@article{d1596ca06a4843c58603dbe204c8c4b3,
title = "Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice",
abstract = "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 p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a-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 p16Ink4a 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.",
keywords = "SASP, aging, brain, cognition, memory, neurodegeneration, senescence, senolytic, telomeres",
author = "Mikolaj Ogrodnik and Evans, {Shane A.} and Edward Fielder and Stella Victorelli and Patrick Kruger and Hanna Salmonowicz and Weigand, {Bettina M.} and Patel, {Ayush D.} and Tamar Pirtskhalava and Inman, {Christine L.} and Johnson, {Kurt O.} and Dickinson, {Stephanie L.} and Azucena Rocha and Schafer, {Marissa J.} and Yi Zhu and Allison, {David B.} and {von Zglinicki}, Thomas and LeBrasseur, {Nathan K.} and Tamar Tchkonia and Nicola Neretti and Passos, {Jo{\~a}o F.} and Kirkland, {James L.} and Diana Jurk",
note = "Funding Information: This research was conducted while M.O. was a Glenn Foundation for Medical Research Postdoctoral Fellow. J.F.P{\textquoteright}s lab was supported by NIA R01 AG069048, UL1 TR0002377 from the National Center for Advancing Translational Sciences (NCATS), the Biotechnology and Biological Sciences Research Council (BBSRC) grants (BB/H022384/1 and BB/K017314/1) and the Ted Nash long life Foundation. D.J. was funded by the Academy of Medical Sciences (SBF003_1179), NIA R01 AG068182‐01, NIA R01 AG062413‐02S1. J.L.K., T.P., C.L.I., K.O.J., Y.Z., and T.T. were supported by R37 AG013925, P01 AG062413, the Connor Group, Robert J. and Theresa W. Ryan, and the Noaber Foundation. The N.N. lab was partially supported by IDeA grant P20GM109035 (Center for Computational Biology of Human Disease) from NIH NIGMS and grant 1R01AG050582‐01A1 from NIH NIA. We would like to thank Ashley Webb and Kaitlyn Hajdarovic for their help with the collection of the hippocampus samples for single‐cell RNA‐seq. The IU statistician was supported in part by NIH grants P30AG050886 and U24AG056053. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or any other organization. Publisher Copyright: {\textcopyright} 2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.",
year = "2021",
month = feb,
doi = "10.1111/acel.13296",
language = "English (US)",
volume = "20",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "2",
}