Association of frailty reversal with cardiovascular disease and the mediating role of proteomic signatures

The impact of frailty reversal on cardiovascular disease (CVD) risk is unclear, and the biological mechanisms involved are poorly understood. A longitudinal cohort study was conducted using data from 468,801 UK Biobank participants. An elastic net regression was used to identify the proteomic signature associated with frailty. A proteome-wide association study identified proteins shared by frailty and CVD. Mediation analyses were adopted to evaluate whether the proteomic signature and hub proteins mediated the frailty-CVD relationship. Frailty reversal was associated with a significantly reduced risk of CVD. A total of 309 proteins were identified as being associated with physical frailty. The constructed proteomic signature was positively associated with CVD risk (HR per SD increase: 1.60; 95% CI: 1.56–1.64). Mediation analyses revealed that the proteomic signature of physical frailty [natural indirect effect: 1.14 (1.12–1.15), proportion mediated: 49.18% (42.73%–53.40%)] and identified hub proteins (e.g., TNF, IL-1β, IL6) partially mediated the relationship between physical frailty and CVD. Reversing physical frailty is associated with improved cardiac morphology and a lower risk of CVD. These findings support the cardiovascular benefits of frailty reversal and suggest a potential mediating role of proteomic pathways in this association.