European Research Institute for the Biology of Aging, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands.
Buck Institute for Research on Aging, 8001 Redwood Boulevard, 94945 Novato CA, USA.
Curr Biol. 2017 Sep 11;27(17):2652-2660.e4. doi: 10.1016/j.cub.2017.07.033. Epub 2017 Aug 30.
Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5-8], and organismal aging [9]. The senescence program is variably characterized by several non-exclusive markers, including constitutive DNA damage response (DDR) signaling, senescence-associated β-galactosidase (SA-βgal) activity, increased expression of the cyclin-dependent kinase (CDK) inhibitors p16INK4A (CDKN2A) and p21CIP1 (CDKN1A), increased secretion of many bio-active factors (the senescence-associated secretory phenotype, or SASP), and reduced expression of the nuclear lamina protein LaminB1 (LMNB1) [1]. Many senescence-associated markers result from altered transcription, but the senescent phenotype is variable, and methods for clearly identifying senescent cells are lacking [10]. Here, we characterize the heterogeneity of the senescence program using numerous whole-transcriptome datasets generated by us or publicly available. We identify transcriptome signatures associated with specific senescence-inducing stresses or senescent cell types and identify and validate genes that are commonly differentially regulated. We also show that the senescent phenotype is dynamic, changing at varying intervals after senescence induction. Identifying novel transcriptome signatures to detect any type of senescent cell or to discriminate among diverse senescence programs is an attractive strategy for determining the diverse biological roles of senescent cells and developing specific drug targets.
细胞衰老（cellular senescence）是一种不可逆的增殖停滞状态，通常由遗传毒性应激诱导[1]。衰老细胞参与多种生理和病理条件，包括肿瘤抑制[2]、胚胎发育[3,4]、组织修复[5-8]和机体衰老[9]。衰老程序的特征是几种非排他性的标志物，包括固有 DNA 损伤反应（DDR）信号、衰老相关β-半乳糖苷酶（SA-βgal）活性、细胞周期蛋白依赖性激酶（CDK）抑制剂 p16INK4A（CDKN2A）和 p21CIP1（CDKN1A）的表达增加、许多生物活性因子的分泌增加（衰老相关分泌表型，或 SASP），以及核纤层蛋白 LaminB1（LMNB1）的核表达减少[1]。许多衰老相关标志物源自转录改变，但衰老表型是多变的，并且缺乏明确鉴定衰老细胞的方法[10]。在这里，我们使用我们或公开获得的大量全转录组数据集来描述衰老程序的异质性。我们确定了与特定的衰老诱导应激或衰老细胞类型相关的转录组特征，并确定和验证了常见差异调控的基因。我们还表明，衰老表型是动态的，在衰老诱导后不同的时间间隔发生变化。鉴定新的转录组特征以检测任何类型的衰老细胞或区分不同的衰老程序是确定衰老细胞的多种生物学作用和开发特定药物靶点的一种有吸引力的策略。
