title: Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice.
abstract: Senescent cells (SCs) accumulate with age and after genotoxic stress, such as total-body irradiation (TBI). Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders, suggesting that SCs play a causative role in certain age-related pathologies. Thus, a 'senolytic' pharmacological agent that can selectively kill SCs holds promise for rejuvenating tissue stem cells and extending health span. To test this idea, we screened a collection of compounds and identified ABT263 (a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL) as a potent senolytic drug. We show that ABT263 selectively kills SCs in culture in a cell type- and species-independent manner by inducing apoptosis. Oral administration of ABT263 to either sublethally irradiated or normally aged mice effectively depleted SCs, including senescent bone marrow hematopoietic stem cells (HSCs) and senescent muscle stem cells (MuSCs). Notably, this depletion mitigated TBI-induced premature aging of the hematopoietic system and rejuvenated the aged HSCs and MuSCs in normally aged mice. Our results demonstrate that selective clearance of SCs by a pharmacological agent is beneficial in part through its rejuvenation of aged tissue stem cells. Thus, senolytic drugs may represent a new class of radiation mitigators and anti-aging agents.
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Jianhui
authors.initials: J
authors.lastname: Chang
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Institute of Radiation Medicine, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Tianjin, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Lijian
authors.initials: L
authors.lastname: Shao
authors.affiliation: Buck Institute for Research on Aging, Novato, California, USA.
authors.forename: Remi-Martin
authors.initials: RM
authors.lastname: Laberge
authors.affiliation: Buck Institute for Research on Aging, Novato, California, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Demaria
authors.affiliation: Buck Institute for Research on Aging, Novato, California, USA.|Lawrence Berkeley National Laboratory, Berkeley, California, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Campisi
authors.affiliation: Department of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Janakiraman
authors.affiliation: Department of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Nukhet
authors.initials: N
authors.lastname: Aykin-Burns
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Krager
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Usha
authors.initials: U
authors.lastname: Ponnappan
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Hauer-Jensen
authors.affiliation: Institute of Radiation Medicine, Peking Union Medical College (PUMC), Chinese Academy of Medical Sciences (CAMS), Tianjin, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Meng
authors.affiliation: Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Daohong
authors.initials: D
authors.lastname: Zhou
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence; D003114:Colony-Forming Units Assay; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D015774:Ganciclovir / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D051379:Mice; D008853:Microscopy; D018482:Muscle, Skeletal / Q000166:cytology; D032446:Myoblasts / Q000187:drug effects* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D012060:Rejuvenation; D013449:Sulfonamides / Q000494:pharmacology*; D014916:Whole-Body Irradiation; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D000998:Antiviral Agents; C000595707:BCL2 protein, human; C494811:BCL2L1 protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013449:Sulfonamides; D051020:bcl-X Protein; D015774:Ganciclovir; C528561:navitoclax