Longevity Papers

Adropin is a bioactive peptide found in the brain and various peripheral tissues. Evidence suggests that aging significantly decreases brain adropin levels, and interventions that elevate adropin may help alleviate age-related neurological disorders such as ischemic stroke and cognitive decline. However, the impact of aging on peripheral tissue adropin levels and its relationship with the neural recognition molecule NB-3/contactin-6 in the brain remains unclear. In this study, we quantified adropin using immunoblotting in brain and peripheral tissues (liver, lung, kidney, spleen, ileum, colon) from young (8-10 weeks) and aged (18-20 months) male mice. Results indicated a significant decrease in brain adropin levels in aged mice, while peripheral tissues showed no significant changes compared to young controls. Additionally, levels of NB-3/contactin-6, a potential adropin receptor and Notch1 ligand, were lower in aged brains. Co-immunoprecipitation demonstrated that adropin physically associates with brain NB-3. Notably, the age-related reduction in brain adropin correlates with increased oxidative stress markers (gp91

The functional capacity of highly proliferative cell populations changes with age. Here, we report that the proliferative capacity of canine lung mesenchymal stromal cells (LMSCs) declines with increasing age of the donor. However, other functional changes such as reduced autophagy, reduced migration/wound healing, increased production of reactive oxygen species, and increased senescence are not significantly altered with increasing age. Furthermore, transcriptomic profiling suggests minimal age-related changes. These data suggest that the reduced proliferative capacity of lung LMSCs isolated from aging donors may be associated with reversible cell cycle arrest (quiescence), rather than irreversible cell cycle arrest (senescence). Similar findings have been reported in other systems, including neural and muscle stem cells that are associated with low turnover-rate tissues.

Magnetic Resonance Imaging (MRI) offers many ways to non-invasively estimate the properties of white matter (WM) in the brain. In addition to the various metrics derived from diffusion-weighted MRI, one can estimate total WM volume from T1-weighted MRI, WM hyper-intensities from T2-weighted MRI, myelination from the T1:T2 ratio, or from the magnetisation-transfer ratio (MTR). Here we utilise the presence of all of these MR contrasts in a population based life-span cohort of 650 healthy adults [CamCAN cohort] to identify the latent factors underlying the covariance of 11 commonly-used WM metrics. Four factors were needed to explain 89% of the variance, which we interpreted in terms of 1) fibre density / myelination, 2) free-water / tissue damage, 3) fibre-crossing complexity and 4) microstructural complexity. These factors showed distinct effects of age and sex. To test the validity of these factors, we related them to measures of cardiovascular health and cognitive performance. Specifically, we ran path analyses 1) linking cardio-vascular measures to the WM factors, given the idea that WM health is related to cardiovascular health, and 2) linking the WM factors to cognitive measure, given the idea that WM health is important for cognition. Even after adjusting for age, we found that a vascular factor related to pulse pressure predicted the WM factor capturing free-water / tissue damage, and that several WM factors made unique predictions for fluid intelligence and processing speed. Our results show that there is both complementary and redundant information across common MR measures of WM, and their underlying latent factors may be useful for pinpointing the differential causes and contributions of white matter health in healthy aging.

Increased life expectancy is associated with a higher risk of age-related diseases, which represent a major public health challenge. Animal models play a crucial role in aging research, enabling the study of diseases at the organism level and facilitating drug development and repurposing. Among these models, zebrafish stands out as an excellent in vivo system due to its unique characteristics. However, the longevity of zebrafish is a limitation for research, as it often takes too long to obtain results within a reasonable timeframe. To address this, we have developed a short telomere zebrafish line (ST2) with a premature aging phenotype during the larval stage. Although less extreme than the tert-deficient G2 larvae, ST2 larvae exhibit reduced telomerase expression and activity, along with shortened telomeres. they also exhibit increased cellular senescence, apoptosis, and premature death. As a proof of concept, we evaluated the antiaging effects of two compounds: resveratrol (a polyphenol) and navitoclax (a senolytic). Our results confirm the antiaging properties of resveratrol, which improves telomere maintenance. However, navitoclax does not attenuate the ST2 phenotype. Taking advantage of the zebrafish larval model, this premature aging system provides a valuable platform for in vivo testing of rejuvenating molecules through drug screening, using telomere length or survival as a readout.

Aging is a complex and heterogeneous biological process characterized by telomere attrition, genomic instability, mitochondrial dysfunction, and disruption in nutrient sensing. Besides contributing to the progression of cancer, metabolic disorders, and neurodegenerative diseases, these manifestations of aging also adversely affect organ function. It is crucial to understand these mechanisms and identify interventions to modulate them to promote healthy aging and prevent age-related diseases. Vitamins have emerged as potential modulators of aging beyond their traditional roles in health maintenance. There is an increasing body of evidence that hormetic effects of vitamins are responsible for activating cellular stress responses, repair mechanisms, and homeostatic processes when mild stress is induced by certain vitamins. It is evident from this dual role that vitamins play a significant role in preventing frailty, promoting resilience, and mitigating age-related cellular damage. Moreover, addressing vitamin deficiencies in the elderly could have a significant impact on slowing aging and extending life expectancy. A review of recent advances in the role of vitamins in delaying aging processes and promoting multiorgan health is presented in this article. The purpose of this paper is to provide a comprehensive framework for using vitamins as strategic tools for fostering longevity and vitality. It offers a fresh perspective on vitamins' role in aging research by bridging biological mechanisms and clinical opportunities.

Ubiquitin-mediated proteolysis plays a critical role in meiotic cell-cycle regulation and must be tightly controlled to achieve correct chromosome segregation. While the role of E2 ubiquitin-conjugating enzymes in mitosis is well-documented, their functions in oocyte meiosis remain largely unexplored. In this study, we identified UBE2D3 as the most highly expressed E2 enzyme in mouse oocytes, which is essential for proper meiotic division. UBE2D3 depletion caused (metaphase I) MI arrest and Cyclin B1 accumulation, whereas its overexpression led to reduced Cyclin B1 levels, kinetochore-microtubule (K-MT) mis-attachments, spindle assembly checkpoint (SAC) dysfunction, and increased aneuploidy. Notably, UBE2D3 upregulation in oocytes from aged mice contributed to age-related meiotic defects, which were partially reversed by UBE2D3 knockdown or Cyclin B1 overexpression. This study underscores the importance of the UBE2D3-Cyclin B1 axis in maintaining meiotic fidelity and highlights its potential as a therapeutic target for improving oocyte quality and fertility in aged females.

The microenvironment of intervertebral disc degeneration (IVDD) is characterized by oxidative stress, leading to the senescence of nucleus pulposus-derived mesenchymal stem cells (NPMSCs). The purpose of this study was to investigate the competitive endogenous RNA mechanism involved in the senescence of NPMSCs induced by tert-butyl hydroperoxide (TBHP).

In orthopedics, intervertebral disc degeneration (IVDD) is a prevalent chronic condition whose cellular molecular processes are yet unclear. The objective of this research was to uncover the molecular causes of aging and identify the immunological microenvironmental alterations and immune cell infiltration in IVDD. IVDD gene datasets were obtained using GeneCards, and gene expression profiles were chosen from the Gene Expression Synthesis database (GSE244889). The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases were used to examine biological processes. The analysis of immune cell infiltration was done using CIBERSORT. To shed light on the variations in cell types among intervertebral discs with varying degrees of degeneration, single-cell analysis was carried out. Lastly, it was confirmed in vitro that important proteins and genes were expressed. At first, 10 hub genes and 58 intersecting genes were found. Major biological processes include the inflammatory response, chemokine-mediated signaling pathways, and immune response. The three main signaling mechanisms in IVDD are HIF, apoptosis, and cellular senescence. Macrophages M0, M1, M2, T cells, CD4 memory resting, NK cells, T cells regulatory (Tregs), and T cells were all markedly infiltrated in IVDD patients. According to in vitro validation, the IVDD model group had higher levels of proteins linked to the immunological microenvironment. In conclusion, immune cell infiltration-particularly macrophage infiltration, which stimulates the release of inflammatory factors that cause the inflammatory response and cellular senescence in NPCs-is linked to the primary molecular mechanisms underlying the pathogenesis of IVDD. Our research may also help direct future investigations into the senescence signaling pathway in IVDD.

Aging is associated with a disruptive decline in gastrointestinal health leading to decreased duodenal cell proliferation ultimately affecting the digestive and absorptive capacity of intestines in all species. This study investigates the novel application of blood plasma therapy to enhance duodenal cell proliferation associated with aging. In the presented study, the effects of middle aged plasma therapy on the aged rat duodenum were investigated. For this purpose, using a randomized controlled design, Female Wistar rats (aged 12-15 months) (n:7) were treated with heterologus pooled plasma (0.5 mL per day for 30 days, infused intravenously into the tail vein) collected from middle aged (6 months old, n:28) rats during all stages of the estrous cycle. The groups were divided into three as the Experimental group (aged 12-15 months) receiving middle aged plasma, the control group (aged 12-15 months) not receiving treatment, and the middle aged rat (6 months) as the positive control group. At the end of the experiment, each group's duodenum were collected, fixed, and analyzed using histological techniques for morphometric parameters. Additionally cell proliferation density and proliferation index were determined by proliferating cell nuclear antigen (PCNA). The finding of the study suggests that plasma therapy significantly improves cell proliferation, villus height (µm), crypt depth (µm), total mucosal thickness (µm), the ratio of villus height to crypt depth (µm), and surface absorption area (mm

In 2015, the World Health Organization introduced the concept of intrinsic capacity (IC), a composite of all the individual-level attributes that contribute to healthy aging. To investigate the genetic basis of IC, we used data from the UK Biobank (UKB; N=44,631) and the Canadian longitudinal study on aging (CLSA; N=13,085). We estimated SNP-based heritability (h2SNP) at 25.2% in UKB and 19.5% in CLSA. A Genome-Wide Association Study (GWAS) identified 38 independent SNPs for IC across 10 genomic loci and 4,289 candidate SNPs mapped to 197 genes. Post-GWAS analysis revealed the role of these genes on cellular processes such as cell proliferation, immune function, metabolism, and neurodegeneration, with high expressions in muscle, heart, brain, adipose, and tibial nerve tissues. Of the 52 traits tested, 23 showed significant genetic correlations with IC, and a higher genetic loading for IC was associated with higher IC scores. This study is the first to identify genetic variants and pathways associated with IC, providing a foundation for future research on healthy aging.

Multicellular organisms are confronted not only with mutation in germline, but also mutations emerging in somatic cells. Somatic mutations can lead cancers and possibly contribute to aging phenotypes. Prevailing wisdom suggests somatic mutations are limited by evolved defences, either targeting DNA or post-mutational cellular states. Here, I analyse simple models for metazoans and humans in particular, incorporating the possibility that mutation rate trades off of organism longevity, defined as the age at which natural selection becomes negligible. The models assume selection acts to reduce mutation rate and prevent disease, both of which contribute to selecting for longer lifespan. We detail equilibrium conditions and find coevolutionary oscillations under certain parameter combinations. Notably, disease prevention can lead to mutational tolerance and this can contribute to explaining empirical cross-species patterns in longevity vs. mutation rate. We conclude that mutational disease and cancer in particular have required characteristics to be mediators of mutation rate-lifespan coevolution. The mutational tolerance that results from this coevolution can contribute to explaining the incidences of other diseases and conditions, including aging.

HIV-1 infection is associated with accelerated aging. The senescence-associated secretory phenotype (SASP) includes biological and cytokine profiles that induce cellular senescence and inflammaging. In this study, we leveraged the Multicenter AIDS Cohort Study (MACS) to evaluate the role of SASP in aging, HIV-1 reservoir, and inflammation in people with HIV-1 (PWH) on long-term suppressive antiretroviral therapy (ART).

Lifestyle behaviors, including engagement in complex mental activities, have been associated with dementia risk and neuroimaging markers of aging and Alzheimer disease. However, the life period(s) at which lifestyle factors have the greatest influence on brain health remains unclear. Our objective was to determine the relative influence of lifestyle (i.e., engagement in complex mental activities) at different life periods on older adults' brain health.

Cellular antioxidant activity and oxidative stress are assumed to be critical factors in the aging process. This study aims to investigate the effects of resistance training (RT) on endogenous antioxidants in healthy older individuals.

Circadian rhythms, intrinsic 24-h cycles regulating physiological processes, are crucial for skin homeostasis. Disruptions in these rhythms are linked to various skin disorders and impaired barrier function. Circadian rhythms can be modulated by botanical compounds, which hold therapeutic potential. However, the effect of cinnamomi cortex (CC), an anti-inflammatory, antioxidant, and antimicrobial agent, on the circadian rhythm of keratinocytes remains unclear. This study aimed to examine the effects of CC extract and its 18 individual components on the circadian rhythm of HaCaT, an immortalized human keratinocyte line. CC extract and its bioactive components epicatechin (EC) and linalool (LO) significantly enhanced the circadian amplitude without altering the period. Gene expression analysis revealed that CC extract, EC, and LO altered the mRNA and protein levels of clock genes in a time-dependent manner. During molecular docking simulations, both EC and LO exhibited strong binding affinities for RORA, a key nuclear receptor involved in circadian regulation. Enhanced BMAL1 promoter activity following EC and LO treatments corroborated these findings. Furthermore, EC and LO demonstrated significant antioxidant activities, as evidenced by reduced reactive oxygen species levels and increased expression of antioxidant enzymes. EC and LO also upregulated skin barrier-related and ceramide synthesis genes and modulated the expression of cellular longevity-promoting genes. In conclusion, CC extract, particularly the components EC and LO, modulated circadian rhythms, reduced oxidative stress, and enhanced skin barrier function in keratinocytes. These findings highlight the potential of CC extract and its components as novel dermatological treatments to improve skin health and combat aging.

DNA methylation (DNAm) provides a window to characterize the impacts of environmental exposures and the biological aging process. Epigenetic clocks are often trained on DNAm using penalized regression of CpG sites, but recent evidence suggests potential benefits of training epigenetic predictors on principal components.

The ubiquitin kinase and ligase PINK1 and PRKN together label damaged mitochondria for their elimination in lysosomes by selective autophagy (mitophagy). This cytoprotective quality control pathway is genetically linked to familial Parkinson disease but is also altered during aging and in other neurodegenerative disorders. However, the molecular mechanisms of these mitophagy changes remain uncertain. In healthy mitochondria, PINK1 protein is continuously imported, cleaved, and degraded, but swiftly accumulates on damaged mitochondria, where it triggers the activation of the mitophagy pathway by phosphorylating its substrates ubiquitin and PRKN. Levels of PINK1 protein can therefore be used as a proxy for mitochondrial damage and mitophagy initiation. However, validated methodologies to sensitively detect and quantify PINK1 protein are currently not available. Here, we describe the development and thorough validation of a novel immunoassay to measure human PINK1 on the Meso Scale Discovery platform. The final assay showed excellent linearity, parallelism, and sensitivity. Even in the absence of mitochondrial stress (i.e. at basal conditions), when PINK1 protein is usually not detectable by immunoblotting, significant differences were obtained when comparing samples from patient fibroblasts or differentiated neurons with and without PINK1 expression. Of note, PINK1 protein levels were found increased in human postmortem brain with normal aging, but not in brains with Alzheimer disease, suggesting that indeed different molecular mechanisms are at play. In summary, we have developed a novel sensitive PINK1 immunoassay that will complement other efforts to decipher the roles and biomarker potential of the PINK1-PRKN mitophagy pathway in the physiological and pathological context.

Cardiac function declines with age, impairing exercise tolerance and negatively impacting healthy aging. However, mechanisms driving age-related declines in cardiac function are not fully understood.

Ferroptosis, a recently discovered form of programmed cell death triggered by the excessive accumulation of iron-dependent lipid peroxidation products, plays a critical role in the development of various diseases. However, whether it is involved in the age-related decline in oocyte quality remains unexplored. Here, we took advantage of nano-proteomics to uncover that reduced ferritin heavy chain (Fth1) level is a major cause leading to the occurrence of ferroptosis in aged oocytes. Specifically, induction of ferroptosis in young oocytes by its activators RSL3 and FAC, or knockdown of Fth1 all phenocopied the meiotic defects observed in aged oocytes, including failed oocyte meiotic maturation, aberrant cytoskeleton dynamics, as well as impaired mitochondrial function. Transcriptome analysis showed that knockdown of Fth1 affected meiosis-related and aging-related pathways in oocytes. Conversely, inhibition of ferroptosis by its inhibitors or expression of Fth1 improved the quality of aged oocytes. We also validated the effects of ferroptosis on the porcine oocyte quality in vitro. Altogether, we demonstrate the contribution of ferroptosis to the age-induced oocyte defects and evidence that inhibition of ferroptosis might be a feasible strategy to ameliorate the reproductive outcomes of female animals at an advanced age.

Aging leads to progressive decline in organ and tissue integrity and function, partly due to loss of proteostasis and autophagy malfunctioning. A decrease with age in chaperone-mediated autophagy (CMA), a selective type of lysosomal degradation, has been reported in various organs and cells from rodents and humans. Disruption of CMA recapitulates features of aging, whereas activating CMA in mice protects against age-related diseases such as Alzheimer's, retinal degeneration and/or atherosclerosis. However, sex-specific and cell-type-specific differences in CMA with aging remain unexplored. Here, using CMA reporter mice and single-cell transcriptomic data, we report that most organs and cell types show CMA decline with age, with males exhibiting a greater decline with aging. Reduced CMA is often associated with fewer lysosomes competent for CMA. Transcriptional downregulation of CMA genes may further contribute to CMA decline, especially in males. These findings suggest that CMA differences may influence organ vulnerability to age-related degeneration.

SIRT6 is a NAD

Aging increases the susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD). Liver sinusoidal endothelial cells (LSECs) help in maintaining hepatic homeostasis, but the contribution of age-associated LSECs dysfunction to MASLD is not clear. The aim of this study was to investigate the effect of aging-associated LSECs dysfunction on MASLD. Free fatty acid-treated AML12 cells were co-cultured with young and etoposide-induced senescent TSEC cells to evaluate the senescence-associated endothelial effects on the lipid accumulation in hepatocytes. In addition, young and aged rats were subjected to methionine-choline-deficient diet-induced metabolic dysfunction-associated steatohepatitis (MASH). Hepatic hemodynamics and endothelial dysfunction were evaluated by in situ liver perfusion. Liver tissue samples from young and aged healthy controls and MASH patients were also analyzed. Steatotic AML12 cells co-cultured with young TSEC cells showed less lipid accumulation, and such effect was abolished by eNOS inhibitor or with senescent TSEC cells. However, co-culture with resveratrol-treated senescent TSEC cells could partially resume the NO-mediated protective effects of endothelial cells. Furthermore, aged MASH rats showed more severe liver injury, steatosis, fibrosis, and endothelial and microcirculatory dysfunction. In addition, aged MASH patients showed more pronounced liver injury and fibrosis with lower hepatic eNOS, p-eNOS, and SIRT1 protein levels than in young patients. Senescence compromises the protective effects of LSECs against hepatocyte steatosis. In addition, aging aggravates not only liver steatosis and fibrosis but also intensifies LSECs dysfunction in MASH rats. Accordingly aged MASH patients also showed endothelial dysfunction with more severe liver injury and fibrosis.

Integration of artificial intelligence (AI) in health and healthcare, especially for older adults, has significantly advanced healthcare delivery. AI technologies, with capabilities such as self-learning and pattern recognition, are employed to address social isolation and monitor older adults' daily activities. However, rapid AI development often fails to consider the heterogeneous needs of older populations, which could exacerbate an existing digital divide and inequality. This scoping review examines older adults' involvement in AI system design, implementation, and evaluation of AI systems in health and healthcare literature, emphasizing the necessity of their input for beneficial AI systems. We conducted a scoping review according to PRISMA-SCR. We reviewed 17 studies, finding that half of these studies (n = 8) engaged older adults during the design phase, a small number (n = 3) during the evaluation stage, and even fewer (n = 2) involved older adults in the implementation stage. Despite AI's growing role, design processes often overlook older adults' needs. Our findings emphasize the need for inclusive, participatory design approaches to address ethical and equity challenges, enhancing user engagement and relevance. We also highlight how these approaches address the needs of older adults and improve outcomes. Specifically, we integrated evidence showing the practical benefits of these approaches for better accessibility, usability, and engagement among older adults. While AI has potential to improve healthcare delivery, these approaches must be part of broader efforts to ensure ethical, inclusive, and equitable AI practices, especially in gerontology.

In our previous research, we have found that melatonin (MEL) affects the osteoporotic process. By balancing bone remoulding, autophagy is involved in age-related bone loss. However, as a regulator of autophagy, whether MEL influences senile osteoporosis via regulating autophagy remains unclear.

Cellular senescence of brain cell types has become an increasingly important perspective for both aging and neurodegeneration, specifically in the context of Parkinson\'s Disease (PD). The characterization of classical hallmarks of senescence is a widely debated topic, whereby the context in which a senescence phenotype is being investigated, such as the cell type, the inducing stressor, and/or the model system, is an extremely important aspect to consider when defining a senescent cell. Here, we describe a cell type-specific profile of senescence through the investigation of various canonical senescence markers in five human midbrain cell lines using chronic 5-Bromodeoxyuridine (BrdU) treatment as a model of DNA damage-induced senescence. We used principal component analysis (PCA) and subsequent regulatory network inference to define both unique and common senescence profiles in the cell types investigated, as well as revealed senescence-associated transcriptional regulators (SATRs). Functional characterization of one of the identified regulators, transcription factor AP4 (TFAP4), further highlights the cell type-specificity of the expression of the various senescence hallmarks. Our data indicates that SATRs modulate cell type-specific profiles of induced senescence in key midbrain cell types that play an important role in the context of aging and PD.

Physical activity can provide health benefits if done regularly and of sufficient duration and intensity. The World Health Organization recommends adults do 150-300 min of moderate-intensity activity per week, 75-150 min of vigorous-intensity activity, or an equivalent combination.Physical inactivity is the fourth leading cause of early death globally, with 31% of the world's population not getting enough physical activity. Aging is defined by rapid decline in physical activity, loss of mobility, and premature morbidity.Low testosterone levels in men decline from 30 to 40 years of age, and this continues until death. Antiaging strategies, such as caloric restriction, balanced diet, regular exercise, weight management, diabetes control, and smoking cessation can prevent and treat aging-related diseases. Exercise significantly boosts testosterone production, with levels varying based on type, frequency, volume, intensity, and duration. It increases muscle steroidogenesis, total testosterone, and free testosterone in the elderly. Testosterone replacement therapy in elderly men improves physical function, strength, protein synthesis, cholesterol, bone density, sexual desire, erectile function, and overall cognition. However, some studies suggest dehydroepiandrosterone supplementation may provide health improvements without negative effects, potentially reversing arterial aging and reducing the risk of cardiovascular diseases. Senolytic therapeutics focus on cellular senescence, and stem cell transplantation investigates the therapeutic potential of older stem cells.

Collagen is essential to skin structure and integrity, and it is continually degraded with aging due to higher oxidative stress. Sleep deprivation accelerates skin aging and reduces collagen production. Good sleep may be a potential adjuvant to the efficacy of oral supplementation with collagenic peptides for the skin.

Epigenetic clocks use DNA methylation (DNAm) levels to predict an individual's biological age. However, relationships between lifestyle/biomarkers and epigenetic age acceleration (EAA) in Asian populations remain unknown. We here explored associations between lifestyle factors, physiological conditions, and epigenetic markers, including HannumEAA, IEAA, PhenoEAA, GrimEAA, DunedinPACE, DNAm-based smoking pack-years (DNAmPACKYRS), and DNAm plasminogen activator inhibitor 1 level (DNAmPAI1). A total of 2474 Taiwan Biobank (TWB) individuals aged between 30 and 70 provided physical health examinations, lifestyle questionnaire surveys, and blood and urine samples. Partial correlation analysis (while adjusting for chronological age, smoking, and drinking status) demonstrated that 29 factors were significantly correlated with at least one epigenetic marker (Pearson's correlation coefficient |r|> 0.15). Subsequently, by exploring the model with the smallest Akaike information criterion (AIC), we identified the best model for each epigenetic marker. As a DNAm-based marker demonstrated to predict healthspan and lifespan with greater accuracy, GrimEAA was also found to be better explained by lifestyle factors and physiological conditions. Totally 15 factors explained 44.7% variability in GrimEAA, including sex, body mass index (BMI), waist-hip ratio (WHR), smoking, hemoglobin A1c (HbA1c), high-density lipoprotein cholesterol (HDL-C), creatinine, uric acid, gamma-glutamyl transferase (GGT), hemoglobin, and five cell-type proportions. In summary, smoking, elevated HbA1c, BMI, WHR, GGT, and uric acid were associated with more than one kind of EAA. At the same time, higher HDL-C and hemoglobin were related to epigenetic age deceleration (EAD). These findings offer valuable insights into biological aging.

Aging is associated with intestinal dysbiosis, a condition characterized by diminished microbial biodiversity and inflammation. This leads to increased vulnerability to extraintestinal manifestations such as autoimmune, metabolic, and neurodegenerative conditions thereby accelerating mortality. As such, modulation of the gut microbiome is a promising way to extend healthspan. In this study, we explore the effects of fecal microbiota transplant (FMT) from long-living Ames dwarf donors to their normal littermates, and vice versa, on the recipient gut microbiota and liver transcriptome. Importantly, our previous studies highlight differences between the microbiome of Ames dwarf mice relative to their normal siblings, potentially contributing to their extended lifespan and remarkable healthspan. Our findings demonstrate that FMT from Ames dwarf mice to normal mice significantly alters the recipient's gut microbiota, potentially reprogramming bacterial functions related to healthy aging, and changes the liver transcriptome, indicating improved metabolic health. Particularly, the microbiome of Ames dwarf mice, characterized by a higher abundance of beneficial bacterial families such as Peptococcaceae, Oscillospiraceae, and Lachnospiraceae, appears to play a crucial role in modulating these effects. Alongside, our mRNA sequencing and RT-PCR validation reveals that FMT may contribute to the significant downregulation of p21, Elovl3, and Insig2, genes involved with cellular senescence and liver metabolic pathways. Our data suggest a regulatory axis exists between the gut and liver, highlighting the potential of microbiome-targeted therapies in promoting healthy aging. Future research should focus on functional validation of altered microbial communities and explore the underlying biomolecular pathways that confer geroprotection.

Telomeres shorten with each cell division, serving as biomarkers of aging, with human tissues exhibiting short telomeres and restricted telomerase expression. In contrast, mice have longer telomeres and widespread telomerase activity, limiting their relevance as models for human telomere biology. To address this, we engineer a mouse strain with a humanized mTert gene (hmTert), replacing specific non-coding sequences with human counterparts. The hmTert gene, which is repressed in adult tissues except the gonads and thymus, closely mimics human TERT regulation. This modification rescues telomere dysfunction in mTert-knockout mice. Successive intercrosses of Tert

Human social connections are complex ecosystems formed of structural, functional and quality components. Deficits in social connections are associated with adverse age-related health outcomes, but we know little about the ageing-related mechanistic processes underlying this. Using data from 7,047 adults aged 50+ in the English Longitudinal Study of Ageing, we explored associations between diverse aspects of social deficits and both perceived and physiological age acceleration, which provide complementary psycho-behavioural and biological mechanistic explanations. We created and validated a novel physiological ageing index using clinical indicators pertaining to the cardiovascular, respiratory, haematologic, metaboloic and cognitive systems using principal component analysis. Doubly-robust estimations using inverse-probability-weighted regression adjustment estimators showed that living alone, low social integration and high social isolation were risk factors for physiological age acceleration, with those who lived alone on average 1.9 years older than those who lived with others (95% CI 0.9-3.0 years older; 32% greater age acceleration than people who live with others). However, social deficits were not related to accelerations in perceived age. Analyses were robust to multiple sensitivity analyses and maintained four years later. These findings provide important mechanistic insight that helps to explain the relationship between social deficits and age-related morbitidy and mortality outcomes.

Higher physical activity (PA) is associated with better neuropsychiatric health, but prior studies have been limited by cross-sectional designs, self-reported PA measures, and small numbers of older individuals. We examined associations between baseline and changes in accelerometer-measured moderate-vigorous PA (MVPA) with neuropsychiatric health among individuals aged ≥ 70 years in the National Health and Aging Trends Study.

Given the rapid aging of the population in Egypt, efforts to slow down or prevent frailty. Virtual reality technology constitutes a promising rehabilitation strategy, but its effect on frailty in older adults remains inconclusive. A non-equivalent control pre, post, and follow-up test design was used with a sample of 70 prefrail or frail older adults. In 3 urbans affiliated to Dakahlia governorate, tools of data collection; Mini-Cog, Structured Interview Schedule, Survey of Health, Aging and Retirement in Europe of the Frailty Indicator (FI), Short Physical Performance Battery, and Falls Efficacy Scale. For each group, a significant improvement in frailty, physical performance, and falls from each measurement period to immediately after (p < 0.001), and within the 30-days study period while those in the control group were relatively stable over time and sometime worsen. The baseline characteristics and assessment results were similar between groups. We observed significant improvements in the intervention group in terms of frailty criteria, standing balance, gait speed, chair stand, and fear of fall. No improvements were observed in the control group, we anticipate a decrease in frailty index, and increase in standing balance, reinforcing the proven benefits of the exercise in this vulnerable population.

Ischemia-reperfusion (I-R) injury represents a predominant etiology of acute kidney injury (AKI), for which effective treatments remain unavailable. In contrast, hibernating mammals exhibit notable resistance to cell death induced by I-R injury. However, the impact of I-R injury on cellular senescence-an important factor in AKI-has not been extensively studied in these species. Comparative biology may offer novel therapeutic insights. Renal proximal tubular epithelial cells (RPTECs) from the native hibernator Syrian hamster or mouse RPTECs were subjected to anoxia-reoxygenation. Proteins involved in DNA damage response (DDR) and cellular senescence were assessed using western blotting, reactive oxygen species (ROS) levels and cell death were quantified colorimetrically, and IL-6 with ELISA. Anoxia-reoxygenation induced oxidative stress in both mouse and hamster RPTECs; however, cell death was observed exclusively in mouse cells. While anoxia-reoxygenation elicited a DDR and subsequent senescence in mouse RPTECs, such responses were not detected in hamster RPTECs. Thus, RPTECs from the Syrian hamster exhibited increased ROS production upon reoxygenation but did not show DDR or cellular senescence. Further research is required to elucidate the specific protective molecular mechanisms in hibernators, which could potentially lead to the development of novel therapeutic approaches for I-R injury in non-hibernating species, including humans.

Arthropod melanization is a crucial defense mechanism mediated by a complex cascade of CLIP domain serine proteases (CLIPs). In this study, it was confirmed that microRNA-11903a (miR-11903a) targets Aedes-CLIPB9 (AeCLIPB9) by bioinformatics prediction and dual-luciferase reporter assays. Following intrathoracic injection of miR-11903a agomir and antagomir, Real-time quantitative polymerase chain reaction confirmed that AeCLIPB9 is negatively regulated by miR-11903a. Spatiotemporal expression analysis revealed that miR-11903a is most abundant in 4th instar larvae, followed by pupae and adults, and highly expressed in the wings, head, and midgut of female adults. Following pathogen infection, AeCLIPB9 and miR-11903a exhibited opposite expression trends, indicating their potential roles in mosquito innate immunity. To further investigate the relationship between AeCLIPB9 and miR-11903a, double-strand CLIPB9 was synthesized and RNA interference was performed. Seven-d survival assays revealed that both AeCLIPB9 and miR-11903a were crucial immune factors in fighting pathogens. Finally, longevity assays demonstrated that miR-11903a influenced mosquito lifespan.

Neuroinflammation is closely linked to aging, which damages the structure and function of the brain. It is caused by the intricate interactions of immune cells in the aged brain, such as the dysregulated glial cells and the dysfunctional astrocytes. Aging-associated chronic low inflammation, referred to as neuroinflammaging, shows an upregulated proinflammatory response. Autophagy and senescence play crucial roles as moderators of aging and neuroinflammatory responses. The dysregulated neuroimmune system, dystrophic glial cells, and release of proinflammatory factors alter blood-brain barrier, causing a neuroinflammatory landscape. Chronic inflammation combined with deteriorating neurons exacerbate neurological disorders and decline in cognitive function. This review highlights the neuroinflammaging and mechanism associated with immune cells interplay with central nervous system and aging, cellular senescence, and autophagy regulation in the brain's immune system under neuroinflammatory conditions. Moreover, the roles of microglia and peripheral immune cells in the neuroinflammatory process in the aging brain have also been discussed. Determining treatment targets and comprehending mechanisms that influence immune cells in the aged brain is necessary to decrease neuroinflammation.

The weight-adjusted waist index (WWI) has emerged as a reliable indicator of abdominal obesity. α-Klotho, a transmembrane protein, functions as a suppressor of aging. However, the relationship between these two factors remains underexplored. This study aims to investigate the association between WWI and serum α-Klotho levels in middle-aged and elderly Americans, with a focus on exploring the potential mediating role of the systemic immune inflammation index (SII). A cross-sectional study was conducted using data from 6997 middle-aged and elderly Americans participating in the National Health and Nutrition Examination Surveys (NHANES) between 2011 and 2016. Multiple linear regression analysis was employed to assess the relationship between WWI and serum α-Klotho concentrations. Additionally, mediation analysis was performed to investigate the mediating effect of SII on the relationships. Our analysis revealed a significant negative correlation between WWI and serum α-Klotho levels in the survey-weighted multiple linear regression models (adjusted percent change: -7.79; 95% CI: -10.15, -5.37). Mediation analysis demonstrated that the association between WWI and α-Klotho levels was partially mediated by SII (adjusted percent change: -0.88; 95% CI: -1.24, -0.45), with the proportion of mediation amounting to 11.6%. Further age-stratified results showed that the mediating role of SII was more pronounced among individuals aged ≥ 60 years, exhibiting a mediating effect of 26.3%, in contrast to 4.2% for those < 60 years. The findings suggest that WWI is inversely associated with serum α-Klotho concentrations and that this association is partially mediated by SII, especially in older people.

Muscle health helps maintain locomotor capacity, a key component of intrinsic capacity, which is required for healthy ageing. Sarcopenia is characterized by the age-related decline in muscle mass and strength leading to impaired physical performance, and has been described as a biological substrate of physical frailty. Both sarcopenia and physical frailty share phenotypic features of weakness and slowness, lead to common adverse outcomes, and have potential for reversal through early identification and intervention. The purpose of this review is to present recent evidence for the impact of lifestyle interventions across the life course on sarcopenia and physical frailty.

Although many studies have addressed the role of the amygdala in modulating long-term memory, it is not known whether weak training plus amygdala stimulation can transform a short-term memory into a remote memory. Object place recognition (OPR) memory after strong training remains hippocampus-dependent through the persistent action of protein kinase Mzeta (PKMζ) for at least 6 days, but it is unknown whether weak training plus amygdala stimulation can transform short-term memory into an even longer memory, and whether such memory is stored through more persistent action of PKMζ in hippocampus. We trained male rats (150 total in our study) to acquire OPR and 15 min or 5 h later induced a brief pattern of electrical stimulation in basolateral amygdala (BLA). Our results reveal that a short-term memory lasting < 4h can be converted into remote memory lasting at least 3 weeks if the BLA is activated 15 min, but not 5 h after learning. To examine how this remote memory is maintained, we injected ZIP, an inhibitor of atypical protein kinase Cs (aPKCs), PKMζ and PKCι/λ, into either hippocampal CA1, dentate gyrus (DG), or anterior cingulate cortex (ACC). Our data reveal amygdala stimulation produces consolidation into remote memory, not by persistent aPKC activation in the hippocampal formation, but in ACC. Our data establish a powerful modulating role of the BLA in forming remote memory and open a path in the search for neurological restoration of memory, based on enhancing synaptic plasticity in aging or neurodegenerative disorders such as Alzheimer's disease.

The success of clinical trials of longevity drugs relies heavily on identifying integrative health and aging biomarkers, such as biological age. Epigenetic aging clocks predict the biological age of an individual using their DNA methylation profiles, commonly retrieved from blood samples. However, there is no standardized methodology to validate and compare epigenetic clock models as yet. We propose ComputAgeBench, a unifying framework that comprises such a methodology and a dataset for comprehensive benchmarking of different clinically relevant aging clocks. Our methodology exploits the core idea that reliable aging clocks must be able to distinguish between healthy individuals and those with aging-accelerating conditions. Specifically, we collected and harmonized 66 public datasets of blood DNA methylation, covering 19 such conditions across different ages, and tested 13 published clock models. Additionally, we compiled 46 separate datasets to facilitate the training of new aging clocks. We believe our work will bring the fields of aging biology and machine learning closer together for the research on reliable biomarkers of health and aging.

Fibrosis of the lower abdominal muscle (LAM) contributes to muscle weakening and inguinal hernia formation, an ailment affecting a noteworthy fifty percent of men by age 75, necessitating surgical correction as the singular therapy. Despite its prevalence, the mechanisms driving LAM fibrosis and hernia development remain poorly understood. Utilizing a humanized mouse model that replicates elevated skeletal muscle tissue estrogen concentrations akin to aging men, we identified estrogen receptor alpha (ESR1) as a key driver of LAM fibroblast proliferation, extracellular matrix deposition, and hernia formation. Fibroblast-specific ESR1 ablation effectively prevented muscle fibrosis and herniation, while pharmacological ESR1 inhibition with fulvestrant reversed hernias and restored normal muscle architecture. Multiomic analyses on in vitro LAM fibroblasts unveiled an estrogen/ESR1-mediated activation of a distinct profibrotic cistrome and gene expression signature, concordant with observations in inguinal hernia tissues in human males. Our findings hold significant promise for prospective medical interventions targeting fibrotic conditions and presenting non-surgical avenues for addressing inguinal hernias.

Growth hormone (GH) is a neuromodulator that binds to receptors in the hippocampus and alters synaptic plasticity. A decline in GH levels is associated with normal aging, stress, and disease, and the mechanisms proposed involve the hippocampal circuit plasticity. To see how GH affects the hippocampal neural code, we recorded single neurons in the CA1 region of male Long-Evans rats with locally altered GH levels. Rats received injections of adeno-associated viruses into the hippocampus to make the cells overexpress either GH or an antagonizing mutated GH (aGH). Place cells were recorded in both familiar and novel environments to allow the assessment of pattern separation in the neural representations termed remapping. All the animals showed intact and stable place fields in the familiar environment. In the novel environment, aGH transfection increased the average firing rate, peak rate, and information density of the CA1 place fields. The tendency of global remapping increased in the GH animals compared with the controls, and only place cells of control animals showed significant rate remapping. Our results suggest that GH increases hippocampal sensitivity to novel information. Our findings show that GH is a significant neuromodulator in the hippocampus affecting how place cells represent the environment. These results could help us to understand the mechanisms behind memory impairments in GH deficiency as well as in normal aging.

Current literature states that early-life exposure to smoking produces adverse health outcomes in later life, primarily as a result of subsequent engagements with firsthand smoking. The implications of prior research are that smoking cessation can reduce health risk in later life to levels comparable to the risk of those who have never smoked. However, recent evidence suggests that smoking exposure during childhood can have independent and permanent negative effects on health-in particular, on epigenetic aging. This investigation examines whether the effect of early-life firsthand smoking on epigenetic aging is more consistent with (1) a sensitive periods model, which is characterized by independent effects due to early firsthand exposures; or (2) a cumulative risks model, which is typified by persistent smoking. The findings support both models. Smoking during childhood can have long-lasting effects on epigenetic aging, regardless of subsequent engagements. Our evidence suggests that adult cessation can be effective but that the epigenetic age acceleration in later life is largely due to early firsthand smoking itself.

Cataract is a progressive loss of eye lens transparency, as a result of age-related chemical modifications or due to congenital mutations in crystallins. A vital antioxidant in the aqueous humor, the vitamin C, has been suggested to hold potential for the prophylaxis of age-related cataract. However, the effect of vitamin C on congenital cataract has not yet been investigated. Here, we explored the aggregation inhibitory effect of vitamin C on the P23T human γD-crystallin mutant, associated with congenital cataract. The effect of vitamin C on the aggregation propensity of P23T human γD-crystallin was investigated by solution NMR, atomic force microscopy (AFM), and other biophysical techniques. We found that vitamin C is able to prevent and reverse P23T human γD-crystallin aggregation in a dose-dependent manner. In particular, NMR data suggest that the inhibitory effect of vitamin C on P23T human γD-crystallin phase-separation is probably mediated by interacting with aggregation prone regions. AFM images of P23T human γD-crystallin under native aggregating conditions revealed the appearance of amorphous aggregates, that disassemble into monomers in the presence of vitamin C. The current study highlights and confirms the possibility that vitamin C is able to dissolve crystallin aggregates, potentially slowing the onset or reversing cataract.

Cellular senescence, a hallmark of aging, has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However, the role of ABCA1 trafficking in cellular senescence associated with APOE4 and AD remains unclear.

While activation of autophagy is vital for cellular survival during exposure to ambient heat and exercise, it remains unclear if autophagic activity differs between these heat stress conditions and if aging mediates this response. Young (n=10, mean [SD]: 22 [2] years) and older males (n=10, 70 [5] years) performed 30 min of semi-recumbent cycling (70% maximal oxygen uptake). On a separate day, participants were immersed in warm water for 30 min, with the water temperature adjusted to induce the same increase in core temperature (rectal) as the prior exercise bout. Proteins associated with autophagy, inflammation, apoptosis, and the heat shock response (HSR) were assessed in peripheral blood mononuclear cells via Western blot before and after each exposure and during a 6-hour seated recovery in a temperate environment (∼22°C). No differences in core temperature occurred at end-exposure to exercise or passive heating in either group (both, p≥0.999). Older adults exhibited greater autophagic regulation (significant LC3-II accumulation) to exercise when compared to passive heating at all timepoints (all, p≤0.022). However, passive heating alone may have impaired autophagy (elevated p62; p=0.044). Pro-inflammatory IL-6 was elevated during both conditions (p<0.001) in older adults. Conversely, greater autophagic initiation (i.e., beclin-2) occurred in young adults at end-exercise and 3h recovery when compared to passive heating (both, p≤0.024). The HSR and apoptotic responses were similar between conditions in both groups. While brief exercise stimulates autophagy, exposure to ambient heat stress of an equivalent heat load may underlie autophagic dysregulation in older adults.

Zebrafish possess the innate ability to regenerate any lost or damaged retinal cell type with Muller glia serving as resident stem cells. Recently, we discovered that this process is aided by a population of damage-induced senescent immune cells. As part of the Senescence Associated Secretory Phenotype (SASP), senescent cells secrete numerous factors that can play a role in the modulation of inflammation and remodeling of the retinal microenvironment during regeneration. However, the identity of specific SASP factors that drive initiation and progression of retina regeneration remains unclear. Here, we mined the SASP Atlas and RNAseq datasets to identify differentially expressed SASP factors after retina injury, including two distinct acute damage regimens, as well as a chronic, genetic model of retina degeneration. We discovered a 31-factor Regeneration-associated Senescence Signature (RASS) that represents SASP factors and senescence markers that are conserved across all data sets and are upregulated after damage. Among these, we show that depletion of Nucleophosmin 1 (npm1a) inhibits retina regeneration. Our data support the model that differential expression of SASP factors promotes regeneration after both acute and chronic retinal damage.

Chikusetsu saponin IVa (CHS) is an essential active triterpenoid saponin found in various medicinal herbs, such as Aralia taibaiensis, Panax japonicus, and Aralia elata. While multiple health benefits have been documented, the effect of CHS on aging remains unclear. By employing the D-galactose-induced aging mice and the replicative senescence of primary mouse embryonic fibroblasts (MEFs) as the aging models, we found that CHS significantly attenuated aging both in vitro and in vivo. RNA sequencing analysis revealed that CHS greatly improved autophagy and mitophagy. Corresponding to the improved mitophagy, CHS remarkably reduced mitochondrial ROS and enhanced mitochondrial respiratory function. Mitophagy inhibition and Atg 7 genetic knockout (KO) almost abolished the anti-aging effect of CHS. AMPK pathway was activated during the attenuation of aging by CHS treatment, and a specific AMPK inhibitor reversed the induction of mitophagy and autophagy, as well as the attenuation of aging by CHS. Molecular docking data indicated AMPK as the direct binding target of CHS. In conclusion, our study initially demonstrates that CHS exhibits a potent anti-aging effect both in vitro and in vivo. CHS may directly bind to AMPK and activate the AMPK-dependent pathway to enhance autophagy and mitophagy, thereby reducing mitochondrial ROS and improving mitochondrial respiratory function, contributing to the anti-aging effect. These findings offer a new clue for the promising application of CHS in the improvement of aging and aging-related diseases in the future.

The repurposing of existing biosafety datasets offers unique opportunities in biomedical research. Here, we demonstrate how pesticide toxicity data, which include long-term survival studies in mammalian models, can be harnessed to uncover potential drug candidates or drug targets that can improve survival. We show that these substances frequently affect mitochondrial bioenergetics and that they can improve animal healthspan.

Background: Cardiovascular diseases are the major cause of death worldwide and their frequency increases with age in association with progressive kidney damages. Endothelial cells (ECs) are early affected in cardiovascular diseases. Although energy production in ECs involves glycolysis, endothelial mitochondria play a role in modulating cellular signalling. A reduction in fusion protein Opa1 level in ECs decreases the vascular response to flow and increased oxidative stress in perfused kidneys. Thus, we hypothesized that reduced Opa1 expression contributes to vascular aging. Methods: We used male and female mice with ECs specific Opa1 knock-out (EC-Opa1), and littermate wild-type (EC-WT) mice aged 6 (young) and 20 months (old). Mesenteric resistance arteries (MRA) and kidneys were collected for vascular reactivity and Western-blot analysis. Results: In old EC-Opa1 mice blood urea was greater than in age-matched EC-WT mice and MRA showed hypercontractilty and reduced endothelium-dependent relaxation. In kidneys, the mitochondria fission protein Fis-1 and the peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1) were increase in old EC-Opa1 mice. The level of eNOS expression was greater in young EC-Opa1 mice and caveolin-1 expression greater in old EC-Opa1 mice. Moreover, in kidneys from EC-Opa1 old mice, NADPH-oxidase subunits gp91, p47 and p67 expression was greater than in age-matched EC-WT mice. No difference was observed between old and young EC-WT mice. Conclusion: Reduced mitochondrial fusion in mouse ECs altered mesenteric vascular reactivity and increased oxidative stress in aging kidneys. Thus, Opa1 might protect the vascular tree in target organs such as the kidney during aging

Despite its prevalence among seniors, the impact of running on trabecular bone microarchitecture, especially in weight-bearing sites, remains relatively unexplored. This cross-sectional study aimed to investigate the impact of habitual running on bone health, specifically bone mineral density (BMD) and trabecular bone microarchitecture, in male older adults.

Cellular senescence prevents the application of mesenchymal stem cells in tissue engineering and stem cell therapy. Effective regulation of senescence is the key to maintain the functional stability of mesenchymal stem cells and improve their clinical application. This study aims to explore the molecular mechanism changes in human dental pulp stem cells (hDPSCs) during replicative senescence, focusing on the potential role of pregnancy-specific glycoprotein (PSGs) family member PSG4 in modulating cellular senescence. RNA sequencing was performed on hDPSCs at different passages and with PSG4 overexpression to reveal changes in gene expression during the process. Gain- and loss-of-function studies suggested that PSG4 regulated cellular senescence. PSG4 expression levels were significantly elevated during cellular senescence and closely correlated with cell cycle regulation. This study provides new insights into the molecular mechanisms underlying of hDPSCs' replicative senescence. PSG4 acts as a pivotal regulator of replicative senescence in hDPSCs by impacting cell cycle process.

To explore the characteristics of cellular senescence in human auricular chondrocytes during long-term in vitro culture and to evaluate the effects of anti-senescence treatments on enhancing their chondrogenic function.

Proteins are subject to aging in the form of spontaneous, nonenzymatic post-translational modifications (PTMs). One such PTM is the formation of the β-linked isomer l-isoaspartic acid (isoAsp) from aspartic acid (Asp) or asparagine residues, which tends to occur in long-lived proteins. Histones can exhibit half-lives on the order of 100 days, and unsurprisingly, isoAsp formation has been observed in nearly every histone family. Delineating the molecular consequences of isoAsp formation in histones is challenging due to the multitude of processes that occur on such time scales. To isolate the effects of a specific isoAsp modification thus necessitates precise

Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ + ) individuals have poorer mental and physical health than heterosexuals, and bisexuals fare worse than individuals who identify as lesbian and gay. However, data on stress biology among sexual minorities are critically insufficient. The current pilot study utilized data from 32 bisexual women - a subset of the National Couples' Health and Time Study - who completed questionnaires and provided blood samples to index biological aging from DNA methylation data (DunedinPACE, GrimAge2). The mean DunedinPACE score was 1.13 (SD = 0.18), which outpaced chronological aging by 13 % (p < 0.001). Likewise, bisexual women in this sample were, on average, 8.67 (SD = 5.96) years older biologically per GrimAge2 as compared to their chronological age. In covariate adjusted models, those reporting greater internalized homonegativity exhibited significantly greater epigenetic age acceleration (GrimAge2: p = 0.01; DunedinPACE: p = 0.041). Those who reported more frequent anti-bisexual experiences also showed accelerated GrimAge2 (p = 0.023). In contrast, those who reported stronger identity centrality (p = 0.017), stronger identity affirmation (p = 0.029), and more friend support (p = 0.018) - a critical type of support for LGBTQ + individuals - had slower GrimAge2. Depressive symptoms, anxiety and loneliness were not associated with GrimAge2 or DunedinPACE. Results suggest that bisexual women are at risk for accelerated aging, and those who have less internal and external affirmation of their sexual identity may be most at risk.