清除衰老细胞在衰老与老龄化相关疾病中的研究进展
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1.1)浙江大学医学院干细胞与再生医学研究中心,杭州 310058;2.2)河南大学药学院,河南大学-麦考瑞大学生物医学联合创新中心,开封 475001;3.3)Department of Biomedical Sciences,Faculty of Medicine and Health Sciences,Macquarie University,Australia;4.4)浙江大学第一附属医院骨髓移植中心,杭州 310003

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国家自然科学基金器官衰老重大专项培育项目(91849131)和杭州师范大学衰老研究所开放基金资助项目.


Research Progress in Clearance of Senescent Cells in Aging and Age-related Diseases
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1.1)Stem Cell and Regenerative Medicine Research Center, Zhejiang University School of Medicine, Hangzhou 310058, China;2.2)School of Pharmacy, Henan-Macquarie University Joint Centre for Biomedical Innovation, Henan University, Kaifeng 475001, China;3.3)Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Australia;4.4)Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China

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This work was supported by a grant from The National Natural Science Foundation (91849131) and Hangzhou Normal University Institute of Aging, Open Fund Project.

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    摘要:

    衰老是一个新兴的重要研究领域,随着该领域相关知识的积累和技术的进步,人们逐渐意识到衰老本身可以被针对性地干预,实现延长寿命并且延缓衰老相关疾病的发生发展,具有重要的科学和现实意义. 引起个体衰老的众多因素中,衰老细胞的积累被认为是导致器官衰老发生退行性变,最终引起衰老相关疾病的重要原因. 近年来,多项研究表明,清除体内衰老细胞可以延缓多种衰老相关疾病的发生,直接证明了衰老细胞是导致衰老相关疾病的重要原因之一,为治疗衰老相关疾病提供了新靶点. 细胞衰老是由于损伤积累诱发了细胞周期抑制通路的激活,细胞永久地退出细胞增殖周期. 衰老细胞会发生细胞形态、转录谱、蛋白质稳态、表观遗传以及代谢等系列特征的改变,同时衰老细胞对凋亡发生抵抗从而在体内多器官组织积累. 衰老细胞会激活炎症因子分泌通路,导致组织局部非感染性炎症微环境,进而导致器官退行性变及多种衰老相关疾病的发生发展. 因此针对衰老细胞对凋亡抵抗的特性,多个研究小组通过筛选小分子化合物库,发现某些化合物能够选择性清除衰老细胞,这些小分子化合物被称为“senolytics”,意为“衰老细胞杀伤性化合物”. 衰老细胞杀伤性化合物在多种衰老相关疾病动物模型中能够延缓疾病的发展并延长哺乳动物寿命. 因此,靶向杀伤衰老细胞对多种衰老相关疾病的治疗从而提高健康寿命具有重要的临床应用前景. 除靶向杀伤衰老细胞策略以外,干细胞移植、基因编辑、异体共生等策略在抗衰老研究发展中也具有重要意义,具有启发性. 本文通过汇总近期衰老细胞清除领域的重要进展和多种抗衰老策略,将细胞衰老研究发展史做简要梳理,就细胞衰老与衰老相关疾病的关系作一综述,重点讨论衰老细胞在多种衰老相关疾病中作为治疗靶点的应用潜力,并就其局限性和进一步的研究方向进行探讨.

    Abstract:

    Aging is an emerging and important research area. With the accumulation of knowledge in related fields and the advancement of technology, people gradually realized that aging itself can be intervened and it is of great scientific and practical significance to delay aging, especially delaying the occurrence and development of age-related diseases. Among the many factors that cause individual aging, the accumulation of senescent cells is considered to be an important reason that leads to organ aging and degeneration, and finally causes the age-related diseases. In recent years, a number of studies have shown that removing senescent cells in vivo can delay the occurrence of multiple age-related diseases, which directly proves that senescent cells are one of the important causes of age-related diseases, providing a new target for the treatment of age-related diseases. Cellular senescence is generally considered due to the activation of cell cycle inhibition pathway induced by accumulation of damages, and the cells permanently exit the proliferation cycle. Senescent cells undergo changes in cell morphology, transcriptional profiles, protein homeostasis, epigenome and metabolism. Moreover, senescent cells resist apoptosis and therefore accumulate in multiple organs and tissues in the body. Senescent cells secrete a number of inflammatory factors, leading to a local non-infectious inflammatory tissue microenvironment, which will cause organ function deterioration and a variety of age-related diseases. Therefore, several research groups have screened the library of small molecular compounds and found that certain compounds can selectively eliminate senescent cells by targeting pathways underpinning senescent cells" resistance to apoptosis. These small molecular compounds are called " senolytics ", denoting compounds for killing senescent cells. Senolytics have been shown to alleviate multiple age-related diseases and prolong the lifespan in animal models. Therefore, targeted killing of senescent cells has an important clinical application prospect for the treatment of a variety of age-related diseases so as to improve the healthy lifespan. In addition, strategies such as stem cell transplantation, gene editing and heterochronic parabiosis are also of great significance and inspiration in the development of anti-aging research. By summarizing the recent important progress in the field of senescent cell clearance and a variety of anti-aging strategies, this paper briefly reviews the history of cellular senescence research, discusses the relationship between cellular senescence and age-related diseases, emphasizing on the potential therapeutic applications by targeting senescent cells and the limitations, as well as the further research directions in this field.

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陈祥宁,刘洋,纪俊峰.清除衰老细胞在衰老与老龄化相关疾病中的研究进展[J].生物化学与生物物理进展,2019,46(12):1150-1161

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  • 收稿日期:2019-08-22
  • 最后修改日期:2019-11-08
  • 接受日期:2019-11-21
  • 在线发布日期: 2020-04-23
  • 出版日期: 2019-12-20
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