Physical activity, sedentary behavior, and the risk of frailty and falling: A Mendelian randomization study

Abstract Background Due to inconclusive evidence from observational studies regarding the impact of physical activity (PA) and sedentary behavior on frailty and falling risk, we conducted a two‐sample Mendelian randomization analysis to investigate the causal associations between PA, sedentary behavior, and frailty and falls. Methods We extracted summary data from genome‐wide association studies conducted among individuals of European ancestry, encompassing PA ( n = 90 667–608 595), sedentary behavior ( n = 372 609‐526 725), frailty index ( n = 175 226), and falling risk ( n = 451 179). Single nucleotide polymorphisms associated with accelerometer assessed fraction >425 milligravities, self‐reported vigorous activity, moderate to vigorous physical acticity (MVPA), leisure screen time (LST), and sedentary behavior at work were taken as instrumental variables. The causal effects were primarily estimated using inverse variance weighted methods, complemented by several sensitivity and validation analyses. Result s Genetically predicted higher levels of PA were significantly associated with a reduction in the frailty index (accelerometer assessed fraction >425 milligravities: β = −0.25, 95% CI = −0.36 to −0.14, p = 1.27 × 10 −5 ; self‐reported vigorous activity: β = −0.13, 95% CI = −0.20 to −0.05, p = 7.9 × 10 −4 ; MVPA: β = −0.28, 95% CI = −0.40 to −0.16, p = 9.9 × 10 −6 ). Besides, LST was significantly associated with higher frailty index ( β = 0.18, 95% CI = 0.14–0.22, p = 5.2 × 10 −20 ) and higher odds of falling (OR = 1.13, CI = 1.07–1.19, p = 6.9 × 10 −6 ). These findings remained consistent throughout sensitivity and validation analyses. Conclusions Our study offers evidence supporting a causal relationship between PA and a reduced risk of frailty. Furthermore, it underscores the association between prolonged LST and an elevated risk of frailty and falls. Therefore, promoting PA and reducing sedentary behavior may be an effective strategy in primary frailty and falls prevention.