School of Medicine
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-/Δ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/Δ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/Δ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/Δ mice never exceeded that observed in old WT mice. Surprisingly, levels of reactive oxygen species (ROS) were increased in tissues of Ercc1-/Δ 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-/Δ and aged WT mice. Chronic treatment of Ercc1-/Δ 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.
Digital Commons Citation
Robinson, Andria R.; Yousefzadeh, Matthew J.; Rozgaja, Tania A.; Wang, Jin; Li, Xuesen; Tilstra, Jeremy S.; Feldman, Chelsea H.; Gregg, Siobhan Q.; Johnson, Caroline H.; Skoda, Erin M.; Frantz, Marie-Celine; Bell-Temin, Harris; Pope-Varsalona, Hannah; Gurkar, Aditi U.; Nasto, Luigi A.; Robinson, Rena A.S.; Fuhrmann-Stroissnigg, Heike; Czerwinska, Jolanta; McGowan, Sara J.; Cantu-Madellin, Nadiezhda; Harris, Jamie B.; Maniar, Salony; Ross, Mark A.; Trussoni, Christy E.; LaRusso, Nicholas F.; Cifuentes-Pagano, Eugenia; Pagano, Patrick J.; Tudek, Barbara; Vo, Nam V.; Rigatti, Lora H.; Opresko, Patricia L.; Stolz, Donna B.; Watkins, Simon C.; Burd, Christin E.; Croix, Claudette M. St,; Siuzdak, Gary; Yates, Nathan A.; Robbins, Paul D.; Wang, Yinsheng; Wipf, Peter; Kelley, Eric E.; and Neidernhofer, Laura J., "Spontaneous DNA damage to the nuclear genome promotes senescence, T redox imbalance and aging" (2018). Faculty & Staff Scholarship. 1542.
Robinson, A. R., Yousefzadeh, M. J., Rozgaja, T. A., Wang, J., Li, X., Tilstra, J. S., Feldman, C. H., Gregg, S. Q., Johnson, C. H., Skoda, E. M., Frantz, M.-C., Bell-Temin, H., Pope-Varsalona, H., Gurkar, A. U., Nasto, L. A., Robinson, R. A. S., Fuhrmann-Stroissnigg, H., Czerwinska, J., McGowan, S. J., … Niedernhofer, L. J. (2018). Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biology, 17, 259–273. https://doi.org/10.1016/j.redox.2018.04.007
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