Key result
PhenoAge acceleration linked to ~44% higher risk of progressing to advanced CKM syndrome.
Why the study?
Chronological age inadequately captures heterogeneous physiological decline, leaving it uncertain whether clinical parameter-based biological age acceleration predicts progression to advanced cardiovascular-kidney-metabolic syndrome or how PhenoAge and KDMAge compare.
Does clinical parameter-based biological age acceleration using PhenoAge better predict progression to advanced cardiovascular-kidney-metabolic syndrome compared to KDMAge across multi-ethnic cohorts?
Cohort (n=389,564)
Yes
Does clinical parameter-based biological age acceleration using PhenoAge better predict progression to advanced cardiovascular-kidney-metabolic syndrome compared to KDMAge across multi-ethnic cohorts?
Clinical parameter-based biological age acceleration, particularly PhenoAge, is a robust predictor of progression to advanced cardiovascular-kidney-metabolic syndrome across diverse populations, outperforming KDMAge for early risk stratification.
PhenoAge acceleration was associated with advanced CKM incidence; hypothesis-generating for biological aging in CKM staging and requires prospective validation before practice change.
Background 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). Methods 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. Results 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). Conclusions 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.
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Chen et al. (2026) conducted a cohort in Cardiovascular-kidney-metabolic (CKM) syndrome (n=389,564). Biological age acceleration (PhenoAge and KDMAge) vs. KDMAge acceleration / lower quartiles of biological age acceleration was evaluated on Prevalent and incident advanced cardiovascular-kidney-metabolic (CKM) syndrome (stages 3-4) (HR 1.44, 95% CI 1.40-1.48). PhenoAge acceleration predicted progression to advanced CKM syndrome better than KDMAge in UK Biobank (HR 1.44, 95% CI 1.40-1.48 vs HR 1.22, 95% CI 1.19-1.25) and Tongzhou cohorts.
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