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.
|Original language||English (US)|
|Number of pages||28|
|Journal||Annual Review of Biochemistry|
|State||Published - Jun 20 2018|
Bibliographical noteFunding Information:
We acknowledge the incredible gift given by patients with genome instability disorders and their families, teaching the world most of what is known about the health impact of DNA damage. We apologize for not adequately citing or describing in depth many important studies that contributed to our understanding of the role of DNA damage in aging, owing to reference and space limitations. We thank Heike Fuhrmann-Stroissnigg, Akaitz Dorronsoro, and Tania Rozgaja for helpful comments on initial drafts of the review. We are grateful to Yuxiang Cui for contributing artwork for figures. L.J.N., A.U.G., Y.W., and P.D.R. are supported by National Institutes of Health/National Institute of Aging (NIH/NIA) grant P01 AG043376. J.V. and J.H. are supported by NIH/NIA grant P01 AG017242.
- DNA damage
- DNA damage response
- DNA repair