Associations of physical frailty with risk of incident cardiovascular disease by mediation of plasma metabolome changes

BACKGROUND: Frailty has been increasingly recognized as a significant contributor to adverse cardiovascular outcomes. However, the metabolic mechanisms underlying this relationship remain unclear. This study aimed to identify metabolomic signatures of frailty and their mediating roles in cardiovascular disease (CVD) risk. METHODS: Using data from 95 770 UK Biobank participants, we applied elastic net regularized regression to construct a frailty-related metabolomic signature score comprising 43 plasma metabolites across lipids, amino acids, fatty acids, and energy metabolism. Cox proportional hazards models were used to assess the association between this metabolomic signatures score and incident CVD, coronary heart disease (CHD), and stroke over a median follow-up of 13.81 years. Mediation analysis under a counterfactual framework was conducted to quantify the extent to which the metabolomic signatures mediated the frailty-CVD association. RESULTS: High metabolomic signature scores were significantly associated with increased risks of CVD (hazard ratio [HR] = 1.44; 95% confidence interval [CI]: 1.36-1.53), CHD (HR = 1.50; 95% CI: 1.41-1.61), and stroke (HR = 1.45; 95% CI: 1.37-1.54). Mediation analysis indicated that the metabolomic signature accounted for 14.9% of the association between frailty and overall CVD, 16.0% for CHD, and 16.9% for stroke. Pathway enrichment analysis revealed 7 metabolic pathways significantly enriched in frailty, with the primary associations implicating carbohydrate and amino acid metabolism. CONCLUSIONS: This study highlights a distinct frailty-related metabolic profile that independently predicts cardiovascular risk and partially mediates the frailty-CVD association. These findings underscore the value of metabolomic profiling in guiding early detection and prevention strategies for frailty-related cardiovascular outcomes.