Tet2 Rescues Age-Related Regenerative Decline and Enhances Cognitive Function in the Adult Mouse Brain
Open accessAbstract
Restoring adult stem cell function provides an exciting approach for rejuvenating the aging brain. However, molecular mechanisms mediating neurogenic rejuvenation remain elusive. Here we report that the enzyme ten eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes the production of 5-hydroxymethylcytosine (5hmC), rescues age-related decline in adult neurogenesis and enhances cognition in mice. We detected a decrease in Tet2 expression and 5hmC levels in the aged hippocampus associated with adult neurogenesis. Mimicking an aged condition in young adults by abrogating Tet2 expression within the hippocampal neurogenic niche, or adult neural stem cells, decreased neurogenesis and impaired learning and memory. In a heterochronic parabiosis rejuvenation model, hippocampal Tet2 expression was restored. Overexpressing Tet2 in the hippocampal neurogenic niche of mature adults increased 5hmC associated with neurogenic processes, offset the precipitous age-related decline in neurogenesis, and enhanced learning and memory. Our data identify Tet2 as a key molecular mediator of neurogenic rejuvenation.
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In the brain, expression of TET2 decreases during ageing in the hippocampal neurogenic niche, and Tet2 knockout mimics aspects of ageing, whereas its overexpression prevents the decline in neuronal differentiation during ageing.
“In the brain, expression of TET2, the enzyme responsible for the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, decreases during ageing in the hippocampal neurogenic niche97, and Tet2 knockout mimics aspects of ageing, whereas its overexpression prevents the decline in neuronal differentiation during ageing97.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [97]
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- Authors
- Gontier, G., Iyer, M., Shea, J. M., Bieri, G., Wheatley, E. G., Ramalho-Santos, M., & Villeda, S. A.
- Affiliations
- University of California, San Francisco (US)
- Corresponding author
- Villeda, Saul A.
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 22
- Issue
- 8
- Pages
- 1974-1981
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5870899
- OpenAlex
- W2788319686
- Cited by
- 197
- References
- 27
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 29 · 2023: 24 · 2022: 23 · 2021: 29 · 2020: 27 · 2019: 20 · 2018: 7
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (acceptedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- American Federation for Aging Research
- Glenn Foundation for Medical Research
- National Institute on Aging (R01 AG055797, R01 AG053382)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- TET2, 5-hydroxymethylcytosine, adult neurogenesis, brain aging, hippocampus, adult neural stem cells, learning and memory, cognitive function, heterochronic parabiosis, epigenetic regulation
- MeSH terms
- Aging, Animals, Brain, Cognition, DNA-Binding Proteins, Male, Mice, Inbred C57BL, Nerve Regeneration, Parabiosis, Proto-Oncogene Proteins, Dentate Gyrus, Models, Animal, 5-Methylcytosine, Dioxygenases, Neurogenesis, Neural Stem Cells
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