The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N6-carboxymethyllysine
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Microbiome-mediated disruption of the intestinal barrier during aging facilitates excessive translocation of N6-carboxymethyllysine across the intestinal mucosal barrier into the bloodstream.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [404]
In the citing paper
“This increased translocation results in the accumulation of N6-carboxymethyllysine in the brain, which in turn contributes to microglial dysfunction by inducing oxidative stress and mitochondrial dysfunction.”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [404]
In the citing paper
“N6-carboxymethyllysine may promote mitochondrial impairment and oxidative stress in microglia [69]”
From Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway (2023) · cites this paper as [69]
In the citing paper
“Reduced oxidative stress and improved mitochondrial dysfunction were recently reported in the brain microglia of old GF mice compared to their SPF counterparts46.”
From Cellular senescence in white matter microglia is induced during ageing in mice and exacerbates the neuroinflammatory phenotype (2023) · cites this paper as [46]
Citations
Cites
QIIME allows analysis of high-throughput community sequencing data
Caporaso, J. G., Kuczynski, J., Stombaugh, J., Bittinger, K., Bushman, F. D., Costello, E. K., Fierer, N., Peña, A. G., Goodrich, J. K., Gordon, J. I., et al. (2010) · Nature Methods · doi:10.1038/nmeth.f.303 · Cited by 34,887
WGCNA: an R package for weighted correlation network analysis
Langfelder, P., & Horvath, S. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-559 · Cited by 27,252
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013) · Cell · doi:10.1016/j.cell.2013.05.039 · Cited by 14,982
Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders
Baker, D. J., Wijshake, T., Tchkonia, T., LeBrasseur, N. K., Childs, B. G., van de Sluis, B., Kirkland, J. L., & van Deursen, J. M. (2011) · Nature · doi:10.1038/nature10600 · Cited by 3,670
The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2018 update
Afgan, E., Baker, D., Batut, B., van den Beek, M., Bouvier, D., Čech, M., Chilton, J., Clements, D., Coraor, N., Grüning, B. A., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky379 · Cited by 3,662
Self-citationHost microbiota constantly control maturation and function of microglia in the CNS
Erny, D., Hrabě de Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., Keren-Shaul, H., Mahlakoiv, T., Jakobshagen, K., Buch, T., et al. (2015) · Nature Neuroscience · doi:10.1038/nn.4030 · Cited by 3,569
Self-citationHammond, T. R., Dufort, C., Dissing-Olesen, L., Giera, S., Young, A., Wysoker, A., Walker, A. J., Segel, M., Nemesh, J., Saunders, A., et al. (2018) · doi:10.1101/406140 · Cited by 2,225
The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update
Afgan, E., Baker, D., van den Beek, M., Blankenberg, D. J., Bouvier, D., Čech, M., Chilton, J. M., Clements, D., Coraor, N., Eberhard, C., et al. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw343 · Cited by 2,150
HIF-1α is essential for myeloid cell-mediated inflammation
Cramer, T., Yamanishi, Y., Clausen, B. E., Förster, I., Pawlinski, R., Mackman, N., Haase, V. H., Jaenisch, R., Corr, M., Nizet, V., et al. (2003) · Cell · doi:10.1016/s0092-8674(03)00154-5 · Cited by 2,046
The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age
Mariat, D., Firmesse, O., Levenez, F., Guimarăes, V., Sokol, H., Doré, J., Corthier, G., & Furet, J.-P. (2009) · BMC Microbiology · doi:10.1186/1471-2180-9-123 · Cited by 1,755
Cited by
Sorted by citations
Aging and aging-related diseases: from molecular mechanisms to interventions and treatments
Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., & Li, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01251-0 · Cited by 1,976
Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193
Microbiota-derived metabolites as drivers of gut–brain communication
Ahmed, H., Leyrolle, Q., Koistinen, V., Kärkkäinen, O., Layé, S., Delzenne, N., & Hanhineva, K. (2022) · Gut Microbes · doi:10.1080/19490976.2022.2102878 · Cited by 462
The microbiota–gut–brain axis and neurodevelopmental disorders
Wang, Q., Yang, Q., & Liu, X. (2023) · Protein & Cell · doi:10.1093/procel/pwad026 · Cited by 429
The gut microbiota-immune-brain axis: therapeutic implications
O’Riordan, K. J., Moloney, G. M., Keane, L., Clarke, G., & Cryan, J. F. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.101982 · Cited by 333
Metadata
- 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
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
