Vitamin C restores healthy aging in a mouse model for Werner syndrome

FASEB J. 2010 Jan;24(1):158-72. doi: 10.1096/fj.09-137133. Epub 2009 Sep 9.

Abstract

Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-like DNA helicase. Mice lacking the helicase domain of the WRN homologue exhibit many phenotypic features of WS, including a prooxidant status and a shorter mean life span compared to wild-type animals. Here, we show that Wrn mutant mice also develop premature liver sinusoidal endothelial defenestration along with inflammation and metabolic syndrome. Vitamin C supplementation rescued the shorter mean life span of Wrn mutant mice and reversed several age-related abnormalities in adipose tissues and liver endothelial defenestration, genomic integrity, and inflammatory status. At the molecular level, phosphorylation of age-related stress markers like Akt kinase-specific substrates and the transcription factor NF-kappaB, as well as protein kinase Cdelta and Hif-1alpha transcription factor levels, which are increased in the liver of Wrn mutants, were normalized by vitamin C. Vitamin C also increased the transcriptional regulator of lipid metabolism PPARalpha. Finally, microarray and gene set enrichment analyses on liver tissues revealed that vitamin C decreased genes normally up-regulated in human WS fibroblasts and cancers, and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Vitamin C did not have such effect on wild-type mice. These results indicate that vitamin C supplementation could be beneficial for patients with WS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / pathology
  • Aging / drug effects*
  • Aging / genetics
  • Aging / metabolism
  • Animals
  • Ascorbic Acid / therapeutic use*
  • Base Sequence
  • DNA, Mitochondrial / genetics
  • Disease Models, Animal
  • Gene Expression Profiling
  • Glutathione / blood
  • Glutathione / metabolism
  • Humans
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Longevity / drug effects
  • Longevity / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Microscopy, Electron, Scanning
  • Oxidative Stress
  • PPAR alpha / genetics
  • RecQ Helicases / genetics
  • Werner Syndrome / drug therapy*
  • Werner Syndrome / genetics
  • Werner Syndrome / metabolism
  • Werner Syndrome / pathology
  • Werner Syndrome Helicase

Substances

  • DNA, Mitochondrial
  • PPAR alpha
  • RecQ Helicases
  • Werner Syndrome Helicase
  • Wrn protein, mouse
  • Glutathione
  • Ascorbic Acid