Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Beijing, China.
Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China; College of Basic Medicine and Life Sciences, Hainan Medical University, Haikou, China.
Mech Ageing Dev. 2021 Apr;195:111468. doi: 10.1016/j.mad.2021.111468. Epub 2021 Mar 16.
Senescent cells (SCs) accumulate with age and cause various age-related diseases. Clearance of SCs by transgenic or pharmaceutical strategies has been demonstrated to delay aging, treat age-related diseases and extend healthspan. SCs are resistant to various stressors because they are protected from apoptosis by SC anti-apoptotic pathways (SCAPs). Targeting the proteins in the SCAPs with small molecules can selectively kill SCs, the effector proteins are called senolytic targets and the small molecules are called senolytics. Until now, a series of senolytic targets, such as BCL-XL, heat shock protein 90 (HSP90), Na/K ATPase, bromodomain containing 4 (BRD4), and oxidation resistance 1 (OXR1) have been identified. However, current senolytics targeting these proteins still have some limitations in killing SCs in terms of safety, specificity and broad-spectrum activity. To overcome the challenges, some new strategies, such as proteolysis-targeting chimera (PROTAC) technology, chimeric antigen receptor (CAR) T cells, and β-galactosidase-modified prodrugs, were developed to clear SCs and shown to have promising therapeutic potential. Here we review the significance of SCs in aging and age-related diseases, summarize the known senolytic targets and highlight the emerging new strategies for clearing SCs.
衰老细胞（SCs）随着年龄的增长而积累，并导致各种与年龄相关的疾病。通过转基因或药物策略清除 SCs 已被证明可以延缓衰老、治疗与年龄相关的疾病并延长健康寿命。SCs 对各种应激源具有抵抗力，因为它们受到 SC 抗细胞凋亡途径（SCAPs）的保护而免于凋亡。用小分子靶向 SCAPs 中的蛋白质可以选择性地杀死 SCs，这些效应蛋白称为衰老细胞选择性杀伤剂（senolytic targets），小分子称为衰老细胞选择性杀伤剂（senolytics）。到目前为止，已经鉴定出一系列衰老细胞选择性杀伤剂靶点，如 BCL-XL、热休克蛋白 90（HSP90）、Na/K ATPase、溴结构域包含蛋白 4（BRD4）和氧化还原酶 1（OXR1）。然而，目前针对这些蛋白质的衰老细胞选择性杀伤剂在安全性、特异性和广谱活性方面仍然存在一些限制，无法有效杀死 SCs。为了克服这些挑战，开发了一些新策略，如蛋白水解靶向嵌合体（PROTAC）技术、嵌合抗原受体（CAR）T 细胞和β-半乳糖苷酶修饰前药，以清除 SCs，并显示出有希望的治疗潜力。本文综述了 SCs 在衰老和与年龄相关的疾病中的重要性，总结了已知的衰老细胞选择性杀伤剂靶点，并强调了新兴的清除 SCs 的新策略。
