Liver aging and pseudocapillarization in a Werner syndrome mouse model

J Gerontol A Biol Sci Med Sci. 2014 Sep;69(9):1076-86. doi: 10.1093/gerona/glt169. Epub 2013 Oct 22.


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.

Keywords: Electron microscopy; Endothelium; Mitochondria; Seahorse analyzer.; Sinusoid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / pathology
  • Aging / physiology
  • Animals
  • Capillaries / pathology
  • DNA Repair / physiology
  • Disease Models, Animal
  • Immunohistochemistry
  • Liver / pathology*
  • Liver / ultrastructure
  • Mice
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Mitochondria, Liver / pathology
  • Mitochondria, Liver / physiology
  • Mitochondria, Liver / ultrastructure
  • RecQ Helicases / genetics
  • Smegmamorpha
  • Werner Syndrome / pathology*
  • Werner Syndrome Helicase


  • RecQ Helicases
  • Werner Syndrome Helicase
  • Wrn protein, mouse