Cardiorespiratory Fitness, Body Composition, Diabetes, and Longevity: A 2-Sample Mendelian Randomization Study

Context: Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO(2)max), has emerged as an important predictor of morbidity and mortality. Objective: We investigated the causality and directionality of the associations of VO(2)max with body composition, physical activity, diabetes, performance enhancers, and longevity. Methods: Using publicly available summary statistics from the largest genome-wide association studies publicly available, we conducted a bidirectional 2-sample Mendelian randomization (MR) study. Bidirectional MR tested directionality, and estimated the total causal effects, whereas multivariable MR (MVMR) estimated independent causal effects. Cardiorespiratory fitness (VO(2)max) was estimated from a submaximal cycle ramp test (N approximate to 70 000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg). Results: Genetically predicted higher (per 1 SD increase) body fat percentage was associated with lower VO(2)max (beta = -0.36; 95% CI: -0.40, -0.32, P = 6 x 10(-77)). Meanwhile, genetically predicted higher appendicular lean mass (beta = 0.10; 95% CI: 0.08 to 0.13), physical activity (beta = 0.29; 95% CI: 0.07 to 0.52), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO(2)max (all P < .01). Genetic predisposition to diabetes had no effect on VO(2)max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO(2)max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO(2)max showed no associations. Conclusion: Cardiorespiratory fitness can be improved by favorable body composition, physical activity, and performance enhancers. Despite being a strong predictor of mortality, VO(2)max is not causally associated with T2D or longevity.