The Application of Metabolomics in Frailty: Trends, Challenges, and Future Directions

Frailty is a geriatric syndrome involving inflammation, oxidative stress, mitochondrial dysfunction, and metabolic disturbances. Metabolomics can systematically elucidate metabolic pathways and identify actionable biomarkers. This study systematically reviews the progress and evolutionary trends of metabolomics applications in frailty research from 2006 to 2025. Based on 1924 publications retrieved from the Web of Science Core Collection, systematic analyses were performed using CiteSpace, VOSviewer, SCImago Graphica, and the R package "bibliometrix", focusing on pathway-level research hotspots and collaboration networks. The United States and China are the leading contributors. Research hotspots have shifted from macro-level biomarkers such as inflammation and protein-energy wasting to specific metabolic pathways including amino acid metabolism, energy metabolism, lipid metabolism, and tryptophan degradation. Key metabolites include sphingomyelin, butyrate, and trimethylamine-N-oxide. Emerging frontiers focus on the association between gut microbiota-derived metabolites and frailty phenotypes, as well as intervention strategies targeting these metabolites. This study provides the first systematic overview of global research progress in metabolomics and frailty, establishes a reproducible evaluation framework integrating physiology, nutrition, geriatrics, and computational biology, and identifies butyrate, trimethylamine-N-oxide, and tryptophan metabolites as potential metabolic targets for early identification and intervention.