Journal
FASEB JOURNAL
Volume 24, Issue 1, Pages 158-172Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.09-137133
Keywords
ascorbate; metabolism; microarrays; liver; adipocyte; inflammation
Categories
Funding
- Canadian Institutes of Health Research
- National Sciences and Engineering Research Council of Canada
- The National Health and Medical Research Council of Australia
- Aging and Alzheimers Research Foundation
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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-kappa B, as well as protein kinase C delta and Hif-1 alpha 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 PPAR alpha. 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.-Massip, L., Garand, C., Paquet, E. R., Cogger, V. C., O'Reilly, J. N., Tworek, L., Hatherell, A., Taylor, C. G., Thorin, E., Zahradka, P., Le Couteur, D. G., Lebel, M. Vitamin C restores healthy aging in a mouse model for Werner syndrome. FASEB J. 24, 158-172 ( 2010). www.fasebj.org
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