Prospective association between biological aging and risk of hospital-diagnosed MASLD: evidence from the UK Biobank

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent metabolic disorder linked to increased all-cause and cardiovascular mortality. While accelerated biological aging is a known risk factor for age-related diseases, its role in MASLD remains unclear. This study explores the association between biological aging and hospital-diagnosed MASLD and investigates the potential mediating effects of biological aging on lifestyle-MASLD relationships. Methods and results: Data were from the UK Biobank, and the biological age was estimated by PhenoAge and Klemera-Doubal method age (KDMAge). The association between biological aging and hospital-diagnosed MASLD (defined as hospital admission or death) was estimated using Cox regression. Biological aging acceleration was defined as positive residuals obtained from regressing biological age on chronological age. Mediation analyses were used to assess the potential mediating role of biological aging in the relationships between lifestyle and hospital-diagnosed MASLD. Among 247,444 participants, 3,254 developed hospital-diagnosed MASLD during a median follow-up of 13.7 years. Accelerated biological aging was significantly associated with hospital-diagnosed MASLD with hazard ratios of 1.46 (95% confidence interval, 1.35, 1.57) for PhenoAge acceleration and 1.35 (1.19, 1.53) for KDMAge acceleration. In mediation analyses, PhenoAge acceleration significantly accounted for the associations between four unhealthy lifestyle factors (smoking, drinking, poor diet, and low physical activity) and MASLD, with mediation proportions ranging from 11.4% to 25.5%, and the strongest effect observed for smoking. In contrast, KDMAge acceleration showed minimal mediation effects (≤2%). Conclusions: Accelerated biological aging was associated with hospital-diagnosed MASLD and may partially mediate the associations between unhealthy lifestyles and hospital-diagnosed MASLD. These findings support the potential relevance of biological aging in MASLD risk stratification and prevention.