title: The Achilles' heel of senescent cells: from transcriptome to senolytic drugs.
abstract: The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and the burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis. Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen-activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these same factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged, radiation-exposed, and progeroid Ercc1(-/Δ) mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose. Following irradiation of one limb in mice, a single dose led to improved exercise capacity for at least 7 months following drug treatment. Periodic drug administration extended healthspan in Ercc1(-/∆) mice, delaying age-related symptoms and pathology, osteoporosis, and loss of intervertebral disk proteoglycans. These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Gower
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Husheng
authors.initials: H
authors.lastname: Ding
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nino
authors.initials: N
authors.lastname: Giorgadze
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Allyson K
authors.initials: AK
authors.lastname: Palmer
authors.affiliation: Departments of Pathology, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX, USA.|Research Service, Geriatric Research and Education Clinical Center, Audie L. Murphy VA Hospital South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ikeno
authors.affiliation: Departments of Pathology, Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center, San Antonio, TX, USA.|Research Service, Geriatric Research and Education Clinical Center, Audie L. Murphy VA Hospital South Texas Veterans Health Care System, San Antonio, TX, USA.
authors.forename: Gene B
authors.initials: GB
authors.lastname: Hubbard
authors.affiliation: Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Lenburg
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: O'Hara
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nicholas F
authors.initials: NF
authors.lastname: LaRusso
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Miller
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Roos
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Grace C
authors.initials: GC
authors.lastname: Verzosa
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: Department of Biochemistry and Molecular Biology, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wren
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joshua N
authors.initials: JN
authors.lastname: Farr
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Sundeep
authors.initials: S
authors.lastname: Khosla
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stout
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: McGowan
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Heike
authors.initials: H
authors.lastname: Fuhrmann-Stroissnigg
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Aditi U
authors.initials: AU
authors.lastname: Gurkar
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Debora
authors.initials: D
authors.lastname: Colangelo
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Akaitz
authors.initials: A
authors.lastname: Dorronsoro
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Yuan Yuan
authors.initials: YY
authors.lastname: Ling
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Amira S
authors.initials: AS
authors.lastname: Barghouthy
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Navarro
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Tokio
authors.initials: T
authors.lastname: Sano
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000375:Aging / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D016922:Cellular Senescence / Q000187:drug effects* / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology*; D004338:Drug Combinations; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D036342:Ephrins / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D007403:Intervertebral Disc / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010024:Osteoporosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D017396:Plasminogen Activator Inhibitor 2 / Q000235:genetics / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D059467:Transcriptome; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; D000069439:Dasatinib; D004338:Drug Combinations; D004720:Endonucleases; D036342:Ephrins; D019869:Phosphatidylinositol 3-Kinases; D017396:Plasminogen Activator Inhibitor 2; D011794:Quercetin; D051020:bcl-X Protein; C494812:Bcl2l1 protein, mouse; C421683:Pik3cd protein, mouse; C499360:Ercc1 protein, mouse
keywords: PI3K delta; dasatinib; dependence receptors; ephrins; p21; plasminogen-activated inhibitor; quercetin