Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders
Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 ( ) as an essential gene for the survival of human senescent cells. The i...
Gespeichert in:
| Veröffentlicht in: | Science (American Association for the Advancement of Science) 2021-01, Vol.371 (6526), p.265-270 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 270 |
|---|---|
| container_issue | 6526 |
| container_start_page | 265 |
| container_title | Science (American Association for the Advancement of Science) |
| container_volume | 371 |
| creator | Johmura, Yoshikazu Yamanaka, Takehiro Omori, Satotaka Wang, Teh-Wei Sugiura, Yuki Matsumoto, Masaki Suzuki, Narumi Kumamoto, Soichiro Yamaguchi, Kiyoshi Hatakeyama, Seira Takami, Tomoyo Yamaguchi, Rui Shimizu, Eigo Ikeda, Kazutaka Okahashi, Nobuyuki Mikawa, Ryuta Suematsu, Makoto Arita, Makoto Sugimoto, Masataka Nakayama, Keiichi I Furukawa, Yoichi Imoto, Seiya Nakanishi, Makoto |
| description | Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (
) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo. |
| doi_str_mv | 10.1126/science.abb5916 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2478596957</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2478596957</sourcerecordid><originalsourceid>FETCH-LOGICAL-c391t-35b5d2a0e4325af4977a115a8c91e6a4bb1a004d2d9651c64ea4cb1b6cfc06063</originalsourceid><addsrcrecordid>eNpdkD1PwzAQhi0EoqUws6FILCxp7fgj9YgqvqRKDIU5OjtOcZXExZcg9d8TaMvAdNJ7z706PYRcMzplLFMztN611k3BGKmZOiFjRrVMdUb5KRlTylU6p7kckQvEDaXDTvNzMuJcCCVlNiarlWtDvUOPidkl67rvoPHHxLcf3vjOhzaBxtU-ROgcJl8QfegxgbVLATFYP8RlUnoMsXQRL8lZBTW6q8OckPfHh7fFc7p8fXpZ3C9TyzXrUi6NLDOgTvBMQiV0ngNjEuZWM6dAGMOAUlFmpVaSWSUcCGuYUbayVFHFJ-Ru37uN4bN32BWNR-vqGlo3_FdkIp9LrbTMB_T2H7oJfWyH734pqnmW64Ga7SkbA2J0VbGNvoG4KxgtfnwXB9_FwfdwcXPo7U3jyj_-KJh_A9DKfyI</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2478093279</pqid></control><display><type>article</type><title>Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders</title><source>MEDLINE</source><source>Science Magazine</source><creator>Johmura, Yoshikazu ; Yamanaka, Takehiro ; Omori, Satotaka ; Wang, Teh-Wei ; Sugiura, Yuki ; Matsumoto, Masaki ; Suzuki, Narumi ; Kumamoto, Soichiro ; Yamaguchi, Kiyoshi ; Hatakeyama, Seira ; Takami, Tomoyo ; Yamaguchi, Rui ; Shimizu, Eigo ; Ikeda, Kazutaka ; Okahashi, Nobuyuki ; Mikawa, Ryuta ; Suematsu, Makoto ; Arita, Makoto ; Sugimoto, Masataka ; Nakayama, Keiichi I ; Furukawa, Yoichi ; Imoto, Seiya ; Nakanishi, Makoto</creator><creatorcontrib>Johmura, Yoshikazu ; Yamanaka, Takehiro ; Omori, Satotaka ; Wang, Teh-Wei ; Sugiura, Yuki ; Matsumoto, Masaki ; Suzuki, Narumi ; Kumamoto, Soichiro ; Yamaguchi, Kiyoshi ; Hatakeyama, Seira ; Takami, Tomoyo ; Yamaguchi, Rui ; Shimizu, Eigo ; Ikeda, Kazutaka ; Okahashi, Nobuyuki ; Mikawa, Ryuta ; Suematsu, Makoto ; Arita, Makoto ; Sugimoto, Masataka ; Nakayama, Keiichi I ; Furukawa, Yoichi ; Imoto, Seiya ; Nakanishi, Makoto</creatorcontrib><description>Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (
) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.</description><identifier>ISSN: 0036-8075</identifier><identifier>EISSN: 1095-9203</identifier><identifier>DOI: 10.1126/science.abb5916</identifier><identifier>PMID: 33446552</identifier><language>eng</language><publisher>United States: The American Association for the Advancement of Science</publisher><subject>Adipose Tissue - enzymology ; Age ; Aging ; Aging - genetics ; Aging - metabolism ; Ammonia ; Ammonia - metabolism ; Animal models ; Animals ; Cell death ; Cell Survival ; Cellular Senescence - genetics ; Cellular Senescence - physiology ; Disorders ; Genes, Essential ; Glutaminase ; Glutaminase - genetics ; Glutaminase - metabolism ; Glutamine ; Humans ; Hydrogen-Ion Concentration ; Inhibition ; Kidneys ; Lung - enzymology ; Male ; Metabolism ; Mice ; Mice, Inbred C57BL ; Obesity ; pH effects ; RNA-mediated interference ; Skin - enzymology ; Survival</subject><ispartof>Science (American Association for the Advancement of Science), 2021-01, Vol.371 (6526), p.265-270</ispartof><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.</rights><rights>Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c391t-35b5d2a0e4325af4977a115a8c91e6a4bb1a004d2d9651c64ea4cb1b6cfc06063</citedby><cites>FETCH-LOGICAL-c391t-35b5d2a0e4325af4977a115a8c91e6a4bb1a004d2d9651c64ea4cb1b6cfc06063</cites><orcidid>0000-0002-5726-3317 ; 0000-0002-7165-6336 ; 0000-0003-3714-2697 ; 0000-0002-0423-7289 ; 0000-0001-9902-0463 ; 0000-0002-6983-8958 ; 0000-0002-7185-1529 ; 0000-0002-3492-117X ; 0000-0003-2113-4369 ; 0000-0003-0462-8631 ; 0000-0001-9874-2392 ; 0000-0002-6974-8119 ; 0000-0002-2989-308X ; 0000-0001-9247-4593 ; 0000-0001-8737-8097 ; 0000-0002-6707-3584 ; 0000-0001-9582-355X ; 0000-0002-6987-0288 ; 0000-0001-6024-9949 ; 0000-0002-2486-2321 ; 0000-0003-0006-9051 ; 0000-0002-6812-9607 ; 0000-0003-1224-227X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,2871,2872,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33446552$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Johmura, Yoshikazu</creatorcontrib><creatorcontrib>Yamanaka, Takehiro</creatorcontrib><creatorcontrib>Omori, Satotaka</creatorcontrib><creatorcontrib>Wang, Teh-Wei</creatorcontrib><creatorcontrib>Sugiura, Yuki</creatorcontrib><creatorcontrib>Matsumoto, Masaki</creatorcontrib><creatorcontrib>Suzuki, Narumi</creatorcontrib><creatorcontrib>Kumamoto, Soichiro</creatorcontrib><creatorcontrib>Yamaguchi, Kiyoshi</creatorcontrib><creatorcontrib>Hatakeyama, Seira</creatorcontrib><creatorcontrib>Takami, Tomoyo</creatorcontrib><creatorcontrib>Yamaguchi, Rui</creatorcontrib><creatorcontrib>Shimizu, Eigo</creatorcontrib><creatorcontrib>Ikeda, Kazutaka</creatorcontrib><creatorcontrib>Okahashi, Nobuyuki</creatorcontrib><creatorcontrib>Mikawa, Ryuta</creatorcontrib><creatorcontrib>Suematsu, Makoto</creatorcontrib><creatorcontrib>Arita, Makoto</creatorcontrib><creatorcontrib>Sugimoto, Masataka</creatorcontrib><creatorcontrib>Nakayama, Keiichi I</creatorcontrib><creatorcontrib>Furukawa, Yoichi</creatorcontrib><creatorcontrib>Imoto, Seiya</creatorcontrib><creatorcontrib>Nakanishi, Makoto</creatorcontrib><title>Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders</title><title>Science (American Association for the Advancement of Science)</title><addtitle>Science</addtitle><description>Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (
) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.</description><subject>Adipose Tissue - enzymology</subject><subject>Age</subject><subject>Aging</subject><subject>Aging - genetics</subject><subject>Aging - metabolism</subject><subject>Ammonia</subject><subject>Ammonia - metabolism</subject><subject>Animal models</subject><subject>Animals</subject><subject>Cell death</subject><subject>Cell Survival</subject><subject>Cellular Senescence - genetics</subject><subject>Cellular Senescence - physiology</subject><subject>Disorders</subject><subject>Genes, Essential</subject><subject>Glutaminase</subject><subject>Glutaminase - genetics</subject><subject>Glutaminase - metabolism</subject><subject>Glutamine</subject><subject>Humans</subject><subject>Hydrogen-Ion Concentration</subject><subject>Inhibition</subject><subject>Kidneys</subject><subject>Lung - enzymology</subject><subject>Male</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Obesity</subject><subject>pH effects</subject><subject>RNA-mediated interference</subject><subject>Skin - enzymology</subject><subject>Survival</subject><issn>0036-8075</issn><issn>1095-9203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkD1PwzAQhi0EoqUws6FILCxp7fgj9YgqvqRKDIU5OjtOcZXExZcg9d8TaMvAdNJ7z706PYRcMzplLFMztN611k3BGKmZOiFjRrVMdUb5KRlTylU6p7kckQvEDaXDTvNzMuJcCCVlNiarlWtDvUOPidkl67rvoPHHxLcf3vjOhzaBxtU-ROgcJl8QfegxgbVLATFYP8RlUnoMsXQRL8lZBTW6q8OckPfHh7fFc7p8fXpZ3C9TyzXrUi6NLDOgTvBMQiV0ngNjEuZWM6dAGMOAUlFmpVaSWSUcCGuYUbayVFHFJ-Ru37uN4bN32BWNR-vqGlo3_FdkIp9LrbTMB_T2H7oJfWyH734pqnmW64Ga7SkbA2J0VbGNvoG4KxgtfnwXB9_FwfdwcXPo7U3jyj_-KJh_A9DKfyI</recordid><startdate>20210115</startdate><enddate>20210115</enddate><creator>Johmura, Yoshikazu</creator><creator>Yamanaka, Takehiro</creator><creator>Omori, Satotaka</creator><creator>Wang, Teh-Wei</creator><creator>Sugiura, Yuki</creator><creator>Matsumoto, Masaki</creator><creator>Suzuki, Narumi</creator><creator>Kumamoto, Soichiro</creator><creator>Yamaguchi, Kiyoshi</creator><creator>Hatakeyama, Seira</creator><creator>Takami, Tomoyo</creator><creator>Yamaguchi, Rui</creator><creator>Shimizu, Eigo</creator><creator>Ikeda, Kazutaka</creator><creator>Okahashi, Nobuyuki</creator><creator>Mikawa, Ryuta</creator><creator>Suematsu, Makoto</creator><creator>Arita, Makoto</creator><creator>Sugimoto, Masataka</creator><creator>Nakayama, Keiichi I</creator><creator>Furukawa, Yoichi</creator><creator>Imoto, Seiya</creator><creator>Nakanishi, Makoto</creator><general>The American Association for the Advancement of Science</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QF</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QQ</scope><scope>7QR</scope><scope>7SC</scope><scope>7SE</scope><scope>7SN</scope><scope>7SP</scope><scope>7SR</scope><scope>7SS</scope><scope>7T7</scope><scope>7TA</scope><scope>7TB</scope><scope>7TK</scope><scope>7TM</scope><scope>7U5</scope><scope>7U9</scope><scope>8BQ</scope><scope>8FD</scope><scope>C1K</scope><scope>F28</scope><scope>FR3</scope><scope>H8D</scope><scope>H8G</scope><scope>H94</scope><scope>JG9</scope><scope>JQ2</scope><scope>K9.</scope><scope>KR7</scope><scope>L7M</scope><scope>L~C</scope><scope>L~D</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-5726-3317</orcidid><orcidid>https://orcid.org/0000-0002-7165-6336</orcidid><orcidid>https://orcid.org/0000-0003-3714-2697</orcidid><orcidid>https://orcid.org/0000-0002-0423-7289</orcidid><orcidid>https://orcid.org/0000-0001-9902-0463</orcidid><orcidid>https://orcid.org/0000-0002-6983-8958</orcidid><orcidid>https://orcid.org/0000-0002-7185-1529</orcidid><orcidid>https://orcid.org/0000-0002-3492-117X</orcidid><orcidid>https://orcid.org/0000-0003-2113-4369</orcidid><orcidid>https://orcid.org/0000-0003-0462-8631</orcidid><orcidid>https://orcid.org/0000-0001-9874-2392</orcidid><orcidid>https://orcid.org/0000-0002-6974-8119</orcidid><orcidid>https://orcid.org/0000-0002-2989-308X</orcidid><orcidid>https://orcid.org/0000-0001-9247-4593</orcidid><orcidid>https://orcid.org/0000-0001-8737-8097</orcidid><orcidid>https://orcid.org/0000-0002-6707-3584</orcidid><orcidid>https://orcid.org/0000-0001-9582-355X</orcidid><orcidid>https://orcid.org/0000-0002-6987-0288</orcidid><orcidid>https://orcid.org/0000-0001-6024-9949</orcidid><orcidid>https://orcid.org/0000-0002-2486-2321</orcidid><orcidid>https://orcid.org/0000-0003-0006-9051</orcidid><orcidid>https://orcid.org/0000-0002-6812-9607</orcidid><orcidid>https://orcid.org/0000-0003-1224-227X</orcidid></search><sort><creationdate>20210115</creationdate><title>Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders</title><author>Johmura, Yoshikazu ; Yamanaka, Takehiro ; Omori, Satotaka ; Wang, Teh-Wei ; Sugiura, Yuki ; Matsumoto, Masaki ; Suzuki, Narumi ; Kumamoto, Soichiro ; Yamaguchi, Kiyoshi ; Hatakeyama, Seira ; Takami, Tomoyo ; Yamaguchi, Rui ; Shimizu, Eigo ; Ikeda, Kazutaka ; Okahashi, Nobuyuki ; Mikawa, Ryuta ; Suematsu, Makoto ; Arita, Makoto ; Sugimoto, Masataka ; Nakayama, Keiichi I ; Furukawa, Yoichi ; Imoto, Seiya ; Nakanishi, Makoto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c391t-35b5d2a0e4325af4977a115a8c91e6a4bb1a004d2d9651c64ea4cb1b6cfc06063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adipose Tissue - enzymology</topic><topic>Age</topic><topic>Aging</topic><topic>Aging - genetics</topic><topic>Aging - metabolism</topic><topic>Ammonia</topic><topic>Ammonia - metabolism</topic><topic>Animal models</topic><topic>Animals</topic><topic>Cell death</topic><topic>Cell Survival</topic><topic>Cellular Senescence - genetics</topic><topic>Cellular Senescence - physiology</topic><topic>Disorders</topic><topic>Genes, Essential</topic><topic>Glutaminase</topic><topic>Glutaminase - genetics</topic><topic>Glutaminase - metabolism</topic><topic>Glutamine</topic><topic>Humans</topic><topic>Hydrogen-Ion Concentration</topic><topic>Inhibition</topic><topic>Kidneys</topic><topic>Lung - enzymology</topic><topic>Male</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Obesity</topic><topic>pH effects</topic><topic>RNA-mediated interference</topic><topic>Skin - enzymology</topic><topic>Survival</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Johmura, Yoshikazu</creatorcontrib><creatorcontrib>Yamanaka, Takehiro</creatorcontrib><creatorcontrib>Omori, Satotaka</creatorcontrib><creatorcontrib>Wang, Teh-Wei</creatorcontrib><creatorcontrib>Sugiura, Yuki</creatorcontrib><creatorcontrib>Matsumoto, Masaki</creatorcontrib><creatorcontrib>Suzuki, Narumi</creatorcontrib><creatorcontrib>Kumamoto, Soichiro</creatorcontrib><creatorcontrib>Yamaguchi, Kiyoshi</creatorcontrib><creatorcontrib>Hatakeyama, Seira</creatorcontrib><creatorcontrib>Takami, Tomoyo</creatorcontrib><creatorcontrib>Yamaguchi, Rui</creatorcontrib><creatorcontrib>Shimizu, Eigo</creatorcontrib><creatorcontrib>Ikeda, Kazutaka</creatorcontrib><creatorcontrib>Okahashi, Nobuyuki</creatorcontrib><creatorcontrib>Mikawa, Ryuta</creatorcontrib><creatorcontrib>Suematsu, Makoto</creatorcontrib><creatorcontrib>Arita, Makoto</creatorcontrib><creatorcontrib>Sugimoto, Masataka</creatorcontrib><creatorcontrib>Nakayama, Keiichi I</creatorcontrib><creatorcontrib>Furukawa, Yoichi</creatorcontrib><creatorcontrib>Imoto, Seiya</creatorcontrib><creatorcontrib>Nakanishi, Makoto</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Aluminium Industry Abstracts</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Ceramic Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Computer and Information Systems Abstracts</collection><collection>Corrosion Abstracts</collection><collection>Ecology Abstracts</collection><collection>Electronics & Communications Abstracts</collection><collection>Engineered Materials Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Materials Business File</collection><collection>Mechanical & Transportation Engineering Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Solid State and Superconductivity Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>METADEX</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ANTE: Abstracts in New Technology & Engineering</collection><collection>Engineering Research Database</collection><collection>Aerospace Database</collection><collection>Copper Technical Reference Library</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Materials Research Database</collection><collection>ProQuest Computer Science Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Civil Engineering Abstracts</collection><collection>Advanced Technologies Database with Aerospace</collection><collection>Computer and Information Systems Abstracts Academic</collection><collection>Computer and Information Systems Abstracts Professional</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Science (American Association for the Advancement of Science)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Johmura, Yoshikazu</au><au>Yamanaka, Takehiro</au><au>Omori, Satotaka</au><au>Wang, Teh-Wei</au><au>Sugiura, Yuki</au><au>Matsumoto, Masaki</au><au>Suzuki, Narumi</au><au>Kumamoto, Soichiro</au><au>Yamaguchi, Kiyoshi</au><au>Hatakeyama, Seira</au><au>Takami, Tomoyo</au><au>Yamaguchi, Rui</au><au>Shimizu, Eigo</au><au>Ikeda, Kazutaka</au><au>Okahashi, Nobuyuki</au><au>Mikawa, Ryuta</au><au>Suematsu, Makoto</au><au>Arita, Makoto</au><au>Sugimoto, Masataka</au><au>Nakayama, Keiichi I</au><au>Furukawa, Yoichi</au><au>Imoto, Seiya</au><au>Nakanishi, Makoto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders</atitle><jtitle>Science (American Association for the Advancement of Science)</jtitle><addtitle>Science</addtitle><date>2021-01-15</date><risdate>2021</risdate><volume>371</volume><issue>6526</issue><spage>265</spage><epage>270</epage><pages>265-270</pages><issn>0036-8075</issn><eissn>1095-9203</eissn><abstract>Removal of senescent cells (senolysis) has been proposed to be beneficial for improving age-associated pathologies, but the molecular pathways for such senolytic activity have not yet emerged. Here, we identified glutaminase 1 (
) as an essential gene for the survival of human senescent cells. The intracellular pH in senescent cells was lowered by lysosomal membrane damage, and this lowered pH induced kidney-type glutaminase (KGA) expression. The resulting enhanced glutaminolysis induced ammonia production, which neutralized the lower pH and improved survival of the senescent cells. Inhibition of KGA-dependent glutaminolysis in aged mice eliminated senescent cells specifically and ameliorated age-associated organ dysfunction. Our results suggest that senescent cells rely on glutaminolysis, and its inhibition offers a promising strategy for inducing senolysis in vivo.</abstract><cop>United States</cop><pub>The American Association for the Advancement of Science</pub><pmid>33446552</pmid><doi>10.1126/science.abb5916</doi><tpages>6</tpages><orcidid>https://orcid.org/0000-0002-5726-3317</orcidid><orcidid>https://orcid.org/0000-0002-7165-6336</orcidid><orcidid>https://orcid.org/0000-0003-3714-2697</orcidid><orcidid>https://orcid.org/0000-0002-0423-7289</orcidid><orcidid>https://orcid.org/0000-0001-9902-0463</orcidid><orcidid>https://orcid.org/0000-0002-6983-8958</orcidid><orcidid>https://orcid.org/0000-0002-7185-1529</orcidid><orcidid>https://orcid.org/0000-0002-3492-117X</orcidid><orcidid>https://orcid.org/0000-0003-2113-4369</orcidid><orcidid>https://orcid.org/0000-0003-0462-8631</orcidid><orcidid>https://orcid.org/0000-0001-9874-2392</orcidid><orcidid>https://orcid.org/0000-0002-6974-8119</orcidid><orcidid>https://orcid.org/0000-0002-2989-308X</orcidid><orcidid>https://orcid.org/0000-0001-9247-4593</orcidid><orcidid>https://orcid.org/0000-0001-8737-8097</orcidid><orcidid>https://orcid.org/0000-0002-6707-3584</orcidid><orcidid>https://orcid.org/0000-0001-9582-355X</orcidid><orcidid>https://orcid.org/0000-0002-6987-0288</orcidid><orcidid>https://orcid.org/0000-0001-6024-9949</orcidid><orcidid>https://orcid.org/0000-0002-2486-2321</orcidid><orcidid>https://orcid.org/0000-0003-0006-9051</orcidid><orcidid>https://orcid.org/0000-0002-6812-9607</orcidid><orcidid>https://orcid.org/0000-0003-1224-227X</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0036-8075 |
| ispartof | Science (American Association for the Advancement of Science), 2021-01, Vol.371 (6526), p.265-270 |
| issn | 0036-8075 1095-9203 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2478596957 |
| source | MEDLINE; Science Magazine |
| subjects | Adipose Tissue - enzymology Age Aging Aging - genetics Aging - metabolism Ammonia Ammonia - metabolism Animal models Animals Cell death Cell Survival Cellular Senescence - genetics Cellular Senescence - physiology Disorders Genes, Essential Glutaminase Glutaminase - genetics Glutaminase - metabolism Glutamine Humans Hydrogen-Ion Concentration Inhibition Kidneys Lung - enzymology Male Metabolism Mice Mice, Inbred C57BL Obesity pH effects RNA-mediated interference Skin - enzymology Survival |
| title | Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-15T20%3A21%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Senolysis%20by%20glutaminolysis%20inhibition%20ameliorates%20various%20age-associated%20disorders&rft.jtitle=Science%20(American%20Association%20for%20the%20Advancement%20of%20Science)&rft.au=Johmura,%20Yoshikazu&rft.date=2021-01-15&rft.volume=371&rft.issue=6526&rft.spage=265&rft.epage=270&rft.pages=265-270&rft.issn=0036-8075&rft.eissn=1095-9203&rft_id=info:doi/10.1126/science.abb5916&rft_dat=%3Cproquest_cross%3E2478596957%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2478093279&rft_id=info:pmid/33446552&rfr_iscdi=true |