As cellular senescence is an important contributor to aging and age-related disorders, new approaches are required to postpone/prevent detrimental effects mediated by dysfunctional SCs. It has been shown that the selective elimination of SCs is able to attenuate numerous aging-related disorders and extend mouse longevity [
87,
88]. For instance, in progeroid BubR1 (BubR1
H/H) mouse model, the selective eradication of SCs reduces age-related disorders, in a process termed senolysis [
88]. It has been shown that removing senescent cells from tissues might inhibit cancer formation in mice suggesting that senolysis in older patients may have healthspan benefits [
87]. Senolytic drugs and novel galacto-oligosaccharide-coated nanomaterials with toxic cargos can be considered to target SCs. Senolytic compounds are able to selectively kill SCs, whereas senomorphic compounds are able to diminish SASP [
15,
43,
88,
89]. It should be pointed out that senolytics must be precisely targeted to eliminate SCs without affecting normal neighboring cells [
30].
Bioinformatics approaches based on RNA and protein expression profiles of senescent versus non-senescent cells have been used for identification of SCAPs. Key pro-survival proteins were recognized as potential targets for senotherapy. It is important to note that inhibition of pro-survival pathways and a decrease in the expression of SCAPs may promote death of SCs [
43,
90,
91,
92]. Selected drugs and small molecules from chemical libraries were found to interfere with key components of pro-survival pathways in senescent cells and were considered as first-generation senolytics [
24]. Until now, several classes of first-generation senolytics such as natural compounds (e.g., fisetin, quercetin, and piperlongumine), a pan-receptor tyrosine kinase inhibitor dasatinib, HSP90 inhibitors (e.g., geldanamycin, 17-AAG, and 17-DMAG), and Bcl-2 family inhibitors (e.g., navitoclax, ABT-737, A1331852, and UBX1967) have been described [
24,
43,
86,
90,
91,
92,
93,
94,
95,
96,
97,
98,
99]. Targeting SCAPs in culture in vitro using senolytics may result in apoptosis of some SCs. For example, it has been documented that a combination of drugs with senolytic activity, namely dasatinib (a tyrosine kinase inhibitor) and quercetin (a flavonoid with estrogenic activity) eliminates SCs in human and murine cultured cells in vitro and in vivo [
90,
93]. In addition, this combined treatment significantly improves physiological function and increases lifespan in prematurely-aged mice [
90,
94,
95,
96]. Another agent having senotherapeutic activity is a naturally-occurring flavonoid with low toxicity, fisetin. It has been shown that treatment of old and progeroid mice with fisetin reduces some senescence markers in multiple tissues and extends animal lifespan [
97,
98]. Moreover, fisetin preferentially induces apoptosis in senescent human umbilical vein endothelial cells [
97]. It has been shown that a natural product, piperlongumine is also a senolytic agent and preferentially induces apoptosis in oncogene-induced senescent human fibroblast cells [
99]. In addition, the senolytic potential of curcumin analog EF24 (a synthetic analog of natural anti-aging compound) in vitro has been reported that was achieved by apoptosis induction in SCs in an ROS-independent manner, and enhanced proteasome mediated-degradation of the Bcl-2 anti-apoptotic protein [
100]. Panobinostat, a histone deacetylase inhibitor, also has post-chemotherapy senolytic activity in senescent cancer cells [
101]. It has been shown that panobinostat is able to increase caspase 3/7 activity and decrease the expression of anti-apoptotic proteins leading to clearance of SCs, which accumulate after anticancer drug treatment. Another approach to removing SCs from aged mice is targeting the pathways involved in senescence such as the FOXO–p53 axis. Activated FOXO4 transcription factor can induce cellular senescence by interacting with p53, which leads to upregulation of the transcription of a major regulator of senescence, p21. A novel FOXO4-interacting peptide disturbs the FOXO4 communication with p53 and also can induce apoptosis in both prematurely- and naturally-aging mice. Treatment with FOXO4-peptide can enhance health and lifespan in old mice [
102]. Recently, several compounds targeting the chaperone protein HSP90, namely 17-AAG (tanespimycin), geldanamycin, and 17-DMAG (alvespimycin) have been demonstrated to be effective in inducing apoptosis in senescent murine and human cells [
43,
103]. Interestingly, the first in-human pilot study (14 patients) demonstrated that dasatinib and quercetin can eliminate SCs in patients with age-related chronic lung disease (idiopathic pulmonary fibrosis), reduce inflammation, and limit frailty [
93]. More recently, senolytic chimeric antigen receptor (CAR) T cells were designed and their efficacy in eliminating of SCs expressing urokinase-type plasminogen activator receptor (uPAR) in vitro and in vivo systems was documented [
104]. It has been shown that uPAR-specific CAR T cells may preferentially eradicate SCs in a number of experimental models of senescence [
104]. Moreover, BET-family protein degrader (BETd) has been tested for a potential senolytic activity in obesity-induced hepatocellular carcinoma mouse model [
105]. It has been reported that BETd may induce senolysis by targeting non-homologous end joining (NHEJ) and autophagy [
105]. Autophagy is generally considered as a protective and adaptive stress response, but in some cellular settings, autophagy may also contribute to cell death [
106]. Indeed, BETd provoked autophagy-induced apoptosis in senescent cells that was achieved, at least in part, by up-regulation of autophagic gene expression [
105].