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Epigenetic clocks use DNA methylation to estimate biological age. Whether body composition and physical activity are associated with these clocks is not well understood. Using blood samples collected at enrollment (2003–2009) from 2,758 women in the US nationwide Sister Study, we calculated 6 epigenetic age acceleration metrics using 4 epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge). Recreational physical activity was self-reported, and adiposity measures were assessed by trained medical examiners (body mass index (BMI), waist-to-hip ratio (WtH), waist circumference). In cross-sectional analyses, all adiposity measures were associated with epigenetic age acceleration. The strongest association was for BMI and PhenoAge, a measure of biological age that correlates with chronic disease (BMI of ≥35.0 vs. 18.5–24.9, β = 3.15 years, 95% confidence interval (CI): 2.41, 3.90; P for trend &amp;lt; 0.001). In a mutual-adjustment model, both were associated with PhenoAge age acceleration (BMI of ≥35.0 vs. 18.5–24.9, β = 2.69 years, 95% CI: 1.90, 3.48; P for trend &amp;lt; 0.001; quartile 4 vs.1 WtH, β = 1.00 years, 95% CI: 0.34, 1.65; P for trend &amp;lt; 0.008). After adjustment, physical activity was associated only with GrimAge (quartile 4 vs. 1, β = −0.42 years, 95% CI: −0.70, −0.14; P for trend = 0.001). Physical activity attenuated the waist circumference associations with PhenoAge and GrimAge. Excess adiposity was associated with epigenetic age acceleration; physical activity might attenuate associations with waist circumference.

Associations of Body Composition and Physical Activity Level With Multiple Measures of Epigenetic Age Acceleration