Cited by 241Neuroinflammation and Neurodegeneration MechanismsGut microbiota and healthGenetics, Aging, and Longevity in Model Organisms

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Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine

Mossad, Omar, Batut, Bérénice, Yilmaz, Bahtiyar, Dokalis, Nikolaos, Mezö, Charlotte, Nent, Elisa, Nabavi, Lara Susann, Mayer, Melanie, Maron, Feres José Mocayar, Buescher, Joerg M., de Agüero, Mercedes Gomez, Szalay, Antal, Lämmermann, Tim, Macpherson, Andrew J., Ganal-Vonarburg, Stephanie C., Backofen, Rolf, Erny, Daniel, Prinz, Marco, Blank, Thomas·2022·Nature Neuroscience

DOI 10.1038/s41593-022-01027-3

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Abstract

Microglial function declines during aging. The interaction of microglia with the gut microbiota has been well characterized during development and adulthood but not in aging. Here, we compared microglial transcriptomes from young-adult and aged mice housed under germ-free and specific pathogen-free conditions and found that the microbiota influenced aging associated-changes in microglial gene expression. The absence of gut microbiota diminished oxidative stress and ameliorated mitochondrial dysfunction in microglia from the brains of aged mice. Unbiased metabolomic analyses of serum and brain tissue revealed the accumulation of N 6-carboxymethyllysine (CML) in the microglia of the aging brain. CML mediated a burst of reactive oxygen species and impeded mitochondrial activity and ATP reservoirs in microglia. We validated the age-dependent rise in CML levels in the sera and brains of humans. Finally, a microbiota-dependent increase in intestinal permeability in aged mice mediated the elevated levels of CML. This study adds insight into how specific features of microglia from aged mice are regulated by the gut microbiota.

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Authors: Mossad, O., Batut, B., Yilmaz, B., Dokalis, N., Mezö, C., Nent, E., Nabavi, L. S., Mayer, M., Maron, F. J. M., Buescher, J. M., de Agüero, M. G., Szalay, A., Lämmermann, T., Macpherson, A. J., Ganal-Vonarburg, S. C., Backofen, R., Erny, D., Prinz, M., & Blank, T.
Affiliations: University of Freiburg (DE)
Max Planck Institute of Immunobiology and Epigenetics (DE)
University of Bern (CH)
Corresponding author: Blank, Thomas
ORCID: Mossad, Omar
Batut, Bérénice
Yilmaz, Bahtiyar
Dokalis, Nikolaos
Nent, Elisa
Buescher, Joerg M.
Lämmermann, Tim
Macpherson, Andrew J.
Ganal-Vonarburg, Stephanie C.
Backofen, Rolf
Erny, Daniel
Prinz, Marco
Blank, Thomas
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2022-03
Volume: 25
Issue: 3
Pages: 295-305
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/s41593-022-01027-3
OpenAlex: W4214818594
Cited by: 241
References: 63
Citations by year: 2026: 41 · 2025: 64 · 2024: 64 · 2023: 45 · 2022: 27
FWCI: 17.55
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
HAL (submittedVersion)
Bern Open Repository and Information System (University of Bern) (submittedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords: gut microbiota, microglia, aging, oxidative stress, mitochondrial dysfunction, advanced glycation end products, germ-free mice, intestinal permeability, reactive oxygen species, ATP metabolism, brain aging, metabolomics
MeSH terms: Gastrointestinal Microbiome, Animals, Lysine, Microglia, Oxidative Stress, Mice

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Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine

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