat diet (HFD) and BNL CL.2 cells are treated with palmitate acid (PA) to establish in vivo and in vitro models of lipotoxicity, respectively. SA-β-gal staining is used to analyze the positively stained senescent hepatocytes. The results show that both PA and HFD induce cellular senescence. Real-time-PCR quantitative analysis reveals that miR-34a is significantly upregulated in the liver tissues of the HFD mice and in the PA-treated BNL CL.2 cells. Western blotting analysis shows that cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21) is upregulated, while cyclin-dependent kinase 6 ([[CDK6]]) is downregulated. Further investigation of the mechanism reveals that [[CDK6]] is a target of miR-34a, which binds to the 3' UTR of [[CDK6]] and inhibits its expression. The findings reveal that miR-34a is upregulated in a high-fat environment in the liver, and induces hepatocyte senescence by targeting [[CDK6]]. The miR-34a-[[CDK6]] signaling axis may promote NAFLD development in a high-fat environment and therefore represents a potential target for NAFLD therapy.

|keywords=* cyclin-dependent kinase 6 (CDK6)
* high-fat diet (HFD)
* miR-34a
* palmitate acid (PA)
* senescence
|full-text-url=https://sci-hub.do/10.1002/mnfr.202000383
}}
{{medline-entry
|title=Hepatoprotective effects of hydroxysafflor yellow A in D-galactose-treated aging mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32454116
|abstract=Hydroxysafflor yellow A (HSYA) is an effective chemical component isolated from Chinese herb Carthamus tinctorius L. In present study, we aimed to evaluate the effects of HSYA on D-galactose- (D-gal-) induced aging in mice, and to elucidate the underlying mechanism. Male C57BL/6 mice were intraperitoneal injection of D-gal and HSYA for 8 weeks. The body weight gain, spleen and thymus coefficients were determined. Levels of super dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in serum and liver were measured using commercial kits. Pathological changes and the SA-β-Gal activity in liver tissues were detected by hematoxylin and eosin and SA-β-Gal staining. The expression levels of p16, CDK4, [[CDK6]] and phosphorylation levels of Retinoblastoma (Rb) were detected by immunohistochemistry and western blot analysis. mRNA levels of genes regulated by p16-Rb pathway were determined by quantitative real-time PCR. In vivo, HSYA improved the aging changes including body weight, organ index and antioxidant status such as activities of SOD, CAT, GSH-Px and MDA in D-gal treated aging mice. HSYA also dramatically attenuated pathologic changes of aging liver tissues induced by D-gal. Furthermore, HSYA significantly decreased the mRNA and protein level of cyclin-dependent kinase inhibitor p16, followed by increasing CDK4/6 protein expression and decreasing the phosphorylation of Retinoblastoma (pRb) which up-regulated the expression of downstream genes CCNE1, CCNA2, P107 and MCM4. Collectively, these data indicated that HSYA could ameliorate aging, especially hepatic replicative senescence resulting from D-gal, the mechanism could be associated with the suppression of p16-Rb pathway.

|keywords=* D-galactose
* Hydroxysafflor yellow A
* Oxidative stress
* Replicative senescence
* p16
|full-text-url=https://sci-hub.do/10.1016/j.ejphar.2020.173214
}}
{{medline-entry
|title=Anti-cell growth and anti-cancer stem cell activity of the CDK4/6 inhibitor palbociclib in breast cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31823286
|abstract=A cyclin-dependent kinase (CDK) 4/6 inhibitor, palbociclib, has been used to treat patients with estrogen receptor (ER)-positive (+) and human epidermal growth factor receptor (HER) 2-negative (-) advanced breast cancer. To investigate the mechanisms underlying the antitumor activity of palbociclib, we conducted a preclinical study on the anti-cell growth and anti-cancer stem cell (CSC) activity of palbociclib in breast cancer cells. The effects of palbociclib on Rb phosphorylation, cell growth, cell cycle progression, apoptosis, cell senescence and the proportion of CSCs were investigated in five human breast cancer cell lines of different subtypes. To investigate the mechanisms of the anti-CSC activity of palbociclib, small-interfering RNAs for CDK4 and/or [[CDK6]] were used. Palbociclib dose-dependently reduced Rb phosphorylation and cell growth in association with G1-S cell cycle blockade and the induction of cell senescence, but without increased apoptosis, in all breast cancer cell lines. The anti-cell growth activity of palbociclib widely differed among the cell lines. Palbociclib also dose-dependently reduced the CSC proportion measured by three different assays in four of five cell lines. The inhibition of CDK4 expression, but not [[CDK6]] expression, reduced the increased proportion of putative CSCs induced by estradiol in ER (+)/HER2 (-) cell lines. These results suggest that palbociclib exhibits significant anti-cell growth and anti-CSC activity in not only ER (+) breast cancer cell lines but also ER (-) cell lines. CDK4 inhibition induced by palbociclib may be responsible for its anti-CSC activity.

|keywords=* Breast cancer
* CDK4
* Cancer stem cells
* Palbociclib
* Senescence
|full-text-url=https://sci-hub.do/10.1007/s12282-019-01035-5
}}
{{medline-entry
|title=Compromising the constitutive p16  expression sensitizes human neuroblastoma cells to Hsp90 inhibition and promotes premature senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31692039
|abstract=The Hsp90 chaperone has become the attractive pharmacological target to inhibit tumor cell proliferation. However, tumor cells can evolve with mechanisms to overcome Hsp90 inhibition. Using human neuroblastoma, we have investigated one such limitation. Here, we demonstrate that neuroblastoma cells overcome the interference of tumor suppressor p16  in cell proliferation, which is due to its latent interaction with CDK4 and [[CDK6]]. Cells also displayed impedance to the pharmacological inhibition of cancer chaperone Hsp90 inhibition with respect to induced cytotoxicity. However, the p16  knockdown has triggered the activation of cyclin-[[CDK6]] axis and enhanced the cell proliferation. These cells are eventually sensitized to Hsp90 inhibition by activating the DNA damage response mediated through p53-p21  axis and G1 cell cycle exit. While both CDK4 and [[CDK6]] have exhibited low affinity to p16  , [[CDK6]] has exhibited high affinity to Hsp90. Destabilizing the [[CDK6]] interaction with Hsp90 has prolonged G2/M cell cycle arrest fostering to premature cellular senescence. The senescence driven cells exhibited compromised metastatic potential both in vitro as well as in mice xenografts. Our study unravels that cancer cells can be adapted to the constitutive expression of tumor suppressors to overcome therapeutic interventions. Our findings display potential implication of Hsp90 inhibitors to overcome such adaptations.

|keywords=* 17AAG
* Hsp90
* cancer
* p16INK4a
* senescence
* tumor suppressor
|full-text-url=https://sci-hub.do/10.1002/jcb.29493
}}
==IGF1==

{{medline-entry
|title=Genetic differences and longevity-related phenotypes influence lifespan and lifespan variation in a sex-specific manner in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33105070
|abstract=Epidemiological studies of human longevity found two interesting features, robust advantage of female lifespan and consistent reduction of lifespan variation. To help understand the genetic aspects of these phenomena, the current study examined sex differences and variation of longevity using previously published mouse data sets including data on lifespan, age of puberty, and circulating insulin-like growth factor 1 ([[IGF1]]) levels in 31 inbred strains, data from colonies of nuclear-receptor-interacting protein 1 (Nrip1) knockout mice, and a congenic strain, B6.C3H-Igf1. Looking at the overall data for all inbred strains, the results show no significant difference in lifespan and lifespan variation between sexes; however, considerable differences were found among and within strains. Across strains, lifespan variations of female and male mice are significantly correlated. Strikingly, between sexes, [[IGF1]] levels correlate with the lifespan variation and maximum lifespan in different directions. Female mice with low [[IGF1]] levels have higher variation and extended maximum lifespan. The opposite is detected in males. Compared to domesticated inbred strains, wild-derived inbred strains have elevated lifespan variation due to increased early deaths in both sexes and extended maximum lifespan in female mice. Intriguingly, the sex differences in survival curves of inbred strains negatively associated with age of female puberty, which is significantly accelerated in domesticated inbred strains compared to wild-derived strains. In conclusion, this study suggests that genetic factors are involved in the regulation of sexual disparities in lifespan and lifespan variation, and dissecting the mouse genome may provide novel insight into the underlying genetic mechanisms.

|keywords=* IGF1
* antagonistic gene
* female sexual maturation
* lifespan variation
* maximum lifespan
* sex difference in lifespan
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681063
}}
{{medline-entry
|title=17α-estradiol modulates [[IGF1]] and hepatic gene expression in a sex-specific manner.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32857104
|abstract=Aging is the greatest risk factor for most chronic diseases. The somatotropic axis is one of most conserved biological pathways that regulates aging across species. 17α-estradiol (17α-E2), a diastereomer of 17β-estradiol (17β-E2), was recently found to elicit health benefits, including improved insulin-sensitivity, and extend longevity exclusively in male mice. Given that 17β-E2 is known to modulate somatotropic signaling in females through actions in the pituitary and liver, we hypothesized that 17α-E2 may be modulating the somatotropic axis in males, thereby contributing to health benefits. Herein, we demonstrate that 17α-E2 increases hepatic [[IGF1]] production in male mice without inducing any changes in pulsatile GH secretion. Using growth hormone receptor knockout (GHRKO) mice, we subsequently determined that the induction of hepatic [[IGF1]] by 17α-E2 is dependent upon GH signaling in male mice, and that 17α-E2 elicits no effects on [[IGF1]] production in female mice. We also determined that 17α-E2 failed to feminize the hepatic transcriptional profile in normal (N) male mice, as evidenced by a clear divergence between the sexes, regardless of treatment. Conversely, significant overlap in transcriptional profiles was observed between sexes in GHRKO mice, and this was unaffected by 17α-E2 treatment. Based on these findings, we propose that 17α-E2 acts as a pleiotropic pathway modulator in male mice by uncoupling [[IGF1]] production from insulin sensitivity. In summary, 17α-E2 treatment upregulates [[IGF1]] production in wild-type (and N) male mice in what appears to be a GH-dependent fashion, while no effects in female [[IGF1]] production are observed following 17α-E2 treatment.

|keywords=* 17α-estradiol
* aging
* growth hormone
* insulin
* insulin-like growth factor-1
* liver
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa215
}}
{{medline-entry
|title=Pan-mammalian analysis of molecular constraints underlying extended lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32043462
|abstract=Although lifespan in mammals varies over 100-fold, the precise evolutionary mechanisms underlying variation in longevity remain unknown. Species-specific genetic changes have been observed in long-lived species including the naked mole-rat, bats, and the bowhead whale, but these adaptations do not generalize to other mammals. We present a novel method to identify associations between rates of protein evolution and continuous phenotypes across the entire mammalian phylogeny. Unlike previous analyses that focused on individual species, we treat absolute and relative longevity as quantitative traits and demonstrate that these lifespan traits affect the evolutionary constraint on hundreds of genes. Specifically, we find that genes related to cell cycle, DNA repair, cell death, the [[IGF1]] pathway, and immunity are under increased evolutionary constraint in large and long-lived mammals. For mammals exceptionally long-lived for their body size, we find increased constraint in inflammation, DNA repair, and NFKB-related pathways. Strikingly, these pathways have considerable overlap with those that have been previously reported to have potentially adaptive changes in single-species studies, and thus would be expected to show decreased constraint in our analysis. This unexpected finding of increased constraint in many longevity-associated pathways underscores the power of our quantitative approach to detect patterns that generalize across the mammalian phylogeny.

|keywords=* RERconverge
* computational biology
* evolution
* genetics
* genomics
* longevity
* mammals
* phylogenomics
* systems biology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012612
}}
{{medline-entry
|title=17α-Estradiol promotes ovarian aging in growth hormone receptor knockout mice, but not wild-type littermates.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31698046
|abstract=Growth hormone receptor knockout mice (GHRKO) have reduced body size and increased insulin sensitivity. These mice are known for having extended lifespan, healthspan and female reproductive longevity. Seventeen α-estradiol (17α-E2) is reported to increase insulin sensitivity and extend lifespan in male mice, with less robust effects in female mice. The aim of this study was to evaluate the ovarian reserve in wild type and GHRKO mice treated with 17α-E2. The mice were divided into four groups, GHRKO mice receiving a standard chow diet, GHRKO mice treated 17α-E2, wild type mice receiving a standard chow diet and WT mice treated with 17α-E2. 17α-E2 was provided in the diet for four months. [[IGF1]] plasma concentrations and changes in body weight were assessed. Histological slides were prepared from the ovaries and the number of follicles was counted. GHRKO mice receiving the control diet had a greater number of primordial follicles and lower numbers of primary follicles compared to the other groups (p < 0.05). 17α-E2 treatment decreased the number of primordial follicles in GHRKO mice (p < 0.05), however had no effect in wild type mice. Treatment with 17α-E2 had no significant effect on the change in body weight during the experiment (p = 0.75). Plasma [[IGF1]] concentrations were significantly lower in GHRKO mice as compared to wild type. In conclusion, we found that GHRKO mice displayed lesser primordial follicle activation as compared to wild type mice, but this phenotype was reversed by 17α-E2 administration, suggesting that ovarian aging is increased by 17α-E2 in long-living mice with extended reproductive longevity.

|keywords=* Follicles
* Ovarian aging
* Ovarian reserve
* Reproductive lifespan
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911620
}}
==ERCC1==

{{medline-entry
|title=Chronic Sildenafil Treatment Improves Vasomotor Function in a Mouse Model of Accelerated Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32630010
|abstract=Aging leads to a loss of vasomotor control. Both vasodilation and vasoconstriction are affected. Decreased nitric oxide-cGMP-mediated relaxation is a hallmark of aging. It contributes to vascular disease, notably hypertension, infarction, and dementia. Decreased vasodilation can be caused by aging independently from cardiovascular risk factors. This process that can be mimicked in mice in an accelerated way by activation of the DNA damage response. Genetic deletion of the DNA repair enzyme [[ERCC1]] endonuclease in mice, as in the case of [i]Ercc1[/i]  mice, can be used as a tool to accelerate aging. [i]Ercc1[/i]  mice develop age-dependent vasomotor dysfunction from two months after birth. In the present study we tested if chronic treatment with sildenafil, a phosphodiesterase 5 inhibitor that augments NO-cGMP signaling, can reduce the development of vasomotor dysfunction in [i]Ercc1[/i]  mice. [i]Ercc1[/i]  mice and wild-type littermates were treated with 10 mg/kg/d of sildenafil from the age of 6 to the age of 14 weeks. Blood pressure and in vivo and ex vivo vasomotor responses were measured at the end of the treatment period. [i]Ercc1[/i]  mice developed decreased reactive hyperemia, and diminished NO-cGMP-dependent acetylcholine responses. The diminished acetylcholine response involved both endothelial and vascular smooth muscle cell signaling. Chronic sildenafil exclusively improved NO-cGMP signaling in VSMC, and had no effect on endothelium-derived hyperpolarization. Sildenafil also improved KCl hypocontractility in [i]Ercc1[/i]  mice. All effects were blood pressure-independent. The findings might be of clinical importance for prevention of morbidities related to vascular aging as well as for progeria patients with a high risk of cardiovascular disease.

|keywords=* aging
* cGMP
* guanylate cyclase
* hypertension
* nitric oxide
* phosphodiesterase
* sildenafil
* vascular dysfunction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369923
}}
{{medline-entry
|title=Local endothelial DNA repair deficiency causes aging-resembling endothelial-specific dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32202295
|abstract=We previously identified genomic instability as a causative factor for vascular aging. In the present study, we determined which vascular aging outcomes are due to local endothelial DNA damage, which was accomplished by genetic removal of [[ERCC1]] (excision repair cross-complementation group 1) DNA repair in mice (EC-knockout (EC-KO) mice). EC-KO showed a progressive decrease in microvascular dilation of the skin, increased microvascular leakage in the kidney, decreased lung perfusion, and increased aortic stiffness compared with wild-type (WT). EC-KO showed expression of DNA damage and potential senescence marker p21 exclusively in the endothelium, as demonstrated in aorta. Also the kidney showed p21-positive cells. Vasodilator responses measured in organ baths were decreased in aorta, iliac and coronary artery EC-KO compared with WT, of which coronary artery was the earliest to be affected. Nitric oxide-mediated endothelium-dependent vasodilation was abolished in aorta and coronary artery, whereas endothelium-derived hyperpolarization and responses to exogenous nitric oxide (NO) were intact. EC-KO showed increased superoxide production compared with WT, as measured in lung tissue, rich in endothelial cells (ECs). Arterial systolic blood pressure (BP) was increased at 3 months, but normal at 5 months, at which age cardiac output (CO) was decreased. Since no further signs of cardiac dysfunction were detected, this decrease might be an adaptation to prevent an increase in BP. In summary, a selective DNA repair defect in the endothelium produces features of age-related endothelial dysfunction, largely attributed to loss of endothelium-derived NO. Increased superoxide generation might contribute to the observed changes affecting end organ perfusion, as demonstrated in kidney and lung.
|mesh-terms=* Age Factors
* Aging
* Animals
* Capillary Permeability
* Cellular Senescence
* Cyclin-Dependent Kinase Inhibitor p21
* DNA Damage
* DNA Repair
* DNA-Binding Proteins
* Endonucleases
* Endothelial Cells
* Endothelium, Vascular
* Mice, Inbred C57BL
* Mice, Knockout
* Nitric Oxide
* Nitric Oxide Synthase Type III
* Superoxides
* Vascular Stiffness
* Vasodilation
|keywords=* DNA damage
* aging
* endothelial dysfunction
* endothelium-dependent dilation
* nitric oxide
|full-text-url=https://sci-hub.do/10.1042/CS20190124
}}
{{medline-entry
|title=Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31981461
|abstract=Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence-associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. [[ERCC1]]-XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16  and p21  mRNA were increased ~15-fold in peripheral lymphocytes from 4- to 5-month-old Ercc1  and 2.5-year-old wild-type (WT) mice, suggesting that these animals exhibit a similar biological age. p16  and p21  mRNA were elevated in 10 of 13 tissues analyzed from 4- to 5-month-old Ercc1  mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16  and p21  mRNA in the same 10 tissues as the mutant mice. Senescence-associated β-galactosidase activity and p21  protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1  mice with a p16  luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1  and aged WT mice support the conclusion that the DNA repair-deficient mice accurately model the age-related accumulation of senescent cells, albeit six-times faster.

|keywords=* DNA repair
* ERCC1-XPF
* aging
* cellular senescence
* endogenous DNA damage
* progeria
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059165
}}
{{medline-entry
|title=Deficiency in the DNA repair protein [[ERCC1]] triggers a link between senescence and apoptosis in human fibroblasts and mouse skin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31737985
|abstract=[[ERCC1]] (excision repair cross complementing-group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross-link repair. Ercc1  mice, carrying one null and one hypomorphic Ercc1 allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. Ercc1  mice display combined features of human progeroid and cancer-prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of Ercc1  mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1  mice are incompletely understood. Here, we show that [[ERCC1]] depletion, both in cultured human fibroblasts and the skin of Ercc1  mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence-associated secretory phenotype) factors. Cellular senescence induced by [[ERCC1]] deficiency was dependent on activity of the p53 tumor-suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring [[ERCC1]]-deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in Ercc1  mouse skin, where the apoptotic cells are localized, compared to age-matched wild-type skin, possibly due to the apoptosis of stem cells. These data suggest that [[ERCC1]]-depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health- or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.

|keywords=* DNA damage repair
* aging
* cell death
* senescence-associated secretory phenotype
* tumor necrosis factor α
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059167
}}
==FH==

{{medline-entry
|title=Genetic Factors of Alzheimer's Disease Modulate How Diet is Associated with Long-Term Cognitive Trajectories: A UK Biobank Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33252089
|abstract=Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer's disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD ([[FH]]) or APOE4 (ɛ4). Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). Daily cheese intake strongly predicted better FIT scores over time ([[FH]]-: β= 0.207, p < 0.001; ɛ4-: β= 0.073, p = 0.008; ɛ4+: β= 0.162, p = 0.001). Alcohol of any type daily also appeared beneficial (ɛ4+: β= 0.101, p = 0.022) and red wine was sometimes additionally protective ([[FH]]+: β= 0.100, p = 0.014; ɛ4-: β= 0.59, p = 0.039). Consuming lamb weekly was associated with improved outcomes ([[FH]]-: β= 0.066, p = 0.008; ɛ4+: β= 0.097, p = 0.044). Among at risk groups, added salt correlated with decreased performance ([[FH]]+: β= -0.114, p = 0.004; ɛ4+: β= -0.121, p = 0.009). Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among [[FH]]- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes.

|keywords=* APOE4
* Aging
* Mediterranean diet
* cognitive decline
* functional food
* lamb
* nutrition policy
* preventive medicine
* red wine
* salt
|full-text-url=https://sci-hub.do/10.3233/JAD-201058
}}
{{medline-entry
|title=Volumetric alterations in the hippocampal subfields of subjects at increased risk of dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32311609
|abstract=The hippocampus is one of the first regions to demonstrate atrophy during the prodromal stage of Alzheimer's disease. Volumetric analysis of its individual subfields could provide biomarkers with higher sensitivity than whole hippocampal volume during an earlier disease stage. We quantified the hippocampal subfields volume in a large cohort comprising healthy participants (aged 40-59) with dementia family history ([[FH]]) and controls (without [[FH]]), examined at 2 time points across 2 years. Subfield volumes were quantified using both a T1-weighted and a high-resolution T2 hippocampal magnetic resonance imaging acquisition with Freesurfer. The participants were stratified based on dementia [[FH]], APOE genotype, and CAIDE (Cardiovascular Risk Factors, Aging and Dementia) risk score. Whole hippocampal volume did not differ between the groups. The volume of the molecular layer was lower in participants with an APOE ε4 genotype, but there were no differences between subjects with and without dementia [[FH]] or with an increasing CAIDE score. The molecular layer may be the first hippocampal region to demonstrate volumetric alterations in subjects at risk of dementia.
|mesh-terms=* Adult
* Aging
* Alzheimer Disease
* Apolipoproteins E
* Atrophy
* Dementia
* Diffusion Magnetic Resonance Imaging
* Educational Status
* Female
* Genotype
* Hippocampus
* Humans
* Male
* Middle Aged
* Organ Size
* Risk
|keywords=* Alzheimer's disease
* Dementia
* Hippocampal subfields
* Hippocampus
* Preclinical dementia
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.03.006
}}
{{medline-entry
|title=Macroscopic hematuria as a risk factor for hypertension in ageing people with hemophilia and a family history of hypertension.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32118768
|abstract=Ageing people with hemophilia (PWH) have a higher prevalence of hypertension than the general population. This study aimed to determine whether macroscopic hematuria was associated with hypertension in PWH in a post hoc analysis using data from a cross-sectional study conducted by the ADVANCE Working Group (the H3 study), which included PWH ≥ 40 years of age. Data from 16 contributing centers, located in 13 European countries and Israel, were analyzed using logistic regression models. Of 532 recruited PWH in the H3 study, 117 had hypertension and a positive family history of hypertension (hypertension [[FH]]+), 75 had hypertension and a negative family history of hypertension (hypertension [[FH]]-), 290 had no diagnosis of hypertension, and the remaining 50 had missing hypertension data. Logistic regressions showed that macroscopic hematuria was associated with hypertension [[FH]]+, both in the univariate (OR = 1.84 [1.17-2.90], P = .01) and in the multivariate model (OR = 1.80 [1.03-3.16], P = .04). Macroscopic hematuria was not associated with hypertension [[FH]]-. Moreover, in a multivariate logistic regression the odds of hypertension [[FH]]+ were increased with the number of macroscopic hematuria episodes. The association between macroscopic hematuria and hypertension was significant for PWH with a family history of hypertension.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Cross-Sectional Studies
* Female
* Hematuria
* Hemophilia A
* Humans
* Hypertension
* Israel
* Logistic Models
* Male
* Middle Aged
* Risk Factors

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478422
}}
{{medline-entry
|title=LDL Receptor Deficiency Does not Alter Brain Amyloid-β Levels but Causes an Exacerbation of Apoptosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31815695
|abstract=Familial hypercholesterolemia ([[FH]]) is a genetic disorder caused by dysfunction of low density lipoprotein receptors (LDLr), resulting in elevated plasma cholesterol levels. [[FH]] patients frequently exhibit cognitive impairment, a finding recapitulated in LDLr deficient mice (LDLr-/-), an animal model of [[FH]]. In addition, LDLr-/- mice are more vulnerable to the deleterious memory impact of amyloid-β (Aβ), a peptide linked to Alzheimer's disease. Here, we investigated whether the expression of proteins involved in Aβ metabolism are altered in the brains of adult or middle-aged LDLr-/- mice. After spatial memory assessment, Aβ levels and gene expression of LDLr related-protein 1, proteins involved in Aβ synthesis, and apoptosis-related proteins were evaluated in prefrontal cortex and hippocampus. Moreover, the location and cell-specificity of apoptosis signals were evaluated. LDLr-/- mice presented memory impairment, which was more severe in middle-aged animals. Memory deficit in LDLr-/- mice was not associated with altered expression of proteins involved in Aβ processing or changes in Aβ levels in either hippocampus or prefrontal cortex. We further found that the expression of Bcl-2 was reduced while the expression of Bax was increased in both prefrontal cortex and hippocampus in 3- and 14-month-old LDLr-/-mice Finally, LDLr-/- mice presented increased immunoreactivity for activated caspase-3 in the prefrontal cortex and hippocampus. The activation of caspase 3 was predominantly associated with neurons in LDLr-/- mice. Cognitive impairment in LDLr-/- mice is thus accompanied by an exacerbation of neuronal apoptosis in brain regions related to memory formation, but not by changes in Aβ processing or levels.
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Animals
* Apoptosis
* Brain Chemistry
* Caspase 3
* Cholesterol
* Gene Expression
* Hippocampus
* Male
* Maze Learning
* Mice
* Mice, Inbred C57BL
* Mice, Knockout
* Prefrontal Cortex
* Receptors, LDL
|keywords=* Familial hypercholesterolemia
* LDLr-/- mice
* amyloid-β
* apoptosis
* memory impairment
|full-text-url=https://sci-hub.do/10.3233/JAD-190742
}}
==BRAF==

{{medline-entry
|title=Conditional reprograming culture conditions facilitate growth of lower grade glioma models.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33258947
|abstract=The conditional reprogramming cell culture method was developed to facilitate growth of senescence-prone normal and neoplastic epithelial cells, and involves co-culture with irradiated fibroblasts and the addition of a small molecule Rho kinase (ROCK) inhibitor. The aim of this study was to determine whether this approach would facilitate the culture of compact low grade gliomas. We attempted to culture 4 pilocytic astrocytomas, 2 gangliogliomas, 2 myxopapillary ependymomas, 2 anaplastic gliomas, 2 difficult-to-classify low grade neuroepithelial tumors, a desmoplastic infantile ganglioglioma, and an anaplastic pleomorphic xanthoastrocytoma using a modified conditional reprogramming cell culture approach. Conditional reprogramming resulted in robust increases in growth for a majority of these tumors, with fibroblast conditioned media and ROCK inhibition both required. Switching cultures to standard serum containing media, or serum free neurosphere conditions, with or without ROCK inhibition, resulted in decreased proliferation and induction of senescence markers. ROCK inhibition and conditioned media both promoted Akt and Erk1/2 activation. Several cultures, including one derived from a NF1-associated pilocytic astrocytoma (JHH-NF1-PA1) and one from a [[BRAF]] p.V600E mutant anaplastic pleomorphic xanthoastrocytoma (JHH-PXA1), exhibited growth sufficient for preclinical testing in vitro. In addition, JHH-NF1-PA1 cells survived and migrated in larval zebrafish orthotopic xenografts, while JHH-PXA1 formed orthotopic xenografts in mice histopathologically similar to the tumor from which it was derived. These studies highlight the potential for the conditional reprogramming cell culture method to promote the growth of glial and glioneuronal tumors in vitro, in some cases enabling the establishment of long-term culture and in vivo models.

|keywords=* BRAFV600E
* Conditional reprogramming
* NF1
* Senescence
* low grade glioma
|full-text-url=https://sci-hub.do/10.1093/neuonc/noaa263
}}
{{medline-entry
|title=Active notch protects MAPK activated melanoma cell lines from MEK inhibitor cobimetinib.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33202284
|abstract=The crosstalk between Notch and MAPK pathway plays a role in MEK inhibitor resistance in [[BRAF]]  metastatic melanoma (MM) and promotes migration in GNAQ  uveal melanoma (UM) cells. We determined the cytotoxicity of combinatorial inhibition of MEK and Notch by cobimetinib and γ-secretase inhibitor (GSI) nirogacestat, in [[BRAF]]  and [[BRAF]] wt MM and GNAQ  UM cells displaying different Erk1/2 and Notch activation status, with the aim to elucidate the impact of Notch signaling in the response to MEK inhibitor. Overall the combination was synergic in [[BRAF]]  MM and GNAQ  UM cells and antagonistic in [[BRAF]] wt one. Focusing on UM cells, we found that cobimetinib resulted in G0/G1 phase arrest and apoptosis induction, whereas the combination with GSI increased treatment efficacy by inducing a senescent-like state of cells and by blocking migration towards liver cancer cells. Mechanistically, this was reflected in a strong reduction of cyclin D1, in the inactivation of retinoblastoma protein and in the increase of p27  expression levels. Of note, each drug alone prevented Notch signaling activation resulting in inhibition of c-jun(Ser63) and Hes-1 expression. The combination achieved the strongest inhibition on Notch signaling and on both c-jun(Ser63) and Erk1/2 activation level. In conclusion we unveiled a coordinate action of MAPK and Notch signaling in promoting proliferation of [[BRAF]]  MM and GNAQ  UM cells. Remarkably, the simultaneous inhibition of MEK and Notch signaling highlighted a role for the second pathway in protecting cells against senescence in GNAQ  UM cells treated with the MEK inhibitor.

|keywords=* Cobimetinib (PubChem CID: 16222096)
* MEK
* Nirogacestat (PubChem CID:46224413)
* Notch
* Senescence
* Uveal melanoma
|full-text-url=https://sci-hub.do/10.1016/j.biopha.2020.111006
}}
{{medline-entry
|title=Mitochondrial metabolic reprograming via [[BRAF]] inhibition ameliorates senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31421186
|abstract=Senescence is defined as irreversible cell cycle arrest and constitutes a major driving force in diseases related to aging or premature aging. Recent studies indicate that activation of the serine/threonine protein kinase B-raf ([[BRAF]]) plays important roles in oncogene-induced senescence. However, it remains elusive whether [[BRAF]] inhibition might be effective for abrogating senescence. In this study, we assessed several [[BRAF]] inhibitors to identify compounds that ameliorate senescence and revealed SB590885 as an effective agent. Senescence-ameliorating effect upon [[BRAF]] inhibition was evident from the observation that SB590885 treatment increased cellular proliferation but diminished senescent phenotypes. Moreover, [[BRAF]] inhibition induced the mitochondrial functional recovery along with the metabolic reprogramming, which comprises two salient features that are altered in senescent cells. Furthermore, mitochondrial metabolic reprogramming via [[BRAF]] inhibition was a prerequisite for senescence amelioration. Taken together, our data revealed a novel mechanism in which senescence amelioration is mediated by mitochondrial metabolic reprogramming upon [[BRAF]] inhibition.
|mesh-terms=* Cell Proliferation
* Cells, Cultured
* Cellular Reprogramming
* Cellular Senescence
* Drug Evaluation, Preclinical
* Humans
* Mitochondria
* Proto-Oncogene Proteins B-raf
|keywords=* BRAF
* Metabolic reprogramming
* Mitochondrial function
* SB590885
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.exger.2019.110691
}}
==ARC==

{{medline-entry
|title=The Polymorphism rs2968 of [i]LSS[/i] Gene Confers Susceptibility to Age-Related Cataract.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32877255
|abstract=Research showed that lanosterol can decrease protein aggregation in lens and reduce cataract formation. Lanosterol synthase (LSS) and 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) are the limiting enzymes in the process of synthesis of lanosterol. We demonstrate to investigate the association between functional single-nucleotide polymorphisms (SNPs) of [i]LSS[/i] and [i]HMGCR[/i] genes and age-related cataract ([[ARC]]) risks in Han Chinese population from Jiangsu Eye Study. This is a case-control study. We collected participants' venous blood for DNA genotyping and lens capsule samples for RNA. The SNPs of the genes were assayed with TaqMan RT-PCR genotyping. The quantitative RT-PCR was used to detect the [i]LSS[/i] mRNA levels of lens epithelial cells (LECs) in individuals. The chi-square test was used to compare differences between [[ARC]] groups and controls of each SNP and to calculate the odds ratio (OR). We found that [i]LSS[/i]-rs2968 of [[ARC]]s was different from controls ([i]p[/i] = 0.018), but the significance was lost after Bonferroni correction ([i]p[/i] = 0.072). We then further performed stratification analysis and found that [i]LSS[/i]-rs2968 A allele was associated with nuclear type of [[ARC]] risk in Chinese population ([i]p[/i] = 0.012, OR = 0.68). Consequently, we found that the mRNA expression of [i]LSS[/i] was lower in LECs of all subtypes of [[ARC]] group than that of control group ([i]p[/i] < 0.05). [i]LSS[/i]-rs2968 A allele might play a role in the formation and development of nuclear type of [[ARC]] risk in Chinese population.
|mesh-terms=* Aged
* Aging
* Alleles
* Cataract
* Female
* Gene Expression Regulation
* Genetic Association Studies
* Genetic Predisposition to Disease
* Genotype
* Haplotypes
* Humans
* Hydroxymethylglutaryl CoA Reductases
* Intramolecular Transferases
* Lens, Crystalline
* Male
* Middle Aged
* Polymorphism, Single Nucleotide
|keywords=* ARC
* HMGCR
* LSS
* SNPs
* lanosterol
|full-text-url=https://sci-hub.do/10.1089/dna.2020.5872
}}
{{medline-entry
|title=Decreased Anti-Müllerian hormone and Anti-Müllerian hormone receptor type 2 in hypothalami of old Japanese Black cows.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32554955
|abstract=Cow fertility decreases with age, but the hypothalamic pathomechanisms are not understood. Anti-Müllerian hormone (AMH) stimulates gonadotropin-releasing hormone (GnRH) neurons via AMH receptor type 2 (AMHR2), and most GnRH neurons in the preoptic area (POA), arcuate nucleus ([[ARC]]), and median eminence (ME) express AMH and AMHR2. Therefore, we hypothesized that both protein amounts would differ in the anterior hypothalamus (containing the POA) and posterior hypothalamus (containing the [[ARC]] and ME) between young post-pubertal heifers and old cows. Western blot analysis showed lower (P<0.05) expressions of AMH and AMHR2 in the posterior hypothalamus, but not in the anterior hypothalamus, of old Japanese Black cows compared to young heifers. Therefore, AMH and AMHR2 were decreased in the posterior hypothalami of old cows.

|keywords=* Müllerian inhibiting substance
* female reproductive senescence
* gonadotropin-releasing hormone neuron
* preoptic area
* ruminant
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468072
}}
{{medline-entry
|title=Resveratrol delay the cataract formation against naphthalene-induced experimental cataract in the albino rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31746523
|abstract=Oxidative stress-induced toxicity plays a major role in ocular diseases such as retinal degeneration, age-related cataract ([[ARC]]) formation and macular dystrophy. In this study, we explored the possible role of resveratrol (RSV) at the different dose levels (10, 20 and 40 mg/kg/day, ip) in an experimental model of naphthalene (1 g/kg/day, po)-induced age-related cataracts. Morphological changes in the eyes of the rats in two groups, the RSV and the [[ARC]] groups, were monitored weekly, and biochemical parameters in the lenses were assessed after completion of the experimental work. A comparison between the rats in the two groups showed that treatments at RSV doses of 20 and 40 mg/kg/day significantly retarded lenticular opacity, restored antioxidants (CAT, SOD, GPX, GSH), Ca  ATPase function, and protein contents, and reduced lipid peroxidation in the lenses of the animals in the RSV group. The treatment with resveratrol at a dose of 10 mg/kg/day did not show any anti-cataractogenic effects. Based on the results of our investigation, we conclude that supplemental doses of resveratrol at 40 mg/kg/day effectively prevent cataract formation associated with the aging via increased soluble protein contents and Ca  homeostasis, apart from the antioxidant restoration. The results demonstrate that RSV treatment may be considered as a promising preventive or supplemental measure for delaying and/or preventing the formation of [[ARC]]s.
|mesh-terms=* Animals
* Cataract
* Dose-Response Relationship, Drug
* Male
* Naphthalenes
* Rats
* Rats, Sprague-Dawley
* Resveratrol
|keywords=* age-related cataracts
* aging
* oxidative stress
* resveratrol
|full-text-url=https://sci-hub.do/10.1002/jbt.22420
}}
==CPM==

{{medline-entry
|title=Test-Retest Instability of Temporal Summation and Conditioned Pain Modulation Measures in Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33083842
|abstract=The temporal stability (test-retest reliability) of temporal summation of pain (TS) and conditioned pain modulation ([[CPM]]) has yet to be established in healthy older adults. The purpose of this study was to compare the temporal stability of TS and [[CPM]] in healthy older and younger adults and to investigate factors that might influence TS and [[CPM]] stability. In a test-retest study, 40 healthy older adults and 30 healthy younger adults completed two sessions of quantitative sensory testing within a two-week period that included TS of heat pain, TS of mechanical pain, and [[CPM]] with pressure pain thresholds and suprathreshold heat pain as test stimuli and a cold water immersion as a conditioning stimulus. Participants also completed self-report measures of situational catastrophizing, anxiety, clinical pain, and physical activity. Absolute and relative stability were examined for each variable. Bivariate correlations examined the associations of age, clinical, behavioral, and psychological variables with the intra-individual stability of TS and [[CPM]]. The results revealed moderate to excellent stability for the TS measures and poor to moderate stability for [[CPM]]. The results also revealed significant age differences for two of the TS measures and [[CPM]], with younger adults having greater stability compared with older adults. Additionally, the magnitude and stability of psychological factors were correlated with stability of TS. These findings suggest that TS and [[CPM]] may be more reliable in younger compared with older adults. Furthermore, psychological states may be an important factor influencing the stability of TS in healthy adults.

|keywords=* Aging
* Anxiety
* Conditioned Pain Modulation
* Pain Catastrophizing
* Reliability
* Temporal Summation of Pain
|full-text-url=https://sci-hub.do/10.1093/pm/pnaa288
}}
{{medline-entry
|title=Age does not affect sex effect of conditioned pain modulation of pressure and thermal pain across 2 conditioning stimuli.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32072094
|abstract=Conditioned pain modulation ([[CPM]]) is a laboratory test resulting in pain inhibition through activation of descending inhibitory mechanisms. Older adults consistently demonstrate reduced [[CPM]] compared with younger samples; however, studies of sex differences in younger cohorts have shown mixed results. This study tested for sex differences in [[CPM]] within samples of younger and older adults. Participants were 67 younger adults (mean age = 25.4 years) and 50 older adults (66.4 years). Study conditioning paradigms were the cold-pressor test and contact heat pain administered in separate sessions. Pressure pain threshold and ramping suprathreshold heat were the test stimuli across three time points after presentation of the conditioning stimuli (CS). Significant inhibition was observed during both testing sessions. The hypothesis for sex differences across both age cohorts was supported only for ∆PPTh. However, sex differences did not reach significance for either paradigm using ascending suprathreshold heat as the test stimuli. The overall trend was that younger males experienced the strongest [[CPM]] and older females the weakest. From a methodological perspective, duration differences were seen in [[CPM]], with inhibition decaying more quickly for PPTh than for suprathreshold heat pain. Furthermore, there were no differences in inhibition induced by cold-pressor test and contact heat pain as CS. Sex differences were similar across both age cohorts with males experiencing greater inhibition than females. Cross-sectional associations were also demonstrated between [[CPM]] inhibition and measures of recent pain, further supporting [[CPM]] as an experimental model with clinical utility.

|keywords=* Aging
* CPM duration
* Conditioned pain modulation
* Conditioning stimulus
* Sex differences
* Test stimulus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004505
}}
{{medline-entry
|title=The Decline of Endogenous Pain Modulation With Aging: A Meta-Analysis of Temporal Summation and Conditioned Pain Modulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31562994
|abstract=The purpose of this article was to examine age-related changes in conditioned pain modulation ([[CPM]]) and temporal summation (TS) of pain using meta-analytic techniques. Five electronic databases were searched for studies, which compared measures of [[CPM]] and TS among healthy, chronic pain-free younger, middle-aged, and older adults. Eleven studies were included in the final review for TS and 11 studies were included in the review of [[CPM]]. The results suggested a moderate magnitude of difference in TS among younger and middle-aged/older adults, with the older cohorts exhibiting enhanced TS of pain. Considerable variability existed in the magnitude of the effect sizes, which was likely due to the different experimental methodologies used across studies (ie, interstimulus interval, stimulus type, and body location). In regards to [[CPM]], the data revealed a large magnitude of difference between younger and older adults, with younger adults exhibiting more efficient pain inhibition. Differences in [[CPM]] between middle-aged and older adults were minimal. The magnitude of pain inhibition during [[CPM]] in older adults may depend on the use of concurrent versus nonconcurrent protocols. In summary, the data provided strong quantitative evidence of a general age-related decline in endogenous pain modulatory function as measured by TS and [[CPM]]. PERSPECTIVE: This review compared [[CPM]] and TS of pain among younger, middle-aged, and older adults. These findings enhance our understanding of the decline in endogenous pain modulatory function associated with normal aging.

|keywords=* Aging
* conditioned pain modulation
* meta-analysis
* pain modulation
* temporal summation
|full-text-url=https://sci-hub.do/10.1016/j.jpain.2019.09.005
}}
==PAH==

{{medline-entry
|title=Changes in light absorption by brown carbon in soot particles due to heterogeneous ozone aging in a smog chamber.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32771846
|abstract=Light absorption by brown carbon (BrC) is dynamic due to atmospheric aging processes, leading to complex and poorly constrained effects on photochemistry and climate. In this study, a smog chamber was used to simulate the heterogeneous ozone (O ) aging of soot particles. Twelve aging times and seven O  concentrations were set to investigate the effects of aging degree on BrC light absorption. The results showed that light absorption by BrC was enhanced after O  aging, but followed a non-monotonic trend with an initial increase and subsequent decrease. An aging time of 60 min and O  concentration of 1.2 ppm were optimal for enhancing BrC absorption, where the contribution of BrC to total absorption and the contribution of BrC relative to black carbon absorption at 370 nm of ozonized soot were 23.0 ± 1.8% and 30.0 ± 3.0%, respectively, much greater than those of fresh soot (8.1 ± 1.1% and 8.8 ± 1.3%, respectively). The absorption Ångström exponent (AAE) and delta C (ΔC) of ozonized soot at 60 min ranged from 1.18 ± 0.01 to 1.31 ± 0.03 and from 13.5 ± 7.0 to 24.3 ± 13.5 μg m , respectively, and were greater than those of fresh soot (1.12 ± 0.02 and 8.0 ± 0.8 μg m ), but also showed non-monotonic trends, suggesting the formation of BrC during O  aging. Comparative results indicated that AAE might be a better BrC indicator for soot than ΔC. The non-monotonic trend was tentatively explained by changes in organic carbon, oxygenated functional groups and conjugated structures, as well as polycyclic aromatic hydrocarbon ([[PAH]]) degradation and oxygenated [[PAH]] formation. The relative intensities of oxidative formation and degradation of chromophores may determine BrC evolution during O  aging. This study will be useful for clarifying BrC evolution in the atmosphere and estimating its radiative forcing.
|mesh-terms=* Aerosols
* Biomass
* Carbon
* Ozone
* Smog
* Soot
|keywords=* Absorption Ångström exponent
* Brown carbon
* Light absorption
* Ozone aging
* Soot particles
|full-text-url=https://sci-hub.do/10.1016/j.envpol.2020.115273
}}
{{medline-entry
|title=Factors associated with pulmonary arterial hypertension ([[PAH]]) in systemic sclerosis (SSc).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32659476
|abstract=Pulmonary arterial hypertension ([[PAH]]) in systemic sclerosis (SSc) is a lethal complication affecting 8-15% of patients. Screening tests such as echocardiography and pulmonary function tests allow for triaging patients for diagnosis by right heart catheterization. Understanding risk factors of SSc-[[PAH]] could help differentiate high-risk patients. A systematic review was conducted to determine associations with SSc-[[PAH]], including clinical/disease characteristics, antibodies, labs and biomarkers. The frequencies of publications featuring each risk/association were reported. Among 2654 articles, 984 duplicates and 1578 irrelevant articles were removed, leaving 92 articles for manual screening. After excluding 55 papers with small sample sizes, publications from identical cohorts, not English language, or [[PAH]] not ascertained by RHC, 37 articles were eligible. A total of 43 factors for SSc-[[PAH]] were identified within seven categories. Several associations were due to [[PAH]] and risk factors such as dynpnea, right heart failure, and short 6-minute walk distance. Patient characteristics (14), pulmonary physiology (6), antibody profiles (6) and genetics/epigenetics (6) had the most numerous and diverse factors, while biomarkers (4) and other labs (2) features were infrequent. Low carbon monoxide (DLCO) (6), older age (4), longer disease duration (4), positive anticentromere antibodies (ACA) (4), telangiectasias (4), high brain natriuretic peptide (4) were frequent associations. Risk factors for SSc-[[PAH]] such as ACA, older age, longer disease duration limited cutaneous SSc subset and presence of ILD may enrich screening programs. Genes and other antibody profiles are inconsistent and requires further validation.
|mesh-terms=* Aging
* Humans
* Natriuretic Peptide, Brain
* Pulmonary Arterial Hypertension
* Risk Factors
* Scleroderma, Systemic

|full-text-url=https://sci-hub.do/10.1016/j.autrev.2020.102602
}}
{{medline-entry
|title=Potentially Avoidable Hospitalization among Long-Term Care Insurance Beneficiaries with Dementia.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32316707
|abstract=This study investigated the differences in the risk of potentially avoidable hospitalization ([[PAH]]) among eligible long-term care insurance (LTCI) beneficiaries with dementia for LTCI services in Korea. Nested case-control study was conducted using the National Health Insurance Service-Senior claim database. Cases of individuals who had a [[PAH]] incident diagnosis and controls were selected by incidence density sampling and matched to cases based on age, sex, and difficulty of daily living among dementia patients. We conducted incidence density sampling three times by [[PAH]] type. Our main results were presented by conditional logistic regression analysis for the matched case-control studies. Out of the 7,352 eligible LTCI beneficiary patients, there were 1,231 cases (16.7%) in overall [[PAH]], 132 cases (19.0%) in acute [[PAH]] and 1,114 cases (16.7%) in chronic [[PAH]] categories. In terms of individual risk of overall and chronic [[PAH]], the odds ratios of those who did not receive any services were 1.336 time higher (95% confidence interval [CI], 1.159-1.540) and 1.280 time higher (95% CI, 1.103-1.485) compared to those who received home care, respectively. For risk of acute [[PAH]], the odds ratios of those who did receive institutional care were 2.046 time higher (95% CI, 1.170-3.578) compared to those who received home care. This study identified the differences in risk of [[PAH]] incidents according to the type of LTCI service in the elderly population in Korea. Therefore, it will require substantial effort and strategy from health policy makers to improve care quality.

|keywords=* Aging
* Dementia
* Long-Term Care
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509129
}}
==DNMT3A==

{{medline-entry
|title=Epigenetic regulation of miR-29a/miR-30c/[[DNMT3A]] axis controls SOD2 and mitochondrial oxidative stress in human mesenchymal stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32961441
|abstract=The use of human mesenchymal stem cells (hMSCs) in clinical applications requires large-scale cell expansion prior to administration. However, the prolonged culture of hMSCs results in cellular senescence, impairing their proliferation and therapeutic potentials. To understand the role of microRNAs (miRNAs) in regulating cellular senescence in hMSCs, we globally depleted miRNAs by silencing the DiGeorge syndrome critical region 8 (DGCR8) gene, an essential component of miRNA biogenesis. DGCR8 knockdown hMSCs exhibited severe proliferation defects and senescence-associated alterations, including increased levels of reactive oxygen species (ROS). Transcriptomic analysis revealed that the antioxidant gene superoxide dismutase 2 (SOD2) was significantly downregulated in DGCR8 knockdown hMSCs. Moreover, we found that DGCR8 silencing in hMSCs resulted in hypermethylation in CpG islands upstream of SOD2. 5-aza-2'-deoxycytidine treatment restored SOD2 expression and ROS levels. We also found that these effects were dependent on the epigenetic regulator DNA methyltransferase 3 alpha ([[DNMT3A]]). Using computational and experimental approaches, we demonstrated that [[DNMT3A]] expression was regulated by miR-29a-3p and miR-30c-5p. Overexpression of miR-29a-3p and/or miR-30c-5p reduced ROS levels in DGCR8 knockdown hMSCs and rescued proliferation defects, mitochondrial dysfunction, and premature senescence. Our findings provide novel insights into hMSCs senescence regulation by the miR-29a-3p/miR-30c-5p/[[DNMT3A]]/SOD2 axis.

|keywords=* Cellular senescence
* DNMT3A
* Human mesenchymal stem cells
* Mitochondrial oxidative stress
* SOD2
* microRNAs
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509080
}}
{{medline-entry
|title=Collagens and DNA methyltransferases in mare endometrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31512314
|abstract=Inflammation and fibroproliferative diseases may be modulated by epigenetic changes. Therefore, we suggest that epigenetic mechanisms could be involved in equine endometrosis pathogenesis. DNA methylation is one of the methods to evaluate epigenetics, through the transcription of methyltransferases (DNMT1, [[DNMT3A]], DNMT3B). The correlation between DNMTs and collagen (COL) transcripts was assessed for the different Kenney and Doig's (Current Therapy in Theriogenology. Philadelphia: WB Saunders; 1986) endometrium categories. Endometrial biopsies were randomly collected from cyclic mares. Histological classification (category I, n = 13; II A, n = 17; II B, n = 12; and III, n = 7) and evaluation of COL1A2, COL3A1 and DNMTs transcripts by qPCR, were performed. Data were analysed by one-way analysis of variance (ANOVA), Kruskal-Wallis test and Pearson correlation. As mares aged, there was an increase in endometrium fibrosis (p < .01), and in DNMT1 mRNA (p < .001). Considering DNMT3B transcripts for each category, there was an increase with fibrosis (p < .05). No changes were observed for DNMT1 and [[DNMT3A]] transcripts. However, [[DNMT3A]] mRNA levels were the highest in all categories (p < .01). In category I endometrium, a positive correlation was observed for transcripts of all DNMTs in both COLs (p < .01). In category IIA, this correlation was also maintained for all DNMTs transcripts in COL1A2 (p < .05), but only for DNMT3B in COL3A1 (p < .05). In category IIB, there was a positive correlation between DNMT3B and COL3A1 (p < .05). In category III, a positive correlation was only observed between DNMT3B and COL3A1 (p < .05). Our results suggest that there is a disturbance in COLs and DNMTs correlation during fibrosis.
|mesh-terms=* Aging
* Animals
* Collagen
* DNA (Cytosine-5-)-Methyltransferases
* DNA Methylation
* Endometritis
* Endometrium
* Female
* Fibrosis
* Horse Diseases
* Horses
* RNA, Messenger
|keywords=* DNA methylation
* collagen
* endometrium
* epigenetic
* fibrosis
* mare
|full-text-url=https://sci-hub.do/10.1111/rda.13515
}}
{{medline-entry
|title=Age-related clonal haemopoiesis is associated with increased epigenetic age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31430471
|abstract=Age-related clonal haemopoiesis (ARCH) in healthy individuals was initially observed through an increased skewing in X-chromosome inactivation [1]. More recently, several groups reported that ARCH is driven by somatic mutations [2], with the most prevalent ARCH mutations being in the [[DNMT3A]] and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers [2]. ARCH also confers an increased risk for non-haematological diseases, such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor [3,4]. Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly used tools to measure age acceleration are epigenetic clocks: they are based on age-related methylation differences at specific CpG sites [5]. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities [5,6]. Here we present evidence of accelerated epigenetic age in individuals with ARCH.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Epigenesis, Genetic
* Female
* Hematopoiesis
* Humans
* Longitudinal Studies
* Male
* Risk Factors
* Scotland

|full-text-url=https://sci-hub.do/10.1016/j.cub.2019.07.011
}}
==TNC==

{{medline-entry
|title=Effects of Tenascin C on the Integrity of Extracellular Matrix and Skin Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33217999
|abstract=Tenascin C ([[TNC]]) is an element of the extracellular matrix (ECM) of various tissues, including the skin, and is involved in modulating ECM integrity and cell physiology. Although skin aging is apparently associated with changes in the ECM, little is known about the role of [[TNC]] in skin aging. In this study, we found that the [i]Tnc[/i] mRNA level was significantly reduced in the skin tissues of aged mice compared with young mice, consistent with reduced [[TNC]] protein expression in aged human skin. [[TNC]]-large ([[TNC]]-L; 330-kDa) and -small ([[TNC]]-S; 240-kDa) polypeptides were observed in conditional media from primary dermal fibroblasts. Both recombinant [[TNC]] polypeptides, corresponding to [[TNC]]-L and [[TNC]]-S, increased the expression of type I collagen and reduced the expression of matrix metalloproteinase-1 in fibroblasts. Treatment of fibroblasts with a recombinant [[TNC]] polypeptide, corresponding to [[TNC]]-L, induced phosphorylation of SMAD2 and SMAD3. [[TNC]] increased the level of transforming growth factor-β1 ([i]TGF-β1[/i]) mRNA and upregulated the expression of type I collagen by activating the TGF-β signaling pathway. In addition, [[TNC]] also promoted the expression of type I collagen in fibroblasts embedded in a three-dimensional collagen matrix. Our findings suggest that [[TNC]] contributes to the integrity of ECM in young skin and to prevention of skin aging.

|keywords=* TGF-β
* aging
* collagen
* extracellular matrix
* fibroblast
* skin
* tenascin C
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698786
}}
{{medline-entry
|title=Tenascin-C expression controls the maturation of articular cartilage in mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32066496
|abstract=Expression of the de-adhesive extracellular matrix protein tenascin-C ([[TNC]]) is associated with the early postnatal development of articular cartilage which is both load-dependent and associated with chondrocyte differentiation. We assessed morphological changes in the articular cartilage of [[TNC]] deficient mice at postnatal ages of 1, 4 and 8 weeks compared to age-matched wildtype mice. Cartilage integrity was assessed based on hematoxylin and eosin stained-sections from the tibial bone using a modified Mankin score. Chondrocyte density and cartilage thickness were assessed morphometrically. [[TNC]] expression was localized based on immunostaining. At 8 weeks of age, the formed tangential/transitional zone of the articular cartilage was 27% thicker and the density of chondrocytes in the articular cartilage was 55% lower in wildtype than the [[TNC]]-deficient mice. [[TNC]] protein expression was associated with chondrocytes. No relevant changes were found in mice at 1 and 4 weeks of age. The findings indicate a role of tenascin-C in the post-natal maturation of the extracellular matrix in articular cartilage. This might be a compensatory mechanism to strengthen resilience against mechanical stress.
|mesh-terms=* Aging
* Animals
* Cartilage, Articular
* Cell Count
* Genotype
* Mice
* Tenascin
|keywords=* Adhesion
* Articular cartilage
* Cartilage defect
* Cell density
* Knock-out mouse
* Load
* Tenascin C
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027060
}}
{{medline-entry
|title=Effects of hydrothermal aging, thermal cycling, and water storage on the mechanical properties of a machinable resin-based composite containing nano-zirconia fillers.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31877525
|abstract=This study aimed to investigate the effects of hydrothermal aging, thermal cycling, and water storage on the mechanical properties of a machinable resin-based composite containing nano-zirconia fillers. A machinable resin-based composite containing nano-zirconia fillers (Lava Ultimate, LU) and a resin-based composite with a similar resin matrix-to-filler ratio but without zirconia fillers (Tetric N-Ceram, [[TNC]]) were prepared into bars and assigned into four groups based on the type of aging treatment (hydrothermal aging, thermal cycling, water storage, or no aging). The phase transformations of the zirconia fillers in LU after aging were evaluated by X-ray diffraction. The flexural strength, Weibull modulus, flexural modulus, and Vickers hardness of each group were investigated. The fracture surface morphologies of both resin-based composites before and after aging were observed by a scanning electron microscopy (SEM). Only Tetragonal zirconia was detected in the LU samples. Both before and after aging, the flexural strength, flexural modulus, and Vickers hardness values of LU were significantly higher than those of [[TNC]] (p < 0.05) with the exception of the flexural modulus of LU, which showed no difference with that of [[TNC]] after water storage (p = 0.68). Hydrothermal aging, thermal cycling, and water storage had no significant effects on the surface Vickers hardnesses of LU or [[TNC]] (p > 0.05). Hydrothermal aging significantly improved the flexural strength of LU (p = 0.00). Thermal cycling (p = 0.00) and water storage (p = 0.00) significantly decreased the flexural strength of LU. The flexural strength of [[TNC]] was not decreased by hydrothermal aging (p = 0.82) or water storage (p = 0.36), while it was decreased by thermal cycling (p = 0.00). The hydrothermal aging group of LU exhibited the highest Weibull modulus. The machinable resin-based composite containing nano-zirconia fillers provides superior flexural strength, flexural modulus, and Vickers hardness compared to the direct-filling resin-based composite with a similar resin matrix-to-filler ratio, although it fails to provide better aging resistance.

|keywords=* Aging
* Mechanical properties
* Nano-zirconia
* Phase transformation
* Resin nano-ceramic
* Resin-based composite
|full-text-url=https://sci-hub.do/10.1016/j.jmbbm.2019.103522
}}
==NRAS==

{{medline-entry
|title=Senescent cholangiocytes release extracellular vesicles that alter target cell phenotype via the epidermal growth factor receptor.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32558183
|abstract=Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by peribiliary inflammation and fibrosis. Cholangiocyte senescence is a prominent feature of PSC. Here, we hypothesize that extracellular vesicles (EVs) from senescent cholangiocytes influence the phenotype of target cells. EVs were isolated from normal human cholangiocytes (NHCs), cholangiocytes from PSC patients and NHCs experimentally induced to senescence. NHCs, malignant human cholangiocytes (MHCs) and monocytes were exposed to 10  EVs from each donor cell population and assessed for proliferation, MAPK activation and migration. Additionally, we isolated EVs from plasma of wild-type and Mdr2  mice (a murine model of PSC), and assessed mouse monocyte activation. EVs exhibited the size and protein markers of exosomes. The number of EVs released from senescent human cholangiocytes was increased; similarly, the EVs in plasma from Mdr2  mice were increased. Additionally, EVs from senescent cholangiocytes were enriched in multiple growth factors, including EGF. NHCs exposed to EVs from senescent cholangiocytes showed increased [[NRAS]] and ERK1/2 activation. Moreover, EVs from senescent cholangiocytes promoted proliferation of NHCs and MHCs, findings that were blocked by erlotinib, an EGF receptor inhibitor. Furthermore, EVs from senescent cholangiocytes induced EGF-dependent Interleukin 1-beta and Tumour necrosis factor expression and migration of human monocytes; similarly, Mdr2  mouse plasma EVs induced activation of mouse monocytes. The data continue to support the importance of cholangiocyte senescence in PSC pathogenesis, directly implicate EVs in cholangiocyte proliferation, malignant progression and immune cell activation and migration, and identify novel therapeutic approaches for PSC.

|keywords=* biliary epithelial cell
* cellular senescence
* extracellular vesicles
* primary sclerosing cholangitis
* senescence-associated secretory phenotype
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669612
}}
{{medline-entry
|title=STAT3 Relays a Differential Response to Melanoma-Associated [i][[NRAS]][/i] Mutations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31906480
|abstract=Melanoma patients carrying an oncogenic [i][[NRAS]][/i] mutation represent 20% of all cases and present worse survival, relapse rate and therapy response than patients with wild type [i][[NRAS]][/i] or with [i]BRAF[/i] mutations. Nevertheless, no efficient targeted therapy has emerged so far for this group of patients in comparison with the classical combination of BRAF and MEK inhibitors for the patient group carrying a [i]BRAF[/i] mutation. [[NRAS]] key downstream actors should therefore be identified for drug targeting, possibly in combination with MEK inhibitors. Here, we investigated the influence of different melanoma-associated [i][[NRAS]][/i] mutations (codon 12, 13 or 61) on several parameters such as oncogene-induced senescence, cell proliferation, migration or colony formation in immortalized melanocytes and in melanoma cell lines. We identified AXL/STAT3 axis as a main regulator of [i][[NRAS]]Q61[/i]-induced oncogene-induced senescence (OIS) and observed that [i][[NRAS]]Q61[/i] mutations are not only more tumorigenic than [i][[NRAS]]G12/13[/i] mutations but also associated to STAT3 activation. In conclusion, these data bring new evidence of the potential tumorigenic role of STAT3 in [i][[NRAS]][/i]-mutant melanomas and will help improving current therapy strategies for this particular patient group.

|keywords=* NRAS
* STAT3
* melanoma
* mutation
* oncogene-induced senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016650
}}
{{medline-entry
|title=Cooperation of Dnmt3a R878H with Nras G12D promotes leukemogenesis in knock-in mice: a pilot study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31703632
|abstract=DNMT3A R882H, a frequent mutation in acute myeloid leukemia (AML), plays a critical role in malignant hematopoiesis. Recent findings suggest that DNMT3A mutant acts as a founder mutation and requires additional genetic events to induce full-blown AML. Here, we investigated the cooperation of mutant DNMT3A and [[NRAS]] in leukemogenesis by generating a double knock-in (DKI) mouse model harboring both Dnmt3a R878H and Nras G12D mutations. DKI mice with both Dnmt3a R878H and Nras G12D mutations were generated by crossing Dnmt3a R878H knock-in (KI) mice and Nras G12D KI mice. Routine blood test, flow cytometry analysis and morphological analysis were performed to determine disease phenotype. RNA-sequencing (RNA-seq), RT-PCR and Western blot were carried out to reveal the molecular mechanism. The DKI mice developed a more aggressive AML with a significantly shortened lifespan and higher percentage of blast cells compared with KI mice expressing Dnmt3a or Nras mutation alone. RNA-seq analysis showed that Dnmt3a and Nras mutations collaboratively caused abnormal expression of a series of genes related to differentiation arrest and growth advantage. Myc transcription factor and its target genes related to proliferation and apoptosis were up-regulated, thus contributing to promote the process of leukemogenesis. This study showed that cooperation of DNMT3A mutation and [[NRAS]] mutation could promote the onset of AML by synergistically disturbing the transcriptional profiling with Myc pathway involvement in DKI mice.
|mesh-terms=* Animals
* Apoptosis
* Carcinogenesis
* Cell Differentiation
* DNA (Cytosine-5-)-Methyltransferases
* Disease Models, Animal
* Disease Progression
* Gene Expression Regulation, Neoplastic
* Gene Knock-In Techniques
* Leukemia, Myeloid, Acute
* Longevity
* Mice
* Mice, Inbred C57BL
* Mice, Transgenic
* Monomeric GTP-Binding Proteins
* Mutation
* Phenotype
* Pilot Projects
* Proto-Oncogene Proteins c-myc
* RNA-Seq
* Transcription, Genetic
|keywords=* Acute myeloid leukemia
* DNMT3A mutation
* Myc activation
* Nras G12D
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842226
}}
==FABP3==

{{medline-entry
|title=[[FABP3]]-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33168829
|abstract=Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that [[FABP3]] is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that [[FABP3]] overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. [[FABP3]]-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. [[FABP3]] knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, [[FABP3]] reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, [[FABP3]] drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.
|mesh-terms=* Aging
* Animals
* Cell Line
* Endoplasmic Reticulum Stress
* Eukaryotic Initiation Factor-2
* Fatty Acid Binding Protein 3
* Female
* Gene Knockdown Techniques
* Lipidomics
* Membrane Fluidity
* Membrane Lipids
* Mice, Inbred C57BL
* Mice, Knockout
* Muscle, Skeletal
* Myoblasts
* Phospholipids
* Protein-Serine-Threonine Kinases
* Sarcopenia
* Up-Regulation

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653047
}}
{{medline-entry
|title=Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing [[FABP3]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33143524
|abstract=Senile osteoporosis (OP) is often concomitant with decreased autophagic activity. OPTN (optineurin), a macroautophagy/autophagy (hereinafter referred to as autophagy) receptor, is found to play a pivotal role in selective autophagy, coupling autophagy with bone metabolism. However, its role in osteogenesis is still mysterious. Herein, we identified [i]Optn[/i] as a critical molecule of cell fate decision for bone marrow mesenchymal stem cells (MSCs), whose expression decreased in aged mice. Aged mice revealed osteoporotic bone loss, elevated senescence of MSCs, decreased osteogenesis, and enhanced adipogenesis, as well as [i]optn [/i]   mice. Importantly, restoring [i]Optn[/i] by transplanting wild-type MSCs to [i]optn [/i]   mice or infecting [i]optn [/i]   mice with [i]Optn[/i]-containing lentivirus rescued bone loss. The introduction of a loss-of-function mutant of [i]Optn [/i] failed to reestablish a bone-fat balance. We further identified [[FABP3]] (fatty acid binding protein 3, muscle and heart) as a novel selective autophagy substrate of OPTN. [[FABP3]] promoted adipogenesis and inhibited osteogenesis of MSCs. Knockdown of [[FABP3]] alleviated bone loss in [i]optn [/i]   mice and aged mice. Our study revealed that reduced OPTN expression during aging might lead to OP due to a lack of [[FABP3]] degradation via selective autophagy. [[FABP3]] accumulation impaired osteogenesis of MSCs, leading to the occurrence of OP. Thus, reactivating OPTN or inhibiting [[FABP3]] would open a new avenue to treat senile OP.   ADIPOQ: adiponectin, C1Q and collagen domain containing; ALPL: alkaline phosphatase, liver/bone/kidney; BGLAP/OC/osteocalcin: bone gamma carboxyglutamate protein; BFR/BS: bone formation rate/bone surface; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CDKN1A/p21: cyclin-dependent kinase inhibitor 1A; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CDKN2B/p15: cyclin dependent kinase inhibitor 2B; CEBPA: CCAAT/enhancer binding protein (C/EBP), alpha; COL1A1: collagen, type I, alpha 1; Ct. BV/TV: cortical bone volume fraction; Ct. Th: cortical thickness; Es. Pm: endocortical perimeter; FABP4/Ap2: fatty acid binding protein 4, adipocyte; H2AX: H2A.X variant histone; HE: hematoxylin and eosin; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MAR: mineral apposition rate; MSCs: bone marrow mesenchymal stem cells; NBR1: NBR1, autophagy cargo receptor; OP: osteoporosis; OPTN: optineurin; PDB: Paget disease of bone; PPARG: peroxisome proliferator activated receptor gamma; Ps. Pm: periosteal perimeter; qRT-PCR: quantitative real-time PCR; γH2AX: Phosphorylation of the Serine residue of H2AX; ROS: reactive oxygen species; RUNX2: runt related transcription factor 2; SA-GLB1: senescence-associated (SA)-GLB1 (galactosidase, beta 1); SP7/Osx/Osterix: Sp7 transcription factor 7; SQSTM1/p62: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; Tb. BV/TV: trabecular bone volume fraction; Tb. N: trabecular number; Tb. Sp: trabecular separation; Tb. Th: trabecular thickness; μCT: micro computed tomography.

|keywords=* Adipogenesis
* autophagy
* bone metabolism
* fabp3
* mesenchymal stem cell
* optineurin
* osteogenesis
* osteoporosis
* senescence
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1839286
}}
{{medline-entry
|title=Myokines as biomarkers of frailty and cardiovascular disease risk in females.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32017952
|abstract=Frailty is a risk factor for cardiovascular disease (CVD). Biomarkers have the potential to detect the early stages of frailty, such as pre-frailty. Myokines may act as biomarkers of frailty-related disease progression, as a decline in muscle health is a hallmark of the frailty phenotype. This study is a secondary analysis of 104 females 55 years of age or older with no previous history of CVD. Differences in systemic myokine concentrations based on frailty status and CVD risk profile were examined using a case-control design. Propensity matching identified two sets of 26 pairs with pre-frailty as the exposure variable in low or elevated CVD risk groups for a total 104 female participants. Frailty was assessed using the Fried Criteria (FC) and CVD risk was assessed using the Framingham Risk Score (FRS). Factorial ANOVA compared the main effects of frailty, CVD risk, and their interaction on the concentrations of 15 myokines. Differences were found when comparing elevated CVD risk status with low for the concentrations of EPO (384.76 ± 1046.07 vs. 206.63 ± 284.61 pg/mL, p = .001), [[FABP3]] (2772.61 ± 3297.86 vs. 1693.31 ± 1019.34 pg/mL, p = .017), FGF21 (193.17 ± 521.09 vs. 70.18 ± 139.51 pg/mL, p = .010), IL-6 (1.73 ± 4.97 vs. 0.52 ± 0.89 pg/mL, p = .023), and IL-15 (2.62 ± 10.56 vs. 0.92 ± 1.25 pg/mL, p = .022). Pre-frail females had lower concentrations of fractalkine compared to robust (27.04 ± 20.60 vs. 103.62 ± 315.45 pg/mL, p = .004). Interaction effects between frailty status and CVD risk for FGF21 and OSM were identified. In elevated CVD risk, pre-frail females, concentrations of FGF21 and OSM were lower than that of elevated CVD risk, robust females (69.10 ± 62.86 vs. 317.24 ± 719.69, p = .011; 1.73 ± 2.32 vs. 24.43 ± 69.21, p = .018, respectively). These data identified specific biomarkers of CVD risk and biomarkers of frailty that are exacerbated with CVD risk.

|keywords=* Aging
* Biomarkers
* Cardiovascular disease
* Females
* Frailty
* Myokines
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110859
}}
==IL10==

{{medline-entry
|title=The beneficial effect of physical exercise on inflammatory makers in older individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32504508
|abstract=Old age is associated with a loss of motor functions and a general progressive decline in cognitive functions. Physical exercise is one of the ways in which inflammatory levels in general can be reduced, and therefore physical exercise can be considered a biological aging decelerator. In this article we examine the relationships between physical exercise and inflammatory markers reported for the different physical exercise protocols that have been used in studies with older individuals, as well as the effects of these regimens. The different types of exercises programmed, and methods used to implement them were very heterogeneous in the articles we analysed. Both, the aerobic exercise and resistance training protocols produced a decrease in plasma levels of IL-6, CRP and TNF-α, and an increase of [[IL10]] plasma levels as a chronic effect. However, the acute-response of physical exercise appeared to be an initial increase in IL-6 expression and plasma IL-6 levels. Continuing with these exercise programs usually subsequently achieved a chronic response in which there was a decrease in both the basal levels of IL-6, CRP and TNF-α, and the IL-6 produced as acute responses. Regardless of the type of exercise performed, it seems that the exercise parameters, intensity, duration, subject variables, fitness, and level of inflammation are key factors in achieving the expected balance between pro-inflammatory and antiinflammatory cytokines.

|keywords=* IL-6 expression
* Inflammatory markers
* aerobic exercise
* aging
* plasma IL-6 levels
* resistance training
|full-text-url=https://sci-hub.do/10.2174/1871530320666200606225357
}}
{{medline-entry
|title=Astrocyte senescence may drive alterations in GFAPα, CDKN2A p14 , and TAU3 transcript expression and contribute to cognitive decline.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31654269
|abstract=The accumulation of senescent cells in tissues is causally linked to the development of several age-related diseases; the removal of senescent glial cells in animal models prevents Tau accumulation and cognitive decline. Senescent cells can arise through several distinct mechanisms; one such mechanism is dysregulation of alternative splicing. In this study, we characterised the senescent cell phenotype in primary human astrocytes in terms of SA-β-Gal staining and SASP secretion, and then assessed splicing factor expression and candidate gene splicing patterns. Finally, we assessed associations between expression of dysregulated isoforms and premature cognitive decline in 197 samples from the InCHIANTI study of ageing, where expression was present in both blood and brain. We demonstrate here that senescent astrocytes secrete a modified SASP characterised by increased IL8, MMP3, MMP10, and TIMP2 but decreased [[IL10]] levels. We identified significant changes in splicing factor expression for 10/20 splicing factors tested in senescent astrocytes compared with early passage cells, as well as dysregulation of isoform levels for 8/13 brain or senescence genes tested. Finally, associations were identified between peripheral blood GFAPα, TAU3, and CDKN2A (P14 ) isoform levels and mild or severe cognitive decline over a 3-7-year period. Our data are suggestive that some of the features of cognitive decline may arise from dysregulated splicing of important genes in senescent brain support cells, and that defects in alternative splicing or splicing regulator expression deserve exploration as points of therapeutic intervention in the future.
|mesh-terms=* Aged
* Alternative Splicing
* Astrocytes
* Cells, Cultured
* Cellular Senescence
* Cognitive Dysfunction
* Cytokines
* Gene Expression
* Glial Fibrillary Acidic Protein
* Humans
* Matrix Metalloproteinases
* Transcription, Genetic
* Tumor Suppressor Protein p14ARF
* tau Proteins
|keywords=* Alternative splicing
* Gene expression
* Neurodegenerative disease
* Senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885035
}}
{{medline-entry
|title=Dietary Spray-Dried Porcine Plasma Prevents Cognitive Decline in Senescent Mice and Reduces Neuroinflammation and Oxidative Stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31562503
|abstract=Aging is characterized by chronic, low-grade inflammation that correlates with cognitive decline. Dietary supplementation with spray-dried porcine plasma (SDP) reduces immune activation in rodent models of inflammation and aging. We investigated whether the anti-inflammatory properties of SDP could ameliorate age-related cognitive deterioration and preserve brain homeostasis in an aging mouse model of senescence. Male senescence-accelerated prone 8 (SAMP8) mice were used. In Experiment 1, cognitive performance (n  = 10-14 mice/group) was analyzed by the novel object recognition test in 2-mo-old mice (2M group) and in mice fed a control diet or a diet supplemented with 8% SDP for 2 (4M-CTL and 4M-SDP groups) and 4 mo (6M-CTL and 6M-SDP groups). In Experiment 2, the permeability of the blood-brain barrier and junctional proteins in brain tissue was assessed, as well as synaptic density, oxidative stress markers, and inflammatory genes and proteins in mice from the 2M, 6M-CTL, and 6M-SDP groups ( n = 5-11). Statistical analyses included one-factor ANOVA followed by Fisher's posthoc test. 6M-SDP mice had better cognitive performance than 6M-CTL mice in both short-term (P = 0.024) and long-term (P = 0.017) memory tests. In brain tissue, 6M-SDP mice showed reduced brain capillary permeability (P = 0.034) and increased ZO1 and E-cadherin expression (both P <0.04) compared with 6M-CTL mice. SDP also prevented the NFκB activation observed in 6M-CTL mice (P = 0.002) and reduced Il6 expression and hydrogen peroxide concentration (both P <0.03) observed in 6M-CTL mice. SDP also increased the concentration of [[IL10]] (P = 0.027), an anti-inflammatory cytokine correlated with memory preservation. In senescent SAMP8 mice, dietary supplementation with SDP attenuated cognitive decline and prevented changes in brain markers of neuroinflammation and oxidative stress.
|mesh-terms=* Animals
* Cognition Disorders
* Encephalitis
* Male
* Mice
* Oxidative Stress
* Plasma
* Swine
|keywords=* aging
* cognitive decline
* dietary supplementation
* neuroinflammation
* spray-dried animal plasma
|full-text-url=https://sci-hub.do/10.1093/jn/nxz239
}}
==CD47==

{{medline-entry
|title=Aging-associated changes in [[CD47]] arrangement and interaction with thrombospondin-1 on red blood cells visualized by super-resolution imaging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32866348
|abstract=[[CD47]] serves as a ligand for signaling regulatory protein α (SIRPα) and as a receptor for thrombospondin-1 (TSP-1). Although [[CD47]], TSP-1, and SIRPα are thought to be involved in the clearance of aged red blood cells (RBCs), aging-associated changes in the expression and interaction of these molecules on RBCs have been elusive. Using direct stochastic optical reconstruction microscopy (dSTORM)-based imaging and quantitative analysis, we can report that [[CD47]] molecules on young RBCs reside as nanoclusters with little binding to TSP-1, suggesting a minimal role for TSP-1/[[CD47]] signaling in normal RBCs. On aged RBCs, [[CD47]] molecules decreased in number but formed bigger and denser clusters, with increased ability to bind TSP-1. Exposure of aged RBCs to TSP-1 resulted in a further increase in the size of [[CD47]] clusters via a lipid raft-dependent mechanism. Furthermore, [[CD47]] cluster formation was dramatically inhibited on thbs1  mouse RBCs and associated with a significantly prolonged RBC lifespan. These results indicate that the strength of [[CD47]] binding to its ligand TSP-1 is predominantly determined by the distribution pattern and not the amount of [[CD47]] molecules on RBCs, and offer direct evidence for the role of TSP-1 in phagocytosis of aged RBCs. This study provides clear nanoscale pictures of aging-associated changes in [[CD47]] distribution and TSP-1/[[CD47]] interaction on the cell surface, and insights into the molecular basis for how these molecules coordinate to remove aged RBCs.

|keywords=* CD47
* aging
* dSTORM
* red blood cells
* thrombospondin-1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576236
}}
{{medline-entry
|title=[[CD47]] Promotes Age-Associated Deterioration in Angiogenesis, Blood Flow and Glucose Homeostasis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32679764
|abstract=The aged population is currently at its highest level in human history and is expected to increase further in the coming years. In humans, aging is accompanied by impaired angiogenesis, diminished blood flow and altered metabolism, among others. A cellular mechanism that impinges upon these manifestations of aging can be a suitable target for therapeutic intervention. Here we identify cell surface receptor [[CD47]] as a novel age-sensitive driver of vascular and metabolic dysfunction. With the natural aging process, [[CD47]] and its ligand thrombospondin-1 were increased, concurrent with a reduction of self-renewal transcription factors OCT4, SOX2, KLF4 and cMYC (OSKM) in arteries from aged wild-type mice and older human subjects compared to younger controls. These perturbations were prevented in arteries from aged [[CD47]]-null mice. Arterial endothelial cells isolated from aged wild-type mice displayed cellular exhaustion with decreased proliferation, migration and tube formation compared to cells from aged [[CD47]]-null mice. [[CD47]] suppressed ex vivo sprouting, in vivo angiogenesis and skeletal muscle blood flow in aged wild-type mice. Treatment of arteries from older humans with a [[CD47]] blocking antibody mitigated the age-related deterioration in angiogenesis. Finally, aged [[CD47]]-null mice were resistant to age- and diet-associated weight gain, glucose intolerance and insulin desensitization. These results indicate that the [[CD47]]-mediated signaling maladapts during aging to broadly impair endothelial self-renewal, angiogenesis, perfusion and glucose homeostasis. Our findings provide a strong rationale for therapeutically targeting [[CD47]] to minimize these dysfunctions during aging.

|keywords=* CD47
* aging
* angiogenesis
* blood flow
* endothelial cells
* glucose homeostasis
* metabolism
* self-renewal
* thrombospondin-1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407670
}}
{{medline-entry
|title=Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused [[CD47]]-SIRPα Expression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32645996
|abstract=Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of [[CD47]]-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.

|keywords=* CD47
* T cell exhaustion
* T cell senescence
* draining lymph nodes
* macrophage checkpoint
* neoadjuvant chemotherapy
* pancreatic ductal adenocarcinoma
* signal regulatory protein alpha (SIRPα)
* spatial heterogeneity
* tumor microenvironment
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408661
}}
==IMPACT==

{{medline-entry
|title=Load-dependent modulation of alpha oscillations during working memory encoding and retention in young and older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33141460
|abstract=Working memory (WM) is vulnerable to age-related decline, particularly under high loads. Visual alpha oscillations contribute to WM performance in younger adults, and although alpha decreases in power and frequency with age, it is unclear if alpha activity supports WM in older adults. We recorded electroencephalography (EEG) while 24 younger (aged 18-35 years) and 30 older (aged 50-86) adults performed a modified Sternberg task with varying load conditions. Older adults demonstrated slower reaction times at all loads, but there were no significant age differences in WM capacity. Regardless of age, alpha power decreased and alpha frequency increased with load during encoding, and the magnitude of alpha suppression during retention was larger at higher loads. While alpha power during retention was lower than fixation in older, but not younger adults, the relative change from fixation was not significantly different between age groups. Individual differences in alpha power did not predict performance for either age groups or at any WM loads. We demonstrate that alpha power and frequency are modulated in a similar task- and load-dependent manner during WM in both older and younger adults when WM performance is comparable across age groups. [[IMPACT]] STATEMENT: Aging is associated with a marked decrease in the power and frequency of alpha oscillations. Here, we demonstrate that when verbal working memory performance is matched across age groups, alpha power and frequency are modulated in a similar task- and load-dependent manner in both young and older adults.

|keywords=* EEG
* alpha oscillations
* cognitive aging
* working memory
|full-text-url=https://sci-hub.do/10.1111/psyp.13719
}}
{{medline-entry
|title=Using Video Telehealth to Deliver Patient-Centered Collaborative Care: The G-[[IMPACT]] Pilot.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32228299
|abstract=: This pilot project aimed to explore a new model of healthcare delivery to older adult medically complex Veterans by combining telehealth technology with an interdisciplinary medical team operating in real time. : The Geriatric-Interdisciplinary Mobile Patient Access Team (G-[[IMPACT]]) was comprised of a field team including a nurse practitioner and technology assistant who visited enrolled patients in their homes using synchronous video to link to a suite of geriatric specialists in a video-enabled room at a Veterans Affairs hospital. Clinicians interacted with patients, caregivers, and each other to develop mutually agreed upon treatment plans that were then immediately implemented in the field. : 11 total visits were conducted with 9 Veteran patients aged 55-91 (mean = 75.3 years). Both patients and clinicians reported a high level of satisfaction across multiple metrics, including visit quality, and positive indirect indicators of effectiveness were apparent from qualitative data. : Nurse practitioner facilitated video visits allowed geriatric patients to meet with multiple specialists simultaneously with both high patient satisfaction and increased real-time care coordination. : This project identified challenges and opportunities afforded by this type of real-time telehealth care delivery and can inform the development of future interdisciplinary mobile medical teams.

|keywords=* Telehealth
* aging
* care coordination
* home care
* interdisciplinary
* medicine
* older adult
* video
|full-text-url=https://sci-hub.do/10.1080/07317115.2020.1738000
}}
{{medline-entry
|title=AGING, HEART RATE VARIABILITY AND METABOLIC [[IMPACT]] OF OBESITY.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31969754
|abstract=The relationship between aging and changes in heart rate variability (HRV) could depend on the metabolic profile of obese people, i.e. metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). We aimed to determine the age at which obesity related autonomic dysfunction becomes significant and whether it decreases differently according to metabolic profile. We analyzed HRV in 99 adults using Wildman's criteria for metabolic profile and 5-minute HRV for autonomic nervous system. In MHO, high frequency (HF) decreased in the 4  decade of life. In MUO, standard deviation of R-R intervals (SDNN), root mean square of successive differences of all R-R intervals (RMSSD), number of adjacent intervals differing by more than 50 ms expressed as percentage of all intervals in the collecting period (pNN50), HF, low frequency (LF), LF/HF (LF divided by HF) and total power (TP) decreased in the 4  decade of life (partial shared variance 28%-36%). In conclusion, an age dependent decrease of HRV occurs in MUO between the third and fifth decade of life. In MHO, HF significantly decreases around the age of 40 years. Cardiometabolic profile influences metabolic aging, altering the autonomic nervous system.
|mesh-terms=* Aging
* Autonomic Nervous System
* Autonomic Nervous System Diseases
* Female
* Heart Rate
* Humans
* Male
* Metabolic Diseases
* Metabolism
* Middle Aged
* Obesity
|keywords=* Aging
* Autonomic nervous system
* Heart rate
* Obesity, metabolically benign
* Parasympathetic nervous system
* Sympathetic nervous system
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971797
}}
==STAT1==

{{medline-entry
|title=[[STAT1]]-p53-p21axis-dependent stress-induced progression of chronic nephrosis in adriamycin-induced mouse model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32953802
|abstract=Chronic nephrosis (CN) is an aging-related disease with high mortality. Signal transduction and transcriptional activator 1 ([[STAT1]]) protein promotes senescence in human glomerular mesangial cells (HMCs), but whether it affects the progression of adriamycin (ADR)-induced CN [i]in vivo[/i] remains unclear. We established an ADR-induced CN mouse model that was completed in wild-type (wt) mice by a single intravenous injection of 10 mg/kg ADR for 2 or 4 weeks. Clinical indexes in each group were determined. Hematoxylin and eosin staining (H&E) was employed to determine renal histopathological damage, SA-β-gal staining was used to evaluate cell senescence phenotype. TUNEL and immunohistochemistry (IHC) staining were used to detect renal apoptosis. Protein levels of Bcl-2, Bax, [[STAT1]], p53 and p21 were measured by Western Blot. [[STAT1]] intervention ameliorated renal function. H&E staining indicated that [[STAT1]]-deficient ([i]stat1 [/i] ) improved the renal tubular injury, and [i]stat1 [/i] obviously inhibited the apoptosis and Caspase-3  number in kidney tissues. Besides, [i]stat1 [/i] decreased proteinuria, and the levels of urea nitrogen and creatinine as well as that of reactive oxygen species induced by ADR. Also, [i]stat1 [/i] resulted in the reduced expression of p53 and p21. Our current study strongly demonstrated the involvement of the [[STAT1]]-p53-p21 axis in the regulation of CN and is a potential target for the nephrosis treatment.

|keywords=* Adriamycin
* STAT1
* chronic nephrosis (CN)
* mitogen-activated protein kinase
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475511
}}
{{medline-entry
|title=Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31906225
|abstract=Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks ("middle-aged") were compared to tissue or cells from mice aged 16 weeks ("adult"). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated [[STAT1]] (PIAS1) and lower expression of [[STAT1]]- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.
|mesh-terms=* Adipose Tissue
* Aging
* Animals
* Carotid Arteries
* Carotid Artery Diseases
* Carotid Artery Injuries
* Humans
* Mice
* Mice, Mutant Strains
* Neointima
* Paracrine Communication
* STAT1 Transcription Factor
|keywords=* aging
* atherosclerosis
* neointima formation
* perivascular adipose tissue
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981748
}}
{{medline-entry
|title=Legumain-deficient macrophages promote senescence of tumor cells by sustaining JAK1/[[STAT1]] activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31857155
|abstract=Macrophages serve as the first line of communication between tumors and the rest of the immune system, and understanding the interplay between macrophage and tumor cells is essential for developing novel macrophage-based strategy against tumor. Here, we show that deletion of legumain in macrophages activates senescence of tumor cells. Macrophage derived IL-1β mediates the pro-senescent effect of Lgmn  macrophages since blockage of IL-1β reverses the senescence phenotype in both a coculture model of macrophage and tumor cells and an orthotopic mouse model of breast cancer. Sustained activation of JAK1/[[STAT1]] signaling and increased iNOS were found in the tumor cell-cocultured Lgmn  macrophages, which were necessary for IL-1β expression and secretion. Applying a specific [[STAT1]] agonist mimics the inductive effect of legumain deletion on IL-1β expression in macrophages, and the effect can be blocked via inhibition of iNOS. Legumain and integrin αvβ3 interact to prevent [[STAT1]] signaling in macrophages, and blockage of integrin αvβ3 stimulates [[STAT1]] activation. Therapeutically, transplantation of bone marrow from Lgmn  mice suppresses the malignant growth of tumor by upregulating tumor cell senescence. Therefore, our finding highlights legumain in macrophages as a potential therapeutic target for tumors.
|mesh-terms=* Animals
* Bone Marrow Transplantation
* Breast Neoplasms
* Cell Cycle Proteins
* Cell Line, Tumor
* Cellular Senescence
* Disease Models, Animal
* Female
* Gene Expression Regulation, Neoplastic
* Humans
* Integrin alphaVbeta3
* Interleukin-1beta
* Janus Kinase 1
* Macrophage Activation
* Macrophages
* Mice
* Mice, Knockout
* STAT1 Transcription Factor
* Signal Transduction
|keywords=* Cellular senescence
* Legumain
* M1 polarization
* Tumor-associated macrophage
|full-text-url=https://sci-hub.do/10.1016/j.canlet.2019.12.013
}}
==VDR==

{{medline-entry
|title=25-Hydroxyvitamin D  positively regulates periodontal inflammaging via SOCS3/STAT signaling in diabetic mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31917967
|abstract=Diabetes is a known age-related disease. Inflammaging has recently been shown to result in diabetic complications. Vitamin D  is related to aging in the latest study but little is known about the underlying mechanism. Here, we investigated the effects of 25-Hydroxyvitamin D  (25(OH)D ) on inflammaging in diabetic periodontitis, a common chronic inflammatory diabetic complication. A model of Porphyromonas gingivalis-infected db/db mice as experimental type 2 diabetic periodontitis was adopted in the whole study. A range of techniques, including microCT, western blotting, ELISA, histological and immunohistochemical analysis, were carried out in this study. The distinctive senescence-associated secretory phenotype (SASP) in serum was measured by Luminex technology. We found an archetypal inflammaging status occurred in db/db mice. An increased SASP, senescent enhancement, and periodontal destruction were observed in periodontitis-db/db mice. Upon administration with 25(OH)D , periodontitis-db/db mice presented increased levels of serum 25(OH)D , 1α,25-Dihydroxyvitamin D  and calcium. Moreover, decreased p16/p21-positive cells, relieved periodontal conditions and ameliorated serum SASP secretion were found in the periodontitis-db/db mice after treatment. Gingival tissue exhibited increased level of [[VDR]] and decreased expression of SOCS3, p-STAT3/STAT3, p-STAT5/STAT5, NF-κB and IL-1β, which were consistent with the change of p16/p21 expression. Diabetic periodontitis appeared to develop an inflammaging status resulted in periodontal infection. 25(OH)D  could inhibit SASP secretion through reducing SOCS3 expression in experimental diabetic periodontitis, dependently inactivating NF-κB pro-inflammatory signaling. The reversible effect further documented that the inflammaging might be a highly likely contributor in diabetic periodontitis.

|keywords=* 25-Hydroxyvitamin D(3)
* Diabetic periodontitis
* Inflammaging
* SOCS3
* Senescence
* Senescence-associated secretory phenotypes
|full-text-url=https://sci-hub.do/10.1016/j.steroids.2019.108570
}}
{{medline-entry
|title=1,25-Dihydroxyvitamin D protects against age-related osteoporosis by a novel [[VDR]]-Ezh2-p16 signal axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31880094
|abstract=To determine whether 1,25-dihydroxyvitamin D (1,25(OH)  D) can exert an anti-osteoporosis role through anti-aging mechanisms, we analyzed the bone phenotype of mice with 1,25(OH)  D deficiency due to deletion of the enzyme, 25-hydroxyvitamin D 1α-hydroxylase, while on a rescue diet. 1,25(OH)  D deficiency accelerated age-related bone loss by activating the p16/p19 senescence signaling pathway, inhibiting osteoblastic bone formation, and stimulating osteoclastic bone resorption, osteocyte senescence, and senescence-associated secretory phenotype (SASP). Supplementation of exogenous 1,25(OH)  D  corrected the osteoporotic phenotype caused by 1,25(OH)  D deficiency or natural aging by inhibiting the p16/p19 pathway. The proliferation, osteogenic differentiation, and ectopic bone formation of bone marrow mesenchymal stem cells derived from mice with genetically induced deficiency of the vitamin D receptor ([[VDR]]) were significantly reduced by mechanisms including increased oxidative stress, DNA damage, and cellular senescence. We also demonstrated that p16 deletion largely rescued the osteoporotic phenotype caused by 1,25(OH)  D  deficiency, whereas 1,25(OH)  D  could up-regulate the enzyme Ezh2 via [[VDR]]-mediated transcription thereby enriching H3K27me3 and repressing p16/p19 transcription. Finally, we demonstrated that treatment with 1,25(OH)  D  improved the osteogenic defects of human BM-MSCs caused by repeated passages by stimulating their proliferation and inhibiting their senescence via the [[VDR]]-Ezh2-p16 axis. The results of this study therefore indicate that 1,25(OH)  D  plays a role in preventing age-related osteoporosis by up-regulating Ezh2 via [[VDR]]-mediated transcription, increasing H3K27me3 and repressing p16 transcription, thus promoting the proliferation and osteogenesis of BM-MSCs and inhibiting their senescence, while also stimulating osteoblastic bone formation, and inhibiting osteocyte senescence, SASP, and osteoclastic bone resorption.
|mesh-terms=* 25-Hydroxyvitamin D3 1-alpha-Hydroxylase
* Aging
* Animals
* Bone and Bones
* Cells, Cultured
* Cyclin-Dependent Kinase Inhibitor p16
* Cyclin-Dependent Kinase Inhibitor p19
* DNA Damage
* Enhancer of Zeste Homolog 2 Protein
* Female
* Histones
* Male
* Mesenchymal Stem Cells
* Mice
* Mice, Knockout
* Osteocytes
* Osteogenesis
* Osteoporosis
* Oxidative Stress
* Receptors, Calcitriol
* Vitamin D
|keywords=* Ezh2
* Vitamin D
* cellular senescence
* osteogenesis
* osteoporosis
* p16
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996957
}}
{{medline-entry
|title=Active vitamin D impedes the progression of non-alcoholic fatty liver disease by inhibiting cell senescence in a rat model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31810868
|abstract=Non-alcoholic fatty liver disease (NAFLD) refers to an accumulation of excess fat in liver due to causes other than alcohol use. The relationship between vitamin D (VD) and NAFLD has been previously studied. Therefore, we aimed to explore the mechanism involved active VD regulating the progression of NAFLD by inhibiting cell senescence and to provide a potential approach for further nutritional treatment of NAFLD. Following the induction with high-fat diet and intraperitoneal injection of corn oil, the successfully established NAFLD rat models were treated with 1,25(OH) D  at 1μg/kg, 5μg/kg or 10μg/kg. Meanwhile, the levels of factors related to oxidative stress, cell senescence, the p53-p21 signaling pathway and inflammation in liver were determined. Then, cell senescence was also measured by using senescence-associated β-galactosidase (SAβ-gal) staining. It was also found that active VD increased the concentration of VD in serum and [[VDR]] in liver of NAFLD rats, and alleviated hepatic fibrosis. Besides, treatment of 1,25(OH) D  at 1μg/kg, 5μg/kg or 10μg/kg reduced oxidative stress and inflammation, inhibited the p53-p21 signaling pathway and consequent cell senescence. Furthermore, treatment of 1,25(OH) D  at a dosage of 5μg/kg made the most impact on these factors. Collectively, the evidences from this study demonstrated that active VD could alleviate the development of NAFLD through blocking the p53-p21 signaling pathway, which provided a novel nutritional therapeutic insight for NAFLD.

|keywords=* Active vitamin D
* Cell senescence
* Non-alcoholic fatty liver disease
* Oxidative stress
* P53-p21 signaling pathway
* Vitamin D receptor
|full-text-url=https://sci-hub.do/10.1016/j.clinre.2019.10.007
}}
==CA3==

{{medline-entry
|title=Features of Postnatal Hippocampal Development in a Rat Model of Sporadic Alzheimer's Disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32581685
|abstract=Aging is the major risk factor of the most common (∼95% of cases) sporadic Alzheimer's disease (AD). Accumulating data indicate middle age as a critical period for the relevant pathological processes, however, the question of when AD starts to develop remains open. It has been reported only recently that in the early postnatal period-when brain development is completing-preconditions for a decrease in cognitive abilities and for accelerated aging can form. Here, we hypothesized that specific features of early postnatal brain development may be considered some of the prerequisites of AD development at an advanced age. To test this hypothesis, we used OXYS rats, which are a suitable model of sporadic AD. The duration of gestation, litter size, and weight at birth were lower in OXYS rats compared to control Wistar rats. The shortened duration of gestation may result in developmental retardation. Indeed, we noted decreased locomotor activity and increased anxiety in OXYS rats already at a young age: possible signs of altered brain development. We demonstrated retardation of the peak of postnatal neurogenesis in the hippocampal dentate gyrus of OXYS rats. Delayed neuronal maturation led to alterations of mossy-fiber formation: a shortened suprapyramidal bundle and longer infrapyramidal bundle, less pronounced fasciculation of granule cells' axons, and smaller size and irregular shape of nuclei in the [[CA3]] pyramidal layer. These changes were accompanied by altered astrocytic migration. The observed features of early development may be considered some of the risk factors of the AD-like pathology that manifests itself in OXYS rats late in life.

|keywords=* Alzheimer’s disease
* OXYS rats
* aging
* hippocampal mossy fibers
* hippocampus
* neurogenesis
* postnatal development
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289999
}}
{{medline-entry
|title=Age-Related Changes in Synaptic Plasticity Associated with Mossy Fiber Terminal Integration during Adult Neurogenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32332082
|abstract=Mouse hippocampus retains the capacity for neurogenesis throughout lifetime, but such plasticity decreases with age. Adult hippocampal neurogenesis (AHN) involves the birth, maturation, and synaptic integration of newborn granule cells (GCs) into preexisting hippocampal circuitry. While functional integration onto adult-born GCs has been extensively studied, maturation of efferent projections onto [[CA3]] pyramidal cells is less understood, particularly in aged brain. Here, using combined light and reconstructive electron microscopy (EM), we describe the maturation of mossy fiber bouton (MFB) connectivity with [[CA3]] pyramidal cells in young adult and aged mouse brain. We found mature synaptic contacts of newborn GCs were formed in both young and aged brains. However, the dynamics of their spatiotemporal development and the cellular process by which these cells functionally integrated over time were different. In young brain newborn GCs either formed independent nascent MFB synaptic contacts or replaced preexisting MFBs, but these contacts were pruned over time to a mature state. In aged brain only replacement of preexisting MFBs was observed and new contacts were without evidence of pruning. These data illustrate that functional synaptic integration of AHN occurs in young adult and aged brain, but with distinct dynamics. They suggest elimination of preexisting connectivity is required for the integration of adult-born GCs in aged brain.

|keywords=* aging
* conditional transgenic
* giant synapse
* stratum lucidum
* synaptogenesis
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240290
}}
{{medline-entry
|title=Metabotropic Glutamate Receptors at the Aged Mossy Fiber - [[CA3]] Synapse of the Hippocampus.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31917351
|abstract=Metabotropic glutamate receptors (mGluRs) are a group of G-protein-coupled receptors that exert a broad array of modulatory actions at excitatory synapses of the central nervous system. In the hippocampus, the selective activation of the different mGluRs modulates the intrinsic excitability, the strength of synaptic transmission, and induces multiple forms of long-term plasticity. Despite the relevance of mGluRs in the normal function of the hippocampus, we know very little about the changes that mGluRs functionality undergoes during the non-pathological aging. Here, we review data concerning the physiological actions of mGluRs, with particular emphasis on hippocampal area [[CA3]]. Later, we examine changes in the expression and functionality of mGluRs during the aging process. We complement this review with original data showing an array of electrophysiological modifications observed in the synaptic transmission and intrinsic excitability of aged [[CA3]] pyramidal cells in response to the pharmacological stimulation of the different mGluRs.

|keywords=* aging
* hippocampal area CA3
* mGluRs
* mossy fibers
* synaptic transmission
|full-text-url=https://sci-hub.do/10.1016/j.neuroscience.2019.12.016
}}
==DMD==

{{medline-entry
|title=Aldehyde dehydrogenases contribute to skeletal muscle homeostasis in healthy, aging, and Duchenne muscular dystrophy patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32157826
|abstract=Aldehyde dehydrogenases (ALDHs) are key players in cell survival, protection, and differentiation via the metabolism and detoxification of aldehydes. ALDH activity is also a marker of stem cells. The skeletal muscle contains populations of ALDH-positive cells amenable to use in cell therapy, whose distribution, persistence in aging, and modifications in myopathic context have not been investigated yet. The Aldefluor® (ALDEF) reagent was used to assess the ALDH activity of muscle cell populations, whose phenotypic characterizations were deepened by flow cytometry. The nature of ALDH isoenzymes expressed by the muscle cell populations was identified in complementary ways by flow cytometry, immunohistology, and real-time PCR ex vivo and in vitro. These populations were compared in healthy, aging, or Duchenne muscular dystrophy ([[DMD]]) patients, healthy non-human primates, and Golden Retriever dogs (healthy vs. muscular dystrophic model, Golden retriever muscular dystrophy [GRMD]). ALDEF  cells persisted through muscle aging in humans and were equally represented in several anatomical localizations in healthy non-human primates. ALDEF  cells were increased in dystrophic individuals in humans (nine patients with [[DMD]] vs. five controls: 14.9 ± 1.63% vs. 3.6 ± 0.39%, P = 0.0002) and dogs (three GRMD dogs vs. three controls: 10.9 ± 2.54% vs. 3.7 ± 0.45%, P = 0.049). In [[DMD]] patients, such increase was due to the adipogenic ALDEF  /CD34  populations (11.74 ± 1.5 vs. 2.8 ± 0.4, P = 0.0003), while in GRMD dogs, it was due to the myogenic ALDEF  /CD34  cells (3.6 ± 0.6% vs. 1.03 ± 0.23%, P = 0.0165). Phenotypic characterization associated the ALDEF  /CD34  cells with CD9, CD36, CD49a, CD49c, CD49f, CD106, CD146, and CD184, some being associated with myogenic capacities. Cytological and histological analyses distinguished several ALDH isoenzymes (ALDH1A1, 1A2, 1A3, 1B1, 1L1, 2, 3A1, 3A2, 3B1, 3B2, 4A1, 7A1, 8A1, and 9A1) expressed by different cell populations in the skeletal muscle tissue belonging to multinucleated fibres, or myogenic, endothelial, interstitial, and neural lineages, designing them as potential new markers of cell type or of metabolic activity. Important modifications were noted in isoenzyme expression between healthy and [[DMD]] muscle tissues. The level of gene expression of some isoenzymes (ALDH1A1, 1A3, 1B1, 2, 3A2, 7A1, 8A1, and 9A1) suggested their specific involvement in muscle stability or regeneration in situ or in vitro. This study unveils the importance of the ALDH family of isoenzymes in the skeletal muscle physiology and homeostasis, suggesting their roles in tissue remodelling in the context of muscular dystrophies.

|keywords=* Aging
* Aldehyde dehydrogenase
* Dog model
* Duchenne muscular dystrophy
* Human
* Myogenic
* Non-human primate
* Skeletal muscle
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432589
}}
{{medline-entry
|title=Life expectancy at birth in Duchenne muscular dystrophy: a systematic review and meta-analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32107739
|abstract=Several studies indicate that prognosis for survival in Duchenne muscular dystrophy ([[DMD]]) has improved in recent decades. However, published evidence is inconclusive and some estimates may be obsolete due to improvements in standards of care, in particular the routine use of mechanical ventilatory support in advanced stages of the disease. In this systematic review and meta-analysis (PROSPERO identifier: CRD42019121800), we searched MEDLINE (through PubMed), CINAHL, Embase, PsycINFO, and Web of Science for studies published from inception up until December 31, 2018, reporting results of life expectancy in [[DMD]]. We pooled median survival estimates from individual studies using the median of medians, and weighted median of medians, methods. Risk of bias was established with the Newcastle-Ottawa Scale. Results were stratified by ventilatory support and risk of bias. We identified 15 publications involving 2662 patients from 12 countries from all inhabited continents except Africa. Median life expectancy without ventilatory support ranged between 14.4 and 27.0 years (pooled median: 19.0 years, 95% CI 18.0-20.9; weighted pooled median: 19.4 years, 18.2-20.1). Median life expectancy with ventilatory support, introduced in most settings in the 1990s, ranged between 21.0 and 39.6 years (pooled median: 29.9 years, 26.5-30.8; weighted pooled median: 31.8 years, 29.3-36.2). Risk of bias had little impact on pooled results. In conclusion, median life expectancy at birth in [[DMD]] seems to have improved considerably during the last decades. With current standards of care, many patients with [[DMD]] can now expect to live into their fourth decade of life.
|mesh-terms=* Female
* Humans
* Life Expectancy
* Male
* Muscular Dystrophy, Duchenne
* Parturition
* Pregnancy
* Prognosis
* Quality of Life
* Respiration, Artificial
* Survival
|keywords=* Mechanical ventilation
* Mortality
* Prognosis
* Survival
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387367
}}
{{medline-entry
|title=Renal dysfunction can occur in advanced-stage Duchenne muscular dystrophy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31725904
|abstract=With improved treatments, patients with Duchenne muscular dystrophy ([[DMD]]) can survive far beyond adolescence. However, advanced-stage [[DMD]] patients are at risk of developing renal dysfunction. In this study, long-term renal function outcomes and associated risk factors in advanced stage [[DMD]] were analyzed. Fifty-one patients were classified into three different age groups (<20, 20-29, and ≥30 years of age), and cystatin C (CysC) levels were compared among groups. Median serum CysC levels were 0.74 mg/L, 0.63 mg/L, and 0.76 mg/L in the age groups of <20, 20-29, and ≥30 years, respectively (P = .003). Five of the nine patients in the ≥30 years age group showed elevated serum CysC and decreased cardiac function compared with the other four in the group (P = .014). Our results indicate an association between cardiac and renal dysfunction in patients with advanced-stage [[DMD]].
|mesh-terms=* Adolescent
* Adult
* Aging
* Child
* Child, Preschool
* Cystatin C
* Disease Progression
* Female
* Heart Diseases
* Heart Function Tests
* Humans
* Kidney Diseases
* Kidney Function Tests
* Male
* Muscular Dystrophy, Duchenne
* Risk Factors
* Young Adult
|keywords=* Duchenne muscular dystrophy
* advanced stage
* cystatin C
* ejection fraction
* fractional shortening
* renal dysfunction
|full-text-url=https://sci-hub.do/10.1002/mus.26757
}}
==MMD==

{{medline-entry
|title=Association between a Deficit Accumulation Frailty Index and Mobility Outcomes in Older Adults: Secondary Analysis of the Lifestyle Interventions and Independence for Elders (LIFE) Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33266358
|abstract=Frailty is a geriatric syndrome represented by susceptibility to precipitating health events and reduced functional reserve. Frailty can be difficult to measure in clinical practice and research. One approach to approximate frailty is based on a deficit accumulation approach, which assesses a larger number of less specific measures such as the presence of comorbidities, physical or cognitive assessments, and lab tests, and summarizes these as a frailty index. The objective of this study was to develop such an index using the Lifestyle Interventions and Independence for Elders (LIFE) Study and evaluate the validity of the frailty measure derived based on baseline information via its association with the primary outcomes of the trial, namely major mobility disability ([[MMD]]) and persistent [[MMD]] (p[[MMD]]). Further, this study aimed to evaluate the effectiveness of the physical activity intervention among participants based on their baseline frailty score. Subjects in the LIFE Study were evaluated at baseline for demographics, clinical history, and a battery of physical and cognitive functioning assessments. In total, 75 possible deficits were scored either as present (yes/no) or based on each score's quintiles for score-based assessments. The frailty index was measured as the total sum of deficits divided by the total number of possible deficits on a continuous scale between 0 and 100 (i.e., percent of deficits present). The frailty index was further divided into quintiles for comparison. A proportional hazards model was estimated for the [[MMD]] outcome controlling for other baseline information. A data driven approach was also used to determine relevant cut-offs in the frailty index where the trial intervention appeared to be modified. Among 1635 trial participants, the mean frailty index was 30.4 ± 6.6 and normally distributed. Over 2.5 years of average follow-up, 14.6%, 16.5%, 18.6%, 22.6%, and 27.6% of participants experienced [[MMD]] in quintiles 1-5, respectively. Each 1-unit increase in the frailty index increased the hazard of [[MMD]] by 4% (2-5%), and there was a nearly 2-fold increase in [[MMD]] between the highest and lowest frailty quintiles. Using log-rank criteria, a cut-point at the median was identified. Further, iterations tested for a frailty cut-off and indicated a subgroup beyond the 85th percentile wherein the physical activity intervention appeared to be no longer be effective. This internally derived deficit accumulation frailty index was uniquely able to identify individuals at higher risk of [[MMD]] and p[[MMD]] and showed that along the spectrum of frailty, the physical activity intervention remained effective for the majority of participants.

|keywords=* LIFE Study
* deficit accumulation
* disability
* frailty
* healthy aging
* mobility
* older adults
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700674
}}
{{medline-entry
|title=Impact of Anticholinergic Medication Burden on Mobility and Falls in the Lifestyle Interventions for Elders (LIFE) Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32947839
|abstract=Anticholinergic cognitive burden (ACB) may be associated with detrimental effects on mobility and physical independence in older adults. We evaluated the incidence of major mobility disability ([[MMD]]), persistent major mobility disability (P[[MMD]]), and injurious falls among participants within the Lifestyle Interventions for Elders (LIFE) trial according to varied anticholinergic burden levels. Participants aged 70-89 years were randomized to a physical activity (PA) or successful aging (SA) intervention and evaluated by ACB medication use as a summed score of a previously developed ACB scale. Confounders included demographic characteristics, physical function, cognitive function, and fall history. Average participant follow-up was 2.6 years and included outcome assessment for [[MMD]], P[[MMD]], and injurious falls every six months. Adjusted proportional hazards models evaluated the independent effects of ACB scores as well as interaction effects with the intervention. Of the 1635 participants, 986 (60%) used ≥1 anticholinergic medication. Compared to those with no burden, participants with an ACB score of 1 demonstrated increased [[MMD]] (HR = 1.42 [1.13-1.78]), P[[MMD]] (HR = 1.53 [1.12-2.09]), and injurious falls (HR = 1.60 [1.10-2.32]). Results similar in magnitude were observed for all other ACB levels versus the no burden group. Stepwise dose-response comparisons between ACB groupings did not demonstrate significant differences in outcomes. Stratification by PA or SA interventions demonstrated few differences from the combined overall trial results. Compared to those not taking anticholinergic medications, participants taking anticholinergic medications generally demonstrated increased risk of [[MMD]], P[[MMD]], and injurious falls. Total anticholinergic burden was not associated with a stepwise dose-response relationship in mobility disability and may lack sensitivity to capture varied responses.

|keywords=* anticholinergic burden
* falls
* mobility
* physical activity
* successful aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564216
}}
{{medline-entry
|title=Impact and Lessons From the Lifestyle Interventions and Independence for Elders (LIFE) Clinical Trials of Physical Activity to Prevent Mobility Disability.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32105353
|abstract=Walking independently is basic to human functioning. The Lifestyle Interventions and Independence for Elders (LIFE) studies were developed to assess whether initiating physical activity could prevent major mobility disability ([[MMD]]) in sedentary older adults. We review the development and selected findings of the LIFE studies from 2000 through 2019, including the planning phase, the LIFE-Pilot Study, and the LIFE Study. The planning phase and the LIFE-Pilot provided key information for the successful implementation of the LIFE Study. The LIFE Study, involving 1635 participants randomized at eight sites throughout the United States, showed that compared with health education, the physical activity program reduced the risk of the primary outcome of [[MMD]] (inability to walk 400 m: hazard ratio = 0.82; 95% confidence interval = 0.69-0.98; P = .03), and that the intervention was cost-effective. There were no significant effects on cognitive outcomes, cardiovascular events, or serious fall injuries. In addition, the LIFE studies provided relevant findings on a broad range of other outcomes, including health, frailty, behavioral outcomes, biomarkers, and imaging. To date, the LIFE studies have generated a legacy of 109 peer-reviewed publications, 19 ancillary studies, and 38 independently funded grants and clinical trials, and advanced the development of 59 early career scientists. Data and biological samples of the LIFE Study are now publicly available from a repository sponsored by the National Institute on Aging (https://agingresearchbiobank.nia.nih.gov). The LIFE studies generated a wealth of important scientific findings and accelerated research in geriatrics and gerontology, benefiting the research community, trainees, clinicians, policy makers, and the general public. J Am Geriatr Soc 68:872-881, 2020.

|keywords=* aging
* mobility disability
* multicenter trialphysical activity
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187344
}}
==HSF1==

{{medline-entry
|title=A Mitochondrial Stress-Specific Form of [[HSF1]] Protects against Age-Related Proteostasis Collapse.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32735771
|abstract=The loss of protein homeostasis (proteostasis) is a primary driver of age-related tissue dysfunction. Recent studies have revealed that the failure of proteostasis with age is triggered by developmental and reproductive cues that repress the activity of proteostasis-related pathways in early adulthood. In Caenorhabditis elegans, reduced mitochondrial electron transport chain (ETC) function during development can override signals that promote proteostasis collapse in aged tissues. However, it is unclear precisely how these beneficial effects are mediated. Here, we reveal that in response to ETC impairment, the PP2A complex generates a dephosphorylated, mitochondrial stress-specific variant of the transcription factor HSF-1. This results in the selective induction of small heat shock proteins in adulthood, thereby protecting against age-related proteostasis collapse. We propose that mitochondrial signals early in life can protect the aging cytosolic proteome by tailoring HSF-1 activity to preferentially drive the expression of non-ATP-dependent chaperones.

|keywords=* HSF1
* PP2A
* aging
* mitochondria
* molecular chaperones
* protein aggregation
* proteostasis
* stress responses
|full-text-url=https://sci-hub.do/10.1016/j.devcel.2020.06.038
}}
{{medline-entry
|title=Heat shock factor 1-mediated transcription activation of Omi/HtrA2 induces myocardial mitochondrial apoptosis in the aging heart.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31627188
|abstract=Increased cardiac apoptosis is a hallmark of the elderly, which in turn increases the risk for developing cardiac disease. The overexpression of Omi/HtrA2 mRNA and protein contributes to apoptosis in the aged heart. Heat shock factor 1 ([[HSF1]]) is a transcription factor that binds to the promoter of Omi/HtrA2 in the aging myocardium. However, whether [[HSF1]] participates in cardiomyocyte apoptosis via transcriptional regulation of Omi/HtrA2 remains unclear. The present study was designed to investigate whether [[HSF1]] plays a role in Omi/HtrA2 transcriptional regulation and myocardial apoptosis. Assessment of the hearts of mice of different ages was performed, which indicated a decrease in cardiac function reserve and an increase in mitochondrial apoptosis. Omi/HtrA2 overexpression in the elderly was negatively correlated with left ventricular function after exercise overload and positively correlated with myocardial Caspase-9 apoptosis. Chromatin immunoprecipitation (ChIP) of aging hearts and plasmid transfection/RNA interference of H9C2 cells revealed that enhancement of [[HSF1]] expression promotes Omi/HtrA2 expression by inducing the promoter activity of Omi/HtrA2 while also increasing mitochondrial apoptosis by upregulating Omi/HtrA2 expression. [[HSF1]] acts as a transcriptional factor that induces Omi/HtrA2 expression and Caspase-9 apoptosis in aged cardiomyocytes, while also decreasing cardiac function reserve.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Heat Shock Transcription Factors
* High-Temperature Requirement A Serine Peptidase 2
* Male
* Mice
* Mice, Inbred C57BL
* Mitochondria, Heart
* Myocytes, Cardiac
* NIH 3T3 Cells
* Transcriptional Activation
* Up-Regulation
|keywords=* Omi/HtrA2
* age-related pathology
* cardiovascular
* mitochondria
* transcriptional regulation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834417
}}
{{medline-entry
|title=Multifactorial Attenuation of the Murine Heat Shock Response With Age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31612204
|abstract=Age-dependent perturbation of the cellular stress response affects proteostasis and other key functions relevant to cellular action and survival. Central to age-related changes in the stress response is loss of heat shock factor 1 ([[HSF1]])-DNA binding and transactivation properties. This report elucidates how age alters different checkpoints of [[HSF1]] activation related to posttranslational modification and protein interactions. When comparing liver extracts from middle aged (12 M) and old (24 M) mice, significant differences are found in [[HSF1]] phosphorylation and acetylation. [[HSF1]] protein levels and messenger RNA decline with age, but its protein levels are stress-inducible and exempt from age-dependent changes. This surprising adaptive change in the stress response has additional implications for aging and chronic physiological stress that might explain an age-dependent dichotomy of [[HSF1]] protein levels that are low in neurodegeneration and elevated in cancer.

|keywords=* Aging
* HSF1
* Stress
|full-text-url=https://sci-hub.do/10.1093/gerona/glz204
}}
==REST==

{{medline-entry
|title=[Brain and Neuronal Aging: Aged Brain Controls via Gene Expression Fidelity and Master Regulatory Factors].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32115559
|abstract=Providing plausible strategies for brain aging protection should be a critical concern for countries with large elderly populations including Japan. Age-related cognitive impairments and movement disorders, such as Alzheimer's and Parkinson's diseases, are caused by neurodegeneration that primarily initiates in the hippocampus and the midbrain substantia nigra, respectively. Neurons are postmitotic, and therefore, the accuracy of cellular metabolism should be crucial for maintaining neural functions throughout their life. Thus accuracy of protein synthesis is a critical concern in discussing mechanisms of aging. The essence of the so-called "error catastrophe theory" of aging was on the fidelity of ribosomal translation and/or aminoacylation of tRNA. There is evidence that reduced protein synthesis accuracy results in neurodegeneration. Similarly, reduced proteostasis via autophagy and proteasomes in aging is crucial for protein quality control and well documented as a risk for aging. In both neurodegeneration and protein quality controls, various proteins are involved in their regulation, but recent evidence suggests that repressor element-1 silencing transcription factor ([[REST]]) could be a master regulatory protein that is crucial for orchestrating the neural protecting events in human brain aging. [[REST]] is induced in the aged brain, and protects neurons against oxidative stress and protein toxicity. Interestingly, [[REST]] is identical with neuron-restrictive silencer factor (NRSF), the master regulator of neural development. Thus NRSF/[[REST]] play important roles in both neurogenesis and neurodegeneration. In this review, I summarize the interesting scientific crossover, and discuss the potential use of NRSF/[[REST]] as a pharmaceutical target for controlling aging, particularly in relation to brain aging.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Animals
* Brain
* Gene Expression
* Gene Expression Regulation, Developmental
* Humans
* Neurodegenerative Diseases
* Protein Biosynthesis
* Repressor Proteins
* Ribosomes
|keywords=* aging
* brain
* gene expression
* neurodegeneration
* ribosome
* translational fidelity
|full-text-url=https://sci-hub.do/10.1248/yakushi.19-00193-4
}}
{{medline-entry
|title=Effect of 9 - PAHSA on cognitive dysfunction in diabetic mice and its possible mechanism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32014256
|abstract=Diabetes mellitus (DM) is currently a major global health problem, which is associated with the development of cognitive dysfunction. However, although numerous clinical drugs for hyperglycemia have been used at present, safer and more effective therapeutic intervention strategies for diabetic cognitive impairments are still a huge challenge. Recently, several studies have indicated that a novel class of branched palmitic acid esters of hydroxyl stearic acids (PAHSAs) may have anti-diabetes and anti-inflammatory effects in insulin-resistant mice. Herein, whether the 9-PAHSA that one of the PAHSAs can attenuates DM-associated cognitive impairment in a mouse model of type 2 diabetes has been investigated. Our results showed that 9-PAHSA mildly prevented deficits of spatial working memory in Y-maze test while reversed the preference bias toward novel mice in Social choice test. Furthermore, the effect of [[REST]] on cognitive impairment of diabetes was explored for the first time. It was found that the expression of [[REST]] in diabetic mice increased, and the expression of target protein BDNF (Brain-derived neurotrophic factor) was decreased. After administration of 9-PAHSA, the situation was reversed. In summary, we conclude that exogenous supplement of 9-PAHSA can improve DM-related cognitive impairment to some extent, and the protective effect may be associated with decreased [[REST]]/NRSF (repressor element-1 silencing transcription factor/neuron-restrictive silence factor) and upregulated BDNF expression in frontal cortex.
|mesh-terms=* Aging
* Animals
* Behavior, Animal
* Blood Glucose
* Body Weight
* Brain
* Brain-Derived Neurotrophic Factor
* Cognitive Dysfunction
* Diabetes Mellitus, Experimental
* Exploratory Behavior
* Male
* Memory Disorders
* Mice
* Palmitic Acid
* Repressor Proteins
* Social Behavior
* Spatial Memory
* Stearic Acids
|keywords=* 9-PAHSA
* BDNF
* Diabetes mellitus
* REST
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2020.01.071
}}
{{medline-entry
|title=Increased [[REST]] to Optimize Life Span?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31762373
|abstract=Reduced levels of neural activity are associated with a longer life span in the nematode [i]Caenorhabditis elegans[/i] and in mice. Augmented neural activity is associated with a shorter life span. Recent studies show that levels of repressor element 1-silencing transcription factor ([[REST]]) increase with normal aging in mice and humans, and reduce neuronal excitation. In [i]C. elegans,[/i] increased expression of [i]spr-4[/i], a functional [[REST]] homologue, increased the worm life span and is required for classical life span increase mediated by reduced DAF-2/insulin-IGF-1 and increased DAF-16. Preliminary evidence shows that [[REST]] and FOXO1, a DAF-16, homologue increase during mammalian aging, and that [[REST]] activity is needed for the age-related FOXO1 increase. On the contrary, [[REST]] is activated in epilepsy and plays a role in the pathogenesis of Huntington's disease. A simple unifying hypothesis suggests that [[REST]] is a "goldilocks-effect factor": too little [[REST]] promotes excitotoxic activity, which in turn leads to neurodegenerative diseases such as Alzheimer's. Appropriate increased levels of [[REST]] maintain the excitation/inhibition (E-I) balance by reducing potential excitotoxic activity. Increased levels of [[REST]] beyond this are toxic as neurons become dysfunctional due to loss of a neuronal phenotype.
|mesh-terms=* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Homeostasis
* Longevity
* Repressor Proteins
* Signal Transduction
|keywords=* life span
* neuronal activity
* neurotoxicity
|full-text-url=https://sci-hub.do/10.1089/rej.2019.2287
}}
==LMNB1==

{{medline-entry
|title=SIRT1 - a new mammalian substrate of nuclear autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33292048
|abstract=Macroautophagic/autophagic degradation of nuclear components (or nuclear autophagy) is a poorly understood area in autophagy research. We previously reported the nuclear lamina protein [[LMNB1]] (lamin B1) as a nuclear autophagy substrate in primary human cells, stimulating the investigation of nuclear autophagy in the mammalian system. We recently reported the sirtuin protein SIRT1 as a new selective substrate of nuclear autophagy in senescence and aging. Upon senescence of primary human cells, SIRT1 degradation is mediated by a direct nuclear SIRT1-LC3 interaction, followed by nucleus-to-cytoplasm shuttling of SIRT1 and autophagosome-lysosome degradation. In vivo, SIRT1 is downregulated by lysosomes in hematopoietic and immune organs upon natural aging in mice and in aged human T cells. Our study identified another substrate of nuclear autophagy and suggests a new strategy to promote SIRT1-mediated health benefits by suppressing its autophagic degradation.

|keywords=* Aging
* SIRT1
* nuclear autophagy
* senescence
* sirtuin
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1860541
}}
{{medline-entry
|title=Cellular senescence as a response to multiwalled carbon nanotube (MWCNT) exposure in human mesothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33279583
|abstract=Cellular senescence is a stable cell cycle arrest induced by diverse triggers, including replicative exhaustion, DNA damaging agents, oncogene activation, oxidative stress, and chromatin disruption. With important roles in aging and tumor suppression, cellular senescence has been implicated also in tumor promotion. Here we show that certain multiwalled carbon nanotubes (MWCNTs), as fiber-like nanomaterials, can trigger cellular senescence in primary human mesothelial cells. Using in vitro approaches, we found manifestation of several markers of cellular senescence, especially after exposure to a long and straight MWCNT. These included inhibition of cell division, senescence-associated heterochromatin foci, senescence-associated distension of satellites, [[LMNB1]] depletion, γH2A.X nuclear panstaining, and enlarged cells exhibiting senescence-associated β-galactosidase activity. Furthermore, genome-wide transcriptome analysis revealed many differentially expressed genes, among which were genes encoding for a senescence-associated secretory phenotype. Our results clearly demonstrate the potential of long and straight MWCNTs to induce premature cellular senescence. This finding may find relevance in risk assessment of workplace safety, and in evaluating MWCNT's use in medicine such as drug carrier, due to exposure effects that might prompt onset of age-related diseases, or even carcinogenesis.

|keywords=* alpha tubulin
* cellular senescence
* mesothelial cells
* microarray analysis
* multiwalled carbon nanotubes
* γH2A.X
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111412
}}
{{medline-entry
|title=Inflammatory Drivers of Cardiovascular Disease: Molecular Characterization of Senescent Coronary Vascular Smooth Muscle Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32523550
|abstract=The senescence of vascular smooth muscle cells (VSMCs) has been implicated as a causal pro-inflammatory mechanism for cardiovascular disease development and progression of atherosclerosis, the instigator of ischemic heart disease. Contemporary limitations related to studying this cellular population and senescence-related therapeutics are caused by a lack of specific markers enabling their detection. Therefore, we aimed to profile a phenotypical and molecular signature of senescent VSMCs to allow reliable identification. To achieve this goal, we have compared non-senescent and senescent VSMCs from two [i]in vitro[/i] models of senescence, replicative senescence (RS) and DNA-damage induced senescence (DS), by analyzing the expressions of established senescence markers: cell cycle inhibitors- p16 INK4a, p14 ARF, p21 and p53; pro-inflammatory factors-Interleukin 1β (IL-1β), IL-6 and high mobility group box-1 (HMGB-1); contractile proteins-smooth muscle heavy chain- (MYH11), smoothelin and transgelin (TAGLN), as well as structural features (nuclear morphology and [[LMNB1]] (Lamin B1) expression). The different senescence-inducing modalities resulted in a lack of the proliferative activity. Nucleomegaly was seen in senescent VSMC as compared to freshly isolated VSMC Phenotypically, senescent VSMC appeared with a significantly larger cell size and polygonal, non-spindle-shaped cell morphology. In line with the supposed switch to a pro-inflammatory phenotype known as the senescence associated secretory phenotype (SASP), we found that both RS and DS upregulated IL-1β and released HMGB-1 from the nucleus, while RS also showed IL-6 upregulation. In regard to cell cycle-regulating molecules, we detected modestly increased p16 levels in both RS and DS, but largely inconsistent p21, p14ARF, and p53 expressions in senescent VSMCs. Since these classical markers of senescence showed insufficient deregulation to warrant senescent VSMC detection, we have conducted a non-biased proteomics and [i]in silico[/i] analysis of RS VSMC demonstrating altered RNA biology as the central molecular feature of senescence in this cell type. Therefore, key proteins involved with RNA functionality, HMGB-1 release, LMNB-1 downregulation, in junction with nuclear enlargement, can be used as markers of VSMC senescence, enabling the detection of these pathogenic pro-inflammatory cells in future therapeutic studies in ischemic heart disease and atherosclerosis.

|keywords=* aging
* cardiovascular
* inflammation
* senescence
* smooth muscle cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261939
}}
==ERF==

{{medline-entry
|title=Angiotensin-Converting Enzyme Gene D/I Polymorphism in Relation to Endothelial Function and Endothelial-Released Factors in Chinese Women.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33041838
|abstract=Many studies have investigated the relationship between angiotensin-converting enzyme ([i]ACE[/i]) D/I polymorphism and cardiovascular disease or endothelial dysfunction; however, hardly any of these studies has taken aging or menopause into consideration. Furthermore, despite that many studies have examined the regulatory effects of endothelial-released factors ([[ERF]]s) on endothelial function, no study has evaluated the relationship between [[ERF]]s and endothelial function with respect to [i]ACE[/i] D/I polymorphism and menopause status. To answer these questions, 391 healthy Chinese women over a wide range of ages (22-75 years) were enrolled and divided into pre-menopause group and post-menopause group. After [i]ACE[/i] D/I genotype being identified, the women were then classified into either DI/II or DD genotype. Flow-mediated dilatation (FMD) of brachial endothelium and plasma levels of [[ERF]]s: nitric oxide (NO), endothelin-1 (ET-1), and angiotensin II (Ang II) were measured. The results showed that frequencies of [i]ACE[/i] D/I genotypes were in accordance with the Hardy-Weinberg equilibrium, and the frequency of I allele was higher than D allele. In pre-menopause group, FMD was significantly higher in women of DI/II than DD ([i]P[/i] = 0.032), and age-dependent in both genotypes (DD, [i]P[/i] = 0.0472; DI/II, [i]P[/i] < 0.0001). In post-menopause group, FMD was similar between women of DI/II and DD, and age-dependent only in women of DI/II ([i]P[/i] < 0.0001). In pre-menopause group, Ang II level was significantly higher in women of DD than DI/II ([i]P[/i] = 0.029), and FMD was significantly correlated with all [[ERF]]s in women of DD (NO, [i]P[/i] = 0.032; ET-1, [i]P[/i] = 0.017; Ang II, [i]P[/i] = 0.002), but only with Ang II in women of DI/II ([i]P[/i] = 0.026). In post-menopause group, no significant difference was observed in any [[ERF]] between women of DI/II and DD, and FMD was only significantly correlated with ET-1 in women of DD ([i]P[/i] = 0.010). In summary, FMD in women of DI/II was superior to DD in pre-menopause and more age-dependent than DD in post-menopause, and FMD was closely associated with [[ERF]]s. In conclusion, Chinese women of DI/II seem to have lower risk than DD in pre-menopause, but similar risk as DD in post-menopause in developing cardiovascular disease.

|keywords=* ACE D/I gene polymorphism
* Chinese women
* aging
* endothelial function
* endothelial-released factors
* menopause
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526498
}}
{{medline-entry
|title=Projections of Ambient Temperature- and Air Pollution-Related Mortality Burden Under Combined Climate Change and Population Aging Scenarios: a Review.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32542573
|abstract=Climate change will affect mortality associated with both ambient temperature and air pollution. Because older adults have elevated vulnerability to both non-optimal ambient temperature (heat and cold) and air pollution, population aging can amplify future population vulnerability to these stressors through increasing the number of vulnerable older adults. We aimed to review recent evidence on projections of temperature- or air pollution-related mortality burden (i.e., number of deaths) under combined climate change and population aging scenarios, with a focus on evaluating the role of population aging in assessing these health impacts of climate change. We included studies published between 2014 and 2019 with age-specific population projections. We reviewed 16 temperature projection studies and 15 air pollution projection studies. Nine of the temperature studies and four of the air pollution studies took population aging into account by performing age-stratified analyses that utilized age-specific relationships between temperature or air pollution exposures and mortality (i.e., age-specific exposure-response functions ([[ERF]]s)). Population aging amplifies the projected mortality burden of temperature and air pollution under a warming climate. Compared with a constant population scenario, population aging scenarios lead to less reduction or even increases in cold-related mortality burden, resulting in substantial net increases in future overall (heat and cold) temperature-related mortality burden. There is strong evidence suggesting that to accurately assess the future temperature- and air pollution-related mortality burden of climate change, investigators need to account for the amplifying effect of population aging. Thus, all future studies should incorporate age-specific population size projections and age-specific [[ERF]]s into their analyses. These studies would benefit from refinement of age-specific [[ERF]] estimates.

|keywords=* Air pollution
* Climate change
* Mortality
* Population aging
* Projection
* Temperature
|full-text-url=https://sci-hub.do/10.1007/s40572-020-00281-6
}}
{{medline-entry
|title=Exome Sequencing Analysis Identifies Rare Variants in [i]ATM[/i] and [i]RPL8[/i] That Are Associated With Shorter Telomere Length.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32425970
|abstract=Telomeres are important for maintaining genomic stability. Telomere length has been associated with aging, disease, and mortality and is highly heritable (∼82%). In this study, we aimed to identify rare genetic variants associated with telomere length using whole-exome sequence data. We studied 1,303 participants of the Erasmus Rucphen Family ([[ERF]]) study, 1,259 of the Rotterdam Study (RS), and 674 of the British Heart Foundation Family Heart Study (BHF-FHS). We conducted two analyses, first we analyzed the family-based [[ERF]] study and used the RS and BHF-FHS for replication. Second, we combined the summary data of the three studies in a meta-analysis. Telomere length was measured by quantitative polymerase chain reaction in blood. We identified nine rare variants significantly associated with telomere length ([i]p[/i]-value < 1.42 × 10 , minor allele frequency of 0.2-0.5%) in the [[ERF]] study. Eight of these variants (in [i]C11orf65[/i], [i]ACAT1[/i], [i]NPAT[/i], [i]ATM[/i], [i]KDELC2[/i], and [i]EXPH5[/i]) were located on chromosome 11q22.3 that contains [i]ATM[/i], a gene involved in telomere maintenance. Although we were unable to replicate the variants in the RS and BHF-FHS ([i]p[/i]-value ≥ 0.21), segregation analysis showed that all variants segregate with shorter telomere length in a family. In the meta-analysis of all studies, a nominally significant association with LTL was observed with a rare variant in [i]RPL8[/i] ([i]p[/i]-[i]value[/i] = 1.48 × 10 ), which has previously been associated with age. Additionally, a novel rare variant in the known [i]RTEL1[/i] locus showed suggestive evidence for association ([i]p[/i]-value = 1.18 × 10 ) with LTL. To conclude, we identified novel rare variants associated with telomere length. Larger samples size are needed to confirm these findings and to identify additional variants.

|keywords=* ATM
* RPL8
* aging
* meta-analysis
* telomere
* whole exome sequencing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204400
}}
==PRL==

{{medline-entry
|title=Mechanism of [[PRL]]2 phosphatase-mediated PTEN degradation and tumorigenesis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32788364
|abstract=Tumor suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) levels are frequently found reduced in human cancers, but how PTEN is down-regulated is not fully understood. In addition, although a compelling connection exists between [[PRL]] (phosphatase of regenerating liver) 2 and cancer, how this phosphatase induces oncogenesis has been an enigma. Here, we discovered that [[PRL]]2 ablation inhibits PTEN heterozygosity-induced tumorigenesis. [[PRL]]2 deficiency elevates PTEN and attenuates AKT signaling, leading to decreased proliferation and increased apoptosis in tumors. We also found that high [[PRL]]2 expression is correlated with low PTEN level with reduced overall patient survival. Mechanistically, we identified PTEN as a putative [[PRL]]2 substrate and demonstrated that [[PRL]]2 down-regulates PTEN by dephosphorylating PTEN at Y336, thereby augmenting NEDD4-mediated PTEN ubiquitination and proteasomal degradation. Given the strong cancer susceptibility to subtle reductions in PTEN, the ability of [[PRL]]2 to down-regulate PTEN provides a biochemical basis for its oncogenic propensity. The results also suggest that pharmacological targeting of [[PRL]]2 could provide a novel therapeutic strategy to restore PTEN, thereby obliterating PTEN deficiency-induced malignancies.
|mesh-terms=* Animals
* Carcinogenesis
* Female
* HEK293 Cells
* Humans
* Immediate-Early Proteins
* Longevity
* Male
* Mice, Inbred C57BL
* Mice, Knockout
* Nedd4 Ubiquitin Protein Ligases
* PTEN Phosphohydrolase
* Protein Tyrosine Phosphatases
* Proto-Oncogene Proteins c-akt
* Ubiquitination
|keywords=* NEDD4
* PRL2
* PTEN
* protein tyrosine phosphatases
* ubiquitination
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456095
}}
{{medline-entry
|title=Prolactin mitigates deficiencies of retinal function associated with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31698287
|abstract=Aging causes the progressive degeneration of retinal cells leading to the eventual loss of vision. The hormone prolactin ([[PRL]]) is a neurotrophic factor able to compensate for photoreceptor cell death and electroretinogram deficits induced by light retinal damage. Here, we used adult 4-month old and aged 20-month old pigmented mice, null or not for the [[PRL]] receptor to explore whether [[PRL]] provides trophic support against age-related retinal dysfunction. Retinal functionality, apoptosis, glia activation, and neurotrophin expression were assessed by electroretinogram, TUNEL, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 immunohistochemistry, and real-time PCR, respectively. Lack of [[PRL]] signaling in aged mice, but not in adult mice, correlated with photosensitive retinal dysfunction, increased photoreceptor apoptosis, differential expression of proapoptotic mediators, and microglia activation. We conclude that [[PRL]] is required for maintaining retinal functionality in both female and male mice during aging and has potential therapeutic value against age-related retinal disorders.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Electroretinography
* Mice, Inbred C57BL
* Nerve Growth Factors
* Neuroglia
* Prolactin
* Retina
* Retinal Degeneration
|keywords=* Aging
* Apoptosis
* Glia activation
* Hormone
* Mesotopic and photopic electroretinogram
* Retina
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2019.10.002
}}
{{medline-entry
|title=A Spontaneous Aggressive ERα+ Mammary Tumor Model Is Driven by Kras Activation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31390566
|abstract=The NRL-[[PRL]] murine model, defined by mammary-selective transgenic rat prolactin ligand rPrl expression, establishes spontaneous ER+ mammary tumors in nulliparous females, mimicking the association between elevated prolactin ([[PRL]]) and risk for development of ER+ breast cancer in postmenopausal women. Whole-genome and exome sequencing in a discovery cohort (n = 5) of end-stage tumors revealed canonical activating mutations and copy number amplifications of Kras. The frequent mutations in this pathway were validated in an extension cohort, identifying activating Ras alterations in 79% of tumors (23 of 29). Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors compared with preneoplastic tissues; in cell-intrinsic processes associated with mitosis, cell adhesion, and invasion; as well as in the surrounding tumor environment. These genomic analyses suggest that [[PRL]] induces a selective bottleneck for spontaneous Ras-driven tumors that may model a subset of aggressive clinical ER+ breast cancers.
|mesh-terms=* Aging
* Animals
* Carcinogenesis
* Datasets as Topic
* Estrogen Receptor alpha
* Female
* Gene Expression Profiling
* Humans
* Mammary Neoplasms, Experimental
* Mice
* Prolactin
* Proto-Oncogene Proteins p21(ras)
* Rats
* Signal Transduction
* Transgenes
|keywords=* ER+ breast cancer
* Ras mutations
* breast cancer
* genomic analyses
* mouse models
* prolactin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6713291
}}
==NEDD8==

{{medline-entry
|title=Targeting Protein Neddylation for Cancer Therapy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31898235
|abstract=Neddylation is a posttranslational modification that conjugates a ubiquitin-like protein [[NEDD8]] to substrate proteins. The best-characterized substrates of neddylation are the cullin subunits of cullin-RING E3 ubiquitin ligase complexes (CRLs). CRLs as the largest family of E3 ubiquitin ligases control many important biological processes, including tumorigenesis, through promoting ubiquitylation and subsequent degradation of a variety of key regulatory proteins. The process of protein neddylation is overactivated in multiple types of human cancers, providing a sound rationale as an attractive anticancer therapeutic strategy, evidenced by the development of the [[NEDD8]]-activating enzyme (NAE) inhibitor MLN4924 (also known as pevonedistat). Recently, increasing evidence strongly indicates that neddylation inhibition by MLN4924 exerts anticancer effects mainly by triggering cell apoptosis, senescence, and autophagy and causing angiogenesis suppression, inflammatory responses, and chemo-/radiosensitization in a context-dependent manner. Here, we briefly summarize the latest progresses in this field, focusing on the preclinical studies to validate neddylation modification as a promising anticancer target.
|mesh-terms=* Animals
* Apoptosis
* Autophagy
* Cyclopentanes
* Humans
* NEDD8 Protein
* Neoplasms
* Pyrimidines
* Ubiquitin-Protein Ligases
* Ubiquitination
|keywords=* Apoptosis
* Autophagy
* Cancer target
* Inflammatory responses
* Neddylation
* Senescence
|full-text-url=https://sci-hub.do/10.1007/978-981-15-1025-0_18
}}
{{medline-entry
|title=Effective targeting of the ubiquitin-like modifier [[NEDD8]] for lung adenocarcinoma treatment.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31907687
|abstract=Protein neddylation, a process of conjugating neural precursor cell expressed, developmentally downregulated 8 ([[NEDD8]]) to substrates, plays a tumor-promoting role in lung carcinogenesis. Our previous study showed MLN4924, an inhibitor of [[NEDD8]] activating enzyme (E1), significantly inhibits the growth of multiple cancer cells. However, resistance can develop to MLN4924 by mutation. Therefore, it is important to further understand how [[NEDD8]] acts in lung cancer. In the present study, we demonstrated [[NEDD8]] is overactivated in lung cancers and confers a worse patient overall survival. Furthermore, we report that in lung adenocarcinoma cells, [[NEDD8]] depletion significantly suppressed lung cancer cell growth and progression both in vitro and in vivo. Mechanistic studies revealed that [[NEDD8]] depletion induced the accumulation of a panel of tumor-suppressive cullin-RING ubiquitin ligase substrates (e.g., p21, p27, and Wee1) via blocking their degradation, triggering cell cycle arrest at G  phase, thus inducing apoptosis or senescence in a cell-line-dependent manner. The present study demonstrates the role of [[NEDD8]] in regulating the malignant phenotypes of lung cancer cells and further validates [[NEDD8]] as a potential therapeutic target in lung cancer.

|keywords=* NEDD8
* apoptosis
* cullin-RING ligases
* neddylation
* senescence
|full-text-url=https://sci-hub.do/10.1007/s10565-019-09503-6
}}
{{medline-entry
|title=Pevonedistat targeted therapy inhibits canine melanoma cell growth through induction of DNA re-replication and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31665821
|abstract=MLN4924 (pevonedistat) is a potent and selective [[NEDD8]]-activating enzyme (NAE) inhibitor. The [[NEDD8]]-regulated neddylation system is responsible for the regulated degradation of intracellular proteins with important cellular functions in cancer cell growth, apoptosis, angiogenesis and metastasis. In human melanoma, inhibition of NAE results in induction of DNA re-replication, S phase cell cycle arrest, DNA damage and apoptosis. The study aimed to assess the anti-cancer effect of MLN4924 on canine malignant melanoma cell lines and patient samples and to elucidate the underlying mechanisms. Canine melanoma cell lines and primary patient samples were evaluated for cell viability after incubation with varying concentrations of MLN4924 or dimethyl sulfoxide. Apoptosis, cell proliferation and senescence assays were performed to address underlying mechanisms of MLN4924-mediated anti-tumour effects. Gene expression of seven previously identified deregulated genes in human melanoma was compared in sensitive vs resistant samples. MLN4924 treatment significantly reduced the viability of canine melanoma cell lines and primary samples in a dose- and time-dependent manners. MLN4924 promoted cell apoptosis and inhibited cell growth through induction of DNA re-replication and cell senescence. While the majority of canine melanoma samples demonstrated sensitivity at nanomolar ranges, some samples were resistant to the treatment. Modulation of P21 levels correlated with canine melanoma cell sensitivity. These results provided justification for further exploration of MLN4924 as a treatment of canine melanoma.

|keywords=* DNA re-replication
* MLN4924
* NAE-inhibitor
* canine
* melanoma
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473101
}}
==EDA==

{{medline-entry
|title=Interplay between aging, lung inflammation/remodeling, and fibronectin [[EDA]] in lung cancer progression.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33222614
|abstract=Lung cancer remains the leading cause of cancer death in the United States. Since most lung cancers occur in aged individuals with chronic lung disorders characterized by inflammation and/or fibrosis, we hypothesized that aging and tissue inflammation/remodeling act in concert to promote lung cancer progression. To test this, we engaged in studies using young and aged C57BL/6 mice in conjunction with bleomycin treatment in a syngeneic model of lung cancer. Wildtype young (3 months) and aged (9 months) C57BL/6 mice were injected with Lewis Lung Carcinoma (LLC) cells at day 14 after injection with phosphate-buffered saline or bleomycin. Untreated aged mice were found to develop more lung metastases than young mice. Bleomycin induced weight loss and lung inflammation/remodeling in both young and aged mice, and it increased the number of lung metastases in aged lungs, but not in young lungs. Since aged lungs show alterations in the expression of fibronectin [[EDA]], we repeated studies in aged WT and aged FN [[EDA]] KO mice. In the absence of tissue remodeling/inflammation, WT and FN [[EDA]] KO mice developed the same number of metastases when injected with LLC cells. However, the increase in lung metastasis due to bleomycin treatment was abolished in FN [[EDA]] KO mice, but only in aged and injured lungs. Together, these studies show increased lung cancer metastasis in aging animals and point to the influence of FN [[EDA]] and injury in this process.

|keywords=* Lung cancer
* aging
* fibronectin EDA
* fibrosis
* inflammation
* lewis lung carcinoma
* metastasis
|full-text-url=https://sci-hub.do/10.1080/15384047.2020.1831372
}}
{{medline-entry
|title=Arousal Detection in Elderly People from Electrodermal Activity Using Musical Stimuli.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32854302
|abstract=The detection of emotions is fundamental in many areas related to health and well-being. This paper presents the identification of the level of arousal in older people by monitoring their electrodermal activity ([[EDA]]) through a commercial device. The objective was to recognize arousal changes to create future therapies that help them to improve their mood, contributing to reduce possible situations of depression and anxiety. To this end, some elderly people in the region of Murcia were exposed to listening to various musical genres (flamenco, Spanish folklore, Cuban genre and rock/jazz) that they heard in their youth. Using methods based on the process of deconvolution of the [[EDA]] signal, two different studies were carried out. The first, of a purely statistical nature, was based on the search for statistically significant differences for a series of temporal, morphological, statistical and frequency features of the processed signals. It was found that Flamenco and Spanish Folklore presented the highest number of statistically significant parameters. In the second study, a wide range of classifiers was used to analyze the possible correlations between the detection of the [[EDA]]-based arousal level compared to the participants' responses to the level of arousal subjectively felt. In this case, it was obtained that the best classifiers are support vector machines, with 87% accuracy for flamenco and 83.1% for Spanish Folklore, followed by K-nearest neighbors with 81.4% and 81.5% for Flamenco and Spanish Folklore again. These results reinforce the notion of familiarity with a musical genre on emotional induction.

|keywords=* aging adults
* arousal
* electrodermal activity
* musical genres
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506973
}}
{{medline-entry
|title=The structure of agricultural microplastics (PT, PU and UF) and their sorption capacities for PAHs and PHE derivates under various salinity and oxidation treatments.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31761592
|abstract=Microplastic (MP) pollution and its potential to concentrate and transport organic contaminants in environments have recently gained widespread attention. Compared to traditional nonpolar plastics such as polypropylene (PP) and polyethylene (PE), study about the environmental behavior of polyurethane (PT), polyuria (PU) and urea-formaldehyde resin (UF), which are typically used as shell materials for pesticide microcapsules and have polar structure is scarce. In the present study, we investigated the sorption capacities and binding mechanisms of PT, PU and UF for three polycyclic aromatic hydrocarbons (PAHs, naphthalene, phenanthrene (PHE), and pyrene) and two PHE derivates (ethylphenanthrene-2-carboxylate (2-CPHE) and 2-methylphenathrene (2-MPHE)) selected as the model compounds, and the effects of salinity and UV and/or H O  aging treatments on PHE sorption to MPs. The results showed that PT, PU and UF had negative surface charges, micron-scaled sizes and abundant polar functional groups containing O and N elements. PT, PU and UF could sorb PAHs efficiently with sorption coefficients (K ) being in the range of 8.11 × 10 -9.53 × 10  (L/Kg) and partitioning was the main sorption mechanism with polar interactions (H-boning and p/π-π [[EDA]] interactions) also contributing. The sorption capacity of the three MPs changed mainly depending on their glass transition temperatures (T ). Furthermore, high salinity decreased the surface zeta-potential of the MPs and enhanced PHE sorption to MPs. In addition, aging treatments with UV and/or H O  markedly decreased the T  of PT and enhanced its sorption capacity for PHE, while opposite results were obtained for PU. The findings on the sorption mechanisms of PAHs to agricultural MPs are useful for predicting the transport, fate and persistence of the co-existing HOCs in agricultural ecosystems and provide a scientific basis for the comprehensive risk assessment of agricultural MPs.
|mesh-terms=* Adsorption
* Agriculture
* Ecosystem
* Environmental Pollutants
* Hydrogen Peroxide
* Microplastics
* Models, Chemical
* Naphthalenes
* Organic Chemicals
* Phenanthrenes
* Plastics
* Polycyclic Aromatic Hydrocarbons
* Polyethylene
* Polypropylenes
* Polyurethanes
* Polyuria
* Pyrenes
* Salinity
|keywords=* Aging
* Microplastics
* Polycyclic aromatic hydrocarbons
* Salinity
* Sorption
|full-text-url=https://sci-hub.do/10.1016/j.envpol.2019.113525
}}
==PFAS==

{{medline-entry
|title=Associations between serum concentrations of perfluoroalkyl substances and DNA methylation in women exposed through drinking water: A pilot study in Ronneby, Sweden.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33007577
|abstract=Perfluoroalkyl substances ([[PFAS]]) are widespread synthetic substances with various adverse health effects. A potential mechanism of toxicity for [[PFAS]] is via epigenetic changes, such as DNA methylation. However, few studies have evaluated associations between [[PFAS]] exposure and DNA methylation among adults, and data is especially scarce for women. Furthermore, exposure to environmental pollutants has been associated with epigenetic age acceleration, but no studies have yet evaluated whether [[PFAS]] is associated with epigenetic age acceleration. To investigate whether exposure to [[PFAS]] is associated with alteration of DNA methylation and epigenetic age acceleration among women. In this observational pilot study, 59 women (aged 20-47 years at enrollment in 2014) from Ronneby, Sweden, an area with historically high [[PFAS]] exposure due to local drinking water contamination, were divided into three [[PFAS]] exposure groups (low, medium, and high). Genome-wide methylation of whole-blood DNA was analyzed using the Infinium MethylationEPIC BeadChip. Ingenuity Pathway Analysis was used for in silico functional assessment. Epigenetic age acceleration was derived from the DNA methylation data using Horvath's epigenetic skin and blood clock. 117 differentially methylated positions (q < 0.017) and one near-significantly differentially methylated region (S100A13, FWER = 0.020) were identified. In silico functional analyses suggested that genes with altered DNA methylation (q < 0.05) were annotated to cancer, endocrine system disorders, reproductive system disease, as well as pathways such as estrogen receptor signaling, cardiac hypertrophy signaling, PPARα/RXRα activation and telomerase signaling. No differences in epigenetic age acceleration between [[PFAS]] exposure groups were noted (p = 0.43). The data suggests that [[PFAS]] exposure alters DNA methylation in women highly exposed to [[PFAS]] from drinking water. The observed associations should be verified in larger cohorts, and it should also be further investigated whether these changes in methylation also underlie potential phenotypic changes and/or adverse health effects of [[PFAS]].

|keywords=* EPIC chip
* Environmental pollutant
* Epigenetic aging
* Epigenetics
* PFAS
* Perfluoroalkyl substance
|full-text-url=https://sci-hub.do/10.1016/j.envint.2020.106148
}}
{{medline-entry
|title=Perfluorinated alkyl substances impede growth, reproduction, lipid metabolism and lifespan in Daphnia magna.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32521362
|abstract=Per- and polyfluorinated alkyl substances ([[PFAS]]s) are synthetic organofluorine compounds with unique stability accompanied with hydrophobic and lipophobic properties. Perfluorooctane sulfonate (PFOS) and Perfluorooctanoic acid (PFOA) are of high concern due to their wide application in consumer and industrial products, extreme persistence, abundant occurrence in the environment and their toxic effect to humans and animals. However, knowledge on the molecular mechanisms of toxicity and the effects on reproduction output remain scarce. In this study, we analyzed the effects of PFOS and PFOA on Daphnia magna. Acute toxicity, development, reproduction, lipid metabolism (lipid-accumulation) and lifespan was investigated, as well as the expression of genes related to these endpoints. Exposure of PFOS and PFOA at 1, 10 and 25 μM did not cause acute lethality. Hatching was reduced following exposure to both compounds, and lifespan was decreased following exposure to 25 μM PFOS. Body length of Daphnia magna was reduced significantly by 25 μM PFOS following 7 days exposure. Lipid staining revealed that all [[PFAS]] exposures increased lipid accumulation. qRT-PCR analysis of genes involved in lipid metabolism suggests that the increase in lipid content could be due to inhibition of genes involved on absorption and catabolism of fatty acids. Exposure to both PFOA and PFOS reduced the fecundity significantly. Downregulation of genes involved in development and reproductive process, including vtg2, vasa, EcRA, EcRB, usp, jhe, HR3, ftz-F1, E74 and E75 were observed. The alterations in developmental and reproductive genes as well as the disturbed lipid metabolism provides mechanistic insight into the possible causes for decreased fecundity and lifespan observed following exposure to both PFOS and PFOA.
|mesh-terms=* Alkanesulfonic Acids
* Animals
* Caprylates
* Daphnia
* Fatty Acids
* Fluorocarbons
* Humans
* Lipid Metabolism
* Longevity
* Reproduction
|keywords=* Fatty acid
* Fecundity
* Gene expression
* PFAS toxicity
* Perfluorooctane sulfonate (PFOS)
* Perfluorooctanoic acid (PFOA)
|full-text-url=https://sci-hub.do/10.1016/j.scitotenv.2020.139682
}}
{{medline-entry
|title=The effect of weathering on per- and polyfluoroalkyl substances ([[PFAS]]s) from durable water repellent (DWR) clothing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32062207
|abstract=To assess the effects of weathering on per- and polyfluoroalkyl substances ([[PFAS]]s) from durable water repellent (DWR) clothing, thirteen commercial textile samples were exposed to elevated ultra violet (UV) radiation, humidity, and temperature in an aging device for 300 h, which mimics the lifespan of outdoor clothing. Before and after aging, the textile samples were extracted and analysed for the ionic [[PFAS]]s (perfluoroalkyl acids (PFAAs), perfluorooctane sulfonamide (FOSA)) and volatile [[PFAS]]s (fluorotelomer alcohols (FTOHs), acrylates (FTACs) and methacrylates (FTMACs)). Results showed that weathering can have an effect on [[PFAS]]s used in DWR of outdoor clothing, both on the [[PFAS]] profile and on the measured concentrations. In most weathered samples the PFAA concentrations increased by 5- to more than 100-fold, while PFAAs not detected in the original textiles were detected in the weathered samples. DWR chemistries are based on side-chain fluorinated polymers. A possible explanation for the increase in concentration of the PFAAs is hydrolysis of the fluorotelomer based polymers (FTPs), or degradation of the FTOHs, which are used in the manufacturing of the FTPs. The concentrations of volatile [[PFAS]]s also increased, by a factor up to 20. Suggested explanations are the degradation of the DWR polymers, making non-extractable fluorines extractable, or the transformation or degradation of unknown precursors. Further research is needed to unravel the details of these processes and to determine the transformation routes. This study shows that setting maximum tolerance limits only for a few individual [[PFAS]]s is not sufficient to control these harmful substances in outdoor clothing.
|mesh-terms=* Acrylates
* Alcohols
* Clothing
* Environmental Monitoring
* Fluorocarbon Polymers
* Fluorocarbons
* Humidity
* Models, Chemical
* Textiles
* Water
* Water Pollutants, Chemical
* Weather
|keywords=* Aging
* Durable water repellency
* Outdoor clothing
* Per- and polyfluoroalkyl substances
* Textile
* Weathering
|full-text-url=https://sci-hub.do/10.1016/j.chemosphere.2020.126100
}}
==P2RY12==

{{medline-entry
|title=Potential caveats of putative microglia-specific markers for assessment of age-related cerebrovascular neuroinflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33261619
|abstract=The ability to distinguish resident microglia from infiltrating myeloid cells by flow cytometry-based surface phenotyping is an important technique for examining age-related neuroinflammation. The most commonly used surface markers for the identification of microglia include CD45 (low-intermediate expression), CD11b, Tmem119, and [[P2RY12]]. In this study, we examined changes in expression levels of these putative microglia markers in in vivo animal models of stroke, cerebral amyloid angiopathy (CAA), and aging as well as in an ex vivo LPS-induced inflammation model. We demonstrate that Tmem119 and [[P2RY12]] expression is evident within both CD45  and CD45  myeloid populations in models of stroke, CAA, and aging. Interestingly, LPS stimulation of FACS-sorted adult microglia suggested that these brain-resident myeloid cells can upregulate CD45 and downregulate Tmem119 and [[P2RY12]], making them indistinguishable from peripherally derived myeloid populations. Importantly, our findings show that these changes in the molecular signatures of microglia can occur without a contribution from the other brain-resident or peripherally sourced immune cells. We recommend future studies approach microglia identification by flow cytometry with caution, particularly in the absence of the use of a combination of markers validated for the specific neuroinflammation model of interest. The subpopulation of resident microglia residing within the "infiltrating myeloid" population, albeit small, may be functionally important in maintaining immune vigilance in the brain thus should not be overlooked in neuroimmunological studies.

|keywords=* Aging
* Brain infiltrating myeloid cells
* CD45
* Cerebral amyloid angiopathy
* Microglia
* Neuroinflammation
* P2RY12
* Stroke
* Tmem119
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709276
}}
{{medline-entry
|title=Microglial changes in the early aging stage in a healthy retina and an experimental glaucoma model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32958210
|abstract=Glaucoma is an age-related neurodegenerative disease that begins at the onset of aging. In this disease, there is an involvement of the immune system and therefore of the microglia. The purpose of this study is to evaluate the microglial activation using a mouse model of ocular hypertension (OHT) at the onset of aging. For this purpose, we used both naive and ocular hypertensives of 15-month-old mice (early stage of aging). In the latter, we analyzed the OHT eyes and the eyes contralateral to them to compare them with their aged controls. In the eyes of aged naive, aged OHT and aged contralateral eyes, microglial changes were observed compared to the young mice, including: (i) aged naive vs young naive: An increased soma size and vertical processes; (ii) aged OHT eyes vs young OHT eyes: A decrease in the area of the retina occupied by Iba-1 cells and in vertical processes; and (iii) aged contralateral vs young contralateral: A decrease in the soma size and arbor area and an increase in the number of microglia in the outer segment layer. Aged OHT eyes and the eyes contralateral to them showed an up-regulation of the CD68 expression in the branched microglia and a down-regulation in the MHCII and [[P2RY12]] expression with respect to the eyes of young OHT mice. Conclusion: in the early phase of aging, morphological microglial changes along with changes in the expression of MHCII, CD68 and [[P2RY12]], in both naive and OHT mice. These changes appear in aged OHT eyes and the eyes contralateral to them eyes.

|keywords=* Aging
* CD68
* Glaucoma
* Iba-1
* Inflammation
* MHCII
* Microglia
* Mouse
* Ocular hypertension
* P2RY12
* Retina
|full-text-url=https://sci-hub.do/10.1016/bs.pbr.2020.05.024
}}
{{medline-entry
|title=Patterns of Expression of Purinergic Receptor [[P2RY12]], a Putative Marker for Non-Activated Microglia, in Aged and Alzheimer's Disease Brains.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31968618
|abstract=Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer's disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach with the goal of characterizing the distribution of purinergic receptor [[P2RY12]]-positive microglia, a marker previously defined as identifying homeostatic or non-activated microglia. We examined the expression of [[P2RY12]] by dual-color light and fluorescence immunohistochemistry using sections of middle temporal gyrus from AD, high plaque and low plaque non-demented cases in relation to amyloid beta (Aβ) plaques and phosphorylated tau, markers of pathology, and HLA-DR, IBA-1, CD68, and progranulin, microglial phenotype markers. In low plaque cases, [[P2RY12]]-positive microglia mostly had non-activated morphologies, while the morphologies of [[P2RY12]]-positive microglia in AD brains were highly variable, suggesting its expression could encompass a wider range of phenotypes than originally hypothesized. [[P2RY12]] expression by microglia differed depending on the types of plaques or tangles they were associated with. Areas of inflammation characterized by lack of [[P2RY12]]-positive microglia around mature plaques could be observed, but many diffuse plaques showed colocalization with [[P2RY12]]-positive microglia. Based on these results, [[P2RY12]] expression by microglia should not be considered solely a marker of resting microglia as [[P2RY12]] immunoreactivity was identifying microglia positive for CD68, progranulin and to a limited extent HLA-DR, markers of activation.
|mesh-terms=* Aging
* Alzheimer Disease
* Biomarkers
* Brain
* Humans
* Immunohistochemistry
* Inflammation
* Macrophages
* Microglia
* Phenotype
* Plaque, Amyloid
* Receptors, Purinergic P2Y2
|keywords=* Alzheimer’s disease
* activation phenotypes
* amyloid
* immunohistochemistry
* microglia
* neuroinflammation
* temporal cortex
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014248
}}
==G6PD==

{{medline-entry
|title=[[G6PD]] overexpression protects from oxidative stress and age-related hearing loss.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33222382
|abstract=Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose-6-phosphate dehydrogenase ([[G6PD]]), which catalyzes the rate-limiting step in the pentose phosphate pathway. We show here that [[G6PD]] transgenic mice ([[G6PD]]-Tg), which show enhanced constitutive [[G6PD]] activity and NADPH production along life, have lower auditory thresholds than wild-type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3-month-old [[G6PD]]-Tg mice than in wild-type counterparts, whereas the levels of pro-apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL  apoptotic cells were all lower in 9-month-old [[G6PD]]-Tg than in wild-type counterparts. Unexpectedly, [[G6PD]] overexpression triggered low-grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression.

|keywords=* ARHL
* NADPH
* TrxR
* aging
* glutathione
|full-text-url=https://sci-hub.do/10.1111/acel.13275
}}
{{medline-entry
|title=The Sickle Effect: The Silent Titan Affecting Glycated Hemoglobin Reliability.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32923278
|abstract=Hemoglobin A1c (HbA1c) is a popular invaluable tool in the diagnosis of Type 2 diabetes for red blood cells (RBCs) with a lifespan of 120 days; however, many factors, including hemoglobinopathies, affect its accuracy. Sickle cell trait, primarily a benign medical condition, is a point mutation in only one of two beta-globin genes on chromosome 11. We performed a traditional review to identify how the sickle cell trait (SCT) affects the interpretation of HbA1c and the further implications it may have on the diagnosis and management of Type 2 diabetes. A literature search was performed using PubMed®/MEDLINE® and Google Scholar with formulated keywords (sickle cell trait, HbAS, HbA1c, glycosylated hemoglobin, diabetes, RBC lifespan, race, and genetics), with the majority of results being mainly observational studies. The National Glycohemoglobin Standardization Program (NGSP) is responsible for standardizing HbA1c results and also highlights factors that can interfere with HbA1c, including hemoglobin variants. Studies that utilize only an NGSP-certified method with no clinically significant interference by HbS in patients with and without SCT showed contrasting results. Additional studies showed that persons of African ancestry, the group to which the majority of SCT patients belong, have a higher HbA1c than non-Hispanic whites (NHWs), just based on race, and a greater probability of having glucose-6-phosphate dehydrogenase ([[G6PD]]) deficiency, which lowers HbA1c. The most extensive study investigating the RBC lifespan in SCT patients showed a reduction in the cell lifespan compared to normal patients; however, other smaller studies were contradictory. Our study highlights the need for hemoglobinopathy detection before or during HbA1c measurement in populations with a high degree of African ancestry and the importance of patient notification. It also shows that SCT affects the accuracy of HbA1c, through its likely reduction of RBC lifespan and its increased association with African ancestry and [[G6PD]] deficiency. This review recommends that for SCT patients with potential Type 2 diabetes, HbA1c should be used in combination with another diagnostic tool such as fasting blood glucose, fructosamine, or glycated albumin to decrease the chances of a missed diagnosis.

|keywords=* diabetes
* genetics
* glycosylated hemoglobin
* hba1c
* hbas
* race
* rbc lifespan
* sickle cell trait
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486097
}}
{{medline-entry
|title=DNA damage and synaptic and behavioural disorders in glucose-6-phosphate dehydrogenase-deficient mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31581069
|abstract=Mice deficient in glucose-6-phosphate dehydrogenase ([[G6PD]]) cannot replenish the cellular antioxidant glutathione, which detoxifies neurodegenerative reactive oxygen species (ROS). To determine the functional consequences of [[G6PD]] deficiency, young and aging [[G6PD]]-deficient mice were evaluated for brain [[G6PD]] activity, DNA damage (comets, γH2AX), Purkinje cell loss, brain function (electrophysiology, behaviour) and lifespan. DNA comet formation was increased and Purkinje cell counts were decreased in a G6pd gene dose-dependent fashion. γH2AX formation varied by age, sex and brain region, with increased levels in [[G6PD]]-deficient young and aging females, and in aging males. Aging male [[G6PD]]-deficient mice exhibited synaptic dysfunction in hippocampal slices. [[G6PD]]-deficient young and aging females exhibited deficits in executive function, and young deficient mice exhibited deficits in social dominance. Conversely, median lifespan in [[G6PD]]-deficient females and males was enhanced. Enhanced ROS-initiated brain damage in [[G6PD]] deficiency has functional consequences, suggesting that [[G6PD]] protects against ROS-mediated neurodegenerative disorders.
|mesh-terms=* Animals
* Brain
* DNA Breaks, Double-Stranded
* DNA Breaks, Single-Stranded
* DNA Damage
* Disease Models, Animal
* Enzyme Activation
* Female
* Glucosephosphate Dehydrogenase
* Glucosephosphate Dehydrogenase Deficiency
* Male
* Mental Disorders
* Mice
* Oxidation-Reduction
* Purkinje Cells
|keywords=* 8-Oxo-2′-deoxyguanine (8-oxodG)
* Aging
* Behavioural disorders
* Comet
* DNA damage
* Electrophysiology
* Gamma-H2AX (γH2AX)
* Glucose-6-phosphate dehydrogenase (G6PD)
* Lifespan
* Neurodegeneration
* Reactive oxygen species (ROS)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812046
}}
==C9==

{{medline-entry
|title=[[C9]]orf72 in myeloid cells suppresses STING-induced inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32814898
|abstract=Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation . Expansions of a hexanucleotide repeat (GGGGCC) in the [[C9]]orf72 gene are the most common cause of familial ALS and FTD ([[C9]]-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased [[C9]]orf72 protein expression in brain and peripheral blood cells . Here we show in mice that loss of [[C9]]orf72 from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout of [[C9]]orf72. Dendritic cells isolated from [[C9]]orf72  mice show marked early activation of the type I interferon response, and [[C9]]orf72  myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished in [[C9]]orf72  myeloid cells, and blocking STING suppresses hyperactive type I interferon responses in [[C9]]orf72  immune cells as well as splenomegaly and inflammation in [[C9]]orf72  mice. Moreover, mice lacking one or both copies of [[C9]]orf72 are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with [[C9]]-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with [[C9]]-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with [[C9]]-ALS/FTD have an altered immunophenotype because their reduced levels of [[C9]]orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.
|mesh-terms=* Aging
* Amyotrophic Lateral Sclerosis
* Animals
* C9orf72 Protein
* Dendritic Cells
* Encephalomyelitis, Autoimmune, Experimental
* Female
* Humans
* Inflammation
* Interferon Type I
* Membrane Proteins
* Mice
* Myeloid Cells
* Neoplasms
* T-Lymphocytes

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484469
}}
{{medline-entry
|title=Glycine-alanine dipeptide repeats spread rapidly in a repeat length- and age-dependent manner in the fly brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31843021
|abstract=Hexanucleotide repeat expansions of variable size in [[C9]]orf72 are the most prevalent genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Sense and antisense transcripts of the expansions are translated by repeat-associated non-AUG translation into five dipeptide repeat proteins (DPRs). Of these, the polyGR, polyPR and, to a lesser extent, polyGA DPRs are neurotoxic, with polyGA the most abundantly detected DPR in patient tissue. Trans-cellular transmission of protein aggregates has recently emerged as a major driver of toxicity in various neurodegenerative diseases. In vitro evidence suggests that the [[C9]] DPRs can spread. However, whether this phenomenon occurs under more complex in vivo conditions remains unexplored. Here, we used the adult fly brain to investigate whether the [[C9]] DPRs can spread in vivo upon expression in a subset of neurons. We found that only polyGA can progressively spread throughout the brain, which accumulates in the shape of aggregate-like puncta inside recipient cells. Interestingly, GA transmission occurred as early as 3 days after expression induction. By comparing the spread of 36, 100 and 200 polyGA repeats, we found that polyGA spread is enhanced upon expression of longer GA DPRs. Transmission of polyGA is greater in older flies, indicating that age-associated factors exacerbate the spread. These data highlight a unique propensity of polyGA to spread throughout the brain, which could contribute to the greater abundance of polyGA in patient tissue. In addition, we present a model of early GA transmission that is suitable for genetic screens to identify mechanisms of spread and its consequences in vivo.
|mesh-terms=* Aging
* Alanine
* Animals
* Animals, Genetically Modified
* Brain
* C9orf72 Protein
* DNA Repeat Expansion
* Dipeptides
* Drosophila
* Female
* Glycine
|keywords=* Ageing
* C9orf72
* Dipeptide repeat proteins
* Drosophila
* PolyGA
* Repeat size
* Spread
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916080
}}
{{medline-entry
|title=Human iPSC-derived astrocytes from ALS patients with mutated [[C9]]ORF72 show increased oxidative stress and neurotoxicity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31787569
|abstract=Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons (MNs). It was shown that human astrocytes with mutations in genes associated with ALS, like [[C9]]orf72 ([[C9]]) or SOD1, reduce survival of MNs. Astrocyte toxicity may be related to their dysfunction or the release of neurotoxic factors. We used human induced pluripotent stem cell-derived astrocytes from ALS patients carrying [[C9]]orf72 mutations and non-affected donors. We utilized these cells to investigate astrocytic induced neuronal toxicity, changes in astrocyte transcription profile as well as changes in secretome profiles. We report that [[C9]]-mutated astrocytes are toxic to MNs via soluble factors. The toxic effects of astrocytes are positively correlated with the length of astrocyte propagation in culture, consistent with the age-related nature of ALS. We show that [[C9]]-mutated astrocytes downregulate the secretion of several antioxidant proteins. In line with these findings, we show increased astrocytic oxidative stress and senescence. Importantly, media conditioned by [[C9]]-astrocytes increased oxidative stress in wild type MNs. Our results suggest that dysfunction of [[C9]]-astrocytes leads to oxidative stress of themselves and MNs, which probably contributes to neurodegeneration. Our findings suggest that therapeutic strategies in familial ALS must not only target MNs but also focus on astrocytes to abrogate nervous system injury.
|mesh-terms=* Amyotrophic Lateral Sclerosis
* Animals
* Astrocytes
* Biomarkers
* C9orf72 Protein
* Cells, Cultured
* Cellular Reprogramming
* Cellular Senescence
* Cerebral Cortex
* Disease Models, Animal
* Gene Expression Profiling
* Glutamic Acid
* Humans
* Induced Pluripotent Stem Cells
* Mice
* Motor Neurons
* Mutation
* Oxidative Stress
* Proteomics
* Reactive Oxygen Species
|keywords=* Amyotrophic lateral sclerosis
* Astrocytes
* Neurotoxicity
* Oxidative stress
* Senescence
* iPSC
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921360
}}
==CD81==

{{medline-entry
|title=Ovarian aging increases small extracellular vesicle [[CD81]]  release in human follicular fluid and influences miRNA profiles.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32554857
|abstract=Ovarian aging affects female reproductive potential and is characterized by alterations in proteins, mRNAs and non-coding RNAs inside the ovarian follicle. Ovarian somatic cells and the oocyte communicate with each other secreting different molecules into the follicular fluid, by extracellular vesicles. The cargo of follicular fluid vesicles may influence female reproductive ability; accordingly, analysis of extracellular vesicle content could provide information about the quality of the female germ cell.In order to identify the most significant deregulated microRNAs in reproductive aging, we quantified the small extracellular vesicles in human follicular fluid from older and younger women and analyzed the expression of microRNAs enclosed inside the vesicles. We found twice as many small extracellular vesicles in the follicular fluid from older women and several differentially expressed microRNAs. Correlating microRNA expression profiles with vesicle number, we selected 46 deregulated microRNAs associated with aging. Bioinformatic analyses allowed us to identify six miRNAs involved in TP53 signaling pathways. Specifically, miR-16-5p, miR214-3p and miR-449a were downregulated and miR-125b, miR-155-5p and miR-372 were upregulated, influencing vesicle release, oocyte maturation and stress response. We believe that this approach allowed us to identify a battery of microRNAs strictly related to female reproductive aging.

|keywords=* extracellular vesicles
* follicular fluid
* microRNAs
* reproductive aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343446
}}
{{medline-entry
|title=Older Adults with Physical Frailty and Sarcopenia Show Increased Levels of Circulating Small Extracellular Vesicles with a Specific Mitochondrial Signature.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32326435
|abstract=Mitochondrial dysfunction and systemic inflammation are major factors in the development of sarcopenia, but the molecular determinants linking the two mechanisms are only partially understood. The study of extracellular vesicle (EV) trafficking may provide insights into this relationship. Circulating small EVs (sEVs) from serum of 11 older adults with physical frailty and sarcopenia (PF&S) and 10 controls were purified and characterized. Protein levels of three tetraspanins (CD9, CD63, and [[CD81]]) and selected mitochondrial markers, including adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2) were quantified by Western immunoblotting. Participants with PF&S showed higher levels of circulating sEVs relative to controls. Protein levels of CD9 and CD63 were lower in the sEV fraction of PF&S older adults, while [[CD81]] was unvaried between groups. In addition, circulating sEVs from PF&S participants had lower amounts of ATP5A, NDUFS3, and SDHB. No signal was detected for MTCOI, NDUFB8, or UQCRC2 in either participant group. Our findings indicate that, in spite of increased sEV secretion, lower amounts of mitochondrial components are discarded through EV in older adults with PF&S. In-depth analysis of EV trafficking might open new venues for biomarker discovery and treatment development for PF&S.

|keywords=* aging
* biomarkers
* exosomes
* mitochondrial dynamics
* mitochondrial quality control
* mitochondrial-derived vesicles (MDVs)
* mitochondrial-lysosomal axis
* mitophagy
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227017
}}
{{medline-entry
|title=Increased production of functional small extracellular vesicles in senescent endothelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32101370
|abstract=Small extracellular vesicles (EVs) are novel players in vascular biology. However, a thorough understanding of their production and function remains elusive. Endothelial senescence is a key feature of vascular ageing and thus, is an attractive therapeutic target for the treatment of vascular disease. In this study, we sought to characterize the EV production of senescent endothelial cells. To achieve this, Human Umbilical Vascular Endothelial Cells (HUVECs) were replicated until they reached senescence, as determined by measurement of Senescence-Associated β-Galactosidase activity via microscopy and flow cytometry. Expression of the endosomal marker Rab7 and the EV marker CD63 was determined by immunofluorescence. Small EVs were isolated by ultracentrifugation and characterized using electron microscopy, nanoparticle tracking analysis and immunoassays to assess morphology, size, concentration and expression of exosome markers CD9 and [[CD81]]. Migration of HUVECs in response to EVs was studied using a transwell assay. The results showed that senescent endothelial cells express higher levels of Rab7 and CD63. Moreover, senescent endothelial cells produced higher levels of CD9- and [[CD81]]-positive EVs. Additionally, small EVs from both young and senescent endothelial cells promoted HUVEC migration. Overall, senescent endothelial cells produce an increased number of functional small EVs, which may have a role in vascular physiology and disease.

|keywords=* endothelium
* exosomes
* extracellular vesicles
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176858
}}
==CTRL==

{{medline-entry
|title=Aging reduces the maximal level of peripheral fatigue tolerable and impairs exercise capacity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32966120
|abstract=The aim of the present study was to determine the magnitude of the maximal level of peripheral fatigue attainable (fatigue threshold) during an all-out intermittent isometric knee-extensor protocol in both younger (24 ± 1 yr, [i]n[/i] = 12) and older (60 ± 2 yr, [i]n[/i] = 12) participants to provide new insights into the effects of aging on neuromuscular function. Participants performed two experimental sessions, in which they performed 60 maximal voluntary contractions (MVCs; 3 s of contraction, 2 s of relaxation). One trial was performed in the unfatigued state ([[CTRL]]) and one other following fatiguing neuromuscular electrical stimulation of the quadriceps (F ). Peripheral fatigue was quantified via pre/postexercise decrease in quadriceps twitch force (∆P ). Critical force (CF) was determined as the mean force output of the last 12 contractions, whereas [i]W[/i]' was calculated as the area above CF. Although F  led to a significant decrease in P  before performing the 60-MVCs protocol ([i]P[/i] = 0.024), ∆P  was not different between [[CTRL]] and F  for both the young group ([i]P[/i] = 0.491) and the old group ([i]P[/i] = 0.523). However, this peripheral fatigue threshold was significantly greater in young versus old participants (∆P  = -48 ± 10% vs. -29 ± 13%, respectively, [i]P[/i] = 0.028). In [[CTRL]], [i]W'[/i] was 55 ± 13% lower in the old group than in the young group ([i]P[/i] < 0.001), but CF was similar (326 ± 10 N vs. 322 ± 12 N, respectively, [i]P[/i] = 0.941). ∆P  was correlated with [i]W'[/i], independently of age ([i]r[/i]  = 0.84, [i]P[/i] < 0.001). Exercise performance decreases with aging consequent to a lower tolerance to peripheral fatigue. However, the peripheral fatigue threshold mechanism persists with healthy aging and continues to play a protective role in preserving locomotor muscle function during exercise.

|keywords=* aging
* critical torque
* exercise performance
* group III/IV muscle afferents
* neuromuscular fatigue
|full-text-url=https://sci-hub.do/10.1152/ajpregu.00151.2020
}}
{{medline-entry
|title=miR-146a Plasma Levels Are Not Altered in Alzheimer's Disease but Correlate With Age and Illness Severity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32009940
|abstract=miR-146a is a microRNA (miRNA) involved in neuroinflammation and aging; alterations in its expression were described in Alzheimer's disease (AD). However, most of the studies conducted so far on this miRNA included a limited number of participants and produced contradictory results. We compared miR-146a levels in plasma from 33 AD patients vs. 28 age-matched non-affected controls ([[CTRL]]) through quantitative real-time polymerase chain reaction (qRT-PCR). No difference between the case and the control group was evidenced, but a correlation was detected between miR-146a levels and subjects' age ([i]p[/i] < 0.001) as well as between miR-146a levels and patients' Mini-Mental State Examination (MMSE) scores ([i]p[/i] = 0.011), in an enlarged group of 51 AD patients and 45 [[CTRL]] supporting a role for this miRNA in aging processes and disease progression.

|keywords=* Alzheimer’s disease
* aging
* blood
* miR-146a
* microRNA
* plasma
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978630
}}
{{medline-entry
|title=Centrally-mediated regulation of peripheral fatigue during knee extensor exercise and consequences on the force-duration relationship in older men.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31397211
|abstract=The aim of the present study was to investigate the existence of a critical threshold beyond which peripheral fatigue would not further decrease during knee extensor (KE) exercise in older men, and the consequences of this mechanism on the force-duration relationship. Twelve old men (59 ± 2 years) randomly performed two different sessions, in which they performed 60 maximum voluntary contractions (MVC; 3s contraction, 2s relaxation). One trial was performed in the unfatigued state ([[CTRL]]) and one other following fatiguing neuromuscular electrical stimulation of the KE (F ). Peripheral and central fatigue were quantified via pre/post-exercise decreases in quadriceps twitch-force (Δ P ) and voluntary activation (ΔVA). Critical torque (CT) was determined as the mean force of the last 12 contractions while W' was calculated as the area above CT. Compared with [[CTRL]], pre-fatigue (Δ P = -10.3 ± 6.2%) resulted in a significant ([i]p[/i] < 0.05) reduction in W' (-18.2 ± 1.6%) in F . However, CT (∼964 N), ΔVA (∼15%) and Δ P  (∼25%) post-MVCs were similar between both conditions. In [[CTRL]], W' was correlated with Δ P  ([i]r[/i]   = 0.78). Moreover, the difference in W' between [[CTRL]] and F  was correlated with the level of pre-fatigue induced in F  ([i]r[/i]   = 0.76). These findings document that peripheral fatigue is confined to an individual threshold during KE exercise in older men. Furthermore, correlative results suggest that mechanisms regulating peripheral fatigue to a critical threshold also restrict W', and therefore play a role in exercise capacity in older men.

|keywords=* Aging
* critical torque
* group III/IV muscle afferents
|full-text-url=https://sci-hub.do/10.1080/17461391.2019.1655099
}}
==TREM2==

{{medline-entry
|title=Loss of [[TREM2]] Confers Resilience to Synaptic and Cognitive Impairment in Aged Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33139402
|abstract=Triggering receptor expressed on myeloid cells 2 ([[TREM2]]), a receptor exclusively expressed by microglia in the brain, modulates microglial immune homeostasis. Human genetic studies have shown that the loss-of-function mutations in [[TREM2]] signaling are strongly associated with an elevated risk of age-related neurodegenerative diseases including Alzheimer's disease (AD). Numerous studies have investigated the impact of [[TREM2]] deficiency in the pathogenic process of AD. However, the role of [[TREM2]] in shaping neuronal and cognitive function during normal aging is underexplored. In the present study, we employed behavioral, electrophysiological, and biochemical approaches to assess cognitive and synaptic function in male and female young and aged [[TREM2]]-deficient ([i]Trem2[/i]-/-) mice compared with age-matched, sex-matched, and genetic background-matched wild-type (WT) C57BL/6J controls. Young [i]Trem2[/i]-/- mice exhibited normal cognitive function and synaptic plasticity but had increased dendritic spine density compared with young WT. Unexpectedly, aged [i]Trem2[/i]-/- mice showed superior cognitive performance compared with aged WT controls. Consistent with the behavioral data, aged [i]Trem2[/i]-/- mice displayed significantly enhanced hippocampal long-term potentiation (LTP) and increased dendritic spine density and synaptic markers compared with aged WT mice. Taken together, these findings suggest that loss of [[TREM2]] affects the neuronal structure and confers resilience to age-related synaptic and cognitive impairment during non-pathogenic aging.  Microglia are innate immune cells of the brain that orchestrates neurodevelopment, synaptic function, and immune response to environmental stimuli. Microglial triggering receptor expressed on myeloid cells 2 ([[TREM2]]) signaling plays pivotal roles in regulating these functions and loss of [[TREM2]] signaling leads to increased risk of developing age-related neurologic disorders. However, the neurologic role of [[TREM2]] in normal aging is poorly understood. The results of the present study unveil the positive impacts of [[TREM2]] deficiency on cognitive and synaptic function during aging and suggest that [[TREM2]] may exert detrimental effects on neuronal function. The possibility of age-related negative impacts from [[TREM2]] is critically important since [[TREM2]] has emerged as a major therapeutic target for Alzheimer's dementia.

|keywords=* TREM2
* aging
* dendritic spine density
* learning and memory
* long-term potentiation
* synaptic plasticity
|full-text-url=https://sci-hub.do/10.1523/JNEUROSCI.2193-20.2020
}}
{{medline-entry
|title=Triggering Receptor Expressed on Myeloid Cell 2 R47H Exacerbates Immune Response in Alzheimer's Disease Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33101276
|abstract=The R47H variant in the microglial triggering receptor expressed on myeloid cell 2 ([[TREM2]]) receptor is a strong risk factor for Alzheimer's disease (AD). To characterize processes affected by R47H, we performed an integrative network analysis of genes expressed in brains of AD patients with R47H, sporadic AD without the variant, and patients with polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), systemic disease with early-onset dementia caused by loss-of-function mutations in [[TREM2]] or its adaptor TYRO protein tyrosine kinase-binding protein (TYROBP). Although sporadic AD had few perturbed microglial and immune genes, [[TREM2]] R47H AD demonstrated upregulation of interferon type I response and pro-inflammatory cytokines accompanied by induction of NKG2D stress ligands. In contrast, PLOSL had distinct sets of highly perturbed immune and microglial genes that included inflammatory mediators, immune signaling, cell adhesion, and phagocytosis. [[TREM2]] knockout (KO) in THP1, a human myeloid cell line that constitutively expresses the [[TREM2]]- TYROBP receptor, inhibited response to the viral RNA mimetic poly(I:C) and phagocytosis of amyloid-beta oligomers; overexpression of ectopic [[TREM2]] restored these functions. Compared with wild-type protein, R47H [[TREM2]] had a higher stimulatory effect on the interferon type I response signature. Our findings point to a role of the [[TREM2]] receptor in the control of the interferon type I response in myeloid cells and provide insight regarding the contribution of R47H [[TREM2]] to AD pathology.

|keywords=* NKG2D ligands
* aging
* inflammation
* interferon type I response
* microglia
* neurodegeneration
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546799
}}
{{medline-entry
|title=Knockdown of astrocytic [[TREM2]] in the hippocampus relieves cognitive decline in elderly male mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32991925
|abstract=With the lengthening of the human lifespan, an increasing proportion of the population is subject to age-related cognitive impairments, making it important to investigate ways to confront the effects of aging. Triggering receptor expressed on myeloid cells 2 ([[TREM2]]) is an innate immune receptor that is expressed mainly on the surfaces of microglia. Previous studies have found a significant positive correlation between age and [[TREM2]] levels. An increased concentration of soluble [[TREM2]] in cerebrospinal fluid was also found in Alzheimer's disease (AD) patients. Although [[TREM2]] is more highly expressed in microglia than in astrocytes, little attention has been focused on astrocytic [[TREM2]], and the precise role of astrocytic [[TREM2]] in the aging process remains unknown. In this study, we injected [[TREM2]] shRNA into the hippocampal CA1 region to specifically knock down the expression of this protein in astrocytes. We found that [[TREM2]] shRNA injection can improve learning and memory ability in elderly mice, as demonstrated by improved learning ability and memory performance in the Morris water maze (MWM) test, an increased freezing duration in the contextual fear conditioning test, a higher preference ratio in the novel object recognition (NOR) test and a higher alternation rate in the T-maze test. Knocking down astrocytic [[TREM2]] can also rescue impaired long-term potentiation (LTP) induction in the hippocampal CA1 of elderly mice through a presynaptic mechanism. Our results suggest that decreased astrocytic [[TREM2]] levels have beneficial effects on learning and memory ability in elderly mice, which may provide new insight into the pathological mechanism and potential targets of age-related dementia.

|keywords=* Aging
* Long-term potentiation
* TREM2
* astrocytes
* learning and memory
|full-text-url=https://sci-hub.do/10.1016/j.bbr.2020.112939
}}
==TPR==

{{medline-entry
|title=Catalytic Performances of Cu/MCM-22 Zeolites with Different Cu Loadings in NH -SCR.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33143192
|abstract=The NH -SCR activities and hydrothermal stabilities of five [i]x[/i]Cu/MCM-22 zeolites with different Cu loadings ([i]x[/i] = 2-10 wt%) prepared by incipient wetness impregnation method were systematically investigated. The physicochemical properties of [i]x[/i]Cu/MCM-22 zeolites were analyzed by XRD, nitrogen physisorption, ICP-AES, SEM, NH -TPD, UV-vis, H -[[TPR]] and XPS experiments. The Cu species existing in [i]x[/i]Cu/MCM-22 are mainly isolated Cu , CuO[i] [/i] and unreducible copper species. The concentrations of both isolated Cu  and CuO[i] [/i] species in [i]x[/i]Cu/MCM-22 increase with Cu contents, but the increment of CuO[i] [/i] species is more distinct, especially in high Cu loadings (>4 wt%). NH -SCR experimental results demonstrated that the activity of [i]x[/i]Cu/MCM-22 is sensitive to Cu content at low Cu loadings (≤4 wt%). When the Cu loading exceeds 4 wt%, the NH -SCR activity of [i]x[/i]Cu/MCM-22 is irrelevant to Cu content due to the severe pore blockage effects caused by aggregated CuO[i] [/i] species. Among the five [i]x[/i]Cu/MCM-22 zeolites, 4Cu/MCM-22 with moderate Cu content has the best NH -SCR performance, which displays higher than 80% NO[i] [/i] conversions in a wide temperature window (160-430 °C). Furthermore, the hydrothermal aging experiments ([i]x[/i]Cu/MCM-22 was treated at 750 °C for 10 h under 10% water vapor atmosphere) illustrated that all the [i]x[/i]Cu/MCM-22 zeolites exhibit high hydrothermal stability in NH -SCR reactions.

|keywords=* Cu loading
* Cu/MCM-22
* NH3-SCR
* hydrothermal aging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694057
}}
{{medline-entry
|title=Do traits of plant species predict the efficacy of species distribution models for finding new occurrences?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32551077
|abstract=Species distribution models (SDMs) are used to test ecological theory and to direct targeted surveys for species of conservation concern. Several studies have tested for an influence of species traits on the predictive accuracy of SDMs. However, most used the same set of environmental predictors for all species and/or did not use truly independent data to test SDM accuracy. We built eight SDMs for each of 24 plant species of conservation concern, varying the environmental predictors included in each SDM version. We then measured the accuracy of each SDM using independent presence and absence data to calculate area under the receiver operating characteristic curve (AUC) and true positive rate ([[TPR]]). We used generalized linear mixed models to test for a relationship between species traits and SDM accuracy, while accounting for variation in SDM performance that might be introduced by different predictor sets. All traits affected one or both SDM accuracy measures. Species with lighter seeds, animal-dispersed seeds, and a higher density of occurrences had higher AUC and [[TPR]] than other species, all else being equal. Long-lived woody species had higher AUC than herbaceous species, but lower [[TPR]]. These results support the hypothesis that the strength of species-environment correlations is affected by characteristics of species or their geographic distributions. However, because each species has multiple traits, and because AUC and [[TPR]] can be affected differently, there is no straightforward way to determine a priori which species will yield useful SDMs based on their traits. Most species yielded at least one useful SDM. Therefore, it is worthwhile to build and test SDMs for the purpose of finding new populations of plant species of conservation concern, regardless of these species' traits.

|keywords=* dispersal
* generalist
* lifespan
* niche models
* range size
* specialist
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297770
}}
{{medline-entry
|title=In-situ modified the surface of Pt-doped perovskite catalyst for soot oxidation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31541957
|abstract=In-situ modification is studied in this work on LaCo Pt O  for soot oxidation. A series of perovskite catalysts LaCo Pt O  (by sol-gel method) are modified with 30% H O . XRD, TEM, SEM, BET, XPS, Raman, in-situ DRIFTS, H -[[TPR]] and TGA are used to investigate physicochemical properties of catalysts. TGA results show that all doped catalysts have a lower temperature of soot conversion, especially LaCo Pt O  (T  = 437 °C). The T  of the catalyst with modification by H O  solution decreases at least 20 °C compared with the doped catalysts. A highly symmetrical structure and an obvious amorphous layer about 3-5 nm are observed in the modified catalysts. According to the XPS study, the symmetrical structure benefits to the movement of oxygen vacancy thus catalyst captures more adsorbed oxygen (about 95%). And the amorphous surface could adsorb more oxygen species. In addition, all catalysts show excellent aging resistance performance. The reaction mechanism of catalyst for soot oxidation is presented in the end.

|keywords=* Aging resistance
* Amorphization
* Surface modification
* Symmetrical structure
|full-text-url=https://sci-hub.do/10.1016/j.jhazmat.2019.121210
}}
==PAM==

{{medline-entry
|title=Relationship between patient activation measurement and self-rated health in patients with chronic diseases.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33148185
|abstract=In the aging population, chronic diseases and multimorbidity are common. Therefore, it is important to engage patients in their self-care. The aim of this study was to analyze the relationship between activity in self-care and self-rated health among primary care patients with chronic diseases. The data of the present study were derived from a research project on the Participatory Patient Care Planning in Primary Care (4PHC). A total of 605 patients were recruited in the Siilinjärvi Health Center from those patients who were being monitored due to the treatment of hypertension, ischemic heart disease or diabetes. We evaluated the level of patient's activity in self-care with the Patient Activation Measurement ([[PAM]]). Self-rated health (SRH) was measured with the 5-item Likert scale. An adjusted hypothesis of linearity across categories of [[PAM]] and self-rated health was estimated using analysis of covariance (ANCOVA). It was found that 76 patients had low activity, 185 had moderate while 336 patients had high activity as measured with [[PAM]]. Patients with the highest activity were younger, less depressed, had a lower body mass index and a higher level of physical activity than those with the lower activity. Correspondingly, good SRH was perceived by 29, 45 and 67% of the patients in these three [[PAM]] groups adjusted with sex, age, depressive symptoms (BDI) and number of diseases. There was a significant linear trend (adjusted with age, number of diseases and depressive symptoms) between SRH and [[PAM]], p < 0.001. Activity in self-care had an independent, linear relationship with the self-rated health. The present findings suggest that Patient Activation Measurement has the potential to categorize the patients according to their perceived health and their needs related to their disease management and self-care. The present results warrant longitudinal studies on the impact of promoting patient activation levels. ClinicalTrials.gov Identifier: NCT02992431 . Registered 14 December 2016 https://clinicaltrials.gov/ct2/show/NCT02992431.

|keywords=* Aging population
* Chronic diseases
* Patient activation measurement
* Primary health care
* Self-rated health
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643260
}}
{{medline-entry
|title=Reversal of Age-Related Neuronal Atrophy by α5-GABAA Receptor Positive Allosteric Modulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33068001
|abstract=Aging is associated with reduced brain volume, altered neural activity, and neuronal atrophy in cortical-like structures, comprising the frontal cortex and hippocampus, together contributing to cognitive impairments. Therapeutic efforts aimed at reversing these deficits have focused on excitatory or neurotrophic mechanisms, although recent findings show that reduced dendritic inhibition mediated by α5-subunit containing GABA-A receptors (α5-GABAA-Rs) occurs during aging and contributes to cognitive impairment. Here, we aimed to confirm the beneficial effect on working memory of augmenting α5-GABAA-R activity in old mice and tested its potential at reversing age-related neuronal atrophy. We show that GL-II-73, a novel ligand with positive allosteric modulatory activity at α5-GABAA-R (α5-[[PAM]]), increases dendritic branching complexity and spine numbers of cortical neurons in vitro. Using old mice, we confirm that α5-[[PAM]] reverses age-related working memory deficits and show that chronic treatment (3 months) significantly reverses age-related dendritic shrinkage and spine loss in frontal cortex and hippocampus. A subsequent 1-week treatment cessation (separate cohort) resulted in loss of efficacy on working memory but maintained morphological neurotrophic effects. Together, the results demonstrate the beneficial effect on working memory and neurotrophic efficacy of augmenting α5-GABAA-R function in old mice, suggesting symptomatic and disease-modifying potential in age-related brain disorders.

|keywords=* GABA
* aging
* cognition
* neurotrophic effect
* positive allosteric modulator
|full-text-url=https://sci-hub.do/10.1093/cercor/bhaa310
}}
{{medline-entry
|title=The ratio of prematurely aging to non-prematurely aging mice cohabiting, conditions their behavior, immunity and lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32330742
|abstract=Adult prematurely aging mice ([[PAM]]) show behavioral deterioration, premature immunosenescence and increased oxidative stress, impairments that are associated with their shorter lifespan, compared to the corresponding exceptional non-prematurely aging mice (EN[[PAM]]). When [[PAM]] live in a predominantly EN[[PAM]] environment (2/5, respectively) they exhibit an improvement of immunity and redox state in their spleen and thymus leukocytes, and an increased lifespan. Nevertheless, it is unknown if other [[PAM]]/EN[[PAM]] ratios could affect behavioral and peritoneal leukocyte functions of [[PAM]] and change their lifespan. EN[[PAM]] and [[PAM]] were divided into the following groups: C-EN[[PAM]] (8 EN[[PAM]] in the cage); C-[[PAM]] (8 [[PAM]] in the cage); EN[[PAM]]>50% and [[PAM]]<50% (5 EN[[PAM]]/2 [[PAM]] in each cage); EN[[PAM]] = 50% and [[PAM]] = 50% (4 EN[[PAM]]/4 [[PAM]] in each cage), and [[PAM]]>50% and EN[[PAM]]<50% (5 [[PAM]]/2 EN[[PAM]] in each cage). After two months, mice were submitted to a battery of behavioral tests. Several functions and oxidative stress parameters were then assessed in their peritoneal leukocytes. Animals were maintained in these conditions to analyze their lifespan. The results showed that [[PAM]]>50%, [[PAM]] = 50% and [[PAM]]<50% exhibited better behavioral responses, immunity and redox states in their peritoneal leukocytes than C-[[PAM]]. This improvement was higher when the number of EN[[PAM]] in the cage was increased, with most of the parameters in [[PAM]]<50% reaching similar values to those in C-EN[[PAM]], and an increased lifespan. However, EN[[PAM]] that cohabited with [[PAM]] showed, in general, an impairment of parameters studied. In conclusion, the [[PAM]]/EN[[PAM]] cohabitation ratio is relevant to behavior and immunity.
|mesh-terms=* Aging
* Aging, Premature
* Animals
* Behavior, Animal
* Female
* Housing, Animal
* Longevity
* Lymphocytes
* Macrophages
* Mice
* Oxidative Stress
* Social Environment
|keywords=* Behavior
* Immunity
* Mean lifespan
* Prematurely aging mice
* Social environmental strategy
|full-text-url=https://sci-hub.do/10.1016/j.jneuroim.2020.577240
}}
==CD36==

{{medline-entry
|title=Liver osteopontin is required to prevent the progression of age-related nonalcoholic fatty liver disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32638492
|abstract=Osteopontin (OPN), a senescence-associated secretory phenotype factor, is increased in patients with nonalcoholic fatty liver disease (NAFLD). Cellular senescence has been associated with age-dependent hepatosteatosis. Thus, we investigated the role of OPN in the age-related hepatosteatosis. For this, human serum samples, animal models of aging, and cell lines in which senescence was induced were used. Metabolic fluxes, lipid, and protein concentration were determined. Among individuals with a normal liver, we observed a positive correlation between serum OPN levels and increasing age. This correlation with age, however, was absent in patients with NAFLD. In wild-type (WT) mice, serum and liver OPN were increased at 10 months old (m) along with liver p53 levels and remained elevated at 20m. Markers of liver senescence increased in association with synthesis and concentration of triglycerides (TG) in 10m OPN-deficient (KO) hepatocytes when compared to WT hepatocytes. These changes in senescence and lipid metabolism in 10m OPN-KO mice liver were associated with the decrease of 78 kDa glucose-regulated protein (GRP78), induction of ER stress, and the increase in fatty acid synthase and [[CD36]] levels. OPN deficiency in senescent cells also diminished GRP78, the accumulation of intracellular TG, and the increase in [[CD36]] levels. In 20m mice, OPN loss led to increased liver fibrosis. Finally, we showed that OPN expression in vitro and in vivo was regulated by p53. In conclusion, OPN deficiency leads to earlier cellular senescence, ER stress, and TG accumulation during aging. The p53-OPN axis is required to inhibit the onset of age-related hepatosteatosis.

|keywords=* Osteopontin
* aging
* lipid metabolism
* nonalcoholic fatty liver disease
* p53
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431823
}}
{{medline-entry
|title=Reduction of senescence-associated beta-galactosidase activity by vitamin E in human fibroblasts depends on subjects' age and cell passage number.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32479666
|abstract=Cell senescence is due to the permanent cell cycle arrest that occurs as a result of the inherent limited replicative capacity toward the Hayflick limit (replicative senescence), or in response to various stressors (stress-induced premature senescence, SIPS). With the acquisition of the senescence-associated secretory phenotype (SASP), cells release several molecules (cytokines, proteases, lipids), and express the senescence-associated beta-galactosidase (SA-β-Gal). Here we tested whether vitamin E affects SA-β-Gal in an in vitro model of cell ageing. Skin fibroblasts from human subjects of different age (1, 13, 29, 59, and 88 years old) were cultured until they reached replicative senescence. At different passages (Passages 2, 9, 13, and 16), these cells were treated with vitamin E for 24 hr. Vitamin E reduced SA-β-Gal in all cells at passage 16, but at earlier passage numbers it reduced SA-β-Gal only in cells isolated from the oldest subjects. Therefore, short time treatment with vitamin E decreases SA-β-Gal in cells both from young and old subjects when reaching replicative senescence; but in cells isolated from older subjects, a decrease in SA-β-Gal by vitamin E occurs also at earlier passage numbers. The possible role of downregulation of [[CD36]] by vitamin E, a scavenger receptor essential for initiation of senescence and SASP, is discussed.

|keywords=* CD36 scavenger receptor
* alpha-tocopherol
* exosomes
* extracellular vesicles
* gene expression
* lysosome
* senescence
* signal transduction
* vitamin E
|full-text-url=https://sci-hub.do/10.1002/biof.1636
}}
{{medline-entry
|title=Niacin-mediated rejuvenation of macrophage/microglia enhances remyelination of the aging central nervous system.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32030468
|abstract=Remyelination following CNS demyelination restores rapid signal propagation and protects axons; however, its efficiency declines with increasing age. Both intrinsic changes in the oligodendrocyte progenitor cell population and extrinsic factors in the lesion microenvironment of older subjects contribute to this decline. Microglia and monocyte-derived macrophages are critical for successful remyelination, releasing growth factors and clearing inhibitory myelin debris. Several studies have implicated delayed recruitment of macrophages/microglia into lesions as a key contributor to the decline in remyelination observed in older subjects. Here we show that the decreased expression of the scavenger receptor [[CD36]] of aging mouse microglia and human microglia in culture underlies their reduced phagocytic activity. Overexpression of [[CD36]] in cultured microglia rescues the deficit in phagocytosis of myelin debris. By screening for clinically approved agents that stimulate macrophages/microglia, we have found that niacin (vitamin B3) upregulates [[CD36]] expression and enhances myelin phagocytosis by microglia in culture. This increase in myelin phagocytosis is mediated through the niacin receptor (hydroxycarboxylic acid receptor 2). Genetic fate mapping and multiphoton live imaging show that systemic treatment of 9-12-month-old demyelinated mice with therapeutically relevant doses of niacin promotes myelin debris clearance in lesions by both peripherally derived macrophages and microglia. This is accompanied by enhancement of oligodendrocyte progenitor cell numbers and by improved remyelination in the treated mice. Niacin represents a safe and translationally amenable regenerative therapy for chronic demyelinating diseases such as multiple sclerosis.

|keywords=* Aging
* Macrophages
* Microglia
* Oligodendrocyte progenitor cells
* Phagocytosis
* Remyelination
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181452
}}
==SOD1==

{{medline-entry
|title=[[SOD1]], more than just an antioxidant.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33259795
|abstract=During cellular respiration, radicals, such as superoxide, are produced, and in a large concentration, they may cause cell damage. To combat this threat, the cell employs the enzyme Cu/Zn Superoxide Dismutase ([[SOD1]]), which converts the radical superoxide into molecular oxygen and hydrogen peroxide, through redox reactions. Although this is its main function, recent studies have shown that the [[SOD1]] has other functions that deviates from its original one including activation of nuclear gene transcription or as an RNA binding protein. This comprehensive review looks at the most important aspects of human [[SOD1]] (h[[SOD1]]), including the structure, properties, and characteristics as well as transcriptional and post-translational modifications (PTM) that the enzyme can receive and their effects, and its many functions. We also discuss the strategies currently used to analyze it to better understand its participation in diseases linked to h[[SOD1]] including Amyotrophic Lateral Sclerosis (ALS), cancer, and Parkinson.

|keywords=* Aging
* Cancer
* Neurodegenerative diseases
* Post-translational modifications
* Superoxide dismutase 1
|full-text-url=https://sci-hub.do/10.1016/j.abb.2020.108701
}}
{{medline-entry
|title=The Exacerbation of Aging and Oxidative Stress in the Epididymis of [i]Sod1[/i] Null Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32054065
|abstract=There is growing evidence that the quality of spermatozoa decreases with age and that children of older fathers have a higher incidence of birth defects and genetic mutations. The free radical theory of aging proposes that changes with aging are due to the accumulation of damage induced by exposure to excess reactive oxygen species. We showed previously that absence of the superoxide dismutase 1 ([i]Sod1[/i]) antioxidant gene results in impaired mechanisms of repairing DNA damage in the testis in young [i]Sod1[/i]  mice. In this study, we examined the effects of aging and the [i]Sod[/i]  mutation on mice epididymal histology and the expression of markers of oxidative damage. We found that both oxidative nucleic acid damage (via 8-hydroxyguanosine) and lipid peroxidation (via 4-hydroxynonenal) increased with age and in [i]Sod1[/i]  mice. These findings indicate that lack of [[SOD1]] results in an exacerbation of the oxidative damage accumulation-related aging phenotype.

|keywords=* 4-hydroxynonenal
* 8-hydroxyguanosine
* aging
* epididymis
* oxidative stress
* reactive oxygen species
* spermatozoa
* superoxide dismutase
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071042
}}
{{medline-entry
|title=Alterations in lipid metabolism of spinal cord linked to amyotrophic lateral sclerosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31406145
|abstract=Amyotrophic lateral sclerosis (ALS) is characterized by progressive loss of upper and lower motor neurons leading to muscle paralysis and death. While a link between dysregulated lipid metabolism and ALS has been proposed, lipidome alterations involved in disease progression are still understudied. Using a rodent model of ALS overexpressing mutant human Cu/Zn-superoxide dismutase gene ([[SOD1]]-G93A), we performed a comparative lipidomic analysis in motor cortex and spinal cord tissues of [[SOD1]]-G93A and WT rats at asymptomatic (~70 days) and symptomatic stages (~120 days). Interestingly, lipidome alterations in motor cortex were mostly related to age than ALS. In contrast, drastic changes were observed in spinal cord of [[SOD1]]-G93A 120d group, including decreased levels of cardiolipin and a 6-fold increase in several cholesteryl esters linked to polyunsaturated fatty acids. Consistent with previous studies, our findings suggest abnormal mitochondria in motor neurons and lipid droplets accumulation in aberrant astrocytes. Although the mechanism leading to cholesteryl esters accumulation remains to be established, we postulate a hypothetical model based on neuroprotection of polyunsaturated fatty acids into lipid droplets in response to increased oxidative stress. Implicated in the pathology of other neurodegenerative diseases, cholesteryl esters appear as attractive targets for further investigations.
|mesh-terms=* Aging
* Amyotrophic Lateral Sclerosis
* Animals
* Cardiolipins
* Cholesterol Esters
* Disease Models, Animal
* Disease Progression
* Fatty Acids, Unsaturated
* Female
* Humans
* Lipid Droplets
* Lipid Metabolism
* Lipidomics
* Male
* Mass Spectrometry
* Motor Cortex
* Motor Neurons
* Mutation
* Oxidative Stress
* Rats
* Rats, Transgenic
* Spinal Cord
* Superoxide Dismutase-1

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691112
}}
==MDM2==

{{medline-entry
|title=SENEBLOC, a long non-coding RNA suppresses senescence via p53-dependent and independent mechanisms.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32030426
|abstract=Long non-coding RNAs (lncRNAs) have emerged as important biological tuners. Here, we reveal the role of an uncharacterized lncRNA we call SENEBLOC that is expressed by both normal and transformed cells under homeostatic conditions. SENEBLOC was shown to block the induction of cellular senescence through dual mechanisms that converge to repress the expression of p21. SENEBLOC facilitates the association of p53 with [[MDM2]] by acting as a scaffold to promote p53 turnover and decrease p21 transactivation. Alternatively, SENEBLOC was shown to affect epigenetic silencing of the p21 gene promoter through regulation of HDAC5. Thus SENEBLOC drives both p53-dependent and p53-independent mechanisms that contribute to p21 repression. Moreover, SENEBLOC was shown to be involved in both oncogenic and replicative senescence, and from the perspective of senolytic agents we show that the antagonistic actions of rapamycin on senescence are dependent on SENEBLOC expression.
|mesh-terms=* Aging
* Animals
* Carcinogenesis
* Cyclin-Dependent Kinase Inhibitor p21
* Gene Expression Regulation, Neoplastic
* HCT116 Cells
* Heterografts
* Histone Deacetylases
* Humans
* Mice
* Neoplasms
* Protein Binding
* RNA, Long Noncoding
* Signal Transduction
* Tumor Suppressor Protein p53

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102969
}}
{{medline-entry
|title=Disruption of Robo2-Baiap2 integrated signaling drives cystic disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31534052
|abstract=Hereditary renal cystic diseases are characterized by defects in primary cilia of renal tubular epithelial cells and abnormality of tubular epithelium, which ultimately result in the development of renal cysts. However, the mechanism leading from abnormality of the tubular epithelium to cystogenesis is not well understood. In this report, we demonstrate a critical role for Robo2 in regulating epithelial development, including ciliogenesis, polarization, and differentiation. We found that Robo2 deficiency results in cystic kidneys, and the cyst cells showed defective cilia and polarity defects in tubular epithelium. The cyst cells, less than terminally differentiated, continue to proliferate. We further established that Robo2 works with p53 as well as polarity and ciliary proteins (Par3, PKCς, ZO-2, and Claudin-2) to regulate these processes. Robo2 binds to Baiap2 (also known as IRSp53) through the IRSp53/MIM homology domain in renal epithelial cells. This binding allows Robo2 to phosphorylate [[MDM2]] at Ser166 via Baiap2 and maintain p53 homeostasis. Disruption of the Robo2-Baiap2 complex causes [[MDM2]] to be subjected to dephosphorylation, leading to a high level of active p53, and initiated p53-mediated cellular senescence via p21 and decreased the expression of ZO-1, ZO-2, PKCς, Par3, and Claudin-2 proteins, resulting in defects in epithelial development, including ciliogenesis, polarization, and differentiation. Importantly, double knockout of Robo2 and p53 rescued all the epithelial defects in kidneys compared with those in Robo2-knockout kidneys. Taken together, the present results demonstrate that Robo2 deficiency causes renal cystic disease, which is largely dependent on defective Robo2-Baiap2 integrated signaling in kidneys.
|mesh-terms=* Animals
* Cell Differentiation
* Cell Proliferation
* Cellular Senescence
* Cilia
* Disease Models, Animal
* Epithelial Cells
* Humans
* Kidney
* Kidney Diseases, Cystic
* Mice
* Mice, Knockout
* Nerve Tissue Proteins
* Protein Binding
* Protein Domains
* Receptors, Immunologic
* Signal Transduction
* Tumor Suppressor Protein p53
|keywords=* Cellular senescence
* Development
* Genetic diseases
* Nephrology
* Signal transduction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795383
}}
{{medline-entry
|title=Senescence-induced immunophenotype, gene expression and electrophysiology changes in human amniocytes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31478614
|abstract=The aim of the study was to evidence replicative senescence-induced changes in human amniocytes via flow cytometry, quantitative reverse-transcription-polymerase chain reaction (qRT-PCR) and automated/manual patch-clamp. Both cryopreserved and senescent amniocytes cultured in BIO-AMF-2 medium featured high percentages of pluripotency cell surface antigens SSEA-1, SSEA-4, TRA1-60, TRA1-81 (assessed by flow cytometry) and expression of pluripotency markers Oct4 (Pou5f1) and Nanog (by qRT-PCR). We demonstrated in senescent vs cryopreserved amniocytes decreases in mesenchymal stem cell surface markers. Senescence-associated β-galactosidase stained only senescent amniocytes, and they showed no deoxyuridine incorporation. The gene expression profile revealed a secretory phenotype of senescent amniocytes (increased interleukin (IL)-1α, IL-6, IL-8, transforming growth factor β, nuclear factor κB p65 expression), increases for cell cycle-regulating genes (p16  ), cytoskeletal elements (β-actin); HMGB1, c-Myc, Bcl-2 showed reduced changes and p21, [[MDM2]] decreased. Via patch-clamp we identified five ion current components: outward rectifier K  current, an inactivatable component, big conductance Ca  -dependent K  channels (BK) current fluctuations, Na  current, and inward rectifier K  current. Iberiotoxin 100 nmol/L blocked 71% of BK fluctuations, and lidocaine 200 μmol/L exerted use-dependent Na  current block. Transient receptor potential (TRP)M7-like current density at -120 mV was significantly increased in senescent amniocytes. The proinflammatory profile acquired by senescent amniocytes in vitro may prevent their use in clinical therapies for immunosuppression, antiapoptotic and healing effects.
|mesh-terms=* Amniocentesis
* Amnion
* Biomarkers
* Cell Proliferation
* Cells, Cultured
* Cellular Senescence
* Electrophysiological Phenomena
* Female
* Gene Expression Regulation
* Humans
* Immunophenotyping
* Phenotype
|keywords=* amniocyte
* automated patch-clamp
* flow cytometry
* mesenchymal stem cell
* qRT-PCR
* replicative senescence
* senescence-associated secretory phenotype
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815807
}}
==CCN1==

{{medline-entry
|title=Sodium tanshinone IIA sulfonate restrains fibrogenesis through induction of senescence in mice with induced deep endometriosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32651107
|abstract=Does sodium tanshinone IIA sulfonate (STS) induce cellular senescence in endometriotic lesions and thus restrict lesional development and fibrogenesis in a recently established mouse model of deep endometriosis? Prospective randomized animal experiment in which deep endometriosis was induced in female Balb/C mice, which were then randomly divided into three groups (low-dose STS, high-dose STS and inert vehicle control) and received treatment for 2 weeks. All mice were then sacrificed and their lesions excised and harvested. Lesion weight was quantified and all lesion samples were subjected to histochemical analysis of the extent of lesional fibrosis by Masson trichrome staining, and of cellular senescence by senescence-associated β-galactosidase (SA-β-gal), along with immunohistochemistry analyses of p53, [[CCN1]], activate Salvador 1 (Sav1), hyaluronan synthase 2 (HAS2), survivin, granulocyte-macrophage colony-stimulating factor (GM-CSF) and CD163-positive M2 macrophages. Plasma P-selectin and hyaluronic acid levels were also quantified. Hotplate testing was also administered before the induction, then before and after treatment. STS treatment resulted in significantly reduced lesion weight, stalled lesional fibrogenesis and improved hyperalgesia, seemingly through the induction of cellular senescence by activating p53, Sav1 and [[CCN1]] while suppressing HAS2, survivin and GM-CSF, resulting in increased apoptosis and reduced lesional infiltration of alternatively activated macrophages. In addition, STS treatment significantly reduced the plasma concentration of P-selectin and hyaluronic acid, possibly leading to reduced lesional platelet aggregation. STS appears to be a promising compound for treating endometriosis. The results suggest that senescence may restrict lesional progression and fibrogenesis, and targeting the senescence pathway may have desirable therapeutic potential.

|keywords=* Deep endometriosis
* Fibrogenesis
* Mouse
* Senescence
* Sodium tanshinone IIA sulfonate
|full-text-url=https://sci-hub.do/10.1016/j.rbmo.2020.04.006
}}
{{medline-entry
|title=Inhibition of cellular communication network factor 1 ([[CCN1]])-driven senescence slows down cartilage inflammaging and osteoarthritis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32622876
|abstract=To explore the role of cellular communication network factor 1 ([[CCN1]]) in cartilage inflammaging and osteoarthritis (OA) pathogenesis in the isolated primary human chondrocytes in vitro, cartilage explants ex vivo, and a pre-clinical mice model. Recombinant human [[CCN1]] stimulation and small interfering RNA inhibition were conducted in human chondrocytes. The RNA was extracted to quantify catabolic targets and pro-inflammatory genes and the proteins were probed with specific antibodies. IL-1β and IL-6 were monitored by ELISA. IHC was performed to evaluate important hypertrophic hallmarks and catabolic markers. The effects of Tanshinone IIA on chondrocytes were investigated in both time-dependent and dose-dependent processes. Cartilage explants were cultured in growth medium and further treated with Tanshinone IIA. The intra-articular injection was performed in 13 months old C57BL/6J mice. Safranin O and fast green staining were performed to evaluate the histological change of cartilage followed by a semi-quantitative analysis using the OARSI scoring system. RNA and protein levels of [[CCN1]] increased in an age-dependent manner compared to young donors. Increased [[CCN1]] expression was also found in the damaged area compared to the non-lesion area which correlated with the advanced pathological change in human OA. The overexpression of [[CCN1]] promoted chondrocytes senescence, while the down-regulation of [[CCN1]] by small interfering RNA reduced [[CCN1]] production and limited inflammation secretion suggesting that [[CCN1]] was a possible novel target to intervene OA. Inhibition of [[CCN1]] by using Tanshinone IIA could reduce SASP components in a dose- and time-dependent manner. Additionally, our data showed that Tanshinone IIA was able to preserve articular cartilage integrity, suppress [[CCN1]] production, and inhibit SASP factors in human cartilage explants and in aged mice model. This study showed that [[CCN1]] signaling aggravated cartilage inflammaing and matrix degradation. Collectively, our findings showed new insight into repurposing Tanshinone IIA for slowing down OA advancement in human and mice by inhibiting the [[CCN1]] axis.

|keywords=* CCN1
* Cartilage inflammaging
* Chondrocyte cluster
* Osteoarthritis
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.bone.2020.115522
}}
{{medline-entry
|title=The senescence-associated matricellular protein [[CCN1]] in plasma of human subjects with idiopathic pulmonary fibrosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31765873
|abstract=Cellular senescence has been linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). [[CCN1]] is a matricellular protein that has been shown to induce cellular senescence and contribute to lung fibrosis in pre-clinical models. In this report, we determined plasma [[CCN1]] levels in patients with IPF and its potential role in clinical outcomes. We evaluated 88 patients diagnosed with IPF at the University of Alabama at Birmingham. [[CCN1]] levels were measured in plasma specimens by ELISA. The primary outcome measure was transplant-free survival (TFS) duration. High-[[CCN1]] levels were associated with a lower transplant-free survival independent of %FVC and %D CO compared to patients with low plasma [[CCN1]] (HR = 2.15; 95%CI 1.04-4.45, p = 0.04). This study demonstrates that plasma levels of [[CCN1]] may be predictive of survival in IPF. Given the plausible role of [[CCN1]] in cellular senescence and pathobiology of IPF, the predictive value of [[CCN1]] in disease progression among patients with IPF warrants further investigation.
|mesh-terms=* Aged
* Cellular Senescence
* Cysteine-Rich Protein 61
* Disease Progression
* Enzyme-Linked Immunosorbent Assay
* Female
* Humans
* Idiopathic Pulmonary Fibrosis
* Male
* Middle Aged
* Outcome Assessment, Health Care
* Predictive Value of Tests
* Survival Rate
|keywords=* CCN1
* Cellular senescence
* Idiopathic pulmonary fibrosis
* Transplant-free survival
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023981
}}
==SOX2==

{{medline-entry
|title=Multiple nanosecond pulsed electric fields stimulation with conductive poly(l-lactic acid)/carbon nanotubes films maintains the multipotency of mesenchymal stem cells during prolonged in vitro culture.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32592324
|abstract=Mesenchymal stem cells (MSCs) gradually lose multipotency when cultured for prolonged durations in vitro, which significantly hinders subsequent clinical applications. Nanosecond pulsed electric fields (nsPEFs) have been recently investigated to overcome this problem in our lab; however, the differentiation potency of MSCs could only be partially and transiently recovered because the nsPEFs can only be delivered to suspended cells once. Here, we develop a new strategy to apply multiple nsPEFs to adherent MSCs with conductive films to mitigate the decreasing multipotency of prolonged cultured MSCs. The poly(l-lactic acid)/graphitized-carboxylated functionalized carbon nanotubes (PLLA/CNT) films were fabricated as conductive cell culture platforms. Both single and multiple nsPEFs stimulation could significantly increase the differentiation potential of MSCs, as evidenced by upregulated expression of chondrogenic, osteogenic, and adipogenic-related gene (SOX9, RUNX2, and PPAR-γ), as well as increased production of proteoglycans, mineralized calcium, and triglycerides. Multiple nsPEFs stimulation demonstrated significant efficacy in upregulating expression of pluripotency genes of OCT4A (3.5- to 4.5-folds), NANOG (3.5- to 4.0-folds), and [[SOX2]] (1.5- to 2.0-folds) and stably maintaining high expression of these genes for nearly 23 days. Notably, nsPEFs stimulation did not significantly shorten telomere length. In conclusion, multiple nsPEFs stimulation could effectively mitigate decreasing multipotency of MSCs during prolonged in vitro culture.

|keywords=* cell physical stimulus
* differentiation
* mesenchymal stem cells
* multipotency
* nanosecond pulsed electric fields
* senescence
|full-text-url=https://sci-hub.do/10.1002/term.3088
}}
{{medline-entry
|title=Subpopulations of miniature pig mesenchymal stromal cells with different differentiation potentials differ in the expression of octamer-binding transcription factor 4 and sex determining region Y-box 2.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32054231
|abstract=Human mesenchymal stromal cells (MSCs) exhibit variable differentiation potential and can be divided accordingly into distinct subpopulations whose ratios vary with donor age. However, it is unknown whether the same is true in pigs. This study investigated MSC subpopulations in miniature pig and compared their characteristics in young (2 to 3 months) and adult (27 to 35 months) pigs. Osteogenic, chondrogenic, and adipogenic capacity of isolated MSCs was evaluated by von Kossa, Alcian blue, and oil red O staining, respectively. Cell surface antigen expression was determined by flow cytometry. Proliferative capacity was assessed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Expression of marker genes was detected by quantitative real-time polymerase chain reaction. Porcine MSCs comprised cells with trilineage and bilineage differentiation potential (tMSCs and bMSCs, respectively) and non-differentiating stromal cells (NDSCs). The tMSC and bMSC fractions were smaller in adult than in young pigs (63.0% vs 71.2% and 11.6% vs 24.0%, respectively, p<0.05); NDSCs showed the opposite trend (25.4% vs 4.8%; p<0.05). Subpopulations showed no differences in morphology, cell surface antigen expression, or proliferative capacity, but octamer-binding transcription factor 4 (OCT4) expression was higher in tMSCs than in bMSCs and NDSCs (p<0.05), whereas sex determining region Y-box 2 ([[SOX2]]) expression was higher in tMSCs and bMSCs than in NDSCs (p<0.05). Aging had no effect on these trends. Porcine MSCs comprise distinct subpopulations that differ in their differentiation potential and OCT4 and [[SOX2]] expression. Aging does not affect the characteristics of each subpopulation but alters their ratios.

|keywords=* Aging
* Mesenchymal Stromal Cell (MSC) Subpopulations
* Miniature Pig
* Octamerbinding Transcription Factor 4 (OCT4)
* Sex Determining Region Y-box 2 (SOX2)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7054621
}}
{{medline-entry
|title=Increased Type I and Decreased Type II Hair Cells after Deletion of Sox2 in the Developing Mouse Utricle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31678344
|abstract=The vestibular system of the inner ear contains Type I and Type II hair cells (HCs) generated from sensory progenitor cells; however, little is known about how the HC subtypes are formed. Sox2 (encoding SRY-box 2) is expressed in Type II, but not in Type I, HCs. The present study aimed to investigate the role of [[SOX2]] in cell fate determination in Type I vs. Type II HCs. First, we confirmed that Type I HCs developed from Sox2-expressing cells through lineage tracing of Sox2-positive cells using a CAG-tdTomato reporter mouse crossed with a Sox2-CreER mouse. Then, Sox2 loss of function was induced in HCs, using Sox2  transgenic mice crossed with a Gfi1-Cre driver mouse. Knockout of Sox2 in HCs increased the number of Type I HCs and decreased the number of Type II HCs, while the total number of HCs and Sox2-positive supporting cells did not change. In addition, the effect of Sox2-knockout persisted into adulthood, resulting in an increased number of Type I HCs. These results demonstrate that [[SOX2]] plays a critical role in the determination of Type II vs. Type I HC fate. The results suggested that Sox2 is a potential target for generating Type I HCs, which may be important for regenerative strategies for balance disorders.
|mesh-terms=* Aging
* Animals
* Cell Count
* Cell Differentiation
* Cell Lineage
* Hair Cells, Vestibular
* Mice
* Mice, Knockout
* Mice, Transgenic
* SOXB1 Transcription Factors
* Saccule and Utricle
|keywords=* SOX2
* balance disorder
* hair cell
* utricle
* vestibule
|full-text-url=https://sci-hub.do/10.1016/j.neuroscience.2019.09.027
}}
==MCC==

{{medline-entry
|title=Multiple chronic conditions and risk of cognitive impairment and dementia among older Americans: findings from the Aging, Demographics, and Memory Study (ADAMS).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32633198
|abstract=This study examined the relationship between multiple chronic conditions ([[MCC]]) and risk of cognitive impairment with no dementia (CIND) and dementia among older Americans. A sample of 637 individuals aged 70 or older was drawn from the Aging, Demographics, and Memory Study, a supplementary dataset of the larger national Health and Retirement Study. Multinomial logistic regression analysis was conducted to investigate the association between [[MCC]] and cognition categorized as (a) no cognitive impairment, (b) CIND, or (c) dementia. Having [[MCC]], particularly three or more chronic conditions, was significantly related to being diagnosed with CIND in our study, but not dementia. Our findings suggest that the presence of [[MCC]] may be a risk factor for cognitive impairment in later life. However, further investigation using a longitudinal design is needed to better understand the mechanism of how [[MCC]] may be related to CIND and dementia among older adults in the United States.

|keywords=* Aging
* and memory study
* cognitive impairment with no dementia
* dementia
* demographics
* multimorbidity
* multiple chronic conditions
|full-text-url=https://sci-hub.do/10.1080/13825585.2020.1790492
}}
{{medline-entry
|title=Behaviour consistency is a sensitive tool for distinguishing the effects of aging on physical activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32348871
|abstract=We attempted to establish a novel parameter of behaviour consistency to help determine the effect of age on physical activity. Using the speed of movement to quantify behaviour might not be sufficient to determine this effect. The slowing of motor activities that occurs with aging is related to the decline of the aging brain. Previous studies have found different running-related hippocampal theta rhythm responses in the aging and exercise model. Therefore, we hypothesized that a familiarity with the environment and physical strength affect behavioural consistency in rats during running exercises. For this study, we used a treadmill and 30-minute running test at constant speeds and compared changes in the triaxial accelerometer and hippocampal theta rhythm between adult and middle-aged rats. No significant differences in RR intervals, mean cross-correlations ([[MCC]]s), or the proportion of good correlation coefficient (PGCC) were observed between adult and middle-aged rats in awake states before running on the treadmill. The root mean square (RMS) of the triaxial acceleration vectors in middle-aged rats was higher than that in adult rats. In the treadmill running tests, the RMS observed in middle-aged rats was significantly lower than that observed in adult rats. [[MCC]] and PGCC, which indicate movement consistencies, were significantly higher in middle-aged rats than they were in adult rats during the entire running test. However, only the RMS of the adult rats showed a negative correlation with exercise duration. Both [[MCC]] and PGCC were positively correlated with exercise duration. By contrast, a similar phenomenon was not found in the changes or differences in hippocampal theta rhythms between these two groups. Therefore, we consider that the [[MCC]] and PGCC could distinguish age-related movement differences and indicate coordination/adaptation during exercise. Changes in physical activity and alterations in the hippocampal theta rhythm were not different between the groups.

|keywords=* Aging
* Behaviour consistency
* Heart rate
* Physical activity
* Treadmill running
|full-text-url=https://sci-hub.do/10.1016/j.bbr.2020.112619
}}
{{medline-entry
|title=Burden on Caregivers of Adults with Multiple Chronic Conditions: Intersectionality of Age, Gender, Education level, Employment Status, and Impact on Social Life.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31475644
|abstract=Intersectionality analysis is the study of overlapping or intersecting social identities. Intersecting social identities may have an impact on the perception of burden by family caregivers of older persons with multiple chronic conditions ([[MCC]]). The purpose of this study was to explore the interaction of social factors on the burden of caring for older adults with [[MCC]]. A total of 194 caregivers of older adults with [[MCC]] were recruited from Alberta and Ontario. Survey data were collected at two time points, six months apart. Additive and multiplicative models were analysed using a generalised linear model to determine the level of caregiver burden. Medium-high social interference (impact on social life) was associated with higher burden when adjusted for age, gender, education, and employment status. The overall results of the five-way interaction suggest that males in general had lower burden scores than females. Irrespective of their education and employment status, females had generally higher burden scores. These results add to the current body of literature, suggesting areas for further research to fill knowledge gaps, and promoting ideas for evidence-guided public health interventions that focus on caregivers.

|keywords=* aging
* analyse d’intersectionnalité
* caregiver burden
* fardeau de l’aidant
* gender
* interférence sociale
* intersectionality analysis
* maladies chroniques multiples
* multiple chronic conditions
* sexe
* social interference
* vieillissement
|full-text-url=https://sci-hub.do/10.1017/S071498081900045X
}}
==ARNT==

{{medline-entry
|title=Loss of [[ARNT]] in skeletal muscle limits muscle regeneration in aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33064329
|abstract=The ability of skeletal muscle to regenerate declines significantly with aging. The expression of aryl hydrocarbon receptor nuclear translocator ([[ARNT]]), a critical component of the hypoxia signaling pathway, was less abundant in skeletal muscle of old (23-25 months old) mice. This loss of [[ARNT]] was associated with decreased levels of Notch1 intracellular domain (N1ICD) and impaired regenerative response to injury in comparison to young (2-3 months old) mice. Knockdown of [[ARNT]] in a primary muscle cell line impaired differentiation in vitro. Skeletal muscle-specific [[ARNT]] deletion in young mice resulted in decreased levels of whole muscle N1ICD and limited muscle regeneration. Administration of a systemic hypoxia pathway activator (ML228), which simulates the actions of [[ARNT]], rescued skeletal muscle regeneration in both old and [[ARNT]]-deleted mice. These results suggest that the loss of [[ARNT]] in skeletal muscle is partially responsible for diminished myogenic potential in aging and activation of hypoxia signaling holds promise for rescuing regenerative activity in old muscle.

|keywords=* aging
* hypoxia signaling
* muscle regeneration
|full-text-url=https://sci-hub.do/10.1096/fj.202000761RR
}}
{{medline-entry
|title=[Arylhydrocarbon receptor nuclear translocator ([[ARNT]]) in human skin during aging.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32593246
|abstract=The aim of this work was to examine the content of arylhydrocarbon receptor nuclear translocator ([[ARNT]]) in fibroblasts of human dermis from 20 weeks of pregnancy until 85 years old, and defining of a role of [[ARNT]] in age-dependent changes in the number of fibroblasts in the dermis. [[ARNT]], proliferating cells nuclear antigen (PCNA) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for [[ARNT]] in the dermis is decreased from 20 weeks of pregnancy to 40 years old. Percent of [[ARNT]] positive fibroblasts in dermis is increased sufficiently since 41 year old until 60-85 years old group. A total number and percent of PCNA positive fibroblasts in dermis decreased with progression of age. Most sufficient age-dependent reduction in a total and PCNA positive number of dermal fibroblast was observed from antenatal until 40 years of life. Age-related changes in the content of [[ARNT]] in fibroblasts is not associated with an age-related decrease in total number and percent of PCNA positive fibroblasts the dermis.
|mesh-terms=* Adolescent
* Adult
* Aged
* Aged, 80 and over
* Aging
* Aryl Hydrocarbon Receptor Nuclear Translocator
* Child
* Child, Preschool
* Dermis
* Fetus
* Fibroblasts
* Humans
* Infant
* Infant, Newborn
* Skin
* Skin Aging
* Young Adult
|keywords=* ARNT
* PCNA
* aging
* fibroblasts
* skin

}}
{{medline-entry
|title=The E3 ubiquitin ligase STUB1 attenuates cell senescence by promoting the ubiquitination and degradation of the core circadian regulator BMAL1.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32041778
|abstract=Cell senescence is one of the most important processes determining cell fate and is involved in many pathophysiological conditions, including cancer, neurodegenerative diseases, and other aging-associated diseases. It has recently been discovered that the E3 ubiquitin ligase STIP1 homology and U-box-containing protein 1 (STUB1 or CHIP) is up-regulated during the senescence of human fibroblasts and modulates cell senescence. However, the molecular mechanism underlying STUB1-controlled senescence is not clear. Here, using affinity purification and MS-based analysis, we discovered that STUB1 binds to brain and muscle [[ARNT]]-like 1 (BMAL1, also called aryl hydrocarbon receptor nuclear translocator-like protein 1 ([[ARNT]]L)). Through biochemical experiments, we confirmed the STUB1-BMAL1 interaction, identified their interaction domains, and revealed that STUB1 overexpression down-regulates BMAL1 protein levels through STUB1's enzymatic activity and that [i]STUB1[/i] knockdown increases BMAL1 levels. Further experiments disclosed that STUB1 enhances BMAL1 degradation, which is abolished upon proteasome inhibition. Moreover, we found that STUB1 promotes the formation of Lys-48-linked polyubiquitin chains on BMAL1, facilitating its proteasomal degradation. Interestingly, we also discovered that oxidative stress promotes STUB1 nuclear translocation and enhances its co-localization with BMAL1. STUB1 expression attenuates hydrogen peroxide-induced cell senescence, indicated by a reduced signal in senescence-associated β-gal staining and decreased protein levels of two cell senescence markers, p53 and p21. [i]BMAL1[/i] knockdown diminishes this effect, and BMAL1 overexpression abolishes STUB1's effect on cell senescence. In summary, the results of our work reveal that the E3 ubiquitin ligase STUB1 ubiquitinates and degrades its substrate BMAL1 and thereby alleviates hydrogen peroxide-induced cell senescence.

|keywords=* E3 ubiquitin ligase
* STIP1 homology and U-box-containing protein 1 (STUB1)
* brain and muscle ARNT-like 1 (BMAL1, ARNTL, MOP3)
* cell cycle regulation
* circadian clock
* hydrogen peroxide
* proteasome
* protein degradation
* senescence
* ubiquitylation (ubiquitination)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7135990
}}
==NAMPT==

{{medline-entry
|title=Over-expression of Nicotinamide phosphoribosyltransferase in mouse cells confers protective effect against oxidative and ER stress-induced premature senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32533606
|abstract=A main feature of aged organisms is the accumulation of senescent cells. Accumulated senescent cells, especially stress-induced premature senescent cells, in aged organisms lead to the decline of the regenerative potential and function of tissues. We recently reported that the over-expression of [[NAMPT]], which is the rate-limiting enzyme in mammalian NAD  salvage pathway, delays replicative senescence in vitro. However, whether Nampt-overexpressing cells are tolerant of stress-induced premature senescence remains unknown. Here, we show that primary mouse embryonic fibroblasts derived from Nampt-overexpressing transgenic mice (Nampt Tg-MEF cells) possess resistance against stress-induced premature senescence in vitro. We found that higher oxidative or endoplasmic reticulum (ER) stress is required to induce premature senescence in Nampt Tg-MEF cells compared to wild-type cells. Moreover, we found that Nampt Tg-MEF cells show acute expression of unfolded protein response (UPR)-related genes, which in turn would have helped to restore proteostasis and avoid cellular senescence. Our results demonstrate that [[NAMPT]]/NAD  axis functions to protect cells not only from replicative senescence, but also from stress-induced premature senescence in vitro. We anticipate that in vivo activation of [[NAMPT]] activity or increment of NAD  would protect tissues from the accumulation of premature senescent cells, thereby maintaining healthy aging.

|keywords=* ER stress
* NAD+
* NAMPT
* oxidative stress
* premature senescence
|full-text-url=https://sci-hub.do/10.1111/gtc.12794
}}
{{medline-entry
|title=Resistance training increases muscle NAD  and NADH concentrations as well as [[NAMPT]] protein levels and global sirtuin activity in middle-aged, overweight, untrained individuals.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32369778
|abstract=We examined if resistance training affected muscle NAD  and NADH concentrations as well as nicotinamide phosphoribosyltransferase ([[NAMPT]]) protein levels and sirtuin (SIRT) activity markers in middle-aged, untrained (MA) individuals. MA participants (59±4 years old; n=16) completed 10 weeks of full-body resistance training (2 d/wk). Body composition, knee extensor strength, and vastus lateralis muscle biopsies were obtained prior to training (Pre) and 72 hours following the last training bout (Post). Data from trained college-aged men (22±3 years old, training age: 6±2 years old; n=15) were also obtained for comparative purposes. Muscle NAD  (+127%, p<0.001), NADH (+99%, p=0.002), global SIRT activity (+13%, p=0.036), and [[NAMPT]] protein (+15%, p=0.014) increased from Pre to Post in MA participants. Additionally, Pre muscle NAD  and NADH in MA participants were lower than college-aged participants (p<0.05), whereas Post values were similar between cohorts (p>0.10). Interestingly, muscle citrate synthase activity levels (i.e., mitochondrial density) increased in MA participants from Pre to Post (+183%, p<0.001), and this increase was significantly associated with increases in muscle NAD  (r =0.592, p=0.001). In summary, muscle NAD , NADH, and global SIRT activity are positively affected by resistance training in middle-aged, untrained individuals. Whether these adaptations facilitated mitochondrial biogenesis remains to be determined.

|keywords=* NAD +
* NADH
* aging
* muscle
* resistance training
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288928
}}
{{medline-entry
|title=Differential Expression of Human N-Alpha-Acetyltransferase 40 (hNAA40), Nicotinamide Phosphoribosyltransferase ([[NAMPT]]) and Sirtuin-1 (SIRT-1) Pathway in Obesity and T2DM: Modulation by Metformin and Macronutrient Intake.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31920356
|abstract=Interactions between environmental factors, such as diet and lifestyle, and metabolic pathways are pivotal in understanding aging mechanisms. hNAA40, Nicotinamide phosphoribosyltransferase ([[NAMPT]]), and NAD-dependent protein deacetylase sirtuin-1 (SIRT-1) have been shown to exert important biological processes, including stress response and aging. hNAA40, [[NAMPT]], and SIRT-1 mRNA expression in peripheral blood mononuclear cells (PBMC) were quantitated in 30 lean adult volunteers of normal weight, 30 obese, 20 drug-naïve obese Type 2 diabetes mellitus (T2DM), and 30 obese T2DM on Metformin. Similarly, hNAA40, [[NAMPT]], and SIRT-1 expression in PBMC were quantitated in 36 normal healthy adults randomly assigned to three different groups (Glucose or Whey proteins or lipids; 300 kcal). Blood samples were obtained at 1, 2, and 3 hrs after the macronutrient intake. There was an increase in hNAA40 and a decrease in [[NAMPT]] and SIRT-1 expression in PBMC from T2DM. Metformin treatment reverted hNAA40, [[NAMPT]], and SIRT-1 expression levels to normal levels. Glucose intake resulted in a significant increase in expression of hNAA40 at 1 hr and decreased significantly at 3 hrs post intake. Lipid intake resulted in an increase in expression of hNAA40 at 2 hr post intake and returned to normal levels at 3 hrs. Neither glucose nor lipid intake resulted in a significant change in [[NAMPT]] or SIRT-1 expression. Whey proteins resulted in significantly lower expression of [[NAMPT]] at 3 hrs and did not alter the expression levels of SIRT-1 significantly. hNAA40, [[NAMPT]], and SIRT-1 pathway could play a role in the determination of the healthy life-span. Metformin modulates this pathway.

|keywords=* NAMPT
* T2DM
* hNAA40
* nicotinamide phosphoribosyltransferase
* obesity
* senescence
* sirtuin-1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938199
}}
==CXCR4==

{{medline-entry
|title=Aging-Related Reduced Expression of [[CXCR4]] on Bone Marrow Mesenchymal Stromal Cells Contributes to Hematopoietic Stem and Progenitor Cell Defects.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32418119
|abstract=Aging impairs the regenerative potential of hematopoietic stem cells (HSC) and skews differentiation towards the myeloid lineage. The bone marrow (BM) microenvironment has recently been suggested to influence HSC aging, however the mechanisms whereby BM stromal cells mediate this effect is unknown. Here we show that aging-associated decreased expression of [[CXCR4]] expression on BM mesenchymal stem cells (MSC) plays a crucial role in the development of the hematopoietic stem and progenitor cells (HSPC) aging phenotype. The BM MSC from old mice was sufficient to drive a premature aging phenotype of young HSPC when cultured together ex vivo. The impaired ability of old MSC to support HSPC function is associated with reduced expression of [[CXCR4]] on BM MSC of old mice. Deletion of the [[CXCR4]] gene in young MSC accelerates an aging phenotype in these cells characterized by increased production of reactive oxygen species (ROS), DNA damage, senescence, and reduced proliferation. Culture of HSPC from young mice with [[CXCR4]] deficient MSC also from young mice led to a premature aging phenotype in the young HSPC, as evidenced by reduced hematopoietic regeneration and enhanced myeloid differentiation. Mechanistically, [[CXCR4]] signaling prevents BM MSC dysfunction by suppressing oxidative stress, as treatment of old or [[CXCR4]] deficient MSC with N-acetyl-L-cysteine (NAC), improved their niche supporting activity, and attenuated the HSPC aging phenotype. Our studies suggest that age-associated reduction in [[CXCR4]] expression on BM MSC impairs hematopoietic niche activity with increased ROS production, driving an HSC aging phenotype. Thus, modulation of the SDF-1/[[CXCR4]] axis in MSC may lead to novel interventions to alleviate the age-associated decline in immune/hematopoietic function.

|keywords=* Aging
* CXCR4 and ROS
* HSPC
* MSC
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395885
}}
{{medline-entry
|title=Transfer of a human gene variant associated with exceptional longevity improves cardiac function in obese type 2 diabetic mice through induction of the SDF-1/[[CXCR4]] signalling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32384208
|abstract=Homozygosity for a four-missense single-nucleotide polymorphism haplotype of the human BPIFB4 gene is enriched in long-living individuals. Delivery of this longevity-associated variant (LAV) improved revascularisation and reduced endothelial dysfunction and atherosclerosis in mice through a mechanism involving the stromal cell-derived factor-1 (SDF-1). Here, we investigated if delivery of the LAV-BPIFB4 gene may attenuate the progression of diabetic cardiomyopathy. Compared with age-matched lean controls, diabetic db/db mice showed altered echocardiographic indices of diastolic and systolic function and histological evidence of microvascular rarefaction, lipid accumulation, and fibrosis in the myocardium. All these alterations, as well as endothelial dysfunction, were prevented by systemic LAV-BPIFB4 gene therapy using an adeno-associated viral vector serotype 9 (AAV9). In contrast, AAV9 wild-type-BPIFB4 exerted no benefit. Interestingly, LAV-BPIFB4-treated mice showed increased SDF-1 levels in peripheral blood and myocardium and up-regulation of the cardiac myosin heavy chain isoform alpha, a contractile protein that was reduced in diabetic hearts. SDF-1 up-regulation was instrumental to LAV-BPIFB4-induced benefit as both haemodynamic and structural improvements were inhibited by an orally active antagonist of the SDF-1 [[CXCR4]] receptor. In mice with type-2 diabetes, LAV-BPIFB4 gene therapy promotes an advantageous remodelling of the heart, allowing it to better withstand diabetes-induced stress. These results support the viability of transferring healthy characteristics of longevity to attenuate diabetic cardiac disease.

|keywords=* BPIFB4
* Cardiomyopathy
* Diabetes
* Gene therapy
* Longevity
|full-text-url=https://sci-hub.do/10.1002/ejhf.1840
}}
{{medline-entry
|title=Stromal Cell-Derived Factor 1 Protects Brain Vascular Endothelial Cells from Radiation-Induced Brain Damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31658727
|abstract=Stromal cell-derived factor 1 (SDF-1) and its main receptor, CXC chemokine receptor 4 ([[CXCR4]]), play a critical role in endothelial cell function regulation during cardiogenesis, angiogenesis, and reendothelialization after injury. The expression of [[CXCR4]] and SDF-1 in brain endothelial cells decreases due to ionizing radiation treatment and aging. SDF-1 protein treatment in the senescent and radiation-damaged cells reduced several senescence phenotypes, such as decreased cell proliferation, upregulated p53 and p21 expression, and increased senescence-associated beta-galactosidase (SA-β-gal) activity, through [[CXCR4]]-dependent signaling. By inhibiting extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription protein 3 (STAT3), we confirmed that activation of both is important in recovery by SDF-1-related mechanisms. A [[CXCR4]] agonist, ATI2341, protected brain endothelial cells from radiation-induced damage. In irradiation-damaged tissue, ATI2341 treatment inhibited cell death in the villi of the small intestine and decreased SA-β-gal activity in arterial tissue. An ischemic injury experiment revealed no decrease in blood flow by irradiation in ATI2341-administrated mice. ATI2341 treatment specifically affected [[CXCR4]] action in mouse brain vessels and partially restored normal cognitive ability in irradiated mice. These results demonstrate that SDF-1 and ATI2341 may offer potential therapeutic approaches to recover tissues damaged during chemotherapy or radiotherapy, particularly by protecting vascular endothelial cells.
|mesh-terms=* Animals
* Blood Vessels
* Brain
* Cell Line
* Cellular Senescence
* Chemokine CXCL12
* Cranial Irradiation
* Disease Models, Animal
* Down-Regulation
* Endothelial Cells
* Female
* Gene Expression Regulation
* Humans
* Lipopeptides
* Mice
* Receptors, CXCR4
* Signal Transduction
|keywords=* CXCR4
* SDF-1
* brain disorder
* endothelial dysfunction
* ionizing radiation
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830118
}}
==MTOR==

{{medline-entry
|title=The roles of [[MTOR]] and miRNAs in endothelial cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32246301
|abstract=Accumulation of senescent cells in vascular endothelium is known to contribute to vascular aging and increases the risk of developing cardiovascular diseases. The involvement of classical pathways such as p53/p21 and p16/pRB in cellular senescence are well described but there are emerging evidence supporting the increasingly important role of mammalian target of rapamycin ([[MTOR]]) as driver of cellular senescence via these pathways or other effector molecules. MicroRNAs (miRNAs) are a highly conserved group of small non-coding RNAs (18-25 nucleotides), instrumental in modulating the expression of target genes associated with various biological and cellular processes including cellular senescence. The inhibition of [[MTOR]] activity is predominantly linked to cellular senescence blunting and prolonged lifespan in model organisms. To date, known miRNAs regulating [[MTOR]] in endothelial cell senescence remain limited. Herein, this review discusses the roles of [[MTOR]] and [[MTOR]]-associated miRNAs in regulating endothelial cell senescence, including the crosstalk between [[MTOR]] Complex 1 ([[MTOR]]C1) and cell cycle pathways and the emerging role of [[MTOR]]C2 in cellular senescence. New insights on how [[MTOR]] and miRNAs coordinate underlying molecular mechanisms of endothelial senescence will provide deeper understanding and clarity to the complexity of the regulation of cellular senescence.

|keywords=* Endothelium
* MTOR
* MicroRNAs
* Senescence
* Vascular aging
|full-text-url=https://sci-hub.do/10.1007/s10522-020-09876-w
}}
{{medline-entry
|title=Autophagy drives fibroblast senescence through [[MTOR]]C2 regulation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31931659
|abstract=Sustained macroautophagy/autophagy favors the differentiation of fibroblasts into myofibroblasts. Cellular senescence, another means of responding to long-term cellular stress, has also been linked to myofibroblast differentiation and fibrosis. Here, we evaluate the relationship between senescence and myofibroblast differentiation in the context of sustained autophagy. We analyzed markers of cell cycle arrest/senescence in fibroblasts [i]in vitro[/i], where autophagy was triggered by serum starvation (SS). Autophagic fibroblasts expressed the senescence biomarkers CDKN1A/p21 and CDKN2A/p16 and exhibited increased senescence-associated GLB1/beta-galactosidase activity. Inhibition of autophagy in serum-starved fibroblasts with 3-methyladenine, LY294002, or [i]ATG7[/i] (autophagy related 7) silencing prevented the expression of senescence-associated markers. Similarly, suppressing [[MTOR]]C2 activation using rapamycin or by silencing [i]RICTOR[/i] also prevented senescence hallmarks. Immunofluorescence microscopy showed that senescence and myofibroblast differentiation were induced in different cells, suggesting mutually exclusive activation of senescence and myofibroblast differentiation. Reactive oxygen species (ROS) are known inducers of senescence and exposing fibroblasts to ROS scavengers decreased ROS production during SS, inhibited autophagy, and significantly reduced the expression of senescence and myofibroblast differentiation markers. ROS scavengers also curbed the AKT1 phosphorylation at Ser473, an [[MTOR]]C2 target, establishing the importance of ROS in fueling [[MTOR]]C2 activation. Inhibition of senescence by shRNA to [i]TP53[/i]/[i]p53[/i] and shRNA [i]CDKN2A[/i]/[i]p16[/i] increased myofibroblast differentiation, suggesting a negative feedback loop of senescence on autophagy-induced myofibroblast differentiation. Collectively, our results identify ROS as central inducers of [[MTOR]]C2 activation during chronic autophagy, which in turn fuels senescence activation and myofibroblast differentiation in distinct cellular subpopulations.  : 3-MA: 3-methyladenine; ACTA2: actin, alpha 2, smooth muscle, aorta; AKT1: AKT serine/threonine kinase 1; p-AKT1: AKT1 Ser473 phosphorylation; t-AKT1: total AKT serine/threonine kinase 1; ATG4A: autophagy related 4A cysteine peptidase; ATG7: autophagy gene 7; C12FDG: 5-dodecanoylaminofluorescein Di-β-D-Galactopyranoside; CDKN1A: cyclin dependent kinase inhibitor 1A; CDKN2A: cyclin dependent kinase inhibitor 2A; Ctl: control; DAPI: 4',6-diamidino-2-phenylindole, dilactate; ECM: extracellular matrix; GSH: L-glutathione reduced; H O : hydrogen peroxide; HLF: adult human lung fibroblasts; Ho: Hoechst 33342 (2'-[4-ethoxyphenyl]-5-[4-methyl-1-piperazinyl]-2.5'-bi-1[i]H[/i]-benzimidazole); HSC: hepatic stellate cells; LY: LY294002; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; [[MTOR]]C1/2: mechanistic target of rapamycin kinase complex 1/2; N: normal growth medium; NAC: N-acetyl-L-cysteine; PBS: phosphate-buffered saline; PDGFA: platelet derived growth factor subunit A; PRKCA/PKCα: protein kinase C alpha; PtdIns3K: class III phosphatidylinositol 3-kinase; PTEN: phosphatase and tensin homolog; R: rapamycin; RICTOR: RPTOR independent companion of [[MTOR]] complex 2; ROS: reactive oxygen species; RPTOR: regulatory associated protein of [[MTOR]] complex 1; SA-GLB1/β-gal: senescence-associated galactosidase beta 1; SGK1: serum/glucocorticoid regulated kinase 1; shRNA: short hairpin RNA; siCtl: control siRNA; siRNA: small interfering RNA; SQSTM1: sequestosome 1; SS: serum-free (serum starvation) medium; TP53: tumor protein p53; TUBA: tubulin alpha; V: vehicle.

|keywords=* Autophagy
* MTORC2
* myofibroblast
* rapamycin
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595590
}}
{{medline-entry
|title=The GID ubiquitin ligase complex is a regulator of AMPK activity and organismal lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31795790
|abstract=The AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by sensing the metabolic status of the cell. AMPK is regulated by phosphorylation and dephosphorylation as a result of changing AMP/ATP levels and by removal of inhibitory ubiquitin residues by USP10. In this context, we identified the GID-complex, an evolutionarily conserved ubiquitin-ligase-complex (E3), as a negative regulator of AMPK activity. Our data show that the GID-complex targets AMPK for ubiquitination thereby altering its activity. Cells depleted of GID-subunits mimic a state of starvation as shown by increased AMPK activity and macroautophagic/autophagic flux as well as reduced [[MTOR]] activation. Consistently, [i]gid[/i]-genes knockdown in [i]C. elegans[/i] results in increased organismal lifespan. This study may contribute to understand metabolic disorders such as type 2 diabetes mellitus and morbid obesity and implements alternative therapeutic approaches to alter AMPK activity. ACTB: actin, beta; ADP: adenosine diphosphate; AMP: adenosine monophosphate; AMPK: AMP-activated protein kinase; ARMC8: armadillo repeat containing 8; ATP: adenosine triphosphate; BafA1: bafilomycin A ; BCAA: branched chain amino acid; BICC1: BicC family RNA binding protein 1; BSA: bovine serum albumin; CAMKK2 kinase: calcium/calmodulin dependent protein kinase kinase 2, beta; CHX: cycloheximide; DMEM: Dulbecco's modified Eagle's medium; E1: ubiquitin-activating enzyme; E2: ubiquitin-conjugating enzyme; E3: ubiquitin ligase; ECAR: extracellular acidification rate; FACS: fluorescent associated cell sorter; FBP1: fructose-bisphosphatase 1; FCCP: carbonyl cyanide-4 (trifluoromethoxy) phenylhydrazone; G6P: glucose-6-phosphate; GDP: guanosine diphosphate; GFP: green fluorescent protein; GID: glucose induced degradation deficient; GMP: guanosine monophosphate; GTP: guanosine triphosphate; HBP1: high mobility group box transcription factor 1; HPRT: hypoxanthine guanine phosphoribosyl transferase; KO: knock out; LE: long exposure; MAEA: macrophage erythroblast attacher; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MKLN1: muskelin 1; mRNA: messenger RNA; [[MTOR]]: mechanistic target of rapamycin; NES: normalized enrichment score; OCR: oxygen consumption rate; PBS: phosphate buffered saline; PCK1: phosphoenolpyruvate carboxykinase 1, cytosolic; PCR: polymerase chain reaction; PFA: paraformaldehyde; RANBP9: RAN binding protein 9; RING: really interesting new gene; RMND5: required for meiotic nuclear division5 homolog; RPS6: ribosomal protein S6; RPTOR: regulatory associated protein of [[MTOR]], complex 1; SE: short exposure; SEM: standard error of the mean; SQSTM1/p62: sequestosome 1; TSC2: tuberous sclerosis complex 2; TUBA4A: tubulin; TUBE: tandem ubiquitin binding entities; Ub: ubiquitin; UPS: ubiquitin proteasome system; WDR26: WD repeat domain 26; WT: wild type.

|keywords=* AMPK
* GID
* autophagy
* longevity
* primary cilium
* ubiquitination
|full-text-url=https://sci-hub.do/10.1080/15548627.2019.1695399
}}
==BRD4==

{{medline-entry
|title=Inhibition of [[BRD4]] triggers cellular senescence through suppressing aurora kinases in oesophageal cancer cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32954665
|abstract=Oesophageal cancer is one of the most frequent solid malignancies and the leading cause of cancer-related death around the world. It is urgent to develop novel therapy strategies to improve patient outcomes. Acetylation modification of histones has been extensively studied in epigenetics. [[BRD4]], a reader of acetylated histone and non-histone proteins, has involved in tumorigenesis. It has emerged as a promising target for cancer therapy. [[BRD4]] inhibitors, such as JQ1, have exerted efficacious anti-proliferation activities in diverse cancers. However, the effects of JQ1 on oesophageal cancer are still not fully described. Here, we demonstrate that JQ1 suppresses cell growth and triggers cellular senescence in KYSE450 cells. Mechanistically, JQ1 up-regulates p21 level and decreases cyclin D1 resulting in G1 cycle arrest. The inhibitory effects of JQ1 on KYSE450 cells are independent on apoptosis. It activates cellular senescence by increasing SA-β-gal activity. [[BRD4]] knockdown by shRNA recapitulates cellular senescence. We also display that administration of JQ1 decreases recruitment of [[BRD4]] on the promoter of aurora kinases A and B. Inhibitors targeting at AURKA/B phenocopy JQ1 treatment in KYSE450 cells. These results identify a novel action manner of [[BRD4]] in oesophageal cancer, which strengthens JQ1 as a candidate drug in oesophageal cancer chemotherapy.

|keywords=* BRD4
* aurora kinase
* cellular senescence
* oesophageal cancer
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701500
}}
{{medline-entry
|title=[[BRD4]] contributes to LPS-induced macrophage senescence and promotes progression of atherosclerosis-associated lipid uptake.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32392533
|abstract=Aging is closely associated with atherosclerosis. Macrophages accumulate in atherosclerotic lesions contributing to the development and progression of atherosclerosis. Although atherosclerotic lesions are known to contain senescent cells, the mechanism underlying the formation of senescent macrophages during atherosclerosis is still unclear. In this study, macrophages with different origins were collected, including THP-1 macrophages, telomerase reverse transcriptase knock out (Tert ) mouse peritoneal macrophages, and human peripheral blood mononuclear cells (PBMCs). We found Lipopolysaccharide (LPS) could induce the formation of senescent macrophages, which was typified by the morphological changes, senescence-associated secretory phenotype (SASP) secretory, and persistent DNA damage response. Mechanistically, bromodomain-containing protein 4 ([[BRD4]]), a chromosomal binding protein related to gene expression, was found to play a key role in the pathological process, which could offer new therapeutic perspectives. Inhibition of [[BRD4]] by si[[BRD4]] or inhibitors such as JQ-1 or I-BET762 prevented the aging of macrophages and lipid accumulation in the LPS-induced senescent macrophages by decreasing expression of SASP in autocrine and paracrine senescence. These findings have significant implications for the understanding of the pathobiology of age-associated diseases and may guide future studies on targeted clinical drug therapy.

|keywords=* BRD4
* gene expression
* inflammation
* macrophage
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288959
}}
{{medline-entry
|title=BET Proteins Are Required for Transcriptional Activation of the Senescent Islet Cell Secretome in Type 1 Diabetes.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31561444
|abstract=Type 1 diabetes (T1D) results from the progressive loss of pancreatic beta cells as a result of autoimmune destruction. We recently reported that during the natural history of T1D in humans and the female nonobese diabetic (NOD) mouse model, beta cells acquire a senescence-associated secretory phenotype (SASP) that is a major driver of disease onset and progression, but the mechanisms that activate SASP in beta cells were not explored. Here, we show that the SASP in islet cells is transcriptionally controlled by Bromodomain ExtraTerminal (BET) proteins, including Bromodomain containing protein 4 ([[BRD4]]). A chromatin analysis of key beta cell SASP genes in NOD islets revealed binding of [[BRD4]] at active regulatory regions. BET protein inhibition in NOD islets diminished not only the transcriptional activation and secretion of SASP factors, but also the non-cell autonomous activity. BET protein inhibition also decreased the extent of SASP induction in human islets exposed to DNA damage. The BET protein inhibitor iBET-762 prevented diabetes in NOD mice and also attenuated SASP in islet cells in vivo. Taken together, our findings support a crucial role for BET proteins in the activation of the SASP transcriptional program in islet cells. These studies suggest avenues for preventing T1D by transcriptional inhibition of SASP.
|mesh-terms=* Animals
* Cell Cycle Proteins
* Cellular Senescence
* Diabetes Mellitus, Type 1
* Female
* Humans
* Insulin-Secreting Cells
* Islets of Langerhans
* Mice
* Mice, Inbred NOD
* Paracrine Communication
* Protein Binding
* Transcription Factors
* Transcriptional Activation
|keywords=* BET proteins
* beta cells
* senescence and SASP
* type 1 diabetes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801956
}}
==CXCL12==

{{medline-entry
|title=Co-option of Neutrophil Fates by Tissue Environments.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33098771
|abstract=Classically considered short-lived and purely defensive leukocytes, neutrophils are unique in their fast and moldable response to stimulation. This plastic behavior may underlie variable and even antagonistic functions during inflammation or cancer, yet the full spectrum of neutrophil properties as they enter healthy tissues remains unexplored. Using a new model to track neutrophil fates, we found short but variable lifetimes across multiple tissues. Through analysis of the receptor, transcriptional, and chromatin accessibility landscapes, we identify varying neutrophil states and assign non-canonical functions, including vascular repair and hematopoietic homeostasis. Accordingly, depletion of neutrophils compromised angiogenesis during early age, genotoxic injury, and viral infection, and impaired hematopoietic recovery after irradiation. Neutrophils acquired these properties in target tissues, a process that, in the lungs, occurred in [[CXCL12]]-rich areas and relied on CXCR4. Our results reveal that tissues co-opt neutrophils en route for elimination to induce programs that support their physiological demands.

|keywords=* angiogenesis
* immune heterogeneity
* immune niche
* innate immunity
* neutrophil lifespan
* neutrophils
* single-cell analysis
* tissue-resident cells
|full-text-url=https://sci-hub.do/10.1016/j.cell.2020.10.003
}}
{{medline-entry
|title=Heme oxygenase-1 deficiency triggers exhaustion of hematopoietic stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31885181
|abstract=While intrinsic changes in aging hematopoietic stem cells (HSCs) are well characterized, it remains unclear how extrinsic factors affect HSC aging. Here, we demonstrate that cells in the niche-endothelial cells (ECs) and [[CXCL12]]-abundant reticular cells (CARs)-highly express the heme-degrading enzyme, heme oxygenase 1 (HO-1), but then decrease its expression with age. HO-1-deficient animals (HO-1  ) have altered numbers of ECs and CARs that produce less hematopoietic factors. HSCs co-cultured in vitro with HO-1  mesenchymal stromal cells expand, but have altered kinetic of growth and differentiation of derived colonies. HSCs from young HO-1  animals have reduced quiescence and regenerative potential. Young HO-1  HSCs exhibit features of premature exhaustion on the transcriptional and functional level. HO-1  HSCs transplanted into HO-1  recipients exhaust their regenerative potential early and do not reconstitute secondary recipients. In turn, transplantation of HO-1  HSCs to the HO-1  recipients recovers the regenerative potential of HO-1  HSCs and reverses their transcriptional alterations. Thus, HSC-extrinsic activity of HO-1 prevents HSCs from premature exhaustion and may restore the function of aged HSCs.

|keywords=* aging
* bone marrow
* cxcl12-abudant reticular cells
* endothelial cells
* niche
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001511
}}
{{medline-entry
|title=Global Transcriptomic Profiling of the Bone Marrow Stromal Microenvironment during Postnatal Development, Aging, and Inflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31801092
|abstract=Bone marrow (BM) stromal cells provide the regulatory framework for hematopoiesis and contribute to developmental stage-specific niches, such as those preserving hematopoietic stem cells. Despite advances in our understanding of stromal function, little is known about the transcriptional changes that this compartment undergoes throughout lifespan and during adaptation to stress. Using RNA sequencing, we perform transcriptional analyses of four principal stromal subsets, namely [[CXCL12]]-abundant reticular, platelet-derived growth factor receptor (PDGFR)-α Sca1 , sinusoidal, and arterial endothelial cells, from early postnatal, adult, and aged mice. Our data reveal (1) molecular fingerprints defining cell-specific anatomical and functional features, (2) a radical reprogramming of pro-hematopoietic, immune, and matrisomic transcriptional programs during the transition from juvenile stages to adulthood, and (3) the aging-driven progressive upregulation of pro-inflammatory gene expression in stroma. We further demonstrate that transcriptomic pathways elicited in vivo by prototypic microbial molecules are largely recapitulated during aging, thereby supporting the inflammatory basis of age-related adaptations of BM hematopoietic function.
|mesh-terms=* Aging
* Animals
* Bone Marrow
* Bone Marrow Cells
* Cell Differentiation
* Cells, Cultured
* Cellular Microenvironment
* Chemokine CXCL12
* Embryonic Development
* Endothelial Cells
* Gene Expression Profiling
* Hematopoiesis
* Hematopoietic Stem Cells
* Inflammation
* Male
* Mesenchymal Stem Cells
* Mice
* Mice, Inbred C57BL
* Stem Cell Niche
* Transcriptome
|keywords=* aging
* bone marrow microenvironment
* hematopoietic stem cells
* inflammation
* niches
* stromal cells
* transcriptomics
|full-text-url=https://sci-hub.do/10.1016/j.celrep.2019.11.004
}}
==SLA==

{{medline-entry
|title=Vaccination of aged mice with adjuvanted recombinant influenza nucleoprotein enhances protective immunity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32540272
|abstract=Elderly individuals are highly susceptible to influenza virus (IAV) infection and respond poorly to influenza vaccines. Although the generally accepted correlate of protection following influenza vaccination is neutralizing antibody titers, cytotoxic T cell activity has been found to be a better correlate in the elderly. This suggests that vaccines designed to protect against influenza in the elderly should induce both humoral and cellular immunity. The co-induction of T cell immunity is additionally advantageous, as virus-specific T cells are frequently cross-reactive against different strains of IAV. Here, we tested the capacity of a synthetic TLR-4 adjuvant, [[SLA]]-SE (second-generation lipid adjuvant formulated in a squalene-based oil-in-water emulsion) to elicit T cell immunity to a recombinant influenza nucleoprotein (rNP), in both young and aged mice. IAV challenge of vaccinated mice resulted in a modest increase in the numbers of NP-specific CD4 and CD8 effector T cells in the spleen, but did not increase numbers of memory phenotype CD8 T cells generated following viral clearance (compared to control vaccinated mice). Cytotoxic activity of CD8, but not CD4 T cells was increased. In addition, [[SLA]]-SE adjuvanted vaccination specifically enhanced the production of NP-specific IgG2c antibodies in both young and aged mice. Although NP-specific antibodies are not neutralizing, they can cooperate with CD8 T cells and antigen-presenting cells to enhance protective immunity. Importantly, [[SLA]]-SE adjuvanted rNP-vaccination of aged mice resulted in significantly enhanced viral clearance. In addition, vaccination of aged mice resulted in enhanced survival after lethal challenge compared to control vaccination, that approached statistical significance. These data demonstrate the potential of [[SLA]]-SE adjuvanted rNP vaccines to (i) generate both cellular and humoral immunity to relatively conserved IAV proteins and (ii) elicit protective immunity to IAV in aged mice.

|keywords=* Adjuvant
* Aging
* Influenza
* Mouse
* Nucleoprotein
* Vaccination
|full-text-url=https://sci-hub.do/10.1016/j.vaccine.2020.05.085
}}
{{medline-entry
|title=Mechanical Anisotropy and Surface Roughness in Additively Manufactured Parts Fabricated by Stereolithography ([[SLA]]) Using Statistical Analysis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32486137
|abstract=In this study, the degree of mechanical anisotropy was investigated through tensile testing of specimens built in different orientations and designed according to the ASTM D638 standard. The mechanical properties that were evaluated include Young's modulus, ultimate tensile strength (UTS), and percentage elongation. Additionally, physical properties, such as mean surface roughness (Ra), density and dimension of the cross-sectional area, were also measured. These properties were then compared with the available standard data to see how [[SLA]] performs comparing to the traditional manufacturing methods. The obtained modulus of elasticity and UTS values of the printed samples were 2481 ± 50 MPa and 51.9 ± 1.3 MPa respectively, which were very similar to the standard data (2550 and 52 MPa, respectively) as provided by the material suppliers. The percentage elongation values (4.8% ± 0.4%) were a bit lower than the expected value of 6%. However, the surfaces of all the printed samples were quite smooth, with a surface roughness range of 2.28 ± 0.59 µm. A design of experiments was created to study the influence of the independent variables such as build orientation and angular orientation on the mechanical properties. Extensive statistical analysis, using the Taguchi method and analysis of variance (ANOVA), was performed to examine the effect of these independent variables on the mechanical properties. The [[SLA]] printed parts can be classified as isotropic since the build orientation and the angular orientation did not have a statistically significant impact on the mechanical properties. The effect of aging on the mechanical properties was also evaluated and it shows that the specimens that had been aged for a longer time resulted in superior mechanical properties. For example, the UTS increased from 24 to 54 MPa when the sample aligned parallel to the XY plane was aged from 1 week to 6 months, respectively. This significant increase implies that aging has a substantial effect on the mechanical properties of the parts fabricated by stereolithography. The resin used for this study, Visijet Sl Clear, produced very consistent mechanical properties in different directions.

|keywords=* Taguchi methods
* additive manufacturing
* aging effect
* analysis of variance
* anisotropy
* design of experiments
* stereolithography
* surface roughness
* tensile testing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321476
}}
{{medline-entry
|title=The Effect of Age of Titanium Dental Implants on Implant Survival and Marginal Bone Resorption: A 5-Year Retrospective Follow-Up Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32369581
|abstract=It has been demonstrated that the osteoconductivity, hydrophilicity, and biological capacity of titanium decreases over time, and this phenomenon was described as the biological aging of titanium. The aim of this study was to evaluate whether the age of sand-blasted and acid-etched ([[SLA]]) titanium dental implants (duration from the production date until the date of dental implant surgery) affects marginal bone resorption and implant survival. This nonrandom convenience-sample retrospective pilot study was carried out in 200 implants of 64 patients. Radiographic measurements were performed on intraoral periapical radiographs. Implants were divided into 2 age groups; group 1 = 0-3 months and group 2 = 36-41 months. A P value < .05 was considered statistically significant. Of the implants, 41% (n = 82) were between 0 and 3 months old, and 59% (n = 118) were between 36 and 41 months old. All (n = 200) of the implants survived and maintained their function. The mean mesial marginal resorption measurement was 0.60 ± 0.65 mm, and the mean distal marginal resorption was 0.77 ± 1.07 mm. There was no statistically significant difference between the amount of mesial and distal marginal bone resorption according to implant age (P > .05). In [[SLA]] surface titanium implants with adequate initial primary stability and a 3-month osseointegration period before loading, biological aging of titanium did not affect implant survival and marginal bone resorption.

|keywords=* 
          
            aged implant
          
        
* 
          
            biological aging
          
        
* 
          
            implant survival
          
        
* 
          
            marginal bone resorption
          
        
* 
          
            titanium dental implant
          
        
|full-text-url=https://sci-hub.do/10.1563/aaid-joi-D-19-00316
}}
==ASL==

{{medline-entry
|title=Increased blood-brain barrier permeability to water in the aging brain detected using noninvasive multi-TE [[ASL]] MRI.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32910547
|abstract=A fundamental goal in the drive to understand and find better treatments for dementia is the identification of the factors that render the aging brain vulnerable to neurodegenerative disease. Recent evidence indicates the integrity of the blood-brain barrier (BBB) to be an important component of functional failure underlying age-related cognitive decline. Practical and sensitive measurement is necessary, therefore, to support diagnostic and therapeutic strategies targeted at maintaining BBB integrity in aging patients. Here, we investigated changes in BBB permeability to endogenous blood water in the aging brain. A multiple-echo-time arterial spin-labeling MRI technique, implemented on a 9.4T Bruker imaging system, was applied to 7- and 27-month-old mice to measure changes in water permeability across the BBB with aging. We observed that BBB water permeability was 32% faster in aged mice. This occurred along with a 2.1-fold increase in mRNA expression of aquaporin-4 water channels and a 7.1-fold decrease in mRNA expression of α-syntrophin protein, which anchors aquaporin-4 to the BBB. Age-related changes to water permeability across the BBB can be captured using noninvasive noncontrast MRI techniques.

|keywords=* aging
* aquaporin-4
* arterial spin labeling
* blood-brain barrier
* blood-brain interface
* water permeability
|full-text-url=https://sci-hub.do/10.1002/mrm.28496
}}
{{medline-entry
|title=Quantitative Cerebrovascular Reactivity in Normal Aging: Comparison Between Phase-Contrast and Arterial Spin Labeling MRI.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32849217
|abstract= Cerebrovascular reactivity (CVR) is an index of the dilatory function of cerebral blood vessels and has shown great promise in the diagnosis of risk factors in cerebrovascular disease. Aging is one such risk factor; thus, it is important to characterize age-related differences in CVR. CVR can be measured by BOLD MRI but few studies have measured quantitative cerebral blood flow (CBF)-based CVR in the context of aging. This study aims to determine the age effect on CVR using two quantitative CBF techniques, phase-contrast (PC), and arterial spin labeling ([[ASL]]) MRI.   In 49 participants (32 younger and 17 older), CVR was measured with PC, [[ASL]], and BOLD MRI. These CVR methods were compared across young and older groups to determine their dependence on age. PC and [[ASL]] CVR were also studied for inter-correlation and mean differences. Gray and white matter CVR values were also studied.   PC CVR was higher in younger participants than older participants (by 17%, [i]p[/i] = 0.046). However, there were no age differences in [[ASL]] or BOLD CVR. [[ASL]] CVR was significantly correlated with PC CVR ([i]p[/i] = 0.042) and BOLD CVR ([i]p[/i] = 0.016), but its values were underestimated compared to PC CVR ([i]p[/i] = 0.045). [[ASL]] CVR map revealed no difference between gray matter and white matter tissue types, whereas gray matter was significantly higher than white matter in the BOLD CVR map.   This study compared two quantitative CVR techniques in the context of brain aging and revealed that PC CVR is a more sensitive method for detection of age differences, despite the absence of spatial information. The [[ASL]] method showed a significant correlation with PC and BOLD, but it tends to underestimate CVR due to confounding factors associated with this technique. Importantly, our data suggest that there is not a difference in CBF-based CVR between the gray and white matter, in contrast to previous observation using BOLD MRI.

|keywords=* MRI
* aging
* arterial spin labeling
* cerebrovascular reactivity
* phase-contrast
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411174
}}
{{medline-entry
|title=Correcting Task fMRI Signals for Variability in Baseline CBF Improves BOLD-Behavior Relationships: A Feasibility Study in an Aging Model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32425745
|abstract=Blood Oxygen Level Dependent (BOLD) functional MRI is a complex neurovascular signal whose magnitude depends on baseline physiological factors such as cerebral blood flow (CBF). Because baseline CBF varies across the brain and is altered with aging, the interpretation of stand-alone aging-related BOLD changes can be misleading. The primary objective of this study was to develop a methodology that combines task fMRI and arterial spin labeling ([[ASL]]) techniques to sensitize task-induced BOLD activity by covarying out the baseline physiology (i.e., CBF) in an aging model. We recruited 11 younger and 13 older healthy participants who underwent [[ASL]] and an overt language fMRI task (semantic category member generation). We measured in-scanner language performance to investigate the effect of BOLD sensitization on BOLD-behavior relationships. The results demonstrate that our correction approach is effective at enhancing the specificity and sensitivity of the BOLD signal in both groups. In addition, the correction strengthens the statistical association between task BOLD activity and behavioral performance. Although CBF has inherent age dependence, our results show that retaining the age factor within CBF aides in greater sensitization of task fMRI signals. From a cognitive standpoint, compared to young adults, the older participants showed a delayed domain-general language-related task activity possibly due to compromised vessel compliance. Further, assessment of functional evolution of corrected BOLD activity revealed biphasic BOLD dynamics in both groups where BOLD deactivation may reflect greater semantic demand or increased premium on domain general executive functioning in response to task difficulty. Although it was promising to note that the predictability of behavior using the proposed methodology outperforms other methodologies (i.e., no correction and normalization by division), and provides moderate stability and adequate power, further work with a larger cohort and other task designs is necessary to improve the stability of predicting associated behavior. In summary, we recommend correction of task fMRI signals by covarying out baseline CBF especially when comparing groups with different neurovascular properties. Given that [[ASL]] and BOLD fMRI are well established and widely employed techniques, our proposed multi-modal methodology can be readily implemented into data processing pipelines to obtain more accurate BOLD activation maps.

|keywords=* BOLD deactivation
* aging
* cerebral blood flow
* domain-general
* language fMRI
* semantic fluency
* sensitization
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205008
}}
==DPP4==

{{medline-entry
|title=Age-Dependent Assessment of Genes Involved in Cellular Senescence, Telomere, and Mitochondrial Pathways in Human Lung Tissue of Smokers, COPD, and IPF: Associations With SARS-CoV-2 COVID-19 ACE2-TMPRSS2-Furin-[[DPP4]] Axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33013423
|abstract=Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF). Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: <55 years and older: >55 years). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function ([i]HSPD1[/i], [i]FEN1[/i], [i]COX18[/i], [i]COX10[/i], [i]UCP2 & 3[/i]), cellular senescence ([i]PCNA[/i], [i]PTEN[/i], [i]KLOTHO[/i], [i]CDKN1C[/i], [i]TNKS2[/i], [i]NFATC1 & 2[/i], [i]GADD45A[/i]), and telomere replication/maintenance ([i]PARP1[/i], [i]SIRT6[/i], [i]NBN[/i], [i]TERT[/i], [i]RAD17[/i], [i]SLX4[/i], [i]HAT1[/i]) target genes. Interestingly, [i]NOX4[/i] and [i]TNKS2[/i] were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and quality control mechanisms like [i]FIS1[/i] and [i]RHOT2[/i] were decreased in young IPF compared to their age matched COPD subjects. ERCC1 and [i]GADD45B[/i] were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases including the SARS-CoV-2 infection. Lung immunoblot analysis of smokers, COPD and IPF subjects revealed increased abundance of proteases and receptor/spike protein like TMPRSS2, furin, and [[DPP4]] in association with a slight increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2 levels. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in COPD and IPF is associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-[[DPP4]] axis as pharmacological targets for COVID-19.

|keywords=* DNA damage
* aging
* cellular senescence
* chronic obstructive pulmonary diseases
* idiopathic pulmonary fibrosis
* mitochondria
* smokers
* telomere
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510459
}}
{{medline-entry
|title=Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32251672
|abstract=Dipeptidyl peptidase-4 ([[DPP4]]) is elevated in numerous cardiovascular pathological processes and [[DPP4]] inhibition is associated with reduced inflammation and oxidative stress. The aim of this study was to examine the role of [[DPP4]] in endothelial senescence. Sprague-Dawley rats (24 months) were orally administrated saxagliptin (10 mg·kg ·d ), a [[DPP4]] inhibitor, for 12 weeks in drinking water. Body weight, heart rate, blood glucose, and blood pressure were measured and vascular histological experiments were performed. In vitro studies were performed using H O -induced senescent human umbilical vein endothelial cells. Both in vivo and in vitro studies confirmed the elevation of [[DPP4]] in senescent vascular endothelium, and inhibition or knockdown of [[DPP4]] ameliorated endothelial senescence. In addition, [[DPP4]] inhibition or silencing reduced endothelial oxidative stress levels in aging vasculature and senescent endothelial cells. Moreover, [[DPP4]] inhibition or knockdown normalized the expression and phosphorylation of AMP-activated protein kinase-α (AMPKα) and sirtuin 1 (SIRT1) expression. Furthermore, the beneficial effects of [[DPP4]] inhibition or knockdown on endothelial cell senescence were at least partly dependent on SIRT1 and Nrf2 activation. In conclusion, our study demonstrated that [[DPP4]] inhibition or silencing ameliorated endothelial senescence both in vivo and in vitro by regulating AMPK/SIRT1/Nrf2. [[DPP4]] may be a new therapeutic target to combat endothelial senescence.

|keywords=* Aging
* Dipeptidyl peptidase-4
* Endothelium
* Oxidative stress
* Vascular
|full-text-url=https://sci-hub.do/10.1016/j.bcp.2020.113951
}}
{{medline-entry
|title=Molecular crosstalk between Y5 receptor and neuropeptide Y drives liver cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31999643
|abstract=Hepatocellular carcinoma (HCC) is clearly age-related and represents one of the deadliest cancer types worldwide. As a result of globally increasing risk factors including metabolic disorders, the incidence rates of HCC are still rising. However, the molecular hallmarks of HCC remain poorly understood. Neuropeptide Y (NPY) and NPY receptors represent a highly conserved, stress-activated system involved in diverse cancer-related hallmarks including aging and metabolic alterations, but its impact on liver cancer had been unclear. Here, we observed increased expression of NPY5 receptor (Y5R) in HCC, which correlated with tumor growth and survival. Furthermore, we found that its ligand NPY was secreted by peritumorous hepatocytes. Hepatocyte-derived NPY promoted HCC progression by Y5R activation. TGF-β1 was identified as a regulator of NPY in hepatocytes and induced Y5R in invasive cancer cells. Moreover, NPY conversion by dipeptidylpeptidase 4 ([[DPP4]]) augmented Y5R activation and function in liver cancer. The TGF-β/NPY/Y5R axis and [[DPP4]] represent attractive therapeutic targets for controlling liver cancer progression.

|keywords=* Aging
* Cancer
* Hepatology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190991
}}
==CA2==

{{medline-entry
|title=Maintaining Aging Hippocampal Function with Safe and Feasible Shaking Exercise in SAMP10 Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32526748
|abstract=The disabling effects of dementia, an incurable disease with little effect on mortality, affect society far more than many other conditions. The aim of this study was to stop or delay the onset of dementia using low-cost methods such as physical exercise. Senescence-accelerated model-prone (SAMP) 10 mice were made to perform a user-friendly shaking exercise for 25 weeks. The motor function and hippocampal functions (learning, spatial cognition) of the mice were evaluated using behavioral experiments. The degree of hippocampal aging was evaluated based on brain morphology. The association between behavioral performance of the mice and the degree of hippocampal aging was then evaluated. The behavioral test results showed that the shaking group had higher motor coordination (p < 0.01) and motor learning (p < 0.05). Significantly higher performances in the learning ability were observed in the shaking group at a middle-period experiment (p < 0.05); the spatial cognitive functions also improved (p < 0.05). The shaking group showed delayed ageing of cells in the dentate gyrus (DG; area: p < 0.01) and cornu Ammonis (CA; area: p < 0.01) regions of the hippocampus. The shaking exercise enhances the activity of mice and reduces age-associated decreases in learning and spatial cognitive functions. Regarding hippocampal morphology, shaking exercise can prevent non-functional protein accumulation, cell atrophy, and cell loss. Specifically, shaking exercise protects cell growth and regeneration in the DG area and enhances the learning function of the hippocampus. Furthermore, shaking exercise maintained the spatial cognitive function of cells in the CA3 and CA1 regions, and prevented the chronic loss of [[CA2]] transmission that decreased the spatial memory decline in mice.

|keywords=* Aging
* Behavior analysis
* Hippocampus
* Shaking exercise
* Spatial cognition
|full-text-url=https://sci-hub.do/10.1159/000507884
}}
{{medline-entry
|title=One-year Follow-up Study of Hippocampal Subfield Atrophy in Alzheimer's Disease and Normal Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32008518
|abstract=In this study, we investigated the effect of hippocampal subfield atrophy on the development of Alzheimer's disease (AD) by analyzing baseline magnetic resonance images (MRI) and images collected over a one-year follow-up period. Previous studies have suggested that morphological changes to the hippocampus are involved in both normal ageing and the development of AD. The volume of the hippocampus is an authentic imaging biomarker for AD. However, the diverse relationship of anatomical and complex functional connectivity between different subfields implies that neurodegenerative disease could lead to differences between the atrophy rates of subfields. Therefore, morphometric measurements at subfield-level could provide stronger biomarkers. Hippocampal subfield atrophies are measured using MRI scans, taken at multiple time points, and shape-based normalization to a Montreal neurological institute (MNI) ICBM 152 nonlinear atlas. Ninety subjects were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI), and divided equally into Healthy Controls (HC), AD, and mild cognitive impairment (MCI) groups. These subjects underwent serial MRI studies at three time-points: baseline, 6 months and 12 months. We analyzed the subfield-level hippocampal morphometric effects of normal ageing and AD based on radial distance mapping and volume measurements. We identified a general trend and observed the largest hippocampal subfield atrophies in the AD group. Atrophy of the bilateral CA1, [[CA2]]- CA4 and subiculum subfields was higher in the case of AD than in MCI and HC. We observed the highest rate of reduction in the total volume of the hippocampus, especially in the CA1 and subiculum regions, in the case of MCI. Our findings show that hippocampal subfield atrophy varies among the three study groups.
|mesh-terms=* Aged
* Aged, 80 and over
* Aging
* Alzheimer Disease
* Atrophy
* Case-Control Studies
* Cognitive Dysfunction
* Disease Progression
* Female
* Follow-Up Studies
* Hippocampus
* Humans
* Magnetic Resonance Imaging
* Male
* Neuroimaging
|keywords=* Alzheimer's disease
* biomarker
* hippocampal
* mild cognitive impairment
* neurodegenerative diseases
* normal aging
* radial distance
* subfield atrophy
|full-text-url=https://sci-hub.do/10.2174/1573405615666190327102052
}}
{{medline-entry
|title=Maturation of PNN and ErbB4 Signaling in Area [[CA2]] during Adolescence Underlies the Emergence of PV Interneuron Plasticity and Social Memory.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31665627
|abstract=Adolescence is a vulnerable period characterized by major cognitive changes. The mechanisms underlying the emergence of new cognitive functions are poorly understood. We find that a long-term depression of inhibitory transmission (iLTD) from parvalbumin-expressing (PV+) interneurons in the hippocampal area Cornu Ammonis 2 ([[CA2]]) is absent in young mice but emerges at the end of adolescence. We demonstrate that the maturation of both the perineuronal net (PNN) and signaling through ErbB4 is required for this plasticity. Furthermore, we demonstrate that social recognition memory displays the same age dependence as iLTD and is impaired by targeted degradation of the PNN or iLTD blockade in area [[CA2]]. Our data reveal an unusual developmental rule for plasticity at the PV+ interneuron transmission in area [[CA2]] and indicate that this plasticity is involved in the emergence of higher cognitive function, such as social memory formation, in late adolescence.
|mesh-terms=* Aging
* Animals
* Animals, Newborn
* CA2 Region, Hippocampal
* Interneurons
* Long-Term Synaptic Depression
* Male
* Memory
* Mice
* Mice, Inbred C57BL
* Neural Inhibition
* Neuregulin-1
* Neuronal Plasticity
* Parvalbumins
* Receptor, ErbB-4
* Receptors, Opioid, delta
* Signal Transduction
* Social Behavior
* Synapses
* gamma-Aminobutyric Acid
|keywords=* ErbB4
* adolescence
* area CA2
* delta opioid receptors
* hippocampus
* long-term depression
* neuregulin 1
* parvalbumin interneuron
* perineuronal net
* social memory
|full-text-url=https://sci-hub.do/10.1016/j.celrep.2019.09.044
}}
==SST==

{{medline-entry
|title=The distance to death perceptions of older adults explain why they age in place: A theoretical examination.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32972627
|abstract=Older persons prefer to age in place or stay put in their current dwellings and move less frequently than any other age group. However, current residential mobility theories do not fully account for these preferences and behaviors because they focus on why older people move rather than on why they remain in their dwellings and do not consider the temporal or human developmental context of these residential decisions. It is essential to understand why older persons are reluctant to move because their ability to age successfully-have healthy, independent, active, and enjoyable lives-depends on where they live. When they stay put, they also rely more on family caregivers and paid home care providers to maintain their independence, rather than on the supportive services offered by senior group facilities, such as assisted living. They demand more home modification and financial service products, and their residential decisions influence the supply of housing that younger populations can potentially buy or rent. This paper's theoretical analysis proposes that Carstensen's socioemotional selectivity theory ([[SST]]), a lifespan theory of motivation, improves our understanding of why older persons age in place-either in their dwellings or more broadly in their communities. It offers an alternative interpretation of how life-changing events, such as retirement, lower incomes, spousal death, physical limitations, and health declines, influence their residential decisions. Whereas residential mobility theories view these transitions as disruptions that change the appropriateness or congruence of where older people live, [[SST]] proposes that older persons perceive these events as signs or cues that they are closer to death and must differently prioritize their goals and emotional experiences. Feeling their time is "running out," older persons are motivated to stay put because moving requires preparations that are physically and emotionally trying and they are able to adapt to their current housing shortcomings. Their residential environments are now also a source of difficult-to-replace positive emotions and provide them with a supportive network of intimate and reliable interpersonal relationships. It is challenging for them to learn how to safely and efficiently conduct their usual activities and routines in another location and to establish new residential attachments and social connections. They would benefit from any net positive emotional payoffs only in a distant future, an unattractive prospect when they perceive a limited time left to live. Empirical studies must test the theoretical propositions presented in this paper. However, the disproportionally large projected future growth of the age 75 and older population with a heightened awareness of their limited time left to live should be a strong rationale for such investigations.

|keywords=* Agency- or belonging-related
* Distance to death, aging in place
* Emotions
* Residential mobility
* Socioemotional selectivity theory
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489887
}}
{{medline-entry
|title=Population Segmentation Based on Healthcare Needs: Validation of a Brief Clinician-Administered Tool.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32607929
|abstract=As populations age with increasingly complex chronic conditions, segmenting populations into clinically meaningful categories of healthcare and related service needs can provide healthcare planners with crucial information to optimally meet needs. However, while conventional approaches typically involve electronic medical records (EMRs), such records do not always capture information reliably or accurately. We describe the inter-rater reliability and predictive validity of a clinician-administered tool, the Simple Segmentation Tool ([[SST]]) for categorizing older individuals into one of six Global Impression (GI) segments and eight complicating factors (CFs) indicative of healthcare and related social needs. Observational study ( ClinicalTrials.gov , number NCT02663037). Patients aged 55 years and above. Emergency department (ED) subjects (between May and June 2016) had baseline [[SST]] assessment by two physicians and a nurse concurrently seeing the same individual. General medical (GM) ward subjects (February 2017) had a [[SST]] assessment by their principal physician. Adverse events (ED visits, hospitalizations, and mortality over 90 days from baseline) were determined by a blinded reviewer. Inter-rater reliability was measured using Cohen's kappa. Predictive validity was evaluated using Cox hazard ratios based on time to first adverse event. Cohen's kappa between physician-physician, service physician-nurse, and physician-nurse pairs for GI were 0.60, 0.71, and 0.68, respectively. Cox analyses demonstrated significant predictive validity of GI and CFs for adverse outcomes. With modest training, clinicians can complete a brief instrument to segment their patient into clinically meaningful categories of healthcare and related service needs. This approach can complement and overcome current limitations of EMR-based instruments, particularly with respect to whole-patient care. ClinicalTrials.gov Identifier: NCT02663037.

|keywords=* aging
* health services research
* psychometrics
|full-text-url=https://sci-hub.do/10.1007/s11606-020-05962-4
}}
{{medline-entry
|title=Examination on how emotion regulation mediates the relationship between future time perspective and well-being: a counter-evidence to the socioemotional selectivity theory.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32158369
|abstract=Previous studies have shown that older people maintain higher well-being than younger people despite their physical and cognitive functioning declining with age. This paradoxical phenomenon has been explained by the socioemotional selectivity theory ([[SST]]), in which a limited future time perspective (FTP) is an antecedent that leads to higher well-being through the use of adaptive emotion regulation. However, few empirical studies have examined the mediation process assumed in the [[SST]]. Moreover, it is unclear whether time left in life (TLL), which was originally referred to in the [[SST]] and is thought to be a different concept from FTP, relates to emotion regulation and well-being. Therefore, the current study investigated how emotion regulation mediates the relationship between FTP, TLL, and well-being by using a cross-sectional questionnaire that was responded to by 1393 Japanese adults (age range 20-89 years, [i]M[/i] = 54.23, SD = 19.01). The results of correlation and mediation analyses indicated that, in contrast to the assumption of the [[SST]], limited (expanded) FTP and TLL generally lead to lower (higher) well-being through the mediation of maladaptive (adaptive) emotion regulation. Although there are some methodological limitations, the findings imply that the relationship between FTP, TLL, and emotion regulation that is assumed in the [[SST]] should be reconsidered and that TLL should be thought of as a distinct variable from FTP.

|keywords=* Aging
* Emotion regulation
* Future time perspective
* Socioemotional selectivity theory
* Time left in life
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040126
}}
==GRK2==

{{medline-entry
|title=G protein-coupled receptor kinase 2 modifies the ability of Caenorhabditis elegans to survive oxidative stress.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33064264
|abstract=Survival and adaptation to oxidative stress is important for many organisms, and these occur through the activation of many different signaling pathways. In this report, we showed that Caenorhabditis (C.) elegans G protein-coupled receptor kinases modified the ability of the organism to resist oxidative stress. In acute oxidative stress studies using juglone, loss-of-function grk-2 mutants were more resistant to oxidative stress compared with loss-of-function grk-1 mutants and the wild-type N2 animals. This effect was Ce-AKT-1 dependent, suggesting that Ce-[[GRK2]] adjusted C. elegans oxidative stress resistance through the IGF/insulin-like signaling (IIS) pathway. Treating C. elegans with a [[GRK2]] inhibitor, the selective serotonin reuptake inhibitor paroxetine, resulted in increased acute oxidative stress resistance compared with another selective serotonin reuptake inhibitor, fluoxetine. In chronic oxidative stress studies with paraquat, both grk-1 and grk-2 mutants had longer lifespan compared with the wild-type N2 animals in stress. In summary, this research showed the importance of both GRKs, especially [[GRK2]], in modifying oxidative stress resistance.

|keywords=* Aging
* Caenorhabditis elegans (C. elegans)
* G protein coupled receptor kinase (GRK)
* Oxidative stress
* Resistance
* Stress response
|full-text-url=https://sci-hub.do/10.1007/s12192-020-01168-z
}}
{{medline-entry
|title=G protein coupled receptor kinases modulate Caenorhabditis elegans reactions to heat stresses.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32768194
|abstract=In this report, we explored if G protein coupled receptor kinases (GRKs) can help modulate the heat stress responses of Caenorhabditis (C.) elegans. Loss of function grk-2 C. elegans mutants were more tolerant to increases in heat and display an ability for heat stress-associated hormesis at a longer exposure time unlike the wild type N2 animals and the loss of function grk-1 C. elegans mutants. The loss of function grk-1 mutants recovered more from acute heat stress compared to the wild type N2 animals. Animals with low Ce-[[GRK2]] protein expression showed increased DAF-16 nuclear localization during the early stages of heat stress exposure compared to the other RNAi-treated animals, demonstrating altered insulin/insulin-like growth factor signaling (IIS) pathway activity in response to the stress. pdk-1 and akt-1 may play key roles in conjunction with Ce-[[GRK2]] in the heat stress response. Collectively, these findings demonstrate that GRKs influence C. elegans heat stress behaviors.

|keywords=* Aging
* Biological control
* Caenorhabditis elegans (C. elegans)
* G protein coupled receptor (GPCR)
* G protein coupled receptor kinase (GRK)
* Heat stress
* Resistance
* Stress response
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2020.07.121
}}
{{medline-entry
|title=Loss of dynamic regulation of G protein-coupled receptor kinase 2 by nitric oxide leads to cardiovascular dysfunction with aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32216616
|abstract=Nitric oxide (NO) and [i]S[/i]-nitrosothiol (SNO) are considered cardio- and vasoprotective substances. We now understand that one mechanism in which NO/SNOs provide cardiovascular protection is through their direct inhibition of cardiac G protein-coupled receptor (GPCR) kinase 2 ([[GRK2]]) activity via [i]S[/i]-nitrosylation of [[GRK2]] at cysteine 340 (C340). This maintains GPCR homeostasis, including β-adrenergic receptors, through curbing receptor [[GRK2]]-mediated desensitization. Previously, we have developed a knockin mouse ([[GRK2]]-C340S) where endogenous [[GRK2]] is resistant to dynamic [i]S[/i]-nitrosylation, which led to increased [[GRK2]] desensitizing activity. This unchecked regulation of cardiac [[GRK2]] activity resulted in significantly more myocardial damage after ischemic injury that was resistant to NO-mediated cardioprotection. Although young adult [[GRK2]]-C340S mice show no overt phenotype, we now report that as these mice age, they develop significant cardiovascular dysfunction due to the loss of SNO-mediated [[GRK2]] regulation. This pathological phenotype is apparent as early as 12 mo of age and includes reduced cardiac function, increased cardiac perivascular fibrosis, and maladaptive cardiac hypertrophy, which are common maladies found in patients with cardiovascular disease (CVD). There are also vascular reactivity and aortic abnormalities present in these mice. Therefore, our data demonstrate that a chronic and global increase in [[GRK2]] activity is sufficient to cause cardiovascular remodeling and dysfunction, likely due to [[GRK2]]'s desensitizing effects in several tissues. Because [[GRK2]] levels have been reported to be elevated in elderly CVD patients, [[GRK2]]-C340 mice can give insight into the aged-molecular landscape leading to CVD.  Research on G protein-coupled receptor kinase 2 ([[GRK2]]) in the setting of cardiovascular aging is largely unknown despite its strong established functions in cardiovascular physiology and pathophysiology. This study uses a mouse model of chronic [[GRK2]] overactivity to further investigate the consequences of long-term [[GRK2]] on cardiac function and structure. We report for the first time that chronic [[GRK2]] overactivity was able to cause cardiac dysfunction and remodeling independent of surgical intervention, highlighting the importance of GRK activity in aged-related heart disease.
|mesh-terms=* Aging
* Animals
* Female
* G Protein-Coupled Inwardly-Rectifying Potassium Channels
* Heart
* Heart Diseases
* Homeostasis
* Male
* Mice
* Mutation
* Myocardium
* Nitric Oxide
|keywords=* S-nitrosylation
* cardiac hypertrophy
* heart disease
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346533
}}
==AIP==

{{medline-entry
|title=[Aryl hydrocarbon receptor interacting protein ([[AIP]]) in human dermis during aging.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33280328
|abstract=The aim of this work was to examine the content of aryl hydrocarbon receptor interacting protein ([[AIP]]) in fibroblasts of human dermis from 20 weeks of pregnancy until 85 years old, and defining of a role of [[AIP]] in age-dependent changes in the number of fibroblasts in the dermis. [[AIP]], proliferating cells nuclear antigen (PCNA) were detected with indirect immunohistochemical technique. Results showed that a portion of fibroblasts with positive staining for [[AIP]] in the dermis is gradually increased from 20 weeks of pregnancy until 85 years old. A total number and percent of PCNA positive fibroblasts in dermis decreased with progression of age. Most sufficient age-dependent reduction in a total and PCNA positive number of dermal fibroblast was observed from antenatal until 40 years of life. Correlation analysis showed that both age-dependent decrease in the number of fibroblasts and retardation of their proliferation are significantly associated with age-related increase in the number of [[AIP]] positive fibroblasts in dermis. Results allow to suggest that [[AIP]] is involved in age-dependent decrease in the number and proliferation of fibroblasts in human dermis.

|keywords=* AIP
* PCNA
* aging
* fibroblasts
* skin

}}
{{medline-entry
|title=Sex-Specific Association between Serum Vitamin D Status and Lipid Profiles: A Cross-Sectional Study of a Middle-Aged and Elderly Chinese Population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32350171
|abstract=Studies have shown that vitamin D status might be associated with dyslipidaemia, but results are conflicting and there might exist sex differences. The aim of our study was to explore the sex-specific association between vitamin D status and serum lipids and atherogenic index of plasma ([[AIP]], a predictor for atherosclerosis) among Chinese middle-aged and elderly adults. A total of 4,021 middle-aged and elderly participants from a health management centre were included in this cross-sectional study. The individuals were classified into tertiles according to serum 25(OH)D. Linear and logistic regression models were used to estimate the association between vitamin D levels and serum lipids among the tertiles. The mean serum 25(OH)D level was 21.60 (16.60-27.20) ng/mL in all participants. After adjusting for potential confounders, a 10 ng/mL increase in 25(OH)D was associated with decreases of 1.156 mmol/L in triglycerides (TGs) and 0.068 in the [[AIP]] and an increase of 0.051 mmol/L in high-density lipoprotein cholesterol (HDL-C) in all subjects. In addition, 25(OH)D deficiency was associated with an increased prevalence of hypertriglyceridaemia (odds ratio (OR), 1.880; 95% confidence interval (CI), 1.351-2.615), hypoalphalipoproteinaemia/HDL (OR, 1.505; 95% CI, 1.146-1.977) and abnormal [[AIP]] (OR, 1.933; 95% CI, 1.474-2.534) in males, and 25(OH)D-deficient women had a 2.02-fold higher risk for hypoalphalipoproteinaemia/HDL than women with sufficient 25(OH)D levels (95% CI, 1.044-3.904; all p values <0.05). Vitamin D deficiency was positively associated with the prevalence of dyslipidaemia and abnormal [[AIP]] in the middle-aged and elderly Chinese population. And this association was stronger in men than in women.

|keywords=* atherogenic index of plasma
* dyslipidaemia
* gerontology
* sex difference
* vitamin D
|full-text-url=https://sci-hub.do/10.3177/jnsv.66.105
}}
{{medline-entry
|title=The oblique effect: The relationship between profiles of visuospatial preference, cognition, and brain connectomics in older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31654648
|abstract=The oblique effect (OE) describes the visuospatial advantage for identifying stimuli oriented horizontally or vertically rather than diagonally; little is known about brain aging and the OE. We investigated this relationship using the Judgment of Line Orientation (JLO) in 107 older adults (∼age = 67.8 ± 6.6; 51% female) together with neuropsychological tests of executive functioning (EF), attention/information processing ([[AIP]]), and neuroimaging. Only JLO lines falling between 36-54° or 126-144° were considered oblique. To quantify the oblique effect, we calculated z-scores for oblique errors (zOblique = #oblique errors/#oblique lines), and similarly, horizontal + vertical line errors (zHV), and a composite measure of oblique relative to HV errors (zOE). Composite z-scores of EF and [[AIP]] reflected domains associated with JLO performance. Graph theory analysis integrated T1-derived volumetry and diffusion MRI-derived white matter tractography into connectivity matrices analyzed for select network properties. Participants produced more zOblique than zHV errors (p < 0.001). Age was not associated with zOE adjusting for sex, education, and MMSE. Similarly adjusted linear regression models revealed that lower EF was associated with a larger oblique effect (p < 0.001). Modular analyses of neural connectivity revealed a differential patterns of network affiliation that varied by high versus low group status determined via median split of zOblique and zHV errors, separately. Older adults exhibit the oblique effect and it is associated with specific cognitive processes and regional brain networks that may facilitate future investigations of visuospatial preference in aging.
|mesh-terms=* Aged
* Brain
* Cognition
* Connectome
* Diffusion Tensor Imaging
* Executive Function
* Female
* Humans
* Judgment
* Male
* Middle Aged
* Neuropsychological Tests
* Pattern Recognition, Visual
* Spatial Processing
|keywords=* Aging
* Executive function
* Oblique effect
* Perception
* Structural connectivity
* Visuospatial processing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887099
}}
==PSD==

{{medline-entry
|title=Quantitative Immunoblotting Analyses Reveal that the Abundance of Actin, Tubulin, Synaptophysin and EEA1 Proteins is Altered in the Brains of Aged Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32652177
|abstract=Optimal synaptic activity is essential for cognitive function, including memory and learning. Evidence indicates that cognitive decline in elderly individuals is associated with altered synaptic function. However, the impact of aging on the expression of neurotransmitter receptors and accessory proteins in brain synapses remains unclear. To fill this knowledge gap, we investigated the effect of aging on the mouse brain by utilizing a subcellular brain tissue fractionation procedure to measure protein abundance using quantitative Western Blotting. Comparing 7-month- (control) and 22-month- (aged) old mouse tissue, no significant differences were identified in the levels of AMPA receptor subunits between the experimental groups. The abundance of GluN2B NMDA receptor subunits decreased in aged mice, whereas the levels of GluN2A did not change. The analysis of cytoskeletal proteins showed an altered level of actin and tubulin in aged mice while [[PSD]]-95 protein did not change. Vesicle protein analysis revealed that synaptophysin abundance is decreased in older brains whereas EEA1 was significantly increased. Thus, our results suggest that physiological aging profoundly impacts the abundance of molecules associated with neurotransmitter release and vesicle cycling, proteins implicated in cognitive function.

|keywords=* aging
* brain
* cortex
* glutamate receptor
* synapse
* vesicle
|full-text-url=https://sci-hub.do/10.1016/j.neuroscience.2020.06.044
}}
{{medline-entry
|title=Exercise Attenuates Brain Aging by Rescuing Down-Regulated Wnt/β-Catenin Signaling in Aged Rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32390823
|abstract=Down-regulated Wnt signaling is involved in brain aging with declined cognitive capacity due to its modulation on neuronal function and synaptic plasticity. However, the molecular mechanisms are still unclear. In the present study, the naturally aged rat model was established by feeding rats from 6 months old to 21 months old. The cognitive capacity of aged rats was compared with young rats as the controls and the aged rats upon 12-week exercise interventions including treadmill running, resistance exercise, and alternating exercise with resistance exercise and treadmill running. Wnt signaling was examined in hippocampal tissues of the rats from different groups. Results indicated that the expression of Dickkopf-1 (DKK-1) as an antagonist of Wnt signal pathway, the activation of GSK-3β, and the hyperphosphorylated Tau were markedly increased as the extension of age. Meanwhile, higher p-β-catenin  promoted neuronal degradation of aged rats. In contrast, three kinds of exercise interventions rescued the abnormal expression of DKK-1 and synaptophysin such as [[PSD]]-93 and [[PSD]]-95 in hippocampal tissues of the aged rats; especially 12-week treadmill running suppressed DKK-1 up-regulation, GSK-3β activation, β-catenin phosphorylation, and hyperphosphorylated Tau. In addition, the down-regulated PI3K/AKT and Wnt signal pathways were observed in aged rats, but could be reversed by resistance exercise and treadmill running. Moreover, the increased Bax and reduced Bcl-2 levels in hippocampal tissues of aged rats were also reversed upon treadmill running intervention. Taken together, down-regulated Wnt signaling suppressed PI3K/Akt signal pathway, aggravated synaptotoxicity, induced neuron apoptosis, and accelerated cognitive impairment of aged rats. However, exercise interventions, especially treadmill running, can attenuate their brain aging process [i]via[/i] restoring Wnt signaling and corresponding targets.

|keywords=* DKK-1
* Wnt
* brain aging
* exercise
* β-catenin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7192222
}}
{{medline-entry
|title=Concurrent nicotine exposure to prenatal alcohol consumption alters the hippocampal and cortical neurotoxicity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31938742
|abstract=This study investigated the neurotoxic effects of prenatal alcohol and nicotine exposure in the cortex and hippocampus of rodents. Behavioral alterations, electrophysiological changes, and biochemical markers associated with cholinergic neurotransmission, neural oxidative stress, mitochondrial function, and apoptosis were evaluated. Prenatal alcohol exposure induced the generation of ROS, nitrite and lipid peroxide, decreased mitochondrial Complex-I and IV activities, increased Caspase-1 and 3 activities, had no effect on cholinergic neurotransmission, increased expression of [[PSD]]-95, decreased LTP and decreased performance on spatial memory tasks. However, nicotine exposure, in addition to alcohol exposure, was found to mitigate the negative effects of alcohol alone on ROS generation and spatial memory task performances. Furthermore, we also studied the role of ILK in prenatal alcohol and nicotine exposure. Prenatal Smoking and/or drinking is a major health concern around the world. Thus, our current study may lead to better insights into the molecular mechanisms of fetal alcohol and nicotine exposure on the developing offspring.

|keywords=* Aging
* Mitochondrial function
* Neuroscience
* Oxidative stress
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953639
}}
==FAP==

{{medline-entry
|title=Rapamycin Extends Life Span in Apc  Colon Cancer [[FAP]] Model.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33132009
|abstract=We previously showed that lifelong rapamycin treatment of short-lived Apc  mice, a model for familial adenomatous polyposis, resulted in a normal lifespan. Apc  mice develop colon polyps with a low frequency but can be converted to a colon cancer model by dextran sodium sulfate (DSS) treatments (Apc -DSS model). We asked, what effect would pretreatment of Apc  mice with chronic rapamycin prior to DSS exposure have on survival and colonic neoplasia? Forty-two ppm enteric formulation of rapamycin diet exacerbated the temporary weight loss associated with DSS treatment in both sexes. However, our survival studies showed that chronic rapamycin treatment significantly extended lifespan of Apc -DSS mice (both sexes) by reductions in colon neoplasia and prevention of anemia. Rapamycin also had prophylactic effects on colon neoplasia induced by azoxymethane and DSS in C57BL/6 males and females. Immunoblot assays showed the expected inhibition of complex 1 of mechanistic or mammalian target of rapamycin (mTORC1) and effectors (S6K→rpS6 and S6K→eEF2K→eEF2) in colon by lifelong rapamycin treatments. To address the question of cell types affected by chronic enteric rapamycin treatment, immunohistochemistry analyses demonstrated that crypt cells had a prominent reduction in rpS6 phosphorylation and increase in eEF2 phosphorylation relative controls. These data indicate that enteric rapamycin prevents or delays colon neoplasia in Apc DSS mice through inhibition of mTORC1 in the crypt cells.

|keywords=* Aging
* Crypt stem cells
* eEF2K
* mTORC1
* rpS6
|full-text-url=https://sci-hub.do/10.1016/j.clcc.2020.08.006
}}
{{medline-entry
|title=Exercise enhances skeletal muscle regeneration by promoting senescence in fibro-adipogenic progenitors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32060352
|abstract=Idiopathic inflammatory myopathies cause progressive muscle weakness and degeneration. Since high-dose glucocorticoids might not lead to full recovery of muscle function, physical exercise is also an important intervention, but some exercises exacerbate chronic inflammation and muscle fibrosis. It is unknown how physical exercise can have both beneficial and detrimental effects in chronic myopathy. Here we show that senescence of fibro-adipogenic progenitors ([[FAP]]s) in response to exercise-induced muscle damage is needed to establish a state of regenerative inflammation that induces muscle regeneration. In chronic inflammatory myopathy model mice, exercise does not promote [[FAP]] senescence or resistance against tumor necrosis factor-mediated apoptosis. Pro-senescent intervention combining exercise and pharmacological AMPK activation reverses [[FAP]] apoptosis resistance and improves muscle function and regeneration. Our results demonstrate that the absence of [[FAP]] senescence after exercise leads to muscle degeneration with [[FAP]] accumulation. [[FAP]]-targeted pro-senescent interventions with exercise and pharmacological AMPK activation may constitute a therapeutic strategy for chronic inflammatory myopathy.
|mesh-terms=* Aging
* Animals
* Apoptosis
* Exercise Therapy
* Female
* Humans
* Mesenchymal Stem Cells
* Mice
* Mice, Inbred BALB C
* Mice, Inbred C57BL
* Muscle, Skeletal
* Muscular Diseases
* Regeneration

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021787
}}
{{medline-entry
|title=Control of Muscle Fibro-Adipogenic Progenitors by Myogenic Lineage is Altered in Aging and Duchenne Muscular Dystrophy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31865646
|abstract=Fibro-adipogenic progenitors ([[FAP]]s), a muscle-resident stem cell population, have recently emerged as important actors of muscle regeneration by interacting with myogenic progenitors (MPs) to promote the formation of new muscle fibers. However, [[FAP]]s are also considered as main contributors of intramuscular fibrotic and fat depositions, resulting in a poor quality of muscles and a defective regeneration in aging and Duchenne Muscular Dystrophy disease (DMD). Therefore, the understanding of the control of [[FAP]] fate is an important aspect of muscle repair and homeostasis, but little is known in humans. We wondered the extent to which human [[FAP]] proliferation, adipogenesis and fibrogenesis can be regulated by human myogenic progenitors (MPs) in physiological and pathological contexts. [[FAP]]s and MPs were isolated from skeletal muscles of healthy young or old donors and DMD patients. [[FAP]]/MP contact co-cultures and conditioned-media from undifferentiated MPs or differentiated myotubes were assessed on both proliferation and fibro-adipogenic differentiation of [[FAP]]s. We showed that soluble molecules released by MPs activate the phosphoinositide 3-kinase (PI3Kinase)/Akt pathway in [[FAP]]s, resulting in the stimulation of [[FAP]] proliferation. [[FAP]] differentiation was regulated by MP-derived myotubes through the secretion of pro-fibrogenic factors and anti-adipogenic factors. Importantly, the regulation of [[FAP]] adipogenic and fibrogenic fates by myotubes was found to be mediated by Smad2 phosphorylation and the gene expression of glioma-associated oncogene homolog 1 (GLI1). Surprisingly, the regulations of proliferation and differentiation were disrupted for [[FAP]]s and MPs derived from aged individuals and patients with DMD. Our results highlight a novel crosstalk between [[FAP]]s and the myogenic lineage in humans that could be crucial in the formation of adipocyte and myofibroblast accumulation in dystrophic and aged skeletal muscle.
|mesh-terms=* Adipogenesis
* Adolescent
* Adult
* Adult Stem Cells
* Aged
* Aging
* Cells, Cultured
* Child
* Child, Preschool
* Female
* Humans
* Infant
* Male
* Middle Aged
* Muscle Development
* Muscular Dystrophy, Duchenne
* Myoblasts
* Young Adult
|keywords=Adipocytes; Myofibroblasts; Muscle progenitors; Myopathies
|full-text-url=https://sci-hub.do/10.33594/000000196
}}
==IRS1==

{{medline-entry
|title=MicroRNA-34a causes ceramide accumulation and effects insulin signaling pathway by targeting ceramide kinase (CERK) in aging skeletal muscle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32056304
|abstract=Aging skeletal muscle shows perturbations in metabolic functions. MicroRNAs have been shown to play a critical role in aging and metabolic functions of skeletal muscle. MicroRNA-34a (miR-34a) is implicated in the brain and cardiac aging, however, its role in aging muscle is unclear. We analyzed levels of miR-34a, ceramide kinase (CERK) and other insulin signaling molecules in skeletal muscle from old mice. In addition to in vivo model, levels of these molecules were also analyzed in myoblast derived from insulin resistant (IR) humans and C2C12 myoblasts overexpressing mir-34a. Our results show that miR-34a is elevated in the muscles of 2-year-old mice and in the myoblasts of IR humans. Overexpression of miR-34a in C2C12 myoblasts leads to alterations in the insulin signaling pathway, which were rescued by its antagonism. Our analyses revealed that miR-34a targets CERK resulting in ceramide accumulation, activation of PP2A and the pJNK pathway in muscle and C2C12 myoblasts. Also, myostatin (Mstn) levels were increased in 2-year-old mouse muscle and Mstn treatment upregulated miR-34a in C2C12 myoblasts. In addition, miR-34a expression and ceramide levels did not increase during aging in Mstn  mice muscle. In summary, we, therefore, propose that Mstn levels increase in aging muscle and upregulate miR-34a, which inhibits CERK resulting in increased ceramide levels. This ceramide accumulation activates PP2A and pJNK causing hypophosphorylation of AKT and hyperphosphorylation of [[IRS1]] (Ser307), respectively, impairing insulin signaling pathway and eventually inhibiting the sarcolemma localization of GLUT4. These changes would result in reduced glucose uptake and insulin resistance. This study is the first to explain the phenomenon of ceramide accrual and impairment of insulin signaling pathway in aging muscle through a miR-34a based mechanism. In conclusion, our results suggest that Mstn and miR-34a antagonism can help ameliorate ceramide accumulation and loss of insulin sensitivity in aging skeletal muscle.

|keywords=* CERK
* aging muscle
* insulin signaling pathway
* miR-34a
|full-text-url=https://sci-hub.do/10.1002/jcb.29312
}}
{{medline-entry
|title=Longevity in response to lowered insulin signaling requires glycine N-methyltransferase-dependent spermidine production.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31721422
|abstract=Reduced insulin/IGF signaling (IIS) extends lifespan in multiple organisms. Different processes in different tissues mediate this lifespan extension, with a set of interplays that remain unclear. We here show that, in Drosophila, reduced IIS activity modulates methionine metabolism, through tissue-specific regulation of glycine N-methyltransferase (Gnmt), and that this regulation is required for full IIS-mediated longevity. Furthermore, fat body-specific expression of Gnmt was sufficient to extend lifespan. Targeted metabolomics showed that reducing IIS activity led to a Gnmt-dependent increase in spermidine levels. We also show that both spermidine treatment and reduced IIS activity are sufficient to extend the lifespan of Drosophila, but only in the presence of Gnmt. This extension of lifespan was associated with increased levels of autophagy. Finally, we found that increased expression of Gnmt occurs in the liver of liver-specific [[IRS1]] KO mice and is thus an evolutionarily conserved response to reduced IIS. The discovery of Gnmt and spermidine as tissue-specific modulators of IIS-mediated longevity may aid in developing future therapeutic treatments to ameliorate aging and prevent disease.

|keywords=* IGF
* aging
* autophagy
* insulin
* lifespan
* metabolism
* polyamine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974722
}}
{{medline-entry
|title=Serine Phosphorylation of [[IRS1]] Correlates with Aβ-Unrelated Memory Deficits and Elevation in Aβ Level Prior to the Onset of Memory Decline in AD.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/31426549
|abstract=The biological effects of insulin signaling are regulated by the phosphorylation of insulin receptor substrate 1 ([[IRS1]]) at serine (Ser) residues. In the brain, phosphorylation of [[IRS1]] at specific Ser sites increases in patients with Alzheimer's disease (AD) and its animal models. However, whether the activation of Ser sites on neural [[IRS1]] is related to any type of memory decline remains unclear. Here, we show the modifications of [[IRS1]] through its phosphorylation at etiology-specific Ser sites in various animal models of memory decline, such as diabetic, aged, and amyloid precursor protein (APP) knock-in   (APPKI ) mice. Substantial phosphorylation of [[IRS1]] at specific Ser sites occurs in type 2 diabetes- or age-related memory deficits independently of amyloid-β (Aβ). Furthermore, we present the first evidence that, in APPKI  mice showing Aβ42 elevation, the increased phosphorylation of [[IRS1]] at multiple Ser sites occurs without memory impairment. Our findings suggest that the phosphorylation of [[IRS1]] at specific Ser sites is a potential marker of Aβ-unrelated memory deficits caused by type 2 diabetes and aging; however, in Aβ-related memory decline, the modifications of [[IRS1]] may be a marker of early detection of Aβ42 elevation prior to the onset of memory decline in AD.
|mesh-terms=* Aging
* Alzheimer Disease
* Amyloid beta-Peptides
* Amyloid beta-Protein Precursor
* Animals
* Brain
* Diabetes Mellitus, Type 2
* Humans
* Insulin
* Insulin Receptor Substrate Proteins
* Male
* Memory
* Memory Disorders
* Mice, Inbred C57BL
* Mice, Transgenic
* Phosphorylation
* Serine
* Signal Transduction
|keywords=* AMPK
* Alzheimer’s disease
* Aβ
* IRS1
* aging
* diabetes
* energy depletion
* hippocampus
* memory decline
* serine phosphorylation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6723493
}}