Tier 3 — preclinical

A metabolic atlas of mouse aging

Pilley SE, Awad D, Latumalea D, New C, Esparza E, Wang S, Shi X, Zhang L, Unfried M, Lee JH, Schmid E, Mohanty I, Blum JLE, Raventhiran S, Wong E, Iyengar PR, Mulondo R, Kashyap SB, Moaddeli D, Sajjakulnukit P, Sutton D, Wong HKA, Gao Y, Wang G, Coakley AJ, Garcia G, Higuchi-Sanabria R, Karlstaedt A, Frankel TL, Pasca di Magliano M, Cohn W, Liu S, Yu B, Dorrestein PC, Fraenkel E, Davidson SM, Tu WB, Kennedy BK, Lyssiotis CA, Mullen PJ
Cell Metabolism 2026 38(2):399-418.e7

Bibliography

PubMed
PMID 41297544
DOI
10.1016/j.cmet.2025.10.016
Funding
Supported in part by NIA grant R01 AG079806 and additional institutional/project funding reported in the article.
Competing interests
Brian K. Kennedy served on the Scientific Advisory Board for and has equity in Rejuvant. Pieter C. Dorrestein disclosed advisory, equity, founder and consulting relationships with several biotechnology companies.

Study snapshot

DesignMulti-organ, multi-age metabolomics atlas with sex-stratified mouse aging clocks and selected human-tissue validation.
ModelMale and female mice across 12 organs and five ages, with selected validation in human pancreas tissue.
SampleLarge multi-organ atlas; sample size varies by organ, age and sex.
InterventionNo AKG supplementation intervention; observational metabolomic profiling across aging.
DurationCross-sectional sampling across five mouse ages.
EndpointsOrgan-specific metabolomic aging; Metabolic aging clocks; Alpha-ketoglutarate as an age predictor; Sex-specific metabolic trajectories; Cross-species metabolite validation

What the study showed, in plain terms

This Cell Metabolism atlas is important for interpreting claims that AKG simply 'declines with age'.

The researchers profiled 12 organs across five ages in male and female mice and found that metabolic aging is strongly tissue- and sex-dependent. AKG emerged as an important predictor in organ-specific aging clocks rather than a universally uniform age marker.

This paper should therefore be used to add nuance to systemic AKG-aging claims, not as evidence that supplementation reverses aging.

Key findings

  • Metabolic aging patterns differed substantially across organs and between sexes.
  • AKG emerged as an important predictor in organ-specific metabolic aging clocks.
  • The study supports a context-dependent relationship between AKG and aging rather than a single whole-body trajectory.

What this study can and cannot tell us

  • Observational metabolic atlas, not a supplementation trial.
  • Mouse tissue metabolism cannot be mapped directly onto circulating human AKG or Ca-AKG dosing.
  • Brian Kennedy disclosed advisory-board service and equity in Rejuvant, which is directly relevant to Ca-AKG interpretation.

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Editorial review

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology