Faculty of Engineering, School of Chemical and Biomolecular Engineering, The University of Sydney, Sydney, New South Wales, Australia.
Centre for Advanced Food Engineering, The University of Sydney, Sydney, New South Wales, Australia.
Aging Cell. 2023 Oct;22(10):e13948. doi: 10.1111/acel.13948. Epub 2023 Aug 7.
Senolytics are a category of drugs that reduce the impact of cellular senescence, an effect associated with a range of chronic and age-related diseases. Since the discovery of the first senolytics in 2015, the number of known senolytic agents has grown dramatically. This review discusses the broad categories of known senolytics-kinase inhibitors, Bcl-2 family protein inhibitors, naturally occurring polyphenols, heat shock protein inhibitors, BET family protein inhibitors, P53 stabilizers, repurposed anti-cancer drugs, cardiac steroids, PPAR-alpha agonists, and antibiotics. The approaches used to screen for new senolytics are articulated including a range of methods to induce senescence, different target cell types, various senolytic assays, and markers. The choice of methods can greatly influence the outcomes of a screen, with high-quality screens featuring robust systems, adequate controls, and extensive validation in alternate assays. Recent advances in single-cell analysis and computational methods for senolytic identification are also discussed. There is significant potential for further drug discovery, but this will require additional research into drug targets and mechanisms of actions and their subsequent rigorous evaluation in pre-clinical models and human trials.
衰老细胞清除剂是一类能够减轻细胞衰老影响的药物，细胞衰老是与一系列慢性和与年龄相关的疾病相关的效应。自 2015 年首次发现衰老细胞清除剂以来，已知的衰老细胞清除剂的数量显著增加。这篇综述讨论了已知的衰老细胞清除剂的广泛类别，包括：激酶抑制剂、Bcl-2 家族蛋白抑制剂、天然存在的多酚、热休克蛋白抑制剂、BET 家族蛋白抑制剂、P53 稳定剂、再利用的抗癌药物、心脏甾体、PPAR-α 激动剂和抗生素。本文还阐述了用于筛选新的衰老细胞清除剂的方法，包括诱导衰老的一系列方法、不同的靶细胞类型、各种衰老细胞清除剂检测和标记物。方法的选择会极大地影响筛选的结果，高质量的筛选需要具有强大系统、充分对照和在其他检测中的广泛验证的方法。本文还讨论了衰老细胞清除剂鉴定中单细胞分析和计算方法的最新进展。进一步的药物发现具有巨大的潜力，但这需要对药物靶点和作用机制进行更多的研究，并在临床前模型和人体试验中对其进行严格的评估。
