Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

Abstract

SummaryClearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.

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).…”

“…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.…”

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice

“…Among other possibilities, this could be related to intimal plaque penetrance by D+Q. Effects of newer senolytics, such as navitoclax (Zhu et al ., 2015a,b), remain to be determined. We did, however, find that intimal plaque calcification was significantly reduced in D+Q‐ vs .…”

“…Recent work suggests senescent cell burden can be dramatically increased by chronological aging or in models of progeria (Lecka‐Czernik et al ., 1997; Baker et al ., 2004; Varela et al ., 2005), high‐fat feeding (Shi et al ., 2007), diabetes (Verzola et al ., 2008), tobacco exposure (Nyunoya et al ., 2006), or atherosclerosis (Wang & Bennett, 2012), and short‐term treatment with ‘senolytic’ drugs in chronologically aged or progeroid mice alleviates several aging‐related phenotypes (Zhu et al ., 2015a,b). However, effects of long‐term senescent cell clearance on vascular reactivity and structure with aging or chronic hypercholesterolemia remain unknown.…”

Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism

“…While Van Deursen's group used a genetic manipulation to eliminate senescent cells, more recently Kirkland's group used a pharmacological approach to attain the same result. Using these so‐called senolytics, they showed that partial removal of senescent cells leads to decreased age‐related phenotypes in wild‐type C57BL/6 mice (Zhu et al ., 2016). …”