New insights into the metabolic mechanisms of frailty are needed. This study aimed to identify serum metabolites linked to frailty phenotype and its component through gas chromatography-mass spectrometry metabolomic analysis among community-dwelling older individuals. An exploratory, cross-sectional case-control study. Setting and participants: The participants were recruited from the ''Otassha Study,'' a cohort study conducted in Itabashi Ward, Tokyo, targeting women aged 65years and older. The study population included 39 frail and 76 robust individuals. Metabolomic analysis was performed using the GCMS-TQTM8040 NX system and the Smart Metabolites Database Ver.2 to explore the primary metabolite characteristic of a frailty state. Conditional logistic regression analysis was conducted with frailty as the outcome and with metabolites as exposures. Concentrations of seven metabolites, including caffeine, catechol, paraxanthine, niacinamide, 5-hydroxymethyl-2-furoic acid, daidzein, and cytosine were lower in the frail than in the robust individuals. Odds ratios [95% confidence intervals] for frailty by halving the value were significant for catechol (1.26 [1.00, 1.59]), 5-hydroxymethyl-2-furoic acid (1.28 [1.04, 1.58]), caffeine (1.37 [1.07, 1.75]), paraxanthine (1.18 [1.00, 1.39]), and daidzein (1.29 [1.02, 1.62]). Furthermore, distinct patterns of metabolites associated with specific frailty symptoms, such as muscle weakness, fatigue, and reduced physical activity, were identified, especially with 5-hydroxymethyl-2-furoic acid and caffeine commonly associated with these components. Metabolomic analysis identified metabolites associated with frailty. In particular, low levels of caffeine, catechol, paraxanthine, niacinamide, 5-hydroxymethyl-2-furoate, daidzein, and cytosine contributed to frailty. These results provide new insights into the pathophysiology of frailty through metabolomic analysis.
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