Physical Fitness Is Negatively Associated With <scp>DNA</scp> Methylation‐Based Risk of Aging‐Related Diseases

max, GripStrength, JumpMax, body mass index (BMI), and cognition-in a cohort of 290 mostly old individuals (mean age of 60 ± 11 years). EpiScores for 109 plasma proteins were obtained using the MethylDetectR tool and tested for associations with fitness traits. We found 33 significant fitness predictor-EpiScore associations independent from age and sex. Integration with available EpiScore-disease associations revealed overlapping pathways linking fitness and chronic disease risk. We found 51 fitness predictor-disease associations based on EpiScores. The BMI was positively associated with diabetes, stroke, ischemic heart disease, lung cancer, COPD, IBD, and depression, while showing a negative association with rheumatoid arthritis. Cognition was negatively associated with rheumatoid arthritis, depression, and COPD. GripStrength showed negative associations with diabetes and COPD. Finally, jump performance was negatively associated with diabetes, stroke, lung cancer, rheumatoid arthritis, and COPD. We also developed a workflow for evaluating patient-level disease risk by using DNA methylation and fitness measurements. The patient-level risk scores showed strong positive correlations with an independent external CVD EpiScore benchmark supporting validity. Our findings highlight the link between cognitive and physical fitness and protein EpiScores as interpretable molecular markers with potential value for early disease risk stratification and for personalized prevention of aging-related diseases.