During the cellular senescence process, the first ideas about the prevention of chronic diseases and cancer, especially by eliminating D-senescent cells, came to the fore in the 2000s [15]. It has been shown that the accumulation of SA β - gal in cells in animal studies has a negative effect on lifespan and stimulates the onset of age-dependent changes in many organs. Subsequent studies have reported that healthy aging can be prolonged in mice with reduced expression of p16Ink4a with calorie restriction or a mutation that decreases growth hormone signaling. These studies showed an inverse relationship between aging cell burden and duration of health [15]. Especially in the period after 2005, drug researches started with the aim of identifying fusion proteins for the recognition of senescent cells and killing D-senescent cells. Studies related to these drugs, which are defined as senolytic drugs, have been based on the knowledge that aging cells are resistant to apoptosis [15].
Apoptosis resistance occurs despite the release of proapoptotic SASP factors from senescent cells. Therefore, hypothetically, anti-apoptotic mechanisms are required to overcome the resistance of aging cells to apoptotic stimuli [15, 16]. After the researches, it has been reported that aging cells may have characteristics similar to cancer cells including apoptosis. As a result of this observation, it is concluded that senescent cells that secrete pro-apoptotic SASP can prevent their own extinction through protective senescent anti-apoptotic pathway (SCAP) networks. From proteomics and transcriptomic databases, SCAP pathways were found to be expressed at a higher rate in senescent cells [16].
Senolytic drugs work through different mechanisms to make the aging process healthier, especially by eliminating D-senescent cells. However, a senolytic drug that has a clear positive effect on this process has not been defined yet. However, promising research continues [16].
The first senolitics were discovered through the approach of identifying agents that temporarily disable SCAP networks that allow these cells to survive in the microenvironment created by D-senescent cells and kill the sensescent cells in their environment. From these drug studies, it has been reported that siRNAs, one of the small RNA types, have an effect against anti-apoptotic regulators in those related to the regulation of the anti-apoptotic process that is effective in selectively reducing aging cell viability, and this effect is dependent on the aging cell type [5, 15, 16]. The basis of this hypothetical approach is the research that is caused by siRNAs that reduce BCL-xL or other BCL-2 family members selectively to apoptosis of aging and decaying human umbilical vein endothelial primary cells (HUVECs) [16, 17]. This effect was proven to be selective, with the finding that they did not increase apoptosis induction against aging human primary adipocyte progenitor cells by the same siRNAs. Unfortunately, it has been reported that multiple SCAP pathways may need to be targeted to kill some senescent cells, and even anti-apoptotic senolytics may be insufficient, as senescent cell defenses against apoptosis are far behind other SASP mechanisms in some senescent cells. Among the drug researches that provide a healthy aging process by eliminating D-senescent cells through SCAP networks, the most important ones are dasatinib, a tyrosine kinase inhibitor that targets JAK1 / 2, and quercetin, a natural flavonoid [5, 15, 17]. Unlike other tyrosine kinase inhibitors such as imatinib, which have been shown to be non-senolytic, dasatinib induces apoptosis caused by addiction receptors such as ephrins by partially inhibiting Src kinase. Fisetin, on the other hand, is another natural flavonoid that is considered senolytic with similar effects like dasatinib and quercetin [17]. Senolytic flavonoids such as quercetin and fisetin have been reported to act by partially inhibiting BCL-2 family members such as BCL-xL, as well as hypoxia-inducing factor (HIF)-1α and other SCAP network components [17, 18]. In a study, it was determined that dasatinib targets senescent human cultured primary adipocyte progenitor cells, while quercetin destroys cultured HUVECs, interestingly, the combination of dansatinib and quercetin causes apoptosis of both senescent human primary adipocyte progenitor cells and senescent HUVECs [5, 15, 17]. However, sensescent adipocyte progenitor cells or HUVECs did not cause. However, due to the abundance of SCAP pathways, in some cell types such as mouse embryonic fibroblasts, neither dasatinib nor quercetin have been reported to be senolytic, while the combination of these two chemicals is senolytic [16–18]. All these studies show that the SASP phenotype and cell type are important in aging cells. However, due to the fact that the target of true senolytics is not a single receptor, enzyme or biochemical pathway, we may think that research may need to be advanced at the molecular and biochemical level. Indeed, agents such as navitoclax or Nutlin3a, a BCL-2 family member inhibitor that are defined as panolytic and act on single or limited targets, have significant non-target apoptotic effects on non-innate cell types such as platelets and the immune system. Also, nutlins can actually cause aging (15,19,20).