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Cellular Senescence: Mechanisms and Therapeutic Potential

發(fā)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層細胞工廠

細胞衰老是一個復雜的、多步驟的生物過程，細胞可以對不同的壓力做出反應。提到高度穩(wěn)定的細胞周期停滯，細胞衰老會影響多種生理過程和病理過程。雖然表型多樣，但衰老的特征包括衰老相關分泌表型的表達、細胞周期停滯因子、衰老相關的 β-半乳糖苷酶、形態(tài)發(fā)生和染色質重塑。持續(xù)衰老與衰老等病理相關，而短暫衰老與有益程序相關，如肢體模式。有了這些影響，基于衰老的轉化研究，即衰老療法和促衰老療法，正在尋找治愈癌癥和動脈粥樣硬化等復雜疾病的方法。作為僅在最近幾十年才受到關注的主要課題，仍有許多需要研究，例如關于衰老細胞獨特生物標志物的鑒定。本綜述試圖全面了解有關衰老的各種文獻，并討論我們迄今為止對衰老的了解。

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.

高效搖瓶5L

衰老細胞清除治療關注減緩治療策略的發(fā)展通過預防，消除或減輕其相關疾病逆轉細胞衰老。雖然這項研究的大部分仍然是探索性的，沒有藥物已被批準用于臨床，已經確定了許多不同的策略。所有人的核心是使用senolytics。溶解療法是其中之一，如果不是大多數，快速發(fā)展的senotherapy戰(zhàn)略。溶解劑是一類小的已經發(fā)現能夠選擇性誘導衰老細胞凋亡的分子細胞干擾SCAP。大多數已經確定的溶解性藥物far是重新使用的抗癌藥物，如達沙替尼和槲皮素（使用結合起來）-首先發(fā)現的幾種衰老細胞清除治療。這些組合兩種藥物已被廣泛證明可誘導衰老細胞凋亡培養(yǎng)的人體組織和小鼠模型[146-148]。在其中一個鼠標模型中，達沙替尼和槲皮素對老齡小鼠的雙周給藥率為36%中位壽命更長，而死亡危險降低至64.9%。這個衰老細胞清除治療藥物的潛力也在臨床試驗中首次被復制1期臨床試驗，達沙替尼和槲皮素治療患者特發(fā)性肺纖維化（IPF；肺部瘢痕減少的肺部疾病他們的功能）顯示了顯著改善身體功能。