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

Redox Biol. 2018 Jul;17:259-273. doi: 10.1016/j.redox.2018.04.007. Epub 2018 Apr 13.


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.

Keywords: Aging; Cellular senescence; Endogenous DNA damage; Free radicals; Genotoxic stress; Oxidative lesions; Reactive oxygen species.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Animals
  • Antioxidants / metabolism
  • Cellular Senescence / genetics*
  • Cellular Senescence / physiology
  • Cyclic N-Oxides / pharmacology
  • DNA Damage / drug effects
  • DNA Repair / drug effects
  • DNA-Binding Proteins / genetics*
  • Endonucleases / genetics*
  • Humans
  • Mice
  • Mice, Knockout
  • Mitochondria / genetics*
  • Mitochondria / metabolism
  • Oxidation-Reduction / drug effects
  • Oxidative Stress / genetics
  • Reactive Oxygen Species / metabolism


  • Antioxidants
  • Cyclic N-Oxides
  • DNA-Binding Proteins
  • Reactive Oxygen Species
  • XJB-5-131
  • Endonucleases
  • Ercc1 protein, mouse