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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)1,2,3,4,5,6. Clearance of SCs in a progeroid mouse model using a transgenic approach delays several age-associated disorders7, 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.

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Figure 1: ABT263 has senolytic activity in cell culture and mice.
Figure 2: ABT263 kills SCs by apoptosis.
Figure 3: SC clearance by treatment with ABT263 or GCV rejuvenates HSCs after TBI.
Figure 4: SC clearance by ABT263 treatment rejuvenates HSCs and MuSCs in normally aged mice.

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Acknowledgements

We thank G. van Zant (University of Kentucky) for FBMD-1 stromal cells. This study was supported by the US National Institutes of Health (NIH) grants R01 CA122023 (D.Z.), R01 AI080421 (D.Z.), P20 GM109005 (M.H.-J. and D.Z.) and R37 AG009909 (J. Campisi); a grant from the Edward P. Evans Foundation (D.Z. and M.H.-J.); National Natural Science Foundation of China grant no. 81129020 (D.Z.); China National Program on Key Basic Research Project 2011CB964800-G (A.M.); and an Arkansas Research Alliance Scholarship from the Arkansas Science & Technology Authority (D.Z.).

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Authors

Contributions

J. Chang and Y.W. designed, performed and analyzed most of the experiments; L.S., R.-M.L. and M.D. designed, performed and analyzed some experiments; W.F., Y.L., X.W., N.A.-B., K.K. and K.J. performed experiments; N.E.S. interpreted data and revised the manuscript; J. Campisi provided mice, designed the study, analyzed and interpreted data, and revised the manuscript; U.P. and M.H.-J. interpreted data and revised the manuscript; S.D. and A.M. designed the study, analyzed and interpreted data, and revised the manuscript; D.Z. conceived, designed and supervised the study, analyzed and interpreted data, and wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Daohong Zhou.

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Competing interests

J. Chang, Y.W., L.S., W.F., Y.L., and D.Z. are inventors of a pending patent application for use of Bcl-2 and/or Bcl-xL inhibitors as anti-aging agents. J. Campisi and D.Z. are co-founders and advisors of Cenexys/Unity that develops senolytic drugs.

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Chang, J., Wang, Y., Shao, L. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 22, 78–83 (2016). https://doi.org/10.1038/nm.4010

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