Joint associations of cardiovascular-kidney-metabolic syndrome and depressive symptoms with incident frailty: the mediating role of body roundness index

Abstract Background Frailty is a multidimensional geriatric syndrome associated with increased vulnerability to adverse outcomes in aging populations. Both cardiovascular-kidney-metabolic (CKM) syndrome and depressive symptoms have been independently linked to frailty, but their combined associations and underlying pathways remain unclear. This study aimed to examine the separate and joint associations of CKM syndrome stages and depressive symptoms with incident frailty, and to explore the potential mediating role of the body roundness index (BRI) in relation to subsequent frailty severity. Methods We analyzed data from 5,513 adults aged ≥ 45 years without frailty at baseline in the China Health and Retirement Longitudinal Study (2011–2020). Cox proportional hazards models were used to estimate the associations of CKM-depressive symptoms profiles with frailty risk. Kaplan-Meier (KM) survival curves illustrated cumulative incidence. Mediation analysis assessed the role of BRI, and exploratory subgroup analysis evaluated potential effect modification. Results During follow-up period, both advanced CKM stages (hazard ratio (HR) = 1.66, 95% confidence interval (CI): 1.44–1.91, P < 0.001) and depressive symptoms (HR = 2.10, 95% CI: 1.87–2.37, P < 0.001) were independently associated with higher risk of incident frailty. Compared with non-advanced stages without depressive symptoms, individuals with both advanced stages and depressive symptoms had the highest risk (HR = 3.26, 95% CI: 2.68–3.96, P < 0.001). KM curves showed a clear and progressive separation in frailty incidence across four profiles. BRI partially mediated the association between advanced CKM with depressive symptoms and frailty, accounting for 10.70% of the total effect. Conclusion The coexistence of advanced CKM syndrome and depressive symptoms markedly increases frailty risk, partly through excess visceral adiposity. Integrating cardiometabolic and mental health assessment with body composition evaluation into screening may improve early identification and enable targeted prevention strategies for high-risk populations.