Associations of phenotypic age acceleration, genetic risk, and lifestyle with chronic digestive diseases: A large-scale longitudinal cohort study.

BACKGROUND

Phenotypic age acceleration (PhenoAgeAccel) is a promising biological aging metric, but its associations with chronic digestive disease risk are unclear. This study evaluated these associations and assessed modification by genetic risk and lifestyle.

METHODS

We analyzed 292,639 UK Biobank participants. PhenoAge and PhenoAgeAccel were calculated using a validated algorithm based on clinical biomarkers. Cox proportional hazards models estimated associations of PhenoAgeAccel, genetic risk, and lifestyle with incident chronic digestive diseases, including interaction and stratified analyses. Variance decomposition quantified contributions of aging, genetics, and lifestyle.

RESULTS

Over a median 13.67-year follow-up, PhenoAgeAccel > 0 (accelerated aging) was independently associated with higher risk of most chronic digestive diseases, notably Crohn's disease (HR per 5-year increase, 1.36; 95%CI, 1.30-1.42) and liver cirrhosis (HR, 1.35; 95%CI, 1.30-1.40). Significant additive interactions occurred between PhenoAgeAccel and genetic risk for diverticulosis, Crohn's disease, ulcerative colitis, liver cirrhosis, and chronic pancreatitis; among biologically older individuals at high genetic risk, interaction-attributable excess risk reached 42.8% of total risk. A healthy lifestyle attenuated aging-related risk for all outcomes except Crohn's disease and ulcerative colitis. Variance decomposition revealed disease-specific risk contribution profiles: biological aging contributed most to Crohn's disease and chronic pancreatitis, genetic risk to diverticulosis and ulcerative colitis, and lifestyle to gastroesophageal reflux disease and nonalcoholic fatty liver.

CONCLUSIONS

Higher PhenoAgeAccel was associated with higher risks of chronic digestive diseases, with associations modified by genetic risk and lifestyle. PhenoAgeAccel may be a useful risk marker and warrants further investigation of aging-targeted strategies.