Accelerated biological aging, inflammatory bowel disease, genetic susceptibility and life expectancy: Evidence from UK Biobank and All of Us Cohorts

Background: Inflammatory bowel disease (IBD) is a chronic condition affecting individuals across all age groups. However, the association between IBD and biological aging remains unclear. Methods: We utilized data from the UK Biobank and the diverse cohort of the All of Us (AoU) Research Programme to investigate the role of biological aging in the development of IBD and its subtypes. Biological age was assessed using the Klemera-Doubal method (KDMAge) and phenotypic biological age (PhenoAge), with KDMAgeAccel and PhenoAgeAccel defined as the residuals of chronological age minus KDMAge and PhenoAge, respectively. We assessed the impact of accelerated biological aging on life expectancy in patients with IBD through survival analysis. Additionally, we examined genetic susceptibility and its potential mediating effects on the association between biological aging and IBD. Findings: In the UK Biobank, accelerated biological aging was associated with an increased risk of IBD (KDMAgeAccel: HR 1.22, 95% CI 1.13-1.32; PhenoAgeAccel: HR 1.57, 95% CI 1.46-1.69). This association was further validated in the AoU cohort, where PhenoAgeAccel was also linked to an elevated risk of IBD (HR 1.57, 95% CI 1.18-2.09). An additive interaction was observed between accelerated biological aging and genetic risk for IBD. Individuals with both high genetic risk and accelerated aging exhibited the highest risk of developing IBD (KDMAgeAccel: HR 1.36, 95% CI 1.20-1.53; PhenoAgeAccel: HR 1.59, 95% CI 1.41-1.79). Life expectancy analysis indicated that IBD patients with accelerated biological aging experienced a significant reduction in life expectancy, with an average decrease of 1.36 years (KDMAgeAccel) and 1.95 years (PhenoAgeAccel). Mediation analyses suggested that accelerated biological aging partially mediated the protective effects of dried fruit and cooked vegetables on the risk of developing IBD. Results from multistate modelling showed that PhenoAgeAccel was also significantly associated with an increased risk of IBD occurrence to mortality (HR 1.44 [95% CI 1.17-1.77]). Interpretation: Biological aging is significantly associated with the risk of IBD and its subtypes, especially in individuals with high genetic susceptibility, and it reduces life expectancy in these patients. Identifying individuals with accelerated biological aging can serve as a marker for the effective prevention and management of IBD.