A metabolic atlas of mouse aging

Steven E Pilley¹, Dominik Awad², Djakim Latumalea³, Connie New⁴, Edgar Esparza¹, Shuo Wang⁵, Xuanyi Shi¹, Li Zhang⁶, Maximilian Unfried³, Jasinda H Lee⁷, Ernst Schmid⁸, Ipsita Mohanty⁹, Jenna L E Blum¹⁰, Shivaanishaa Raventhiran⁷, Esther Wong⁷, Preeti R Iyengar¹, Racheal Mulondo¹, Sriraksha Bharadwaj Kashyap¹, Darius Moaddeli¹¹, Peter Sajjakulnukit⁶, Damien Sutton⁶, Harrison K A Wong⁶, Yaqi Gao¹², George Wang¹³, Aeowynn J Coakley¹¹, Gilberto Garcia¹¹, Ryo Higuchi-Sanabria¹¹, Anja Karlstaedt¹², Timothy L Frankel¹⁴, Marina Pasca di Magliano¹⁵, Whitaker Cohn¹³, Sophia Liu¹⁶, Bingfei Yu¹⁷, Pieter C Dorrestein¹⁸, Ernest Fraenkel¹⁹, Shawn M Davidson¹⁰, William B Tu²⁰, Brian K Kennedy²¹, Costas A Lyssiotis²², Peter J Mullen²³

Affiliations

¹ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
³ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
⁷ Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁸ Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
⁹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
¹⁰ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹¹ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, US.
¹² Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³ Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
¹⁷ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁸ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁰ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
²¹ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
²² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: clyssiot@umich.edu.
²³ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, US. Electronic address: petermul@usc.edu.

PMID: 41297544
DOI: 10.1016/j.cmet.2025.10.016

A metabolic atlas of mouse aging

Steven E Pilley et al. Cell Metab. 2026.

. 2026 Feb 3;38(2):399-418.e7.

doi: 10.1016/j.cmet.2025.10.016. Epub 2025 Nov 25.

Authors

Affiliations

¹ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
³ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁴ Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁵ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
⁷ Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
⁸ Department of Biological Chemistry & Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
⁹ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA.
¹⁰ Department of Medicine, Division of Pulmonary and Critical Care Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹¹ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, US.
¹² Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
¹³ Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁴ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
¹⁵ Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Surgery, University of Michigan, Ann Arbor, MI, USA; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
¹⁷ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences, University of Southern California, Los Angeles, CA, USA.
¹⁸ Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁹ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
²⁰ Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA, USA.
²¹ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Healthy Longevity Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Centre for Healthy Longevity, National University Health System, Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
²² Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA. Electronic address: clyssiot@umich.edu.
²³ Department of Immunology and Immune Therapeutics, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, US. Electronic address: petermul@usc.edu.

PMID: 41297544
DOI: 10.1016/j.cmet.2025.10.016

Abstract

Humans are living longer and experiencing more age-related diseases, many of which involve metabolic dysregulation, but how metabolism changes in multiple organs during aging is not known. Answering this could reveal new mechanisms of aging and therapeutics. Here, we profile metabolic changes in 12 organs in male and female mice at 5 different ages. We also develop organ-specific metabolic aging clocks that identify metabolic drivers of aging, including alpha-ketoglutarate, previously shown to extend lifespan in mice. We also use the clocks to uncover that carglumic acid is a potential driver of aging and show that it is synthesized by human cells. Finally, we validate that hydroxyproline decreases with age in the human pancreas, emphasizing that our approach reveals insights across species. This study reveals fundamental insights into the aging process and identifies new therapeutic targets to maintain organ health.

Keywords: LC-MS/MS; MALDI-MSI; aging; aging clocks; healthspan; human tissue; hydroxyproline; metabolism; scRNA-seq; sex.

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Conflict of interest statement

Declaration of interests B.K.K. served on the Scientific Advisory Board for and has equity in Rejuvant. P.C.D. is an advisor for and holds equity in Cybele, BileOmix, and Sirenas and is a scientific co-founder, advisor, and equity holder and/or received income from Ometa, Enveda, and Arome with prior approval by UC-San Diego. P.C.D. also consulted for DSM Animal Health in 2023.

Update of

A metabolic atlas of mouse aging.
Pilley SE, Awad D, Latumalea D, Esparza E, Zhang L, Shi X, Unfried M, Wang S, Mulondo R, Kashyap SB, Moaddeli D, Sajjakulnukit P, Sutton D, Wong H, Coakley AJ, Garcia G, Higuchi-Sanabria R, Liu S, Yu B, Tu WB, Kennedy BK, Lyssiotis CA, Mullen PJ. Pilley SE, et al. bioRxiv [Preprint]. 2024 May 5:2024.05.04.592445. doi: 10.1101/2024.05.04.592445. bioRxiv. 2024. Update in: Cell Metab. 2026 Feb 3;38(2):399-418.e7. doi: 10.1016/j.cmet.2025.10.016. PMID: 38746230 Free PMC article. Updated. Preprint.

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A metabolic atlas of mouse aging

Affiliations

A metabolic atlas of mouse aging

Authors

Affiliations

Abstract

Conflict of interest statement

Update of

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Medical