Bhatia-Dey Naina, Kanherkar Riya R, Stair Susan E, Makarev Evgeny O, Csoka Antonei B
Epigenetics Laboratory, Department of Anatomy, Howard University Washington, DC, USA.
Vision Genomics, LLC Washington, DC, USA.
Front Genet. 2016 Feb 12;7:13. doi: 10.3389/fgene.2016.00013. eCollection 2016.
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.
在本文中，我们提出细胞衰老作为衰老过程的最终驱动因素，作为一种“因果关系纽带”，将微观的亚细胞损伤与衰老的表型、宏观效应联系起来。了解与衰老过程相关的各种亚细胞损伤如何导致解剖学衰老的更大、可见效应非常重要。虽然一直以来都认为亚细胞损伤（原因）会导致宏观衰老（结果），但两者之间的桥梁却难以界定。在此，我们提出这座桥梁，我们称之为“因果关系纽带”，实际上就是细胞衰老。亚细胞损伤本身并不会直接导致衰老的可见迹象，而是随着损伤的积累并达到临界值，细胞停止增殖并获得有害的“衰老相关分泌表型”（SASP），进而导致组织分解的宏观后果，从而形成生理上衰老的表型。因此，衰老是解剖学衰老的先决条件，这就解释了为什么衰老在其大部分进程中是一个渐进的过程，且在很大程度上仍然不可见。亚细胞损伤包括端粒缩短、线粒体损伤、非整倍体以及由各种遗传、表观遗传和环境因素引发的DNA双链断裂。单独或协同作用的损伤途径在细胞衰老的因果关系纽带上汇聚。在每个物种中，某些类型的损伤可能比其他损伤更具因果性，且作用速度各不相同；例如，端粒侵蚀似乎是人类细胞中的主要原因，而肿瘤抑制基因的激活在啮齿动物中更具因果性。这种物种特异性机制表明，尽管初始原因不同，但大多数衰老都可追溯到一个单一的汇聚因果关系纽带：衰老。例外情况是一些逃避衰老的无脊椎动物物种，以及诸如神经元等非分裂细胞，在这些细胞中衰老仍然会发生，但会导致SASP，而不是增殖丧失加SASP。衰老目前仍然是大多数生物不可避免的终点，但细胞衰老领域正迎来复兴，随着我们对衰老的理解不断完善，能够延缓衰老过程的策略将会出现。
