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

Abstract Accumulation of senescentcells over time contributes to aging and age-related diseases. However, what drives senescencein vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNAdamage is sufficient to initiate senescencein mammals. Ercc1-/∆ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/∆ mice accumulated spontaneous, oxidative DNA damagemore rapidly than wild-type (WT) mice. As a consequence, senescentcells accumulated more rapidly in Ercc1-/∆ mice compared to repair-competent animals. However, the levels of DNA damageand senescentcells 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, senescenceand age-related pathology. Our findings indicate that nuclear genotoxic stress arises, at least in part, due to mitochondrial-derived ROS, and this spontaneous DNA damageis sufficient to drive increased levels of ROS, cellular senescence, and the consequent age-related physiological decline.