Accelerated biological aging drives the progression from MASLD to cirrhosis

Abstract

Aim: Although the association between biological age (BA) and liver dysfunction is well-established, epidemiological evidence on the relationship between BA acceleration and cirrhosis risk in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) remains limited.

Methods: This study included 89,935 individuals with MASLD from the UK Biobank. We used Klemera-Doubal method-BA (KDM-BA), phenotypic age (PhenoAge) and leukocyte telomere length (LTL) as BA indicators. Twelve genetic variants were used to construct polygenic risk scores (PRS). Multivariable Cox proportional hazards models were employed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cirrhosis incidence.

Results: During a median follow-up of 12.05 years, 519 individuals developed cirrhosis. Acceleration in PhenoAge and KDM-BA was associated with a 39% (HR 1.39, 95%CI: 1.32-1.47) and 12% (HR 1.12, 95%CI: 1.03-1.22) higher risk of incident cirrhosis, respectively. Longer LTL was associated with a lower risk of cirrhosis (HR 0.84, 95%CI: 0.77-0.91). Participants with the greatest BA acceleration and highest PRS exhibited the highest risk of cirrhosis. Additionally, participants at a high genetic risk level had the greatest 10-year absolute risk reduction of cirrhosis (17.74 per 1,000 person-years) if their PhenoAge acceleration decreased.

Conclusion: Our findings demonstrate that alleviating biological aging in individuals with MASLD is important for preventing cirrhosis and could mitigate the adverse effects of high genetic risk.

Keywords

Biological aging / metabolic dysfunction-associated steatotic / cirrhosis / polygenic risk score / cohort study

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