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

By Jianhui Chang, Yingying Wang, Lijian Shao, Rémi-Martin Laberge, M. Demaria, J. Campisi, Krishnamurthy Janakiraman, N. Sharpless, Sheng Ding, W. Feng and 8 more. Nature Medicine, 2015

1,619 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Genetics, Physiology

View Paper: https://www.semanticscholar.org/paper/746910d6ca10b45156a5d5cfbbcb2de8232fbdff

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Citations in the corpus

Measuring biological aging in humans: A quest (2019, result): “…others, a notion that is strengthened by emerging evidence in recent literature, although most is derived from animal studies (Acosta et al., 2013; Chang et al., 2015; Childs, Li, & van Deursen, 2018; García-Prat et al., 2016; GonzalesEbsen, Gregersen, & Olsen, 2017; Hall et al., 2017; Herranz &…”
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging (2017, background): “Two classes of anti-senescence compounds have been reported so far: Quercetin/Dasatinib, either alone or in combination (Zhu et al., 2015), and the pan-BCL inhibitors ABT-263/737 (Chang et al., 2016; Yosef et al., 2016).”
Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL (2016, neutral): “The relevance of these observations to different tissues and conditions is strongly supported by similar recent observations in the haematopoietic system 42 .”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “The elimination of senescent MuSCs increases the ability of the remaining MuSCs to form muscle cell colonies (Chang et al., 2016).”
Cellular senescence promotes adverse effects of chemotherapy and cancer relapse (2016, methodology): “Cobblestone areaforming cell (CAFC) assay was performed as described (24).”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “In particular, inhibitors of Bcl-2 family have shown the potential to alleviate age-related diseases, such as in the case of atherosclerosis, and enhance radioprotection and rejuvenation of the hematopoietic system in mice (55, 63, 88).”
Kidney fibrosis: from mechanisms to therapeutic medicines (2023, background): “Recently, several creative studies validated the efficacy and safety of senescent cell clearances, applying transgenic mice with selectively sensitive pharmacological agents,(92,93) or the mice access to antiapoptotic drugs.(92,94,95) Moreover, various strategies are being tested to prevent the form”