Cellular Senescence: Mechanisms and Therapeutic Potential—

Cellular Senescence: Mechanisms and Therapeutic Potential

发表日期：2021-11-26

Cellular senescence is a complex and multistep biological process which cells can undergo in response to different stresses. Referring to a highly stable cell cycle arrest, cellular senescence can influence a multitude of biological processes—both physiologically and pathologically. While phenotypically diverse, characteristics of senescence include the expression of the senescence-associated secretory phenotype, cell cycle arrest factors, senescence-associated β-galactosidase, morphogenesis, and chromatin remodelling. Persistent senescence is associated with pathologies such as aging, while transient senescence is associated with beneficial programmes, such as limb patterning. With these implications, senescence-based translational studies, namely senotherapy and pro-senescence therapy, are well underway to find the cure to complicated diseases such as cancer and atherosclerosis. Being a subject of major interest only in the recent decades, much remains to be studied, such as regarding the identification of unique biomarkers of senescent cells. This review attempts to provide a comprehensive understanding.

40层细胞工厂

细胞衰老是一个复杂的、多步骤的生物过程，细胞可以对不同的压力做出反应。提到高度稳定的细胞周期停滞，细胞衰老会影响多种生理过程和病理过程。虽然表型多样，但衰老的特征包括衰老相关分泌表型的表达、细胞周期停滞因子、衰老相关的 β-半乳糖苷酶、形态发生和染色质重塑。持续衰老与衰老等病理相关，而短暂衰老与有益程序相关，如肢体模式。有了这些影响，基于衰老的转化研究，即衰老疗法和促衰老疗法，正在寻找治愈癌症和动脉粥样硬化等复杂疾病的方法。作为仅在最近几十年才受到关注的主要课题，仍有许多需要研究，例如关于衰老细胞独特生物标志物的鉴定。本综述试图全面了解有关衰老的各种文献，并讨论我们迄今为止对衰老的了解。

Senotherapy is concerned with the development of therapeutic strategies to slowthe ageing process and alleviate its associated diseases by preventing, eliminating, or reversing senescence in cells [145]. Although much of this study is still exploratory, and no drugs have been approved for clinical use, many different strategies have been identified.Central to all is the use of senolytics. Senolytic therapy is one of the more, if not the most, rapidly developing strategy for senotherapy. Senolytic agents are a class of small molecules that have been found to be able to selectively induce the apoptosis of senescent cells by interfering with the SCAPs. Most senolytic drugs that have been identified so far are repurposed anti-cancer drugs, such as the likes of dasatinib and quercetin (used in combination)—the first few senolytics to be discovered. The combination of these two drugs has been widely demonstrated to induce the apoptosis of senescent cells in cultured human tissues and in mouse models [146–148]. In one of the mouse models,the bi-weekly administration of dasatinib and quercetin on aged mice showed a 36% higher median lifespan, while the mortality hazard was reduced to 64.9% [145]. This potential of the senolytic drugs has also been replicated in clinical trials—in the first-of-itskind Phase 1 clinical trial, the administration of dasatinib and quercetin on patients withidiopathic pulmonary fibrosis (IPF; a lung disease in which scarring of the lungs reduces their function) showed a significant improvement in physical functions (such as walking endurance) in the participants [149]. The following subsections briefly discusses some potential senolytics and some recent findings. The information is summarised in Table.

高效摇瓶5L

衰老细胞清除治疗关注减缓治疗策略的发展通过预防，消除或减轻其相关疾病逆转细胞衰老。虽然这项研究的大部分仍然是探索性的，没有药物已被批准用于临床，已经确定了许多不同的策略。所有人的核心是使用senolytics。溶解疗法是其中之一，如果不是大多数，快速发展的senotherapy战略。溶解剂是一类小的已经发现能够选择性诱导衰老细胞凋亡的分子细胞干扰SCAP。大多数已经确定的溶解性药物far是重新使用的抗癌药物，如达沙替尼和槲皮素（使用结合起来）-首先发现的几种衰老细胞清除治疗。这些组合两种药物已被广泛证明可诱导衰老细胞凋亡培养的人体组织和小鼠模型[146-148]。在其中一个鼠标模型中，达沙替尼和槲皮素对老龄小鼠的双周给药率为36%中位寿命更长，而死亡危险降低至64.9%。这个衰老细胞清除治疗药物的潜力也在临床试验中首次被复制1期临床试验，达沙替尼和槲皮素治疗患者特发性肺纤维化（IPF；肺部瘢痕减少的肺部疾病他们的功能）显示了显着改善身体功能。