Frailty predicts death in advanced cirrhosis and among transplant candidates, but whether a frailty-like functional index identifies mortality risk in the far larger population of community-dwelling adults with liver disease, who are rarely assessed for it, is unsettled. We examined whether a survey-based functional vulnerability index (FVI) was associated with all-cause mortality among US adults reporting a history of hepatitis or a chronic liver condition, independent of poverty and insurance status.

Retrospective cohort study using the National Health Interview Survey (2008–2018) linked to the National Death Index through December 31, 2019. Adults 18 years or older reporting a history of hepatitis or a chronic liver condition, eligible for mortality linkage, and without baseline liver cancer were included. The FVI was defined as the proportion of 9 self-reported deficits present (fair/poor self-rated health, ADL or IADL difficulty, work limitation; and difficulty walking, climbing, standing, carrying, or grasping), modeled per 0.10-unit higher score and by deficit count (0, 1, 2, or ≥ 3). Survey-weighted Cox models estimated hazard ratios (HRs) for all-cause mortality, and survey-weighted modified Poisson models estimated 5-year mortality risk ratios.

Among 9291 adults (1151 deaths; 59,732 person-years; mean follow-up of 6.4 years), 64.6% had no functional deficit. In the fully adjusted model, each 0.10-unit higher FVI was associated with higher mortality (HR: 1.19, 95% confidence interval [CI]: 1.15–1.22), corresponding to an HR of 1.56 (95% CI: 1.44–1.68) per 1 − SD higher FVI. Versus no deficit, mortality increased with increasing burden: 1 deficit (HR: 1.37, 95% CI: 1.05–1.80); 2 deficits (HR: 2.49, 95% CI: 1.86–3.33); and ≥3 deficits (HR: 3.29, 95% CI: 2.65–4.08). Weighted 5-year mortality increased from 3.2% with no deficit to 23.0% with ≥3 deficits. The association was nonproportional and strongest during the first 2 years (HR: 1.28, 95% CI: 1.22–1.35), but persisted beyond 5 years (HR: 1.12, 95% CI: 1.07–1.18). Multiple imputation yielded similar results (HR: 1.20, 95% CI: 1.17–1.23). Poverty predicted mortality before but not after FVI adjustment; uninsurance did not.

Among community-dwelling US adults with hepatitis or chronic liver disease, a survey-based functional index was strongly and gradually associated with all-cause mortality, capturing risk not explained by poverty or insurance status. Brief functional assessment may identify high-risk patients well outside the transplant clinic.

Metabolic dysfunction–associated steatotic liver disease (MASLD) is a growing global health burden. Geroscience posits that accelerated biological aging is a key driver of chronic disease. We systematically reviewed the evidence to define the role of biological aging (BA) across the MASLD disease spectrum.

A systematic literature search of PubMed/MEDLINE and Embase was conducted from inception through August 2025 for observational studies in adults assessing validated BA measures (phenotypic age, Klemera–Doubal method, Homeostatic Dysregulation, epigenetic clocks, telomere length) and MASLD outcomes. A narrative synthesis was performed following SWiM guidelines because of substantial methodological heterogeneity.

Nineteen studies were included. BA was operationalized using clinical composite clocks (KDM-BA, PhenoAge, Homeostatic Dysregulation), epigenetic clocks, leukocyte telomere length, homeostatic dysregulation indices, and one machine-learning BA metric. Accelerated BA generally referred to BA higher than expected for chronological age or shorter telomere length. Across large cross-sectional studies, individuals with accelerated BA had higher odds of MASLD/nonalcoholic fatty liver disease (NAFLD), and in prospective cohorts, higher BA at baseline predicted increased hazards of incident NAFLD after multivariable adjustment, suggesting BA functions as an upstream integrator of risk rather than only a consequence of liver disease. Accelerated BA was also associated with greater fibrosis burden and with higher all-cause mortality among people with MASLD. Several studies indicated that BA mediates part of the effect of environmental toxicants on MASLD and acts as an effect modifier, with higher risk observed when accelerated BA co-occurs with unfavorable genetic profiles or environmental exposures. Mendelian randomization analyses supported a potential causal role of cellular aging in liver fibrogenesis.

Across 19 observational studies, accelerated biological aging (assessed using clinical composite indices, epigenetic clocks, and telomere length) was consistently associated with higher MASLD/NAFLD risk, greater fibrosis severity, and higher mortality. These findings support BA as potentially a clinically relevant risk integrator in MASLD spectrum diseases. However, heterogeneity in BA measures and disease definitions limits comparability and highlight the need for harmonized BA measures in longitudinal studies.