Associations between phenotypic age and carotid atherosclerosis among the general population: evidence from a multi-stage study

BACKGROUND: Cardiovascular disease onset and mortality vary substantially among individuals of the same chronological age, reflecting differences in the pace of biological aging. This multi-stage study aimed to investigate the association between phenotypic age acceleration (PhenoAgeAccel) and subclinical carotid atherosclerosis. METHODS: We conducted a case-control study (2,088 matched pairs) and a prospective validation cohort (n = 3,833) to assess the association between PhenoAgeAccel and carotid atherosclerotic plaque (CAP) presence in a Chinese general population. We then extended the analysis to occlusion and stenosis of the carotid artery (OSCA) in an external UK Biobank cohort (n = 362,893). PhenoAgeAccel was calculated using chronological age and nine clinical parameters, and PhenoAgeAccel ≤ 0 and > 0 were defined as biologically younger and older, respectively. Multivariable logistic regression and Cox proportional hazards regression models were employed for analyses. RESULTS: In the case-control study, each 1-SD increase in PhenoAgeAccel was associated with a 17% higher risk of CAP presence (OR: 1.17, 95% CI: 1.07-1.26) after adjusting for multiple covariates. A similar association was observed for incident CAP, with each 1-SD increase in PhenoAgeAccel associated with an 17% increase in hazard (HR: 1.17, 95% CI: 1.08-1.27). The transportability analysis in the UK Biobank revealed a 26% increased risk of OSCA per-SD increase in PhenoAgeAccel (HR:1.26, 95% CI: 1.20-1.33). The area under receiver operating characteristic curve (AUC) for a model containing PhenoAgeAccel (AUC = 0.700) was significantly (P = 0.026) larger than the standard model (AUC = 0.689). The restricted cubic splines further confirmed a dose-response association between PhenoAgeAccel and risk of CAP or OSCA (P for overall < 0.001). Subgroup analyses showed significant interactions with diabetes and BMI, with stronger associations in non-diabetic and normal-weight individuals (P < 0.001). CONCLUSIONS: PhenoAgeAccel was independently associated with an increased risk of CAP presence and incident OSCA, suggesting its potential as a complementary indicator for identifying individuals at higher risk of carotid atherosclerosis.