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Removing Senescent Cells Gives Back HSCs their Youth

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Review of “Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice” from Nature Medicine by Stuart P. Atkinson

The accumulation of senescent cells in tissue caused by aging and/or various stressors can cause stem cell and tissue malfunction and reduced lifespan. However, the clearance of senescent cells via a transgenic approach can reduce age-associated pathologies [1]. This knowledge gave the laboratory of Daohong Zhou (University of Arkansas for Medical Sciences, USA) the inspiration to search for a pharmacological agent which could be easily administered and would selectively kill senescent cells. Their study, reported in Nature Medicine, has identified such a compound and they show that it can rejuvenate the hematopoietic stem cell (HSC) system in a disease model [2].

The authors screened for what they term “seno-lytic” drugs by treating human embryonic fibroblasts with various compounds and assessing survival following the induction of senescence by a number of different means. This identified ABT263, a specific inhibitor of the anti-apoptotic proteins BCL-2 and BCL-xL, as a selective, potent, and rapid inducer of cell death in various senescent cell types. ABT263 effected cell death by inducing the intrinsic apoptotic pathway, and the authors found that senescence, and not DNA damage per se, specifically sensitized cells to the presence of ABT263.

The authors tested the in vivo effect of oral ABT263 administration using a reporter mouse (p16-3MR) in which senescent cells can be identified, tracked and selectively killed following treatment with ganciclovir (a nucleoside analogue that inhibits DNA synthesis) [3] after a sublethal dose of total body irradiation (TBI) to induce the accumulation of senescent cells. Excitingly, they found that treating the mice with ABT263 was as effective at clearing senescent cells and also reducing the expression of senescence-associated factors, as ganciclovir.

But are there any consequences to the selective removal of senescent cells in vivo? The authors answered this question by assessing the hematopoietic system in mice following sub-lethal TBI. While mice not treated with ABT263 demonstrated signs of premature aging of the hematopoietic system, those that were treated had a significant reduction in the number of senescent HSCs in the bone marrow. Furthermore, ABT263 treatment did not reduce the percentages or numbers of HSCs in the bone marrow and actually improved their stem cell characteristics. Furthermore, ABT263 treatment in naturally aging mice also led to a reduction in the numbers of normally accrued senescent HSCs in the bone marrow and MuSCs in the skeletal muscle and rejuvenated those that remained.

Will ABT263 represent an effective treatment for radiation injury or the accruement of wear and tear in our stem cells as we age? Unfortunately, the authors report that there are some toxic side effects linked to ABT263 use [4], including platelet and neutrophil deficiency. However, as a recent Nature paper demonstrates [5], this may be worth the side effects, as the removal of senescent cells has the ability to extend normal lifespan.

References

  1. Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 2011;479:232-236.
  2. Chang J, Wang Y, Shao L, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med 2016;22:78-83.
  3. Demaria M, Ohtani N, Youssef SA, et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev Cell 2014;31:722-733.
  4. Rudin CM, Hann CL, Garon EB, et al. Phase II study of single-agent navitoclax (ABT-263) and biomarker correlates in patients with relapsed small cell lung cancer. Clin Cancer Res 2012;18:3163-3169.
  5. Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016;530:184-189.