Vitamin C restores healthy aging in a mouse model for Werner syndrome.
FASEB J
; 24(1): 158-72, 2010 Jan.
Article
in En
| MEDLINE
| ID: mdl-19741171
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.
Full text:
1
Database:
MEDLINE
Main subject:
Ascorbic Acid
/
Werner Syndrome
/
Aging
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
FASEB J
Journal subject:
BIOLOGIA
/
FISIOLOGIA
Year:
2010
Type:
Article
Affiliation country:
Canada