Physical activity linked to lower biological age by DNA methylation clocks
A systematic review and meta-analysis of 44 studies (145,465 participants) found that higher physical activity was associated with lower biological age measured by DNA methylation clocks, particularly for GrimAge and Horvath measures.
Researchers conducted a systematic review and meta-analysis searching six major databases from 2011 to June 2025 for studies linking physical activity to biological age measured by DNA methylation (DNAm) clocks. They identified 44 peer-reviewed studies with 145,465 participants (mean ages 24–79 years), of which 7 cross-sectional studies provided data for quantitative synthesis.
The meta-analysis found that each additional standard deviation of metabolic equivalent of tasks-minutes per week was associated with 0.03 SD lower Horvath epigenetic age acceleration (95% CI −0.05 to −0.01) and 0.09 SD lower GrimAge epigenetic age acceleration (−0.12 to −0.05). However, no statistically significant associations emerged for Hannum or PhenoAge measures. Across all 44 included studies, higher physical activity was generally associated with lower DNAm age, although many individual findings did not reach statistical significance. A major limitation is that the meta-analysis drew exclusively from cross-sectional studies, which cannot establish causation or rule out reverse causation. The authors concluded that while physical activity shows a significant association with biological age measured by certain DNA methylation clocks, longitudinal studies and randomized trials using standardized, objectively measured activity are needed to clarify whether activity causally slows aging.
The strength of association differed markedly between clock types: GrimAge showed a threefold stronger effect (−0.09 SD per SD of activity) than Horvath (−0.03 SD), suggesting that DNA methylation's link to aging varies by which aging biomarkers the clock emphasizes. GrimAge incorporates smoking history and mortality risk factors, which may explain its stronger responsiveness to physical activity. The Hannum and PhenoAge clocks, which use different epigenetic markers, showed no significant association, highlighting that "biological age" is not a single, unified measure—different clocks capture different aspects of aging biology. All 44 studies were cross-sectional or observational; no randomized controlled trials comparing physical activity interventions to control groups using DNAm clocks were identified, making it impossible to determine whether activity directly causes slower aging or whether people with slower aging simply exercise more. The dose-response relationship also remains unclear: the meta-analysis expressed results per SD of activity units, but the practical question of how many hours or what intensity of weekly activity produces these effects is unanswered.
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- Physical activity and biological age measured by DNA methylation clocks: a systematic review and meta-analysis. — The lancet. Healthy longevity (Read the original)