Fisetin is a senotherapeutic that extends health and lifespan
Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combina...
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| creator | Yousefzadeh, Matthew J. Zhu, Yi McGowan, Sara J. Angelini, Luise Fuhrmann-Stroissnigg, Heike Xu, Ming Ling, Yuan Yuan Melos, Kendra I. Pirtskhalava, Tamar Inman, Christina L. McGuckian, Collin Wade, Erin A. Kato, Jonathon I. Grassi, Diego Wentworth, Mark Burd, Christin E. Arriaga, Edgar A. Ladiges, Warren L. Tchkonia, Tamara Kirkland, James L. Robbins, Paul D. Niedernhofer, Laura J. |
| description | Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.
A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.
Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.
The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies.
NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401–1 (JLK, EAA). |
| doi_str_mv | 10.1016/j.ebiom.2018.09.015 |
| format | Article |
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A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.
Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.
The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies.
NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401–1 (JLK, EAA).</description><identifier>ISSN: 2352-3964</identifier><identifier>EISSN: 2352-3964</identifier><identifier>DOI: 10.1016/j.ebiom.2018.09.015</identifier><identifier>PMID: 30279143</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Adipose Tissue - metabolism ; Aging ; Animals ; Biological Products - pharmacology ; Biological Products - therapeutic use ; Biomarkers ; Cellular Senescence - drug effects ; Cellular Senescence - genetics ; Female ; Fibroblasts - drug effects ; Fibroblasts - metabolism ; Flavonoids - pharmacology ; Flavonoids - therapeutic use ; Flavonols ; Gene Expression ; Genes, Reporter ; Health Status ; Healthspan ; Humans ; Lifespan ; Lipid Peroxidation ; Longevity - drug effects ; Male ; Mice ; Mice, Knockout ; Progeria ; Research paper ; Senescence ; Senolytic</subject><ispartof>EBioMedicine, 2018-10, Vol.36, p.18-28</ispartof><rights>2018 The Authors</rights><rights>Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.</rights><rights>2018 The Authors 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-a4bdbcbc05f3acdb3773cfc6803e69da178bdb7ae7239bd9e52add8f54f0e6693</citedby><cites>FETCH-LOGICAL-c509t-a4bdbcbc05f3acdb3773cfc6803e69da178bdb7ae7239bd9e52add8f54f0e6693</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197652/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30279143$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yousefzadeh, Matthew J.</creatorcontrib><creatorcontrib>Zhu, Yi</creatorcontrib><creatorcontrib>McGowan, Sara J.</creatorcontrib><creatorcontrib>Angelini, Luise</creatorcontrib><creatorcontrib>Fuhrmann-Stroissnigg, Heike</creatorcontrib><creatorcontrib>Xu, Ming</creatorcontrib><creatorcontrib>Ling, Yuan Yuan</creatorcontrib><creatorcontrib>Melos, Kendra I.</creatorcontrib><creatorcontrib>Pirtskhalava, Tamar</creatorcontrib><creatorcontrib>Inman, Christina L.</creatorcontrib><creatorcontrib>McGuckian, Collin</creatorcontrib><creatorcontrib>Wade, Erin A.</creatorcontrib><creatorcontrib>Kato, Jonathon I.</creatorcontrib><creatorcontrib>Grassi, Diego</creatorcontrib><creatorcontrib>Wentworth, Mark</creatorcontrib><creatorcontrib>Burd, Christin E.</creatorcontrib><creatorcontrib>Arriaga, Edgar A.</creatorcontrib><creatorcontrib>Ladiges, Warren L.</creatorcontrib><creatorcontrib>Tchkonia, Tamara</creatorcontrib><creatorcontrib>Kirkland, James L.</creatorcontrib><creatorcontrib>Robbins, Paul D.</creatorcontrib><creatorcontrib>Niedernhofer, Laura J.</creatorcontrib><title>Fisetin is a senotherapeutic that extends health and lifespan</title><title>EBioMedicine</title><addtitle>EBioMedicine</addtitle><description>Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.
A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.
Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.
The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies.
NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401–1 (JLK, EAA).</description><subject>Adipose Tissue - metabolism</subject><subject>Aging</subject><subject>Animals</subject><subject>Biological Products - pharmacology</subject><subject>Biological Products - therapeutic use</subject><subject>Biomarkers</subject><subject>Cellular Senescence - drug effects</subject><subject>Cellular Senescence - genetics</subject><subject>Female</subject><subject>Fibroblasts - drug effects</subject><subject>Fibroblasts - metabolism</subject><subject>Flavonoids - pharmacology</subject><subject>Flavonoids - therapeutic use</subject><subject>Flavonols</subject><subject>Gene Expression</subject><subject>Genes, Reporter</subject><subject>Health Status</subject><subject>Healthspan</subject><subject>Humans</subject><subject>Lifespan</subject><subject>Lipid Peroxidation</subject><subject>Longevity - drug effects</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Progeria</subject><subject>Research paper</subject><subject>Senescence</subject><subject>Senolytic</subject><issn>2352-3964</issn><issn>2352-3964</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1LxDAQhoMorqz7CwTp0cvWfLRpc1AQ8QsEL3oOaTK1WbppTVLRf2_WVdGLpwyZZ94ZHoSOCM4JJvx0lUNjh3VOMalzLHJMyh10QFlJl0zwYvdXPUOLEFYYJ6RIn_U-mjFMK0EKdoDOrm2AaF1mQ6ayAG6IHXg1whStzmKnYgZvEZwJWQeqj12mnMl620IYlTtEe63qAyy-3jl6ur56vLxd3j_c3F1e3C91iUVcqqIxjW40LlumtGlYVTHdal5jBlwYRao6AZWCijLRGAElVcbUbVm0GDgXbI7Ot7nj1KzBaHDRq16O3q6Vf5eDsvJvx9lOPg-vkhNR8ZKmgJOvAD-8TBCiXNugoe-Vg2EKkhLCCa1qxhPKtqj2Qwge2p81BMuNe7mSn-7lxr3EQiaxaer494U_M9-mE3C2BSB5erXgZdAWnAZjPegozWD_XfABdnWYVg</recordid><startdate>20181001</startdate><enddate>20181001</enddate><creator>Yousefzadeh, Matthew J.</creator><creator>Zhu, Yi</creator><creator>McGowan, Sara J.</creator><creator>Angelini, Luise</creator><creator>Fuhrmann-Stroissnigg, Heike</creator><creator>Xu, Ming</creator><creator>Ling, Yuan Yuan</creator><creator>Melos, Kendra I.</creator><creator>Pirtskhalava, Tamar</creator><creator>Inman, Christina L.</creator><creator>McGuckian, Collin</creator><creator>Wade, Erin A.</creator><creator>Kato, Jonathon I.</creator><creator>Grassi, Diego</creator><creator>Wentworth, Mark</creator><creator>Burd, Christin E.</creator><creator>Arriaga, Edgar A.</creator><creator>Ladiges, Warren L.</creator><creator>Tchkonia, Tamara</creator><creator>Kirkland, James L.</creator><creator>Robbins, Paul D.</creator><creator>Niedernhofer, Laura J.</creator><general>Elsevier B.V</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20181001</creationdate><title>Fisetin is a senotherapeutic that extends health and lifespan</title><author>Yousefzadeh, Matthew J. ; Zhu, Yi ; McGowan, Sara J. ; Angelini, Luise ; Fuhrmann-Stroissnigg, Heike ; Xu, Ming ; Ling, Yuan Yuan ; Melos, Kendra I. ; Pirtskhalava, Tamar ; Inman, Christina L. ; McGuckian, Collin ; Wade, Erin A. ; Kato, Jonathon I. ; Grassi, Diego ; Wentworth, Mark ; Burd, Christin E. ; Arriaga, Edgar A. ; Ladiges, Warren L. ; Tchkonia, Tamara ; Kirkland, James L. ; Robbins, Paul D. ; Niedernhofer, Laura J.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c509t-a4bdbcbc05f3acdb3773cfc6803e69da178bdb7ae7239bd9e52add8f54f0e6693</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adipose Tissue - metabolism</topic><topic>Aging</topic><topic>Animals</topic><topic>Biological Products - pharmacology</topic><topic>Biological Products - therapeutic use</topic><topic>Biomarkers</topic><topic>Cellular Senescence - drug effects</topic><topic>Cellular Senescence - genetics</topic><topic>Female</topic><topic>Fibroblasts - drug effects</topic><topic>Fibroblasts - metabolism</topic><topic>Flavonoids - pharmacology</topic><topic>Flavonoids - therapeutic use</topic><topic>Flavonols</topic><topic>Gene Expression</topic><topic>Genes, Reporter</topic><topic>Health Status</topic><topic>Healthspan</topic><topic>Humans</topic><topic>Lifespan</topic><topic>Lipid Peroxidation</topic><topic>Longevity - drug effects</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Progeria</topic><topic>Research paper</topic><topic>Senescence</topic><topic>Senolytic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yousefzadeh, Matthew J.</creatorcontrib><creatorcontrib>Zhu, Yi</creatorcontrib><creatorcontrib>McGowan, Sara J.</creatorcontrib><creatorcontrib>Angelini, Luise</creatorcontrib><creatorcontrib>Fuhrmann-Stroissnigg, Heike</creatorcontrib><creatorcontrib>Xu, Ming</creatorcontrib><creatorcontrib>Ling, Yuan Yuan</creatorcontrib><creatorcontrib>Melos, Kendra I.</creatorcontrib><creatorcontrib>Pirtskhalava, Tamar</creatorcontrib><creatorcontrib>Inman, Christina L.</creatorcontrib><creatorcontrib>McGuckian, Collin</creatorcontrib><creatorcontrib>Wade, Erin A.</creatorcontrib><creatorcontrib>Kato, Jonathon I.</creatorcontrib><creatorcontrib>Grassi, Diego</creatorcontrib><creatorcontrib>Wentworth, Mark</creatorcontrib><creatorcontrib>Burd, Christin E.</creatorcontrib><creatorcontrib>Arriaga, Edgar A.</creatorcontrib><creatorcontrib>Ladiges, Warren L.</creatorcontrib><creatorcontrib>Tchkonia, Tamara</creatorcontrib><creatorcontrib>Kirkland, James L.</creatorcontrib><creatorcontrib>Robbins, Paul D.</creatorcontrib><creatorcontrib>Niedernhofer, Laura J.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>EBioMedicine</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yousefzadeh, Matthew J.</au><au>Zhu, Yi</au><au>McGowan, Sara J.</au><au>Angelini, Luise</au><au>Fuhrmann-Stroissnigg, Heike</au><au>Xu, Ming</au><au>Ling, Yuan Yuan</au><au>Melos, Kendra I.</au><au>Pirtskhalava, Tamar</au><au>Inman, Christina L.</au><au>McGuckian, Collin</au><au>Wade, Erin A.</au><au>Kato, Jonathon I.</au><au>Grassi, Diego</au><au>Wentworth, Mark</au><au>Burd, Christin E.</au><au>Arriaga, Edgar A.</au><au>Ladiges, Warren L.</au><au>Tchkonia, Tamara</au><au>Kirkland, James L.</au><au>Robbins, Paul D.</au><au>Niedernhofer, Laura J.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Fisetin is a senotherapeutic that extends health and lifespan</atitle><jtitle>EBioMedicine</jtitle><addtitle>EBioMedicine</addtitle><date>2018-10-01</date><risdate>2018</risdate><volume>36</volume><spage>18</spage><epage>28</epage><pages>18-28</pages><issn>2352-3964</issn><eissn>2352-3964</eissn><abstract>Senescence is a tumor suppressor mechanism activated in stressed cells to prevent replication of damaged DNA. Senescent cells have been demonstrated to play a causal role in driving aging and age-related diseases using genetic and pharmacologic approaches. We previously demonstrated that the combination of dasatinib and the flavonoid quercetin is a potent senolytic improving numerous age-related conditions including frailty, osteoporosis and cardiovascular disease. The goal of this study was to identify flavonoids with more potent senolytic activity.
A panel of flavonoid polyphenols was screened for senolytic activity using senescent murine and human fibroblasts, driven by oxidative and genotoxic stress, respectively. The top senotherapeutic flavonoid was tested in mice modeling a progeroid syndrome carrying a p16INK4a-luciferase reporter and aged wild-type mice to determine the effects of fisetin on senescence markers, age-related histopathology, disease markers, health span and lifespan. Human adipose tissue explants were used to determine if results translated.
Of the 10 flavonoids tested, fisetin was the most potent senolytic. Acute or intermittent treatment of progeroid and old mice with fisetin reduced senescence markers in multiple tissues, consistent with a hit-and-run senolytic mechanism. Fisetin reduced senescence in a subset of cells in murine and human adipose tissue, demonstrating cell-type specificity. Administration of fisetin to wild-type mice late in life restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.
The natural product fisetin has senotherapeutic activity in mice and in human tissues. Late life intervention was sufficient to yield a potent health benefit. These characteristics suggest the feasibility to translation to human clinical studies.
NIH grants P01 AG043376 (PDR, LJN), U19 AG056278 (PDR, LJN, WLL), R24 AG047115 (WLL), R37 AG013925 (JLK), R21 AG047984 (JLK), P30 DK050456 (Adipocyte Subcore, JLK), a Glenn Foundation/American Federation for Aging Research (AFAR) BIG Award (JLK), Glenn/AFAR (LJN, CEB), the Ted Nash Long Life and Noaber Foundations (JLK), the Connor Group (JLK), Robert J. and Theresa W. Ryan (JLK), and a Minnesota Partnership Grant (AMAY-UMN#99)-P004610401–1 (JLK, EAA).</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>30279143</pmid><doi>10.1016/j.ebiom.2018.09.015</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Adipose Tissue - metabolism Aging Animals Biological Products - pharmacology Biological Products - therapeutic use Biomarkers Cellular Senescence - drug effects Cellular Senescence - genetics Female Fibroblasts - drug effects Fibroblasts - metabolism Flavonoids - pharmacology Flavonoids - therapeutic use Flavonols Gene Expression Genes, Reporter Health Status Healthspan Humans Lifespan Lipid Peroxidation Longevity - drug effects Male Mice Mice, Knockout Progeria Research paper Senescence Senolytic |
| title | Fisetin is a senotherapeutic that extends health and lifespan |
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