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bioRxiv · 10.1101/2025.01.22.634160

Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice

Zhu, D.·Wu, J. Z.·Griffin, P. T.·Samuelson, B. A.·Sinclair, D. A.·Kane, A. E.
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Abstract

Frailty is an age-related geriatric syndrome, for which the mechanisms remain largely unknown. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index and derived metabolomics data from plasma samples. We identify differentially abundant metabolites related to aging, determine frailty related metabolites via a machine learning approach, and generate a union set of frailty features, both in the whole cohort and in sex-stratified subgroups. Using the features, we perform an association study and build a metabolomics-based frailty clock. We find that frailty related metabolites are enriched for amino acid metabolism and metabolism of cofactors and vitamins, include ergothioneine, tryptophan, and alpha-ketoglutarate, and present sex dimorphism. We identify B vitamin metabolism related flavin adenine dinucleotide and pyridoxate as female-specific frailty biomarkers, and lipid metabolism related sphingomyelins, glycerophosphoethanolamine and glycerophosphocholine as male-specific frailty biomarkers. These associations are confirmed in a validation cohort, with ergothioneine and perfluorooctanesulfonate identified as robust frailty biomarkers. In summary, our results identify sex-specific metabolite biomarkers of frailty in aging, and shed light on potential mechanisms involved in frailty.

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Zhu, D., Wu, J. Z., Griffin, P. T., Samuelson, B. A., Sinclair, D. A., Kane, A. E.. 2025-01-22. Metabolomics biomarkers of frailty: a longitudinal study of aging female and male mice. https://doi.org/10.1101/2025.01.22.634160

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