Search Results (114)

Human ageing and longevity are increasingly understood as biologically integrated and heterogeneous processes shaped by interactions among genetic susceptibility, epigenetic remodelling, and environmental modulation. This narrative review examines these interconnections within a nutrigenomic framework, with particular emphasis on how inherited variation and epigenetic plasticity may influence responses to ageing-related interventions. A structured literature search was conducted in PubMed, Scopus, Web of Science, and Embase, focusing on English-language studies published during the last 10 years. The review was organized into three major domains: (i) genetic determinants of longevity, (ii) epigenetic mechanisms of ageing, and (iii) intervention-responsive pathways relevant to precision geroscience. Current evidence supports a polygenic model of longevity in which loci such as FOXO3 and APOE show the most consistent human associations, while telomere maintenance, insulin/IGF-1 and mTOR signalling, sirtuins, Klotho, inflammatory mediators, and DNA repair remain biologically important but variably supported at the variant level. Epigenetic mechanisms, including DNA methylation drift, epigenetic clocks, histone modifications, chromatin remodelling, heterochromatin loss, and non-coding RNA regulation, provide an environmentally responsive interface linking genetic background to ageing phenotypes. Nutritional, pharmacological, behavioural, and circadian interventions converge on overlapping molecular pathways involving AMPK, mTOR, FOXO, sirtuins, autophagy, mitochondrial maintenance, and inflammatory signalling, although human evidence remains heterogeneous and biomarker modulation should not be equated with clinically meaningful slowing of organismal ageing. Overall, this review highlights the value of integrating genetics, epigenetics, and intervention biology to support a more cautious and translationally relevant model of healthy ageing. It also underscores the need for precision nutrigeroscience approaches that account for tissue context, baseline physiology, and inter-individual molecular variability. Full article

The exon 3 deletion polymorphism in the growth hormone receptor gene (d3GHR) is associated with altered GH signaling and longevity-related phenotypes, yet its relationship with blood-based epigenetic aging remains unclear. We analyzed whole-blood DNA from 21 unrelated adults recruited at Laniado Medical Center to determine whether the d3GHR genotype was associated with differential DNA methylation in skin-aging-related genes and altered age acceleration across established DNA methylation clocks. Genome-wide methylation was profiled using the Infinium MethylationEPIC v2.0 array, focusing on 1098 CpG sites linked to wrinkling, pigmentation, and extracellular matrix remodeling. No significant single-CpG methylation differences were detected within the targeted panel. However, two promoter-proximal differentially methylated regions (DMRs) were identified near CYP1A1 (FWER = 0.014) and ACAT2 (FWER = 0.026). Notably, only the pan-tissue Horvath clock showed a significant genotype effect, with marked age acceleration in d3/d3 carriers (mean Δ ≈ +14.5 years, p = 0.0179) that persisted after adjustment for chronological age. In contrast, second-generation clocks such as PhenoAge showed a non-significant trend toward deceleration. These findings suggest a preliminary association between d3GHR genotype, clock-specific epigenetic age acceleration and promoter-level methylation signatures near metabolic and stress-response genes. The observed Horvath acceleration may reflect systemic metabolic or immune adaptation rather than direct structural senescence in core skin-aging gene programs in blood. Given the very small d3/d3 subgroup, these findings should be interpreted strictly as exploratory pilot observations and cannot establish reproducible genotype-specific effects without validation in larger independent cohorts. Full article

Chronological age is a poor indicator of interindividual differences in biological aging. DNA methylation-based epigenetic clocks provide a reliable measure of biological age and epigenetic age acceleration (EAA). Although modifiable behavioral, environmental, and social factors appear to influence EAA, the magnitude, consistency, and potential preventability of these associations have never been systematically quantified. We conducted a systematic review and meta-analysis following PRISMA 2020 guidelines. PubMed/MEDLINE and Scopus were searched from inception to 7 April 2026 for English-language observational and interventional studies reporting quantitative associations between modifiable determinants and EAA measured using validated clocks (Horvath, PhenoAge, GrimAge, DunedinPACE). Effect sizes were harmonized into four analytical pools. Random-effects meta-analyses were performed using the DerSimonian–Laird estimator, with pre-specified subgroup analyses by exposure category. Heterogeneity, publication bias, and robustness were thoroughly assessed. A novel Modifiable Epigenetic Aging Burden Index (MEAB-Index) was developed to quantify the cumulative preventable burden. Only studies conducted in adult populations (≥18 years) were eligible. Eighty-three studies providing 118 distinct exposure–clock associations were included. In the primary analysis (Pool A, n = 60), adverse modifiable exposures were associated with accelerated EAA (pooled β = +0.310 years per unit exposure, 95% CI 0.255–0.366). The strongest associations were observed for metabolic and inflammatory markers (β = +0.913) and environmental exposures (β = +0.466). The MEAB-Index yielded a Cumulative Preventable Burden of +1.566 years (bootstrap 95% CI 1.011–2.123). Findings were robust across sensitivity analyses and remained directionally consistent in secondary pools (B–D). This study provides the most comprehensive quantitative synthesis to date on the modifiability of epigenetic aging. Our findings demonstrate that EAA is meaningfully shaped by behavioral, environmental, and social determinants. The MEAB-Index introduces a novel framework for estimating the preventable burden of biological aging and for prioritizing interventions. Reducing key modifiable risk factors, particularly metabolic/inflammatory and environmental exposures, could substantially slow biological aging at the population level and support the transition toward ageing-centered preventive strategies. Full article

Background/Objectives: Spaceflight presents a combination of physical and psychosocial stressors that may impact biological aging and health. Understanding how spaceflight influences molecular aging processes is essential as commercial and professional space travel continue to expand. Methods: We analyzed publicly available DNA methylation data to evaluate longitudinal changes in 10 epigenetic aging biomarkers, 6 leukocyte proportion estimates, and 109 DNA methylation-derived protein scores in two astronauts participating in Axiom Space’s AX1 17-day low Earth orbit mission. We calculated mean values for all biomarkers across three timepoints: two weeks before spaceflight (T0), 24 h after spaceflight (T1), and three months after spaceflight (T2). Using the mean values, we next calculated the fold change from baseline for all biomarkers. Because the sample size precluded statistical testing, we identified the top 5% of absolute fold changes to highlight the largest shifts across candidate biomarkers. Results: Across epigenetic clocks, MiAge showed the greatest T0–T1 decrease (−4.26-fold), and DNAmFitAge showed the greatest T0–T2 increase (2.47-fold). NK cells exhibited the largest T0–T1 change, decreasing by 49% (−0.49-fold). B cells exhibited the largest T0–T2 change, decreasing by 11% (−0.11-fold). Proteins meeting a predefined top 5% fold change from baseline criterion at both T1 and T2, included BMP1, CLEC11A, CXCL11, FAP, and LTF. Enrichment analysis indicated involvement of serine-type endopeptidase activity, molecular function activator activity, and cell aggregation pathways. Conclusions: These findings suggest that spaceflight influences methylation-derived biomarkers of aging and immunity even in short-duration missions. These results, though exploratory, contribute to emerging efforts to characterize molecular resilience and vulnerability in human spaceflight. Full article

Environmental contaminants such as per- and polyfluoroalkyl substances (PFAS) and toxic metals have been implicated in biological aging, yet their combined effects remain poorly understood. This study evaluated the associations of PFAS, lead, and cadmium mixtures with multiple DNA methylation-based measures of epigenetic aging in a nationally representative sample of U.S. adults aged ≥ 50 years. Data were obtained from the 1999–2000 and 2001–2002 National Health and Nutrition Examination Survey (NHANES). The analytic sample included 1119 participants with available data on seven PFAS, blood lead, cadmium, and DNA methylation measures. Epigenetic aging outcomes included HannumAge, HorvathAge, SkinBloodAge, PhenoAge, GrimAge, and DunedinPoAm. Multivariable linear regression and Bayesian Kernel Machine Regression (BKMR) were used to assess individual and joint exposure–response relationships. Cadmium showed the most consistent positive associations with epigenetic aging measures, particularly for the second-generation clocks PhenoAge and GrimAge. Lead was positively associated with GrimAge, while PFAS showed more variable and generally weaker associations, with PFNA demonstrating the most consistent signal. Mixture analyses indicated that higher combined exposure levels were associated with higher DNA methylation age estimates, with stronger patterns observed for second-generation clocks. These findings suggest that combined exposure to PFAS, lead, and cadmium is associated with higher epigenetic aging in older U.S. adults, with cadmium emerging as a key contributor to the observed mixture effects. Evaluating environmental exposures as mixtures may provide important insight into how co-occurring contaminants jointly influence biological aging. Full article

DNA methylation constitutes a primary layer of epigenetic regulation in plants, operating across three sequence contexts (CG, CHG, and CHH) through distinct enzymatic pathways. Over the past fifteen years, accumulating evidence has shown that DNA methylation varies substantially among individuals and populations of wild plants, sometimes independently of underlying genetic polymorphism. This variation can influence gene expression, transposable element activity, and phenotypic traits relevant to ecological adaptation. Population epigenetics, the study of methylation variation at the population scale, has matured from initial surveys using methylation-sensitive amplified fragment length polymorphism (MS-AFLP) into a discipline increasingly reliant on reduced-representation bisulfite sequencing (epiGBS, bsRADseq), whole-genome bisulfite sequencing (WGBS), enzymatic methyl-seq (EM-seq), and direct long-read detection by nanopore sequencing. These methodological advances are opening population epigenetics to non-model organisms across the full breadth of the plant phylogeny, from angiosperms and gymnosperms to ferns and bryophytes. We cover (i) the molecular machinery underlying plant DNA methylation, including the debated status of N6-methyladenine (6mA); (ii) empirical evidence for natural epigenetic variation in plant populations, spanning clonal, invasive, and outcrossing species; (iii) the methodological toolkit available for population-scale methylation profiling, with emphasis on approaches suitable for non-model taxa; and (iv) the ecological and evolutionary significance of population epigenetic variation, including transgenerational inheritance, stress memory, epigenetic clocks, conservation applications, and the emerging integration of epigenetics into the extended evolutionary synthesis. We identify critical knowledge gaps, particularly the near-complete absence of population-level epigenetic data for bryophytes, ferns, and lycophytes, and outline priorities for future research. Full article

With global life expectancy steadily rising, promoting healthy aging is becoming a critical objective of public health. Physical function tends to decline gradually, often beginning in midlife, when subtle changes start to occur and accumulate undetected until later years. This study examines the feasibility of using DNA methylation-based epigenetic clocks as biomarkers for cumulative physical performance in 24 community-dwelling adults aged 39 years and older. Our findings reveal that several epigenetic age estimators, particularly DNAmAgeHannum, are significantly associated with a novel composite score criterion derived from standardized motor function assessments (DNAmAge: ρ = −0.48, p < 0.026; DNAmPhenoAge: ρ = −0.48, p < 0.026) with DNAmAgeHannum (ρ = −0.59, p < 0.005). These findings support the potential of using epigenetic aging markers to detect early physiological decline, even in relatively healthy, midlife populations, offering a promising tool for the early identification of age-related functional deterioration. Full article

Reproductive aging is characterized by progressive decline in ovarian reserve, reduced oocyte competence, and impaired endocrine coordination. Although these phenotypic changes are well documented, the molecular mechanisms that integrate aging-associated stress signals into coordinated ovarian dysfunction remain incompletely understood. Increasing evidence indicates that DNA methylation remodeling is closely associated with ovarian aging. Rather than representing isolated promoter-specific events, age-related methylation alterations may reflect progressive imbalance between DNA methyltransferases (DNMTs) and TET-mediated demethylation. Stress-responsive DNMT/TET dysregulation has been linked to distributed epigenetic remodeling across regulatory elements governing PI3K–AKT, TGF-β/SMAD, metabolic, and DNA damage response pathways in ovarian cell populations. We propose a network-level framework in which methylation drift preferentially affects highly connected regulatory hubs, potentially reducing transcriptional robustness and intercellular coordination within the follicular microenvironment. However, current human data remain largely correlative, and functional validation is required to determine whether methylation remodeling acts as a driver, amplifier, or biomarker of ovarian aging. Finally, we discuss translational implications, including circulating cell-free DNA signatures and epigenetic clock models, while emphasizing the importance of cell type-resolved and longitudinal studies. Collectively, the available evidence supports a model in which progressive DNMT/TET imbalance is associated with distributed pathway-level regulatory instability during ovarian aging. Full article

Background: Sustaining long-term lifestyle change remains a major challenge in preventive health. Epigenetic clocks offer a dynamic, modifiable measure of biological ageing that may enhance motivation when returned to individuals. Objectives: This study had two aims: (1) to evaluate whether personalised health reports integrating epigenetic age, polygenic cancer risk scores, and lifestyle metrics could motivate sustained behavioural change; and (2) to examine variability across epigenetic clock generations to inform the selection of a suitable model for participant feedback. Methods: A total of 178 adults were recruited via the Graham Fulford Charitable Trust community testing programme, and 91 completed a one-year follow-up survey assessing behavioural, psychological, and knowledge-related outcomes. DNA methylation data from 140 samples were used to compare 14 epigenetic clocks across four generations. Results: Most participants reported positive lifestyle changes, including feeling healthier (72.5%), increased physical activity (60.4%), and improved diet (47.3%). Gains were also observed in health knowledge (63.7%) and psychological well-being (31.9%). Epigenetic clock comparisons revealed substantial heterogeneity across models. Zhang2019-BLUP was selected as a stable and interpretable measure of biological age that can be readily communicated to participants, supporting empowerment and improved health literacy, rather than serving only as a risk prediction metric. Conclusions: Personalised biomarker feedback including epigenetic age combined with lifestyle and wearable data can support self-reported improvements in health-related behaviours. Community-based delivery through trusted local networks proved effective. The marked variation between epigenetic clocks highlights the importance of selecting models designed for clear communication when used in public-facing health interventions. Full article

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 (p-value = 7 × 10⁻⁴, β = −0.085, 95%CI [−0.135, −0.036]), as was lifetime stress/trauma (p-value = 0.01, β = −0.209, 95%CI [−0.370, −0.049]). In contrast, maternal stress showed no significant associations with DNAm age acceleration (p-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. Full article

Background/Objectives: Lipid metabolism is fundamental to energy homeostasis and cellular structural integrity, and its dysregulation is a hallmark of biological aging. While DNA methylation clocks are well-established, it remains unclear whether epigenetic sites associated with specific lipid markers—High-Density Lipoprotein (HDL), Total Cholesterol (TCH), and Triglycerides (TGY)—are evolutionarily conserved across mammals and how they manifest across different metabolic tissues. Methods: We identified lipid-associated CpG sites in humans using the Korean Genome and Epidemiology Study (KoGES) cohort and projected these sites onto the Mammalian Methylation Consortium (GSE223748) dataset. Using the Hybrid Pi (HyPi) score, we selected robust markers to analyze their evolutionary conservation, tissue specificity, and age-related dynamics across over 300 mammalian species. Specifically, we examined the phylogenetic concordance between blood and three major metabolic organs (Liver, Adipose, Muscle) in five representative species. Results: Lipid-related CpGs were highly conserved across diverse mammals. t-SNE analysis revealed that these epigenetic signatures clustered samples by tissue identity and species. Methylation levels of these CpGs showed significant correlations with maximum lifespan and distinct aging rates across tissues. Notably, phylogenetic tanglegram analysis revealed a high degree of concordance between blood and key metabolic organs, suggesting that blood methylation profiles mirror the evolutionary trajectory of internal metabolic tissues. Furthermore, these patterns were consistent between sexes, indicating a fundamental, non-dimorphic regulation of lipid epigenetics. Conclusions: Our findings suggest that epigenetic mechanisms governing lipid metabolism are deeply conserved to maintain tissue identity and regulate biological aging, with blood serving as a reliable evolutionary proxy for internal metabolic states. Full article

Epigenetic clocks have successfully estimated biological age by identifying CpG sites whose DNA methylation levels correlate with chronological age. However, these statistical models provide limited mechanistic insight into the biological underpinnings of ageing. While they capture the “pace” of ageing, they fail to quantify the “resilience” of biological systems—the capacity to recover, reorganize, and maintain homeostasis under stress. To overcome this limitation, we introduce EpiAge-R (Epigenetic Age with Resilience), a mechanistic framework that shifts the focus from passive correlation to active recovery potential. The EpiAge-R framework integrates multilayered biological information—including long-read methylation sequencing, chromatin context, histone modification balance, 3D genome topology, and mitochondrial dynamics—into a unified Resilience Index. By distinguishing between degenerative methylation drift (damage) and adaptive repair processes (resilience), EpiAge-R aligns with nonlinear multi-omics ageing trajectories. This framework provides a quantitative foundation for next-generation biomarkers and precision longevity interventions, aiming to define optimal health rather than statistical normality. Full article

Survival rates for children, adolescents, and young adults (CAYA) with cancer have markedly improved over recent decades, resulting in a rapidly growing population of long-term survivors. However, many of these individuals experience late and long-term treatment-related effects that resemble conditions typically associated with advanced age, including cardiovascular disease, endocrine dysfunction, neurocognitive impairment, and secondary malignancies. This clinical constellation has led to the concept of therapy-induced accelerated aging, suggesting that cancer treatments provoke biological changes that mirror, and may accelerate, physiological aging processes. In this review, we examine current evidence for aging-associated molecular hallmarks in CAYA cancer survivors, focusing on epigenetic alterations, genomic instability, chronic inflammation, cellular senescence, telomere attrition, and mitochondrial dysfunction. Epigenetic age acceleration is consistently observed across multiple survivor cohorts and correlates with treatment exposures, lifestyle factors, and chronic health conditions, positioning DNA methylation-based clocks as promising integrative biomarkers. Likewise, clonal hematopoiesis—reflecting persistent genomic stress—appears enriched in survivors, particularly decades after therapy, and may serve as an indicator of long-term cardiovascular and hematologic risk. Immune dysregulation, inflammaging, and senescence markers further underscore the systemic impact of cancer therapies on biological aging pathways. While telomere shortening and mitochondrial alterations also contribute to this phenotype, their standalone biomarker utility remains limited. Together, these hallmarks highlight the multifaceted nature of accelerated aging in CAYA survivors. Future work integrating multi-omics biomarkers with clinical phenotyping will be essential to identify high-risk individuals, guide targeted interventions, and advance personalized survivorship care. Full article

There is considerable interest in the connection between alcohol-induced oxidative stress, DNA methylation, antioxidants, and accelerated aging across diverse populations. Nevertheless, self-reported alcohol consumption is prone to bias, and objective biomarkers of alcohol intake are needed. Our aims were to investigate the performance of an epigenomic biomarker of alcohol consumption in a Mediterranean population using self-reported data and the biomarker gamma-glutamyl transferase (GGT); to examine the effects of alcohol (self-reported and biomarker-assessed) on epigenome-wide methylation; to analyze the association between alcohol (self-reported and biomarker-assessed) and telomere length and other aging biomarkers; and to explore the modulating effect of the Mediterranean diet (MedDiet). We performed blood epigenome-wide methylation studies (EWAS) in a Mediterranean cohort (aged 55–75 years). Self-reported alcohol consumption and MedDiet were assessed by questionnaires. A replication cohort (cohort 2) from the same area was also analyzed. For both cohorts, the DNA methylation-based biomarker (450-CpGs) was computed alongside epigenetic clocks for the following biological age acceleration metrics: DNAm telomere length, GrimAgeAcceleration, PhenoAgeAcceleration, and CausalityAgeYing (cohort 1). The association between the epigenomic biomarker and self-reported alcohol consumption was significant (p < 0.001) in both cohorts, but modest. However, the association was stronger when predicting high alcohol intake (AUC: 0.76; 95%CI: 0.65–0.86; p < 0.0001). In the EWAS, the hit (cg06690548-SLC7A11, in a cystine transporter that enhances glutathione production for antioxidant defense) was shared among the self-reported alcohol consumption, GGT, and the epigenomic biomarker, with alcohol linked to hypomethylation. We detected differential methylation in pre-selected oxidative stress-related genes. Enrichment analysis revealed “Rap1 signaling pathway” as the hit (p < 0.00001). High self-reported alcohol consumption and the epigenomic biomarker were associated with shorter telomere length (p < 0.05) in cohort 1. Additionally, a modulation by Mediterranean diet adherence was hypothesized. No significant associations were found between self-reported alcohol intake and the other aging biomarkers; however, the epigenomic score was directly associated with GrimAge, PhenoAge and CausAgeYing biomarkers in cohort 1 (p < 0.001), and two were replicated in cohort 2. In conclusion, alcohol intake has an impact on DNA methylation at the epigenome-wide level in this Mediterranean population, replicating the main hits from other populations and validating the epigenomic biomarker for intake, although improvement is needed. Moreover, several associations with aging biomarkers were observed. Full article

DNA methylation regulates plant growth by modulating gene expression; however, its contribution to hormone responsiveness and photomorphogenesis remains only partially understood. We examined Arabidopsis thaliana DNA methylation mutants met1 and drm1, drm2, and cmt3 (ddc) under defined light regimes and following exogenous treatments with auxin, gibberellin, and the auxin transport inhibitor TIBA. Hypocotyl elongation and cotyledon expansion exhibited strong light dependency across all genotypes, with met1 seedlings developing a consistently reduced cotyledon area and ddc seedlings displaying impaired hypocotyl elongation under specific light qualities. Exogenous auxin inhibited growth in all genotypes, whereas GA₃ promoted elongation in hypocotyls and roots (by approximately 75–80% and 15–35%, respectively, in Col0 and met1), with ddc exhibiting delayed and non-linear dose-dependent sensitivity. Quantitative RT–PCR analysis revealed differential expression of genes involved in auxin transport (PIN1, PIN3, PIN7), auxin signalling (ARF7, IAA3, LAX3), circadian regulation (TOC1, LHY, CCA1), and light signalling (PIFs, HY5, HYH), supporting a link between DNA methylation status and coordinated regulation of hormone-, light-, and clock-controlled transcriptional networks. Together, these findings demonstrate that MET1- and DRM/CMT-dependent methylation pathways integrate epigenetic regulation with environmental and hormonal cues, modulating the intensity, timing, and organ specificity of growth responses, thereby fine-tuning growth plasticity during early Arabidopsis seedling development. Full article