Abstract
BACKGROUND: Metformin is a widely used antidiabetic agent for obesity-related type 2 diabetes mellitus, providing significant health benefits such as reduced blood glucose levels and body weight. Emerging evidence suggests that metformin may play a beneficial role in delaying aging. However, the causal relationship between metformin use and frailty index (FI) remains uncertain and warrants further investigation. This study aimed to explore the genetically predicted causal relationship between metformin targets and FI. METHODS: A two-sample Mendelian randomization (MR) analysis was conducted. Genetic proxies for the target effects of metformin were identified as single nucleotide polymorphisms (SNPs) associated with body weight and corresponding gene expression levels. Summary statistics for the FI were obtained from the genome-wide association study (GWAS) meta-analysis. Additionally, a two-step MR approach was employed to explore whether glycated haemoglobin (HbA1c) exhibits a mediating effect on the relationship between body weight and frailty risk. In the MR analysis, the inverse variance weighted method served as the primary analytical approach, supplemented by sensitivity analyses. RESULTS: A total of 10 SNPs were included as genetic predictors of metformin. The average effect of the genetic proxies for metformin targets, equivalent to a 1 standard deviation reduction in body weight, was associated with a reduced FI (β: -0.41, 95% CI: -0.74 to -0.07, P = 0.017). Notably, weight reduction induced by the target Mitochondrial complex I (MCI) showed a role in reducing FI. Furthermore, HbA1c mediated 5.5% of the total effect of body weight on FI. CONCLUSIONS: The findings of this study support the notion that metformin may reduce frailty risk through the target MCI, with this effect potentially being partially attributable to weight reduction. These findings provide new insights for developing therapeutic strategies targeting aging and frailty prevention.