Cellular Senescence as the Causal Nexus of Aging.
Cellular Senescence as the Causal Nexus of Aging.
复制标题
细胞衰老作为衰老的因果关系。
DOI：
10.3389/fgene.2016.00013
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发表时间：
2016
影响因子：
3.7
通讯作者：
Csoka AB
中科院分区：
文献类型：
--
作者：
Bhatia-Dey N;Kanherkar RR;Stair SE;Makarev EO;Csoka AB
在本文中，我们认为细胞衰老是衰老过程的最终驱动因素，是连接微观亚细胞损伤与表型、宏观衰老效应的“因果关系”。重要的是要了解各种类型的亚细胞损伤如何与衰老过程相关，从而导致更大的、可见的解剖衰老效应。虽然人们一直认为亚细胞损伤（因）导致宏观衰老（果），但两者之间的桥梁联系一直难以界定。在这里，我们提出这个桥梁，我们称之为“因果关系”，实际上是细胞衰老。亚细胞损伤本身并不直接导致可见的衰老迹象，但是，随着损伤的积累和达到临界质量，细胞停止增殖并获得有害的“衰老相关分泌表型”（SASP），这将导致组织破坏的宏观后果，从而产生生理衰老表型。因此，衰老是解剖老化的先决条件，这就解释了为什么衰老是一个渐进的过程，在其大部分进展过程中基本上是看不见的。亚细胞损伤包括端粒缩短、线粒体损伤、非整倍体和由各种遗传、表观遗传和环境因素引发的DNA双链断裂。在细胞衰老的因果关系中，单独或协同作用的损伤途径汇聚在一起。在每个物种中，某些类型的损害可能比其他物种更具有致病性，并以不同的速度运作；例如，端粒侵蚀似乎是人类细胞的主要原因，而肿瘤抑制基因的激活在啮齿动物中更具致病性。这种物种特异性机制表明，尽管不同的初始原因，大多数衰老可追溯到一个单一的趋同因果关系：衰老。例外的是一些无脊椎动物，它们可以避免衰老，而在非分裂细胞中，如神经元，衰老仍然发生，但结果是SASP，而不是增殖和SASP的丧失。对于大多数生物来说，衰老目前仍然是一个不可避免的终点，但细胞衰老领域正准备复兴，随着我们对衰老的理解不断完善，能够减缓衰老过程的策略将会出现。
In this paper we present cellular senescence as the ultimate driver of the aging process, as a “causal nexus” that bridges microscopic subcellular damage with the phenotypic, macroscopic effect of aging. It is important to understand how the various types of subcellular damage correlated with the aging process lead to the larger, visible effects of anatomical aging. While it has always been assumed that subcellular damage (cause) results in macroscopic aging (effect), the bridging link between the two has been hard to define. Here, we propose that this bridge, which we term the “causal nexus”, is in fact cellular senescence. The subcellular damage itself does not directly cause the visible signs of aging, but rather, as the damage accumulates and reaches a critical mass, cells cease to proliferate and acquire the deleterious “senescence-associated secretory phenotype” (SASP) which then leads to the macroscopic consequences of tissue breakdown to create the physiologically aged phenotype. Thus senescence is a precondition for anatomical aging, and this explains why aging is a gradual process that remains largely invisible during most of its progression. The subcellular damage includes shortening of telomeres, damage to mitochondria, aneuploidy, and DNA double-strand breaks triggered by various genetic, epigenetic, and environmental factors. Damage pathways acting in isolation or in concert converge at the causal nexus of cellular senescence. In each species some types of damage can be more causative than in others and operate at a variable pace; for example, telomere erosion appears to be a primary cause in human cells, whereas activation of tumor suppressor genes is more causative in rodents. Such species-specific mechanisms indicate that despite different initial causes, most of aging is traced to a single convergent causal nexus: senescence. The exception is in some invertebrate species that escape senescence, and in non-dividing cells such as neurons, where senescence still occurs, but results in the SASP rather than loss of proliferation plus SASP. Aging currently remains an inevitable endpoint for most biological organisms, but the field of cellular senescence is primed for a renaissance and as our understanding of aging is refined, strategies capable of decelerating the aging process will emerge.