Liver-specific phenotypic aging, behavior and genetic risks, and long-term liver-related outcomes

Phenotypic age, an aging indicator derived from clinical biomarkers, is associated with morbidities and mortality. However, a liver-specific phenotypic aging indicator is still lacking, and its longitudinal associations with liver-related outcomes, as well as the underlying biological mechanisms, remain elusive. We developed a liver-specific phenotypic age using 11 selected clinical blood markers within the England-White cohort of the UK Biobank and validated this metric in both the Scotland-Wales cohort and Non-White-British cohort. We calculated phenotypic age acceleration (PhenoAgeAccel) and examined its association with long-term liver-related outcomes. We also explored the extent to which liver-specific PhenoAgeAccel mediated the impact of modifiable risk behaviors on liver-related outcomes. The metabolic and proteomic signatures of liver-specific PhenoAgeAccel were subsequently characterized. Liver-specific PhenoAgeAccel was significantly associated with a 1.23- to 2.97-fold increased risks of all-cause mortality and liver-related events. The impact of liver-specific PhenoAgeAccel on liver outcomes were more pronounced in males and in individuals with high genetic risk compared to their respective counterparts, and was stronger than that observed with systemic PhenoAgeAccel. Approximately 10–27% of the associations between risk behaviors and liver-related outcomes were mediated by liver-specific PhenoAgeAccel. Proteomic analysis identified 211 proteins associated with both liver-specific PhenoAgeAccel and liver-related outcomes, of which 22 (e.g., AGXT and SULT2A1) were liver-enriched and significantly mediated this relationship. Liver-specific PhenoAgeAccel is a strong predictor of liver-related outcomes, partially mediates the impact of modifiable behaviors, and is linked to liver-enriched proteins. This accessible tool may enhance risk stratification and support preventive strategies targeting liver health and aging.