Accelerated biological aging and incident degenerative valvular heart disease: Findings from 408,783 UK Biobank participants

Accelerated biological aging and degenerative valvular heart disease risk. Abbreviations: VHD, valvular heart disease; AS, aortic stenosis; AR, aortic regurgitation; MR, mitral regurgitation. • Both PhenoAge and KDM-BA acceleration are independently associated with incident AS/AR and related events. • BAA metrics are associated with MR risk, but not with MR-related adverse events. • BAA may serve as a novel biomarker for early risk stratification and prevention. Although prior studies have linked frailty and accelerated biological aging to aortic stenosis, comprehensive evidence across the spectrum of degenerative valvular diseases (VHD) and related clinical events remains unclear in middle-aged adults. We analyzed 408,783 UK Biobank participants free of baseline valvular disease. Biological age accelerations (BAA) measures were derived from clinical traits using Phenotypic Age (PhenoAge) algorithm and the Klemera-Doubal method Biological Age (KDM-BA). Outcomes included incident aortic stenosis (AS), aortic regurgitation (AR), mitral regurgitation (MR), and related interventions or mortality. Over a median follow-up of 13.9 years, 10,364 incident degenerative VHD events (2.5 %) were documented, comprising 4602 AS, 1678 AS-related events, 1639 AR, and 4903 MR cases. Elevated BAA was significantly associated with higher AS risk. For PhenoAge, adjusted AS incidence rates (per 10,000 person-years; 95 % confidence interval) across quartiles (Q1–Q4) were 3.73 (3.37–4.12), 4.44 (4.05–4.88), 5.11 (4.67–5.59), and 7.79 (7.18–8.46), yielding an adjusted hazard ratio (HR) of 2.15 (1.96–2.35) for Q4. Comparable trends were observed for KDM-BA, with an adjusted HR of 1.98 (1.83–2.15) for Q4 vs Q1. AS-related events followed a similar pattern, with HRs of 1.80 (1.55–2.09) for PhenoAge Q4 and 2.22 (1.94–2.54) for KDM-BA Q4. Significant associations were also found for AR, AR-related events, and MR, but not for MR-related events. Among middle-aged adults, both BAA metrics were associated with increased risks of degenerative VHD and related adverse events, except for MR-related events. These findings highlight BAA as a potential tool for early risk stratification and targeted prevention.