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

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 +11 more·2022·Nature Neuroscience

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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Crossref · 10.1038/s41593-022-01027-3

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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
Venue
Nature Neuroscience
Published
2022-03
Volume
25
Issue
3
Pages
295-305
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
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
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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