Biological Ageing and the Risk of Inflammatory Bowel Disease: Exploring the Role of Lifestyle and Genetic Susceptibility in a Nationwide Prospective Study

Abstract Background Accelerated biological aging has been linked to an increased risk of inflammatory bowel disease (IBD), though its interplay with genetic susceptibility remains unclear. Methods We analyzed data from 310 441 UK Biobank participants to investigate associations between PhenoAge acceleration (a measure of biological aging), genetic risk, and the incidence of ulcerative colitis (UC) and Crohn’s disease (CD). Results During follow-up, 3364 participants (1.08%) developed UC and 1831 (0.59%) developed CD. After adjusting for all confounders, each 1-year increase in PhenoAge acceleration was associated with a 6.9% increase in UC risk (HR = 1.069, 95% CI, 1.063-1.074) and an 8.5% increase in CD risk (HR = 1.085, 95% CI, 1.079-1.092). Participants who were biologically older showed a higher risk of UC (HR = 1.928, 95% CI, 1.799-2.067) and CD (HR = 2.557, 95% CI, 2.330-2.807) compared with their younger counterparts. Moreover, PhenoAge acceleration partially mediated the associations of alcohol consumption and cigarette smoking with UC and CD risk (11.2%-27.2%). We observed dose–response associations between polygenic risk scores and both UC and CD. Compared with the bottom quintile, high-risk participants (top quintile) showed a 439.9% increase (HR = 2.229, 95% CI, 1.949-2.550) in UC risk and a 501.7% increase (HR = 6.017, 95% CI, 5.254-6.891) in CD risk. Notably, individuals with both high genetic risk and accelerated aging exhibited the greatest susceptibility (UC: HR = 11.569, 95% CI, 9.658-13.858; CD: HR = 12.018, 95% CI, 9.569-15.094). Conclusions PhenoAge acceleration may serve as a useful biomarker for identifying high-risk individuals, offering potential for integration into targeted prevention strategies and personalized treatment approaches for IBD. This study explores how accelerated biological aging (PhenoAge acceleration) and genetic susceptibility influence the risk of inflammatory bowel disease. Findings indicate that higher PhenoAge acceleration and genetic risk scores significantly increase the likelihood of developing ulcerative colitis and Crohn’s disease.