Abstract
Individuals with cardiovascular-kidney-metabolic (CKM) syndrome face an elevated risk of stroke, yet effective risk stratification indicators remain limited. This prospective study aims to investigate the associations of biological age acceleration (BioAge-gap) and heart age acceleration (HeartAge-gap) with new-onset stroke in individuals with CKM syndrome Stages 0-3, utilizing data from the China Health and Retirement Longitudinal Study (CHARLS) collected between 2015 and 2020. Baseline BioAge-gap and HeartAge-gap were calculated via the Klemera-Doubal method (KDM) and Framingham risk score (FRS), respectively. The primary outcome was self-reported physician-diagnosed stroke identified during the 2018 and 2020 follow-ups. Analysis of 7283 eligible participants aged 45-75 years revealed a positive association between BioAge-gap and new-onset stroke (odds ratio [OR] = 1.05, p < 0.01). Furthermore, compared to participants with a non-positive HeartAge-gap, those with HeartAge-gaps of 0-5 years and ≥5 years exhibited significantly increased risks of stroke by 74% and 141%, respectively. Subgroup analyses and interaction tests identified a significant gender interaction in the association between HeartAge-gap and stroke, indicating that men with accelerated heart age represent a vulnerable subgroup. Restricted cubic splines (RCSs) confirmed a linear association, and sensitivity analyses validated the robustness of these findings. Integrating these intuitive indicators into clinical practice could facilitate primary stroke prevention and mitigate CKM syndrome progression.