Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice
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...
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| creator | Ogrodnik, Mikolaj Evans, Shane A. Fielder, Edward Victorelli, Stella Kruger, Patrick Salmonowicz, Hanna Weigand, Bettina M. Patel, Ayush D. Pirtskhalava, Tamar Inman, Christine L. Johnson, Kurt O. Dickinson, Stephanie L. Rocha, Azucena Schafer, Marissa J. Zhu, Yi Allison, David B. Zglinicki, Thomas LeBrasseur, Nathan K. Tchkonia, Tamar Neretti, Nicola Passos, João F. Kirkland, James L. Jurk, Diana |
| description | 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.
Senescence is a major contributor to aging and age‐related diseases. However, it is still unknown whether senolytics impact on cognitive function during the aging process. We found that both pharmacogenetic clearance of p16Ink4a senescent cells or treatment with senolytic cocktail Dasatinib and Quercetin, reduced senescent microglia in the hippocampus and improved cognitive function in aged mice. |
| doi_str_mv | 10.1111/acel.13296 |
| format | Article |
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Senescence is a major contributor to aging and age‐related diseases. However, it is still unknown whether senolytics impact on cognitive function during the aging process. We found that both pharmacogenetic clearance of p16Ink4a senescent cells or treatment with senolytic cocktail Dasatinib and Quercetin, reduced senescent microglia in the hippocampus and improved cognitive function in aged mice.</description><identifier>ISSN: 1474-9718</identifier><identifier>EISSN: 1474-9726</identifier><identifier>DOI: 10.1111/acel.13296</identifier><identifier>PMID: 33470505</identifier><language>eng</language><publisher>England: John Wiley & Sons, Inc</publisher><subject>Age ; Age Factors ; Aging ; Alzheimer's disease ; Amyotrophic lateral sclerosis ; Animal models ; Animals ; Apoptosis ; Brain ; Cell cycle ; Cellular Senescence ; cognition ; Cognitive ability ; Cognitive Dysfunction - metabolism ; Cognitive Dysfunction - pathology ; Cyclin-Dependent Kinase Inhibitor p16 - metabolism ; Cytokines ; Datasets ; Encephalitis - metabolism ; Encephalitis - pathology ; Glial stem cells ; Growth factors ; Inflammation ; INK4a protein ; memory ; Mice ; Mice, Transgenic ; Microglia ; Multiple sclerosis ; Nervous system diseases ; neurodegeneration ; Neurodegenerative diseases ; Original Paper ; Original Papers ; p16 Protein ; Parkinson's disease ; Phenotypes ; Population ; Progenitor cells ; Quercetin ; Ribonucleic acid ; RNA ; SASP ; Senescence ; senolytic ; telomeres</subject><ispartof>Aging cell, 2021-02, Vol.20 (2), p.e13296-n/a</ispartof><rights>2021 The Authors. published by the Anatomical Society and John Wiley & Sons Ltd.</rights><rights>2021 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.</rights><rights>COPYRIGHT 2021 John Wiley & Sons, Inc.</rights><rights>2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021. This article is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6096-cd74baa53fa02ec5cd884053fb6cb8193ea8cfdcde552b6db7af1e13e984f1c23</citedby><cites>FETCH-LOGICAL-c6096-cd74baa53fa02ec5cd884053fb6cb8193ea8cfdcde552b6db7af1e13e984f1c23</cites><orcidid>0000-0003-4486-0857</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884042/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884042/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1417,11562,27924,27925,45574,45575,46052,46476,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33470505$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ogrodnik, Mikolaj</creatorcontrib><creatorcontrib>Evans, Shane A.</creatorcontrib><creatorcontrib>Fielder, Edward</creatorcontrib><creatorcontrib>Victorelli, Stella</creatorcontrib><creatorcontrib>Kruger, Patrick</creatorcontrib><creatorcontrib>Salmonowicz, Hanna</creatorcontrib><creatorcontrib>Weigand, Bettina M.</creatorcontrib><creatorcontrib>Patel, Ayush D.</creatorcontrib><creatorcontrib>Pirtskhalava, Tamar</creatorcontrib><creatorcontrib>Inman, Christine L.</creatorcontrib><creatorcontrib>Johnson, Kurt O.</creatorcontrib><creatorcontrib>Dickinson, Stephanie L.</creatorcontrib><creatorcontrib>Rocha, Azucena</creatorcontrib><creatorcontrib>Schafer, Marissa J.</creatorcontrib><creatorcontrib>Zhu, Yi</creatorcontrib><creatorcontrib>Allison, David B.</creatorcontrib><creatorcontrib>Zglinicki, Thomas</creatorcontrib><creatorcontrib>LeBrasseur, Nathan K.</creatorcontrib><creatorcontrib>Tchkonia, Tamar</creatorcontrib><creatorcontrib>Neretti, Nicola</creatorcontrib><creatorcontrib>Passos, João F.</creatorcontrib><creatorcontrib>Kirkland, James L.</creatorcontrib><creatorcontrib>Jurk, Diana</creatorcontrib><title>Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice</title><title>Aging cell</title><addtitle>Aging Cell</addtitle><description>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.
Senescence is a major contributor to aging and age‐related diseases. However, it is still unknown whether senolytics impact on cognitive function during the aging process. We found that both pharmacogenetic clearance of p16Ink4a senescent cells or treatment with senolytic cocktail Dasatinib and Quercetin, reduced senescent microglia in the hippocampus and improved cognitive function in aged mice.</description><subject>Age</subject><subject>Age Factors</subject><subject>Aging</subject><subject>Alzheimer's disease</subject><subject>Amyotrophic lateral sclerosis</subject><subject>Animal models</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Brain</subject><subject>Cell cycle</subject><subject>Cellular Senescence</subject><subject>cognition</subject><subject>Cognitive ability</subject><subject>Cognitive Dysfunction - metabolism</subject><subject>Cognitive Dysfunction - pathology</subject><subject>Cyclin-Dependent Kinase Inhibitor p16 - metabolism</subject><subject>Cytokines</subject><subject>Datasets</subject><subject>Encephalitis - metabolism</subject><subject>Encephalitis - pathology</subject><subject>Glial stem cells</subject><subject>Growth factors</subject><subject>Inflammation</subject><subject>INK4a protein</subject><subject>memory</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Microglia</subject><subject>Multiple sclerosis</subject><subject>Nervous system diseases</subject><subject>neurodegeneration</subject><subject>Neurodegenerative diseases</subject><subject>Original Paper</subject><subject>Original Papers</subject><subject>p16 Protein</subject><subject>Parkinson's disease</subject><subject>Phenotypes</subject><subject>Population</subject><subject>Progenitor cells</subject><subject>Quercetin</subject><subject>Ribonucleic 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cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ogrodnik, Mikolaj</au><au>Evans, Shane A.</au><au>Fielder, Edward</au><au>Victorelli, Stella</au><au>Kruger, Patrick</au><au>Salmonowicz, Hanna</au><au>Weigand, Bettina M.</au><au>Patel, Ayush D.</au><au>Pirtskhalava, Tamar</au><au>Inman, Christine L.</au><au>Johnson, Kurt O.</au><au>Dickinson, Stephanie L.</au><au>Rocha, Azucena</au><au>Schafer, Marissa J.</au><au>Zhu, Yi</au><au>Allison, David B.</au><au>Zglinicki, Thomas</au><au>LeBrasseur, Nathan K.</au><au>Tchkonia, Tamar</au><au>Neretti, Nicola</au><au>Passos, João F.</au><au>Kirkland, James L.</au><au>Jurk, Diana</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice</atitle><jtitle>Aging cell</jtitle><addtitle>Aging Cell</addtitle><date>2021-02</date><risdate>2021</risdate><volume>20</volume><issue>2</issue><spage>e13296</spage><epage>n/a</epage><pages>e13296-n/a</pages><issn>1474-9718</issn><eissn>1474-9726</eissn><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.
Senescence is a major contributor to aging and age‐related diseases. However, it is still unknown whether senolytics impact on cognitive function during the aging process. We found that both pharmacogenetic clearance of p16Ink4a senescent cells or treatment with senolytic cocktail Dasatinib and Quercetin, reduced senescent microglia in the hippocampus and improved cognitive function in aged mice.</abstract><cop>England</cop><pub>John Wiley & Sons, Inc</pub><pmid>33470505</pmid><doi>10.1111/acel.13296</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0003-4486-0857</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Aging cell, 2021-02, Vol.20 (2), p.e13296-n/a |
| issn | 1474-9718 1474-9726 |
| language | eng |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Access via Wiley Online Library; Wiley Online Library Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Age Age Factors Aging Alzheimer's disease Amyotrophic lateral sclerosis Animal models Animals Apoptosis Brain Cell cycle Cellular Senescence cognition Cognitive ability Cognitive Dysfunction - metabolism Cognitive Dysfunction - pathology Cyclin-Dependent Kinase Inhibitor p16 - metabolism Cytokines Datasets Encephalitis - metabolism Encephalitis - pathology Glial stem cells Growth factors Inflammation INK4a protein memory Mice Mice, Transgenic Microglia Multiple sclerosis Nervous system diseases neurodegeneration Neurodegenerative diseases Original Paper Original Papers p16 Protein Parkinson's disease Phenotypes Population Progenitor cells Quercetin Ribonucleic acid RNA SASP Senescence senolytic telomeres |
| title | Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice |
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