Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute Florida, Jupiter, Florida 33458, USA; email:
Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Annu Rev Biochem. 2018 Jun 20;87:295-322. doi: 10.1146/annurev-biochem-062917-012239.
The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.
随着生物体的衰老，核基因组会发生衰变。许多研究表明，与年轻哺乳动物相比，老年哺乳动物体内多种类型的 DNA 损伤负担更大。更具挑战性的是证明这是衰老的原因而不是结果。衰老的 DNA 损伤理论认为，基因组不稳定性在衰老过程中起因果作用，最近这一理论得到了更多的支持。这一理论的部分依据来自于早老综合征，其中 DNA 修复的遗传缺陷增加了 DNA 损伤的负担，导致一个或多个器官的加速衰老。此外，越来越多的证据表明，DNA 损伤的累积会引发细胞衰老和代谢变化，从而导致组织功能下降和增加患与年龄相关疾病的易感性。在这里，我们检查了与核 DNA 损伤与衰老相关的多种证据。然后，我们考虑从机制上看，核基因毒性应激如何促进衰老。我们的结论是，总的来说，证据支持 DNA 损伤作为衰老的核心的作用。
