Biological age acceleration and cardiovascular–kidney–metabolic syndrome progression: evidence from UK Biobank and NHANES

Objective: We examined associations of biological age acceleration with cardiovascular–kidney–metabolic (CKM) syndrome progression and baseline stage burden.Methods: Longitudinal analyses included 326,218 UK Biobank participants, and cross-sectional analyses included 5,228 NHANES adults. PhenoAge and KDMAge acceleration were residuals from regressing each biological age measure on chronological age. We modeled two UK Biobank transitions using cause-specific Cox and competing-risk models and compared NHANES stages using survey-weighted logistic regression.Results: Over a median 13.48 years, 2,567 participants progressed from stage 0/1 to stage 2/3 and 42,835 from stage 1 or 2/3 to stage 4. Per 1-SD increment, PhenoAge acceleration was associated with both transitions [hazard ratios (HRs) 1.234, 95% confidence interval (CI) 1.189–1.281; HR 1.208, 95% CI 1.197–1.218]. KDMAge acceleration showed corresponding HRs of 1.229 (95% CI 1.180–1.280) and 1.220 (95% CI 1.207–1.232), all P < 0.001. Results remained directionally consistent after accounting for competing mortality. Associations for dichotomized accelerated aging remained significant after false discovery rate correction, and UK Biobank splines suggested possible non-linearity. In NHANES, PhenoAge acceleration was associated with stages 1, 2/3, and 4 versus stage 0. Corresponding odds ratios (ORs) were 1.154 (95% CI 1.107–1.202), 1.221 (95% CI 1.176–1.268) and 1.333 (95% CI 1.249–1.423), all P < 0.001. KDMAge acceleration ORs were 1.025 (95% CI 1.006–1.044; P = 0.012), 1.038 (95% CI 1.019–1.057; P < 0.001), and 1.041 (95% CI 1.011–1.073; P = 0.010).Conclusions: Biological age acceleration was associated with CKM progression and baseline burden. KDMAge comparability remains uncertain. Incremental predictive and clinical utility remained untested.