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Vitamin C restores healthy aging in a mouse model for Werner syndrome
Author(s) -
Massip Laurent,
Garand Chantal,
Paquet Eric R.,
Cogger Victoria C.,
O'Reilly Jennifer N.,
Tworek Leslee,
Hatherell Avril,
Taylor Carla G.,
Thorin Eric,
Zahradka Peter,
Le Couteur David G.,
Lebel Michel
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.09-137133
Subject(s) - premature aging , werner syndrome , biology , endocrinology , medicine , vitamin , wild type , mutant , kinase , knockout mouse , helicase , gene , microbiology and biotechnology , genetics , rna
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‐κB, as well as protein kinase Cδ and Hif‐1α 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 PPARα. 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