Association of accelerated phenotypic aging, lifestyle and genetic risk with progression of cardiometabolic multimorbidity: a multi-state model analysis.

Abstract

We aimed to use multi-state models to assess joint impacts of lifestyle and genetic risk with phenotypic age acceleration on cardiometabolic multimorbidity (CMM) trajectory, and to further explore whether phenotypic age acceleration mediates association between lifestyle and each transitions. We conducted a prospective cohort study included 365,573 adults free of cardiometabolic diseases (CMDs) at baseline in UK Biobank. Multi-state model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of joint impacts of lifestyle and genetic risk with PhenoAgeAccel on CMM progression. Mediation analyses were conducted to explore indirect effect of PhenoAgeAccel on association between lifestyle and all transitions. During a median follow-up of 13.68 years, 54,483 participants developed first cardiometabolic diseases (FCMD), 7,397 developed CMM, and 27,288 died from any causes. Participants with accelerated phenotypic aging and unfavorable lifestyles had higher risks of all transitions, with HRs ranging from 1.53 (95% CI 1.37, 1.71) to 2.80 (2.62, 3.00). Additionally, those with accelerated phenotypic aging and high genetic risk showed a higher risk of FCMD incidence (HR 1.46; 95% CI 1.32, 1.61) and transition from FCMD to CMM (2.09; 2.02, 2.17). Furthermore, phenotypic age acceleration partially mediated the impact of lifestyle on all transitions, with mediation proportion varying from 6.28% (3.46, 9.10%) to 9.92% (6.37, 13.46%). Participants with phenotypic age acceleration have increased risk of CMM progression, especially among those with unfavorable lifestyles and high genetic risk. Phenotypic age acceleration partially mediated the relationship between lifestyle and CMM progression.