This study aims to evaluate the associations of Klemera-Doubal Method Biological Age Acceleration (KDM-BAA) and Phenotypic Age Acceleration (PAA) with all-cause and cause-specific mortality in U.S. adults with Cardio-Kidney-Metabolic (CKM) syndrome stages 0-3 and to establish risk prediction models. Data were obtained from 16,837 participants in NHANES 1999-2010 and 2015-2018, linked to mortality through 2019. Biological age was estimated using KDM-BA and Phenotypic Age algorithms, with residuals defining Biological Age Acceleration (BAA). Cox proportional hazards models were applied, and LASSO-Cox nomograms were developed for mortality prediction. Over a median follow-up of 11.33 years, 10.8% of the weighted population (9.75 million adults) died. After full adjustment for confounders, KDM-BAA positivity increased the risk of all-cause, CVD, and non-CVD mortality by 41%, 74%, and 31%, respectively; PAA positivity showed even larger increases - 103%, 79%, and 112%. Both metrics consistently exhibited a positive association in multiple subgroups and sensitivity analyses. The LASSO-Cox-based nomogram showed favorable discrimination (training AUCs 0.776 and 0.775 at 10 and 20 years; validation AUCs 0.765 and 0.757, respectively) and good calibration, suggesting potential clinical applicability. BAA independently predicts long-term mortality among individuals with CKM stages 0-3. PAA provides superior prognostic value, supporting the importance of monitoring biological aging to guide early intervention and improve long-term outcomes.
