Liver aging and pseudocapillarization in a werner syndrome mouse model

Victoria C. Cogger, Dmitri Svistounov, Alessandra Warren, Svetlana Zykova, Richard G. Melvin, Samantha M. Solon-Biet, Jennifer N. O'reilly, Aisling C. Mcmahon, J. William O. Ballard, Rafa De Cabo, David G. Le Couteur, Michel Lebel

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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 (WrnΔhel/Δhel) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that WrnΔhel/Δhel 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 Δhel/Δhel mice also have altered mitochondrial function and altered nuclei. Microarray data revealed that the Wrn Δhel/Δhel genotype does not affect the expression of many genes within the isolated hepatocytes or liver sinusoidal endothelial cells. This study reveals that WrnΔhel/Δhel 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.

Original languageEnglish (US)
Pages (from-to)1076-1086
Number of pages11
JournalJournals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume69
Issue number9
DOIs
StatePublished - Sep 2014
Externally publishedYes

Keywords

  • Electron microscopy
  • Endothelium
  • Mitochondria
  • Seahorse analyzer
  • Sinusoid

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