Nuclear Genomic Instability and Aging

• Published in: Annual review of biochemistry Vol. 87; no. 1; pp. 295 - 322
• Main Authors: Niedernhofer, Laura J, Gurkar, Aditi U, Wang, Yinsheng, Vijg, Jan, Hoeijmakers, Jan H.J, Robbins, Paul D
• Format: Journal Article
• Language: English
• Published: United States Annual Reviews 20.06.2018; Annual Reviews, Inc
• Subjects: Aging; Aging - drug effects; Aging - genetics; Aging - radiation effects; Animals; Autophagy - genetics; Cell Nucleus - genetics; Cellular Senescence - genetics; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA damage response; DNA repair; DNA Repair - genetics; Genomes; Genomic Instability; Genomics; Genotoxicity; Humans; Lesions; Longevity - genetics; Mammals; Mitochondria - genetics; Mitochondria - metabolism; Models, Genetic; Mutation; mutations; Neoplasms - genetics; Neoplasms - therapy; Organs; Progeroid syndromes; Proteostasis - genetics; Regeneration - genetics; Senescence; Signal Transduction - genetics; Stability; senescence; mutations; aging; DNA damage response; DNA repair; DNA damage
• ISSN: 0066-4154; 1545-4509
• 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.