Accelerated biological aging, genetic susceptibility, and incident severe MASLD, liver cirrhosis and cancer

Background There is an explicit link between biological age (BA) and chronic liver disease (CLD). This study aimed to explore the association between clinical biomarker-based BA and potential interaction with genetic risk on incident CLD. Methods This prospectively cohort study was conducted in UK Biobank included 347,917 participants. We quantified clinical biomarker-based BAs using the KDM-BA and PhenoAge algorithms and constructed the polygenic risk score (PRS) to examine its interactions with BAs on CLD risk. Results We first identified acceleration for KDM-BA (KDM-BAaccel) and PhenoAge (PhenoAgeAccel) were significantly associated with prevalent severe metabolic dysfunction-associated steatotic liver disease (MASLD), as well as liver cirrhosis and cancer. Each SD increase in KDM-BAaccel and PhenoAgeAccel was correlated with an 10% elevated risk of MASLD. Particularly, we observed the deleterious effects of advanced biological aging on three CLDs in males were mostly stronger than in females. In predicting MASLD, the two BA indicators showed better performance than chronological age, with AUC values of 0.526, 0.571 and 0.595 for chronological age, KDM-BAaccel and PhenoAgeAccel, respectively. Moreover, individuals with the highest BA acceleration and PRS had the highest risk of developing severe MASLD, although no significant additive and multiplicative interactions were found. Additionally, participants who at a high genetic risk level had the greatest 10-year absolute risk reduction of severe MASLD (6.74 per 1000 person-years) if their PhenoAgeAccel decreased. Conclusion Our findings elucidate that relieving biological aging is important for preventing serious fatty liver-related diseases and could offset the adverse effects of inherent genetic risk.