The role of epigenetic aging in the relationship between physical activity and cardiovascular mortality among U.S. adults: Insights from the NHANES 1999-2002 cohort

Recent advances in DNA methylation (DNAm)-based aging biomarkers have empowered the investigation of biological mechanisms underlying the cardiovascular benefits of physical activity that have yet to be fully elucidated. In this study, we examined the associations between physical activity and DNAm clocks and identified the DNAm clock most strongly implicated in mediating the relationship between physical activity and cardiovascular mortality. Participants were U.S. adults aged 50 years and older from the National Health and Nutrition Examination Survey 1999-2002 cohort (N=2324), with cardiovascular mortality tracked through December 2019 via Linked Mortality Files. Thirteen epigenetic clocks measuring chronological age, physiological functioning, and pace of aging were assessed. No significant associations were observed between physical activity and DNAm clocks. However, GrimAge2Mort significantly mediated the relationship between physical activity and cardiovascular mortality, with average causal mediation effects of 0.432 (95% CI: 0.024, 1.090) for aerobic physical activity, and 0.438 (95% CI: 0.028, 1.060) for muscle-strengthening activity. The corresponding proportions mediated were 20.4% (95% CI: -114.5%, 215%) and 15.2% (95% CI: -474.4%, 326.0%). These findings suggested the potential utility of GrimAge2Mort as a surrogate biomarker to evaluate the impact of exercise interventions on age-related risks of cardiovascular morbidity and mortality.