Abstract
BACKGROUND: Observational studies have indicated that increased cardiorespiratory fitness is associated with a decreased risk of cardiovascular disease (CVD), Alzheimer's disease (AD), and Parkinson's disease (PD). However, the causal mechanisms remain unclear. The objective of this study was to assess the role of fitness in the early detection and reduction of disease risk within the framework of predictive, preventive, and personalized medicine (PPPM/3PM). METHODS: The associations of fitness with CVD, AD, and PD were explored in a large cohort of up to 502,486 individuals between the ages of 40 and 69 years from the UK Biobank. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CVD, AD, and PD among participants who completed a submaximal fitness test. Causality relationships were assessed via two-sample Mendelian randomization (MR). RESULTS: After a median of 11 years of follow-up, each 3.5 ml of O(2)⋅min(-1)⋅kg(-1) increase in total body mass (equivalent to 1 metabolic equivalent of task (MET), approximately 0.5 standard deviations (SDs)) was associated with decreased risks of CVD (20.0%, 95% CI 17.6-22.3%), AD (31.9%, 95% CI 26.7-33.6%), and PD (21.2%, 95% CI 11.2-31.8%). After adjusting for obesity, the observational associations were attenuated. According to the MR analyses, fitness was associated with PD (OR (IVW) 0.937, 95% CI 0.897-0.978) and small vessel stroke (OR (IVW) 0.964, 95% CI 0.933-0.995). CONCLUSION: Our results indicate that fitness has an effect on age-related diseases. Protective associations of higher fitness levels with the risk of CVD, AD, and PD were validated in this cohort study. These findings might be valuable for predicting, preventing, and reducing disease morbidity and mortality through primary prevention and healthcare in the context of PPPM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-024-00382-4.