Pan-mTOR inhibitors sensitize the senolytic activity of navitoclax via mTORC2 inhibition-mediated apoptotic signaling.

Compounds with senolysis activity are discovered in recent years, featuring by their capacity to specifically eliminate senescent cells in vitro or in vivo. These compounds, referring to as Senolytics, provide a new method for aging counteraction and probably for geriatric disease amelioration. However, their clinical application is unpractical still, mainly because of the safety issue. In fact, the effective dose range even of the most potent senolytic cannot guarantee the safety requirements application for human being. Here, we report a study which investigated the combinational application of one potential senolytic molecule navitoclax, a Bcl-2 inhibitor with several mTOR inhibitors, to assess the influence of this combination on the senolytic outcome. Our results reveal that pan-mTOR inhibitors can reduce the dosage or timespan of navitoclax necessary for reaching IC50 and LT50 in senescent cells, also extend the lifespan of premature-aged Drosophila and mitigate the aging-related phenotype. Our results also confirmed that mTOR inhibitor sensitized senolytic cell death is apoptotic and pan-mTOR inhibitors PP242 and AZD8055 works more effectively than mTORC1 inhibitor Rapamycin. Mechanically, we verified the crucial role of mTORC2 inhibition contributes sensitization by increasing the expression of the pro-apoptotic protein Bim. In summary, this study firstly exposes the sensitization effect of pan-mTOR inhibitors on navitoclax-induced senolytic apoptosis, therefore providing novel evidence to show the advantage of drug combination on setting senotherapy. It also provides an intriguing clue to demonstrate the value of mTORC2 inhibition for apoptotic death of senescent cells.