title: A mouse model of accelerated liver aging caused by a defect in DNA repair.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Siobhán Q
authors.initials: SQ
authors.lastname: Gregg
authors.forename: Verónica
authors.initials: V
authors.lastname: Gutiérrez
authors.forename: Andria Rasile
authors.initials: AR
authors.lastname: Robinson
authors.forename: Tyler
authors.initials: T
authors.lastname: Woodell
authors.forename: Atsunori
authors.initials: A
authors.lastname: Nakao
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ross
authors.forename: George K
authors.initials: GK
authors.lastname: Michalopoulos
authors.forename: Lora
authors.initials: L
authors.lastname: Rigatti
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Rothermel
authors.forename: Irene
authors.initials: I
authors.lastname: Kamileri
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Niedernhofer
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology*; D000818:Animals; D016922:Cellular Senescence; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D004720:Endonucleases / Q000235:genetics*; D020869:Gene Expression Profiling; D008099:Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018384:Oxidative Stress; D011371:Progeria / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*
chemical_list: D004268:DNA-Binding Proteins; D004720:Endonucleases; C499360:Ercc1 protein, mouse