Journal
REDOX BIOLOGY
Volume 17, Issue -, Pages 259-273Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.redox.2018.04.007
Keywords
Reactive oxygen species; Free radicals; Genotoxic stress; Oxidative lesions; Endogenous DNA damage; Cellular senescence; Aging
Categories
Funding
- National Institutes of Health [P01-AG043376, ES016114, P20 GM109098, K99-AG049126, R00AG036817, CA076541, CA101864, AG044376, AI068021, P30AG024827, 5P20GM109098, P30CA047904]
- Ellison Medical Foundation [AG-NS-0303-05]
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Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1(-/Delta) mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1(-/Delta) mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1(-/Delta) mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1(-/Delta) mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1(-/Delta) mice to an extent identical to naturally-aged WT mice. Increased enzymatic production of ROS and decreased antioxidants contributed to the elevation in oxidative stress in both Ercc1(-/Delta) and aged WT mice. Chronic treatment of Ercc1(-/Delta) mice with the mitochondrial-targeted radical scavenger XJB-5-131 attenuated oxidative DNA damage, senescence and age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damage is sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline.
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