Physical Activity Is Associated With Decreased Epigenetic Aging: Findings From the Health and Retirement Study

ABSTRACT Background Epigenetic aging measures or clocks are DNA methylation‐based indicators of biological aging, linked to health outcomes and disease risk. Physical activity and exercise may influence epigenetic aging, suggesting a pathway through which it promotes healthier aging and reduces chronic disease burden. In this study, we assessed the association between self‐reported moderate‐to‐vigorous physical activity and epigenetic age acceleration (EAA) in participants of the Health and Retirement Study, followed biennially for 12 years from 2004 to 2016. Methods Leukocyte DNA methylation was measured from venous blood samples collected in 2016 and second‐generation epigenetic clocks (GrimAge, PhenoAge and DunedinPACE) were used to assess EAA. Physical activity was assessed at each wave, with participants reporting vigorous activity at least once per week or moderate activity more than once per week or more categorized as ‘physically active’. We used weighted linear regression models for cross‐sectional analysis in 2016. Additionally, we used a structured life‐course modelling approach (SLCMA) to assess how the timing of physical activity is associated with EAA, testing both wave‐specific physical activity measures and an accumulation measure indicative of sustained physical activity over the follow‐up period. Results In 2016, 58% of the participants were classified as physically active. In cross‐sectional analysis, physically active participants had lower EAA than inactive participants: −1.26 (95% confidence interval (CI): −1.59, −0.93) years for GrimAge acceleration, −1.70 (95% CI: −2.26, −1.15) for PhenoAge acceleration and −0.05 (95% CI: −0.06, −0.04) years per chronological year for DunedinPACE, adjusted for age, gender, race/ethnicity, education, total wealth and current smoking status. The associations attenuated slightly but remained significant after further adjusting for body mass index, mobility limitations and chronic disease diagnosis. We found evidence of effect modification in the association between physical activity and EAA by social factors, with stronger associations in males compared to females for DunedinPACE (Pinteraction = 0.04) and a positive association between physical activity and increased EAA among Hispanics compared to non‐Hispanic Whites for GrimAge (Pinteraction = 0.009). Our longitudinal analysis using SLCMA identified both accumulation and most recent physical activity in 2016 as the strongest predictors of EAA. Conclusions Our findings highlight physical activity as a robust factor associated with slower epigenetic aging, with both accumulation and concurrent physical activity as the strongest predictors. These results underscore the role of physical activity in promoting healthier biological aging, suggesting its potential as a target for interventions aimed at mitigating age‐related health decline.