Apoptosis-resistance of senescent cells is an intrinsic barrier for senolysis induced by cardiac glycosides

Targeted elimination of senescent cells - senolysis - is one of the core trends in the anti-aging therapy. Cardiac glycosides were recently proved to be a broad-spectrum senolytics. Here we tested senolytic properties of cardiac glycosides towards human mesenchymal stem cells (hMSCs). Cardiac glycosides had no senolytic ability towards senescent hMSCs of various origins. Using biological and bioinformatic approaches we compared senescence development in cardiac glycosides-sensitive A549 and -insensitive hMSCs. The absence of senolysis was found to be mediated by the effective potassium import and increased apoptosis-resistance in senescent hMSCs. We revealed that apoptosis-resistance, previously recognized as a common characteristic of senescence, in fact, is not a general feature of senescent cells. Moreover, only apoptosis-prone senescent cells are sensitive to cardiac glycosides-induced senolysis. Thus, we can speculate that the effectiveness of senolysis might depend on whether senescent cells indeed become apoptosis-resistant compared to their proliferating counterparts.