Advancements in therapeutic drugs targeting of senescence

Abstract

Aging leads to a high burden on society, both medically and economically. Cellular senescence plays an essential role in the initiation of aging and age-related diseases. Recent studies have highlighted the therapeutic value of senescent cell deletion in natural aging and many age-related disorders. However, the therapeutic strategies for manipulating cellular senescence are still at an early stage of development. Among these strategies, therapeutic drugs that target cellular senescence are arguably the most highly anticipated. Many recent studies have demonstrated that a variety of drugs exhibit healthy aging effects. In this review, we summarize different types of drugs promoting healthy aging – such as senolytics, senescence-associated secretory phenotype (SASP) inhibitors, and nutrient signaling regulators – and provide an update on their potential therapeutic merits. Taken together, our review synthesizes recent advancements in the therapeutic potentialities of drugs promoting healthy aging with regard to their clinical implications.

Cellular Senescence in Brain Aging

“…Dendritic arborization, length, synapse number, and spine density decrease to variable degrees in cortical areas. This is accompanied by reductions in most aspects of cognitive performance including memory, awareness, and intellectual abilities (Zhu et al, 2020 ). It can be speculated that brain aging, similarly to that of other organs, is caused by senescent cells.…”

“…The senolytic treatment, without genetic manipulations, has already been applied in many mouse models of age-related disease ( Figure 5B ). In general, senolytics can be classified into BCL family inhibitors, PI3K/AKT inhibitors, and FOXO regulators (Zhu et al, 2020 ). Briefly, the BCL family is composed of anti-apoptotic and pro-survival proteins, including BCL-2 and BCL-xL, the selective inhibition of which has been previously shown to cause cell death in some cancers (e.g., Souers et al, 2013 ).…”

Donor and Recipient Age-Mismatches: The Potential of Transferring Senescence

“…Senolytics are a class of drugs that selectively clear senescent cells through inhibiting their SCAPs, thus driving them into apoptosis. According to their targeted SCAP, first generation senolytics can be subdivided in groups including, i), BCL-2 inhibitors such as navitoclax that inhibit the pro-survival pathway BCL-2/BCL-xL, ii), PI3AK/AKT inhibitors including Dasitinib and Quercetin (D & Q) that constrain the synergistic effects of PI3K and Akt inactivating the apoptosis mediating proteins Bad, caspase-9 and FKHRL1 and iii), FOXO regulators such as Foxo4-DRI interfering with the inhibition of p53mediated apoptosis (52). In addition, cardiac glycosides have been shown to exert senolytics activity through targeting the Na + /K + Atpase (53,54) while most recently a BET family protein degrader targeting the non-homologous end joining and autophagy has been delineated as a promising novel senolytic drug (55) (Table 1).…”

Cisplatin and Pemetrexed Have Distinctive Growth-inhibitory Effects in Monotherapy and Combination Therapy onKRAS-dependent A549 Lung Cancer Cells

“…Previous studies have reported that chemotherapy drugs can induce cellular senescence of cancer cells (56)(57)(58)(59). Some claim that some chemotherapy drugs can remove cellular senescence (60,61). Therefore, it is crucial to characterize the senescence status correctly when managing patients with cancer.…”