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-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.

Non-B DNA-forming Sequences and WRN Deficiency Independently Increase the Frequency of Base Substitution in Human Cells

“…This conclusion concurs with the view that the senescent phenotype induced by WRN deficiency is associated with oxidative stress and consequent DNA damage (43,44). Indeed, the increase in life-span of WS patients treated with pioglitazone, a potent PPAR␥ agonist that mediates the up-regulation of antioxidant enzymes, such as catalase and copper/zinc superoxide dismutase, has been interpreted in terms of a reduction in oxidative stress (28).…”

“…Because no synergy was observed, a role for WRN in reducing mutation frequencies via a mechanism(s) that is dependent upon its cellular helicase activity appears unlikely. Moreover, the higher level of 8-oxodG in WRN-KD as compared with wild-type U2OS cells suggests that the observed 2-fold increase in mutations was probably caused by an overall hyperoxidative state in the WRN-deficient cells (43).…”

“…WRN deficiency has also been shown to be associated with a profound reprogramming of genome-wide gene expression profiles (39 -42) and increased intracellular levels of reactive oxygen species, suggesting that cellular senescence may result from the pleiotropic effect of several genes in association with redox imbalance (43)(44)(45)(46).…”

Vitamin E prevents the age-dependent and palmitate-induced disturbances of sphingolipid turnover in liver cells

“…However, it has been recently shown that generation of reactive oxygen species an important step for aSMase activation in cells (Dumitru and Gulbins 2006;Charruyer et al 2005).The aSMase could be activated by the protein kinase Cδ (PKCδ), which is overexpressed under oxidative stress (Zeidan and Hannun 2007) and a premature aging disorderWerner syndrome (Massip et al 2010). Based on these results, reasonable assumption can be made that α-tocopherol prevents ceramide accumulation in the liver of old rats, at least in part, via the glutathionedependent nSMase and PKCδ-dependent aSMase inhibition.…”

Ascorbic Acid Levels in Various Tissues, Plasma and Urine of Mice during Aging

“…Werner syndrome is a very rare, autosomal recessive disorder characterized by the appearance of premature aging in humans. Massip et al ( 6 ) reported that AA increased the mean life span of Werner syndrome model mice.…”