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

Authors: Massip L; Garand C; Paquet ER; Cogger VC; O'Reilly JN; Tworek L; Hatherell A; Taylor CG; Thorin E; Zahradka P; Le Couteur DG; Lebel M

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.

Keywords: Adipose Tissue/drug effects/pathology; Aging/*drug effects/genetics/metabolism; Animals; Ascorbic Acid/*therapeutic use; Base Sequence; DNA, Mitochondrial/genetics; Disease Models, Animal; Gene Expression Profiling; Glutathione/blood/metabolism; Humans; Liver/drug effects/metabolism/pathology; Longevity/drug effects/genetics; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron, Scanning; Oxidative Stress; PPAR alpha/genetics; RecQ Helicases/genetics; Werner Syndrome/*drug therapy/genetics/metabolism/pathology
Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume: 24
Issue: 1
Pages: 158-72
Date: Sept. 11, 2009
PMID: 19741171
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Citation:

Massip L, Garand C, Paquet ER, Cogger VC, O'Reilly JN, Tworek L, Hatherell A, Taylor CG, Thorin E, Zahradka P, Le Couteur DG, Lebel M (2010) Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 24: 158-72.


Study Lifespan Factors:
  • Wrn


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