Sex-Specific Mediation of Biological Age Acceleration in the Associations between Cardiovascular– Kidney–Metabolic and All-Cause Mortality

Background Cardiovascular-kidney-metabolic (CKM) syndrome represents a major contributor to premature mortality and is strongly linked to the aging process. However, it remains unclear whether the association between CKM and mortality risk is mediated through biological aging acceleration (BAacc), particularly with respect to potential sex-specific differences. Methods We included 12,722 participants from the China Health and Retiremalet Longitudinal Study (CHARLS) from 2011 to 2020. BAacc was estimated using the Klemera-Doubal method. Mediation analysis was used to assess the mediating role of BAacc in associations between CKM and all-cause mortality. Models were adjusted for key cardiovascular risk factors. Results During the follow-up, 439 participants (3.45%) died. After multivariable adjustment, CKM was significantly associated with an increased risk of all-cause mortality in both men (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.30–1.36) and women (1.28; 1.25–1.31). Notably, the mediating effect of biological aging acceleration (BAacc) on the association between CKM and mortality was more pronounced among women (natural indirect effect [NIE]: 1.05; 1.02–1.08) than among men (1.02; 1.00-1.05; P-for-interaction = 0.01). Regarding individual CKM components, the associations of hypertension (1.24; 1.05–1.47 for women vs. 1.06; 0.93–1.21 for men; P-for-interaction = 0.04), diabetes (1.15; 1.05–1.26 for women vs. 1.06; 0.98–1.14 for men), and heart disease (1.03; 1.00-1.06 for women vs. 1.02; 1.00-1.04 for men) with mortality were significantly mediated by BAacc among women but not among men. BAacc did not significantly mediate the associations of stroke or chronic kidney disease with mortality in either sex. Conclusions We found that aging acceleration significantly mediates the association between CKM and all-cause mortality, and this mediating pathway appears more pronounced among women. These findings emphasize the importance of incorporating aging-targeted strategies into CKM management to reduce residual mortality risk.