Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-01

AUTHORS

Jianhui Chang, Yingying Wang, Lijian Shao, Remi-Martin Laberge, Marco Demaria, Judith Campisi, Krishnamurthy Janakiraman, Norman E Sharpless, Sheng Ding, Wei Feng, Yi Luo, Xiaoyan Wang, Nukhet Aykin-Burns, Kimberly Krager, Usha Ponnappan, Martin Hauer-Jensen, Aimin Meng, Daohong Zhou

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. More... »

PAGES

78-83

Journal

TITLE

Nature Medicine

ISSUE

1

VOLUME

22

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nm.4010

DOI

http://dx.doi.org/10.1038/nm.4010

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1026527727

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/26657143


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