Frailty and major late-life transitions in very old adults: contrasting biomarker patterns of GDF-15 and NT-proBNP in the Kawasaki Aging and Wellbeing Project

Frailty is a heterogeneous aging phenotype that represents accumulated biological vulnerability among very old adults. How frailty relates to key late-life transitions at advanced ages remains incompletely understood. We examined the longitudinal association between frailty status and a composite endpoint of incident long-term care insurance certification (level ≥ 2) or death, and assessed whether circulating biomarkers (growth differentiation factor-15 [GDF-15] and N-terminal pro-B-type natriuretic peptide [NT-proBNP]) provided information beyond frailty. In this cohort study, 992 community-dwelling adults aged 85-89 years in Japan, classified using physical frailty criteria at baseline as either robust, prefrail, or frail, were followed up to 7.5 years. Risk over time was compared using Kaplan-Meier methods, and Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs). Kaplan-Meier curves showed clear separation across the frailty groups. In multivariable models, prefrail and frail status were associated with a higher risk of the composite endpoint (aHRs 1.62 and 2.13 vs. robust, respectively). After adjusting for frailty status and covariates, higher GDF-15 and NT-proBNP levels were independently associated with greater risk. The GDF-15 association was adequately described by a linear term, whereas NT-proBNP showed evidence of nonlinearity with a steeper gradient toward the upper range. As a supportive summary of risk stratification, 5-year discrimination changed only modestly after adding biomarkers. Frailty strongly stratified the risk of major late-life transitions, and baseline GDF-15 and NT-proBNP may help characterize residual biological heterogeneity beyond frailty, with contrasting dose-response patterns.