Physical activity volume and aging indicators: a meta-analysis and genetic causality assessment

Aging is a multifaceted degenerative process involving mechanisms from cellular to organismal level, driving a series of age-related diseases and posing significant public health challenge. Physical activity (PA), as a potential attenuating aging intervention, its precise effects remain unclear. This study systematically evaluates the associations of PA with specific aging indicators, explores potential dose-response patterns and estimated peak intensity, as well as investigates genetically predicted mediating pathways. We conducted a meta-analysis of randomized controlled trials (RCTs) to assess the impact of PA on five key aging indicators: Telomere length (TL), Telomerase activity, global DNA methylation, Appendicular lean mass (ALM), and Frailty index (FI). The volume of PA was harmonized using metabolic equivalent task (MET). Non-linear dose-response relationships were modeled using restricted cubic spline (RCS) regression. Concurrently, Mendelian randomization (MR) analysis was performed to establish causal linkages between moderate-to-vigorous physical activity (MVPA) and seven aging-related outcomes, including leukocyte TL (LTL), ALM, FI, and four epigenetic clocks (Hannum, PhenoAge, GrimAge, IEAA). Mediation analysis incorporating multi-omics data (proteomics, metabolomics, and immunomics) was conducted to identify potential molecular pathways. We further evaluated the effects and difference of MVPA on biological age gap (BAG) across nine major human organs. The meta-analysis included 32 studies (49 RCTs) with 5189 participants. PA significantly increased TL (SMD: 0.18 [0.01, 0.35], P = 0.0340), telomerase activity (SMD: 0.46 [0.21, 0.71], P = 0.0003), ALM (SMD: 0.29 [0.14, 0.43], P = 0.0001), and decreased FI (SMD: −0.13 [−0.21, −0.04], P = 0.0042). Dose-response RCS curves between PA and different aging markers revealed similar pattern, and exhibited the maximal effect estimated PA level of approximately 11.5 mMET-h/week on TL (10.9 [10.07, 12.7]) and ALM (12.1 [11.48, 19.65]). MR analysis supported causal effects of MVPA on LTL, ALM, FI, and epigenetic clocks. Mediation analysis identified genetically inferred mediators (e.g. ELANE, NEU1) and pathways involved in. Genetically predicted MVPA was linked to the mitigation of pulmonary BAG. Appropriate PA is associated with improvements in aging-related indicators, with an estimated peak intensity of approximately 11.5 mMET-h/week. This study provides evidence-based PA recommendation to mitigate aging and identifies potential molecular targets for future interventions. PROSPERO CRD42024603875.