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==ACE2==
==ABCG2==


{{medline-entry
{{medline-entry
|title=How Does SARS-CoV-2 Affect the Central Nervous System? A Working Hypothesis.
|title=[[ABCG2]] rs2231142 variant in hyperuricemia is modified by SLC2A9 and SLC22A12 polymorphisms and cardiovascular risk factors in an elderly community-dwelling population.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33304284
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32183743
|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.
|abstract=The [[ABCG2]] rs2231142 single nucleotide polymorphism (SNP) is one of the most significant genetic variants associated with hyperuricemia (HUA) in Asian populations. However, the risk of [[ABCG2]] rs2231142 variants for HUA could interact with other important HUA risk variants and cardiovascular factors. This study investigated the effects of the combined association among [[ABCG2]] rs2231142 and multiple HUA genetic variants or cardiovascular risk factors on HUA risk and serum uric acid (sUA) levels in an elderly Chinese population. A total of 1206 participants over 65 years old were enrolled in this study. Physical and laboratory examinations were performed for all participants. The [[ABCG2]] rs2231142, SLC2A9 rs3733591, and SLC22A12 rs893006 SNPs were assayed using a standardized protocol. Logistic regression analysis and liner regression were adjusted respectively to account for the association between [[ABCG2]] rs2231142 and other genetic variants, as well as between cardiovascular risk factors and HUA risk and sUA levels. The prevalence of HUA was 14.71% in the elderly community-dwelling population. The [[ABCG2]] rs2231142 risk T allele was associated with HUA risk (odds ratio (OR) = 1.63, 95% confidence interval (CI): 1.27-2.11; p = 1.65 × 10 ) and with increased sUA levels (Beta = 0.16, p = 6.75 × 10 ) in the whole study population. Linear regression analysis showed that the mean sUA level increased linearly with the number of risk alleles of the three candidate genetic variants (Beta = 0.18, p = 1.94 × 10 ) The joint effect of the [[ABCG2]] rs2231142 T allele and cardiovascular risk factors (obesity, hypertension and dyslipidemia) was also associated with increased HUA risk and sUA levels. Each copy of the risk T allele was significantly associated with enhanced HUA risk in patients with hypertriglyceridemia (OR = 2.52, 95% CI: 1.33-4.60; p = 0.003) compared to controls. Our findings reinforce the importance of the [[ABCG2]] rs2231143 variant as a crucial genetic locus for HUA in Chinese populations and demonstrated the combined effects of multiple genetic risk variants and cardiovascular risk exposures on HUA risk and increased sUA level.
|mesh-terms=* ATP Binding Cassette Transporter, Subfamily G, Member 2
* Aged
* Aged, 80 and over
* Aging
* Cardiovascular Diseases
* China
* Cohort Studies
* Effect Modifier, Epidemiologic
* Epistasis, Genetic
* Female
* Genes, Modifier
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Glucose Transport Proteins, Facilitative
* Humans
* Hyperuricemia
* Independent Living
* Male
* Neoplasm Proteins
* Organic Anion Transporters
* Organic Cation Transport Proteins
* Polymorphism, Single Nucleotide
* Risk Factors
* Uric Acid
|keywords=* ABCG2
* Hypertension
* Polymorphisms
* Triglyceridemia
* Uric acid
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077001
}}
==ABL1==


|keywords=* ACE2
{{medline-entry
* Alzheimer disease
|title=European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.
* Ang(1-7)/Mas
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32127639
|abstract=The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-[[ABL1]] at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.
|mesh-terms=* Aniline Compounds
* Antineoplastic Agents
* Clinical Decision-Making
* Consensus Development Conferences as Topic
* Dasatinib
* Disease Management
* Fusion Proteins, bcr-abl
* Gene Expression
* Humans
* Imatinib Mesylate
* Leukemia, Myelogenous, Chronic, BCR-ABL Positive
* Life Expectancy
* Monitoring, Physiologic
* Nitriles
* Protein Kinase Inhibitors
* Pyrimidines
* Quality of Life
* Quinolines
* Survival Analysis
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214240
}}
==ACE==
 
{{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
* COVID-19
* RAAS
* Coronavirus Infections
* SARS-CoV
* Dipeptidyl Peptidase 4
* brain aging
* Humans
* neurodegenerative and psychiatric disorders abstract
* Hydroxychloroquine
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701095
* 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
}}
==ACR==
 
{{medline-entry
|title=Progenitor cell niche senescence reflects pathology of the parotid salivary gland in primary Sjögren's syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32159757
|abstract=Salivary gland (SG) progenitor cells (SGPCs) maintain SG homeostasis. We have previously shown that in primary Sjögren's syndrome (pSS), SGPCs are likely to be senescent, and may underpin SG dysfunction. This study assessed the extent of senescence of cells in a SGPC niche in pSS patients' SGs, and its correlation with functional and clinical parameters. The expression of p16 and p21 as markers of senescence in both total SG epithelium and a SGPC niche (basal striated duct cells, BSD) was examined in SGs of pSS (n = 35), incomplete pSS (n = 13) (patients with some signs of pSS, but not fulfilling all classification criteria) and non-SS sicca control (n = 21) patients. This was correlated with functional and clinical parameters. pSS patient SGs contained significantly more p16+ cells both in the epithelium in general (P <0.01) and in the BSD layer (P <0.001), than non-SS SGs. Significant correlations were found in pSS patients between p16+ BSD cells and secretion of unstimulated whole saliva, stimulated whole saliva, stimulated parotid saliva, CD45+ infiltrate, ultrasound total score and [[ACR]]-EULAR classification score, but not with EULAR Sjögren's syndrome disease activity index (ESSDAI) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) scores. Correlations with total epithelium p16+ cells were weaker. Incomplete pSS patients also had increased numbers of p16+ epithelial and BSD cells. Based on protein and mRNA expression, p21+ appears not to play a significant role in the SG in pSS. These findings suggest SGPC senescence may be an early feature of primary Sjögren's syndrome and may contribute to defective SG function in pSS but not to systemic disease activity.
 
|keywords=* p16
* primary Sjögren’s syndrome
* salivary gland
* salivary gland progenitor cells
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516109
}}
==ADAM10==
 
{{medline-entry
|title=NKG2D Ligand Shedding in Response to Stress: Role of [[ADAM10]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32269567
|abstract=NKG2D is an activating receptor expressed by NK cells and some subsets of T cells and represents a major recognition receptor for detection and elimination of cancer cells. The ligands of NKG2D are stress-induced self-proteins that can be secreted as soluble molecules by protease-mediated cleavage. The release of NKG2D ligands in the extracellular milieu is considered a mode of finely controlling their surface expression levels and represents a relevant immune evasion mechanism employed by cancer cells to elude NKG2D-mediated immune surveillance. A disintegrin and metalloproteinase 10 ([[ADAM10]]), a catalytically active member of the ADAM family of proteases, is involved in the cleavage of some NKG2D ligands in various types of cancer cells either in steady state conditions and in response to an ample variety of stress stimuli. Appealing immunotherapeutic strategies devoted to promoting NK cell-mediated recognition and elimination of cancer cells are based on the upregulation of NK cell activating ligands. In particular, activation of DNA damage response (DDR) and the induction of cellular senescence by chemotherapeutic agents are associated with increased expression of NKG2D ligands on cancer cell surface. Herein, we will review advances on the protease-mediated cleavage of NKG2D ligands in response to chemotherapy-induced stress focusing on: (i) the role played by [[ADAM10]] in this process and (ii) the implications of NKG2D ligand shedding in the course of cancer therapy and in senescent cells.
 
|keywords=* ADAM10
* NKG2D
* NKG2D ligands
* cancer
* chemotherapy
* senescence
* shedding
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109295
}}
==AFM==
 
{{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
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042263
}}
}}
==ADH5==
==ALOX12==


{{medline-entry
{{medline-entry
|title=Can Serum Nitrosoproteome Predict Longevity of Aged Women?
|title=Arachidonate 12-lipoxygenase and 12-hydroxyeicosatetraenoic acid contribute to stromal aging-induced progression of pancreatic cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33260845
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32265301
|abstract=Aging is characterized by increase in reactive oxygen (ROS) and nitrogen (RNS) species, key factors of cardiac failure and disuse-induced muscle atrophy. This study focused on serum nitroproteome as a trait of longevity by adopting two complementary gel-based techniques: two-dimensional differential in gel electrophoresis (2-D DIGE) and Nitro-DIGE coupled with mass spectrometry of albumin-depleted serum of aged (A, [i]n[/i] = 15) and centenarian (C, [i]n[/i] = 15) versus young females (Y, [i]n[/i] = 15). Results indicate spots differently expressed in A and C compared to Y and spots changed in A vs. C. Nitro-DIGE revealed nitrosated protein spots in A and C compared to Y and spots changed in A vs. C only ([i]p[/i]-value < 0.01). Nitro-proteoforms of alpha-1-antitripsin (SERPINA1), alpha-1-antichimotripsin (SERPINA3), ceruloplasmin (CP), 13 proteoforms of haptoglobin (HP), and inactive glycosyltransferase 25 family member 3 (CERCAM) increased in A vs. Y and C. Conversely, nitrosation levels decreased in C vs. Y and A, for immunoglobulin light chain 1 (IGLC1), serotransferrin (TF), transthyretin (TTR), and vitamin D-binding protein (VDBP). Immunoblottings of alcohol dehydrogenase 5/S-nitrosoglutathione reductase ([[ADH5]]/GSNOR) and thioredoxin reductase 1 (TRXR1) indicated lower levels of [[ADH5]] in A vs. Y and C, whereas TRXR1 decreased in A and C in comparison to Y. In conclusion, the study identified putative markers in C of healthy aging and high levels of [[ADH5]]/GSNOR that can sustain the denitrosylase activity, promoting longevity.
|abstract=The incidence of pancreatic cancer increases with age, suggesting that chronological aging is a significant risk factor for this disease. Fibroblasts are the major nonmalignant cell type in the stroma of human pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated whether the chronological aging of normal human fibroblasts (NHFs), a previously underappreciated area in pancreatic cancer research, influences the progression and therapeutic outcomes of PDAC. Results from experiments with murine xenografts and 2D and 3D co-cultures of NHFs and PDAC cells revealed that older NHFs stimulate proliferation of and confer resistance to radiation therapy of PDAC. MS-based metabolite analysis indicated that older NHFs have significantly increased arachidonic acid 12-lipoxygenase ([[ALOX12]]) expression and elevated levels of its mitogenic metabolite, 12-([i]S[/i])-hydroxy-5,8,10,14-eicosatetraenoic acid (12-([i]S[/i])-HETE) compared with their younger counterparts. In co-cultures with older rather than with younger NHFs, PDAC cells exhibited increases in mitogen-activated protein kinase signaling and cellular metabolism, as well as a lower oxidation state that correlated with their enhanced proliferation and resistance to radiation therapy. Expression of [[ALOX12]] was found to be significantly lower in PDAC cell lines and tumor biopsies, suggesting that PDAC cells rely on a stromal supply of mitogens for their proliferative needs. Pharmacological (hydroxytyrosol) and molecular (siRNA) interventions of [[ALOX12]] in older NHFs suppressed their ability to stimulate proliferation of PDAC cells. We conclude that chronological aging of NHFs contributes to PDAC progression and that [[ALOX12]] and 12-([i]S[/i])-HETE may be potential stromal targets for interventions that seek to halt progression and improve therapy outcomes.


|keywords=* aging
|keywords=* aging
* cardiovascular disease
* arachidonic acid (AA) (ARA)
* muscle atrophy
* cancer biology
* nitrosative stress
* cell proliferation
* proteomics
* fibroblast
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731247
* pancreatic cancer
* stromal cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242692
}}
==AMH==
 
{{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
}}
}}
==AIP==
==AMT==


{{medline-entry
{{medline-entry
|title=[Aryl hydrocarbon receptor interacting protein ([[AIP]]) in human dermis during aging.]
|title=A multi-method comparison of autobiographical memory impairments amongst younger and older adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33280328
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32162531
|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.
|abstract= Research indicates that, compared to younger adults, older adults have difficulty recalling memories of specific past events (those lasting less than 24 h) and this difficulty is associated with depression. These studies are largely confined to a single measure of specific memory recall and there are conflicting findings when alternative measures are used. This investigation provides the first comparison of memory specificity between younger and older adults using several different measures.  Older ([i]n[/i] = 105) and younger ([i]n[/i] = 88) adults completed the Autobiographical Memory Test ([[AMT]]), Autobiographical Memory Interview (AMI) and Sentence Completion for Events from the Past Test (SCEPT) and the number of specific memories was quantified for each measure. Participants also completed the Beck Depression Inventory Version II (BDI-II).  Compared to younger adults, older adults recalled fewer specific memories in the [[AMT]] and more specific memories in the AMI. This latter effect was particularly pronounced for memories related to childhood. There was no group difference in responses in the SCEPT. There was no evidence of an association between memory specificity and depression for any of the measures.  Older adults have difficulty retrieving specific memories after cuing by nouns and adjectives, as in the [[AMT]], but they have enhanced recall of specific memories after cuing by life periods, as in the AMI, and this is particularly true of memories related to childhood. Individual differences in memory specificity are not related to depression symptoms in healthy samples.


|keywords=* AIP
|keywords=* Depression
* PCNA
* aging
* aging
* fibroblasts
* episodic memory
* skin
* overgeneral
* specificity
|full-text-url=https://sci-hub.do/10.1080/13607863.2020.1729338
}}
==APOE==


{{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
}}
}}
==ALAS1==
{{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
{{medline-entry
|title=Heterozygous disruption of [[ALAS1]] in mice causes an accelerated age-dependent reduction in free heme, but not total heme, in skeletal muscle and liver.
|title=Longitudinal Maintenance of Cognitive Health in Centenarians in the 100-plus Study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33307066
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32101309
|abstract=5-Aminolevulinic acid (ALA) is the rate-limiting intermediate in heme biosynthesis in vertebrate species; a reaction catalyzed by the mitochondrial ALA synthase 1 ([[ALAS1]]) enzyme. Previously we reported that knockdown of the ubiquitously expressed [[ALAS1]] gene in mice disrupts normal glucose metabolism, attenuates mitochondrial function and results in a prediabetic like phenotype when animals pass 20-weeks of age (Saitoh et al., 2018). Contrary to our expectations, the cytosolic and mitochondrial heme content of [[ALAS1]] heterozygous (A1+/-) mice were similar to WT animals. Therefore, we speculated that regulatory "free heme" may be reduced in an age dependent manner in A1 ± mice, but not total heme. Here, we examine free and total heme from the skeletal muscle and liver of WT and A1 ± mice using a modified acetone extraction method and examine the effects of aging on free heme by comparing the amounts at 8-12 weeks and 30-36 weeks of age, in addition to the mRNA abundance of [[ALAS1]]. We found an age-dependent reduction in free heme in the skeletal muscle and liver of A1 ± mice, while WT mice showed only a slight decrease in the liver. Total heme levels showed no significant difference between young and aged WT and A1 ± mice. [[ALAS1]] mRNA levels showed an age-dependent reduction similar to that of free heme levels, indicating that [[ALAS1]] mRNA expression levels are a major determinant for free heme levels. The free heme pools in skeletal muscle tissue were almost 2-fold larger than that of liver tissue, suggesting that the heme pool varies across different tissue types. The expression of heme oxygenase 1 (HO-1) mRNA, which is expressed proportionally to the amount of free heme, were similar to those of free heme levels. Taken together, this study demonstrates that the free heme pool differs across tissues, and that an age-dependent reduction in free heme levels is accelerated in mice heterozygous for [[ALAS1]], which could account for the prediabetic phenotype and mitochondrial abnormality observed in these animals.
|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
|keywords=* 5-Aminolevulinate synthase 1 (ALAS1)
* 5-Aminolevulinic acid (ALA)
* Aging
* Aging
* Free heme
* Apolipoprotein E4
* Liver
* Cognition
* Skeletal muscle
* Female
|full-text-url=https://sci-hub.do/10.1016/j.abb.2020.108721
* Humans
* Longitudinal Studies
* Male
* Mental Status and Dementia Tests
* Prospective Studies
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137688
}}
}}
==ALB==
==APP==


{{medline-entry
{{medline-entry
|title=Effects of Age on Inflammatory Profiles and Nutrition/Energy Metabolism in Domestic Cats.
|title=Transcriptomic profiling of microglia and astrocytes throughout aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33262938
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32238175
|abstract=Animals tend to increase in body weight and body condition score (BCS) with aging. Serum diagnostic markers related to energy metabolism may show changes even in healthy cats with aging. Seventy domestic cats were recruited for this study. Based upon the modified AAFP-AAHA Feline Life Stage Guidelines, animals were divided into six groups: Junior (7 months-2 years), Prime (3 -6 years), Mature (7-10 years), Senior (11-14 years), Geriatric-obese (15 years ≤) and Geriatric-thin (15 years ≤). Their body condition scores (BCS) ranged from 3/9 to 9/9. Changes in metabolites, inflammatory markers, hormone concentrations and enzyme activities related to energy metabolism were investigated in serum of 70 domestic cats of various ages. Serum glucose (GLU) concentrations in the Mature, Senior, and Geriatric-obese groups were significantly higher than those in the Junior group. Serum amyloid A (SAA) concentrations in the Geriatric-thin group were significantly increased compared with the Junior group. SAA concentrations in the Geriatric-obese group tended to increase although there were no statistically significant differences. In the Mature, Senior, Geriatric-obese and Geriatric-thin groups, malate dehydrogenase/lactate dehydrogenase (M/L) ratio, an energy metabolic indicator, tended to decrease compared with the Junior group. In the Senior group, triglyceride (TG) concentrations were significantly increased compared with the Junior group. In the Geriatric-obese and Geriatric-thin groups, blood urea nitrogen (BUN) concentrations were significantly increased compared with the Junior group. In the Geriatric-obese group, albumin ([[ALB]]) concentrations were decreased compared with the Junior group. Aged domestic cats tend to increase in body weight and BCS. In addition, serum GLU, TG, SAA, and BUN concentrations increased and serum [[ALB]] concentrations and M/L ratio decreased. These diagnostic markers may be useful to detect small changes related to energy metabolism with aging that may cause obesity with light inflammation in healthy cats.
|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=* M/L ratio
|keywords=* Aging
* SAA
* 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
* aging
* domestic cats
* astrocytes
* obesity
* platelets
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695597
* vascular pathology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063083
}}
}}
==ASB7==
==ATF6==


{{medline-entry
{{medline-entry
|title=[[ASB7]] Is a Novel Regulator of Cytoskeletal Organization During Oocyte Maturation.
|title=ER stress activates immunosuppressive network: implications for aging and Alzheimer's disease.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33251222
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32279085
|abstract=Ankyrin repeat and SOCS box (ASB) family members have a [i]C[/i]-terminal SOCS box and an [i]N[/i]-terminal ankyrin-related sequence of variable repeats. To date, the roles of ASB family members remain largely unknown. In the present study, by employing knockdown analysis, we investigated the effects of [[ASB7]] on mouse oocyte meiosis. We show that specific depletion of [[ASB7]] disrupts maturational progression and meiotic apparatus. In particular, abnormal spindle, misaligned chromosomes, and loss of cortical actin cap are frequently observed in [[ASB7]]-abated oocytes. Consistent with this observation, incidence of aneuploidy is increased in these oocytes. Meanwhile, confocal scanning reveals that loss of [[ASB7]] impairs kinetochore-microtubule interaction and provokes the spindle assembly checkpoint during oocyte meiosis. Furthermore, we find a significant reduction of [[ASB7]] protein in oocytes from aged mice. Importantly, increasing [[ASB7]] expression is capable of partially rescuing the maternal age-induced meiotic defects in oocytes. Together, our data identify [[ASB7]] as a novel player in regulating cytoskeletal organization and discover the potential effects of [[ASB7]] on quality control of aging oocytes.
|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=* ASBs
|keywords=* Ageing
* maternal aging
* Immunometabolism
* meiosis
* Immunosenescence
* oocyte
* Immunosuppression
* reproduction
* Inflammaging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674779
* Neurodegeneration
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220864
}}
}}
==ATF4==
==ATG3==


{{medline-entry
{{medline-entry
|title=Endoplasmic Reticulum Stress Mediates Vascular Smooth Muscle Cell Calcification via Increased Release of Grp78-Loaded Extracellular Vesicles.
|title=Estrogen Signaling Induces Mitochondrial Dysfunction-Associated Autophagy and Senescence in Breast Cancer Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33297752
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32244623
|abstract=Vascular calcification is common among aging populations and mediated by vascular smooth muscle cells (VSMCs). The endoplasmic reticulum (ER) is involved in protein folding and ER stress has been implicated in bone mineralization. The role of ER stress in VSMC-mediated calcification is less clear. Approach and Results: mRNA expression of the ER stress markers PERK (PKR (protein kinase RNA)-like ER kinase), ATF (activating transcription factor) 4, ATF6, and Grp78 was detectable in human vessels with levels of PERK decreased in calcified plaques compared to healthy vessels. Protein deposition of Grp78/Grp94 was increased in the matrix of calcified arteries. Induction of ER stress accelerated human primary VSMC-mediated calcification, elevated expression of some osteogenic markers (Runx2, Osterix, ALP, BSP, and OPG), and decreased expression of SMC markers. ER stress potentiated extracellular vesicle (EV) release via SMPD3. EVs from ER stress-treated VSMCs showed increased Grp78 levels and calcification. Electron microscopy confirmed the presence of Grp78/Grp94 in EVs. siRNA knock-down of Grp78 decreased calcification. Warfarin-induced Grp78 and [[ATF4]] expression in rat aortas and VSMCs and increased calcification in an ER stress-dependent manner via increased EV release. ER stress induces vascular calcification by increasing release of Grp78-loaded EVs. Our results reveal a novel mechanism of action of warfarin, involving increased EV release via the PERK-[[ATF4]] pathway, contributing to calcification. This study is the first to show that warfarin induces ER stress and to link ER stress to cargo loading of EVs.
|abstract=Previous work has shown that although estrogen (E2) disrupts cellular iron metabolism and induces oxidative stress in breast and ovarian cancer cells, it fails to induce apoptosis. However, E2 treatment was reported to enhance the apoptotic effects of doxorubicin in cancer cells. This suggests that E2 can precipitate anti-growth effects that render cancer cells more susceptible to chemotherapy. To investigate such anti-growth non-apoptotic, effects of E2 in cancer cells, MDA-MB-231 and MCF-7 cells were evaluated for the expression of key autophagy and senescence markers and for mitochondrial damage following E2 treatment. Treated cells experienced mitochondrial membrane depolarization along with increased expression of LC3-I/II, Pink1 and LAMP2, increased LC3-II accumulation and increased lysosomal and mitochondrial accumulation and flattening. E2-treated MCF-7 cells also showed reduced P53 and pRb780 expression and increased Rb and P21 expression. Increased expression of the autophagy markers [[ATG3]] and Beclin1 along with increased levels of β-galactosidase activity and IL-6 production were evident in E2-treated MCF-7 cells. These findings suggest that E2 precipitates a form of mitochondrial damage that leads to cell senescence and autophagy in breast cancer cells.


|keywords=* aging
|keywords=* Estrogen
* arteries
* MCF-7
* endoplasmic reticulum
* MDA-MB-231
* vascular calcification
* autophagy
* warfarin
* mitochondria
|full-text-url=https://sci-hub.do/10.1161/ATVBAHA.120.315506
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235898
}}
}}
==ATF6==
==ATM==


{{medline-entry
{{medline-entry
|title=Cellular proteostasis decline in human senescence.
|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/33257563
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32201398
|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.
|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=* UPR
|keywords=* ATM
* chaperones
* DNA damage response
* heat shock response
* NF-κB
* protein homeostasis
* 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
* senescence
|full-text-url=https://sci-hub.do/10.1073/pnas.2018138117
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073100
}}
}}
==ATG7==
==ATR==


{{medline-entry
{{medline-entry
|title=Age-related impairment of autophagy in cervical motor neurons.
|title=Supraphysiological protection from replication stress does not extend mammalian lifespan.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33290859
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32253367
|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.
|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=* Aging
|keywords=* DNA damage
* Autophagy
* aging
* Motor neuron
* cancer
* Neuromuscular dysfunction
* mouse models
* Spinal cord
* replication stress
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.111193
|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
}}
==BAZ2B==
 
{{medline-entry
|title=Two conserved epigenetic regulators prevent healthy ageing.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32103178
|abstract=It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated . Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan . Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases  shows that expression of the human orthologues of these C. elegans regulators, [[BAZ2B]] and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer's disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.
|mesh-terms=* Aging
* Animals
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Cognition
* Cognitive Dysfunction
* Epigenesis, Genetic
* Healthy Aging
* Histone-Lysine N-Methyltransferase
* Histones
* Humans
* Longevity
* Lysine
* Male
* Memory
* Methylation
* Mice
* Mitochondria
* Neurons
* Proteins
* RNA Interference
* Spatial Learning
* Transcription Factors, General
|keywords=#f
|full-text-url=https://sci-hub.do/10.1038/s41586-020-2037-y
}}
}}
==BDNF==
==BDNF==


{{medline-entry
{{medline-entry
|title=Influence of [i][[BDNF]][/i] Genetic Polymorphisms in the Pathophysiology of Aging-related Diseases.
|title=Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33269104
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32268299
|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.
|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
}}
==BMP2==
 
{{medline-entry
|title=Interleukin-1β-Induced Senescence Promotes Osteoblastic Transition of Vascular Smooth Muscle Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32126555
|abstract=Interleukin (IL)-1β, as a key biomarker and mediator of vascular calcification in patients with end-stage renal disease (ESRD), may be involved in the process of premature senescence of vascular smooth muscle cells (VSMCs). This work sought to investigate whether IL-1β-induced premature senescence contributes to the process of osteoblastic transition and vascular calcification in VSMCs. Eighty-eight patients with ESRD (aged 25-81 years), 11 healthy individuals, and 15 cases of lesion-free distal radial arteries from dialysis ESRD patients with angiostomy were collected in this study. Immunohistochemical analysis was performed to detect expression of IL-1β, p21, and bone morphogenetic protein-2 ([[BMP2]]) in the distal radial arteries. Primary human VSMCs from healthy neonatal umbilical cords were incubated with test agents for 1-3 days. Intracellular levels of reactive oxygen species (ROS) and senescence-associated-β-galactosidase (SA-β-gal) staining were used to detect senescent cells. Alizarin red staining and the calcium content of the cell layer were used to detect mineral deposition in VSMCs. Coincident with positive staining of IL-1β, p21, and [[BMP2]] in the lesion-free distal radial arteries, 66.67% patients showed mineral deposition. Serum IL-1β was 0.24 ± 0.57, 1.20 ± 2.95, and 9.41 ± 40.52 pg/mL in 11 healthy individuals, 20 patients without calcification, and 53 patients with calcification, respectively. Analysis of the cross-table chi-square test showed cardiovascular calcification is not correlated with levels of serum IL-1β in patients with ESRD (p = 0.533). In response to IL-1β, VSMCs showed a senescence-like phenotype, such as flat and enlarged morphology, increased expression of p21, an increased activity of SA-β-gal, and increased levels of ROS. IL-1β-induced senescence of VSMCs was required for the activation of IL-1β/NF-κB/p53/p21 signaling pathway. IL-1β-induced senescent VSMCs underwent calcification due to osteoblastic transition mainly depending upon the upregulation of [[BMP2]]. Resveratrol, an activator of sirtuin-1, postponed the IL-1β-induced senescence through blocking the NF-κB/p53/p21 pathway and attenuated the osteoblastic transition and calcification in VSMCs. High levels of IL-1β in medial smooth muscles of arteries may play roles in inducing senescence-associated calcification. IL-1β-induced senescence depending on the activation of the NF-κB/p53/p21 signaling pathway and contributing to osteoblastic transition of VSMCs.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Female
* Humans
* Interleukin-1beta
* Male
* Middle Aged
* Muscle, Smooth, Vascular
* Osteoblasts
|keywords=* Interleukin-1β
* Osteoblastic transition
* Senescence
* Vascular calcification
|full-text-url=https://sci-hub.do/10.1159/000504298
}}
==BOC==
 
{{medline-entry
|title=Protein Requirements of Elderly Chinese Adults Are Higher than Current Recommendations.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32140711
|abstract=Due to a lack of research data on the protein requirements of the elderly in China, the estimated average requirement (EAR) and the recommended nutrient intake (RNI) of protein in the elderly remain the same as those in young and middle-aged people at 0.98 g/(kg·d). The objective of this study was to determine the protein requirements of healthy Chinese adults >65y old through use of the indicator amino acid oxidation (IAAO) method. Seven healthy adult men and 7 healthy adult women participated in the study, with protein intakes ranging from 0.3 to 1.8 g/(kg·d). The diets were isocaloric and provided energy at a 1.5 resting energy expenditure. Protein was given based on the lactalbumin. Phenylalanine and tyrosine were added to protein doses of 0.3-1.5 g/kg according to the highest dose of protein content [1.8 g/(kg·d)]. Phenylalanine and tyrosine concentrations were kept constant at each protein dose. The mean protein requirement was determined by applying a nonlinear mixed-effects model analysis to the F13CO2, which identified a breakpoint in F13CO2 in response to graded amounts of protein. This trial was registered with the Chinese clinical trial registry as ChiCTR-[[BOC]]-17010930. Protein EAR and RNI for healthy elderly Chinese adults were determined to be 0.91 and 1.17 g/(kg·d), respectively, based on the indicator amino acid oxidation technique. The estimates of protein requirements for Chinese adults >65 y in the present study are 3.4% and 19.4% higher than the current estimated requirements, 0.88 g/(kg·d) for EAR and 0.98 g/(kg·d) for RNI.
|mesh-terms=* Aged
* Aging
* Amino Acids
* Body Weight
* China
* Dietary Proteins
* Energy Intake
* Energy Metabolism
* Female
* Humans
* Male
* Nutritional Requirements
* Oxidation-Reduction
* Phenylalanine
* Recommended Dietary Allowances
* Tyrosine
|keywords=* indicator amino acid oxidation
* older adults
* phenylalanine oxidation
* protein requirement
* stable isotope
|full-text-url=https://sci-hub.do/10.1093/jn/nxaa031
}}
==C3==


{{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
|keywords=* Aging
* BDNF gene
* GNE
* aging-related diseases
* Glycocalyx
* polymorphism
* Microglia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673859
* Neurodegeneration
* Neuroinflammation
* Sialic acid
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.01.008
}}
}}
==BRAF==
==CA1==


{{medline-entry
{{medline-entry
|title=Conditional reprograming culture conditions facilitate growth of lower grade glioma models.
|title=Functional Connectivity of Hippocampal CA3 Predicts Neurocognitive Aging via [[CA1]]-Frontal Circuit.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33258947
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32239141
|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.
|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=* BRAFV600E
|keywords=* aging
* Conditional reprogramming
* functional connectivity
* NF1
* hippocampus
* Senescence
* spatial memory
* low grade glioma
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325802
|full-text-url=https://sci-hub.do/10.1093/neuonc/noaa263
}}
}}
==CAD==
{{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
{{medline-entry
|title=Serum soluble Klotho is inversely related to coronary artery calcification assessed by intravascular ultrasound in patients with stable coronary artery disease.
|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/33303310
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32186114
|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.
|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
|keywords=* Aging
* Coronary artery calcification
* Alzheimer's disease
* Intravascular ultrasound
* Hippocampal subfields
* Klotho
* MRI
|full-text-url=https://sci-hub.do/10.1016/j.jjcc.2020.11.014
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.01.011
}}
}}
==CCK==
==CCK==


{{medline-entry
{{medline-entry
|title=Senolytic agent Quercetin ameliorates intervertebral disc degeneration via the Nrf2/NF-κB axis.
|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/33242601
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32268554
|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.
|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
}}
==CCL20==


|keywords=* Intervertebral disc degeneration
{{medline-entry
* NF-κB pathway
|title=p53 and p53-related mediators PAI-1 and IGFBP-3 are downregulated in peripheral blood mononuclear cells of HIV-patients exposed to non-nucleoside reverse transcriptase inhibitors.
* Nrf2
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32272174
* Quercetin
|abstract=The improved effectiveness and safety of the combined antiretroviral therapy (cART) has largely diminished mortality and AIDS-defining morbidity of HIV-patients. Nevertheless, chronic age-related diseases in these individuals are more common and their underlying pathogenic mechanisms of these actions seem to involve accelerated aging and enhanced inflammation. The present study explores markers of these processes in a heterogenous Spanish HIV cohort using peripheral blood samples of HIV-patients and matched uninfected controls. We isolated periheral blood mononuclear cells (PBMCs) and i) compared the expression of a panel of 14 genes related to inflammation and senescence in PBMCs of HIV-patients vs matched uninfected controls, ii) analyzed the expression in HIV-patients in association with a number of demographic, biochemical and immunological parameters and iii) in relation with the current cART they received. PBMCs of HIV-patients displayed significantly increased expression of general inflammatory genes (IL6, IL18 and CXCL10) and this occurs irrespectively of the antiviral therapy they have been receiving. Conversely, levels of senescence-associated genes TP53, SERPINE1andIGFBP3 were slightly but significantly reduced in patients compared to uninfected matched individuals and this effect is related to NNRTI-containing treatments. The expression of the inflammatory markers IL6, IL18, IL1B, TNFA, RELA, CCL2, [[CCL20]] and CXCL10 displayed correlation with certain demographic, morbidity- and HIV infection-related parameters. The levels of TP53 mRNA were positively associated only with plasma LDL. Correlation analysis between the expressions of pairs of genes revealed a different pattern between HIV-patients and controls. The diminished expression of TP53 and SERPINE1 in HIV-patients was also observed at a protein level, and the correlation between the two proteins (p53 and PAI1) in patients and controls showed the opposite trend. In conclusion, HIV-patients show dysregulation of p53 and p53-related mediators, a phenomenon which may be of pathophysiological relevance and could be related to the shorter health- and/or life-span observed in these individuals.
 
|keywords=* Aging
* Antiretroviral drugs
* HIV
* Inflammation
* NNRTI
* Senescence
* Senescence
|full-text-url=https://sci-hub.do/10.1016/j.joca.2020.11.006
* p53
|full-text-url=https://sci-hub.do/10.1016/j.antiviral.2020.104784
}}
}}
==CCN3==
==CCL28==


{{medline-entry
{{medline-entry
|title=[[CCN3]] Signaling Is Differently Regulated in Placental Diseases Preeclampsia and Abnormally Invasive Placenta.
|title=Age-related chemokine alterations affect IgA secretion and gut immunity in female mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33304321
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32277312
|abstract=An adequate development of the placenta includes trophoblast differentiation with the processes of trophoblast migration, invasion, cellular senescence and apoptosis which are all crucial to establishing a successful pregnancy. Altered placental development and function lead to placental diseases such as preeclampsia (PE) which is mainly characterized by insufficient trophoblast invasion and abnormally invasive placenta (AIP) disorders ([i]Placenta accreta[/i], [i]increta[/i], or [i]percreta)[/i] which are characterized by excessive trophoblast invasion. Both of them will cause maternal and fetal morbidity/mortality. However, the etiology of these diseases is still unclear. Our previous study has shown that the matricellular protein [i]nephroblastoma overexpressed[/i] (NOV, [[CCN3]]) induces G0/G1 cell cycle arrest, drives trophoblast cells into senescence and activates FAK and Akt kinases resulting in reduced cell proliferation and enhanced migration capability of the human trophoblast cell line SGHPL-5. The present study focuses on whether [[CCN3]] can alter cell cycle-regulated pathways associated with trophoblast senescence and invasion activity in pathological versus gestational age-matched control placentas. Cell cycle regulator proteins were investigated by immunoblotting and qPCR. For localization of [[CCN3]], p16, p21, and Cyclin D1 proteins, co-immunohistochemistry was performed. In early-onset PE placentas, [[CCN3]] was expressed at a significantly lower level compared to gestational age-matched controls. The decrease of [[CCN3]] level is associated with an increase in p53, Cyclin E1 and pRb protein expression, whereas the level of cleaved Notch-1, p21, Cyclin D1, pFAK, pAKT, and pmTOR protein decreased. In term AIP placentas, the expression of [[CCN3]] was significantly increased compared to matched term controls. This increase was correlated to an increase in p53, p16, p21, Cyclin D1, cleaved Notch-1, pFAK, pAkt, and pmTOR whereas pRb was significantly decreased. However, in late PE and early AIP placentas, no significant differences in [[CCN3]], p16, p21, Cyclin D1, p53, and cleaved Notch-1 expression were found when matched to appropriate controls. [[CCN3]] expression levels are correlated to markers of cell cycle arrest oppositely in PE and AIP by activating the FAK/AKT pathway in AIP or down-regulating in PE. This may be one mechanism to explain the different pathological features of placental diseases, PE and AIP.
|abstract=The chemokines CCL25 and [[CCL28]], which promote immune cell migration, are primarily expressed in the small and large intestines and play critical roles in sustaining gut immunity. In particular, these chemokines are closely related to intestinal IgA secretion. However, there is no research regarding the effects of aging on CCL25 and [[CCL28]] expression and function. Therefore, in the present study, we investigated the effects of aging on production of CCL25 and [[CCL28]], and on gut immunity, especially IgA secretion, using young and aged female mice. By aging, the levels of small intestinal mRNA and protein of CCL25 lowered, while these levels of [[CCL28]] in colon became higher. Moreover, the number of IgA-antibody secreting cells (IgA-ASCs) and total IgA concentration decreased in the small intestine due to the age-associated reduction of CCL25. In contrast, colonic IgA production was increased due to up-regulation of [[CCL28]], while the number of colonic IgA-ASCs was unchanged with aging. These results clearly demonstrate that aging-associated decrease in small intestinal CCL25 production and increase in colonic [[CCL28]] production c be involved in aging-associated deterioration of gut immunity.


|keywords=* CCN3
|keywords=* Aging
* abnormally invasive placenta
* CCL25
* invasion
* CCL28
* preeclampsia
* Gut immunity
* senescence
* IgA
* trophoblast
|full-text-url=https://sci-hub.do/10.1007/s10522-020-09877-9
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701218
}}
}}
==CCS==
==CCR2==


{{medline-entry
{{medline-entry
|title=Frailty Significantly Associated with a Risk for Mid-term Outcomes in Elderly Chronic Coronary Syndrome Patients: a Prospective Study.
|title=Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33306315
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32154790
|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.
|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
|keywords=* Aging
* Canada
* Bone marrow transplantation
* Confidence Intervals
* Cardiology
* Death
* Hematopoietic stem cells
* Frail Elderly
* Macrophages
* Frailty
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213793
* Heart
}}
* Multivariate Analysis
==CD27==
* Prognosis
 
* Risk Factors
{{medline-entry
|full-text-url=https://sci-hub.do/10.21470/1678-9741-2019-0484
|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
}}
}}
==CD28==
==CD28==


{{medline-entry
{{medline-entry
|title=Premature CD4  T Cells Senescence Induced by Chronic Infection in Patients with Acute Coronary Syndrome.
|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/33269101
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32280463
|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.
|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=* CD28null T cells
|keywords=* CD28− T cells
* CD4+ T cells
* HaploSCT
* acute coronary syndrome
* immune monitoring
* immunosenescence
* immunosenescence
* infection
* telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673853
|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
}}
}}
==CD34==
{{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
{{medline-entry
|title=ACE2/ACE imbalance and impaired vasoreparative functions of stem/progenitor cells in aging.
|title=T cells, aging and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33247425
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32092501
|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.
|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=* ACE2
|keywords=* Aging
* Aging
* Senescence
* Angiotensin-(1-7)
* T cells
* Hematopoietic stem/progenitor cells
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110887
* Ischemia
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694587
}}
}}
==CD38==
{{medline-entry
{{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.
|title=[[CD38]] in Neurodegeneration and Neuroinflammation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33271899
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32085567
|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.
|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=* SUSD2
|keywords=* ALS.
* adipose tissue
* Alzheimer’s disease
* apoptosis
* CD38
* bone marrow
* NAD
* clonogenicity
* Parkinson’s disease
* endometrium
* aging
* menstrual fluid
* neurodegeneration
* perivascular mesenchymal stromal cells
* neuroinflammation
* placenta
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072759
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712261
}}
}}
==CD4==
==CD4==


{{medline-entry
{{medline-entry
|title=IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A Foxp3  Cells During Mucosal Infection and Is Dysregulated With Aging.
|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/33240286
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32279324
|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.
|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=* Candida
|keywords=* age-related involution
* Foxp3
* IL-1β
* Treg
* Treg17
* aging
* aging
* fungal infection
* 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
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677307
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996562
}}
}}
{{medline-entry
{{medline-entry
|title=Thymus involution sets the clock of declined immunity and repair with aging.
|title=Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33248315
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32082401
|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.
|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
|keywords=* Aging
* Chronic systemic inflammation
* Head and neck cancer
* Dysregulated CD4 T cells
* Immune escape
* Immune-mediated repair
* Immunosenescence
* Thymus
* T cells
|full-text-url=https://sci-hub.do/10.1016/j.arr.2020.101231
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017629
}}
}}
==CD68==
{{medline-entry
{{medline-entry
|title=Food insecurity and T-cell dysregulation in women living with HIV on antiretroviral therapy.
|title=Cellular senescence in recurrent tonsillitis and tonsillar hypertrophy in children.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33247896
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32200310
|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.
|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
}}
==CD80==


|keywords=* HIV
{{medline-entry
* exhaustion
|title=The aging common marmoset's immune system: From junior to senior.
* food insecurity
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32246726
* immune activation
|abstract=The social, health, and economic challenges of a steadily increasing aging population demand the use of appropriate translational animal models to address questions like healthy aging, vaccination strategies, or potential interventions during the aging process. Due to their genetic proximity to humans, especially nonhuman primates (NHPs) with a relatively short generation period compared to humans, qualify as excellent animal models for these purposes. The use of common marmosets (Callithrix jacchus) in gerontology research steadily increased over the last decades, yet important information about their aging parameters are still missing. We therefore aimed to characterize their aging immune system by comprehensive flow cytometric phenotyping of blood immune cells from juvenile, adult, aging, and geriatric animals. Aged and geriatric animals displayed clear signs of immunosenescence. A decline in CD4/CD8 ratio, increased expression of HLA-DR and PD-1, higher frequencies of CD95  memory cells, alterations in cytokine secretion, and a decline in the proliferative capacity proved T cell senescence in aging marmosets. Also, the B cell compartment was affected by age-related changes: while overall B cell numbers remained stable with advancing age, expression of the activation marker [[CD80]] increased and immunoglobulin M expression decreased. Interestingly, marmoset B cell memory subset distribution rather mirrored the human situation than that of other NHP. CD21  CD27  naïve B cell frequencies decreased while those of CD21  CD27  tissue memory B cells increased with age. Furthermore, frequencies and numbers of NK cells as part of the innate immune system declined with advancing age. Thus, the observed immunological changes in common marmosets over their life span revealed several similarities to age-related changes in humans and encourages further studies to strengthen the common marmoset as a potential aging model.
|mesh-terms=* Aging
* Animals
* CD4-CD8 Ratio
* Callithrix
* Female
* Flow Cytometry
* Immune System
* Longevity
* Male
* Models, Animal
* Sex Factors
|keywords=* aging
* common marmoset
* immune system
* immunosenescence
* innate and adaptive immunity
* sex
|full-text-url=https://sci-hub.do/10.1002/ajp.23128
}}
==CD81==
 
{{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
* senescence
|full-text-url=https://sci-hub.do/10.1093/cid/ciaa1771
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176858
}}
}}
==CDK2==
{{medline-entry
{{medline-entry
|title=Rapamycin Eyedrops Increased [[CD4]] Foxp3 Cells and Prevented Goblet Cell Loss in the Aged Ocular Surface.
|title=p57  is a master regulator of human adipose derived stem cell quiescence and senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33255287
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32224418
|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.
|abstract=Although human adipose derived stem cells (hADSCs) hold great promises for regenerative medicine, their key biological properties remain poorly understood. In particular, proliferation defects resulted from deep quiescence (dormancy) and senescence represent a major hurdle in hADSC production and clinical application. We have developed a model system for mechanistic dissection of hADSC quiescence and senescence. p57 , a major CDK inhibitor, was highly expressed in quiescent and senescent hADSCs but its level quickly declined upon stem cell activation. p57  overexpression induced quiescence in spite of proliferative signals and its knockdown promoted cell cycle reentry even with induction of quiescence presumably through modulating the [[CDK2]]-CyclinE1 complex. Given its key role in quiescence and senescence, p57 may be exploited for innovative strategies to amplify hADSCs of high quality for clinics.
 
|keywords=* Human adipose derived stem cells
* Quiescence
* Senescence
* p57(Kip2)
|full-text-url=https://sci-hub.do/10.1016/j.scr.2020.101759
}}
==CDKN1A==
 
{{medline-entry
|title=Involvement of [[CDKN1A]] (p21) in cellular senescence in response to heat and irradiation stress during preimplantation development.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32253738
|abstract=This study examined the role of cyclin-dependent kinase inhibitor 1a (CDK1A, p21) in response to exogenous stressors during mouse preimplantation embryo development. [[CDKN1A]] knockdown (KD) one-cell zygotes were exposed to 39 °C heat stress (HS) for 4 days or irradiated by 1 (1-Gy) or 3 (3-Gy) Gy X-rays, and their developmental competence and gene expression were compared with control embryos. [[CDKN1A]] KD and HS did not influence early cleavage or subsequent embryonic development; however, HS delayed cavitation and induced elevated Cdkn1a expression in control embryos. Exposure to 1- or 3-Gy had no effect on development to the morula stage; however, a significant number of morulae failed to develop to the blastocyst stage. Interestingly, under the 1-Gy condition, the blastocyst rate of [[CDKN1A]] KD embryos (77.7%) was significantly higher than that of the controls (44.4%). In summary, exposure to cellular stressors resulted in the upregulation of Cdkn1a in embryos exposed to HS or X-ray irradiation, particularly in response to heat stress or low-dose X-ray irradiation, and depleting Cdkn1a mRNA alleviated cell cycle arrest. These findings suggest that [[CDKN1A]] plays a vital role in cellular senescence during preimplantation embryo development.
 
|keywords=* Cdkn1a
* Heat stress
* Irradiation
* Preimplantation
* Senescence
* p21
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193008
}}
==CFI==
 
{{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
}}
==CIT==
 
{{medline-entry
|title=The Relationship Between the Striatal Dopaminergic Neuronal and Cognitive Function With Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32184717
|abstract=Both cognitive function and striatal dopamine function decline by normal aging. However, the relationship among these three factors remains unclear. The aim of this study was to elucidate the association among age-related changes in the striatal dopamine transporter (DAT) and cognitive function in healthy subjects. The 30 healthy volunteers were enrolled in this research, the age ranged from 41 to 82 (64.5 ± 11.5, mean ± SD). All subjects were scanned with both T1-weighted magnetic resonance imaging (MRI) and I-FP-[[CIT]] single-photon emission computed tomography (SPECT) images. The Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) was used to evaluate cognitive function. Six spherical regions of interest (ROI) using 10 mm in diameter on the caudate nucleus, anterior putamen and posterior putamen were manually drawn on MRI image which was applied onto SPECT image. The relationship between striatal occipital ratio (SOR) values and WAIS-III subscore were analyzed by multiple regression analysis. Subscores which was significant were further analyzed by path analyses. Full intelligence quotient (IQ), verbal IQ, verbal comprehension were all positively correlated with age-adjusted striatal DAT binding ([i]P[/i] < 0.01). Multiple regression analyses revealed that the coding digit symbol correlated with all striatal regions except for the left caudate ([i]P[/i] < 0.04). Picture completion and right caudate, similarities and left caudate also showed a positive correlation ([i]P[/i] < 0.04). Path analysis found that the right caudate and picture completion; the left caudate and similarities were correlated independently from age, whereas the models of coding digit symbol were not significant. These results suggest that age-based individual diversity of striatal DAT binding was associated with verbal function, and the caudate nucleus plays an important role in this association.
 
|keywords=* SPECT
* Wechsler Adult Intelligence Scale
* aging
* cognitive function
* dopamine transporter
* verbal function
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058549
}}
==COPE==
 
{{medline-entry
|title=Patterns and characteristics of cognitive functioning in older patients approaching end stage kidney disease, the [[COPE]]-study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32272897
|abstract=The prevalence of impaired cognitive functioning in older patients with end stage kidney disease (ESKD) is high. We aim to describe patterns of memory, executive function or psychomotor speed and to identify nephrologic, geriatric and neuroradiologic characteristics associated with cognitive impairment in older patients approaching ESKD who have not yet started with renal replacement therapy (RRT). The [[COPE]]-study (Cognitive Decline in Older Patients with ESRD) is a prospective cohort study including 157 participants aged 65 years and older approaching ESKD (eGFR ≤20 ml/min/1.73 m ) prior to starting with RRT. In addition to routinely collected clinical parameters related to ESKD, such as vascular disease burden and parameters of metabolic disturbance, patients received a full geriatric assessment, including extensive neuropsychological testing. In a subgroup of patients (n = 93) a brain MRI was performed. The median age was 75.3 years. Compared to the normative data of neuropsychological testing participants memory performance was in the 24th percentile, executive function in the 18th percentile and psychomotor speed in the 20th percentile. Independent associated characteristics of impairment in memory, executive and psychomotor speed were high age, low educational level and low functional status (all p-values < 0.003). A history of vascular disease (p = 0.007) and more white matter hyperintensities on brain MRI (p = 0.013) were associated with a lower psychomotor speed. Older patients approaching ESKD have a high prevalence of impaired memory, executive function and psychomotor speed. The patterns of cognitive impairment and brain changes on MRI are suggestive of vascular cognitive impairment. These findings could be of potentially added value in the decision-making process concerning patients with ESKD.
 
|keywords=* Cognitive function
* End stage renal disease
* Geriatric assessment
* Geriatrics
* Older patients
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147053
}}
==CPM==
 
{{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
}}
==CRABP2==
 
{{medline-entry
|title=Preconception resveratrol intake against infertility: Friend or foe?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32273814
|abstract=Resveratrol is an antiaging, antioxidant, anti-inflammatory, and insulin-sensitizing natural polyphenolic compound. Growing evidence indicates that resveratrol has potential therapeutic effects in infertile women with diminished ovarian function, polycystic ovary syndrome (PCOS), or endometriosis. However, only one clinical trial in women undergoing in vitro fertilization (IVF) cycles using resveratrol has ever been reported. This review focuses on the potential therapeutic effects of resveratrol on pregnancy and on its advantages and disadvantages in pregnancy outcomes during infertility treatment. We performed a literature review to describe the known impacts of resveratrol on the ovary and endometrium. Resveratrol upregulates sirtuin (SIRT)1 expression in ovaries, which is associated with protection against oxidative stress. It leads to the activation of telomerase activity and mitochondrial function, improving ovarian function. In the endometrium, resveratrol downregulates the [[CRABP2]]-RAR pathway leading to suppressing decidual and senescent changes of endometrial cells, which is essential for embryo implantation and placentation. Moreover, resveratrol may also induce deacetylation of important decidual-related genes. Resveratrol has potential therapeutic effects for improving ovarian function; however, it also has anti-deciduogenic actions in uterine endometrium. In addition, its teratogenicity has not yet been ruled out; thus, resveratrol should be avoided during the luteal phase and pregnancy.


|keywords=* aging
|keywords=* aging
* dry eye
* assisted reproductive technology
* goblet cell
* infertility
* resveratrol
* sirtuin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138940
}}
==CRP==
 
{{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
* inflammation
* lacrimal gland
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7020308
* ocular surface
* rapamycin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727717
}}
}}
{{medline-entry
{{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.
|title=Intentional Switching Between Bimanual Coordination Patterns in Older Adults: Is It Mediated by Inhibition Processes?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33228213
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32132919
|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.
|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=* NAC
|keywords=* Stroop task
* T cells
* aging
* aging
* antioxidants
* bimanual coordination
* immunosenescence
* inhibition
* vaccination
* mediation analysis
* vitamin C
* switching
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699597
|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
}}
==CTSB==
 
{{medline-entry
|title=Myocardial cathepsin D is downregulated in sudden cardiac death.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32176724
|abstract=Cathepsins are the major lysosomal proteases that maintain intracellular homeostasis. Herein, we investigated the alterations in myocardial cathepsin expression during aging, cardiac hypertrophy, and sudden cardiac death (SCD). Cardiac tissue and blood were sampled from autopsy cases. Subjects were classified into three groups: SCD with cardiac hypertrophy (SCH), compensated cardiac hypertrophy (CCH), and control. Immunoblotting was performed for the major cardiac cathepsins and their targets: cathepsin B, D, and L ([[CTSB]]/D/L), p62, ATP synthase subunit c (ATPSC), and α-synuclein (ASNC). Immunohistochemical analysis and ELISA using serum samples were performed for CTSD. Cardiac [[CTSB]] and CTSD were upregulated with age (r = 0.63 and 0.60, respectively), whereas the levels of CTSL, p62, ATPSC, and ASNC remained unchanged. In age-matched groups, cardiac CTSD was significantly downregulated in SCH (p = 0.006) and CTSL was moderately downregulated in CCH (p = 0.021); however, p62, ATPSC, and ASNC were not upregulated in cardiac hypertrophy. Immunohistochemistry also revealed decreased myocardial CTSD levels in SCH, and serum CTSD levels were relatively lower in SCH cases. Overall, these results suggest that upregulation of cardiac [[CTSB]] and CTSD with age may compensate for the elevated proteolytic demand, and that downregulation of CTSD is potentially linked to SCH.
|mesh-terms=* Adult
* Aged
* Aged, 80 and over
* Aging
* Cathepsin D
* Death, Sudden, Cardiac
* Down-Regulation
* Female
* Humans
* Male
* Middle Aged
* Myocardium
* Substrate Specificity
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075574
}}
}}
==CX3CR1==
{{medline-entry
{{medline-entry
|title=Distinct Age-Related Epigenetic Signatures in [[CD4]] and CD8 T Cells.
|title=Monocytes present age-related changes in phospholipid concentration and decreased energy metabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33262764
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32107839
|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.
|abstract=Age-related changes at the cellular level include the dysregulation of metabolic and signaling pathways. Analyses of blood leukocytes have revealed a set of alterations that collectively lower their ability to fight infections and resolve inflammation later in life. We studied the transcriptomic, epigenetic, and metabolomic profiles of monocytes extracted from younger adults and individuals over the age of 65 years to map major age-dependent changes in their cellular physiology. We found that the monocytes from older persons displayed a decrease in the expression of ribosomal and mitochondrial protein genes and exhibited hypomethylation at the HLA class I locus. Additionally, we found elevated gene expression associated with cell motility, including the [[CX3CR1]] and ARID5B genes, which have been associated with the development of atherosclerosis. Furthermore, the downregulation of two genes, PLA2G4B and ALOX15B, which belong to the arachidonic acid metabolism pathway involved in phosphatidylcholine conversion to anti-inflammatory lipoxins, correlated with increased phosphatidylcholine content in monocytes from older individuals. We found age-related changes in monocyte metabolic fitness, including reduced mitochondrial function and increased glycose consumption without the capacity to upregulate it during increased metabolic needs, and signs of increased oxidative stress and DNA damage. In conclusion, our results complement existing findings and elucidate the metabolic alterations that occur in monocytes during aging.


|keywords=* T-cell
|keywords=* DNA methylation
* T-cell homeostasis
* aging
* aging
* chromatin accessibility
* glucose metabolism
* epigenetics
* monocytes
* ribosomal proteins
* phosphatidylcholines
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686576
* transcriptome
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189998
}}
{{medline-entry
|title=Muscle Injury Induces Postoperative Cognitive Dysfunction.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32066806
|abstract=Postoperative cognitive dysfunction (POCD) is a major complication affecting patients of any age undergoing surgery. This syndrome impacts everyday life up to months after hospital discharge, and its pathophysiology still remains unclear. Translational research focusing on POCD is based on a wide variety of rodent models, such as the murine tibial fracture, whose severity can limit mouse locomotion and proper behavioral assessment. Besides, influence of skeletal muscle injury, a lesion encountered in a wide range of surgeries, has not been explored in POCD occurrence. We propose a physical model of muscle injury in [[CX3CR1]]  mice (displaying green fluorescent microglial cells) to study POCD, with morphological, behavioral and molecular approaches. We highlighted: alteration of short- and long-term memory after muscle regeneration, wide microglial reactivity in the brain, including hippocampus area, 24 hours after muscle injury, and an alteration of central brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) balance, 28 days after muscle injury. Our results suggest for the first time that muscle injury can have early as well as late impacts on the brain. Our [[CX3CR1]]  model can also facilitate microglial investigation, more specifically their pivotal role in neuroinflammation and synaptic plasticity, in the pathophysiology of POCD.
|mesh-terms=* Aging
* Animals
* Brain
* Brain-Derived Neurotrophic Factor
* CX3C Chemokine Receptor 1
* Cytokines
* Disease Models, Animal
* Hippocampus
* Humans
* Male
* Mice
* Microglia
* Muscle, Skeletal
* Nerve Growth Factor
* Postoperative Cognitive Complications
* Postoperative Complications
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026159
}}
==CYP2E1==
 
{{medline-entry
|title=DNA methylation and histone acetylation changes to cytochrome P450 2E1 regulation in normal aging and impact on rates of drug metabolism in the liver.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32221779
|abstract=Aging is associated with reduced liver function that may increase the risk for adverse drug reactions in older adults. We hypothesized that age-related changes to epigenetic regulation of genes involved in drug metabolism may contribute to this effect. We reviewed published epigenome-wide studies of human blood and identified the cytochrome P450 2E1 ([[CYP2E1]]) gene as a top locus exhibiting epigenetic changes with age. To investigate potential functional changes with age in the liver, the primary organ of drug metabolism, we obtained liver tissue from mice aged 4-32 months from the National Institute on Aging. We assayed global DNA methylation (5-methylcytosine, 5mC), hydroxymethylation (5-hydroxymethylcytosine, 5hmC), and locus-specific 5mC and histone acetylation changes around mouse Cyp2e1. The mouse livers exhibit significant global decreases in 5mC and 5hmC with age. Furthermore, 5mC significantly increased with age at two regulatory regions of Cyp2e1 in tandem with decreases in its gene and protein expressions. H3K9ac levels also changed with age at both regulatory regions of Cyp2e1 investigated, while H3K27ac did not. To test if these epigenetic changes are associated with varying rates of drug metabolism, we assayed clearance of the [[CYP2E1]]-specific probe drug chlorzoxazone in microsome extracts from the same livers. [[CYP2E1]] intrinsic clearance is associated with DNA methylation and H3K9ac levels at the Cyp2e1 locus but not with chronological age. This suggests that age-related epigenetic changes may influence rates of hepatic drug metabolism. In the future, epigenetic biomarkers could prove useful to guide dosing regimens in older adults.
 
|keywords=* Aging
* Cyp2e1
* DNA methylation
* Drug metabolism
* Histone acetylation
* Pharmacokinetics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287002
}}
==DCX==
 
{{medline-entry
|title=Doublecortin and IGF-1R protein levels are reduced in spite of unchanged DNA methylation in the hippocampus of aged rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32236698
|abstract=The aim of the current study was to investigate whether doublecortin ([[DCX]]), insulin-like growth factor receptor 1 (IGF-1R) and metabotropic glutamate receptor 5 (mGluR5) levels are indeed modified in the aging rat hippocampal individual subareas (rather than total hippocampal tissue as in previous reports) at the protein and mRNA level and whether the methylation status contributes to these changes. Since the aging population is not homogeneous in terms of spatial memory performance, we examined whether changes in [[DCX]], IGF-1R and mGluR5 are linked to cognitive aging. Aged (22 months) male Sprague Dawley rats were trained in the hole-board, a spatial memory task, and were subdivided according to performance to aged impaired and aged unimpaired groups. Age- and memory performance-dependent changes in mRNA steady-state levels, protein levels and DNA methylation status of [[DCX]], IGF-1R and mGluR5 were evaluated by RT-PCR, immunoblotting and bisulfite pyrosequencing. Extending previous findings, we detected decreased [[DCX]] protein and mRNA levels in dentate gyrus (DG) of aged animals. IGF-1 signaling is a key event and herein we show that mRNA levels for IGF-1R were unchanged although reduced at the protein level. This finding may simply reflect that these protein levels are regulated at the level of protein synthesis as well as protein degradation. We provide evidence that promoter methylation is not involved in regulation of mRNA and protein levels of [[DCX]], IGF-1R and mGluR5 during aging. Moreover, there was no significant difference between aged rats with impaired and aged rats with unimpaired memory at the protein and mRNA level. Findings propose that changes in the abovementioned protein levels may not be relevant for performance in the spatial memory task used in aged rats.
 
|keywords=* Aging
* DNA methylation
* Doublecortin
* Hippocampus
* IGF-1R
* mGluR5
|full-text-url=https://sci-hub.do/10.1007/s00726-020-02834-3
}}
}}
==DKC1==
{{medline-entry
{{medline-entry
|title=Identification of Key Genes and Potential New Biomarkers for Ovarian Aging: A Study Based on RNA-Sequencing Data.
|title=Successful liver transplantation in short telomere syndromes without bone marrow failure due to [[DKC1]] mutation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33304387
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32166868
|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.
|abstract=Short telomere syndromes are a heterogenous spectrum of disorders leading to premature cellular aging. These may involve bone marrow failure, adult-onset idiopathic pulmonary fibrosis, and liver disease, and classical entities such as dyskeratosis congenita. We report a patient who presented with common variable immunodeficiency at 3 years of age and autoimmune cytopenias at 8 years of age. He was found to have short telomeres, and genetic testing confirmed a hemizygous mutation NM_001363.4: c.-142C > G in [[DKC1]] gene. He subsequently developed cirrhosis with severe portal hypertension and hepatopulmonary syndrome, prompting liver transplantation at 11 years of age. He remains well 10 years after transplant with no progression of bone marrow failure or progressive lung disease. In conclusion, short telomere syndromes should be considered as a potential cause of pediatric liver disease of unknown etiology, and in severe cases, isolated liver transplantation may be both appropriate and successful.


|keywords=* GEO database
|keywords=* DKC1
* bioinformatics
* cell death: senescence
* biomarker
* cirrhosis
* immune cell infiltration
* hepatopulmonary syndrome
* ovarian aging
* liver transplantation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7701310
* short telomere syndromes
|full-text-url=https://sci-hub.do/10.1111/petr.13695
}}
}}
==CPNE1==
==DMD==


{{medline-entry
{{medline-entry
|title=Prevalent intron retention fine-tunes gene expression and contributes to cellular senescence.
|title=Aldehyde dehydrogenases contribute to skeletal muscle homeostasis in healthy, aging, and Duchenne muscular dystrophy patients.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33274830
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32157826
|abstract=Intron retention (IR) is the least well-understood alternative splicing type in animals, and its prevalence and function in physiological and pathological processes have long been underestimated. Cellular senescence contributes to individual aging and age-related diseases and can also serve as an important cancer prevention mechanism. Dynamic IR events have been observed in senescence models and aged tissues; however, whether and how IR impacts senescence remain unclear. Through analyzing polyA RNA-seq data from human replicative senescence models, we found IR was prevalent and dynamically regulated during senescence and IR changes negatively correlated with expression alteration of corresponding genes. We discovered that knocking down (KD) splicing factor U2AF1, which showed higher binding density to retained introns and decreased expression during senescence, led to senescence-associated phenotypes and global IR changes. Intriguingly, U2AF1-KD-induced IR changes also negatively correlated with gene expression. Furthermore, we demonstrated that U2AF1-mediated IR of specific gene ([[CPNE1]] as an example) contributed to cellular senescence. Decreased expression of U2AF1, higher IR of [[CPNE1]], and reduced expression of [[CPNE1]] were also discovered in dermal fibroblasts with age. We discovered prevalent IR could fine-tune gene expression and contribute to senescence-associated phenotypes, largely extending the biological significance of IR.
|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=* CPNE1
|keywords=* Aging
* U2AF1
* Aldehyde dehydrogenase
* intron retention
* 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
}}
==DNAJB9==
 
{{medline-entry
|title=[[DNAJB9]] Inhibits p53-Dependent Oncogene-Induced Senescence and Induces Cell Transformation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32264658
|abstract=[i][[DNAJB9]][/i] is known to be a member of the molecular chaperone gene family, whose cellular function has not yet been fully characterized. Here, we investigated the cellular function of [[DNAJB9]] under strong mitogenic signals. We found that [[DNAJB9]] inhibits p53-dependent oncogene-induced senescence (OIS) and induces neoplastic transformation under oncogenic RAS activation in mouse primary fibroblasts. In addition, we observed that [[DNAJB9]] interacts physically with p53 under oncogenic RAS activation and that the p53-interacting region of [[DNAJB9]] is critical for the inhibition of p53-dependent OIS and induction of neoplastic transformation by [[DNAJB9]]. These results suggest that [[DNAJB9]] induces cell transformation under strong mitogenic signals, which is attributable to the inhibition of p53-dependent OIS by physical interactions with p53. This study might contribute to our understanding of the cellular function of [[DNAJB9]] and the molecular basis of cell transformation.
 
|keywords=* DNAJB9
* RAS
* p53
* senescence
* senescence
* splicing factor
* transformation
|full-text-url=https://sci-hub.do/10.1111/acel.13276
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191047
}}
}}
==CRP==
==DNMT3L==


{{medline-entry
{{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.
|title=Transient [[DNMT3L]] Expression Reinforces Chromatin Surveillance to Halt Senescence Progression in Mouse Embryonic Fibroblast.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33284965
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32195249
|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.
|abstract=Global heterochromatin reduction, which is one of the hallmarks of senescent cells, is associated with reduced transposable element repression and increased risk of chromatin instability. To ensure genomic integrity, the irreparable cells in a population exit permanently from the cell cycle, and this process is termed "senescence." However, senescence only blocks the expansion of unwanted cells, and the aberrant chromatin of senescent cells remains unstable. Serendipitously, we found that the transient ectopic expression of a repressive epigenetic modulator, DNA methyltransferase 3-like ([[DNMT3L]]) was sufficient to delay the premature senescence progression of late-passage mouse embryonic fibroblasts (MEFs) associated with a tightened global chromatin structure. [[DNMT3L]] induces more repressive H3K9 methylation on endogenous retroviruses and downregulates the derepressed transposons in aging MEFs. In addition, we found that a pulse of ectopic [[DNMT3L]] resulted in the reestablishment of H3K27me3 on polycomb repressive complex 2 (PRC2)-target genes that were derepressed in old MEFs. We demonstrated that ectopic [[DNMT3L]] interacted with PRC2 in MEFs. Our data also suggested that ectopic [[DNMT3L]] might guide PRC2 to redress deregulated chromatin regions in cells undergoing senescence. This study might lead to an epigenetic reinforcement strategy for overcoming aging-associated epimutation and senescence.
 
|keywords=* DNA methyltransferase 3-like (DNMT3L)
* chromatin surveillance
* epigenetics
* polycomb repressive complex 2 (PRC2)
* senescence
* transposable element (TE)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064442
}}
==DOCK11==


|keywords=* Muscle wasting
{{medline-entry
* aging
|title=[Immunosenescence: The Forefront of Infection and Trophic Control].
* anabolic resistance
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32115558
* inflammation
|abstract=Recently, aging is becoming an important social problem in many developed countries including Japan. It is socially and universally important to unveil the impact of aging and extend healthy life expectancy. Here we show our recent finding that dedicator of cytokinesis 11 ([[DOCK11]], also known as Zizimin2) may be involved in immunosenescence of B cells. [[DOCK11]] was identified as a guanine nucleotide exchange factor for a small GTPase called cell division cycle 42. Expression of [[DOCK11]] is restricted to lymphoid tissues, and becomes downregulated with age. Thus we examined the involvement of [[DOCK11]] in immunosenescence of B-1a B cells as an example. B-1a cells are the main source of antibodies at steady state, and function as the first line of defense against infection. Although [[DOCK11]] was expressed by B-1a cells, the expression levels declined with age. Furthermore, production of anti-pneumococcal immunoglobulin M antibodies was suppressed in aged mice, and was recovered by adoptive transfer with B-1a cells in a [[DOCK11]]-dependent manner. Thus [[DOCK11]] may be involved in immunosenescence of B-1a cells.
* resistance training
|mesh-terms=* Aging
* sarcopenia
* Animals
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa309
* B-Lymphocytes
* Cytokinesis
* Gene Expression
* Guanine Nucleotide Exchange Factors
* Humans
* Immunoglobulin M
* Immunosenescence
* Mice
* Nutritional Status
* Streptococcus pneumoniae
|keywords=* B-1a B cell
* dedicator of cytokinesis 11
* immunosenescence
|full-text-url=https://sci-hub.do/10.1248/yakushi.19-00193-3
}}
}}
==CTSA==
==DPP4==


{{medline-entry
{{medline-entry
|title=A [[CTSA]]-based consultation service to advance research on special and underserved populations.
|title=Dipeptidyl peptidase-4 inhibition improves endothelial senescence by activating AMPK/SIRT1/Nrf2 signaling pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33244406
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32251672
|abstract=In this report, we describe the implementation and short-term outcomes of a Special Populations Consultation Service within the University of California, Los Angeles (UCLA) Clinical and Translational Science Institute (CTSI). With the goal of increasing the quality and quantity of special population (SP) research, the UCLA CTSI Integrating Special Populations program designed a consultation service to support faculty and trainees conducting research involving one of three CTSI "special populations:" children, older adults, and/or minority; underserved; or health disparity populations. The Special Populations Consultation Service offers three types of activities: grant proposal studios, career consultations, and project reviews. UCLA CTSI faculty with appropriate content expertise serve as consultants. We evaluated this consultation model using satisfaction surveys and by quantifying funded grants and reported changes in career goals in SP research. Between 2016 and 2019, the Special Populations Consultation Service provided 59 consultations including 42 grant studios and was used by researchers at all levels from all four UCLA CTSI institutions. Recipients rated the consultations very highly. Funding success rates were 57% following K-level grant studios and 28% following R-level grant studios. Users of project and career consultations commonly attributed career accomplishments in part to their consultation experiences. The SP Consultation Service is feasible and acceptable and appears to enhance careers of investigators studying special populations.
|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=* faculty development
|keywords=* Aging
* geriatrics
* Dipeptidyl peptidase-4
* grant review
* Endothelium
* grant studio
* Oxidative stress
* pediatrics
* Vascular
* peer review
|full-text-url=https://sci-hub.do/10.1016/j.bcp.2020.113951
* research consultation service
* special populations
* underrepresented minorities
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7681147
}}
}}
==CXCL14==
==DST==


{{medline-entry
{{medline-entry
|title=Identification of genes associated with endometrial cell aging.
|title=Ancestral germen/soma distinction in microbes: Expanding the disposable soma theory of aging to all unicellular lineages.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33258951
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32268207
|abstract=Aging of the uterine endometrium is a critical factor that affects reproductive success, but the mechanisms associated with uterine aging are unclear. In this study, we conducted a qualitative examination of age-related changes in endometrial tissues and identified candidate genes as markers for uterine aging. Gene expression patterns were assessed by two RNA sequencing experiments using uterine tissues from wild type (WT) C57BL/6 mice. Gene expression data obtained by RNA-sequencing were validated by real-time PCR. Genes expressing the pro-inflammatory cytokines Il17rb and chemokines Cxcl12 and Cxcl14 showed differential expression between aged WT mice and a group of mice composed of 5 and 8 week-old WT (young) animals. Protein expression levels of the above-mentioned genes and of IL8, which functions downstream of IL17RB, were analysed by quantitative immunohistochemistry of unaffected human endometrium tissue samples from patients in their 20 s and 40 s (10 cases each). In the secretory phase samples, 3,3'- diaminobenzidine (DAB) staining intensities of IL17RB, CXCL12 and [[CXCL14]] for patients in their 40 s were significantly higher than that for patients in their 20 s, as detected by a Mann Whitney U test. These results suggest that these genes are candidate markers for endometrial aging and for prediction of age-related infertility, although confirmation of these findings is needed in larger studies involving fertile and infertile women.
|abstract=Life has persisted for about 3.5 billion years (Gy) despite fluctuating environmental pressures and the aging and mortality of individuals. The disposable soma theory ([[DST]]) notoriously contributes to explain this persistence for lineages with a clear soma/germen distinction. Beyond such lineages however, the phylogenetic scope of application of the [[DST]] is less obvious. Typically, the [[DST]] is not expected to explain the survival of microbial species that comprise single-celled organisms apparently lacking a germen/soma distinction. Here, we present an evolutionary argument that generalizes the explanatory scope of [[DST]] to the entire microbial world and provides a novel characterization of the deep molecular and evolutionary roots supporting this expanded disposable soma theory of aging. Specifically, we argue that the germen/soma distinction arose early in evolution and identify DNA semi-conservative replication as a critical process through which two forms of rejuvenation could have evolved in the first microbes. Our hypothesis has fundamental and practical implications. First, whereas unicellular organisms were long thought of as potentially immortal, we suggest instead that all unicellular individuals (prokaryotes or protists alike) are very likely to age, either replicatively or physiologically, or both. Second, our theory introduces a profound reconsideration of microbial individuality, whereby, all microbial individuals, as seen by natural selection, present an obligate transient germen/soma distinction during their life cycles. Third, our work promotes the study of cellular division in prokaryotes and in protist mitosis to illuminate the evolutionary origin of the soma and germen division, traditionally studied in animals. These ideas set the stage for progress in the evolutionary theory of aging from a heretofore overlooked microbial perspective.
|mesh-terms=* Aging
* Animals
* Biological Evolution
* DNA Replication
* Humans
* Phylogeny
|keywords=* Aging
* Asymmetric cell division
* DNA replication
* Disposable Soma Theory
* Epigenetics
* Evolution
* Germen/Soma
* Prokaryotes
* Protists
* Rejuvenation
* Unicellular
|full-text-url=https://sci-hub.do/10.1016/j.arr.2020.101064
}}
==EGF==


|keywords=* CXCL12
{{medline-entry
* CXCL14
|title=Insulin Signaling in Intestinal Stem and Progenitor Cells as an Important Determinant of Physiological and Metabolic Traits in [i]Drosophila[/i].
* IL17RB
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32225024
* endometrial cell aging
|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.
* infertility
 
* quantitative
|keywords=* ISC
immunohistochemistry
* fruit fly
|full-text-url=https://sci-hub.do/10.1093/molehr/gaaa078
* insulin signaling pathway
* lifespan
* metabolism
* midgut
* progenitor cells
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226132
}}
==EGFR==
 
{{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
|keywords=#f
|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
}}
}}
==DCN==
==EHF==


{{medline-entry
{{medline-entry
|title=Decorin inhibits the insulin-like growth factor I signaling in bone marrow mesenchymal stem cells of aged humans.
|title=Extended high frequency hearing and speech perception implications in adults and children.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33257596
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32111404
|abstract=Aging impairs the IGF-I signaling of bone marrow mesenchymal stem cells (bmMSCs), but the mechanism is unclear. Here, we found that the ability to auto-phosphorylate IGF-I receptor (IGF-IR) in response to IGF-I was decreased in the bmMSCs of aged donors. Conversely, data showed that decorin ([[DCN]]) expression was prominently increased in aged bmMSCs, and that under IGF-I treatment, [[DCN]] knockdown in serum-starved aged bmMSCs potentiated their mitogenic activity and IGF-IR auto-phosphorylation, whereas [[DCN]] overexpression in serum-starved adult bmMSCs decreased both activities. Co-immunoprecipitation assays suggested that IGF-I and [[DCN]] bound to IGF-IR in a competitive manner. Online MethPrimer predicted 4 CpG islands (CGIs) in the introns of [i][[DCN]][/i] gene. RT-qPCR and bisulfite sequencing showed that dimethyloxalylglycine, an inhibitor of DNA demethylation, increased [i][[DCN]][/i] mRNA expression and CGI-I methylation in adult bmMSCs, whereas 5-aza-2'-deoxycytidine, a DNA methylation inhibitor, decreased [i][[DCN]][/i] mRNA expression and CGI-I methylation in aged bmMSCs, and ultimately enhanced the proliferation of serum-starved aged bmMSCs under IGF-I stimulation. Thus, IGF-IR could be the prime target of aging in down-regulating the IGF-I signaling of bmMSCs, where [[DCN]] could be a critical mediator.
|abstract=Extended high frequencies ([[EHF]]), above 8 kHz, represent a region of the human hearing spectrum that is generally ignored by clinicians and researchers alike. This article is a compilation of contributions that, together, make the case for an essential role of [[EHF]] in both normal hearing and auditory dysfunction. We start with the fundamentals of biological and acoustic determinism - humans have [[EHF]] hearing for a purpose, for example, the detection of prey, predators, and mates. [[EHF]] hearing may also provide a boost to speech perception in challenging conditions and its loss, conversely, might help explain difficulty with the same task. However, it could be that [[EHF]] are a marker for damage in the conventional frequency region that is more related to speech perception difficulties. Measurement of [[EHF]] hearing in concert with otoacoustic emissions could provide an early warning of age-related hearing loss. In early life, when [[EHF]] hearing sensitivity is optimal, we can use it for enhanced phonetic identification during language learning, but we are also susceptible to diseases that can prematurely damage it. [[EHF]] audiometry techniques and standardization are reviewed, providing evidence that they are reliable to measure and provide important information for early detection, monitoring and possible prevention of hearing loss in populations at-risk. To better understand the full contribution of [[EHF]] to human hearing, clinicians and researchers can contribute by including its measurement, along with measures of speech in noise and self-report of hearing difficulties and tinnitus in clinical evaluations and studies.
 
|keywords=* Aging
* Development
* Extended high frequency audiometry
* Otitis media
* Ototoxicity
* Speech in noise
* Speech perception
* Tinnitus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431381
}}
==ERCC1==


|keywords=* IGF-I
{{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
* aging
* bone marrow mesenchymal stem cell
* endothelial dysfunction
* osteoporosis
* endothelium-dependent dilation
* small leucine-rich proteoglycan
* nitric oxide
|full-text-url=https://sci-hub.do/10.18632/aging.202166
|full-text-url=https://sci-hub.do/10.1042/CS20190124
}}
==F3==
 
{{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
}}
==FAAH==
 
{{medline-entry
|title=Endocannabinoid genetic variation enhances vulnerability to THC reward in adolescent female mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32095523
|abstract=Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ -tetrahydrocannabinol (THC). Using a genetic knock-in mouse model ([[FAAH]] ) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this [[FAAH]] polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female [[FAAH]]  mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.
|mesh-terms=* Aging
* Amidohydrolases
* Animals
* Axons
* Choice Behavior
* Dronabinol
* Endocannabinoids
* Female
* Genetic Variation
* Male
* Mice, Inbred C57BL
* Nerve Net
* Nucleus Accumbens
* Polymorphism, Single Nucleotide
* Receptor, Cannabinoid, CB1
* Reward
* Tyrosine 3-Monooxygenase
* Ventral Tegmental Area
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015690
}}
}}
==EDF1==
==FAS==


{{medline-entry
{{medline-entry
|title=Silencing of FOREVER YOUNG FLOWER Like Genes from Phalaenopsis Orchids Promotes Flower Senescence and Abscission.
|title=Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33237274
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32064756
|abstract=Ectopic expression of FOREVER YOUNG FLOWER (FYF) delays floral senescence and abscission in transgenic Arabidopsis. To analyze the FYF function in Phalaenopsis orchids, two FYF-like genes (PaFYF1/2) were identified. PaFYF1/2 were highly expressed in young Phalaenopsis flowers, and their expression decreased significantly afterward until flower senescence. This pattern was strongly correlated with the process of flower senescence and revealed that PaFYF1/2 function to suppress senescence/abscission during early flower development. Interestingly, in flowers, PaFYF1 was consistently expressed less in petals than in lips/sepals, whereas PaFYF2 was expressed relatively evenly in all flower organs. This difference suggests a regulatory modification of the functions of PaFYF1 and PaFYF2 during Phalaenopsis flower evolution. Delayed flower senescence and abscission, which were unaffected by ethylene treatment, were observed in 35S::PaFYF1/2 and 35S::PaFYF1/2+SRDX transgenic Arabidopsis plants due to downregulation of the ethylene signaling and abscission-associated genes [[EDF1]]-4, IDA and BOP1/2. These results suggest a possible repressor role for Phalaenopsis PaFYF1/2 in controlling floral senescence/abscission by suppressing ethylene signaling and abscission-associated genes. To further validate the function of PaFYF1/2, PaFYF1/2-VIGS (virus-induced gene silencing) Phalaenopsis were generated and analyzed. Promotion of senescence and abscission was observed in PaFYF1/2-VIGS Phalaenopsis flowers by the upregulation of Pe[[EDF1]]/2, PeSAG39 and PeBOP1/2 expression, early occurrence of greening according to their increased chlorophyll content and reduction of water content in flower organs. Our results support that PaFYF1/2 function as transcriptional repressors to prohibit flower senescence and abscission in Phalaenopsis.
|abstract=The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin-proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and [[FAS]] and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.


|keywords=*  
|keywords=* MDM2
          FOREVER YOUNG FLOWER
       
*
          Phalaenopsis orchids
* Abscission
* Ethylene responses
* MADS-box gene
* Senescence
* Senescence
|full-text-url=https://sci-hub.do/10.1093/pcp/pcaa145
* USP7
* apoptosis
* p53
* senolytics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059172
}}
==FES==
 
{{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
}}
}}
==EGF==
==FEV==


{{medline-entry
{{medline-entry
|title=Acute, exercise-induced alterations in cytokines and chemokines in the blood distinguish physically active and sedentary aging.
|title=Current Bronchodilator Responsiveness Criteria Underestimate Asthma in Older Adults.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33289019
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32071132
|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.
|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=* growth factors
|keywords=* aging
* human aging
* albuterol
* inflammation
* asthma
* physical activity
* bronchodilator effect
|full-text-url=https://sci-hub.do/10.1093/gerona/glaa310
* lung diseases
* older adult
* spirometry
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538007
}}
}}
==F3==
==FGF19==


{{medline-entry
{{medline-entry
|title=A Comprehensive Analysis of Age and Gender Effects in European Portuguese Oral Vowels.
|title=Bile acid receptor agonists in primary biliary cholangitis: Regulation of the cholangiocyte secretome and downstream T cell differentiation.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33293174
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32123836
|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.
|abstract=Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease. Approximately 30% of patients do not respond to therapy with ursodeoxycholic acid (UDCA). Previous studies have implicated increased senescence of cholangiocytes in patients who do not respond to UDCA. This may increase the release of cytokines which drive pathogenic T cell polarization. As FXR agonists are beneficial in treating UDCA non-responsive patients, the current study was designed to model the interactions between cholangiocytes and CD4+ T cells to investigate potential immunomodulatory mechanisms of bile acid receptor agonists. Human cholangiocytes were co-cultured with CD4+ T cells to model the biliary stress response. Senescent cholangiocytes were able to polarize T cells toward a Th17 phenotype and suppressed expression of FoxP3 ([i]P[/i] = 0.0043). Whilst FXR and TGR5 receptor agonists were unable directly to alter cholangiocyte cytokine expression, [[FGF19]] was capable of significantly reducing IL-6 release ([i]P[/i] = 0.044). Bile acid receptor expression was assessed in PBC patients with well-characterized responsiveness to UDCA therapy. A reduction in FXR staining was observed in both cholangiocytes and hepatocytes in PBC patients without adequate response to UDCA. Increased IL-6 expression by senescent cholangiocytes represents a potential mechanism by which biliary damage in PBC could contribute to excessive inflammation.


|keywords=* Acoustic
|keywords=* FGF19
* Aging voice
* FXR
* European Portuguese
* TGR5
* Oral vowel
* autoimmunity
|full-text-url=https://sci-hub.do/10.1016/j.jvoice.2020.10.021
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996327
}}
}}
==FES==
==FGFR1==


{{medline-entry
{{medline-entry
|title=An outpatient Tai Chi program: Effects on veterans' functional outcomes.
|title=Satellite cell-specific ablation of Cdon impairs integrin activation, FGF signalling, and muscle regeneration.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33241873
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32103583
|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.
|abstract=Perturbation in cell adhesion and growth factor signalling in satellite cells results in decreased muscle regenerative capacity. Cdon (also called Cdo) is a component of cell adhesion complexes implicated in myogenic differentiation, but its role in muscle regeneration remains to be determined. We generated inducible satellite cell-specific Cdon ablation in mice by utilizing a conditional Cdon allele and Pax7  . To induce Cdon ablation, mice were intraperitoneally injected with tamoxifen (tmx). Using cardiotoxin-induced muscle injury, the effect of Cdon depletion on satellite cell function was examined by histochemistry, immunostaining, and 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. Isolated myofibers or myoblasts were utilized to determine stem cell function and senescence. To determine pathways related to Cdon deletion, injured muscles were subjected to RNA sequencing analysis. Satellite cell-specific Cdon ablation causes impaired muscle regeneration with fibrosis, likely attributable to decreased proliferation, and senescence, of satellite cells. Cultured Cdon-depleted myofibers exhibited 32 ± 9.6% of EdU-positive satellite cells compared with 58 ± 4.4% satellite cells in control myofibers (P < 0.05). About 32.5 ± 3.7% Cdon-ablated myoblasts were positive for senescence-associated β-galactosidase (SA-β-gal) while only 3.6 ± 0.5% of control satellite cells were positive (P < 0.001). Transcriptome analysis of muscles at post-injury Day 4 revealed alterations in genes related to mitogen-activated protein kinase signalling (P < 8.29 e  ) and extracellular matrix (P < 2.65 e  ). Consistent with this, Cdon-depleted tibialis anterior muscles had reduced phosphorylated extracellular signal-regulated kinase (p-ERK) protein levels and expression of ERK targets, such as Fos (0.23-fold) and Egr1 (0.31-fold), relative to mock-treated control muscles (P < 0.001). Cdon-depleted myoblasts exhibited impaired ERK activation in response to basic fibroblast growth factor. Cdon ablation resulted in decreased and/or mislocalized integrin β1 activation in satellite cells (weak or mislocalized integrin1 in tmx = 38.7 ± 1.9%, mock = 21.5 ± 6%, P < 0.05), previously linked with reduced fibroblast growth factor (FGF) responsiveness in aged satellite cells. In mechanistic studies, Cdon interacted with and regulated cell surface localization of [[FGFR1]] and FGFR4, likely contributing to FGF responsiveness of satellite cells. Satellite cells from a progeria model, Zmpste24  myofibers, showed decreased Cdon levels (Cdon-positive cells in Zmpste24  = 63.3 ± 11%, wild type = 90 ± 7.7%, P < 0.05) and integrin β1 activation (weak or mislocalized integrin β1 in Zmpste24  = 64 ± 6.9%, wild type = 17.4 ± 5.9%, P < 0.01). Cdon deficiency in satellite cells causes impaired proliferation of satellite cells and muscle regeneration via aberrant integrin and FGFR signalling.


|keywords=* Tai Chi
|keywords=* Cdon
* balance
* Cellular senescence
* exercise
* FGFR
* gait
* Growth factor signalling
* geriatrics
* Muscle regeneration
|full-text-url=https://sci-hub.do/10.1111/nuf.12532
* Satellite cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7432598
}}
}}
==FH==
==FH==


{{medline-entry
{{medline-entry
|title=Genetic Factors of Alzheimer's Disease Modulate How Diet is Associated with Long-Term Cognitive Trajectories: A UK Biobank Study.
|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/33252089
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32118768
|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.
|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
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7478422
}}
==FOS==


|keywords=* APOE4
{{medline-entry
* Aging
|title=Muscle atrophy-related myotube-derived exosomal microRNA in neuronal dysfunction: Targeting both coding and long noncoding RNAs.
* Mediterranean diet
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32233025
* cognitive decline
|abstract=In mammals, microRNAs can be actively secreted from cells to blood. miR-29b-3p has been shown to play a pivotal role in muscle atrophy, but its role in intercellular communication is largely unknown. Here, we showed that miR-29b-3p was upregulated in normal and premature aging mouse muscle and plasma. miR-29b-3p was also upregulated in the blood of aging individuals, and circulating levels of miR-29b-3p were negatively correlated with relative appendicular skeletal muscle. Consistently, miR-29b-3p was observed in exosomes isolated from long-term differentiated atrophic C2C12 cells. When C2C12-derived miR-29b-3p-containing exosomes were uptaken by neuronal SH-SY5Y cells, increased miR-29b-3p levels in recipient cells were observed. Moreover, miR-29b-3p overexpression led to downregulation of neuronal-related genes and inhibition of neuronal differentiation. Interestingly, we identified HIF1α-AS2 as a novel c-[[FOS]] targeting lncRNA that is induced by miR-29b-3p through down-modulation of c-[[FOS]] and is required for miR-29b-3p-mediated neuronal differentiation inhibition. Our results suggest that atrophy-associated circulating miR-29b-3p may mediate distal communication between muscle cells and neurons.
* functional food
 
* lamb
|keywords=* HIF-1α-AS2
* nutrition policy
* aging
* preventive medicine
* lncRNAs
* red wine
* miR-29b-3p
* salt
* muscle atrophy
|full-text-url=https://sci-hub.do/10.3233/JAD-201058
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253071
}}
}}
==FOXO3==
==FOSL2==


{{medline-entry
{{medline-entry
|title=The DNA methylation of [[FOXO3]] and TP53 as a blood biomarker of late-onset asthma.
|title=LncRNA GUARDIN suppresses cellular senescence through a LRP130-PGC1α-FOXO4-p21-dependent signaling axis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33298101
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32149459
|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.
|abstract=The long noncoding RNA GUARDIN functions to protect genome stability. Inhibiting GUARDIN expression can alter cell fate decisions toward senescence or apoptosis, but the underlying molecular signals are unknown. Here, we show that GUARDIN is an essential component of a transcriptional repressor complex involving LRP130 and PGC1α. GUARDIN acts as a scaffold to stabilize LRP130/PGC1α heterodimers and their occupancy at the FOXO4 promotor. Destabilizing this complex by silencing of GUARDIN, LRP130, or PGC1α leads to increased expression of FOXO4 and upregulation of its target gene p21, thereby driving cells into senescence. We also found that GUARDIN expression was induced by rapamycin, an agent that suppresses cell senescence. FOS-like antigen 2 ([[FOSL2]]) acts as a transcriptional repressor of GUARDIN, and lower [[FOSL2]] levels in response to rapamycin correlate with increased levels of GUARDIN. Together, these results demonstrate that GUARDIN inhibits p21-dependent senescence through a LRP130-PGC1α-FOXO4 signaling axis, and moreover, GUARDIN contributes to the anti-aging activities of rapamycin.


|keywords=* Aging
|keywords=*  
* DNA methylation
GUARDIN
* FOXO3
 
* Late-onset asthma
* LRP130-PGC1α
* TP53
* cellular senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726856
* lncRNAs
* p21
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132339
}}
}}
==FOXP1==
==FSHR==


{{medline-entry
{{medline-entry
|title=GATA6 regulates aging of human mesenchymal stem/stromal cells.
|title=[[FSHR]] ablation induces depression-like behaviors.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33252174
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32203083
|abstract=Cellular reprogramming forcing the expression of pluripotency markers can reverse aging of cells but how molecular mechanisms through which reprogrammed cells alter aging-related cellular activities still remain largely unclear. In this study, we reprogrammed human synovial fluid-derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs) using six reprogramming factors and reverted the iPSCs back to MSCs, as an approach to cell rejuvenation. Using the parental and reprogrammed MSCs as control nonrejuvenated and rejuvenated cells, respectively, for comparative analysis, we found that aging-related activities were greatly reduced in reprogrammed MSCs compared with those in their parental lines, indicating reversal of cell aging. Global transcriptome analysis revealed differences in activities of regulatory networks associated with inflammation and proliferation. Mechanistically, we demonstrated that, compared with control cells, the expression of GATA binding protein 6 (GATA6) in reprogrammed cells was attenuated, resulting in an increase in the activity of sonic hedgehog signaling and the expression level of downstream forkhead box P1 ([[FOXP1]]), in turn ameliorating cellular hallmarks of aging. Lower levels of GATA6 expression were also found in cells harvested from younger mice or lower passage cultures. Our findings suggest that GATA6 is a critical regulator increased in aged MSCs that controls the downstream sonic hedgehog signaling and [[FOXP1]] pathway to modulate cellular senescence and aging-related activities.
|abstract=Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) [[FSHR]] knockout mice (Fshr ). We found that Fshr  mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg  · d , i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr  mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.


|keywords=* aging
|keywords=* FSH
* cell signaling
* ROS
* mesenchymal stem cells
* aging
* reprogramming
* antioxidants
* transcription factors
* depression
|full-text-url=https://sci-hub.do/10.1002/stem.3297
* metabolism
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468367
}}
==GAP43==
 
{{medline-entry
|title=HDAC inhibition leads to age-dependent opposite regenerative effect upon PTEN deletion in rubrospinal axons after SCI.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32171589
|abstract=Epigenetic changes associated with aging have been linked to functional and cognitive deficits in the adult CNS. Histone acetylation is involved in the control of the transcription of plasticity and regeneration-associated genes. The intrinsic axon growth capacity in the CNS is negatively regulated by phosphatase and tensin homolog (Pten). Inhibition of Pten is an effective method to stimulate axon growth following an injury to the optic nerve, corticospinal tract (CST), and rubrospinal tract (RST). Our laboratory has previously demonstrated that the deletion of Pten in aged animals diminishes the regenerative capacity in rubrospinal neurons. We hypothesize that changes in the chromatin structure might contribute to this age-associated decline. Here, we assessed whether Trichostatin A (TSA), a histone deacetylases (HDACs) inhibitor, reverses the decline in regeneration in aged Pten  mice. We demonstrate that HDAC inhibition induces changes in the expression of [[GAP43]] in both young and aged Pten  mice. The regenerative capacity of the RST did not improve significantly in young mice, neither their motor function on the horizontal ladder or cylinder test after TSA treatment for 7 days. Interestingly, TSA treatment in the aged mice worsened their motor function deficits, suggesting that the systemic treatment with TSA might have an overall adverse effect on motor recovery after SCI in aged animals.
|mesh-terms=* Aging
* Animals
* Axons
* GAP-43 Protein
* Gene Deletion
* Gene Expression
* Histone Deacetylase Inhibitors
* Histone Deacetylases
* Hydroxamic Acids
* Mice, Transgenic
* Motor Activity
* Nerve Regeneration
* PTEN Phosphohydrolase
* Recovery of Function
* Spinal Cord
* Spinal Cord Injuries
|keywords=* Aging
* Epigenetics
* Histone deacetylase
* Pten
* Regeneration
* Spinal cord injury
|full-text-url=https://sci-hub.do/10.1016/j.neurobiolaging.2020.02.006
}}
}}
==GC==
==GC==


{{medline-entry
{{medline-entry
|title=Body Size and Cuticular Hydrocarbons as Larval Age Indicators in the Forensic Blow Fly, Chrysomya albiceps (Diptera: Calliphoridae).
|title=Physicochemical characterization of a polysaccharide from Agrocybe aegirita and its anti-ageing activity.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33274739
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32172871
|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.
|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
}}
==GDF11==


|keywords=*  
{{medline-entry
          Chrysomya albiceps
|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
* body size
|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.
* cuticular hydrocarbon
 
* forensic
|keywords=* GDF11
* larval longevity
* aging
|full-text-url=https://sci-hub.do/10.1093/jme/tjaa256
* immunoprecipitation
* myostatin/GDF8
* serum
* targeted-quantitative proteomics
|full-text-url=https://sci-hub.do/10.1002/pmic.201900104
}}
}}
==GNE==
==GFAP==


{{medline-entry
{{medline-entry
|title=Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2  mice.
|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/33300446
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32138778
|abstract=Mitochondrial dysfunction causes energy deficiency and nigrostriatal neurodegeneration which is integral to the pathogenesis of Parkinson disease (PD). Clearance of defective mitochondria involves fission and ubiquitin-dependent degradation via mitophagy to maintain energy homeostasis. We hypothesize that LRRK2 (leucine-rich repeat kinase 2) mutation disrupts mitochondrial turnover causing accumulation of defective mitochondria in aging brain. We found more ubiquitinated mitochondria with aberrant morphology associated with impaired function in aged (but not young) LRRK2  knockin mutant mouse striatum compared to wild-type (WT) controls. LRRK2  mutant mouse embryonic fibroblasts (MEFs) exhibited reduced MAP1LC3/LC3 activation indicating impaired macroautophagy/autophagy. Mutant MEFs under FCCP-induced (mitochondrial uncoupler) stress showed increased LC3-aggregates demonstrating impaired mitophagy. Using a novel flow cytometry assay to quantify mitophagic rates in MEFs expressing photoactivatable [i]mito[/i]-PAmCherry, we found significantly slower mitochondria clearance in mutant cells. Specific LRRK2 kinase inhibition using [[GNE]]-7915 did not alleviate impaired mitochondrial clearance suggesting a lack of direct relationship to increased kinase activity alone. DNM1L/Drp1 knockdown in MEFs slowed mitochondrial clearance indicating that DNM1L is a prerequisite for mitophagy. DNM1L knockdown in slowing mitochondrial clearance was less pronounced in mutant MEFs, indicating preexisting impaired DNM1L activation. DNM1L knockdown disrupted mitochondrial network which was more evident in mutant MEFs. DNM1L-Ser616 and MAPK/ERK phosphorylation which mediate mitochondrial fission and downstream mitophagic processes was apparent in WT using FCCP-induced stress but not mutant MEFs, despite similar total MAPK/ERK and DNM1L levels. In conclusion, aberrant mitochondria morphology and dysfunction associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in mutant LRRK2 MEFs and mouse brain.  ATP: adenosine triphosphate; BAX: BCL2-associated X protein; CDK1: cyclin-dependent kinase 1; CDK5: cyclin-dependent kinase 5; CQ: chloroquine; CSF: cerebrospinal fluid; DNM1L/DRP1: dynamin 1-like; ELISA: enzyme-linked immunosorbent assay; FACS: fluorescence-activated cell sorting; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; LAMP2A: lysosomal-associated membrane protein 2A; LRRK2: leucine-rich repeat kinase 2; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK1/ERK2: mitogen-activated protein kinase 1; MEF: mouse embryonic fibroblast; MFN1: mitofusin 1; MMP: mitochondrial membrane potential; PAmCherry: photoactivatable-mCherry; PD: Parkinson disease; PINK1: PTEN induced putative kinase 1; PRKN/PARKIN: parkin RBR E3 ubiquitin protein ligase; RAB10: RAB10, member RAS oncogene family; RAF: v-raf-leukemia oncogene; SNCA: synuclein, alpha; TEM: transmission electron microscopy; VDAC: voltage-dependent anion channel; WT: wild type; SQSTM1/p62: sequestosome 1.
|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
|keywords=* Aging
* Dnm1l/DRP1
* Meta-analysis
* SQSTM1/p62
* Prefrontal cortex
* knockin mice
* Sex-specific
* macroautophagy
* Transcriptome
* mitochondria dysfunction
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059712
* mitochondrial fission
}}
* mitophagy
==GHRH==
* parkinson disease
 
* ubiquitination
{{medline-entry
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1850008
|title=Transcriptomic and metabolomic profiling of long-lived growth hormone releasing hormone knock-out mice: evidence for altered mitochondrial function and amino acid metabolism.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32091406
|abstract=Numerous genetic manipulations that extend lifespan in mice have been discovered over the past two decades, the most robust of which has arguably been the down regulation of growth hormone (GH) signaling. However, while decreased GH signaling has been associated with improved health and lifespan, many of the underlying physiological changes and molecular mechanisms associated with GH signaling have yet to be elucidated. To this end, we have completed the first transcriptomic and metabolomic study on long-lived growth hormone releasing hormone knockout ([[GHRH]]-KO) and wild-type mice in brown adipose tissue (transcriptomics) and blood serum (metabolomics). We find that [[GHRH]]-KO mice have increased transcript levels of mitochondrial and amino acid genes with decreased levels of extracellular matrix genes. Concurrently, mitochondrial metabolites are differentially regulated in [[GHRH]]-KO. Furthermore, we find a strong signal of genotype-by-sex interactions, suggesting the sexes have differing physiological responses to GH deficiency. Overall, our results point towards a strong influence of mitochondrial metabolism in [[GHRH]]-KO mice which potentially is tightly intertwined with their extended lifespan phenotype.
 
|keywords=* aging
* growth hormone
* metabolite
* mouse
* transcriptomics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066919
}}
==GREM1==
 
{{medline-entry
|title=[[GREM1]] inhibits osteogenic differentiation, senescence and BMP transcription of adipose-derived stem cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32151168
|abstract=: Adipose-derived stem cells (ADSCs) are ideal for cell-based therapies to support bone regeneration. It is vital to understand the critical genes and molecular mechanisms involved in the functional regulation of ADSCs for enhancing bone regeneration. In the present study, we investigated the Gremlin 1 ([[GREM1]]) effect on ADSCs osteogenic differentiation and senescence. : The [i]in vitro[/i] ADSCs osteogenic differentiation potential was evaluated by determining alkaline phosphatase (ALP) activity, mineralization ability, and the expression of osteogenic markers. Cell senescence is determined by SA-β-gal staining, telomerase assay, and the expression of aging markers. : [[GREM1]] overexpression in ADSCs reduced ALP activity and mineralization, inhibited the expression of osteogenic related genes [i]OCN, OPN, DSPP, DMP1[/i], and [i]BSP[/i], and key transcription factors, [i]RUNX2[/i] and [i]OSX[/i]. [[GREM1]] knockdown in ADSCs enhanced ALP activity and mineralization, promoted the expression of [i]OCN, OPN, DSPP, DMP1, BSP, RUNX2[/i], and [i]OSX[/i]. [[GREM1]] overexpression in ADSCs reduced the percent SA-β-Gal positive cells, [i]P16[/i] and [i]P53[/i] expressions, and increased telomerase activity. [[GREM1]] knockdown in ADSCs increased the percentage of SA-β-Gal positive cells, [i]P16[/i] and [i]P53[/i] expressions, and reduced telomerase activity. Furthermore, [[GREM1]] reduced the mRNA expression levels of BMP2, BMP6, and BMP7. : In summary, our findings suggested that [[GREM1]] inhibited ADSCs senescence and osteogenic differentiation and antagonized BMP transcription.
 
|keywords=* BMP
* GREM1
* adipose-derived stem cells (ADSCs)
* osteogenic differentiation
* senescence
|full-text-url=https://sci-hub.do/10.1080/03008207.2020.1736054
}}
}}
==GRN==
==GRID1==


{{medline-entry
{{medline-entry
|title=Stressful development: Integrating endoderm development, stress, and longevity.
|title=Gene discovery for high-density lipoprotein cholesterol level change over time in prospective family studies.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33307045
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32109663
|abstract=In addition to performing digestion and nutrient absorption, the intestine serves as one of the first barriers to the external environment, crucial for protecting the host from environmental toxins, pathogenic invaders, and other stress inducers. The gene regulatory network ([[GRN]]) governing embryonic development of the endoderm and subsequent differentiation and maintenance of the intestine has been well-documented in C. elegans. A key regulatory input that initiates activation of the embryonic [[GRN]] for endoderm and mesoderm in this animal is the maternally provided SKN-1 transcription factor, an ortholog of the vertebrate Nrf-1 and -2, which, like C. elegans SKN-1, perform conserved regulatory roles in mediating a variety of stress responses across metazoan phylogeny. Other key regulatory factors in early gut development also participate in stress response as well as in innate immunity and aging and longevity. In this review, we discuss the intersection between genetic nodes that mediate endoderm/intestine differentiation and regulation of stress and homeostasis. We also consider how direct signaling from the intestine to the germline, in some cases involving SKN-1, facilitates heritable epigenetic changes, allowing transmission of adaptive stress responses across multiple generations. These connections between regulation of endoderm/intestine development and stress response mechanisms suggest that varying selective pressure exerted on the stress response pathways may influence the architecture of the endoderm [[GRN]], thereby leading to genetic and epigenetic variation in early embryonic [[GRN]] regulatory events.
|abstract=Several genes are known to contribute to the levels and metabolism of HDL-C, however, their protective effects in cardiovascular disease (CVD), healthy aging, and longevity are complex and poorly understood. It is also unclear if these genes predict longitudinal HDL-C change. We aimed to identify loci influencing HDL-C change. We performed a genome-wide association study (GWAS) with harmonized HDL-C and imputed genotype in three family-based studies recruited for exceptional survival (Long Life Family Study), from community-based (Framingham Heart Study) and enriched for CVD (Family Heart Study). In 7738 individuals with at least 2 visits, we employed a growth curve model to estimate the random linear trajectory parameter of age-sex-adjusted HDL-C for each person. GWAS was performed using a linear regression model on HDL-C change accounting for kinship correlations, population structure, and differences among studies. We identified a novel association for HDL-C with [[GRID1]] (p = 5.43 × 10 ), which encodes a glutamate receptor channel subunit involved in synaptic plasticity. Seven suggestive novel loci (p < 1.0 × 10 ; MBOAT2, LINC01876-NR4A2, NTNG2, CYSLTR2, SYNE2, CTXND1-LINC01314, and CYYR1) and a known lipid gene (ABCA10) showed associations with HDL-C change. Two additional sex-specific suggestive loci were identified in women (DCLK2 and KCNJ2). Several of these genetic variants are associated with lipid-related conditions influencing cardiovascular and metabolic health, have predictive regulatory function, and are involved in lipid-related pathways. Modeling longitudinal HDL-C in prospective studies, with differences in healthy aging, longevity and CVD risk, contributed to gene discovery and provided insights into mechanisms of HDL-C regulation.


|keywords=* Caenorhabditis elegans
|keywords=* GWAS
* Embryonic development
* HDL-C metabolism
* Epigenetics inheritance
* Healthy aging
* Innate immunity
* Longevity
* Longevity
* Pleiotropy
* Longitudinal HDL-C change
* Stress
|full-text-url=https://sci-hub.do/10.1016/j.atherosclerosis.2020.02.005
|full-text-url=https://sci-hub.do/10.1016/j.ydbio.2020.12.002
}}
}}
==GSTM1==
==GRK2==


{{medline-entry
{{medline-entry
|title=The effects of everyday-life exposure to polycyclic aromatic hydrocarbons on biological age indicators.
|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/33272294
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32216616
|abstract=Further knowledge on modifiable aging risk factors is required to mitigate the increasing burden of age-related diseases in a rapidly growing global demographic of elderly individuals. We explored the effect of everyday exposure to polycyclic aromatic hydrocarbons (PAHs), which are fundamental constituents of air pollution, on cellular biological aging. This was determined via the analysis of leukocyte telomere length (LTL), mitochondrial DNA copy number (LmtDNAcn), and by the formation of anti-benzo[a]pyrene diolepoxide (B[a]PDE-DNA) adducts. The study population consisted of 585 individuals living in North-East Italy. PAH exposure (diet, indoor activities, outdoor activities, traffic, and residential exposure) and smoking behavior were assessed by questionnaire and anti-B[a]PDE-DNA by high-performance-liquid-chromatography. LTL, LmtDNAcn and genetic polymorphisms [glutathione S-transferase M1 and T1 ([[GSTM1]]; GSTT1)] were measured by polymerase chain reaction. Structural equation modelling analysis evaluated these complex relationships. Anti-B[a]PDE-DNA enhanced with PAH exposure (p = 0.005) and active smoking (p = 0.0001), whereas decreased with detoxifying [[GSTM1]] (p = 0.021) and in females (p = 0.0001). Subsequently, LTL and LmtDNAcn reduced with anti-B[a]PDE-DNA (p = 0.028 and p = 0.018), particularly in males (p = 0.006 and p = 0.0001). Only LTL shortened with age (p = 0.001) while elongated with active smoking (p = 0.0001). Besides this, the most significant determinants of PAH exposure that raised anti-B[a]PDE-DNA were indoor and diet (p = 0.0001), the least was outdoor (p = 0.003). New findings stemming from our study suggest that certain preventable everyday life exposures to PAHs reduce LTL and LmtDNAcn. In particular, the clear association with indoor activities, diet, and gender opens new perspectives for tailored preventive measures in age-related diseases. Everyday life exposure to polycyclic aromatic hydrocarbons reduces leukocyte telomere length and mitochondrial DNA copy number through anti-B[a]PDE-DNA adduct formation.
|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
}}
==GRM3==


|keywords=* Biological aging
{{medline-entry
* DNA adduct
|title=Profiling gene expression in the human dentate gyrus granule cell layer reveals insights into schizophrenia and its genetic risk.
* Mitochondrial DNA copy number
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32203495
* Polycyclic aromatic hydrocarbon
|abstract=Specific cell populations may have unique contributions to schizophrenia but may be missed in studies of homogenate tissue. Here laser capture microdissection followed by RNA sequencing (LCM-seq) was used to transcriptomically profile the granule cell layer of the dentate gyrus (DG-GCL) in human hippocampus and contrast these data to those obtained from bulk hippocampal homogenate. We identified widespread cell-type-enriched aging and genetic effects in the DG-GCL that were either absent or directionally discordant in bulk hippocampus data. Of the ~9 million expression quantitative trait loci identified in the DG-GCL, 15% were not detected in bulk hippocampus, including 15 schizophrenia risk variants. We created transcriptome-wide association study genetic weights from the DG-GCL, which identified many schizophrenia-associated genetic signals not found in transcriptome-wide association studies from bulk hippocampus, including [[GRM3]] and CACNA1C. These results highlight the improved biological resolution provided by targeted sampling strategies like LCM and complement homogenate and single-nucleus approaches in human brain.
* Structural equation modelling
|mesh-terms=* Adolescent
* Telomere length
* Adult
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713168
* Aged
* Aged, 80 and over
* Aging
* Bipolar Disorder
* Dentate Gyrus
* Depressive Disorder, Major
* Female
* Gene Expression Profiling
* Genetic Predisposition to Disease
* Genome-Wide Association Study
* Humans
* Male
* Middle Aged
* Neurons
* Quantitative Trait Loci
* Schizophrenia
* Transcriptome
* Young Adult
|keywords=#f
|full-text-url=https://sci-hub.do/10.1038/s41593-020-0604-z
}}
==GUK1==
 
{{medline-entry
|title=Characterization of the impact of GMP/GDP synthesis inhibition on replicative lifespan extension in yeast.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32232569
|abstract=Slowing down aging-associated accumulation of molecular damage or its prevention represents a promising therapeutic paradigm to combat aging-related disease and death. While several chemical compounds extend lifespan in model organisms, their mechanism of action is often unknown, reducing their therapeutic potential. Using a systematic approach, here we characterize the impact of the GMP pathway on yeast lifespan and elucidate GMP synthesis inhibition as a lifespan extension mechanism. We further discover that proteasome activation extends lifespan in part through the GMP pathway. GMP synthesis inhibition exerts its lifespan extension effect independently of the canonical nutrient-sensing pathway regulating lifespan. Exposing longitudinally aging yeast cells to GMP pathway inhibition in an age-dependent manner, we demonstrate that the lifespan extension is facilitated by slowing, rather than reversing, the aging process in cells. Using a [[GUK1]] mutant with lower GMP-to-GDP conversion activity, we observe lifespan extension, suggesting that reduced GDP level by itself can also extend yeast lifespan. These findings elucidate the involvement of nucleotide metabolism in the aging process. The existence of clinically-approved GMP pathway inhibitors elicits the potential of a new class of therapeutics for aging-related disorders.
 
|keywords=* Aging
* GDP
* GMP
* Mycophenolic acid
* Proteasome
* Replicative lifespan
* Yeast
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367712
}}
==H2AX==
 
{{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
}}
}}
==GZMK==
==HCN1==


{{medline-entry
{{medline-entry
|title=Comprehensive Profiling of an Aging Immune System Reveals Clonal [[GZMK]] CD8  T Cells as Conserved Hallmark of Inflammaging.
|title=Protein expression changes of [[HCN1]] and HCN2 in hippocampal subregions of gerbils during the normal aging process.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33271118
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32128096
|abstract=Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K ([[GZMK]])-expressing CD8  T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of [[GZMK]], which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating [[GZMK]] CD8  T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify [[GZMK]] Taa cells as a potential target to address age-associated dysfunctions of the immune system.
|abstract=Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play essential roles in various hippocampal functions, including regulation of long-term potentiation, synaptic plasticity, and hippocampal-dependent cognitive process. The objective of this study was to investigate age-related changes in [[HCN1]] and HCN2 protein expressions in gerbil hippocampus at various ages. In this study, the protein expressions of [[HCN1]] and HCN2 were compared in the hippocampus at the ages of 1, 3, 12, and 24 months using Western blot analysis and immunohistochemistry. Immunoreactivity of both [[HCN1]] and HCN2 was shown primarily in cells of the pyramidal cell layer in the hippocampus proper and in cells of the granule cell layer in the dentate gyrus. [[HCN1]] and HCN2 protein expression levels and immunoreactivity were significantly increased at three months (3 M) of age compared with those at 1 M of age. After that, both [[HCN1]] and HCN2 expression levels in the hippocampus were gradually decreased with age. Our results show that the normal aging process affects the expression levels of [[HCN1]] and HCN2 in hippocampal cells in gerbils. There are marked reductions in [[HCN1]] and HCN2 expressions in the aged hippocampus compared to the young hippocampus. Such reductions might be related to aging in the hippocampus.


|keywords=* Aging
|keywords=* Aging
* CD8 T cells
* Dentate gyrus
* CITE-seq
* Granule cells
* granzyme K
* HCN channel
* immune system
* Hippocampus proper
* inflammaging
* Pyramidal cells
* single-cell ATAC-sequencing
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038419
* single-cell BCR-sequencing
}}
* single-cell RNA-sequencing
==HDC==
* single-cell TCR-sequencing
 
|full-text-url=https://sci-hub.do/10.1016/j.immuni.2020.11.005
{{medline-entry
|title=Induced pluripotency and spontaneous reversal of cellular aging in supercentenarian donor cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32115145
|abstract=Supercentenarians (≥110-year-old, SC) are a uniquely informative population not only because they surpass centenarians in age, but because they appear to age more slowly with fewer incidences of chronic age-related disease than centenarians. We reprogramed donor B-lymphoblastoid cell lines (LCL) derived from a 114-year-old (SC), a 43-year-old healthy disease-free control ([[HDC]]) and an 8-year-old with a rapid aging disease (Hutchinson-Gilford progeria syndrome (HGPS)) and compared SC-iPSC to [[HDC]]-iPSC and HGPS-iPSCs. Reprogramming to pluripotency was confirmed by pluripotency marker expression and differentiation to 3 germ-layers. Each iPSC clone differentiated efficiently to mesenchymal progenitor cells (MPC) as determined by surface marker expression and RNAseq analysis. We identified supercentenarian and HGPS associated gene expression patterns in the differentiated MPC lines that were not evident in the parental iPSC lines. Importantly, telomere length resetting occurred in iPSC from all donors albeit at a lower incidence in supercentenarian iPSCs. These data indicate the potential to use reprogramming to reset both developmental state and cellular age in the "oldest of the old." We anticipate that supercentenarian iPSC and their differentiated derivatives will be valuable tools for studying the underlying mechanisms of extreme longevity and disease resistance.
|mesh-terms=* Adult
* Aged, 80 and over
* Cell Differentiation
* Cell Line
* Cellular Reprogramming
* Cellular Senescence
* Child
* Clone Cells
* Gene Expression Regulation
* Humans
* Induced Pluripotent Stem Cells
* Mesenchymal Stem Cells
* Telomere Homeostasis
* Tissue Donors
* Transcriptome
|keywords=* Aging
* Longevity
* Reprogramming
* Supercentenarian
* Telomere
* iPSC
|full-text-url=https://sci-hub.do/10.1016/j.bbrc.2020.02.092
}}
==HGF==
 
{{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
}}
}}
==HES1==
==HMGA2==


{{medline-entry
{{medline-entry
|title=A Single-Cell Transcriptomic Atlas of Human Skin Aging.
|title=4D Genome Rewiring during Oncogene-Induced and Replicative Senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33238152
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32220303
|abstract=Skin undergoes constant self-renewal, and its functional decline is a visible consequence of aging. Understanding human skin aging requires in-depth knowledge of the molecular and functional properties of various skin cell types. We performed single-cell RNA sequencing of human eyelid skin from healthy individuals across different ages and identified eleven canonical cell types, as well as six subpopulations of basal cells. Further analysis revealed progressive accumulation of photoaging-related changes and increased chronic inflammation with age. Transcriptional factors involved in the developmental process underwent early-onset decline during aging. Furthermore, inhibition of key transcription factors [[HES1]] in fibroblasts and KLF6 in keratinocytes not only compromised cell proliferation, but also increased inflammation and cellular senescence during aging. Lastly, we found that genetic activation of [[HES1]] or pharmacological treatment with quercetin alleviated cellular senescence of dermal fibroblasts. These findings provide a single-cell molecular framework of human skin aging, providing a rich resource for developing therapeutic strategies against aging-related skin disorders.
|abstract=To understand the role of the extensive senescence-associated 3D genome reorganization, we generated genome-wide chromatin interaction maps, epigenome, replication-timing, whole-genome bisulfite sequencing, and gene expression profiles from cells entering replicative senescence (RS) or upon oncogene-induced senescence (OIS). We identify senescence-associated heterochromatin domains (SAHDs). Differential intra- versus inter-SAHD interactions lead to the formation of senescence-associated heterochromatin foci (SAHFs) in OIS but not in RS. This OIS-specific configuration brings active genes located in genomic regions adjacent to SAHDs in close spatial proximity and favors their expression. We also identify DNMT1 as a factor that induces SAHFs by promoting [[HMGA2]] expression. Upon DNMT1 depletion, OIS cells transition to a 3D genome conformation akin to that of cells in replicative senescence. These data show how multi-omics and imaging can identify critical features of RS and OIS and discover determinants of acute senescence and SAHF formation.
|mesh-terms=* Cells, Cultured
* Cellular Senescence
* Chromatin Assembly and Disassembly
* DNA (Cytosine-5-)-Methyltransferase 1
* DNA Methylation
* Fibroblasts
* Genome, Human
* Heterochromatin
* Humans
* In Situ Hybridization, Fluorescence
* Oncogenes
|keywords=* 3D genome architecture
* DNMT1
* Hi-C
* chromatin compartments
* gene regulation
* oncogene-induced senescence
* replicative senescence
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7208559
}}
{{medline-entry
|title=The protective effects of [[HMGA2]] in the senescence process of bone marrow-derived mesenchymal stromal cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32068957
|abstract=Bone marrow-derived mesenchymal stromal cells (MSCs) have been wildly applied to cell-based strategies for tissue engineering and regenerative medicine; however, they have to undergo the senescence process and thus appeared to be less therapeutic effective. [[HMGA2]], a protein belonged to high mobility group A (HMGA) family, exhibits an inverse expression level related to embryonic development and acts as a developmental regulator in stem cell self-renewal progression. Therefore, we performed senescence-associated β-galactosidase (SA-β-gal) staining, transwell assay, to examine the changes of MSCs in different stages and then over-expressed [[HMGA2]] in MSCs by lentivirus transfection. We found the percentage of SA-β-gal staining positive cells in MSCs from 24-month-old Sprague-Dawley (SD) rats (O-MSCs) was significantly higher compared with MSCs from 2-week-old SD rats (Y-MSCs), and the expression levels of P21 and P53, two senescence-related molecules, were also significantly up-regulated in O-MSCs than in Y-MSCs. In contrast, the [[HMGA2]] expression level in O-MSCs was dramatically down-regulated in contrast to Y-MSCs. In additional, the migration ability in O-MSCs was significantly attenuated than in Y-MSCs. After successfully over-expressed [[HMGA2]] in O-MSCs, the percentage of SA-β-gal staining positive cells and the expression levels of P21 and P53 were reduced, and the migration ability was improved compared with O-MSCs without treatment. Further, mRNA sequencing analysis revealed that overexpression of [[HMGA2]] changed the expression of genes related to cell proliferation and senescence, such as Lyz2, Pf4, Rgs2, and Mstn. Knockdown of Rgs2 in [[HMGA2]] overexpression O-MSCs could antagonize the protective effect of [[HMGA2]] in the senescence process of O-MSCs.
 
|keywords=* bone marrow derived mesenchymal stromal cells (MSCs)
* high-mobility group AT-hook 2 (HMGA2)
* regulator of G protein signaling 2 (Rgs2)
* senescence
|full-text-url=https://sci-hub.do/10.1002/term.3023
}}
==HP==


|keywords=* HES1
{{medline-entry
* KLF6
|title=Beta Human Papillomavirus 8E6 Attenuates LATS Phosphorylation after Failed Cytokinesis.
* aging
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32238586
* fibroblast
|abstract=Beta genus human papillomaviruses (β-[[HP]]Vs) cause cutaneous squamous cell carcinomas (cSCCs) in a subset of immunocompromised patients. However, β-[[HP]]Vs are not necessary for tumor maintenance in the general population. Instead, they may destabilize the genome in the early stages of cancer development. Supporting this idea, β-[[HP]]V's 8E6 protein attenuates p53 accumulation after failed cytokinesis. This paper offers mechanistic insight into how β-[[HP]]V E6 causes this change in cell signaling. An [i]in silico[/i] screen and characterization of HCT 116 cells lacking p300 suggested that the histone acetyltransferase is a negative regulator of Hippo pathway ([[HP]]) gene expression. [[HP]] activation restricts growth in response to stimuli, including failed cytokinesis. Loss of p300 resulted in increased [[HP]] gene expression, including proproliferative genes associated with [[HP]] inactivation. β-[[HP]]V 8E6 expression recapitulates some of these phenotypes. We used a chemical inhibitor of cytokinesis (dihydrocytochalasin B [H2CB]) to induce failed cytokinesis. This system allowed us to show that β-[[HP]]V 8E6 reduced activation of large tumor suppressor kinase (LATS), an [[HP]] kinase. LATS is required for p53 accumulation following failed cytokinesis. These phenotypes were dependent on β-[[HP]]V 8E6 destabilizing p300 and did not completely attenuate the [[HP]]. It did not alter H2CB-induced nuclear exclusion of the transcription factor YAP. β-[[HP]]V 8E6 also did not decrease [[HP]] activation in cells grown to a high density. Although our group and others have previously described inhibition of DNA repair, to the best of our knowledge, this marks the first time that a β-[[HP]]V E6 protein has been shown to hinder [[HP]] signaling.  β-[[HP]]Vs contribute to cSCC development in immunocompromised populations. However, it is unclear if these common cutaneous viruses are tumorigenic in the general population. Thus, a more thorough investigation of β-[[HP]]V biology is warranted. If β-[[HP]]V infections do promote cSCCs, they are hypothesized to destabilize the cellular genome. [i]In vitro[/i] data support this idea by demonstrating the ability of the β-[[HP]]V E6 protein to disrupt DNA repair signaling events following UV exposure. We show that β-[[HP]]V E6 more broadly impairs cellular signaling, indicating that the viral protein dysregulates the [[HP]]. The [[HP]] protects genome fidelity by regulating cell growth and apoptosis in response to a myriad of deleterious stimuli, including failed cytokinesis. After failed cytokinesis, β-[[HP]]V 8E6 attenuates phosphorylation of the [[HP]] kinase (LATS). This decreases some, but not all, [[HP]] signaling events. Notably, β-[[HP]]V 8E6 does not limit senescence associated with failed cytokinesis.
* keratinocyte
|mesh-terms=* Apoptosis
* quercetin
* Cell Cycle Proteins
* Cell Line, Tumor
* Cell Proliferation
* Cell Survival
* Cytochalasin B
* Cytokinesis
* DNA Repair
* E1A-Associated p300 Protein
* Gene Expression Regulation
* HCT116 Cells
* Host-Pathogen Interactions
* Humans
* Keratinocytes
* Oncogene Proteins, Viral
* Osteoblasts
* Papillomaviridae
* Phenotype
* Phosphorylation
* Primary Cell Culture
* Protein-Serine-Threonine Kinases
* Signal Transduction
* Transcription Factors
* Tumor Suppressor Protein p53
|keywords=* Hippo signaling pathway
* apoptosis
* cancer
* cytokinesis
* human papillomavirus
* senescence
* senescence
* single-cell RNA sequencing
* skin cancer
* skin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307087
|full-text-url=https://sci-hub.do/10.1016/j.devcel.2020.11.002
}}
}}
==HGS==
==HPSE==


{{medline-entry
{{medline-entry
|title=Handgrip strength asymmetry is associated with future falls in older Americans.
|title=Distribution of heparan sulfate correlated with the expression of heparanase-1 and matrix metalloproteinase-9 in an ovariectomized rats skin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33247424
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32159248
|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.
|abstract=There are few studies on heparan sulfate (HS) in the skin, during aging, when estrogen is suppressed. The enzyme heparanase-1 ([[HPSE]]-1), has its 17β-estrogen-regulated expression in pathological conditions such as cancer and chronic inflammatory diseases. [[HPSE]]-1 is correlated with the matrix metalloproteinase-9 (MMP-9), an endopeptidase that also undergoes estrogen action. We investigated the distribution of HS, expression [[HPSE]]-1 and MMP-9 in the skin of adult rats at different ages and in the age-matched ovariectomized rats to evaluate the influence of low estrogen on the distribution of HS. Thirty female Wistar rats were used. Rats underwent to a sham surgery (ctr, n = 15) or to a bilateral ovariectomy (ovx, n = 15) and were euthanized after 45, 75, and 90 days after ovariectomy. Morphological, morphometric, biochemical, and reverse transcriptase polymerase chain reaction (RT-PCR) methodologies were used. A significant decrease (P < 0.001) in total skin thickness was observed in the ctr and ovx animals, being higher in the older animals. The thickness of the epidermis and dermis decreased; however, the proportion in the total skin remained similar comparing ctr and ovx. An increase of HS with increasing age and ovariectomy was observed. The expression of the [[HPSE]]-1 and MMP-9 enzymes decreased, being higher in old animals. A correlation between the increase of HS and the decrease of the [[HPSE]]-1 was demonstrated in both groups. Overall, these data suggested that estrogen acts in the regulation of the expression of the [[HPSE]]-1, not only in pathological states, as already established, but also in aging.


|keywords=* Aging
|keywords=* aging
* Functional laterality
* estrogen
* Geriatric assessment
* extracellular matrix
* Geriatrics
* heparan sulfate
* Muscle strength dynamometer
* heparanase-1
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01757-z
* matrix metalloproteinase-9
|full-text-url=https://sci-hub.do/10.1002/cbin.11339
}}
}}
==HR==
==HR==


{{medline-entry
{{medline-entry
|title=Patients with hip fracture and total hip arthroplasty surgery differ in anthropometric, but not cardiovascular screening abnormalities.
|title=Physical activity trajectories, mortality, hospitalization, and disability in the Toledo Study of Healthy Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33267795
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32163233
|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.
|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
|keywords=* AGING
* Cardiovascular reactivity
* ANALYSIS/QUANTITATION OF BONE
* Heart rate variability
* BONE QCT/μCT
* Hip fracture
* EPIDEMIOLOGY
* Total hip arthroplasty
* GENERAL POPULATION STUDIES
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713041
|full-text-url=https://sci-hub.do/10.1002/jbmr.3998
}}
==HRAS==
 
{{medline-entry
|title=How do combinations of unhealthy behaviors relate to attitudinal factors and subjective health among the adult population in the Netherlands?
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32245376
|abstract=Health behaviours like smoking, nutrition, alcohol consumption and physical activity (SNAP) are often studied separately, while combinations can be particularly harmful. This study aims to contribute to a better understanding of lifestyle choices by studying the prevalence of (combinations of) unhealthy SNAP behaviours in relation to attitudinal factors (time orientation, risk attitude) and subjective health (self-rated health, life expectancy) among the adult Dutch population. In total 1006 respondents, representative of the Dutch adult population (18-75 years) in terms of sex, age, and education, were drawn from a panel in 2016. They completed an online questionnaire. Groups comparisons and logistic regression analyses (crude and adjusted) were applied to analyse (combinations of) SNAP behaviours in relation to time orientation (using the Consideration of Future Consequences scale comprising Immediate (CFC-I) and Future (CFC-F) scales) and risk attitude (Health-Risk Attitude Scale; [[HRAS]]-6), as well as subjective health (visual analogue scale and subjective life expectancy). In the analyses, 989 respondents (51% men, average 52 years, 22% low, 48% middle, and 30% high educated) were included. About 8% of respondents engaged in four unhealthy SNAP behaviours and 18% in none. Self-rated health varied from 5.5 to 7.6 in these groups, whilst subjective life expectancy ranged between 73.7 and 85.5 years. Logistic regression analyses, adjusted for socio-demographic variables, showed that smoking, excessive drinking and combining two or more unhealthy SNAP behaviours were significantly associated with CFC-I scores, which increased the odds by 30%, 18% and 19%, respectively. Only physical inactivity was significantly associated with CFC-F scores, which increased the odds by 20%. Three out of the four SNAP behaviours were significantly associated with [[HRAS]]-6, which increased the odds between 6% and 12%. An unhealthy diet, excessive drinking, and physical inactivity were significantly associated with SRH, which decreased the odds by 11%. Only smoking was significantly associated with subjective life expectancy, which decreased the odds by 3%. Our findings suggest that attitudinal factors and subjective health are relevant in the context of understanding unhealthy SNAP behaviours and their clustering. This emphasizes the relevance of a holistic approach to health prevention rather than focusing on a single unhealthy SNAP behaviour.
|mesh-terms=* Adult
* Alcohol Drinking
* Attitude to Health
* Cluster Analysis
* Diagnostic Self Evaluation
* Diet, Healthy
* Exercise
* Female
* Health Risk Behaviors
* Humans
* Life Expectancy
* Life Style
* Logistic Models
* Male
* Middle Aged
* Netherlands
* Prevalence
* Sedentary Behavior
* Smoking
* Surveys and Questionnaires
* Young Adult
|keywords=* Clustering risk attitude
* Health behaviours
* Subjective health
* Time orientation
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7126128
}}
==IHH==
 
{{medline-entry
|title=Indian Hedgehog regulates senescence in bone marrow-derived mesenchymal stem cell through modulation of ROS/mTOR/4EBP1, p70S6K1/2 pathway.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32235006
|abstract=Premature senescence of bone marrow-derived mesenchymal stem cells (BMSC) remains a major concern for their application clinically. Hedgehog signaling has been reported to regulate aging-associated markers and MSC skewed differentiation. Indian Hedgehog ([[IHH]]) is a ligand of Hedgehog intracellular pathway considered as an inducer in chondrogenesis of human BMSC. However, the role of [[IHH]] in the aging of BMSC is still unclear. This study explored the role [[IHH]] in the senescence of BMSC obtained from human samples and senescent mice. Isolated BMSC were transfected with [[IHH]] siRNA or incubated with exogenous [[IHH]] protein and the mechanisms of aging and differentiation investigated. Moreover, the interactions between [[IHH]], and mammalian target of rapamycin (mTOR) and reactive oxygen species (ROS) were evaluated using the corresponding inhibitors and antioxidants. BMSC transfected with [[IHH]] siRNA showed characteristics of senescence-associated features including increased senescence-associated β-galactosidase activity (SA-β-gal), induction of cell cycle inhibitors (p53/p16), development of senescence-associated secretory phenotype (SASP), activation of ROS and mTOR pathways as well as the promotion of skewed differentiation. Interestingly, BMSC treatment with [[IHH]] protein reversed the senescence markers and corrected biased differentiation. Moreover, [[IHH]] shortage-induced senescence signs were compromised after mTOR and ROS inhibition. Our findings presented anti-aging activity for [[IHH]] in BMSC through down-regulation of ROS/mTOR pathways. This discovery might contribute to increasing the therapeutic, immunomodulatory and regenerative potency of BMSC and introduce a novel remedy in the management of aging-related diseases.
 
|keywords=* Indian hedgehog
* aging
* differentiation
* mammalian target of rapamycin
* mesenchymal stem cell
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185126
}}
==IL15==
 
{{medline-entry
|title=Moderate physical activity associated with a higher naïve/memory T-cell ratio in healthy old individuals: potential role of [[IL15]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32221610
|abstract=ageing is accompanied by impairments in immune responses due to remodelling of the immune system (immunesenescence). Additionally, a decline in habitual physical activity has been reported in older adults. We have recently published that specific features of immunesenescence, such as thymic involution and naïve/memory T-cell ratio, are prevented by maintenance of a high level of physical activity. This study compares immune ageing between sedentary and physically active older adults. a cross-sectional study recruited 211 healthy older adults (60-79 years) and assessed their physical activity levels using an actigraph. We compared T- and B-cell immune parameters between relatively sedentary (n = 25) taking 2,000-4,500 steps/day and more physically active older adults (n = 25) taking 10,500-15,000 steps/day. we found a higher frequency of naïve CD4 (P = 0.01) and CD8 (P = 0.02) and a lower frequency of memory CD4 cells (P = 0.01) and CD8 (P = 0.04) T cells in the physically active group compared with the sedentary group. Elevated serum IL7 (P = 0.03) and [[IL15]] (P = 0.003), cytokines that play an essential role in T-cell survival, were seen in the physically active group. Interestingly, a positive association was observed between [[IL15]] levels and peripheral CD4 naïve T-cell frequency (P = 0.023). we conclude that a moderate level of physical activity may be required to give a very broad suppression of immune ageing, though 10,500-15,000 steps/day has a beneficial effect on the naïve T-cell pool.
 
|keywords=* T cells
* ageing
* immune senescence
* older people
* physical activity
|full-text-url=https://sci-hub.do/10.1093/ageing/afaa035
}}
}}
==IMPACT==
{{medline-entry
{{medline-entry
|title=Clinical Role of Lung Ultrasound for the Diagnosis and Prognosis of Coronavirus Disease Pneumonia in Elderly Patients: A Pivotal Study.
|title=Using Video Telehealth to Deliver Patient-Centered Collaborative Care: The G-[[IMPACT]] Pilot.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33271558
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32228299
|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.
|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=* Aging
|keywords=* Telehealth
* Coronavirus disease
* aging
* Elderly
* care coordination
* Lung ultrasound
* home care
* Severe acute respiratory syndrome-coronavirus-2
* interdisciplinary
|full-text-url=https://sci-hub.do/10.1159/000512209
* medicine
* older adult
* video
|full-text-url=https://sci-hub.do/10.1080/07317115.2020.1738000
}}
}}
==IRS2==
==IQGAP1==


{{medline-entry
{{medline-entry
|title=Effects of Heshouwuyin on gene expression of the insulin/IGF signalling pathway in rat testis and spermatogenic cells.
|title=Hyaluronan-binding protein 1 (HABP1) overexpression triggers induction of senescence in fibroblasts cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33264567
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32068317
|abstract=The Chinese herbal formula Heshouwu decoction (Heshouwuyin) has protective effects on testicular function in aging male rats, but the mechanism is unknown. This study investigated whether Heshouwuyin affects the testicular function of aging rats by regulating the insulin/IGF signalling pathway. Sixteen-month-old male Wistar rats in the Heshouwuyin group and the natural-aging group were orally administered Heshouwuyin granules (0.056 g/kg) or equivalent normal saline for 60 d. The testicular tissue of 12-month-old male Wistar rats was removed as a young control group ([i]n[/i] = 10). The testicular tissue and spermatogenic cells were studied. The immunofluorescence results revealed that the insulin receptor (INSR)- (0.056 ± 0.00548), insulin receptor substrate 1(IRS1)- (0.251 ± 0.031), [[IRS2]] (0.230 ± 0.019)- and insulin-like growth factor 1 (IGF1)-positive cell rate (0.33 ± 0.04) in the aging group was higher than that in the young control group (0.116 ± 0.011, 0.401 ± 0.0256, 0.427 ± 0.031, 0.56 ± 0.031; [i]p[/i] < 0.01), and the IGF-binding protein 3 (IGFBP3)-positive cell rate (0.42 ± 0.024) was lower than that (0.06 ± 0.027) in the young group ([i]p[/i] < 0.01). The intervention of Heshouwuyin reversed the above phenomena. The qPCR and immunoblot results were consistent with those of the immunofluorescence. The same results were obtained in spermatogenic cells. Our research shows that Heshouwuyin can regulate the insulin/IGF signalling pathway to improve testicular function, and provides an experimental basis for further clinical use.
|abstract=Hyaluronan-binding protein 1 (HABP1), a multi-compartmental, multi-functional protein has a wide range of functions, which can be attributed to its ability to associate with a variety of cellular ligands. Earlier we have reported that HABP1 overexpression in rat normal fibroblasts (F-HABP07) shows chronic generation of reactive oxygen species (ROS), induction of autophagy, and apoptosis. However, a significant proportion of cells remained viable after the majority went through apoptosis from 60 to 72 h. In this study, an attempt has been made to delineate the cellular events in the declined population of surviving cells. It has been elucidated here that, these cells at later time points of growth, that is, 72 and 84 h, not only appeared to shrink but also are devoid of autophagic vacuoles and displayed polyploidy. F-HABP07 cells exhibited an altered cytoskeletal structure from their parental cell line F111, assumed to be caused upon inhibition of actin polymerization and decrease in IQ motif-containing GTPase activating protein 1 ([[IQGAP1]]), a key protein associated with maintenance of cytoskeletal integrity. Enhanced expression and nuclear localization of AKT observed in F-HABP07 cells appears to be contributing toward the maintenance of high ROS levels in these cells and also potentially modulating the [[IQGAP1]] activity. These observations, in fact have been considered to result in sustained DNA damage, which then leads to increased expression of p53 and activation of p21 and carry out the cellular events responsible for senescence. Subsequent assessment of the presence of positive β-gal staining and enhanced expression of p16  in F-HABP07, confirmed that HABP1 overexpressing fibroblasts undergo senescence.


|keywords=* IGF1
|keywords=* F-HABP07
* IGFBP3
* HABP1
* INSR
* IQGAP1
* IRS1
* IRS2
* Male reproduction
* senescence
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717869
|full-text-url=https://sci-hub.do/10.1002/cbin.11326
}}
}}
==LMNB1==
==JAK1==


{{medline-entry
{{medline-entry
|title=Cellular senescence as a response to multiwalled carbon nanotube (MWCNT) exposure in human mesothelial cells.
|title=Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33279583
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32233952
|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.
|abstract=The role of cellular senescence induced by radiation in bone loss has attracted much attention. As one of the common complications of anticancer radiotherapy, irradiation-induced bone deterioration is common and clinically significant, but the pathological mechanism has not been elucidated. This study was performed to explore the cellular senescence and senescence-associated secretory phenotype (SASP) induction of bone marrow-derived mesenchymal stem cells (BMSCs) by irradiation and its role in osteogenic differentiation dysfunction. It was observed that irradiated BMSCs lost typical fibroblast-like morphology, exhibited suppressed viability and differentiation potential accompanied with senescence phenotypes, including an increase in senescence-associated β-galactosidase (SA-β-gal) staining-positive cells, and upregulated senescence-related genes [i]p53/p21[/i], whereas no changes happened to [i]p16[/i]. Additionally, DNA damage γ-H2AX foci, G0/G1 phase of cell cycle arrest, and cellular and mitochondrial reactive oxygen species (ROS) increased in an irradiation dose-dependent manner. Meanwhile, the [[JAK1]]/STAT3 pathway was activated and accompanied by an increase in SASP secretion, such as IL-6, IL-8, and matrix metalloproteinase-9 (MMP9), whereas 0.8 μM [[JAK1]] inhibitor (JAKi) treatment effectively inhibited the JAK pathway and SASP production. Furthermore, conditioned medium (CM) from irradiation-induced senescent (IRIS) BMSCs exhibited a markedly reduced ability in osteogenic differentiation and marker gene expression of osteoblasts, whereas CM with JAKi intervention may effectively improve these deterioration effects. In conclusion, irradiation could provoke BMSC senescence and SASP secretion and further aggravate osteogenic differentiation dysfunction via paracrine signaling, whereas SASP targeting may be a possible intervention strategy for alleviating irradiation-induced bone loss.
|mesh-terms=* Bone Resorption
* Cell Cycle Checkpoints
* Cell Differentiation
* Cell Proliferation
* Cellular Senescence
* DNA Damage
* Gene Expression Regulation, Developmental
* Histones
* Humans
* Janus Kinase 1
* Mesenchymal Stem Cells
* Mitochondria
* Osteogenesis
* Paracrine Communication
* Radiation
* Reactive Oxygen Species
* STAT3 Transcription Factor
* Signal Transduction
|keywords=* SASP
* bone marrow mesenchymal stem cells
* cellular senescence
* irradiation
* osteogenic differentiation
|full-text-url=https://sci-hub.do/10.1152/ajpcell.00520.2019
}}
==KDM2B==


|keywords=* alpha tubulin
{{medline-entry
|title=Identification of Structural Elements of the Lysine Specific Demethylase 2B CxxC Domain Associated with Replicative Senescence Bypass in Primary Mouse Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32270414
|abstract=Lysine specific demethylase 2B, [[KDM2B]], regulates genes that participate in cellular development, morphogenesis, differentiation and metabolism as a component of the polycomb repressive complex 1 (PRC1). The CxxC finger of [[KDM2B]] is responsible for the DNA binding capacity of this epigenetic regulator, acting as a sampling mechanism across chromatin for gene repression OBJECTIVES: The molecular determinants of the CxxC-DNA interaction remain largely unknown, revealing a significant knowledge gap to be explored. Our goal was to elucidate the key residues of the CxxC domain that contribute to its function as well as to further elaborate on the significance of this domain in the [[KDM2B]] role METHODS: By using electrophoresis mobility swift assay, we identified structural elements of CxxC domain that participate in the DNA recognition. We created mouse embryonic fibroblasts overexpressing different truncated and point-mutated mouse [[KDM2B]] variants to examine the contribution of the [[KDM2B]] domains in replicative senescence bypass RESULTS: In this study, we show that only the CxxC finger is essential for the ability of m[[KDM2B]] to bypass replicative senescence in primary cells by ink4A-Arf-ink4B locus repression, and that this is mediated by specific interactions of residues R585, K608 and K616 with non-methylated CpG containing DNA CONCLUSIONS: These results provide new structural insights into the molecular interactions of CxxC and could serve as a stepping-stone for developing domain-specific inhibitors for [[KDM2B]].
 
|keywords=* Lysine demethylase
* Non-methylated CpG
* Oncogene
* Polycomb repressive complex
* Replicative senescence
* Zn-finger
|full-text-url=https://sci-hub.do/10.1007/s10930-020-09895-z
}}
==KIT==
 
{{medline-entry
|title=Prediction of ovarian aging using ovarian expression of BMP15, GDF9, and C-[[KIT]].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32223330
|abstract=Ovarian aging is becoming a more important issue in terms of fertility preservation and infertility treatment. Serum anti-Mullerian hormone (AMH) level and antral follicle count (AFC) are being practically used as markers of ovarian aging as well as ovarian reserve in human. However, these factors have some drawbacks in assessing ovarian aging and reserve. Therefore, the identification of ovarian expressions of BMP15, GDF9, and C-[[KIT]] according to female could be applied as a potent predictor of ovarian aging. This work provides new information on the development of diagnosis and treatment strategy of age-related fertility decline and premature ovarian insufficiency.
 
|keywords=* BMP15
* C-KIT
* GDF9
* Ovarian aging
* biomarkers
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221484
}}
==KRAS==
 
{{medline-entry
|title=Senescence-Induced Vascular Remodeling Creates Therapeutic Vulnerabilities in Pancreas Cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32234521
|abstract=[[KRAS]] mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, immunosuppression, and resistance to chemo- and immunotherapies. We show that a combination of MEK and CDK4/6 inhibitors that target [[KRAS]]-directed oncogenic signaling can suppress PDAC proliferation through induction of retinoblastoma (RB) protein-mediated senescence. In preclinical mouse models of PDAC, this senescence-inducing therapy produces a senescence-associated secretory phenotype (SASP) that includes pro-angiogenic factors that promote tumor vascularization, which in turn enhances drug delivery and efficacy of cytotoxic gemcitabine chemotherapy. In addition, SASP-mediated endothelial cell activation stimulates the accumulation of CD8  T cells into otherwise immunologically "cold" tumors, sensitizing tumors to PD-1 checkpoint blockade. Therefore, in PDAC models, therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies through SASP-dependent effects on the tumor vasculature and immune system.
|mesh-terms=* Aging
* Animals
* CD8-Positive T-Lymphocytes
* Carcinoma, Pancreatic Ductal
* Cell Line, Tumor
* Cell Proliferation
* Cyclin-Dependent Kinase 4
* Cyclin-Dependent Kinase 6
* Gene Expression Regulation, Neoplastic
* Genes, ras
* Humans
* Immunotherapy
* MAP Kinase Signaling System
* Mice
* Pancreatic Neoplasms
* Retinoblastoma Protein
* Signal Transduction
* Tumor Microenvironment
* Vascular Remodeling
|keywords=* T cells
* chemotherapy resistance
* endothelial cell activation
* immunotherapy
* pancreatic cancer
* senescence
* senescence-associated secretory phenotype
* targeted therapy
* tumor microenvironment
* vascular biology
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278897
}}
==LBP==
 
{{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
}}
==LBR==
 
{{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
}}
==LMNA==
 
{{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
* cellular senescence
* mesothelial cells
* progeria
* microarray analysis
* ruxolitinib
* multiwalled carbon nanotubes
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189991
* γH2A.X
|full-text-url=https://sci-hub.do/10.1016/j.mad.2020.111412
}}
}}
==LOX==
{{medline-entry
{{medline-entry
|title=SIRT1 - a new mammalian substrate of nuclear autophagy.
|title=12-[[LOX]] catalyzes the oxidation of 2-arachidonoyl-lysolipids in platelets generating eicosanoid-lysolipids that are attenuated by iPLA γ knockout.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33292048
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32161117
|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.
|abstract=The canonical pathway of eicosanoid production in most mammalian cells is initiated by phospholipase A -mediated release of arachidonic acid, followed by its enzymatic oxidation resulting in a vast array of eicosanoid products. However, recent work has demonstrated that the major phospholipase in mitochondria, iPLA γ (patatin-like phospholipase domain containing 8 (PNPLA8)), possesses [i]sn[/i]-1 specificity, with polyunsaturated fatty acids at the [i]sn[/i]-2 position generating polyunsaturated [i]sn[/i]-2-acyl lysophospholipids. Through strategic chemical derivatization, chiral chromatographic separation, and multistage tandem MS, here we first demonstrate that human platelet-type 12-lipoxygenase (12-[[LOX]]) can directly catalyze the regioselective and stereospecific oxidation of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) and 2-arachidonoyl-lysophosphatidylethanolamine (2-AA-LPE). Next, we identified these two eicosanoid-lysophospholipids in murine myocardium and in isolated platelets. Moreover, we observed robust increases in 2-AA-LPC, 2-AA-LPE, and their downstream 12-[[LOX]] oxidation products, 12([i]S[/i])-HETE-LPC and 12([i]S[/i])-HETE-LPE, in calcium ionophore (A23187)-stimulated murine platelets. Mechanistically, genetic ablation of iPLA γ markedly decreased the calcium-stimulated production of 2-AA-LPC, 2-AA-LPE, and 12-HETE-lysophospholipids in mouse platelets. Importantly, a potent and selective 12-[[LOX]] inhibitor, ML355, significantly inhibited the production of 12-HETE-LPC and 12-HETE-LPE in activated platelets. Furthermore, we found that aging is accompanied by significant changes in 12-HETE-LPC in murine serum that were also markedly attenuated by iPLA γ genetic ablation. Collectively, these results identify previously unknown iPLA γ-initiated signaling pathways mediated by direct 12-[[LOX]] oxidation of 2-AA-LPC and 2-AA-LPE. This oxidation generates previously unrecognized eicosanoid-lysophospholipids that may serve as biomarkers for age-related diseases and could potentially be used as targets in therapeutic interventions.
 
|keywords=* 2-arachidonoyl-lysophospholipids
* aging
* calcium
* eicosanoid
* iPLA2γ
* lysophospholipid
* myocardium
* platelet
* platelet-type 12-lipoxygenase (12-LOX)
* polyunsaturated fatty acids (PUFAs)
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170522
}}
==LPA==


{{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
|keywords=* Aging
* SIRT1
* Compensation
* nuclear autophagy
* High intensity
* senescence
* Movement behaviours
* sirtuin
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01502-6
|full-text-url=https://sci-hub.do/10.1080/15548627.2020.1860541
}}
{{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
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049087
}}
==LPO==
 
{{medline-entry
|title=[Features of the changes in lipid peroxidation and activity of Na+/K+-ATPase in the brain of the aged rats in the conditions of two-vessel cerebral ischemia/reperfusion.]
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32160433
|abstract=The success of preclinical neuroprotection studies depends on the model used in animal research. The methodological approaches developed on young animals and widely used for modeling cerebral ischemia/reperfusion injury may not be so effective or not suitable for its modeling on senescent animals, which usage is recommended for preclinical trials. The aim of this study was to investigate the age-related features on the effect of brain reperfusion with different duration (1 and 3 h) after 2-vessel forebrain ischemia on the level of lipid peroxidation ([[LPO]]) products and on the activity of Na+/K+-ATPase in the cerebral cortex of rats aged 22-24 months. We found a later accumulation of [[LPO]] products (3 h instead of 1 h after blood recirculation), specifically triene conjugates and Schiff bases, and a decrease in the activity of Na+/K+-ATPase in the cerebral cortex of aged rats compared to young animals. The data obtained reveal the difference in the molecular and physiological mechanisms of the development of disorders in the brain during ischemia/reperfusion in aged and young animals. The revealed differences in these mechanisms should be consider in developing and testing compounds, which will be further used for the treatment of elderly patients with stroke and ischemic brain damage.
|mesh-terms=* Aging
* Animals
* Brain Ischemia
* Disease Models, Animal
* Lipid Peroxidation
* Rats
* Reperfusion Injury
* Sodium-Potassium-Exchanging ATPase
|keywords=* Na+/K+-ATPase
* aging
* brain
* lipid peroxidation
* oxidative stress
* stroke
 
}}
==LRP1==
 
{{medline-entry
|title=Drug Targeting of Plasminogen Activator Inhibitor-1 Inhibits Metabolic Dysfunction and Atherosclerosis in a Murine Model of Metabolic Syndrome.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32268785
|abstract=Enhanced expression of PAI-1 (plasminogen activator inhibitor-1) has been implicated in atherosclerosis formation in humans with obesity and metabolic syndrome. However, little is known about the effects of pharmacological targeting of PAI-1 on atherogenesis. This study examined the effects of pharmacological PAI-1 inhibition on atherosclerosis formation in a murine model of obesity and metabolic syndrome. Approach and Results: LDL receptor-deficient ([i]ldlr[/i] ) mice were fed a Western diet high in cholesterol, fat, and sucrose to induce obesity, metabolic dysfunction, and atherosclerosis. Western diet triggered significant upregulation of PAI-1 expression compared with normal diet controls. Addition of a pharmacological PAI-1 inhibitor (either PAI-039 or MDI-2268) to Western diet significantly inhibited obesity and atherosclerosis formation for up to 24 weeks without attenuating food consumption. Pharmacological PAI-1 inhibition significantly decreased macrophage accumulation and cell senescence in atherosclerotic plaques. Recombinant PAI-1 stimulated smooth muscle cell senescence, whereas a PAI-1 mutant defective in [[LRP1]] (LDL receptor-related protein 1) binding did not. The prosenescent effect of PAI-1 was blocked by PAI-039 and R2629, a specific anti-[[LRP1]] antibody. PAI-039 significantly decreased visceral adipose tissue inflammation, hyperglycemia, and hepatic triglyceride content without altering plasma lipid profiles. Pharmacological targeting of PAI-1 inhibits atherosclerosis in mice with obesity and metabolic syndrome, while inhibiting macrophage accumulation and cell senescence in atherosclerotic plaques, as well as obesity-associated metabolic dysfunction. PAI-1 induces senescence of smooth muscle cells in an [[LRP1]]-dependent manner. These results help to define the role of PAI-1 in atherosclerosis formation and suggest a new plasma-lipid-independent strategy for inhibiting atherogenesis.
|mesh-terms=* Animals
* Atherosclerosis
* Cellular Senescence
* Diet, Western
* Disease Models, Animal
* Indoleacetic Acids
* Macrophages
* Metabolic Syndrome
* Mice
* Mice, Knockout
* Obesity
* Plaque, Atherosclerotic
* Plasminogen Activator Inhibitor 1
* Receptors, LDL
|keywords=* atherosclerosis
* cellular senescence
* fibrinolysis
* metabolic syndrome
* muscle, smooth
* obesity
* plasminogen activator inhibitor-1
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255962
}}
==LRP6==
 
{{medline-entry
|title=Low-density lipoprotein receptor-related protein 6-mediated signaling pathways and associated cardiovascular diseases: diagnostic and therapeutic opportunities.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32076828
|abstract=Low-density lipoprotein receptor-related protein 6 ([[LRP6]]) is a member of the low-density lipoprotein receptors (LDLRs) family and accumulating evidence points to the critical role of [[LRP6]] in cardiovascular health and homeostasis. In addition to presenting the well-appreciated roles in canonical signaling regulating blood pressure, blood glucose, lipid metabolism, atherosclerosis, cardiac valve disease, cardiac development, Alzheimer's disease and tumorigenesis, [[LRP6]] also inhibits non-canonical Wnt signals that promote arterial smooth muscle cell proliferation and vascular calcification. Noticeably, the role of [[LRP6]] is displayed in cardiometabolic disease, an increasingly important clinical burden with aging and obesity. The prospect for cardiovascular diseases treatment via targeting [[LRP6]]-mediated signaling pathways may improve central blood pressure and lipid metabolism, and reduce neointima formation and myocardial ischemia-reperfusion injury. Thus, a deep and comprehensive understanding of [[LRP6]] structure, function and signaling pathways will contribute to clinical diagnosis, therapy and new drug development for [[LRP6]]-related cardiovascular diseases.
|mesh-terms=* Aging
* Animals
* Cardiovascular Diseases
* Humans
* Low Density Lipoprotein Receptor-Related Protein-6
* Muscle, Smooth, Vascular
* Myocytes, Smooth Muscle
* Obesity
* Signal Transduction
* Structure-Activity Relationship
* Vascular Calcification
* Wnt Signaling Pathway
|keywords=#f
|full-text-url=https://sci-hub.do/10.1007/s00439-020-02124-8
}}
==LRRK2==
 
{{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
}}
==MBP==
 
{{medline-entry
|title=Demyelination associated with chronic arsenic exposure in Wistar rats.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32171569
|abstract=Inorganic arsenic is among the major contaminants of groundwater in the world. Worldwide population-based studies demonstrate that chronic arsenic exposure is associated with poor cognitive performance among children and adults, while research in animal models confirms learning and memory deficits after arsenic exposure. The aim of this study was to investigate the long-term effects of environmentally relevant arsenic exposure in the myelination process of the prefrontal cortex (PFC) and corpus callosum (CC). A longitudinal study with repeated follow-up assessments was performed in male Wistar rats exposed to 3 ppm sodium arsenite in drinking water. Animals received the treatment from gestation until 2, 4, 6, or 12 months of postnatal age. The levels of myelin basic protein ([[MBP]]) were evaluated by immunohistochemistry/histology and immunoblotting from the PFC and CC. As plausible alterations associated with demyelination, we considered mitochondrial mass (VDAC) and two axonal damage markers: amyloid precursor protein (APP) level and phosphorylated neurofilaments. To analyze the microstructure of the CC in vivo, we acquired diffusion-weighted images at the same ages, from which we derived metrics using the tensor model. Significantly decreased levels of [[MBP]] were found in both regions together with significant increases of mitochondrial mass and slight axonal damage at 12 months in the PFC. Ultrastructural imaging demonstrated arsenic-associated decreases of white matter volume, water diffusion anisotropy, and increases in radial diffusivity. This study indicates that arsenic exposure is associated with a significant and persistent negative impact on microstructural features of white matter tracts.
|mesh-terms=* Aging
* Amyloid beta-Protein Precursor
* Animals
* Arsenic Poisoning
* Arsenites
* Axons
* Corpus Callosum
* Demyelinating Diseases
* Diffusion Tensor Imaging
* Drinking Water
* Immunohistochemistry
* Male
* Mitochondria
* Myelin Basic Protein
* Neurofilament Proteins
* Prefrontal Cortex
* Rats
* Rats, Wistar
* Sodium Compounds
* White Matter
|keywords=* Amyloid
* Anisotropy
* Arsenic
* Axonal damage
* DTI
* Demyelination
* Development
* MRI
* Microstructure
* Mitochondria
|full-text-url=https://sci-hub.do/10.1016/j.taap.2020.114955
}}
{{medline-entry
|title=Natural killer cells as participants in pathogenesis of rat experimental autoimmune encephalomyelitis (EAE): lessons from research on rats with distinct age and strain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32140045
|abstract=Natural killer (NK) cells, influencing dendritic cell (DC)-mediated CD4+ lymphocyte priming in draining lymph nodes (dLNs) and controlling spinal cord (SC) infiltration with encephalitogenic CD4+T lymphocytes, modulate EAE (multiple sclerosis model). This study examined their putative contribution to age-related differences in EAE development in Dark Agouti (DA) (exhibiting age-related decrease in EAE susceptibility) and Albino Oxford (AO) (becoming susceptible to EAE with aging) rats. Aging increased NK cell number in dLNs from rats of both strains. In AO rats, but not in DA ones, it also increased the numbers of IFN-γ-producing NK cells (important for DC activation) and activated/matured DCs, thereby increasing activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated CD25+Foxp3-CD4+ cell number. Aging in DA rats diminished activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated Foxp3-CD4+ cell number. However, [[MBP]]-stimulated CD4+ cell proliferation did not differ in dLN cell cultures from young and aged AO rats (as more favorable activated/matured DC/Foxp3-CD4+ cell ratio was abrogated by lower intrinsic CD4+ cell proliferative capacity and a greater regulatory CD25+Foxp3+CD4+ lymphocyte frequency), but was lower in those from aged compared with young DA rats. At SC level, aging shifted Foxp3-CD4+/cytotoxic CX3CR1+ NK cell ratio towards the former in AO rats, so it was less favorable in aged AO rats exhibiting prolonged neurological deficit compared with their DA counterparts. The study showed strain and age differences in number of IFN-γ-producing NK cells in EAE rat dLNs, and suggested that their pathogenetic relevance depends on frequency and/or activity of other cells involved in CD4+ T cell (auto)immune response.
 
|keywords=* EAE
* NK cells
* aging
* dendritic cells
* strain differences
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050050
}}
==MDH1==
 
{{medline-entry
|title=Oxidative Damage to the TCA Cycle Enzyme [[MDH1]] Dysregulates Bioenergetic Enzymatic Activity in the Aged Murine Brain.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32175745
|abstract=Aging can have profound effects on the mammalian brain leading to neurodegeneration and cognitive impairment. The brain has exceptionally high-energy requirements and is particularly susceptible to damage within its bioenergetic pathways. Here, we asked how the bioenergetic proteome of the murine brain changed with age and how this might affect brain function. Using label-free LC-MS/MS proteomics for the discovery phase and quantitative multiple reaction monitoring LC-MRM-MS/MS for the validation phase, we found dysregulated expression of multiple components of the tricarboxylic acid cycle, which is key for mitochondrial energy production, including SULA2, IDH1, IDH2, SDHB, PDHB, [[MDH1]], FH1, and NDUFS3, in old murine brains. We also saw that the oxidoreductases, thioredoxin and glutaredoxin, were significantly down-regulated in the old mouse brain and showed through MS that this correlated with the accumulation of trioxidation in the key metabolic enzyme [[MDH1]] at Cys137. 3D modeling of [[MDH1]] predicted that the damaged sites were located at the protein active zone, and enzymatic kinetic analysis confirmed that [[MDH1]] function was significantly reduced in the old mouse brain. These findings identify the tricarboxylic acid cycle as a key target of degenerative protein modifications with deleterious effects on the aging brain's bioenergetic function.
 
|keywords=* DPM
* MRM
* TCA cycle
* aging
* brain
|full-text-url=https://sci-hub.do/10.1021/acs.jproteome.9b00861
}}
}}
==MB==
==MET==


{{medline-entry
{{medline-entry
|title=Probing menstrual bloodstain aging with fluorescence spectroscopy.
|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/33279406
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32170049
|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.
|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=* Aging
|keywords=* exercise
* Analytical methods
* healthy aging
* Blood
* physical activity
* Fluorescence spectroscopy
* retirement
* Forensics
* successful aging
|full-text-url=https://sci-hub.do/10.1016/j.saa.2020.119172
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7093185
}}
}}
==MMD==
==MMD==


{{medline-entry
{{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.
|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/33266358
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32105353
|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.
|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
}}
==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
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026423
}}
==MPHOSPH6==
 
{{medline-entry
|title=Genome-wide Association Analysis in Humans Links Nucleotide Metabolism to Leukocyte Telomere Length.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32109421
|abstract=Leukocyte telomere length (LTL) is a heritable biomarker of genomic aging. In this study, we perform a genome-wide meta-analysis of LTL by pooling densely genotyped and imputed association results across large-scale European-descent studies including up to 78,592 individuals. We identify 49 genomic regions at a false dicovery rate (FDR) < 0.05 threshold and prioritize genes at 31, with five highlighting nucleotide metabolism as an important regulator of LTL. We report six genome-wide significant loci in or near SENP7, MOB1B, CARMIL1, PRRC2A, TERF2, and RFWD3, and our results support recently identified PARP1, POT1, ATM, and [[MPHOSPH6]] loci. Phenome-wide analyses in >350,000 UK Biobank participants suggest that genetically shorter telomere length increases the risk of hypothyroidism and decreases the risk of thyroid cancer, lymphoma, and a range of proliferative conditions. Our results replicate previously reported associations with increased risk of coronary artery disease and lower risk for multiple cancer types. Our findings substantially expand current knowledge on genes that regulate LTL and their impact on human health and disease.
|mesh-terms=* Genome-Wide Association Study
* Humans
* Leukocytes
* Nucleotides
* Telomere
|keywords=* Mendelian randomisation
* age-related disease
* biological aging
* telomere length
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058826
}}
==MPI==
 
{{medline-entry
|title=Age-related decline of lymphatic drainage from the eye: A noninvasive in vivo photoacoustic tomography study.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32251650
|abstract=We aim to determine whether lymphatic drainage from the eye changes with age. Using quantitative photoacoustic tomography, groups of young and older mice were studied in the live state. 10 CD-1 mice of 2-3 months (5M/5F) were studied in addition to 13 older mice of 12-13 months (6M/7F). In each of 23 mice, near-infrared tracer (a near-infrared dye, QC-1 conjugated with Bovine Serum Albumin) was injected into the right eye, and imaging of ipsilateral cervical lymph nodes was performed with laser pulses at 11 different wavelengths prior to and 20 min, 2, 4 and 6 h after injection. Mean pixel intensities ([[MPI]]s) of nodes were calculated at each imaging session. The areas under the curves (AUC) were calculated for both groups of mice and compared using the t-test. The slopes of [[MPI]] of each region of interest were compared using the linear mixed model before and after adjusting for sex, body weight and intraocular pressure of the right eye. The mean intraocular pressure of right eyes before injection was similar in older and younger groups (12.77 ± 2.01 mmHg and 12.90 ± 2.38 mmHg, respectively; p = 0.888). In each mouse, the photoacoustic signal was detected in the right cervical lymph nodes at the 2-h time point following tracer injection into the right eye. At the 4 and 6 h imaging times, a steady increase of tracer signal was observed. Areas under the curve in the right cervical nodes were decreased significantly in older mice compared to younger mice (p = 0.007). The slopes of [[MPI]] in the nodes were significantly decreased in old mice compared to young mice both before and after adjusting for sex, body weight and intraocular pressure of the right eye (p = 0.003). In conclusion, lymphatic drainage from the eye is significantly reduced in older eyes. This finding suggests that impaired lymphatic clearance of aqueous humor, proteins and antigens from the eye may contribute to age-related disease of the eye such as glaucoma and inflammatory eye disease.


|keywords=* LIFE Study
|keywords=* Age-related
* deficit accumulation
* Aging
* disability
* Aqueous humor
* frailty
* Drainage
* healthy aging
* Eye
* mobility
* Glaucoma
* older adults
* Imaging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700674
* In vivo
* Lymph node
* Lymphatic
* Mice
* Photoacoustic tomography
* Uveoscleral
|full-text-url=https://sci-hub.do/10.1016/j.exer.2020.108029
}}
}}
==MSC==
==MSC==


{{medline-entry
{{medline-entry
|title=Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys.
|title=Human Obesity Induces Dysfunction and Early Senescence in Adipose Tissue-Derived Mesenchymal Stromal/Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33264634
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32274385
|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.
|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=* Aging
|keywords=* adipose tissue
* Cortical injury
* cellular dysfunction
* Extracellular vesicles
* cellular senescence
* Monkeys
* mesenchymal stem cells
* Myelin
* obesity
* Non-human primates
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7113401
* Oligodendrocytes
}}
* Stroke
{{medline-entry
* White matter
|title=miR-155-5p inhibition rejuvenates aged mesenchymal stem cells and enhances cardioprotection following infarction.
|full-text-url=https://sci-hub.do/10.1016/j.expneurol.2020.113540
|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
{{medline-entry
|title=Rejuvenation of Senescent Endothelial Progenitor Cells by Extracellular Vesicles Derived From Mesenchymal Stromal Cells.
|title=Mesenchymal Stem Cell Derived Extracellular Vesicles in Aging.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33294742
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32154253
|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.
|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=* BM, bone marrow
|keywords=* aging
* CVD, cardiovascular disease
* clinical translation
* 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
* extracellular vesicles
* lin− BMC, lineage negative bone marrow cell
* mesenchymal stem cells
* miR, microRNA
* regenerative medicine
* qPCR, quantitative transcription polymerase chain reaction
* regeneration
* senescence
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691285
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047768
}}
}}
==MYSM1==
{{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
{{medline-entry
|title=[[MYSM1]] Suppresses Cellular Senescence and the Aging Process to Prolong Lifespan.
|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/33240758
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32125888
|abstract=Aging is a universal feature of life that is a major focus of scientific research and a risk factor in many diseases. A comprehensive understanding of the cellular and molecular mechanisms of aging are critical to the prevention of diseases associated with the aging process. Here, it is shown that [[MYSM1]] is a key suppressor of aging and aging-related pathologies. [[MYSM1]] functionally represses cellular senescence and the aging process in human and mice primary cells and in mice organs. [[MYSM1]] mechanistically attenuates the aging process by promoting DNA repair processes. Remarkably, [[MYSM1]] deficiency facilitates the aging process and reduces lifespan, whereas [[MYSM1]] over-expression attenuates the aging process and increases lifespan in mice. The functional role of [[MYSM1]] is demonstrated in suppressing the aging process and prolonging lifespan. [[MYSM1]] is a key suppressor of aging and may act as a potential agent for the prevention of aging and aging-associated diseases.
|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=* DNA repair
|keywords=* RG108
* Myb‐like, SWIRM, and MPN domains‐containing protein 1 (MYSM1)
* apoptosis
* aging
* pluripotency
* porcine bone marrow mesenchymal stem cells
* senescence
* senescence
* senescence‐associated secretory phenotype (SASP)
|full-text-url=https://sci-hub.do/10.1089/cell.2019.0060
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675055
}}
{{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
}}
==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
}}
==MTR==
 
{{medline-entry
|title=Amide proton transfer-weighted magnetic resonance imaging of human brain aging at 3 Tesla.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32269932
|abstract=Amide proton transfer-weighted (APTw) imaging has been revealed to hold great potential in the diagnosis of several brain diseases. The purpose of this proof-of-concept study was to evaluate the feasibility and value of APTw magnetic resonance imaging (MRI) in characterizing normal brain aging. A total of 106 healthy subjects were recruited and scanned at 3.0 Tesla, with APTw and conventional magnetization transfer (MT) sequences. Quantitative image analyses were performed in 12 regions of interest (ROIs) for each subject. The APTw or MT ratio ([[MTR]]) signal differences among five age groups (young, mature, middle-aged, young-old, and middle-old) were assessed using the one-way analysis of variance, with the Benjamini-Hochberg correction for multiple comparisons. The relationship between APTw and [[MTR]] signals and the age dependencies of APTw and [[MTR]] signals were assessed using the Pearson correlation and non-linear regression. There were no significant differences between the APTw or [[MTR]] values for males and females in any of the 12 ROIs analyzed. Among the five age groups, there were significant differences in the three white matter regions in the temporal, occipital, and frontal lobes. Overall, the mean APTw values in the older group were higher than those in the younger group. Positive correlations were observed in relation to age in most brain regions, including four with significant positive correlations (r=0.2065-0.4182) and five with increasing trends. As a comparison, the mean [[MTR]] values did not appear to be significantly different among the five age groups. In addition, the mean APTw and [[MTR]] values revealed significant positive correlations in 10 ROIs (r=0.2214-0.7269) and a significant negative correlation in one ROI (entorhinal cortex, r=-0.2141). Our early results show that the APTw signal can be used as a promising and complementary imaging biomarker with which normal brain aging can be evaluated at the molecular level.
 
|keywords=* Aging
* amide proton transfer imaging
* biomarkers
* chemical exchange saturation transfer (CEST)
* molecular imaging
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136735
}}
}}
==NLRP3==
==NLRP3==


{{medline-entry
{{medline-entry
|title=Innate and Adaptive Immunity in Aging and Longevity: The Foundation of Resilience.
|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/33269094
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32114413
|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.
|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
}}
==PC==


|keywords=* adaptive immunity
{{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
|keywords=#f
|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
}}
==PCNA==
 
{{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
* aging
* innate immunity
* blood vessels
* longevity
* fibroblasts
* resilience
* skin
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673842
 
}}
}}
==NOX4==
==PGC==


{{medline-entry
{{medline-entry
|title=Sestrin2 Attenuates Cellular Senescence by Inhibiting NADPH Oxidase 4 Expression.
|title=[Metabolic Alteration in Aging Process: Metabolic Remodeling in White Adipose Tissue by Caloric Restriction].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33227845
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32115557
|abstract=Sestrin2 (Sesn2) is involved in the maintenance of metabolic homeostasis and aging via modulation of the 5' AMP-activated protein kinase-mammalian target of rapamycin (AMPK-mTOR) pathway. Wild-type and Sesn2 knockout (KO) mice of the 129/SvJ background were maintained in a pathogen-free authorized facility under a 12-hour dark/light cycle at 20°C-22°C and 50%-60% humidity. Mouse embryonic fibroblasts (MEFs) were prepared from 13.5-day-old embryos derived from Sesn2-KO mice mated with each other. The MEFs from Sesn2-KO mice showed enlarged and flattened morphologies and senescence-associated β-galactosidase activity, accompanied by an elevated level of reactive oxygen species. These senescence phenotypes recovered following treatment with N-acetyl-cysteine. Notably, the mRNA levels of NADPH oxidase 4 ([[NOX4]]) and transforming growth factor (TGF)-β were markedly increased in Sesn2-KO MEFs. Treatment of Sesn2-KO MEFs with the NOX inhibitor diphenyleneiodonium and the TGF-β inhibitor SB431542 restored cell growth inhibited by Sesn2-KO. Sesn2 attenuates cellular senescence via suppression of TGF-β- and [[NOX4]]-induced reactive oxygen species generation and subsequent inhibition of AMPK.
|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=* NOX4
|keywords=* Aging
* Reactive oxygen species
* Kynurenine aminotransferases
* Mitochondria
* Muscle fiber-type
* Skeletal muscle
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110880
}}
==PINK1==
 
{{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
}}
==PLK4==
 
{{medline-entry
|title=A novel lncRNA [[PLK4]] up-regulated by talazoparib represses hepatocellular carcinoma progression by promoting YAP-mediated cell senescence.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32243714
|abstract=A growing number of studies recognize that long non-coding RNAs (lncRNAs) are essential to mediate multiple tumorigenic processes, including hepatic tumorigenesis. However, the pathological mechanism of lncRNA-regulated liver cancer cell growth remains poorly understood. In this study, we identified a novel function lncRNA, named polo-like kinase 4 associated lncRNA (lncRNA [[PLK4]], GenBank Accession No. RP11-50D9.3), whose expression was dramatically down-regulated in hepatocellular carcinoma (HCC) tissues and cells. Interestingly, talazoparib, a novel and highly potent poly-ADP-ribose polymerase 1/2 (PARP1/2) inhibitor, could increase lncRNA [[PLK4]] expression in HepG2 cells. Importantly, we showed that talazoparib-induced lncRNA [[PLK4]] could function as a tumour suppressor gene by Yes-associated protein (YAP) inactivation and induction of cellular senescence to inhibit liver cancer cell viability and growth. In summary, our findings reveal the molecular mechanism of talazoparib-induced anti-tumor effect, and suggest a potential clinical use of talazoparib-targeted lncRNA [[PLK4]]/YAP-dependent cellular senescence for the treatment of HCC.
 
|keywords=* Yes-associated protein
* cellular senescence
* hepatocellular carcinoma
* polo-like kinase 4 associated lncRNA
* talazoparib
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205816
}}
{{medline-entry
|title=Differential expression of AURKA/[[PLK4]] in quiescence and senescence of osteosarcoma U2OS cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32200684
|abstract=This study aimed to identify co-expressed differentially expressed genes (DEGs) in quiescence and senescence of osteosarcoma (OS) U2OS cells and investigate their biological functions. GSE94805 from Gene Expression Omnibus database was extracted, involving 12 samples of OS U2OS cells (4 quiescence, 4 senescence, and 4 control samples). After analysis of DEGs by limma package, VENN analysis was performed to identify co-expressed DEGs in quiescence and senescent. The Cytoscape software was used to construct an interactive network of co-expressed DEGs. Finally, box-plot was drawn for the co-expressed DEGs in sub-network. Besides, the relation literatures were selected in GenCLiP database for the co-expressed DEGs. Seven hundred and forty-three DEGs (255 up-regulated genes, 488 down-regulated genes) were obtained in quiescence and 2135 DEGs (1189 up-regulated genes, 946 down-regulated genes) in senescence. Through VENN analysis, 448 DEGs (131 up-regulated genes, 317 down-regulated genes) were co-expressed in quiescent and senescence. In the co-expressed DEGs network, 896 nodes (448 nodes in quiescent, 448 nodes in senescent) were obtained. Finally, 16 co-expressed DEGs were obtained in the sub-network analysis, in which Aurora kinase A (AURKA) and polo-like kinase ([[PLK4]]) had been reported in OS. AURKA and [[PLK4]] might be the key genes in quiescence and senescence of OS U2OS cells.
 
|keywords=* AURKA
* Osteosarcoma
* PLK4
* quiescence
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217361
}}
==PRDX3==
 
{{medline-entry
|title=Proteomic analyses reveal that ginsenoside Rg3([i]S[/i]) partially reverses cellular senescence in human dermal fibroblasts by inducing peroxiredoxin.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32148389
|abstract=The cellular senescence of primary cultured cells is an irreversible process characterized by growth arrest. Restoration of senescence by ginsenosides has not been explored so far. Rg3([i]S[/i]) treatment markedly decreased senescence-associated β-galactosidase activity and intracellular reactive oxygen species levels in senescent human dermal fibroblasts (HDFs). However, the underlying mechanism of this effect of Rg3([i]S[/i]) on the senescent HDFs remains unknown. We performed a label-free quantitative proteomics to identify the altered proteins in Rg3([i]S[/i])-treated senescent HDFs. Upregulated proteins induced by Rg3([i]S[/i]) were validated by real-time polymerase chain reaction and immunoblot analyses. Finally, 157 human proteins were identified, and variable peroxiredoxin (PRDX) isotypes were highly implicated by network analyses. Among them, the mitochondrial [[PRDX3]] was transcriptionally and translationally increased in response to Rg3([i]S[/i]) treatment in senescent HDFs in a time-dependent manner. Our proteomic approach provides insights into the partial reversing effect of Rg3 on senescent HDFs through induction of antioxidant enzymes, particularly [[PRDX3]].
 
|keywords=* Ginsenoside Rg3(S)
* Human dermal fibroblast
* Label-free quantitative proteomics
* Restoration
* Senescence
* Senescence
* Sestrin2
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7033328
|full-text-url=https://sci-hub.do/10.4235/agmr.20.0051
}}
==PSMD14==
 
{{medline-entry
|title=Upregulation of deubiquitinase [[PSMD14]] in lung adenocarcinoma (LUAD) and its prognostic significance.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32226511
|abstract=[[PSMD14]] is a 19S-proteasome-associated deubiquitinating enzyme that facilitates protein degradation by the 20S proteasome core particle. Although accumulating evidence indicates that [[PSMD14]] has emerged as a critical oncogenic factor by promoting tumor growth, the expression and function of [[PSMD14]] in non-small cell lung cancer (NSCLC) remain largely unknown. In this study, we assessed [[PSMD14]] expression and correlated it with clinical-pathological features and patient survival in NSCLC. We also determined the roles of [[PSMD14]] in the regulation of lung adenocarcinoma (LUAD) cell growth. The results showed that [[PSMD14]] expression was significantly upregulated in human NSCLC tissues compared with adjacent non-cancerous tissues. The [[PSMD14]] level was associated with tumor size, lymph node invasion, and TNM stage in LUAD patients. Importantly, high [[PSMD14]] expression was associated with poor overall survival (OS) and disease-free survival (DFS) in LUAD patients. Further, knockdown of [[PSMD14]] significantly inhibited cell growth and caused G1 arrest and cellular senescence by increasing p21 stability in LUAD cells. [[PSMD14]] knockdown also promoted cell apoptosis by increasing cleaved caspase-3 levels in H1299 cells. [[PSMD14]] may serve as a potential prognostic marker and therapeutic target for LUAD patients.
 
|keywords=* PMSD14
* apoptosis
* deubiquitinating enzyme
* lung adenocarcinoma
* prognosis
* senescence
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7086243
}}
==PTH==
 
{{medline-entry
|title=Parathyroid hormone ameliorates temporomandibular joint osteoarthritic-like changes related to age.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32154622
|abstract=Ageing could be a contributing factor to the progression of temporomandibular joint osteoarthritis (TMJ OA), whereas its pathogenesis and potential therapeutic strategy have not been comprehensively investigated. We generated ageing mouse models (45-week and 60-week; 12-week mice as control) and intermittently injected 45-week mice with parathyroid hormone ([[PTH]](1-34)) or vehicle for 4 weeks. Cartilage and subchondral bone of TMJ were analysed by microCT, histological and immunostaining. Western blot, qRT-PCR, ChIP, ELISA and immunohistochemical analysis were utilized to examination the mechanism of [[PTH]](1-34)'s function. We showed apparent OA-like phenotypes in ageing mice. [[PTH]] treatment could ameliorate the degenerative changes and improve bone microarchitecture in the subchondral bone by activating bone remodelling. Moreover, [[PTH]] inhibited phosphorylation level of Smad3, which can combine with p16  gene promoter region, resulting in reduced senescent cells accumulation and increased cellular proliferation of marrow mesenchymal stem cells (MSCs). ELISA also showed relieved levels of specific senescent-associated secretory phenotype (SASP) in ageing mice after [[PTH]] treatment. In summary, [[PTH]] may reduce the accumulation of senescent cells in subchondral bone by inhibiting p16  and improve bone marrow microenvironment to active bone remodelling process, indicating [[PTH]] administration could be a potential preventative and therapeutic treatment for age-related TMJ OA.
|mesh-terms=* Aging
* Animals
* Calcium-Regulating Hormones and Agents
* Cells, Cultured
* Disease Models, Animal
* Male
* Mice
* Mice, Inbred C57BL
* Osteoarthritis
* Osteogenesis
* Parathyroid Hormone
* Temporomandibular Joint
|keywords=* cellular senescence
* cyclin-dependent kinase inhibitor P16INK4A
* marrow mesenchymal stem cells
* osteoarthritis
* temporomandibular joint disorders
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162802
}}
==PTTG1==
 
{{medline-entry
|title=[Down-regulated [[PTTG1]] expression promotes the senescence of human prostate cancer LNCaP-AI].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32216239
|abstract=To investigate the effect of the down-regulated expression of pituitary tumor-transforming gene 1 ([[PTTG1]]) on the senescence of human castration-resistant prostate cancer LNCaP-AI cells. Human castration-resistant prostate cancer LNCaP-AI cells were induced in vitro and transfected with siRNA targeting [[PTTG1]] (the siRNA-[[PTTG1]] group), the reagent lip3000 only (the mock group) or siRNA negative control vector (the NC group). All the cells were cultured in fetal bovine serum (FBS) or charcoal-stripped bovine serum (CSS) and counted with the cell counting chamber. The senescence characteristics of the transfected LNCaP-AI cells were examined by senescence-associated β-galactosidase (SA-β-Gal) staining, and the expressions of the senescence-related β-galactosidase-1-like proteins (Glb1), the cyclin-dependent kinase inhibitors p-21CIP1 and p-27Kip1, and the chromatin-regulating heterochromatin protein 1γ (HP1γ) were detected by Western blot. The expression of [[PTTG1]] in the human prostate cancer LNCaP-AI cells was significantly reduced in the siRNA-[[PTTG1]] group compared with those in the mock and NC groups (0.21 ± 0.01 vs 0.56 ± 0.02 and 0.61 ± 0.02, P < 0.05). Culture with FBS markedly increased while that with CSS decreased the number of LNCaP-AI cells transfected with siRNA, but both FBS and CSS enhanced the proliferation of the LNCaP-AI cells in the mock and NC groups. SA-β-Gal staining revealed that reducing the expression of [[PTTG1]] induced a remarkably higher positive rate of the LNCaP-AI cells in the siRNA-[[PTTG1]] than in the mock and NC groups (［63.5 ± 2.35］% vs ［11.3 ± 1.24］% and ［12.4 ± 1.15］%, P < 0.05). The siRNA-[[PTTG1]] group, in comparison with the mock and NC groups, showed a significantly down-regulated expression of [[PTTG1]] (0.21 ± 0.01 vs 0.56 ± 0.02 and 0.61 ± 0.02, P < 0.05), but up-regulated expressions of p-21CIP1 (0.32 ± 0.03 vs 0.20 ± 0.02 and 0.21 ± 0.03, P < 0.05), p-27Kip1 (0.38 ± 0.02 vs 0.20 ± 0.03 and 0.22 ± 0.01, P < 0.05), Glb1 (0.24 ± 0.01 vs 0.13 ± 0.01 and 0.15 ± 0.01, P < 0.05), and HP1γ (0.41 ± 0.01 vs 0.26 ± 0.01 and 0.27 ± 0.02, P < 0.05) in the LNCaP-AI cells. Down-regulated expression of [[PTTG1]] induces senescence of human castration-resistant prostate cancer LNCaP-AI cells.
|mesh-terms=* Cell Line, Tumor
* Cell Proliferation
* Humans
* Male
* Prostatic Neoplasms, Castration-Resistant
* RNA, Small Interfering
* Securin
* beta-Galactosidase
|keywords=*  LNCaP-AI cell
 
*  castration-resistant prostate cancer
*  cellular senescence
*  pituitary tumor-transforming gene-1
* prostate cancer
 
}}
==RELB==
 
{{medline-entry
|title=New control of the senescence barrier in breast cancer.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32158912
|abstract=Normal cells exposed to cancer-causing events respond by triggering cellular senescence, a stress response which halts cell proliferation and constitutes a protective anti-cancer barrier. We have uncovered a previously unknown signaling pathway implicating p21-activated kinase 4 (PAK4) in the control of senescence in breast cancer, via the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunit [[RELB]] and the CCAAT-enhancer-binding protein beta (C/EBPβ).
 
|keywords=* CEBPB
* Cellular senescence
* PAK4
* RELB
* p21-activated kinase
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051141
}}
==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
}}
==RET==
 
{{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
}}
==RHO==
 
{{medline-entry
|title=SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32246845
|abstract=The SARS-CoV-2 pandemic affecting the human respiratory system severely challenges public health and urgently demands for increasing our understanding of COVID-19 pathogenesis, especially host factors facilitating virus infection and replication. SARS-CoV-2 was reported to enter cells via binding to ACE2, followed by its priming by TMPRSS2. Here, we investigate ACE2 and TMPRSS2 expression levels and their distribution across cell types in lung tissue (twelve donors, 39,778 cells) and in cells derived from subsegmental bronchial branches (four donors, 17,521 cells) by single nuclei and single cell RNA sequencing, respectively. While TMPRSS2 is strongly expressed in both tissues, in the subsegmental bronchial branches ACE2 is predominantly expressed in a transient secretory cell type. Interestingly, these transiently differentiating cells show an enrichment for pathways related to [[RHO]] GTPase function and viral processes suggesting increased vulnerability for SARS-CoV-2 infection. Our data provide a rich resource for future investigations of COVID-19 infection and pathogenesis.
|mesh-terms=* Adult
* Aging
* Angiotensin-Converting Enzyme 2
* Bronchi
* COVID-19
* Cells, Cultured
* Chronic Disease
* Coronavirus Infections
* Epithelial Cells
* Female
* Gene Expression
* Gene Expression Profiling
* Germany
* Goblet Cells
* Humans
* Lung
* Male
* Middle Aged
* Pandemics
* Peptidyl-Dipeptidase A
* Pneumonia, Viral
* Reference Standards
* Sequence Analysis, RNA
* Serine Endopeptidases
* Sex Characteristics
* Single-Cell Analysis
* Smoking
* Tissue Banks
|keywords=*
FURIN
 
* COVID-19
* Human Cell Atlas
* epithelial differentiation
* respiratory tract
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7232010
}}
}}
==NPR1==
==RPE==


{{medline-entry
{{medline-entry
|title=The [[NPR1]]-WRKY46-WRKY6 signaling cascade mediates probenazole/salicylic acid-elicited leaf senescence in Arabidopsis thaliana.
|title=CSF1R blockade induces macrophage ablation and results in mouse choroidal vascular atrophy and [[RPE]] disorganization.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33270345
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32234210
|abstract=Endogenous salicylic acid (SA) regulates leaf senescence, but the underlying mechanism remains largely unexplored. The exogenous application of SA to living plants is not efficient for inducing leaf senescence. By taking advantage of probenazole (PBZ)-induced biosynthesis of endogenous SA, we previously established a chemical inducible leaf senescence system that depends on SA biosynthesis and its core signaling receptor [[NPR1]] in Arabidopsis thaliana. Here, using this system, we identified WRKY46 and WRKY6 as key components of the transcriptional machinery downstream of [[NPR1]] signaling. Upon PBZ treatment, the wrky46 mutant exhibited significantly delayed leaf senescence. We demonstrate that [[NPR1]] is essential for PBZ/SA-induced WRKY46 activation, whereas WRKY46 in turn enhances [[NPR1]] expression. WRKY46 interacts with [[NPR1]] in the nucleus, binding to the W-box of the WRKY6 promoter to induce its expression in response to SA signaling. Dysfunction of WRKY6 abolished PBZ-induced leaf senescence, while overexpression of WRKY6 was sufficient to accelerate leaf senescence even under normal growth conditions, suggesting that WRKY6 may serve as an integration node of multiple leaf senescence signaling pathways. Taken together, these findings reveal that the [[NPR1]]-WRKY46-WRKY6 signaling cascade plays a critical role in PBZ/SA-mediated leaf senescence in Arabidopsis. This article is protected by copyright. All rights reserved.
|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=* Leaf senescence
|keywords=* RPE disorganization
* NPR1
* aging
* Probenazole
* choroid
* Salicylic acid
* choroidal macrophage
* WRKY46
* choroidal vasculature
* WRKY6
* immunology
|full-text-url=https://sci-hub.do/10.1111/jipb.13044
* inflammation
* mouse
* neuroscience
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156269
}}
}}
==P2RY12==
{{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
{{medline-entry
|title=Potential caveats of putative microglia-specific markers for assessment of age-related cerebrovascular neuroinflammation.
|title=Water-based continuous and interval training in older women: Cardiorespiratory and neuromuscular outcomes (WATER study).
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33261619
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32145293
|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.
|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
}}
==S100B==
 
{{medline-entry
|title=Aging protects rat cortical slices against to oxygen-glucose deprivation induced damage.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32064981
|abstract= In present study, we aimed to clarify effect of aging on the susceptibility of brain tissue to neurodegeneration induced by ischemia.  Damage induced by oxygen-glucose deprivation (OGD) followed by reoxygenation (REO) were compared in cortical slices prepared from young (3 months of age) and aged (22-24 months of age) male Sprague Dawley rats.  After incubation of the slices in an oxygen and glucose containing control condition, 2,3,5-triphenyl tetrazolium chloride (TTC) staining intensity was found significantly high in aged cortical slices. Although thirty minutes incubation of the slices in OGD medium followed by REO (OGD-REO) caused similar decline in TTC staining in young and aged cortical slices, staining intensity was still significantly higher in the slices prepared from aged animals. Thirty minutes of OGD-REO, on the other hand, also caused more increase in lactate dehydrogenase (LDH) leakage from young slices. While water contents of the slices were almost equal under control condition, it was significantly high in young cortical slices after OGD-REO incubations. In contrary to these findings, OGD and REO caused more increases in [[S100B]] output from aged rat cortical slices. [[S100B]] levels in brain regions including the cerebral cortex were also found higher in aged rats.  All these results indicate that, cortical slices prepared from aged male rats are significantly less responsive to [i]in vitro[/i] OGD-REO induced alterations. Since protein [[S100B]] outputs were almost doubled from aged cortical slices, a possible involvement of this enhanced [[S100B]] output seems to be likely.


|keywords=* Aging
|keywords=* Aging
* Brain infiltrating myeloid cells
* LDH
* CD45
* S100B
* Cerebral amyloid angiopathy
* edema
* Microglia
* oxygen-glucose deprivation
* Neuroinflammation
|full-text-url=https://sci-hub.do/10.1080/00207454.2020.1730830
* P2RY12
* Stroke
* Tmem119
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709276
}}
}}
==PDK1==
==SAG==


{{medline-entry
{{medline-entry
|title=Inhibition of 3-phosphoinositide-dependent protein kinase 1 ([[PDK1]]) can revert cellular senescence in human dermal fibroblasts.
|title=Neurogenesis in the inner ear: the zebrafish statoacoustic ganglion provides new neurons from a Neurod/Nestin-positive progenitor pool well into adulthood.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33229519
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32165493
|abstract=Cellular senescence is defined as a stable, persistent arrest of cell proliferation. Here, we examine whether senescent cells can lose senescence hallmarks and reenter a reversible state of cell-cycle arrest (quiescence). We constructed a molecular regulatory network of cellular senescence based on previous experimental evidence. To infer the regulatory logic of the network, we performed phosphoprotein array experiments with normal human dermal fibroblasts and used the data to optimize the regulatory relationships between molecules with an evolutionary algorithm. From ensemble analysis of network models, we identified 3-phosphoinositide-dependent protein kinase 1 ([[PDK1]]) as a promising target for inhibitors to convert the senescent state to the quiescent state. We showed that inhibition of [[PDK1]] in senescent human dermal fibroblasts eradicates senescence hallmarks and restores entry into the cell cycle by suppressing both nuclear factor κB and mTOR signaling, resulting in restored skin regeneration capacity. Our findings provide insight into a potential therapeutic strategy to treat age-related diseases associated with the accumulation of senescent cells.
|abstract=The vertebrate inner ear employs sensory hair cells and neurons to mediate hearing and balance. In mammals, damaged hair cells and neurons are not regenerated. In contrast, hair cells in the inner ear of zebrafish are produced throughout life and regenerate after trauma. However, it is unknown whether new sensory neurons are also formed in the adult zebrafish statoacoustic ganglion ([[SAG]]), the sensory ganglion connecting the inner ear to the brain. Using transgenic lines and marker analysis, we identify distinct cell populations and anatomical landmarks in the juvenile and adult [[SAG]]. In particular, we analyze a Neurod/Nestin-positive progenitor pool that produces large amounts of new neurons at juvenile stages, which transitions to a quiescent state in the adult [[SAG]]. Moreover, BrdU pulse chase experiments reveal the existence of a proliferative but otherwise marker-negative cell population that replenishes the Neurod/Nestin-positive progenitor pool at adult stages. Taken together, our study represents the first comprehensive characterization of the adult zebrafish [[SAG]] showing that zebrafish, in sharp contrast to mammals, display continued neurogenesis in the [[SAG]] well beyond embryonic and larval stages.
|mesh-terms=* Adult Stem Cells
* Aging
* Animals
* Animals, Genetically Modified
* Basic Helix-Loop-Helix Transcription Factors
* Cell Differentiation
* Ear, Inner
* Embryo, Nonmammalian
* Ganglia, Sensory
* Gene Expression Regulation, Developmental
* Hair Cells, Auditory
* Larva
* Nerve Tissue Proteins
* Nestin
* Neural Stem Cells
* Neurogenesis
* Sensory Receptor Cells
* Stem Cell Niche
* Zebrafish
|keywords=* Inner ear
* Neuronal stem cells
* PNS
* Zebrafish
|full-text-url=https://sci-hub.do/10.1242/dev.176750
}}
==SCN2B==


|keywords=* PDK1
{{medline-entry
* cellular senescence
|title=MicroRNA‑449a regulates the progression of brain aging by targeting [[SCN2B]] in SAMP8 mice.
* network modeling
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32124967
* skin aging
|abstract=Our previous study demonstrated that the expression of sodium channel voltage‑gated beta 2 ([[SCN2B]]) increased with aging in senescence‑accelerated mouse prone 8 (SAMP8) mice, and was identified to be associated with a decline in learning and memory, while the underlying mechanism is unclear. In the present study, multiple differentially expressed miRNAs, which may be involved in the process of aging by regulating target genes, were identified in the prefrontal cortex and hippocampus of SAMP8 mice though miRNA microarray analysis. Using bioinformatics prediction, [[SCN2B]] was identified to be one of the potential target genes of miR‑449a, which was downregulated in the hippocampus. Previous studies demonstrated that miR‑449a is involved in the occurrence and progression of aging by regulating a variety of target genes. Therefore, it was hypothesized that miR‑449a may be involved in the process of brain aging by targeting [[SCN2B]]. To verify this hypothesis, the following experiments were conducted: A reverse transcription‑quantitative polymerase chain reaction assay revealed that the expression level of miR‑449a was significantly decreased in the prefrontal cortex and hippocampus of 12‑month old SAMP8 mice; a dual‑luciferase reporter assay verified that miR‑449a regulated [[SCN2B]] expression by binding to the 3'‑UTR 'seed region'; an anti‑Ago co‑immunoprecipitation combined with Affymetrix microarray analyses demonstrated that the target mRNA highly enriched with Ago‑miRNPs was confirmed to be [[SCN2B]]. Finally, overexpression of miR‑449a or inhibition of [[SCN2B]] promoted the extension of hippocampal neurons in vitro. The results of the present study suggested that miR‑449a was downregulated in the prefrontal cortex and hippocampus of SAMP8 mice and may regulate the process of brain aging by targeting [[SCN2B]].
* systems biology
|mesh-terms=* Aging
|full-text-url=https://sci-hub.do/10.1073/pnas.1920338117
* Animals
* Brain
* Gene Expression Regulation
* Male
* Mice
* Mice, Transgenic
* MicroRNAs
* Voltage-Gated Sodium Channel beta-2 Subunit
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053848
}}
}}
==PGC==
==SCO1==


{{medline-entry
{{medline-entry
|title=The Aging Stress Response and Its Implication for AMD Pathogenesis.
|title=Real-Time PCR Analysis of Metabolism-Related Genes in a Long-Lived Model of C. elegans.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33266495
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32219749
|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].
|abstract=In the nematode Caenorhabditis elegans, the mammalian tumor suppressor p53 ortholog CEP-1 (C. elegans p53-like protein) is associated not only with the stress response, germline apoptosis, and meiotic chromosome segregation but also with longevity through the modification of energy metabolism during aging. The mitochondrial respiration-related gene sco-1 in C. elegans is orthologous to the human [[SCO1]] gene and a target of p53/CEP-1. Using quantitative real-time polymerase chain reaction (PCR) analysis, we recently found that the expression levels of sco-1 gene were increased in wild-type C. elegans in an aging-related manner and decreased in long-lived cep-1 mutants. Here, we describe the relative quantitative strategy using a commercial real-time PCR system to detect more accurately differences in the levels of expressed genes between long-lived and wild-type C. elegans strains. To estimate the expression levels of target genes compared with wild-type using relative quantification, we used the expression levels of an endogenous control gene, such as a housekeeping gene. In addition, it is critical to normalize differences in the expression levels of the common housekeeping gene among the strains analyzed for an accurate comparison of the quantitative expression levels of target genes.


|keywords=* AMD
|keywords=* Caenorhabditis elegans
* DNA damage response
* Energy metabolism
* PGC-1α
* Longevity
* SIRT1
* TaqMan real-time PCR
* age-related macular degeneration
* p53/CEP-1
* aging
|full-text-url=https://sci-hub.do/10.1007/978-1-0716-0471-7_12
* autophagy
* insulin/IGF-1
* mitochondrial quality control
* the aging stress response
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7700335
}}
}}
==PNN==
==SFPQ==


{{medline-entry
{{medline-entry
|title=Hyaluronan degradation and release of a hyaluronan-aggrecan complex from perineuronal nets in the aged mouse brain.
|title=Downregulation of LncRNA NORAD promotes Ox-LDL-induced vascular endothelial cell injury and atherosclerosis.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33253804
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32267831
|abstract=Perineuronal nets ([[PNN]]s) are insoluble aggregates of extracellular matrix molecules in the brain that consist of hyaluronan (HA) and chondroitin sulfate proteoglycans (CSPGs). [[PNN]]s promote the acquisition and storage of memories by stabilizing the formation of synapses in the adult brain. Although the deterioration of [[PNN]]s has been suggested to contribute to the age-dependent decline in brain function, the molecular mechanisms underlying age-related changes in [[PNN]]s remain unclear. The amount and solubility of [[PNN]] components were investigated by sequential extraction followed by a disaccharide analysis and immunoblotting. We examined the interaction between HA and aggrecan, a major HA-binding CSPG, by combining mass spectrometry and pull-down assays. The solubility and amount of HA increased in the brain with age. Among several CSPGs, the solubility of aggrecan was selectively elevated during aging. In contrast to alternations in biochemical properties, the expression of [[PNN]] components at the transcript level was not markedly changed by aging. The increased solubility of aggrecan was not due to the loss of HA-binding properties. Our results indicated that the degradation of high-molecular-mass HA induced the release of the HA-aggrecan complex from [[PNN]]s in the aged brain. The present study revealed a novel mechanism underlying the age-related deterioration of [[PNN]]s in the brain.
|abstract=Long noncoding RNAs (lncRNAs) play important roles in the development of vascular diseases. However, the effect of lncRNA NORAD on atherosclerosis remains unknown. This study aimed to investigate the effect NORAD on endothelial cell injury and atherosclerosis. Ox-LDL-treated human umbilical vein endothelial cells (HUVECs) and high-fat-diet (HFD)-fed ApoE  mice were used as [i]in vitro[/i] and [i]in vivo[/i] models. Results showed that NORAD-knockdown induced cell cycle arrest in G0/G1 phase, aggravated ox-LDL-induced cell viability reduction, cell apoptosis, and cell senescence along with the increased expression of Bax, P53, P21 and cleaved caspase-3 and the decreased expression of Bcl-2. The effect of NORAD on cell viability was further verified via NORAD-overexpression. NORAD- knockdown increased ox-LDL-induced reactive oxygen species, malondialdehyde, p-IKBα expression levels and NF-κB nuclear translocation. Proinflammatory molecules ICAM, VCAM, and IL-8 were also increased by NORAD- knockdown. Additionally, we identified the strong interaction of NORAD and IL-8 transcription repressor [[SFPQ]] in HUVECs. In ApoE  mice, NORAD-knockdown increased the lipid disorder and atherosclerotic lesions. The results have suggested that lncRNA NORAD attenuates endothelial cell senescence, endothelial cell apoptosis, and atherosclerosis via NF-κB and p53-p21 signaling pathways and IL-8, in which NORAD-mediated effect on IL-8 might through the direct interaction with [[SFPQ]].


|keywords=* Brain aging
|keywords=* IL-8
* Chondroitin sulfate proteoglycan
* NORAD
* Extracellular matrix
* cell apoptosis
* Hyaluronan
* cell senescence
* Perineuronal net
* ox-LDL
|full-text-url=https://sci-hub.do/10.1016/j.bbagen.2020.129804
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185106
}}
}}
==RNF10==
==SGK1==


{{medline-entry
{{medline-entry
|title=Reduced RING finger protein 10 expression in macrophages is associated with aging-related inflammation.
|title=Epigenetic Regulation of KL (Klotho) via H3K27me3 (Histone 3 Lysine [K] 27 Trimethylation) in Renal Tubule Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33249776
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32223380
|abstract=Age-associated decline of the immune system is referred to as immunosenescence. The E3 ligase RING finger 10 ([[RNF10]]) has long been associated with the innate immune response, but a potential role in immunosenescence has not previously been reported. In the present study, we identified that [[RNF10]] expression is lower in aged mouse macrophages than in young cells. After lipopolysaccharide (LPS) stimulation, [[RNF10]] expression remained at a basal low level in aged mouse cells, but declined sharply in young mouse cells. Knockdown of [[RNF10]] enhanced both the nuclear factor-κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways and thus enhanced proinflammatory cytokines and type I interferons (IFN-I) in macrophages, promoting clearance of L. monocytigenes. These findings indicate that dysregulated expression of [[RNF10]] is associated with age-associated immune dysfunction, and [[RNF10]] may thus be a potential target for the treatment of age-related inflammatory diseases.
|abstract=KL (klotho) levels decline with age, which is an important mechanistic driver of aging. [i]KL[/i] gene deficiency is associated with hypertension. The purpose of this study is to investigate the potential role of H3K27me3 (histone 3 lysine [K] 27 trimethylation) in the regulation of [i]KL[/i] gene expression and examine the related molecular pathways that may drive kidney cell aging. Kidneys were collected from 6-month-old WT (wild type; young WT), 30-month-old WT (aged WT), and 6- (young) and 20-month-old (aged) [i]KL[/i] mutant mice, respectively. We demonstrated that the H3K27me3 level was increased in kidneys of aged WT and KL mutant mice versus young WT mice. Elevation of H3K27me3 levels was likely due to downregulation of the H3K27 (histone H3 Lys 27)-specific demethylase JMJD3 (the Jumonji domain containing-3) in the aged kidneys. Inhibition of PRC2 (polycomb repressive complex C2; histone trimethyltransferase) decreased the H3K27me3 levels leading to an increase in the expression of KL in cultured primary renal tubule cells assessed by Western blot and [i]KL[/i] promoter activity assays. The chromatin immunoprecipitation qPCR assay revealed that H3K27me3 was physically associated with the [i]KL[/i] promoter region. Furthermore, aging impaired the [[SGK1]] (serum- and glucocorticoid-induced protein kinase 1)/FOXO3a (the forkhead box class O 3a) signaling leading to upregulation of p53 and p16 (aging markers) in the kidney of aged WT mice. KL may regulate the [[SGK1]]/FOXO3 signaling, which was decreased due to KL deficiency. Thus, aging-associated downregulation of [i]KL[/i] gene expression may be partly attributed to upregulation of H3K27me3 levels. Downregulation of KL may impair the [[SGK1]]/FOXO3 signaling contributing to kidney cell aging.


|keywords=* E3 ubiquitin ligase
|keywords=* AKT
* RNF10
* EZH2
* immunosenescence
* aging
* inflammation
* mTOR
* macrophages
* p53
|full-text-url=https://sci-hub.do/10.1002/2211-5463.13049
|full-text-url=https://sci-hub.do/10.1161/HYPERTENSIONAHA.120.14642
}}
}}
==RPE==
==SI==


{{medline-entry
{{medline-entry
|title=Transcriptomic Profiling of Human Pluripotent Stem Cell-derived Retinal Pigment Epithelium over Time.
|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/33307245
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32161695
|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.
|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
|keywords=* Aging
* Human embryonic stem cell
* Depressive symptoms
* Human pluripotent stem cell
* Mediterranean diet
* Retinal pigment epithelium
* Mental health
* Single-cell RNA sequencing
* Multimorbidity
|full-text-url=https://sci-hub.do/10.1016/j.gpb.2020.08.002
|full-text-url=https://sci-hub.do/10.1016/j.archger.2020.104022
}}
}}
==SIRT1==
==SIRT1==


{{medline-entry
{{medline-entry
|title=Anthocyanins attenuate endothelial dysfunction through regulation of uncoupling of nitric oxide synthase in aged rats.
|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/33274583
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32270742
|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.
|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=* NO
|keywords=* Aging
* Deacetylate
* NAD(+)
* SIRT1
* SIRT1
* anthocyanins
* Signaling pathways
* eNOS deacetylation
|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
}}
==SIRT3==
 
{{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
}}
==SOX9==
 
{{medline-entry
|title=Positive Effects of a Young Systemic Environment and High Growth Differentiation Factor 11 Levels on Chondrocyte Proliferation and Cartilage Matrix Synthesis in Old Mice.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32067417
|abstract=To investigate the effects of a young systemic environment and growth differentiation factor 11 (GDF-11) on aging cartilage. A heterochronic parabiosis model (2-month-old mouse and 12-month-old mouse [Y/O]), an isochronic parabiosis model (12-month-old mouse and 12-month-old mouse [O/O]), and 12-month-old mice alone (O) were evaluated. Knee joints and chondrocytes from old mice were examined by radiography, histology, cell proliferation assays, immunohistochemistry, Western blotting, and quantitative reverse transcriptase-polymerase chain reaction 16 weeks after parabiosis surgery. GDF-11 was injected into 12-month-old mouse joints daily for 16 weeks. Cartilage degeneration, cell proliferation, and osteoarthritis-related gene expression were evaluated. Osteoarthritis Research Society International scores in old mice were significantly lower in the Y/O group than in the O/O and O groups (both P < 0.05). The percentage of 5-ethynyl-2'-deoxyuridine-positive chondrocytes in old mice was significantly higher in the Y/O group than in the other groups (P < 0.05). Type II collagen (CII) and [[SOX9]] messenger RNA levels differed in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). RUNX-2, CX, and matrix metalloproteinase 13 levels were significantly lower in cartilage from old mice in the Y/O group compared to the O/O and O groups (both P < 0.05). Similar results were obtained for protein expression levels and after GDF-11 treatment in vitro and in vivo. Phosphorylated Smad2/3 (pSmad2/3) levels were higher in the recombinant GDF-11-treated group than in the control group. A young systemic environment promotes chondrocyte proliferation and cartilage matrix synthesis in old mice. GDF-11, a "young factor," contributes to these effects through the up-regulation of pSmad2/3.
|mesh-terms=* Adolescent
* Aged
* Aging
* Animals
* Arthroplasty, Replacement, Knee
* Bone Morphogenetic Proteins
* Cartilage, Articular
* Cell Proliferation
* Chondrocytes
* Collagen Type II
* Collagen Type X
* Core Binding Factor Alpha 1 Subunit
* Extracellular Matrix
* Female
* Growth Differentiation Factors
* Humans
* In Vitro Techniques
* Knee Joint
* Male
* Matrix Metalloproteinase 13
* Mice
* Osteoarthritis, Knee
* Parabiosis
* Phosphorylation
* RNA, Messenger
* Reverse Transcriptase Polymerase Chain Reaction
* SOX9 Transcription Factor
* Smad2 Protein
* Smad3 Protein
* Stifle
* Young Adult
|keywords=#f
|full-text-url=https://sci-hub.do/10.1002/art.41230
}}
==SRD5A2==
 
{{medline-entry
|title=Extract of Plumbago zeylanica enhances the growth of hair follicle dermal papilla cells with down-regulation of 5α-reductase type II.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32125089
|abstract=Cellular senescence, a phenomenon of irreversible growth arrest of mammalian cells, is involved in various age-related phenomena in organisms. Hair follicle dermal papilla (DP) cells play important roles in the regulation of hair growth and loss. We examined the implication of cellular senescence of DP cells in androgenetic alopecia (AGA), the most common form of male hair loss, and searched for the compounds that have a beneficial effect on the prevention of AGA. Expression of the 5α-reductase type II ([[SRD5A2]]) gene, which plays a key role in the development of AGA, was examined by quantitative RT-PCR and Western blotting analysis in DP cells. Besides, DP cells were cultured with the extracts of herbs used in traditional Ayurvedic medicine to search for the compounds that have a beneficial effect on the growth of DP cells. We found that expression of the [[SRD5A2]] was up-regulated in senescent DP cells. We also found that the herbal extract of Plumbago zeylanica (root) enhanced the growth of DP cells and down-regulated the expression of [[SRD5A2]] in DP cells. Further, plumbagin, an ingredient of P zeylanica, would be responsible for the above effects of P zeylanica. These results suggested the possibility that senescent DP cells may have a role in the development of AGA through up-regulating [[SRD5A2]] expression, and the P zeylanica extract and plumbagin may suppress its development through enhancing the growth of DP cells and down-regulating [[SRD5A2]] expression in DP cells.
 
|keywords=*
P zeylanica
 
* 5α-reductase
* dermal papilla
* hair
* plumbagin
* senescence
* senescence
|full-text-url=https://sci-hub.do/10.1111/acel.13279
|full-text-url=https://sci-hub.do/10.1111/jocd.13355
}}
}}
==SST==
{{medline-entry
{{medline-entry
|title=Sirtuins and Their Implications in Neurodegenerative Diseases from a Drug Discovery Perspective.
|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/33280374
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32158369
|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.
|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
|keywords=* Aging
* neurodegenerative diseases
* Emotion regulation
* neuroprotective
* Future time perspective
* sirtuin
* Socioemotional selectivity theory
* sirtuin activators
* Time left in life
* sirtuin inhibitors
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040126
|full-text-url=https://sci-hub.do/10.1021/acschemneuro.0c00696
}}
==STAT3==
 
{{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
}}
==STS==
 
{{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
}}
==SUCNR1==
 
{{medline-entry
|title=[The effect of Mexidol on cerebral mitochondriogenesis at a young age and during aging].
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32105271
|abstract=To study the ability of mexidol to induce cerebral mitochondriogenesis in the brain of young and aging rats. Expression level of marker proteins of cerebral mitochondriogenesis was evaluated during treatment with mexidol (20, 40, 100 mg/kg; 20 days; intraperitoneally) in the cerebral cortex of young (3 month) and aging (6, 9, 12, and 15 month) outbred male rats, using the Western blot analysis. It has been shown for the first time that the course injections of mexidol in doses of 40 and 100 mg/kg is accompanied by dose-dependent induction of the succinate receptor [[SUCNR1]] and protein markers of mitochondrial biogenesis: transcription coactivator PGC-1α, transcription factors (NRF1, TFAM), catalytic subunits of respiratory enzymes (NDUV2, NDUV2,cytb, COX2) and ATP synthase (ATP5A) in the cerebral cortex of young and aging outbred male rats. Mexidol-dependent overexpression of subunits of mitochondrial enzymes and PGC-1α is observed only with the course of the drug. The results indicate the ability of mexidol to induce cerebral mitochondriogenesis and eliminate mitochondrial dysfunction in young and aging animals and, thus, exert an effect on one of the key pathogenetic links of the development of disorders in aging and neurodegenerative diseases.
|mesh-terms=* Age Factors
* Aging
* Animals
* Male
* Mitochondria
* Neurodegenerative Diseases
* Picolines
* Rats
* Receptors, G-Protein-Coupled
* Transcription Factors
|keywords=* Western blot analysis
* aging
* cerebral mitochondriogenesis
* mexidol
* mitochondrial dysfunction
* rats
* respiratory enzyme subunits
* succinate receptor
* transcriptional coactivator PGC-1α
|full-text-url=https://sci-hub.do/10.17116/jnevro202012001162
}}
}}
==SIRT6==
==TEC==


{{medline-entry
{{medline-entry
|title=Association between [[SIRT6]] Methylation and Human Longevity in a Chinese Population.
|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/33238266
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32194555
|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.
|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=* DNA Methylation
|keywords=* aging
* Longevity
* chemotherapy
* Messenger RNA
* gender
* SIRT6
* luteinizing hormone-releasing hormone
|full-text-url=https://sci-hub.do/10.1159/000508832
* regeneration
* sex hormone deprivation
* thymic epithelial cell
* thymus
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062683
}}
}}
==SOD1==
==TEF==


{{medline-entry
{{medline-entry
|title=[[SOD1]], more than just an antioxidant.
|title=Expression of human HSP27 in yeast extends replicative lifespan and uncovers a hormetic response.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33259795
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32189112
|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.
|abstract=Human HSP27 is a small heat shock protein that modulates the ability of cells to respond to heat shock and oxidative stress, and also functions as a chaperone independent of ATP, participating in the proteasomal degradation of proteins. The expression of HSP27 is associated with survival in mammalian cells. In cancer cells, it confers resistance to chemotherapy; in neurons, HSP27 has a positive effect on neuronal viability in models of Alzheimer's and Parkinson's diseases. To better understand the mechanism by which HSP27 expression contributes to cell survival, we expressed human HSP27 in the budding yeast Saccharomyces cerevisiae under control of different mutant [[TEF]] promoters, that conferred nine levels of graded basal expression, and showed that replicative lifespan and proteasomal activity increase as well as the resistance to oxidative and thermal stresses. The profile of these phenotypes display a dose-response effect characteristic of hormesis, an adaptive phenomenon that is observed when cells are exposed to increasing amounts of stress or toxic substances. The hormetic response correlates with changes in expression levels of HSP27 and also with its oligomeric states when correlated to survival assays. Our results indicate that fine tuning of HSP27 concentration could be used as a strategy for cancer therapy, and also for improving neuronal survival in neurodegenerative diseases.


|keywords=* Aging
|keywords=* Aging
* Cancer
* Cancer
* Neurodegenerative diseases
* HSP27
* Post-translational modifications
* Hormesis
* Superoxide dismutase 1
* Neurodegeneratve diseases
|full-text-url=https://sci-hub.do/10.1016/j.abb.2020.108701
* Proteasome
|full-text-url=https://sci-hub.do/10.1007/s10522-020-09869-9
}}
==TERT==
 
{{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
}}
==TF==
 
{{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
}}
==TG==
 
{{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
|keywords=#f
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7101400
}}
==TH==
 
{{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
}}
==TNC==
 
{{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
}}
}}
==TNF==
==TNF==


{{medline-entry
{{medline-entry
|title=Naringenin alleviates nonalcoholic steatohepatitis in middle-aged Apoe mice: role of SIRT1.
|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/33234364
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32252879
|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.
|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
|keywords=#f
|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=* AML-12 cells
|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
* Aging
* ApoE(−/−) mice
* Female
* Naringenin
* Humans
* Nonalcoholic steatohepatitis
* Longevity
* SIRT1
* Male
|full-text-url=https://sci-hub.do/10.1016/j.phymed.2020.153412
* 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
}}
==TP53==
 
{{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
|keywords=#f
|full-text-url=https://sci-hub.do/10.1182/blood.2019004362
}}
}}
==TPH1==
==TRAF3==


{{medline-entry
{{medline-entry
|title=[i]Lactobacillus plantarum[/i] DR7 improved brain health in aging rats via the serotonin, inflammatory and apoptosis pathways.
|title=[[TRAF3]], a Target of MicroRNA-363-3p, Suppresses Senescence and Regulates the Balance Between Osteoblastic and Adipocytic Differentiation of Rat Bone Marrow-Derived Mesenchymal Stem Cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33245015
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32111144
|abstract=Aging processes affect the brain in many ways, ranging from cellular to functional levels which lead to cognitive decline and increased oxidative stress. The aim of this study was to investigate the potentials of [i]Lactobacillus plantarum[/i] DR7 on brain health including cognitive and memory functions during aging and the impacts of high fat diet during a 12-week period. Male Sprague-Dawley rats were separated into six groups: (1) young animals on normal diet (ND, (2) young animals on a high fat diet (HFD), (3) aged animals on ND, (4) aged animals on HFD, (5) aged animals on HFD and [i]L. plantarum[/i] DR7 (10  cfu/day) and (6) aged animals receiving HFD and lovastatin. To induce ageing, all rats in group 3 to 6 were injected sub-cutaneously at 600 mg/kg/day of D-galactose daily. The administration of DR7 has reduced anxiety accompanied by enhanced memory during behavioural assessments in aged-HFD rats ([i]P[/i]<0.05). Hippocampal concentration of all three pro-inflammatory cytokines were increased during aging but reduced upon administration of both statin and DR7. Expressions of hippocampal neurotransmitters and apoptosis genes showed reduced expressions of indoleamine dioxygenase and P53 accompanied by increased expression of [[TPH1]] in aged- HFD rats administered with DR7, indicating potential effects of DR7 along the pathways of serotonin and oxidative senescence. This study provided an insight into potentials of [i]L. plantarum[/i] DR7 as a prospective dietary strategy to improve cognitive functions during aging. This study provided an insight into potentials of [i]L. plantarum[/i] DR7 as a prospective dietary strategy to improve cognitive functions during aging.
|abstract=Bone marrow-derived mesenchymal stem cells (BMSCs) have the potential to differentiate into osteoblasts or adipocytes, and an imbalance between adipogenesis and osteogenesis causes age-related bone loss. In this study, we determined the influence of tumor necrosis factor receptor-associated factor 3 ([[TRAF3]]) on senescence and osteoblastic and adipocytic differentiation of rat BMSCs. [[TRAF3]] expression increased during osteogenic differentiation but decreased during adipocytic differentiation of rat BMSCs, and compared with day 0 cultures, on day 14, the differences were significant. Overexpression of [[TRAF3]] significantly promoted BMSC osteogenic differentiation and suppressed adipogenic differentiation and senescence. Furthermore, [i]Traf3[/i] was determined to be a target gene of miR-363-3p in BMSCs, and [[TRAF3]] expression in BMSCs was reduced by miR-363-3p overexpression. This overexpression attenuated the effects of [[TRAF3]] on BMSC adipogenic differentiation, osteogenic differentiation, and senescence. Taken together, these results uncovered the mechanism by which [[TRAF3]] promotes BMSC osteogenic differentiation and suppresses adipogenic differentiation and senescence, indicating that the miR-363-3p-[[TRAF3]] axis might be a novel therapeutic target for BMSC-based bone tissue engineering in osteoporosis.


|keywords=* Lactobacillus spp.
|keywords=* TRAF3
* aging
* adipogenic differentiation
* brain
* bone marrow-derived mesenchymal stem cells
|full-text-url=https://sci-hub.do/10.3920/BM2019.0200
* miR-363-3p
* osteogenic differentiation
* senescence
|full-text-url=https://sci-hub.do/10.1089/scd.2019.0276
}}
}}
==TRIM27==
==TRIM21==


{{medline-entry
{{medline-entry
|title=[[TRIM27]] Functions as a Novel Oncogene in Non-Triple-Negative Breast Cancer by Blocking Cellular Senescence through p21 Ubiquitination.
|title=[[TRIM21]] overexpression promotes tumor progression by regulating cell proliferation, cell migration and cell senescence in human glioma.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/33251042
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32064156
|abstract=In the current study, we aimed to explore the correlation between [[TRIM27]] and breast cancer prognosis, as well as the functions of [[TRIM27]] in breast cancer and their underlying mechanisms. Bioinformatics analyses were used to examine the correlation between [[TRIM27]] and breast cancer prognosis. Moreover, [[TRIM27]] knockdown and overexpression in breast cancer cells were performed to investigate its functions in breast cancer. Tamoxifen (TAM) was applied to evaluate the influence of [[TRIM27]] on chemoresistance of breast cancer cells, while co-immunoprecipitation (coIP) was performed to identify the E3 ubiquitin ligase capability of [[TRIM27]]. High expression of [[TRIM27]] was found in non-triple-negative breast cancer (non-TNBC) tumor tissues and was positively correlated with the mortality of non-TNBC patients. Moreover, [[TRIM27]] could suppress non-TNBC cell apoptosis and senescence, promote cell viability and tumor growth, counteract the anti-cancer effects of TAM, and mediate ubiquitination of p21. In addition, EP300 could enhance the expression of [[TRIM27]] and its transcription promoter H3K27ac. [[TRIM27]], through ubiquitination of p21, might serve as a prognostic biomarker for non-TNBC prognosis. [[TRIM27]] functions as a novel oncogene in non-TNBC cellular processes, especially suppressing cell senescence and interfering with non-TNBC chemoresistance.
|abstract=Molecular biomarkers combined with histopathological examination are of critical importance in the diagnosis and treatment of gliomas. Although recent studies have shown that many tripartite motif-containing (TRIM) family proteins could regulate the cell cycle, cell proliferation, and differentiation in cancers, the precise role of [[TRIM21]] has been unknown in glioma. In this study, we analyzed [[TRIM21]], which was upregulated in gliomas and identified its role in tumor proliferation, migration and drug resistance. By using immunohistochemical analysis, we found that the expression level of [[TRIM21]] was upregulated in glioma specimens and the higher expression level of [[TRIM21]] was associated with poorer clinical outcomes in glioma patients. Moreover, we demonstrated that [[TRIM21]] could act as a regulator of the proliferation, cell cycle, and migration of glioma cells by gain- and loss-of function assays in vitro. In vivo, [[TRIM21]] could also modulate glioma progression in murine intracranial xenografts. Furthermore, we found that [[TRIM21]] suppressed cellular senescence via the p53-p21 pathway, and increased drug resistance in glioma cells by RNA-seq analysis, SA-[i]β[/i]-Gal activity assay, and Cell Counting Kit-8 (CCK-8) assay. These results indicated that [[TRIM21]] is a novel regulator in the diagnosis, prognosis, and therapy of gliomas.


|keywords=* EP300
|keywords=* Glioma
* TRIM27
* TRIM21
* breast cancer
* cell apoptosis
* cell senescence
* cell senescence
* chemoresistance
* drug resistance
* p21
* p53-p21 pathway
* prognosis
* prognosis
* transcription
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017742
* ubiquitination
}}
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666371
==TST==
 
{{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
}}
==U2AF1==
 
{{medline-entry
|title=Isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis of mRNA splicing relevant proteins in aging HSPCs.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32141009
|abstract=HSPC (hematopoietic stem/progenitor cell) aging was closely associated with the organism aging, senile diseases and hematopoietic related diseases. Therefore, study on HSPC aging is of great significance to further elucidate the mechanisms of aging and to treat hematopoietic disease resulting from HSPC aging. Little attention had been paid to mRNA splicing as a mechanism underlying HSPC senescence. We used our lab's patented in vitro aging model of HSPCs to analyze mRNA splicing relevant protein alterations with iTRAQ-based proteomic analysis. We found that not only the notable mRNA splicing genes such as SR, hnRNP, WBP11, Sf3b1, Ptbp1 and [[U2AF1]] but also the scarcely reported mRNA splicing relevant genes such as Rbmxl1, Dhx16, Pcbp2, Pabpc1 were significantly down-regulated. We further verified their gene expressions by qRT-PCR. In addition, we reported the effect of Spliceostatin A (SSA), which inhibits mRNA splicing in vivo and in vitro, on HSPC aging. It was concluded that mRNA splicing emerged as an important factor for the vulnerability of HSPC aging. This study improved our understanding of the role of mRNA splicing in the HSPC aging process.
 
|keywords=* Aging
* DEPs
* HSPC
* iTRAQ
* mRNA splicing
|full-text-url=https://sci-hub.do/10.1007/s40520-020-01509-z
}}
==UCP1==
 
{{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
}}
==VDAC1==
 
{{medline-entry
|title=Changes in the expression of oxidative phosphorylation complexes in the aging intestinal mucosa.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32173460
|abstract=Mitochondria produce cellular energy via oxidative phosphorylation (OXPHOS), mediated by respiratory chain complexes I to IV and ATP synthase (complex V). Mitochondrial respiratory complexes have been shown to decline with age in several tissues. As the intestinal epithelium is a tissue with a high energy demand, the aim of the present study was to establish whether the expression profile of OXPHOS subunits in the intestinal mucosa changes during the aging process. Biopsies of intestinal mucosa with no evidence of endoscopic or histomorphologic abnormalities, taken from 55 patients (mean age 42 years, age range 4-82 years; 62% female), were divided into four age groups (4-19, 20-39, 40-59, ≥60 years). Sections from different intestinal segments (terminal ileum, ascending colon, and sigmoid colon/rectum) were stained immunohistochemically (IHC) for subunits of OXPHOS complexes I-V and the voltage-dependent anion-selective channel 1 protein ([[VDAC1]], porin), a marker of mitochondrial mass. Scores for IHC staining were determined by multiplication of the staining intensity and the percentage of positive cells. In addition, the numbers of intestinal crypts staining positive, partly positive, and negative were assessed. The average protein expression levels of OXPHOS subunits increased continuously from childhood onward, peaked in persons aged 20 to 59 years, and declined thereafter. This was seen for complexes II to V in the terminal ileum, complexes I to V in the ascending colon, and complexes I to IV in the sigmoid colon/rectum. Across all age groups, no effect of age on expression of the porin subunit [[VDAC1]] was detected. The number of complex I- and IV-negative crypts in different intestinal segments increased with age. The protein expression levels of OXPHOS complexes increases from childhood onward and declines in elderly individuals, while the numbers of crypts with partial or complete loss of expression of complexes I and IV increase continuously with age. These data suggest that the continued reductions in the levels of mitochondrial OXPHOS complexes in crypts might be compensated in adulthood, but that, ultimately, reduced expression levels occur in persons aged 60 years and older. These findings raise two important questions: first, can the process of aging could be delayed through (pharmacological) intervention of mitochondrial pathways, and second, pathophysiologically, are these findings associated with disorders of the intestinal mucosa, e.g. inflammation?
 
|keywords=* Aging
* Colonic crypt
* Expression
* Intestine
* Mitochondria
* OXPHOS
|full-text-url=https://sci-hub.do/10.1016/j.exger.2020.110924
}}
==WNT3A==
 
{{medline-entry
|title=Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32109549
|abstract=The rapid expansion of the elderly population has led to the recent epidemic of age-related diseases, including increased incidence and mortality of chronic lung diseases, such as Idiopathic Pulmonary Fibrosis (IPF). Cellular senescence is a major hallmark of aging and has a higher occurrence in IPF. The lung epithelium represents a major site of tissue injury, cellular senescence and aberrant activity of developmental pathways such as the WNT/β-catenin pathway in IPF. The potential impact of WNT/β-catenin signaling on alveolar epithelial senescence in general as well as in IPF, however, remains elusive. Here, we characterized alveolar epithelial cells of aged mice and assessed the contribution of chronic WNT/β-catenin signaling on alveolar epithelial type (AT) II cell senescence. Whole lungs from old (16-24 months) versus young (3 months) mice had relatively less epithelial (EpCAM ) but more inflammatory (CD45 ) cells, as assessed by flow cytometry. Compared to young ATII cells, old ATII cells showed decreased expression of the ATII cell marker Surfactant Protein C along with increased expression of the ATI cell marker Hopx, accompanied by increased WNT/β-catenin activity. Notably, when placed in an organoid assay, old ATII cells exhibited decreased progenitor cell potential. Chronic canonical WNT/β-catenin activation for up to 7 days in primary ATII cells as well as alveolar epithelial cell lines induced a robust cellular senescence, whereas the non-canonical ligand WNT5A was not able to induce cellular senescence. Moreover, chronic [[WNT3A]] treatment of precision-cut lung slices (PCLS) further confirmed ATII cell senescence. Simultaneously, chronic but not acute WNT/β-catenin activation induced a profibrotic state with increased expression of the impaired ATII cell marker Keratin 8. These results suggest that chronic WNT/β-catenin activity in the IPF lung contributes to increased ATII cell senescence and reprogramming. In the fibrotic environment, WNT/β-catenin signaling thus might lead to further progenitor cell dysfunction and impaired lung repair.
 
|keywords=* ATII cells
* Aging
* Cellular senescence
* IPF
* WNT signaling
|full-text-url=https://sci-hub.do/10.1016/j.cellsig.2020.109588
}}
==XDH==
 
{{medline-entry
|title=Enhancing xanthine dehydrogenase activity is an effective way to delay leaf senescence and increase rice yield.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32162142
|abstract=Xanthine dehydrogenase ([[XDH]]) is an important enzyme in purine metabolism. It is involved in regulation of the normal growth and non-biological stress-induced ageing processes in plants. The present study investigated [[XDH]]'s role in regulating rice leaf senescence. We measured physical characteristics, chlorophyll content and fluorescence parameters, active oxygen metabolism, and purine metabolism in wild-type Kitaake rice (Oryza sativa L.), an Os[[XDH]] over-expression transgenic line (OE9), and an Os[[XDH]] RNA interference line (Ri3) during different growth stages. The expression patterns of the Os[[XDH]] gene confirmed that [[XDH]] was involved in the regulation of normal and abiotic stress-induced ageing processes in rice. There was no significant difference between the phenotypes of transgenic lines and wild type at the seedling stage, but differences were observed at the full heading and maturation stages. The OE9 plants were taller, with higher chlorophyll content, and their photosystems had stronger light energy absorption, transmission, dissipation, and distribution capacity, which ultimately improved the seed setting rate and 1000-seed weight. The opposite effect was found in the Ri3 plants. The OE9 line had a strong ability to remove reactive oxygen species, with increased accumulation of allantoin and alantoate. Experimental spraying of allantoin on leaves showed that it could alleviate chlorophyll degradation and decrease the content of H O  and malonaldehyde (MDA) in rice leaves after the full heading stage. The urate oxidase gene (UO) expression levels in the interference line were significantly lower than those in the over-expression line and wild-type lines. The allantoinase (ALN) and allantoate amidinohydrolase (AAH) genes had significantly higher expression in the Ri3 plants than the in OE9 or wild-type plants, with OE9 plants showing the lowest levels. The senescence-related genes ACD1, WRKY23, WRKY53, SGR, XERO1, and GH27 in Ri3 plants had the highest expression levels, followed by those in the wild-type plants, with OE9 plants showing the lowest levels. These results suggest that enhanced activity of [[XDH]] can regulate the synthesis of urea-related substances, improve plant antioxidant capacity, effectively delay the ageing process in rice leaves, and increase rice yield.
 
|keywords=* Allantoin
* Reactive oxygen species
* Rice (Oryza sativa L.)
* Senescence
* Xanthine dehydrogenase
* Yield
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065298
}}
==ZEB2==
 
{{medline-entry
|title=miR-200b regulates cellular senescence and inflammatory responses by targeting [[ZEB2]] in pulmonary emphysema.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/32070140
|abstract=Smoking is an important factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), which is commonly characterised by cellular senescence and inflammation. Recently, miR-200b has emerged as an important target to cure lung disease; however, the function of miR-200b in reducing cellular senescence and inflammatory responses has not been reported. In this study, we found that miR-200b was downregulated in the lungs of COPD model mice, and its expression is correlated with cellular senescence and inflammatory responses. We hypothesised that miR-200b may be a potential novel therapy for treating COPD. We performed senescence-Associated-β-galactosidase (SA-β-GAL) staining, western blot, qRT-PCR and ELISA; our data suggested that miR-200b is an anti-aging factor in the lungs that is involved in inflammatory responses. We also confirmed that [[ZEB2]] (Zinc finger E-box binding homeobox 2) is a target gene of miR-200b using luciferase reporter assay. In addition, we verified the function of [[ZEB2]] in cellular senescence and inflammatory responses through transfection experiments. Moreover, we found that the protective effects of miR-200b are inhibited when cells overexpress the [[ZEB2]] protein. In conclusion, our results suggest that miR-200b may attenuate cellular senescence and inflammatory responses by targeting [[ZEB2]] in pulmonary emphysema.
|mesh-terms=* Animals
* Cell Line
* Cellular Senescence
* Disease Models, Animal
* Gene Expression
* Gene Expression Regulation
* Inflammation
* Lung
* Mice
* MicroRNAs
* Pulmonary Emphysema
* Zinc Finger E-box Binding Homeobox 2
|keywords=* ZEB2
* cellular senescence
* inflammation
* miR-200b
* pulmonary emphysema
|full-text-url=https://sci-hub.do/10.1080/21691401.2020.1725029
}}
}}
Источник — https://transhumanist.ru/Служебная:Сравнение_версий/2633