Joint effects of social determinants of health on NAFLD mortality: the mediating role of phenotypic age acceleration.

Although individual social determinants of health (SDoH) are known to influence non-alcoholic fatty liver disease (NAFLD) outcomes, the cumulative effect of comprehensive SDoH exposure and the underlying biological pathways remain largely unaddressed. We analyzed 3025 adults with NAFLD from the National Health and Nutrition Examination Survey (NHANES) 1999-2018 cycles. We utilized weighted Cox proportional hazards models to evaluate individual SDoH variables. To assess the joint effect of the SDoH mixture, we employed the quantile-based g-computation (Q-gcomp) model. Furthermore, mediation analysis based on weighted logistic regression was performed to investigate whether accelerated biological aging (PhenoAge and KDM acceleration) mediated the SDoH-mortality association. During a median follow-up of 10.83 years, 585 deaths were recorded. In fully adjusted models, the composite SDoH exposure was significantly associated with an increase in risks for all-cause and cardiovascular mortality, exhibiting a linear dose-response relationship. Employment status, family income-to-poverty ratio (PIR), and housing instability were identified as the primary contributors to this joint effect. Mediation analysis revealed that PhenoAge acceleration significantly mediated 11.3% of the total effect of the composite SDoH score on all-cause mortality. In contrast, KDM acceleration did not exert a significant mediating effect. In summary, unfavorable SDoH exposure is associated with an increased mortality risk in patients with NAFLD, a relationship that may be partially explained by accelerated biological aging. This study highlights the importance of integrating a comprehensive social risk assessment into NAFLD management to help mitigate profound health disparities and improve survival outcomes.