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Merck
CN
  • Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging.

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

Redox biology (2018-05-11)
Andria R Robinson, Matthew J Yousefzadeh, Tania A Rozgaja, Jin Wang, Xuesen Li, Jeremy S Tilstra, Chelsea H Feldman, Siobhán Q Gregg, Caroline H Johnson, Erin M Skoda, Marie-Céline Frantz, Harris Bell-Temin, Hannah Pope-Varsalona, Aditi U Gurkar, Luigi A Nasto, Renã A S Robinson, Heike Fuhrmann-Stroissnigg, Jolanta Czerwinska, Sara J McGowan, Nadiezhda Cantu-Medellin, Jamie B Harris, Salony Maniar, Mark A Ross, Christy E Trussoni, Nicholas F LaRusso, Eugenia Cifuentes-Pagano, Patrick J Pagano, Barbara Tudek, Nam V Vo, Lora H Rigatti, Patricia L Opresko, Donna B Stolz, Simon C Watkins, Christin E Burd, Claudette M St Croix, Gary Siuzdak, Nathan A Yates, Paul D Robbins, Yinsheng Wang, Peter Wipf, Eric E Kelley, Laura J Niedernhofer
摘要

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.