Authors

Andria R. Robinson, University of Pittsburgh
Matthew J. Yousefzadeh, The Scripps Research Institute
Tania A. Rozgaja, The Scripps Research Institute
Jin Wang, University of California
Xuesen Li, The Scripps Research Institute
Jeremy S. Tilstra, University of Pittsburgh
Chelsea H. Feldman, University of Pittsburgh
Siobhan Q. Gregg, University of Pittsburgh
Caroline H. Johnson, The Scripps Research Institute California
Erin M. Skoda, University of Pittsburgh
Marie-Celine Frantz, University of Pittsburgh
Harris Bell-Temin, University of Pittsburgh
Hannah Pope-Varsalona, University of Pittsburgh
Aditi U. Gurkar, The Scripps Research Institute
Luigi A. Nasto, University of Pittsburgh
Rena A.S. Robinson, University of Pittsburgh
Heike Fuhrmann-Stroissnigg, The Scripps Research Institute
Jolanta Czerwinska, Polish Academy of Sciences
Sara J. McGowan, The Scripps Research Institute
Nadiezhda Cantu-Madellin, University of Pittsburgh
Jamie B. Harris, The Scripps Research Institute
Salony Maniar, University of Pittsburgh
Mark A. Ross, University of Pittsburgh
Christy E. Trussoni, Mayo Clinic
Nicholas F. LaRusso, Mayo Clinic
Eugenia Cifuentes-Pagano, University of Pittsburgh
Patrick J. Pagano, University of Pittsburgh
Barbara Tudek, Polish Academy & University of Warsaw
Nam V. Vo, University of Pittsburgh
Lora H. Rigatti, University of Pittsburgh
Patricia L. Opresko, University of Pittsburgh
Donna B. Stolz, University of Pittsburgh
Simon C. Watkins, University of Pittsburgh
Christin E. Burd, The Ohio State University
Claudette M. St, Croix, University of Pittsburgh
Gary Siuzdak, The Scripps Research Institute California
Nathan A. Yates, University of Pittsburgh
Paul D. Robbins, University of Pittsburgh
Yinsheng Wang, University of California
Peter Wipf, University of Pittsburgh
Eric E. Kelley, West Virginia UniversityFollow
Laura J. Neidernhofer, University of Pittsburgh

Document Type

Article

Publication Date

2018

College/Unit

School of Medicine

Department/Program/Center

Medicine

Abstract

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.

Source Citation

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

Comments

© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).

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