Sedentary lifestyle, physical activity, and aging: evidence from genetic correlation and mendelian randomization.

Background: Observational studies have shown that physical activity and sedentary behavior are associated with aging. However, whether these associations underlie causal effects remains unknown. Thus, this study aimed to assess the genetic correlation and causal relationships between genetically predicted physical activity, sedentary behavior, and aging.

Methods: Using linkage disequilibrium score regression (LDSC) and Mendelian Randomization (MR). Genetic variants associated with leisure screen time (LST, as an indicator of sedentary behavior), moderate-to-vigorous physical activity (MVPA), and four aging-related traits (90th survival percentile, facial aging, telomere length, and frailty index) were obtained from genome-wide association studies (GWAS). The primary MR analyses were performed using the inverse variance weighted (IVW) method, followed by various sensitivity and validation analyses.

Results: Univariable MR analysis indicated significant associations of LST with telomere length (β = - 0.04, P = 4.95E-06), and facial aging (β = 0.11, P = 2.28E-09), frailty index (β = 0.17, P = 1.93E-35). MVPA had a significant causality with the frailty index (β = - 0.28, P = 6.46E-09). These associations weakened in Multivariable MR Analysis, but the frailty index remained significantly correlated after adjustment. LDSC further supported the genetic correlations identified in the MR analysis. Additionally, pathway analyses, including the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), highlighted potential mechanisms linking LST and aging outcomes.

Conclusions: This study reveals that LST and MVPA may play a causal role in the process of aging. Accordingly, public health efforts to promote increased physical activity and reduce sedentary time can effectively combat accelerated aging.