Directed elimination of senescent cells by inhibition of BCL-W and BCL-XL

By Reut Yosef, Noam Pilpel, Ronit Tokarsky-Amiel, Anat Biran, Yossi Ovadya, S. Cohen, E. Vadai, Liat Dassa, Elisheva Shahar, R. Condiotti and 2 more. Nature Communications, 2016

887 citations recorded by the source corpus.

Senescent cells, formed in response to physiological and oncogenic stresses, facilitate protection from tumourigenesis and aid in tissue repair. However, accumulation of such cells in tissues contributes to age-related pathologies. Resistance of senescent cells to apoptotic stimuli may contribute to their accumulation, yet the molecular mechanisms allowing their prolonged viability are poorly characterized. Here we show that senescent cells upregulate the anti-apoptotic proteins BCL-W and BCL-XL. Joint inhibition of BCL-W and BCL-XL by siRNAs or the small-molecule ABT-737 specifically induces apoptosis in senescent cells. Notably, treatment of mice with ABT-737 efficiently eliminates senescent cells induced by DNA damage in the lungs as well as senescent cells formed in the epidermis by activation of p53 through transgenic p14ARF. Elimination of senescent cells from the epidermis leads to an increase in hair-follicle stem cell proliferation. The finding that senescent cells can be eliminated pharmacologically paves the way to new strategies for the treatment of age-related pathologies. The accumulation of senescent cells within tissues plays a role in numerous age-related pathologies. Yosef and Pilpel et al. demonstrate that the resistance of these cells to apoptosis is driven by upregulation of survival proteins, whose pharmacological inhibition triggers senescent cell elimination in mice.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/328ac3c09185e514aacf8e10d8321b07ce188bd1

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Citations in the corpus

Unmasking Transcriptional Heterogeneity in Senescent Cells (2017, background): “Nevertheless, within the senescence core signature, we found genes that had been previously linked to senescence: BCL2L2 (also known as Bcl-w), a negative regulator of apoptosis [26]; PATZ1, a transcriptional repressor whose expression Hernandez-Segura et al.”
Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “One of the first molecules to be identified as inhibitor of Bcl-W and Bcl-XL proteins, the ABT-737, induced apoptosis preferentially in senescent cells both in vivo and in vivo (358) and opened the door to new strategies for the treatment of age-related pathologies.”
Physiological frailty index (PFI): quantitative in-life estimate of individual biological age in mice (2017, neutral): “Others confirmed that N targets senescent cells, but Bcl-2 family inhibitors that do not target BCL-XL are not senolytic [12, 13].”
Hallmarks of Cellular Senescence. (2018, positive): “Members of the BCL-2 family, specifically antiapoptotic BCL-XL and BCL-W, are essential for the survival of senescent cells [85].”
Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “Its senolytic activity is explained by an overreliance of senescent cells on BCL-xL and BCL-w, both of which are up-regulated during senescence (Yosef et al., 2016).”
Cellular Senescence: A Translational Perspective (2017, background): “Ten months later, two groups simultaneously reported that navitoclax (N; ABT-263), which targets components of the Bcl 2 pathway, is senolytic (Zhu et al., 2015a; Chang et al., 2016), as later confirmed by another group (Yosef et al., 2016).”
Mechanisms and functions of cellular senescence. (2018, positive): “Recent studies have suggested that this is a result of the upregulation of BCL-2 family proteins such as BCL-W and BCL-XL (123).”