Accelerated biological aging, inflammatory bowel disease, genetic susceptibility and life expectancy: Evidence from Multi-national Prospective Cohorts

Background: Inflammatory bowel disease (IBD) affects all age groups, but its link to biological aging is unclear. Methods: We analyzed data from the UK Biobank and the All of Us (AoU) Research Programme to explore the role of biological aging in IBD development. Biological age was measured using Klemera-Doubal method (KDMAge) and phenotypic biological age (PhenoAge). Accelerated aging was defined as residuals of chronological age minus these measures (KDMAgeAccel and PhenoAgeAccel). We used survival analysis to assess the impact on life expectancy and examined genetic susceptibility and mediation effects. Findings: In UK Biobank, accelerated biological aging significantly increased IBD risk (KDMAgeAccel: HR 1.22, 95% CI 1.13-1.32; PhenoAgeAccel: 1.57, 1.46-1.69). This was validated in the AoU cohort (PhenoAgeAccel: HR 1.57, 1.18-2.09). An additive interaction was observed between accelerated aging and genetic risk. Individuals with both high genetic risk and accelerated aging had the highest IBD risk (KDMAgeAccel: HR 1.36, 1.20-1.53; PhenoAgeAccel: HR 1.59, 1.41-1.79). Life expectancy analysis showed IBD patients with accelerated aging had a significant reduction in life expectancy (KDMAgeAccel (1.36 years reduction) and 1.95 years for PhenoAgeAccel). Mediation analyses suggested accelerated aging mediated the protective effects of dried fruit and cooked vegetables on IBD risk. Multistate modeling indicated PhenoAgeAccel increased the risk of IBD occurrence to mortality (HR 1.44, 1.17-1.77). Interpretation: Accelerated biological aging is significantly associated with IBD risk, particularly in individuals with high genetic susceptibility, and reduces life expectancy. Identifying such individuals can aid in IBD prevention and management.