Figure 2. Avenues for the selective killing of senescent cells.

A. Genetic deletion models encode a protein (skull) that can be exogenously activated by the addition of an activator compound (AP20187, GCV, DT) to trigger cell death under promoters that regulate major elements of the senescence signaling cascade. B. Resistance to cell death in senescent cells is bestowed by the up-regulation of pro-survival and or anti-apoptotic networks. Senolytic compounds target different elements of these networks to kill senescent cells. C. Chimeric antigen receptors cytotoxic T cells (CAR-T) have been implemented as a novel senolytic approach. CARs are design to target surface proteins, which then activates the cytotoxic function of the T-cell. By targeting membrane-bound ligands present only on senescent cells, CAR-T can be used as a live cell senolytic intervention strategy. The skull represents INK-ATTAC product FK506 binding protein-caspase 8 (FKB-Casp8) fusion protein, the p16-3MR product truncated herpes simplex virus thymidine kinase (HSV-TK), and the ARF-DTR product diphtheria toxin receptor (DTR). AP20187 is a synthetic drug that induces the dimerization of FKB-Casp8 and initiates apoptosis (Baker et al., 2012). GCV, ganciclovir, DT, diphtheria toxin. In p16-3MR mice, HSV-TK phosphorylates GCV, a nucleotide analogue, and converts it into a toxic DNA chain terminator (Laberge et al., 2013; Ray et al., 2004). In ARG-DTR mice, DT activated the DTR which initiates cell death (Hashimoto et al., 2016).