细胞衰老的过去、现在和未来:从科学解析到主动干预

The past,present,and future of cellular senescence:from scientific insights to active interventions

高等生物体内的细胞衰老是机体衰老的原始驱动力,通过终止细胞周期循环来应对内外源胁迫性刺激。衰老细胞在整个生命周期中均可出现,但若长期或持续性出现,组织器官的正常功能会因其分泌的大量促炎性蛋白而受到病理性损害。在临床前模型中,针对那些持续存在并导致组织紊乱和器官损伤的衰老细胞进行干预已被证明可以有效延缓衰老、预防或缓解多种增龄相关疾病。尤其重要的,衰老医学界针对选择性清除衰老细胞的小分子药物senolytics的研发为积极预防或干预人类多种增龄相关疾病提供了强大的动力和灿烂的远景。在这篇综述中,笔者将介绍将衰老细胞作为老年疾病治疗靶点的基本原理,讨论近年正在兴起并迅速推广的人类临床试验的技术策略和发展前景,包括那些将小分子化合物senolytics及其相关衰老干预措施转化为临床应用的国际前沿探索。

In the kingdom of higher organisms,cell senescence represents the original driving force of organismal aging,which occurs in response to endogenous and exogenous stressful stimuli by terminating the cell cycle circulation.Senescent cells can arise throughout the life cycle,but if they are present for long-term or persistent,the normal function of tissues and organs will be pathologically affected by their continued secretion of numerous pro-inflammatory protein factors.Interventions specifically targeting senescent cells that persist and cause tissue disorders and organ dysfunctions have demonstrated their effectiveness in delaying,preventing or alleviating a wide variety of aging-related diseases in preclinical models.Particularly,the development of a class of small molecule drugs,namely senolytics,which can selectively remove senescent cells from the microenvironment,provides a strong impetus and a fascinating vision for the active prevention or intervention of multiple aging-related pathologies in humans.In this review,I will introduce the basic principles of employing senescent cells as a therapeutic target for geriatric disorders,and discuss the technical strategies and development prospects of human clinical trials which are emerging and rapidly progressing in recent years,including those leading international explorations in translating small molecule compounds senolytics and related antiaging interventions into clinical practices.