Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice
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- Mikolaj Ogrodnik
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- Shane A. Evans
- Department of Molecular Biology, Cell Biology and Biochemistry Brown University Providence RI USA
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- Edward Fielder
- Biostatistics Consulting Center School of Public Health‐Bloomington Indiana University Bloomington IN USA
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- Stella Victorelli
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- Patrick Kruger
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- Hanna Salmonowicz
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- Bettina M. Weigand
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- Ayush D. Patel
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- Tamar Pirtskhalava
- Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA
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- Christine L. Inman
- Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA
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- Kurt O. Johnson
- Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA
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- Stephanie L. Dickinson
- Biostatistics Consulting Center School of Public Health‐Bloomington Indiana University Bloomington IN USA
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- Azucena Rocha
- Department of Molecular Biology, Cell Biology and Biochemistry Brown University Providence RI USA
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- Marissa J. Schafer
- Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA
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- Yi Zhu
- Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA
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- David B. Allison
- Biostatistics Consulting Center School of Public Health‐Bloomington Indiana University Bloomington IN USA
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- Thomas von Zglinicki
- Faculty of Medical Sciences Biosciences Institute Campus for Ageing and Vitality Newcastle University Newcastle upon Tyne UK
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- Nathan K. LeBrasseur
- Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA
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- Tamar Tchkonia
- Robert and Arlene Kogod Center on Aging Mayo Clinic Rochester MN USA
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- Nicola Neretti
- Department of Molecular Biology, Cell Biology and Biochemistry Brown University Providence RI USA
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- João F. Passos
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- James L. Kirkland
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
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- Diana Jurk
- Department of Physiology and Biomedical Engineering Mayo Clinic Rochester MN USA
説明
<jats:title>Abstract</jats:title><jats:p>Cellular senescence is characterized by an irreversible cell cycle arrest and a pro‐inflammatory senescence‐associated secretory phenotype (SASP), which is a major contributor to aging and age‐related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single‐nuclei and single‐cell RNA‐seq in the hippocampus from young and aged mice. We observed an age‐dependent increase in p16<jats:sup>Ink4a</jats:sup> senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged <jats:italic>INK</jats:italic>‐<jats:italic>ATTAC</jats:italic> mice, in which p16<jats:sup>Ink4a</jats:sup>‐positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16<jats:sup>Ink4a</jats:sup> exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof‐of‐concept for senolytic interventions' being a potential therapeutic avenue for alleviating age‐associated cognitive impairment.</jats:p>
収録刊行物
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- Aging Cell
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Aging Cell 20 (2), 2021-01-20
Wiley