Clearance of Senescent Cells by ABT263 Rejuvenates Aged Hematopoietic Stem Cells in Mice

Nat Med. 2016 Jan;22(1):78-83. doi: 10.1038/nm.4010. Epub 2015 Dec 14.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aniline Compounds / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antiviral Agents / pharmacology
  • Apoptosis / drug effects*
  • B-Lymphocytes / drug effects
  • Blotting, Western
  • Cell Cycle
  • Cell Line
  • Cell Survival / drug effects
  • Cellular Senescence*
  • Colony-Forming Units Assay
  • Cyclin-Dependent Kinase Inhibitor p16 / drug effects
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • DNA Damage
  • Ganciclovir / pharmacology
  • Gene Knockdown Techniques
  • Hematopoietic Stem Cells / drug effects*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Mice
  • Microscopy
  • Muscle, Skeletal / cytology
  • Myoblasts / drug effects*
  • Myoblasts / pathology
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • RNA, Messenger / drug effects*
  • RNA, Messenger / metabolism
  • Rejuvenation
  • Sulfonamides / pharmacology*
  • Whole-Body Irradiation
  • bcl-X Protein / genetics

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Antiviral Agents
  • BCL2 protein, human
  • BCL2L1 protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Messenger
  • Sulfonamides
  • bcl-X Protein
  • Ganciclovir
  • navitoclax