Association of serum metabolites with frailty phenotype and its components: a cross-sectional case-control study

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 65 years and older. The study population included 39 frail and 76 robust individuals. Metabolomic analysis was performed using the GCMS-TQ^TM8040 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.