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Scientific Journal Article Review
The following is a review of the scientific study published in FASEB. A link to the original article can be found at the bottom of the page.
The authors of the primary literature article chose to use mice as the mammalian model organism to study Werner syndrome. They begin the article by outlining definitions of aging and Werner syndrome (WS), as well as outlining the defective enzyme responsible for WS and the gene associated with it, WRN. The experiments focused on metabolic problems in the liver of the affected mice, because metabolic syndrome is considered age-related and profoundly affected by WS. By observing the phenotypes of the mutant mice they were able to hypothesize that “The metabolic syndrome developed by Wrn knockout mice is due to an abnormal regulation of the redox environment and a rise in reactive oxygen species (ROS) production leading to a premature liver dysfunction normally associated with old age.”
The authors go on to establish how they generated Wrn knockout mice by homologous recombination, creating a deletion in the helicase domain of the Wrn gene. The two categories of treatment that were outlined by the experiments were a 30-week vitamin C treatment that began at weaning, and an 8 week vitamin C treatment that began at the age of 7 months. Nutrient uptake was accomplished by adding Vitamin C to the drinking water.
The effect of the Wrn mutation on endothelial cells was visualized using electron microscopy, and can be seen by clicking on the link “Endothelial Liver Cells.” “Defenestration of sinusoidal endothelial liver cells” was used to compare wild-type (WT) controls against both treated and untreated Wrn knockout mice. This complicated phrase simply means that the authors examined the porosity of a specific type of liver cell, and found that in the untreated mice, the endothelial cells were much less porous. This can lead to diabetes, and is much more prevalent in old age. Additionally, the liver cells in the Wrn knockout mice that were treated with vitamin C were rescued and looked like normal WT cells.
The authors go on to establish how they generated Wrn knockout mice by homologous recombination, creating a deletion in the helicase domain of the Wrn gene. The two categories of treatment that were outlined by the experiments were a 30-week vitamin C treatment that began at weaning, and an 8 week vitamin C treatment that began at the age of 7 months. Nutrient uptake was accomplished by adding Vitamin C to the drinking water.
The effect of the Wrn mutation on endothelial cells was visualized using electron microscopy, and can be seen by clicking on the link “Endothelial Liver Cells.” “Defenestration of sinusoidal endothelial liver cells” was used to compare wild-type (WT) controls against both treated and untreated Wrn knockout mice. This complicated phrase simply means that the authors examined the porosity of a specific type of liver cell, and found that in the untreated mice, the endothelial cells were much less porous. This can lead to diabetes, and is much more prevalent in old age. Additionally, the liver cells in the Wrn knockout mice that were treated with vitamin C were rescued and looked like normal WT cells.
| Endothelial Liver Cells |
Other aspects of the liver that were examined included levels of ATP, blood insulin, glutathione, glucose, triglycerides, cholesterol, reactive oxygen species (ROS), and inflammatory response. Among these variables, they found lowered plasma glutathione levels in Wrn knockout mice, as well as elevated ROS, greater DNA damage, lower ATP levels, higher triglyceride levels, higher glucose levels, higher blood insulin levels, higher cholesterol levels, and increased inflammatory response.
Multiple aging symptoms were also observed in Wrn knockout mice such as heart failure, oxidative DNA damage, and several types of cancer formation. The authors found that the Wrn knockout mice that were treated with vitamin C showed significant improvement in most aspects tested to restore a phenotype near that of the WT controls, with the 30-week treatment yielding more success than the 8-week treatment.
Interestingly, the authors found that vitamin C inhibited genes that were upregulated in Wrn knockout mice; in addition to upregulating genes that normally show decreased expression in cancer. The vitamin C treatment also rescued the mean life-span decrease that was observed in Wrn knockout mice. It is important to note that they also created a provisional group of WT mice in which they administered the vitamin C treatment that did not display any measurable response. This was necessary to show that the vitamin C did not have the same effect on individuals who lacked the Wrn knockout.
Lastly, the authors of the paper insist that future work is needed to more fully understand how vitamin C influences gene expression. A great deal of research still needs to be done to more fully understand this phenomenon, especially with Wrn deficient mice lacking telomerase activity (an important enzyme related to aging and chromosome maintenance).
Multiple aging symptoms were also observed in Wrn knockout mice such as heart failure, oxidative DNA damage, and several types of cancer formation. The authors found that the Wrn knockout mice that were treated with vitamin C showed significant improvement in most aspects tested to restore a phenotype near that of the WT controls, with the 30-week treatment yielding more success than the 8-week treatment.
Interestingly, the authors found that vitamin C inhibited genes that were upregulated in Wrn knockout mice; in addition to upregulating genes that normally show decreased expression in cancer. The vitamin C treatment also rescued the mean life-span decrease that was observed in Wrn knockout mice. It is important to note that they also created a provisional group of WT mice in which they administered the vitamin C treatment that did not display any measurable response. This was necessary to show that the vitamin C did not have the same effect on individuals who lacked the Wrn knockout.
Lastly, the authors of the paper insist that future work is needed to more fully understand how vitamin C influences gene expression. A great deal of research still needs to be done to more fully understand this phenomenon, especially with Wrn deficient mice lacking telomerase activity (an important enzyme related to aging and chromosome maintenance).
References
1. Massip L, Garand C, Paquet E, Cogger V et al. (2009). Vitamin C restores healthy aging in a mouse model for Werner syndrome. The FASEB journal 24, 158-174. doi:10.1096/fj.09-137133.
*Picture and file retrieved from referenced article
*Picture and file retrieved from referenced article
