Elevated serum gamma-glutamyl transferase and frailty risk: evidence from prospective cohort, metabolomic, and integrative genetic evidence

Background Against the backdrop of accelerated population aging, the effective identification and intervention of frailty have become an important priority. Gamma-glutamyl transferase (GGT) is considered a potential biomarker of biological aging. We aimed to investigate the association between GGT and frailty through prospective cohort and integrative genetic analyses. Methods A total of 85,716 participants from the UK Biobank (UKB) were included in the prospective cohort analysis. Frailty was defined using the frailty index (FI). Cox proportional hazards models were used to evaluate the association between GGT and incident frailty, and mediation analyses examined the role of metabolites. Genetic analyses included linkage disequilibrium score regression (LDSC), two-sample Mendelian randomization (MR), and summary-data-based MR (SMR). Results After multivariable adjustment, log-transformed GGT was positively associated with the risk of incident frailty (HR 1.21, 95% CI 1.14–1.27). Participants in the highest GGT group had a 30% higher risk of frailty than those in the lowest GGT group (HR 1.30, 95% CI 1.19–1.43). Metabolites related to lipoprotein metabolism, amino acid metabolism, glycolysis, and systemic inflammation jointly mediated 47.16% of the association between GGT and frailty. LDSC analysis revealed a significant positive genetic correlation between GGT and FI (rg = 0.32, P = 2.33 × 10⁻²⁵). MR analysis provided evidence for a positive relationship between genetically predicted GGT levels and FI (IVW: β = 0.046, 95% CI 0.022–0.070; P < 0.001). SMR analysis identified 36 genes shared between GGT and frailty. Representative shared genes included EP300, FCGR2B, ITGAL, RASIP1, FOS, and MAPK3. KEGG enrichment analysis revealed significant enrichment in pathways related to immune signaling, lipid metabolism and atherosclerosis, adherens junctions, growth hormone signaling, estrogen signaling, and osteoclast differentiation. Conclusion Elevated GGT was associated with an increased risk of frailty in both observational and genetic analyses. These findings suggest that GGT may serve as a promising biomarker for identifying individuals at high risk of frailty, with metabolic, immune, vascular, and musculoskeletal pathways potentially contributing to the underlying mechanisms.