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Liver Biology and Pathobiology
Article first published online: 27 JAN 2012
Copyright © 2011 American Association for the Study of Liver Diseases
Volume 55, Issue 2, pages 609–621, February 2012
How to Cite
Gregg, S. Q., Gutiérrez, V., Rasile Robinson, A., Woodell, T., Nakao, A., Ross, M. A., Michalopoulos, G. K., Rigatti, L., Rothermel, C. E., Kamileri, I., Garinis, G. A., Beer Stolz, D. and Niedernhofer, L. J. (2012), A mouse model of accelerated liver aging caused by a defect in DNA repair. Hepatology, 55: 609–621. doi: 10.1002/hep.24713
Potential conflict of interest: Nothing to report.
This work was supported by grants from the National Institute of Environmental Health Sciences (ES016114), the Ellison Medical Foundation (AG-NS-0303-05), and the University of Pittsburgh Claude D. Pepper Center (P30AG024827; to L.J.N.), the American Federation of Aging Research MSTAR Program (to T.W.), and the Pittsburgh Center for Kidney Research Pilot Program (P30DK079307; to D.B.S. and L.J.N). This project used the UPCI Cell and Tissue Imaging and Animal Facilities and was supported, in part, by award P30CA047904.
- Issue published online: 27 JAN 2012
- Article first published online: 27 JAN 2012
- Accepted manuscript online: 27 SEP 2011 01:32PM EST
- Manuscript Accepted: 20 SEP 2011
- Manuscript Received: 30 JUN 2011
The liver changes with age, leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging-related liver changes. One potential opportunity is murine models of human progerias or diseases of accelerated aging. Ercc1−/Δ mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine whether hepatic changes that occur with normal aging occur prematurely in Ercc1−/Δ mice, we systematically compared liver from 5-month-old progeroid Ercc1−/Δ mice to old (24-36-month-old) wild-type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration, and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in Ercc1−/Δ mice than in old WT mice. Liver enzymes were significantly elevated in serum of Ercc1−/Δ mice and old WT mice, whereas albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of Ercc1−/Δ liver after partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in Ercc1−/Δ and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein, as well as increased hepatocellular senescence. There was a highly significant correlation in genome-wide transcriptional changes between old WT and 16-week-old, but not 5-week-old, Ercc1−/Δ mice, emphasizing that the Ercc1−/Δ mice acquire an aging profile in early adulthood. Conclusion: There are strong functional, regulatory, and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging-related hepatic changes. (HEPATOLOGY 2012)