Metabolomic and Proteomic Signatures of Cardiorespiratory Fitness for Predicting All-Cause Mortality and Non-Communicable Disease Risk: A Prospective Study in the UK Biobank

Abstract Background Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified two signatures of CRF (one metabolomic and one proteomic) from UK Biobank participants who completed a risk-stratified submaximal cycle ergometer test, with CRF estimated from the heart rate response to incremental workload. Methods These signatures were validated in an independent sample of UK participants with data on metabolomics (n=354,222) and proteomics (n=29,961) to investigate prospective associations with all-cause mortality and non-communicable diseases. Prospective associations were evaluated using Cox proportional hazards models adjusted for age, sex, ethnicity, socioeconomic status, lifestyle factors (including smoking, alcohol intake, diet, and BMI), and relevant medical history. Results Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed two novel signatures of CRF (one metabolomic and one proteomic) that robustly reflect CRF levels (R 2 : 0.50-0.60). Over an average of 9 years of follow-up, we observed 27,659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic signature of CRF was strongly associated with a 39–54% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (90% in both), cardiovascular disease (42–47%), and colorectal cancer (33–39%). Additionally, the proteomic signature of CRF was associated with a 17% lower risk of all-cause mortality, and with a 22–39% lower risk of type 2 diabetes and cardiovascular disease. Conclusion Together, these findings indicate that circulating metabolites and proteins are associated with CRF and with subsequent risk of mortality and non-communicable diseases.