Accelerated biological ageing and cardiovascular disease trajectories: a multistate analysis

BACKGROUND: Accelerated biological ageing has been linked to elevated risks of hypertension (HTN) and cardiovascular diseases (CVDs), yet its role in shaping the dynamic progression from health to HTN, to CVDs, and ultimately to mortality remains poorly understood. We aimed to investigate these transitions using biological ageing measures and to assess the mediating role of intermediate disease states. METHODS: We analysed data from 136 614 UK Biobank participants aged 38-73 years, all free of HTN and CVDs at baseline. Accelerated biological ageing was assessed using phenotypical age (PhenoAge) and the Klemera-Doubal Method Biological Age (KDM-BA). Multistate models were used to evaluate the impact of accelerated biological ageing on disease progression, and mediation analyses assessed the role of intermediate diseases in these transitions. RESULTS: Over a median follow-up of 13.52 years, 8068 participants developed HTN, 11 795 developed CVDs and 6225 died. Each SD increase in PhenoAge acceleration was associated with higher risk of transitioning from healthy to HTN (HR 1.14, 95% CI 1.12 to 1.17), to CVDs (HR 1.14, 95% CI 1.11 to 1.16), and from HTN to CVDs (HR 1.06, 95% CI 1.02 to 1.10). Similarly, KDM-BA acceleration was associated with increased risk for these transitions: HRs of 1.28 (1.25-1.31), 1.12 (1.10-1.15) and 1.06 (1.01-1.11), respectively. Accelerated biological ageing was also significantly associated with higher risk of mortality from healthy, HTN and CVD states. Intermediate diseases were identified as important pathways through which biological ageing influenced disease progression. CONCLUSIONS: Accelerated biological ageing is a strong predictor of cardiovascular health trajectories. It offers a valuable framework for forecasting cardiovascular ageing, supporting subclinical CVD prevention and identifying opportunities for early intervention.