Institute on the Biology of Aging and Metabolism, Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA; email:
Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota 55905, USA.
Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:779-803. doi: 10.1146/annurev-pharmtox-050120-105018. Epub 2020 Sep 30.
Senescence is the consequence of a signaling mechanism activated in stressed cells to prevent proliferation of cells with damage. Senescent cells (Sncs) often develop a senescence-associated secretory phenotype to prompt immune clearance, which drives chronic sterile inflammation and plays a causal role in aging and age-related diseases. Sncs accumulate with age and at anatomical sites of disease. Thus, they are regarded as a logical therapeutic target. Senotherapeutics are a new class of drugs that selectively kill Sncs (senolytics) or suppress their disease-causing phenotypes (senomorphics/senostatics). Since 2015, several senolytics went from identification to clinical trial. Preclinical data indicate that senolytics alleviate disease in numerous organs, improve physical function and resilience, and suppress all causes of mortality, even if administered to the aged. Here, we review the evidence that Sncs drive aging and disease, the approaches to identify and optimize senotherapeutics, and the current status of preclinical and clinical testing of senolytics.
衰老的发生是一种信号机制的结果，该机制在应激细胞中被激活，以防止受损细胞的增殖。衰老细胞（Sncs）通常会发展出一种衰老相关的分泌表型，以促使免疫清除，从而引发慢性无菌性炎症，并在衰老和与年龄相关的疾病中起因果作用。随着年龄的增长和在疾病的解剖部位，Sncs 会积累。因此，它们被认为是一个合理的治疗靶点。Senotherapeutics 是一类新的药物，可选择性杀死 Sncs（senolytics）或抑制其致病表型（senomorphics/senostatics）。自 2015 年以来，几种 senolytics 从鉴定到临床试验。临床前数据表明，senolytics 可缓解许多器官的疾病，改善身体功能和恢复能力，并抑制所有导致死亡的原因，即使在老年时给药。在这里，我们回顾了 Sncs 驱动衰老和疾病的证据，识别和优化 senotherapeutics 的方法，以及 senolytics 的临床前和临床测试的现状。
