Circadian Syndrome and Incident Cardiometabolic Multimorbidity: The Mediating Role of Biological Age Acceleration in the CHARLS Cohort

Background Evidence has linked circadian syndrome (CircS), an extension of metabolic syndrome incorporating sleep and mental health dimensions, to cardiometabolic diseases. However, whether CircS contributes to cardiometabolic multimorbidity (CMM) through accelerated biological aging remains unclear. Methods This prospective analysis included 6,260 participants from the China Health and Retirement Longitudinal Study (CHARLS, 2011–2020). CircS was defined as the presence of ≥ 4 of 7 components: central obesity, elevated blood pressure, elevated triglycerides, reduced high-density lipoprotein cholesterol, elevated fasting glucose, short sleep duration, and depressive symptoms. CircS was evaluated both as a binary status and as a component score. Biological age acceleration was quantified using two biomarker-based aging measures, Klemera–Doubal method biological age acceleration (KDM BioAgeAccel) and Light biological age acceleration (Light BioAgeAccel), calculated as biological age minus chronological age. We examined the associations of CircS status and CircS score with incident heart disease, stroke, diabetes, and CMM using Kaplan–Meier curves and multivariable Cox proportional hazards models. Restricted cubic splines were used to characterize potential nonlinear associations, and mediation analyses assessed whether KDM BioAgeAccel and Light BioAgeAccel mediated these associations. Results During follow-up, 1,165 (18.6%) participants developed heart disease, 510 (8.1%) developed stroke, 891 (14.3%) developed diabetes, and 373 (6.0%) developed CMM. In fully adjusted Cox models, CircS was significantly associated with higher risks of incident heart disease, stroke, diabetes, and CMM, with HRs of 1.30, 2.13, 2.15, and 2.39, respectively (all P < 0.001). Each 1-point increment in CircS score was also positively associated with these outcomes, with HRs of 1.13, 1.31, 1.35, and 1.42, respectively (all P < 0.001). Biological age acceleration partially mediated the associations of CircS with incident diabetes, stroke, and CMM, with significant proportions mediated ranging from 5.2% to 11.1% (P for indirect effects ≤ 0.028). Conclusions CircS was independently associated with increased risks of incident CMM and its component diseases, including heart disease, stroke, and diabetes. Higher CircS score showed nonlinear dose–response associations with all four outcomes, and biological age acceleration partly mediated these relationships. These findings support CircS as an accessible multidimensional marker for early cardiometabolic risk stratification.