Molecular Bases of Aging Laboratory, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland.
Ageing Res Rev. 2011 Jan;10(1):146-52. doi: 10.1016/j.arr.2010.10.002. Epub 2010 Oct 12.
Cellular senescence as the state of permanent inhibition of cell proliferation is a tumour-suppressive mechanism. However, due to the associated secretory phenotype senescence can also contribute to cancer and possibly other age-related diseases, such as obesity, diabetes, atherosclerosis and Alzheimer's disease. There are two major mechanisms of cellular senescence; replicative senescence depends on telomere erosion or dysfunction whilst stress-induced premature senescence (SIPS) is telomere-independent and also includes oncogene-induced senescence (OIS). The senescence phenotype is characterised by altered cellular morphology, increased activity for senescence-associated-β-galactosidase (SA-β-GAL), increased formation of senescence-associated heterochromatin foci (SAHF) and promyelocytic leukemia protein nuclear bodies (PML NBs), permanent DNA damage, chromosomal instability and an inflammatory secretome. Some of these markers have been identified in cells from age-related pathologies. However, to improve our understanding of the contribution of cellular senescence to organismal ageing and age-related disease, it is imperative to define an unequivocal signature of cellular senescence that is functionally connected with normal and pathological ageing. Herein, we describe the processes leading to senescence, and the current biomarkers of cellular senescence, with particular emphasis on the causal role of DNA damage responses involved in the process. We highlight the gaps in our knowledge both of the processes leading to senescence, and the signature of cellular senescence both in vitro and in vivo. A well-defined set of senescence biomarkers for ageing and age-related disease would have a strong impact on the diagnosis, staging and predicted outcomes of age-related disease, providing the basis for a pharmacological intervention to postpone ageing and age-related disease.
细胞衰老作为细胞增殖永久抑制的状态是一种肿瘤抑制机制。然而，由于与衰老相关的分泌表型，衰老也可能导致癌症和其他与年龄相关的疾病，如肥胖、糖尿病、动脉粥样硬化和阿尔茨海默病。细胞衰老有两种主要机制；复制性衰老取决于端粒磨损或功能障碍，而应激诱导的过早衰老（SIPS）是端粒独立的，还包括癌基因诱导的衰老（OIS）。衰老表型的特征是细胞形态改变、衰老相关-β-半乳糖苷酶（SA-β-GAL）活性增加、衰老相关异染色质焦点（SAHF）和早幼粒细胞白血病蛋白核体（PML NBs）形成增加、永久性 DNA 损伤、染色体不稳定和炎症分泌组。这些标志物中的一些已在与年龄相关的病理细胞中被识别。然而，为了更好地理解细胞衰老对机体衰老和与年龄相关疾病的贡献，必须定义一个与正常和病理衰老功能相关的明确的细胞衰老特征。本文描述了导致衰老的过程，以及目前细胞衰老的生物标志物，特别强调了参与这一过程的 DNA 损伤反应的因果作用。我们强调了我们在导致衰老的过程以及体外和体内细胞衰老特征方面的知识差距。一组定义明确的衰老生物标志物，用于衰老和与年龄相关的疾病，将对与年龄相关的疾病的诊断、分期和预测结果产生重大影响，为延缓衰老和与年龄相关的疾病提供药理学干预的基础。
