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. 2025 Nov 4;37(11):2280-2294.e4.
doi: 10.1016/j.cmet.2025.09.009. Epub 2025 Oct 16.

Aged mice exhibit widespread metabolic changes but preserved major fluxes

Connor S R Jankowski  1 , Laith Z Samarah  2 , Michael R MacArthur  2 , Sarah J Mitchell  3 , Daniel R Weilandt  2 , Craig J Hunter  2 , Xianfeng Zeng  4 , Melanie R McReynolds  5 , Joshua D Rabinowitz  6
Affiliations

Aged mice exhibit widespread metabolic changes but preserved major fluxes

Connor S R Jankowski et al. Cell Metab. .

Abstract

Metabolic dysregulation is a hallmark of aging. Here, we investigate in mice age-induced metabolic alterations using metabolomics and stable isotope tracing. Circulating metabolite fluxes and serum and tissue concentrations were measured in young and old (20-30 months) C57BL/6J mice, with young obese (ob/ob) mice as a comparator. For major circulating metabolites, concentrations changed more with age than fluxes, and fluxes changed more with obesity than with aging. Specifically, glucose, lactate, 3-hydroxybutryate, and many amino acids (but notably not taurine) change significantly in concentration with age. Only glutamine circulatory flux does so. The fluxes of major circulating metabolites remain stable despite underlying metabolic changes. For example, lysine catabolism shifts from the saccharopine toward the pipecolic acid pathway, and both pipecolic acid concentration and flux increase with aging. Other less-abundant metabolites also show coherent, age-induced concentration and flux changes. Thus, while aging leads to widespread metabolic changes, major metabolic fluxes are largely preserved.

Keywords: aging; fluxomics; glutamine; metabolic flux; metabolism; metabolomics; obesity; stable isotope tracing; systemic metabolism.

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Conflict of interest statement

Declaration of interests J.D.R. is a member of the Rutgers Cancer Institute of New Jersey (RCINJ) and the University of Pennsylvania Diabetes Research Center (U Penn DRC); a director of the U Penn DRC-Princeton inter-institutional metabolomics core and RCINJ metabolomics core; an advisor to and stockholder in Colorado Research Partners, Bantam Pharmaceuticals, Barer Institute, Rafael Pharmaceuticals, Empress Therapeutics, and Marea Therapeutics; a founder, director, and stockholder of Farber Partners, Raze Therapeutics; a founder of, advisor to, and stockholder in Marea Therapeutics and Fargo Biotechnologies; and an inventor of patents held by Princeton University.

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