文章：

形成体内衰老的标志

Forging a signature of in vivo senescence

原文发布日期：2015-03-19

DOI: 10.1038/nrc3960

类型: Review Article

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要点：

1. Although the term 'cellular senescence' was originally used to define the state of irreversible proliferative arrest by cultured cells that had reached their replicative limit, it is now widely used to describe states of cell cycle arrest in different in vivo biological settings, including age-associated loss of regenerative capacity, tumour suppression, inflammation, wound healing and embryogenesis.
2. A central problem in the senescence field is the lack of a uniform definition of cellular senescence, coupled with inconsistent application of biomarkers to identify and enumerate senescent cells in vivo.
3. Although frequently used in various combinations to denote putatively senescent cells in vivo, senescence-associated biomarkers — such as robust expression of lysosomal β-galactosidase and the cyclin D-dependent kinase inhibitor p16^INK4A, activation of the DNA-damage response, alterations in paracrine secretion and changes in heterochromatin — are individually nonspecific. There is no consensus on which amalgamation of these biomarkers describes the senescent state.
4. Many cancer-associated stress factors activate senescence biomarkers, supporting the roles of senescence-associated processes in tumour suppression. A commonly used senescence marker, the tumour suppressor p16^INK4A, progressively increases during organismal ageing and may indeed restrict longevity in certain animal models, but it is unclear whether its expression marks the accumulation of senescent cells per se or, instead, accompanies proliferative arrest in response to many forms of cellular stress.
5. We advocate that 'cellular senescence' should be strictly defined as stress-induced proliferative arrest accompanied by the failure to re-enter the cell division cycle in response to mitogenic and oncogenic stimuli. More-specific descriptors could then be applied to characterize many of the diverse phenotypes that define complex and possibly distinct cellular states currently aggregated under the umbrella term 'senescence'.

要点翻译：

1. 尽管“细胞衰老”一词最初用于定义培养细胞达到其复制极限时不可逆增殖停滞的状态，但现在它被广泛用于描述不同体内生物学环境中的细胞周期停滞状态，包括与年龄相关的再生能力丧失、肿瘤抑制、炎症、伤口愈合和胚胎发生。
2. 衰老领域的一个核心问题是缺乏对细胞衰老的统一定义，再加上生物标志物在识别和计数体内衰老细胞时应用不一致。
3. 虽然衰老相关生物标志物——如溶酶体β-半乳糖苷酶的稳定表达和细胞周期蛋白D依赖性激酶抑制剂p16INK4A、DNA损伤反应的激活、旁分泌的改变和异染色质的变化——经常以各种组合用于表示体内推定的衰老细胞，但每个标志物本身都是非特异性的。对于这些生物标志物的何种组合可以描述衰老状态，目前尚无共识。
4. 许多癌症相关应激因素会激活衰老生物标志物，这支持了衰老相关过程在肿瘤抑制中的作用。常用的衰老标记物——肿瘤抑制因子p16INK4A——在机体衰老过程中逐渐增加，并可能确实限制某些动物模型的寿命，但尚不清楚其表达是标记了衰老细胞本身的积累，还是伴随细胞对多种形式应激反应而出现的增殖停滞。
5. 我们主张，“细胞衰老”应严格定义为应激诱导的增殖停滞，同时伴随对促有丝分裂和致癌刺激无法重新进入细胞分裂周期。然后可以应用更具体的描述符来定义许多目前被归入“衰老”这一总称下的复杂且可能不同的细胞状态表型。

英文摘要：

'Cellular senescence', a term originally defining the characteristics of cultured cells that exceed their replicative limit, has been broadened to describe durable states of proliferative arrest induced by disparate stress factors. Proposed relationships between cellular senescence, tumour suppression, loss of tissue regenerative capacity and ageing suffer from lack of uniform definition and consistently applied criteria. Here, we highlight caveats in interpreting the importance of suboptimal senescence-associated biomarkers, expressed either alone or in combination. We advocate that more-specific descriptors be substituted for the now broadly applied umbrella term 'senescence' in defining the suite of diverse physiological responses to cellular stress.

摘要翻译： 

“细胞衰老”一词最初用于描述培养细胞超过其复制极限的特征，现已扩展为指由不同应激因素诱导的持久性增殖停滞状态。关于细胞衰老与肿瘤抑制、组织再生能力下降及衰老之间的关联，因缺乏统一定义和一致标准而备受争议。在此，我们强调解读次优衰老相关生物标志物（单独或联合表达）重要性时需谨慎。我们主张，对于当前广泛使用的“衰老”这一总括性术语，应以更具体的描述替代，以界定细胞应激所引发的多样化生理反应。

原文链接：

Forging a signature of in vivo senescence