title: Liver aging and pseudocapillarization in a Werner syndrome mouse model.
abstract: Werner syndrome is a progeric syndrome characterized by premature atherosclerosis, diabetes, cancer, and death in humans. The knockout mouse model created by deletion of the RecQ helicase domain of the mouse Wrn homologue gene (Wrn(∆hel/∆hel)) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that Wrn(∆hel/∆hel) mice exhibit increased extracellular matrix, defenestration, decreased fenestration diameter, and changes in markers of liver sinusoidal endothelial cell inflammation, consistent with age-related pseudocapilliarization. In addition, hepatocytes are larger, have increased lipofuscin deposition, more frequent nuclear morphological anomalies, decreased mitochondria number, and increased mitochondrial diameter compared to wild-type mice. The Wrn(∆hel/∆hel) mice also have altered mitochondrial function and altered nuclei. Microarray data revealed that the Wrn(∆hel/∆hel) genotype does not affect the expression of many genes within the isolated hepatocytes or liver sinusoidal endothelial cells. This study reveals that Wrn(∆hel/∆hel) mice have accelerated typical age-related liver changes including pseudocapillarization. This confirms that pseudocapillarization of the liver sinusoid is a consistent feature of various aging models. Moreover, it implies that DNA repair may be implicated in normal aging changes in the liver.
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia.
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Svistounov
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Warren
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Zykova
authors.affiliation: School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, Australia.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Melvin
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia. School of Biological Sciences, University of Sydney, New South Wales, Australia.
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Solon-Biet
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia.
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: O'Reilly
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia.
authors.forename: Aisling C
authors.initials: AC
authors.lastname: McMahon
authors.affiliation: School of Biotechnology and Biomolecular Science, University of New South Wales, Sydney, Australia.
authors.forename: J William O
authors.initials: JW
authors.lastname: Ballard
authors.affiliation: Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
authors.forename: Rafa
authors.initials: R
authors.lastname: De Cabo
authors.affiliation: Centre for Education and Research on Aging and ANZAC Medical Research Institute, University of Sydney and Concord Hospital, New South Wales, Australia.
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.affiliation: Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hotel-Dieu de Quebec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Lebel
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology; D000818:Animals; D002196:Capillaries / Q000473:pathology; D004260:DNA Repair / Q000502:physiology; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008930:Mitochondria, Liver / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D053484:RecQ Helicases / Q000235:genetics; D023701:Smegmamorpha; D014898:Werner Syndrome / Q000473:pathology*; D000071657:Werner Syndrome Helicase
chemical_list: D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse
keywords: Electron microscopy; Endothelium; Mitochondria; Seahorse analyzer.; Sinusoid