Multivariable Mendelian randomization study supports the causal effects of circulating metabolites on frailty

Aging-related frailty increases the risk of falls, disability, and mortality. Frailty is linked to abnormalities in whole-body metabolism. However, the causal relationship between circulating metabolic traits and frailty remains unclear. This study aims to clarify the causal effects of circulating metabolites on frailty. We used bidirectional two sample and multivariable Mendelian Randomization (MVMR) methods to assess associations between circulating metabolites and the Frailty Index (FI). Genetic data on relevant single-nucleotide polymorphisms (SNPs) were obtained from publicly available genome-wide association studies (GWAS). Five MR methods were employed: Inverse-variance weighted (IVW), MR-Egger, weighted median, simple mode, and weighted mode methods were used for Mendelian Randomization (MR) analysis. MVMR analyses examined the effects of selected circulating metabolites (identified via multivariate LASSO regression), obesity, alcohol consumption, and sleep disorders on FI. Preliminary analyses identified 12 circulating metabolites as potential frailty risk factors, while secondary analyses revealed 25 circulating metabolites. Notably, MVMR established a causal relationship between free cholesterol in large low-density lipoprotein (LDL) and frailty. This study establishes a causal link between free cholesterol in large LDL and frailty risk based on genetic evidence, potentially guiding targeted prevention strategies.