Accelerated biological aging, genetic susceptibility, and the risk of peripheral arterial disease: Evidence from the UK Biobank cohort study.

BACKGROUND

Peripheral artery disease (PAD) is a condition in which atherosclerosis causes narrowing or blockage of the peripheral arteries, leading to insufficient blood supply to the limbs. Although accelerated biological aging has been recognized as a driving factor in the development and progression of many age-related diseases, its exact role in the risk of developing PAD remains unclear. This study investigated the relationship of biological aging and genetic susceptibility with the risk of incident PAD.

METHODS

This prospective study included 403,780 UK Biobank participants free of PAD at baseline. Biological age was estimated from routine clinical biomarkers using the Klemera-Doubal method (KDM-BA) and PhenoAge algorithms. BAA was defined as the residual from regression of biological age on chronological age. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) for incident PAD after adjustment for demographic, socioeconomic, lifestyle, and clinical covariates. A polygenic risk score (PRS) was constructed to evaluate genetic predisposition to PAD. We also examined the interaction between genetic susceptibility and accelerated biological aging in relation to PAD risk.

RESULTS

Our findings indicated that accelerated biological aging was significantly associated with an increased risk of PAD, whether assessed by the KDM residual (HR 1.21, 95% CI 1.18-1.24) or the PhenoAge residual (HR 1.34, 95% CI 1.31-1.37). Furthermore, joint association analysis showed that participants with both accelerated biological aging and high genetic risk had the greatest risk of PAD (KDMAge: HR 2.07, 95% CI 1.83-2.34; PhenoAge: HR 6.14, 95% CI 5.30-7.12). A significant additive interaction was also observed between high genetic risk and accelerated biological aging as measured by PhenoAge.

CONCLUSION

Accelerated biological ageing were independently and jointly associated with incident PAD. This finding support the potential value of integrating biological ageing metrics into PAD risk assessment.