Biological age acceleration and progression of cardiovascular-kidney-metabolic syndrome: a multi-cohort comparative analysis of phenoage and KDMAge
TL;DR
Accelerated biological aging was robustly associated with advanced CKM across all populations, with PhenoAge consistently outperforming KDMAge, and PhenoAge demonstrated superior risk stratification capability compared to KDMAge, highlighting its potential utility in early risk assessment.
Abstract
The American Heart Association's cardiovascular-kidney-metabolic (CKM) syndrome framework emphasizes integrated management. Since chronological age inadequately captures heterogeneous physiological decline, we investigated whether clinical parameter-based biological age acceleration (BAA) predicts progression to advanced CKM and compared the efficacy of Phenotypic Age (PhenoAge) versus Klemera-Doubal Method Biological Age (KDMAge). We analyzed data from three multi-ethnic cohorts: cross-sectional NHANES (n=34,694), longitudinal UK Biobank (n=347,889), and longitudinal Tongzhou Cohort Study (n=6,981). Biological aging was quantified using KDMAge and PhenoAge. Advanced CKM (stage 3-4) was defined per AHA guidelines. Associations with prevalent (NHANES) and incident (longitudinal cohorts) advanced CKM were assessed using multivariable regression. Additionally, leukocyte telomere length was assessed in UK Biobank for molecular validation. Accelerated biological aging was robustly associated with advanced CKM across all populations, with PhenoAge consistently outperforming KDMAge. In NHANES, PhenoAge acceleration showed stronger associations with advanced CKM than KDMAge (OR: 1.07, 95%CI 1.07-1.08 vs. 1.03, 95%CI 1.03-1.03). Longitudinal analysis in the UK Biobank confirmed this trend: participants in the highest quartile of PhenoAge acceleration had a significantly higher risk (HR: 1.44, 95% CI: 1.40–1.48) compared to those assessed by KDMAge (HR: 1.22, 95%CI:1.19-1.25). This was validated in the Chinese Tongzhou cohort study (PhenoAge HR: 1.64, 95%CI: 1.38-1.94 vs. KDMAge HR: 1.24, 95%CI 1.24-1.60). Furthermore, PhenoAge exhibited a distinct non-linear dose-response relationship. Molecular analysis in the UK Biobank reinforced these findings, showing longer telomeres were associated with reduced risk (HR: 0.78, 95%CI 0.72-0.84). Clinical parameter-based BAA is a robust, universal predictor of CKM progression. Notably, PhenoAge demonstrated superior risk stratification capability compared to KDMAge, highlighting its potential utility in early risk assessment.Graphical AbstractFigure1