Differential contributions of cardiovascular health-related lifestyle factors to epigenetic ageing: implications for healthy longevity

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BACKGROUND: Lifestyle and cardiovascular health (CVH) are key determinants of the biological ageing process, which is closely linked to healthy ageing and longevity. Multiple CVH factors may interact and exert combined effects on the biological ageing process; however, studies exploring their collective association, particularly in Asian cohorts, remain limited. In this cross-sectional study, we investigated the relative contributions of CVH-related behaviours (diet, sleep, avoidance of nicotine, and physical activity) and clinical indicators (BMI, blood lipids, blood glucose, and blood pressure) to epigenetic age acceleration (EAA), as well as their collective associations. METHODS: We included 1940 participants from two large-scale prospective cohorts within the Korean Genome and Epidemiology Study. We assessed CVH based on the American Heart Association's Life's Essential 8 and measured five EAA (intrinsic EAA (Horvath DNAmAge acceleration), extrinsic EAA (Hannum DNAmAge acceleration), PhenoAge acceleration, GrimAge2 acceleration, and Dunedin Pace of Ageing Calculated from the Epigenome (DunedinPACE)). We employed quantile-based g-computation to delineate the sex-specific relative contributions of CVH to EAA. RESULTS: Better CVH was associated with lower EAA (ψ, the estimates of collective associations, ranged from - 4.29 to - 0.79, depending on the EAA measure). The CVH components contributing most to lower EAA varied by sex. In males, nicotine avoidance and better glucose contributed most to lower EAA, accounting for 91% and 77% of the overall associations of CVH with lower Grim2AA and DunedinPACE, respectively, whereas better blood glucose accounted for 86% and 94%. In females, physical activity and better glucose or BMI were the greatest contributors to lower EAA. Physical activity accounted for 44% of the CVH-Grim2AA association. Better glucose explained 54% and 50% of the association with Grim2AA and DunedinPACE, respectively. Better BMI contributed 46% to lower PhenoAA. CONCLUSIONS: Simultaneous improvements in multiple CVH components were associated with lower EAA, with sex-specific differences in the most influential factors. Tailored health strategies-emphasizing smoking cessation and glucose control for males, and physical activity, glucose control, and weight management for females-may help slow ageing. These findings highlight the need for public and clinical interventions that incorporate sex differences in health behaviours and the potential biological mechanisms of ageing.

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