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

Abstract

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.

Oxidation resistance 1 is a novel senolytic target

“…Indeed, we and others have recently discovered that the upregulation of the antiapoptotic Bcl‐2 family proteins is primarily responsible for the resistance of SCs to apoptosis, and Bcl‐2/xl/w inhibitors such as ABT‐263 are potent senolytic agents (Chang et al., 2016; Yosef et al., 2016; Zhu et al., 2016). Because long‐term treatment with a senolytic drug may be required to prevent/treat age‐related diseases and extend lifespan, there is a concern that Bcl‐2/xl/w inhibitors might be not safe for humans because of their known on‐target (thrombocytopenia) and off‐target toxicities (Roberts et al., 2011; Rudin et al., 2012; Vogler et al., 2011).…”

“…This hypothesis is supported by recent studies demonstrating that the genetic clearance of SCs prolongs the lifespan of mice and delays the onset of several age‐related diseases and disorders in both progeroid and naturally aged mice (Baker et al., 2011, 2016). Therefore, the pharmacological clearance of SCs with a small molecule, a senolytic agent that can selectively kill SCs, is potentially a novel anti‐aging strategy and a new treatment for chemotherapy‐ and radiotherapy‐induced side effects (Baar et al., 2017; Chang et al., 2016; Childs et al., 2016; Demaria et al., 2017; Jeon et al., 2017; Ogrodnik et al., 2017; Pan et al., 2017; Schafer et al., 2017; Yosef et al., 2016; Zhu et al., 2015). …”

“…Since the first senolytic was published (Zhu et al., 2015), twelve molecular targets have been identified (Childs et al., 2017), including the prosurvival Bcl‐2 family proteins (Chang et al., 2016; Yosef et al., 2016; Zhu et al., 2016) and forkhead Box O4 (FOXO4) (Baar et al., 2017). These findings led to the discovery of a few senolytic agents, including ABT‐263 and ABT‐737, two Bcl‐2/xl/w inhibitors, and FOXO4‐DRI, a peptide molecule that interferes with the interaction of FOXO4 and p53.…”

Elimination of p19ARF‐expressing cells protects against pulmonary emphysema in mice

“…We used the anti‐apoptotic Bcl‐2 family inhibitor, ABT‐263, in the PPE‐induced emphysema model. ABT‐263, or its related molecule ABT‐737, has been shown to alleviate senescence‐associated pathologies (Chang et al, 2016; Childs et al, 2016; Demaria et al, 2017; Yosef et al, 2016; Zhu et al, 2016, 2015 ), but it may not be effective in all cell types (Schafer et al, 2017). In the PPE‐induced emphysema model, an 8‐week treatment with ABT‐263 resulted in a partial decrease in p19 ARF ‐expressing cell numbers, with a concomitant reduction in INK4a expression in lung tissues.…”

“…The combination of dasatinib and quercetin, which inhibits pro‐survival kinase pathways, ameliorates cardiovascular and vasomotor functions (Roos et al, 2016; Zhu et al, 2015), hepatic steatosis (Ogrodnik et al, 2017), and IPF (Schafer et al, 2017), similar to the semi‐genetic elimination of senescent cells. The anti‐apoptotic bcl‐2 family protein inhibitors ABT‐263/737 are effective in atherosclerosis and osteoarthritis models (Childs et al, 2016; Jeon et al, 2017) and improve stem cell functions and other aging‐associated phenotypes (Chang et al, 2016; Yosef et al, 2016). …”