Phenotypic age acceleration is associated with higher long-term cardiovascular and mortality risk: evidence from 319,256 UK Biobank participants

Background Chronological age is a major risk factor for cardiovascular diseases. However, it does not capture interindividual differences in physiological ageing. Phenotypic Age is a biomarker-based measure of biological ageing. It integrates multisystem dysfunction and may better reflect cardiovascular vulnerability. Purpose To test the hypothesis that phenotypic age acceleration is associated with higher long-term risks of heart failure, myocardial infarction, angina, cardiovascular mortality, and atherosclerotic cardiovascular disease in a large UK population cohort. Methods This population-based longitudinal study used data from the UK Biobank, which recruited 502,369 adults aged 40 to 69 years between 2006 and 2010. After excluding those with missing biomarker data or covariates, 319,256 participants were included. Phenotypic age acceleration was defined as the residual of phenotypic age regressed on chronological age. Incident heart failure, myocardial infarction, angina pectoris, and cardiovascular mortality were identified through linkage to national hospital and death registries. Multivariable Cox proportional hazards models were used to assess associations of phenotypic age acceleration with cardiovascular diseases and mortality. Results Among 319,256 participants (46.8% male) with a mean age of 56.6 years, 42.1% had accelerated phenotypic ageing (PhenoAgeAccel >0) with a mean of +4.13 years. Over a median follow-up of 13.7 years, 9,824 incident heart failure, 7,123 myocardial infarction, 10,714 angina, 5,120 cardiovascular deaths, and 41,237 ASCVD incidents occurred. Each 1-year increase in PhenoAgeAccel was associated with higher risks of heart failure (HR=1.04; 95%CI: 1.04,1.05), myocardial infarction (HR=1.03; 95%CI: 1.02,1.03), angina (HR=1.01; 95%CI: 1.01,1.02), cardiovascular mortality (HR=1.05; 95%CI: 1.05,1.06), and ASCVD (HR=1.03; 95%CI: 1.03,1.03). Adding phenotypic age acceleration led to a 0.01 increase in C-index compared to using SCORE2 risk factors only. Results were consistent across subgroup and sensitivity analyses. Conclusions Accelerated phenotypic ageing was independently associated with increased risks of major cardiovascular diseases and cardiovascular mortality. However, its incremental value in cardiovascular risk stratification appears limited.