Serum metabolomic signatures associated with frailty-related phenotypes in a cohort of older people.

Frailty is a geriatric syndrome characterized by reduced physiological reserves and increased vulnerability to stressors. Given its complex phenotypes and underlying biology, robust multidimensional biomarkers are needed to advance personalized care. We aimed to identify serum metabolomics signatures associated with frailty phenotypes and related features. We analyzed serum metabolomics data in 901 participants (47.5% males, mean age 68.3 ± 3.5 years) from the Berlin Aging Study II, classified as non-frail, pre-frail, or frail using Fried's criteria at baseline (T0) and after 7 years (T1). Linear models assessed associations between metabolite levels, frailty, and related parameters. At T0, 1% were frail, increasing to 4.8% at T1. Over follow-up, 323 participants transitioned to a worse frailty category. Across 82 metabolites, no significant differences emerged for frailty status. However, in males, 27 and 30 circulating metabolites were negatively associated with handgrip strength at T0 and T1, respectively. Also in males, L-tyrosine was positively associated with fat mass, while 22 metabolites (carbohydrate-related, maltose, fructose, glucose, galactitol, mannose, lactate, acetylcarnitine; amino acid-related, valine, tyrosine, isoleucine, α-hydroxybutyrate) correlated with nutritional status at T0. In females, dimethylsulfone was positively associated with changes in handgrip strength over time, and glycerol with appendicular lean mass at T0. While serum metabolomics showed weak associations with frailty itself, clear links were observed with frailty-related features, notably muscle strength and nutritional status. These findings highlight insulin sensitivity as a central determinant, suggesting that early metabolic alterations may contribute to impaired muscle health in aging.