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

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

Author information

1
Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA; University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
2
Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
3
Department of Chemistry, University of California, Riverside, CA 92521, USA.
4
Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
5
University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA.
6
University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
7
The Scripps Research Institute California, La Jolla, CA 92037, USA.
8
Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA.
9
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
10
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.
11
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA; Department of Paediatric Orthopaedics, G. Gaslini Children's Hospital, Genoa, Italy.
12
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.
13
Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
14
Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
15
Division of Gastroenterology and Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN 55905, USA.
16
Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
17
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.
18
Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA.
19
University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, PA 15213, USA.
20
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
21
Department of Molecular Genetics, Cancer Biology and Genetics, The Ohio State University, Columbus OH 43210 USA.
22
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA; Biomedical Mass Spectrometry Center, Schools of the Health Sciences University of Pittsburgh, Pittsburgh, PA 15213, USA.
23
University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA.
24
Department of Physiology & Pharmacology, West Virginia University, Morgantown, WV 26506, USA. Electronic address: eric.kelley@hsc.wvu.edu.
25
University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA 15232, USA; Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA; Department of Molecular Medicine and the Center on Aging, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: lniedern@scripps.edu.

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-/∆ 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

PMID:
29747066
PMCID:
PMC6006678
DOI:
10.1016/j.redox.2018.04.007
[Indexed for MEDLINE]
Free PMC Article

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