RGD Reference Report - Vitamin C restores healthy aging in a mouse model for Werner syndrome. - Rat Genome Database

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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 
Citation: Massip L, etal., FASEB J. 2010 Jan;24(1):158-72. doi: 10.1096/fj.09-137133. Epub 2009 Sep 9.
RGD ID: 10402544
Pubmed: PMID:19741171   (View Abstract at PubMed)
PMCID: PMC3712979   (View Article at PubMed Central)
DOI: DOI:10.1096/fj.09-137133   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Werner syndrome treatmentISOHif1a (Mus musculus)10402544; 10402544 RGD 
Werner syndrome treatmentIEP 10402544 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hif1a  (hypoxia inducible factor 1 subunit alpha)

Genes (Mus musculus)
Hif1a  (hypoxia inducible factor 1, alpha subunit)

Genes (Homo sapiens)
HIF1A  (hypoxia inducible factor 1 subunit alpha)


Additional Information