Leisure-time physical activity, sedentary behavior, and biological aging: evidence from genetic correlation and Mendelian randomization analyses

Physical inactivity and sedentary behavior are associated with higher risks of age-related morbidity and mortality. However, whether they causally contribute to accelerating biological aging has not been fully elucidated. Utilizing the largest available genome-wide association study (GWAS) summary data, we implemented a comprehensive analytical framework to investigate the causal relationships between moderate-to-vigorous leisure-time physical activity (MVPA), leisure screen time (LST), and four epigenetic age acceleration (EAA) measures: HannumAgeAccel, intrinsic HorvathAgeAccel, PhenoAgeAccel, and GrimAgeAccel. Shared genetic backgrounds across these traits were quantified through genetic correlation analysis. Overall and independent causal effects were assessed through univariable and multivariable Mendelian randomization (MR). A recently developed tissue-partitioned MR approach was further adopted to explore potential tissue-specific pathway that contributes to the observed causal relationships. Among the four EAA measures investigated, consistent results were identified for PhenoAgeAccel and GrimAgeAccel. These two measures were negatively genetically correlated with MVPA (r_g=−0.18~−0.29) and positively genetically correlated with LST (r_g=0.22~0.37). Univariable MR yielded a robust effect of genetically predicted LST on GrimAgeAccel (β_IVW=0.69, P=1.10×10⁻⁷), while MVPA (β_IVW=−1.02, P=1.50×10⁻²) and LST (β_IVW=0.37, P=1.90×10⁻²) showed marginal causal effects on PhenoAgeAccel. Multivariable MR suggested an independent causal role of LST in GrimAgeAccel after accounting for effects of MVPA and other important confounders. Tissue-partitioned MR suggested skeletal muscle tissue associated variants be predominantly responsible for driving the effect of LST on GrimAgeAccel. Findings support sedentary lifestyles as a modifiable causal risk factor in accelerating epigenetic aging, emphasizing the need for preventive strategies to reduce sedentary screen time for healthy aging.