<h4>Background</h4>Physical activity reduces the risk of mortality and age-related chronic diseases, yet its association with biological age measured by DNA methylation (DNAm) clocks remains unclear. This systematic review and meta-analysis aims to evaluate the association between physical activity and biological age measured by DNAm clocks.<h4>Methods</h4>In this systematic review and meta-analysis, we conducted a systematic search of Embase, Cochrane Central Register of Controlled Trials, PubMed, Ovid, Scopus, and Web of Science from Jan 1, 2011, to June 6, 2025, to identify articles on the associations of physical activity and DNAm age, epigenetic age acceleration (EAA), or epigenetic age deviation in humans. Studies were included if they were peer-reviewed, published in English, included a study population with a mean or median age of 18 years or older, and investigated the association between DNAm clocks and physical activity in humans. Studies were excluded if the study population was a disease-specific population without controls. We evaluated risk of bias using an adapted Newcastle-Ottawa Scale and Cochrane Risk of Bias scale. We then performed a random-effects meta-analysis using reported or estimated standardised β coefficients and SEs. We also conducted a publication bias analysis and influence analysis. The study was registered with PROSPERO, CRD42024499021.<h4>Findings</h4>We identified 34 437 articles and, after removal of duplicates and screening, 44 studies were included in the systematic review comprising 145 465 participants: 62 887 (43·2%) females and 82 578 (56·8%) males, with mean ages ranging from 24·1 years to 78·5 years. Across studies, higher levels of physical activity were generally associated with lower DNAm age, although many individual associations did not reach statistical significance. Seven cross-sectional studies contributed to the meta-analysis. Each one SD higher in metabolic equivalent of tasks-min per week was associated with 0·03 SD lower Horvath EAA (β=-0·03 [95% CI -0·05 to -0·01]) and 0·09 SD lower GrimAge EAA (-0·09 [-0·12 to -0·05]). No statistically significant association was observed for Hannum EAA or PhenoAge EAA.<h4>Interpretation</h4>Higher physical activity is significantly associated with lower biological age as measured by Horvath EAA and GrimAge EAA. However, evidence is predominantly from cross-sectional studies, limiting causal inference. Future longitudinal studies and clinical trials using standardised, objectively measured physical activity are warranted to clarify dose-response relationships, and to determine whether physical activity can causally modify ageing trajectories, thereby informing precision strategies for healthy longevity.<h4>Funding</h4>The National University of Singapore and the National Medical Research Council of Singapore.

<h4>Background</h4>Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.<h4>Methods</h4>In a systematic search of six databases (Embase, Cochrane Central Register of Controlled Trials, PubMed, Ovid, Scopus, and Web of Science) from Jan 1, 2011, to June 6, 2025, we identified population-based cohort studies reporting associations between DNA methylation age, EAA, or age deviation and frailty from general or disease-specific populations with a control group. Risk of bias was assessed using an adapted Newcastle-Ottawa Scale. Random-effects meta-analyses with Hartung-Knapp adjustments were performed on standardised β coefficients and SEs. Publication bias, influence, and sensitivity analyses were conducted.<h4>Findings</h4>From 34 437 records screened, 24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28 325 participants (14 757 [52·1%] female; median of mean age 65·2 years [IQR 62·2-69·4]). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11 162; standardised β coefficient 0·06 [95% CI 0·02-0·09], I²=71·4%), PhenoAge EAA (eight studies; n=10 371; 0·07 [0·03-0·11], I²=81·7%), GrimAge EAA (eight studies; n=10 371; 0·11 [0·06-0·15], I²=90·5%), and pace of ageing (five studies; n=7895; 0·10 [0·01-0·19], I²=91·0%) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6143; 0·02 [0·00-0·05], I²=46·0%, p=0·0481) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.<h4>Interpretation</h4>Higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.<h4>Funding</h4>National University of Singapore.

Maternal stress during lifetime and pregnancy may influence offspring epigenetic age, impacting long-term health. We conducted a systematic review and meta-analysis of associations between maternal stress and epigenetic aging markers: telomere length (TL) and DNA methylation (DNAm) age acceleration. The systematic search was performed according to PRISMA guidelines and registered on PROSPERO (ref. CRD42023474640). Fixed and random effect meta-analyses were carried out, stratified by stress type and marker type (TL, DNAm). Sixteen studies met inclusion criteria; 12 were meta-analyzed (10 TL, 2 DNAm). Due to high heterogeneity, restricted maximum likelihood meta-analysis suggested significant inverse associations between maternal stress and offspring TL. Perceived stress was associated with shorter TL (<i>p</i>-value = 7 × 10^-4, β = -0.085, 95%CI [-0.135, -0.036]), as was lifetime stress/trauma (<i>p</i>-value = 0.01, β = -0.209, 95%CI [-0.370, -0.049]). In contrast, maternal stress showed no significant associations with DNAm age acceleration (<i>p</i>-value = 0.32). Both perceived maternal stress and maternal stress were associated with shorter offspring TL, suggesting that stress exposure across the maternal lifespan influences offspring biological aging markers. No significant association was observed with DNAm-based aging clocks. Further studies with larger sample sizes and more homogeneous settings are needed to confirm and expand upon our observations.

Clonal haematopoiesis of indeterminate potential (CHIP) represents somatic mutations in haematopoietic stem cells that drive clonal expansion. Epigenetic age acceleration (EAA), estimated from DNA methylation (DNAm) clocks, may capture age-related changes in haematopoiesis. This systematic review and meta-analysis was conducted to synthesise evidence on associations between CHIP and EAA and explore shared biological mechanisms that may underlie this relationship. Six databases were searched from January 1, 2011, to June 6, 2025, adhering to PRISMA 2020. Random-effects meta-analyses were performed. Five studies comprising 7483 individuals (ages 55-79, 67.1% female) assessing associations between CHIP and DNAm clocks were included. Across studies, CHIP individuals had higher EAA than no-CHIP individuals, and larger clones were associated with higher EAA. Meta-analysis of three cross-sectional studies (n = 6946) showed that CHIP had higher EAA versus no-CHIP for Horvath1Age IEAA (mean difference, MD=2.84 years, 95% confidence interval, CI: 1.49-4.19), HannumAge EEAA (MD=2.31 years, 95% CI: 1.14-3.49), PhenoAge (MD=1.84 years, 95% CI: 0.96-2.71), and GrimAge (MD=1.20 years, 95% CI: 0.80-1.61). Both DNMT3A- and TET2-mutated CHIP were associated with higher EAA with TET2-mutated CHIP showing larger effect sizes and more consistent associations than DNMT3A-mutated CHIP across DNAm clocks tested. Higher EAA may also act as an effect modifier for morbidity and mortality in CHIP. Larger longitudinal studies are needed to verify a temporal relationship and determine whether EAA provides incremental prognostic value for morbidity and mortality in CHIP.

The continued development in methylome analysis has enabled a more precise assessment of DNA methylation, but treatment of target tissue prior to analysis may affect DNA analysis. Prediction of age based on methylation levels in the genome (DNAmAge) has gained much interest in disease predisposition (biological age estimation), but also in chronological donor age estimation in crime case samples. Various epigenetic clocks were designed to predict the age. However, it remains unknown how the storage of the tissues affects the DNAmAge estimation. In this study, we investigated the storage method

evaluate effects. The pan-mammalian epigenetic clock is a molecular biomarker designed to measure the age of all mammalian tissues and species using cytosine This timeline lists notable events in the history of research into senescence or biological aging, including the research and development of life extension methods, brain aging delay methods and rejuvenation. People have long been interested in making their lives longer and healthier. The most ancient Egyptian, Indian and Chinese books contain reasoning about aging. Ancient Egyptians used garlic i Nutrition-related results A study reports results of the first longevity caloric restriction (CR) trial, CALERIE, finding that two years of nonintermittent CR slowed the pace of aging as measured by one of three aging clocks (modest DunedinPACE effects). Development and application of aging clocks and combination therapies A study reports the development of deep learning software using anatomic magnetic resonance images to estimate brain age with the highest accuracy for AI so far, including detecting early signs of Alzheimer's disease and varying neuroanatomical patterns of neurological aging. A study shows DNA methylation aging clocks could be useful indicators of health while social factors – such as health behaviors and poverty – are at least as good predictors and e.g. can better predict cognitive functioning. Around February, Bryan Johnson's Project Blueprint for one of the first comprehensive, possibly largely public, self-experimentations of a comprehensive combination therapy informed by the large scientific corpus on the topic and organ measurements to maximally reverse biological age and (epigenetic) aging markers achieves substantial media attention, with such activities previously largely reserved to biohackers without resources and means to evaluate effects. The pan-mammalian epigenetic clock is a molecular biomarker designed to measure the age of all mammalian tissues and species using cytosine methylation in highly conserved DNA regions. A study indicates chest radiographs evaluated using AI could be a performant biomarker for aging clocks. A study using plasma proteomics aging clocks suggests nearly 20% of the population may show strongly accelerated age in one of 11 major organs, which it links to higher mortality risk. Biological and biotechnical rejuvenation-related results In January, a team led by David Sinclair shows in a 13-year-long international study how DNA breaks or epigenetic damage are a major driver of epigenetic change, and how the loss of epigenetic information is a cause of aging in mammals. It concluded that the loss of epigenetic information can drive aging independently of changes to the genetic code, suggesting that…

Aging involves a diverse set of biological changes accumulating over time that leads to increased risk of morbidity and mortality. Epigenetic clocks are now widely used to quantify biological aging, in order to investigate determinants that modify the rate of aging and to predict age-related outcomes. Numerous biological, social and environmental factors have been investigated for their relationship to epigenetic clock acceleration and deceleration. The aim of this review was to synthesize general trends concerning the associations between human epigenetic clocks and these investigated factors. We conducted a systematic review of all available literature and included 156 publications across 4 resource databases. We compiled a list of all presently existing blood-based epigenetic clocks. Subsequently, we created an extensive dataset of over 1300 study findings in which epigenetic clocks were utilized in blood tissue of human subjects to assess the relationship between these clocks and numeral environmental exposures and human traits. Statistical analysis was possible on 57 such relationships, measured across 4 different epigenetic clocks (Hannum, Horvath, Levine and GrimAge). We found that the Horvath, Hannum, Levine and GrimAge epigenetic clocks tend to agree in direction of effects, but vary in size. Body mass index, HIV infection, and male sex were significantly associated with acceleration of one or more epigenetic clocks. Acceleration of epigenetic clocks was also significantly related to mortality, cardiovascular disease, cancer and diabetes. Our findings provide a graphical and numerical synopsis of the past decade of epigenetic age estimation research and indicate areas where further attention could be focused in the coming years.

Abstract Glucagon-like peptide-1 (GLP-1) receptor agonists have attracted interest as gerotherapeutics, yet clinical-trial evidence for their effects on biological aging is lacking. We report a post hoc exploratory epigenetic age analysis of a 32-week, randomized, double-blind, placebo-controlled phase 2b trial (NCT04019197) of semaglutide in adults with human immunodeficiency virus (HIV)-associated lipohypertrophy (semaglutide n = 45; placebo n = 39). The parent trial’s primary endpoint was change in visceral adipose tissue, with secondary cardiometabolic and body-composition endpoints; epigenetic aging was not pre-specified. To address this gap, we profiled peripheral-blood DNA methylation (DNAm) at baseline and week 32 to assess semaglutide versus placebo on first-, second-, and third-generation epigenetic aging measures. In adjusted analyses, semaglutide reduced epigenetic aging across multiple second- and third-generation clocks, including PhenoAge ( − 4.9 years/year, p = 0.004), PCGrimAge ( − 3.1, p = 0.007), GrimAge V2 ( − 2.3, p = 0.009), OMICmAge ( − 2.2, p = 0.009), RetroAge ( − 2.2, p = 0.030), and DunedinPACE ( − 0.09 units, 9% slower, p = 0.01). Systems-based clocks showed parallel reductions in inflammation, brain, and heart aging measures. The post hoc design, modest sample size, HIV-specific cohort, and 32-week follow-up limit generalizability. Prospective trials are needed to determine whether GLP-1 receptor agonists can be repurposed as gerotherapeutics.

People who develop high blood pressure before turning 50 years old face increased risk of severe heart problems compared to others. Scientists developed epigenetic clocks as advanced methods to determine biological age and study aging processes. The research project employed a case-control design to examine how accelerated epigenetic aging affects premature hypertension development among Uzbek study participants. The research study enrolled 80 participants who had premature hypertension and 80 participants with matching age and sex who did not have health problems. The researchers used five epigenetic clocks to establish epigenetic age through Horvath, Hannum, PhenoAge, GrimAge, and SkinBloodClock analysis of DNA methylation data from peripheral blood leukocytes. The study found that all epigenetic clocks measured higher epigenetic age in patients compared to the control group. The biggest difference between the two groups appeared on the GrimAge clock, which assessed patients as 7.4 years older their actual age, while the control group showed no age difference. The patients who experienced systolic blood pressure measurements above 160 mmHg showed greater disease progression than those with lower blood pressure standards. The research showed that every year of GrimAge aging acceleration raised the risk of premature hypertension development by 38 percent (OR = 1.48). The study found that accelerated aging showed a strong positive relationship with C-reactive protein and inter

Introduction: Aging is the strongest risk factor for most chronic diseases. The rising burden of an aging population and non-communicable diseases (NCDs), contributes to escalating costs for society. Several non-pharmaceutical interventions can lower the risk of NCDs, including common mental disorders (CMDs), and may slow down biological aging, as evidenced by outcome markers such as epigenetic clocks. However, a comprehensive overview of whether and which non-pharmaceutical interventions may impact human epigenetic aging is missing. Synthesizing evidence of interventions on epigenetic aging t