TY - JOUR
T1 - Cardiorespiratory fitness, body composition, diabetes, and longevity
T2 - A 2-Sample Mendelian Randomization Study
AU - Kjaergaard, Alisa D
AU - Ellervik, Christina
AU - Jessen, Niels
AU - Lessard, Sarah J
N1 - © The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected]. See the journal About page for additional terms.
PY - 2025/5
Y1 - 2025/5
N2 - CONTEXT: Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality.OBJECTIVE: We investigated the causality and directionality of the associations of VO2max 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 two-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 (VO2max) was estimated from a submaximal cycle ramp test (N≈90,000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg).RESULTS: Genetically predicted higher (per one standard deviation increase) body fat percentage was associated with lower VO2max (β=-0.36 [95% CI: -0.40, -0.32], p=6E-77). Meanwhile, genetically predicted higher appendicular lean mass (0.10 [0.08,0.13] p=3E-16), physical activity (0.29 [0.07,0.52]), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (p<0.01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max 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, VO2max is not causally associated with T2D or longevity.
AB - CONTEXT: Cardiorespiratory fitness, commonly assessed as maximal volume of oxygen consumption (VO2max), has emerged as an important predictor of morbidity and mortality.OBJECTIVE: We investigated the causality and directionality of the associations of VO2max 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 two-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 (VO2max) was estimated from a submaximal cycle ramp test (N≈90,000) and scaled to total body weight, and in additional analyses to fat-free mass (mL/min/kg).RESULTS: Genetically predicted higher (per one standard deviation increase) body fat percentage was associated with lower VO2max (β=-0.36 [95% CI: -0.40, -0.32], p=6E-77). Meanwhile, genetically predicted higher appendicular lean mass (0.10 [0.08,0.13] p=3E-16), physical activity (0.29 [0.07,0.52]), and performance enhancers (fasting insulin, hematocrit, and free testosterone in men) were all positively associated with VO2max (p<0.01). Genetic predisposition to diabetes had no effect on VO2max. MVMR showed independent causal effects of body fat percentage, appendicular lean mass, physical activity, and hematocrit on VO2max, as well as of body fat percentage and type 2 diabetes (T2D) on longevity. Genetically predicted VO2max 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, VO2max is not causally associated with T2D or longevity.
KW - Mendelian randomization analysis
KW - Cardiorespiratory fitness
KW - Diabetes mellitus
KW - Longevity
KW - Obesity
KW - Sex hormone-binding globulin
KW - Type 2
U2 - 10.1210/clinem/dgae393
DO - 10.1210/clinem/dgae393
M3 - Article
C2 - 38864459
SN - 0021-972X
VL - 110
SP - 1451
EP - 1459
JO - The Journal of clinical endocrinology and metabolism
JF - The Journal of clinical endocrinology and metabolism
IS - 5
M1 - dgae393
ER -