Cell两篇文章提出重要新观点:衰老不仅仅是老化

【字体: 时间:2013年11月15日 来源:生物通

编辑推荐:

  两篇发表于Cell杂志上的文章提出了一种新观点:衰老(Senescence)是胚胎发育过程中的一种正常的关键过程,其在这一过程中扮演了一个全新的,出乎人意料的作用,并与老化(aging)和癌症有关。

  

生物通报道:两篇发表于Cell杂志上的文章提出了一种新观点:衰老(Senescence)是胚胎发育过程中的一种正常的关键过程,其在这一过程中扮演了一个全新的,出乎人意料的作用,并与老化(aging)和癌症有关。

这两项研究分别由西班牙基因组调控研究中心(CRG),以及西班牙国家癌症研究中心(CNIO)的研究人员完成,同期发表于Cell杂志在线版上。

衰老是细胞在应激压力下对其增殖做出限制的一种状态。这种细胞内状态历来在老化和癌症中都会被描述到。然而最新的这两项研究,第一次指出这种状态并不仅仅只与应激压力和肿瘤增殖有关,在胚胎发育的正常过程中也需要这种状态。

“这是第一次有研究如此清楚地表明,衰老是一个程序性发育机制,这种新的描述有助于我们理解正常细胞进程中衰老过程中的作用和意义,”CRG癌症与老化机制实验室主任Bill Keyes解释道, “我们的研究工作表明,在胚胎中,衰老细胞是必需的,并且通过它们的正常分泌功能能指导组织生长和模式发生 ” 。

Keyes和他的同事将衰老描述为胚胎中两个主要信号中心的一个基本组成部分,这能帮助调控正常的肢体和神经系统的发育。同样,另外一项由CNIO的 Manuel Serrano领导的,博士后研究员Daniel Munoz-Espin等人完成的研究中,也在两个其它的组织:发育中的肾脏和耳朵里发现了这些相同的进程。

此后这两个研究组也都分析了巨噬细胞对衰老细胞的协调剔除,是如何在发育组织的重塑中扮演关键作用的,这个过程是正常模式化所必需的。

有趣的是,研究人员描述衰老发生的组织正是最容易受到先天性出生缺陷影响的部位,这表明解析胚胎中衰老调控的机制,将有助于解释一些发育异常的病因。

这些研究提出了对衰老的新见解,由此科学家认为与老化和癌症有关的衰老过程是一种发育机制的渐进适应。“希望随着在胚胎正常环境中发现的衰老过程,我们未来能够找到一些新的介导作用因子,以及衰老生物标志物” 其中一项研究的第一作者,博士生的研究,Mekayla Storer表示,“这些发现改变了我们过去对衰老的理解,也令我们对癌症和老化有了全新的认识。 ”(生物通:张迪)

原文摘要:
Programmed Cell Senescence during Mammalian Embryonic Development

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-β/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence

Senescence Is a Developmental Mechanism that Contributes to Embryonic Growth and Patterning
Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states. Here we describe senescence as a normal developmental mechanism found throughout the embryo, including the apical ectodermal ridge (AER) and the neural roof plate, two signaling centers in embryonic patterning. Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.


 

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