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Annu Rev Biochem. 2018 Jun 20;87:295-322. doi: 10.1146/annurev-biochem-062917-012239.

Nuclear Genomic Instability and Aging.

Author information

1
Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute Florida, Jupiter, Florida 33458, USA; email: lniedern@scripps.edu.
2
Department of Medicine, Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
3
Department of Chemistry, University of California, Riverside, California 92521, USA.
4
Department of Genetics, Albert Einstein College of Medicine, Michael F. Price Center, Bronx, New York 10461, USA.
5
Department of Molecular Genetics, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands.

Abstract

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.

KEYWORDS:

DNA damage; DNA damage response; DNA repair; aging; mutations; senescence

[Indexed for MEDLINE]

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