title: Vitamin C restores healthy aging in a mouse model for Werner syndrome.
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.
authors.affiliation: Centre de Recherche en Cancérologie, Hôpital Hôtel-Dieu de Québec, 9 McMahon St., Québec, Québec, Canada.
authors.forename: Laurent
authors.initials: L
authors.lastname: Massip
authors.forename: Chantal
authors.initials: C
authors.lastname: Garand
authors.forename: Eric R
authors.initials: ER
authors.lastname: Paquet
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.forename: Jennifer N
authors.initials: JN
authors.lastname: O'Reilly
authors.forename: Leslee
authors.initials: L
authors.lastname: Tworek
authors.forename: Avril
authors.initials: A
authors.lastname: Hatherell
authors.forename: Carla G
authors.initials: CG
authors.lastname: Taylor
authors.forename: Eric
authors.initials: E
authors.lastname: Thorin
authors.forename: Peter
authors.initials: P
authors.lastname: Zahradka
authors.forename: David G
authors.initials: DG
authors.lastname: Le Couteur
authors.forename: Michel
authors.initials: M
authors.lastname: Lebel
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000473:pathology; D000375:Aging / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001205:Ascorbic Acid / Q000627:therapeutic use*; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D005978:Glutathione / Q000097:blood / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008136:Longevity / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008855:Microscopy, Electron, Scanning; D018384:Oxidative Stress; D047493:PPAR alpha / Q000235:genetics; D053484:RecQ Helicases / Q000235:genetics; D014898:Werner Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071657:Werner Syndrome Helicase
chemical_list: D004272:DNA, Mitochondrial; D047493:PPAR alpha; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse; D005978:Glutathione; D001205:Ascorbic Acid