Accelerated biological aging, genetic susceptibility, and lifestyle in relation to abdominal aortic aneurysm: A prospective study

This study aimed to investigate the associations of biological age (BA) acceleration and genetic risk with the incidence of abdominal aortic aneurysm (AAA), and to evaluate the extent to which BA acceleration mediates the impact of a healthy lifestyle on AAA risk. A large prospective cohort study. This study included 279,944 participants from the UK Biobank. Two validated measures of BA, Klemera-Doubal Method Biological Age (KDM-BA) and PhenoAge, were estimated using clinical biomarkers. BA acceleration was calculated as the residual from regressing BA on chronological age. A polygenic risk score (PRS) was constructed based on AAA-associated genetic variants, and a healthy lifestyle score was derived from key behavioral factors. Cox proportional hazards models were used to assess the independent and joint associations of BA acceleration, PRS, and lifestyle score with AAA risk. Interaction and mediation analyses were also conducted. Among the 279,944 participants, 1305 developed AAA over a mean follow-up of 15.5 years. Acceleration in both KDM-BA (HR, 1.89; 95% CI, 1.49–2.41) and PhenoAge (HR, 2.65; 95% CI, 2.21–3.17) was significantly positively associated with an increased risk of AAA. Significant interaction and joint effects were observed between genetic risk and BA acceleration. Compared with individuals with low genetic risk and low BA acceleration, those with both high PRS and high BA acceleration, particularly PhenoAge acceleration, had the highest risk of AAA (HR, 7.14; 95% CI, 5.64–8.46). Furthermore, a higher healthy lifestyle score was inversely associated with AAA risk, with approximately 7% of this association mediated through reduced BA acceleration. Both BA acceleration and genetic predisposition were significant risk factors for AAA, highlighting their potential utility in guiding precision prevention strategies and targeted interventions.