寻找抗衰老药物的策略。
Strategies for senolytic drug discovery.
发表日期:2023 Aug 07
作者:
Helen Power, Peter Valtchev, Fariba Dehghani, Aaron Schindeler
来源:
AGING CELL
摘要:
抗衰老药物是一类可减轻细胞衰老影响的药物,该效果与一系列慢性病和与年龄相关的疾病有关。自2015年首次发现抗衰老药物以来,已知的抗衰老药物数量显著增长。本综述讨论了已知抗衰老药物的广泛类别,包括激酶抑制剂、Bcl-2家族蛋白抑制剂、天然多酚类物质、热休克蛋白抑制剂、BET家族蛋白抑制剂、P53稳定剂、重复利用的抗癌药物、心脏类固醇、PPAR-α激动剂和抗生素。文章还阐明了筛选新型抗衰老药物所使用的方法,包括多种诱导细胞衰老的方法、不同的靶细胞类型、各种抗衰老试验和标记物。方法的选择可能会极大地影响筛选的结果,高质量的筛选系统具有稳健的系统、充足的对照和在其他试验中的广泛验证。文章还讨论了单细胞分析和计算方法在抗衰老物质鉴定方面的最新进展。进一步的药物发现有重要的潜力,但需要进一步研究药物靶标及其作用机制,并在临床前模型和人体试验中进行严格评估。© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.
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.© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.