Independent and joint effects of biological aging and physical activity on incident gallstone disease and all-cause mortality: a retrospective cohort study

The independent and joint effects of biological aging and physical activity (PA) on incident gallstone disease (GSD) remain unclear. Using data from UK Biobank, Cox regression models were constructed to explore the association of Klemera-Doubal method biological age (KDMAge), phenotypic age (PhenoAge), and PA with GSD incidence. We further explored their joint and interactive effects, the mediating role of biological aging in the PA‑GSD association, and impacts of biological aging and PA on all‑cause mortality in GSD patients. Sensitivity analyses were applied to verify the robustness of results. A total of 200,906 individuals were enrolled with a median follow-up time of 14.5 years. Each 1-SD increase in PhenoAge and KDMAge was associated with 32% (95%CI = 1.27–1.38, P <0.001) and 8% (95% CI = 1.05–1.12, P <0.001) higher GSD risk, respectively. Individuals with accelerated PhenoAge had 1.34-fold higher GSD risk compared to those with non-accelerated aging (95%CI = 1.26–1.41, P <0.001). PA conferred a protective effect, which was strengthened with increasing PA levels. The joint group of accelerated biological aging with high-intensity PA exhibited the most substantial reduction in GSD risk. Among GSD patients, the combination of KDMAge acceleration and moderate-intensity PA was associated with a 32% (95%CI = 0.53–0.88, P <0.01) lower all-cause mortality risk. Mediation analysis revealed that PhenoAge mediated 8.2% of the association between PA and incident GSD. Accelerated PhenoAge aging increases GSD risk, while PA exerts a protective effect against GSD. Individuals with both youthful physiological status and high-intensity PA show marked GSD risk reduction and the effect is independent, not interactive.