Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of the global population and is a key driver of cirrhosis and liver-related mortality. While chronological age is a known risk factor, biological age (BA), reflecting physiological and functional status, may better capture individual susceptibility to liver disease progression.

In this study, 89,935 MASLD participants from the UK Biobank were followed for a median of 12.05 years, during which 519 developed cirrhosis. BA was assessed using Klemera-Doubal method (KDM-BA), PhenoAge, and leukocyte telomere length (LTL), while 12 SNPs were used to construct a polygenic risk score (PRS). Cox proportional hazards models examined associations between BA, PRS, and cirrhosis risk.

Higher BA acceleration was significantly associated with increased cirrhosis risk: each standard deviation increase in PhenoAge acceleration corresponded to a 39% higher risk (HR 1.39), and in KDM-BA acceleration to a 12% higher risk (HR 1.12). Shorter LTL was linked to increased risk (HR 0.84 per SD increase). Participants with both high BA acceleration and high PRS had the greatest risk of cirrhosis (up to 7.65-fold higher compared to low-risk individuals). Notably, reducing BA acceleration could lower the 10-year absolute risk of cirrhosis by 17.74 per 1,000 person-years in high genetic risk participants.

These associations were consistent across subgroups defined by sex, age, BMI, and comorbidities and remained robust in multiple sensitivity analyses. Biological aging likely drives MASLD progression through hepatocyte senescence, telomere shortening, mitochondrial dysfunction, inflammation, and fibrosis promotion.

This study highlights that accelerated biological aging is a critical driver of MASLD-related cirrhosis, interacting additively with genetic susceptibility. Interventions targeting biological aging may offer effective strategies to prevent progression to cirrhosis, particularly in genetically high-risk populations.
DOI:10.20517/mtod.2025.161