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Vitamin C restores healthy aging in a mouse model for Werner syndrome

Laurent Massip^*, Chantal Garand^*, Eric R. Paquet^*, Victoria C. Cogger, Jennifer N. O'Reilly, Leslee Tworek, Avril Hatherell, Carla G. Taylor, Eric Thorin, Peter Zahradka, David G. Le Couteur and Michel Lebel^*,1

^* Centre de Recherche en Cancérologie de l’Université Laval, Hôpital Hôtel-Dieu de Québec, Québec, Québec, Canada;

Centre for Education and Research on Ageing and ANZAC Research Institute, University of Sydney and Concord RG Hospital, Sydney, Australia;

Canadian Centre for Agri-food Research in Health and Medicine, University of Manitoba and St. Boniface Hospital Research Centre, Winnipeg, Manitoba, Canada; and

Université de Montréal, Montreal Heart Institute, Montreal, Québec, Canada

¹ Correspondence: Centre de Recherche en Cancérologie, Hôpital HôDieu de Québec, 9 McMahon St., Québec, Québec G1R 2J6, Canada. E-mail: michel.lebel{at}crhdq.ulaval.ca

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-B, as well as protein kinase C and Hif-1 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. 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.

Key Words: ascorbate • metabolism • microarrays • liver • adipocyte • inflammation