Публикации о генах и старении (titles)
MYSM1 Suppresses Cellular Senescence and the Aging Process to Prolong Lifespan.
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.
MeSH Terms
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Keywords
DNA repair; Myb‐like, SWIRM, and MPN domains‐containing protein 1 (MYSM1); aging; senescence; senescence‐associated secretory phenotype (SASP)
The Aging Stress Response and Its Implication for AMD Pathogenesis.
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].
MeSH Terms
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Keywords
AMD; DNA damage response; PGC-1α; SIRT1; age-related macular degeneration; aging; autophagy; insulin/IGF-1; mitochondrial quality control; the aging stress response
Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2 mice.
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.
MeSH Terms
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Keywords
Aging; Dnm1l/DRP1; SQSTM1/p62; knockin mice; macroautophagy; mitochondria dysfunction; mitochondrial fission; mitophagy; parkinson disease; ubiquitination
Innate and Adaptive Immunity in Aging and Longevity: The Foundation of Resilience.
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.
MeSH Terms
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Keywords
adaptive immunity; aging; innate immunity; longevity; resilience
Genetic Factors of Alzheimer's Disease Modulate How Diet is Associated with Long-Term Cognitive Trajectories: A UK Biobank Study.
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.
MeSH Terms
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Keywords
APOE4; Aging; Mediterranean diet; cognitive decline; functional food; lamb; nutrition policy; preventive medicine; red wine; salt
Protective effects of saponins from Panax japonicus on neurons of the colon myenteric plexus in aging rats through reduction of α-synuclein through endoplasmic reticulum stress.
Abstract
The enteric nervous system degenerates gradually with age, and α-synuclein (α-syn) is a suitable marker of enteric nervous system degeneration, which is intimately related with endoplasmic reticulum stress and unfolded protein response (UPR ). Saponins from Panax japonicus (SPJ) have obvious protective effects on neurons in several degenerative disease models. Here, the study was designed to investigate whether SPJ could reverse the neuron degeneration through regulating the UPR in the colon myenteric plexus of aging rats. Aging rats had been treated with SPJ for 6 months since they were aged 18 months. Then, the colon samples were collected and neuron morphology in the myenteric plexus was observed. Immunohistochemistry staining was used to detect the expressions of NeuN, α-syn, GRP78 and three different UPR branches. Double immunofluorescence was used to determine the co-localization of α-syn and NeuN, GRP78 and NeuN. Neurons degenerated in the colon myenteric plexus of aging rats, but co-localization of α-syn and NeuN increased. In addition, both the expressions of GRP78 and three UPR branch signaling pathway proteins decreased in the colon myenteric plexus of aging rats. Treatment of SPJ almost alleviated the above effects in aging rats, except for ATF6. SPJ could reverse the neuron loss caused by accumulation of α-syn in the myenteric plexus of colon in aging rats, which is potentially associated with increased GRP78 and most URP changes. Geriatr Gerontol Int 2020; ••: ••-••.
MeSH Terms
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Keywords
aging; myenteric plexus; saponins from Panax japonicus; unfolded protein response of endoplasmic reticulum; α-synuclein
Exploration on the effect of predeposit autotransfusion on bone marrow hematopoiesis after femoral shaft fracture.
Abstract
By observing the changes in the number and activity of CD34+ cells in bone marrow after predeposit autotransfusion (PAT) to patients with femoral shaft fracture (FSF), to evaluate the effects of PAT on hematopoietic function and hematopoietic stem cells in bone marrow. Selected FSF patients were randomly divided into 2 groups: the control group (patients did not receive blood transfusion after surgery) and PAT group (patients received PAT after surgery). The content of RBC and Plt in blood samples were counted by blood routine. The cell cycle and proportion of CD34+ myelinated cells in blood samples was analyzed by flow cytometry. The telomere DNA length of hematopoietic stem cells (HSCs) in the control groups and PAT group at postoperation 24 was analyzed by southern blot. The content of RBC and Plt in postoperation 6h and 24h in the control group was evidently higher compared to that in PAT group, while Hb content in control group was significantly lower compared to that in PAT group. The proportion of CD34+ myelinated cells in post-transfusion 6h and postoperation 24h in PAT group was evidently higher compared to that in the control group. In PAT group, S phase at postoperation 24h was significantly larger compared to that at post-transfusion 6h. The telomere DNA length of HSCs in PAT group was longer than that in the control group. PAT can increase the number of HSC, while does not cause the abnormal aging of HSCs. PAT is suitable for postoperative blood transfusion of patients with FSF.
MeSH Terms
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Keywords
Aging; CD34+ myelinated cells; Fracture; HSCs; PAT
ACE2/ACE imbalance and impaired vasoreparative functions of stem/progenitor cells in aging.
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.
MeSH Terms
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Keywords
ACE2; Aging; Angiotensin-(1-7); Hematopoietic stem/progenitor cells; Ischemia
The effects of everyday-life exposure to polycyclic aromatic hydrocarbons on biological age indicators.
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.
MeSH Terms
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Keywords
Biological aging; DNA adduct; Mitochondrial DNA copy number; Polycyclic aromatic hydrocarbon; Structural equation modelling; Telomere length
Food insecurity and T-cell dysregulation in women living with HIV on antiretroviral therapy.
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.
MeSH Terms
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Keywords
HIV; exhaustion; food insecurity; immune activation; senescence
Identification of genes associated with endometrial cell aging.
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.
MeSH Terms
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Keywords
CXCL12; CXCL14; IL17RB; endometrial cell aging; infertility; quantitative immunohistochemistry
Premature CD4 T Cells Senescence Induced by Chronic Infection in Patients with Acute Coronary Syndrome.
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.
MeSH Terms
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Keywords
CD28null T cells; CD4+ T cells; acute coronary syndrome; immunosenescence; infection
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.
MeSH Terms
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Keywords
E3 ubiquitin ligase; RNF10; immunosenescence; inflammation; macrophages
Omega-3 supplementation improves isometric strength but not muscle anabolic and catabolic signaling in response to resistance exercise in healthy older adults.
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.
MeSH Terms
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Keywords
Muscle wasting; aging; anabolic resistance; inflammation; resistance training; sarcopenia
Endoplasmic Reticulum Stress Mediates Vascular Smooth Muscle Cell Calcification via Increased Release of Grp78-Loaded Extracellular Vesicles.
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.
MeSH Terms
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Keywords
aging; arteries; endoplasmic reticulum; vascular calcification; warfarin
A Comprehensive Analysis of Age and Gender Effects in European Portuguese Oral Vowels.
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.
MeSH Terms
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Keywords
Acoustic; Aging voice; European Portuguese; Oral vowel
Cellular proteostasis decline in human senescence.
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.
MeSH Terms
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Keywords
UPR; chaperones; heat shock response; protein homeostasis; senescence
The NPR1-WRKY46-WRKY6 signaling cascade mediates probenazole/salicylic acid-elicited leaf senescence in Arabidopsis thaliana.
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.
MeSH Terms
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Keywords
Leaf senescence; NPR1; Probenazole; Salicylic acid; WRKY46; WRKY6
Comparing the Effect of TGF-β Receptor Inhibition on Human Perivascular Mesenchymal Stromal Cells Derived from Endometrium, Bone Marrow and Adipose Tissues.
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.
MeSH Terms
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Keywords
SUSD2; adipose tissue; apoptosis; bone marrow; clonogenicity; endometrium; menstrual fluid; perivascular mesenchymal stromal cells; placenta; senescence