Cellular senescence in bone
Cellular senescence in bone
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DOI：
10.1016/j.bone.2019.01.015
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发表时间：
2019-04-01
期刊：
影响因子：
4.1
通讯作者：
Khosla, Sundeep
中科院分区：
文献类型：
--
作者：
Farr, Joshua N.;Khosla, Sundeep
细胞衰老是指由各种类型的应激诱导的过程，其引起不可逆的细胞周期停滞和不同的细胞改变，包括基因表达、代谢和染色质组织的深刻变化以及抗凋亡途径的激活/增强和促炎分泌组或衰老相关分泌表型（SASP）的发展。然而，由于在识别和表征活生物体中的衰老细胞方面的挑战和技术限制，直到最近才发现这些独特细胞的一些不同的体内作用。新的发现表明，衰老细胞及其SASP可以具有急性有益功能，例如组织再生和伤口愈合。然而，相比之下，当衰老细胞在病理部位或旧组织中长期过量积累时，它们会导致多种与年龄相关的慢性疾病。已经开发了选择性消除衰老细胞（“senolytics”）或抑制其有害SASP（“senomorphics”）的衰老治疗剂，并在衰老的临床前模型中进行了测试。这些研究已经确定，针对衰老是一种强大的抗衰老策略，以改善“健康寿命”-即，没有慢性病的健康生活时期。衰老在介导年龄相关性骨丢失中的作用是近年来研究的热点。对小鼠和人类的研究表明，随着年龄的增长，骨微环境中大多数细胞类型的至少一个子集变得衰老并形成异质性SASP。此外，年龄相关的骨丢失可以在老年小鼠中得到缓解，与抗再吸收疗法相比具有明显的优势，通过遗传学方法减少衰老细胞负荷，或者用第一类senolytics或senomorphic治疗。总的来说，这些发现指出，将衰老作为延长健康寿命的转型策略，因此为识别和优化senotherapeutics以减轻多种慢性衰老疾病（包括骨质疏松症）提供了强有力的理由，并为将senotherapeutics转化为人类奠定了基础，目前正在进行临床试验。
Cellular senescence refers to a process induced by various types of stress that causes irreversible cell cycle arrest and distinct cellular alterations, including profound changes in gene expression, metabolism, and chromatin organization as well as activation/reinforcement of anti-apoptotic pathways and development of a pro-inflammatory secretome or senescence-associated secretory phenotype (SASP). However, because of challenges and technical limitations in identifying and characterizing senescent cells in living organisms, only recently have some of the diverse in vivo roles of these unique cells been discovered. New findings indicate that senescent cells and their SASP can have acute beneficial functions, such as in tissue regeneration and wound healing. However, in contrast, when senescent cells accumulate in excess chronically at sites of pathology or in old tissues they drive multiple age-associated chronic diseases. Senotherapeutics that selectively eliminate senescent cells ("senolytics") or inhibit their detrimental SASP ("senomorphics") have been developed and tested in aged preclinical models. These studies have established that targeting senescence is a powerful anti-aging strategy to improve "healthspan" - ie., the healthy period of life free of chronic disease. The roles of senescence in mediating age-related bone loss have been a recent focus of rigorous investigation. Studies in mice and humans demonstrate that with aging, at least a subset of most cell types in the bone microenvironment become senescent and develop a heterogeneous SASP. Furthermore, age-related bone loss can be alleviated in old mice, with apparent advantages over anti-resorptive therapy, by reducing the senescent cell burden genetically or pharmacologically with the first class of senolytics or a senomorphic. Collectively, these findings point to targeting senescence as a transformational strategy to extend healthspan, therefore providing strong rationale for identifying and optimizing senotherapeutics to alleviate multiple chronic diseases of aging, including osteoporosis, and set the stage for translating senotherapeutics to humans, with clinical trials currently ongoing.