Age-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation
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Significance: Depletion of the neural stem cell (NSC) pool is a major driver of age-related regenerative decline in the hippocampus. While increased quiescence is a major contributor to this decline, NSCs can also undergo terminal differentiation into astrocytes, thus restricting the stem cell pool. The mechanisms underlying this fate switch and their relation to age-related regenerative decline have not yet been fully elucidated. In this study, we report an age-related decline in NSC O-GlcNAcylation, coincident with reduced neurogenesis and increased gliogenesis. We identify loss of O-GlcNAcylation at STAT3 T717 in the hippocampus with age, and demonstrate that O-GlcNAcylation of this site is a critical determinant of NSC fate. Our work expands our understanding of how posttranslational modifications influence the aging brain.
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In the brain, old progenitors exhibit reduced differentiation dynamics during ageing, and their fate potential is predominantly skewed towards astrocytes.
“In the brain, old progenitors exhibit reduced differentiation dynamics during ageing45, and their fate potential is predominantly skewed towards astrocytes46.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [46]
STAT3 is modified by O-linked β-N-acetylglucosamine, and this post-translational modification is lost during ageing, contributing to the ageing-dependent bias towards glia.
“STAT3 is modified by O-linked β-N-acetylglucosamine, and this post-translational modification is lost during ageing, contributing to the ageing-dependent bias towards glia46.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [46]
STAT3, a transcription factor activated by inflammatory cytokines, is at least in part responsible for NSC differentiation being biased towards glial cells (rather than neurons) during ageing.
“STAT3 — a transcription factor activated by inflammatory cytokines — is at least in part responsible for NSC differentiation being biased towards glial cells (rather than neurons) during ageing46,94.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [46]
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- Authors
- White, C. W., Fan, X., Maynard, J. C., Wheatley, E. G., Bieri, G., Couthouis, J., Burlingame, A. L., & Villeda, S. A.
- Affiliations
- University of California, San Francisco (US)
- Stanford Medicine (US)
- Corresponding author
- Villeda, Saul A.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2020-08-26
- Volume
- 117
- Issue
- 36
- Pages
- 22214-22224
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC7486730
- OpenAlex
- W3080531673
- Cited by
- 98
- References
- 48
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 12 · 2023: 26 · 2022: 17 · 2021: 15
- FWCI
- 6.10
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute (NA)
- HHS | NIH | National Institute of General Medical Sciences (8P41GM103481)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (NA)
- HHS | National Institutes of Health (F31-AG050415)
- HHS | NIH | National Institute on Aging (R01 AG055797, RF1 AG062357)
- Marc and Lynne Benioff (NA)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- O-GlcNAc, neural stem cells, aging, STAT3, astrocyte differentiation, neurogenesis, gliogenesis, hippocampus, post-translational modification, cognitive decline
- MeSH terms
- Aging, Animals, Cell Differentiation, Gene Expression Regulation, Glucosamine, Hippocampus, Neuroglia, Sequence Analysis, RNA, Computational Biology, Cell Proliferation, STAT3 Transcription Factor, Mice, Neurogenesis, Neural Stem Cells
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