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Publication : Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging.

First Author  Robinson AR Year  2018
Journal  Redox Biol Volume  17
Pages  259-273 PubMed ID  29747066
Mgi Jnum  J:273757 Mgi Id  MGI:6282488
Doi  10.1016/j.redox.2018.04.007 Citation  Robinson AR, et al. (2018) Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol 17:259-273
abstractText  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(-/) mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1(-/) mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1(-/) mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1(-/) mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1(-/) 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(-/) and aged WT mice. Chronic treatment of Ercc1(-/) 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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