Body mass index, physical activity, and epigenetic aging: a cross-population study

Observational studies have suggested that body mass index (BMI) is associated with accelerated epigenetic aging; however, the age at which this association begins and the duration of its effects have not been fully established. This study evaluated the effects of BMI and physical activity on epigenetic aging from early life to adulthood. We integrated multi-source data from populations of different racial backgrounds, including genome-wide association study (GWAS) data, the National Health and Nutrition Examination Survey (NHANES), clinical visceral adipose tissue, and blood samples from obese and physically active populations. Specifically, Mendelian randomization (MR) analysis was used to infer the causal relationship between early-life BMI and epigenetic age acceleration and to identify potential mediators. NHANES data were then analyzed to validate this association at the population level. Finally, biomarkers in blood and adipose tissue were examined to assess whether physical activity is associated with reduced aging-related signatures. The Mendelian randomization analyses indicated that high early-life BMI was causally associated with accelerated epigenetic aging across multiple epigenetic clocks, with β ranging from 0.231 to 0.506; similar associations were also observed for childhood obesity, with β ranging from 0.139 to 0.231. Physical activity was identified as an important mediator that attenuated epigenetic aging acceleration, with mediation effects accounting for 10.70% to 16.22%. Analysis of the NHANES dataset further confirmed that epigenetic age acceleration increases progressively with increasing BMI: 25 ≤ BMI < 30: β = 0.83, 95% CI (0.66, 1.00); 30 ≤ BMI < 35: β = 1.73, 95% CI (1.54, 1.93); 35 ≤ BMI < 40: β = 2.93, 95% CI (2.67, 3.20); BMI ≥ 40: β = 4.64, 95% CI (4.30, 4.99). Subgroup analysis showed that, at the same BMI level, female exhibited more severe PhenoAA acceleration than male. Validation using multi-tissue samples showed that obesity accelerates DNA damage and significantly upregulates genes involved in cell cycle regulation. Physical activity significantly inhibited the upregulation of aging-related genes and reduced oxidative stress. BMI is strongly associated with accelerated epigenetic aging. This association is evident in children with obesity, becomes stronger with higher BMI, and is also observed in adults, whereas physical activity may partially attenuate this process. Trial registration Name of the registry: China-Japan Friendship Hospital National Integrated Chinese and Western Medicine Medical Center. Unique identifying number or registration ID: NCT06452303. Hyperlink to your specific registration (must be publicly accessible and will be checked): https://www.centerwatch.com/clinical-trials/listings/NCT06452303/the-patient-cohort-for-bariatric-surgery.