Biological Age Acceleration Associated with the Progression Trajectory of Cardio-Renal–Metabolic Multimorbidity: A Prospective Cohort Study

Objectives: Previous studies have confirmed that biological age (BA) acceleration is associated with single cardio-renal–metabolic diseases (CRMDs), typically including type 2 diabetes mellitus, cardiovascular disease, and chronic kidney disease. However, its association with progression to cardio-renal–metabolic multimorbidity (CRMM, coexistence of ≥2 CRMDs) and subsequent mortality remains unexplored. Methods: Using the multi-state model, we analyzed 278,927 UK Biobank participants free of CRMDs at baseline to investigate the association between BA acceleration—measured by phenotypic age (PhenoAge) and Klemera–Doubal method age (KDMAge)—and CRMM progression trajectory, from health to the first CRMD and then to CRMM and death. BA acceleration was the residual from regressing BA on chronological age; positive values indicated a biologically older individual. Results: PhenoAge acceleration showed stronger associations than KDMAge acceleration. Per the 1-SD increase in PhenoAge acceleration; HRs (95% CIs) were observed at 1.18 (1.17–1.19) for baseline to first CRMD; 1.24 (1.22–1.26) for first CRMD to CRMM; 1.25 (1.22–1.27) for baseline to death; 1.13 (1.11–1.15) for first CRMD to death; and 1.09 (1.06–1.12) for CRMM to death. Biologically older individuals by PhenoAge acceleration showed greater reductions in CRMD-free and total life expectancy than those by KDMAge acceleration. Age, socioeconomic status, education, smoking status, alcohol consumption, physical activity, and diet-modified risks for specific transitions. Conclusions: BA acceleration, particularly PhenoAge acceleration, relates to higher CRMM progression risk and shorter life expectancy. Combining BA acceleration with sociodemographic or lifestyle factors improves risk identification for specific transitions. BA acceleration offers the potential to guide CRMM prevention across its entire progression.