Metabolomic signatures mediate the association between physical frailty and metabolic dysfunction-associated...

Physical frailty is linked to metabolic dysfunction-associated steatotic liver disease (MASLD), but the underlying metabolic mechanisms remain unclear. This study aimed to identify a frailty-related metabolic signature and examine its association with incident MASLD and its mediating role in the frailty-MASLD relationship.

We analysed data from 244,187 UK Biobank participants. Frailty was assessed using the Fried Frailty Phenotype. Incident MASLD was ascertained via hospital records and death registries. An elastic net regression model identified frailty-associated metabolites to construct a weighted metabolic signature. Cox proportional hazards models estimated associations with MASLD risk, and mediation analysis quantified the signature's contribution.

Over a median follow-up of 13.7 years, 3,408 incident MASLD cases occurred. A 96-metabolite signature was identified. Each 1-standard deviation increase in the signature was associated with a 21% higher MASLD risk (HR = 1.21, 95% CI: 1.16-1.25). Compared with robust participants, pre-frail and frail individuals had HRs of 1.51 (95% CI: 1.40-1.63) and 2.22 (95% CI: 1.97-2.50), respectively. The metabolic signature mediated 4.25% of the frailty-MASLD association.

Frailty and its associated metabolic signature are independently associated with increased incident MASLD risk. The signature partially mediates this relationship, suggesting metabolic dysregulation links physical frailty to hepatic steatosis. Identifying this signature may enable earlier MASLD detection in frail individuals.