Associations of combined accelerated biological aging and genetic susceptibility with incidence of heart failure in a population‐based cohort study

The global aging population raises concerns about heart failure (HF), yet its association with accelerated biological age (BA) remains inadequately understood. We aimed to examine the longitudinal association between BA acceleration and incident HF risk, assess its modifying effect on genetic susceptibility, and how much BA acceleration mediates the impact of modifiable health behaviors on incident HF. We analyzed 274,608 UK Biobank participants without HF at baseline. Two BA accelerations (Biological Age Acceleration [BioAgeAccel] and Phenotypic Age Acceleration [PhenoAgeAccel]) were calculated by regressing clinical biomarker-based BA on chronological age, with higher values indicating accelerated aging. Health behavior scores were computed based on diet, physical activity, tobacco/nicotine, sleep, and BMI. Genetic risk scores (GRS) were calculated by 12 HF-associated loci. During a median follow-up of 13.5 years, 8915 HF cases were documented. Each standard deviation increase in BioAgeAccel and PhenoAgeAccel was associated with an increased incident HF risk, yielding HRs of 1.45 (95% CI, 1.42-1.48) and 1.42 (95% CI, 1.40-1.45), respectively. Participants with high GRS and highest quartile of BioAgeAccel had an HR of 2.69 (95% CI, 2.42-2.99), and for PhenoAgeAccel, an HR of 2.83 (95% CI, 2.52-3.18), compared to those with low GRS, and lowest quartile. Additive interactions were observed between GRS and BA accelerations. Health behaviors reduced HF risk, with 21.1% (95% CI, 19.5%-22.8%) mediated by decreased BioAgeAccel and 20.9% (95% CI, 19.5%-22.6%) by decreased PhenoAgeAccel. Accelerated BA is associated with an increased incident HF risk, with an additive effect when combined with genetic susceptibility. Maintaining health behaviors may help mitigate BA aging and reduce HF risk.