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

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-{kappa}B, as well as protein kinase C{delta} and Hif-1{alpha} 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{alpha}. 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. news from fasebj.org  –  Vitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate (an ion of ascorbic acid) is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms; notable mammalian exceptions are most or all of the order chiroptera (bats), and the entire suborder Anthropoidea (Haplorrhini) (tarsiers, monkeys and apes). It is also needed by guinea pigs and some species of birds and fish. Deficiency in this vitamin causes the disease scurvy in humans. It is also widely used as a food additive. The pharmacophore of vitamin C is the ascorbate ion. In living organisms, ascorbate is an anti-oxidant, since it protects the body against oxidative stress, and is a cofactor in several vital enzymatic reactions. Scurvy has been known since ancient times. People in many parts of the world assumed it was caused by a lack of fresh plant foods.

The British Navy started giving sailors lime juice to prevent scurvy in 1795. Ascorbic acid was finally isolated in 1933 and synthesized in 1934. The uses and recommended daily intake of vitamin C are matters of on-going debate, with RDI ranging from 45 to 95 mg/day. Proponents of megadosage propose from 200 to upwards of 2000 mg/day. A recent meta-analysis of 68 reliable antioxidant supplementation experiments, involving a total of 232,606 individuals, concluded that consuming additional ascorbate from supplements may not be as beneficial as thought , though most of these studies so far generally do not evaluate the effects of megadosages at the levels recommended by megadosage activists. Vitamin C is purely the L-enantiomer of ascorbate; the opposite D-enantiomer has no physiological significance. Both forms are mirror images of the same molecular structure. When L-ascorbate, which is a strong reducing agent, carries out its reducing function, it is converted to its oxidized form, L-dehydroascorbate L-dehydroascorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione. During this process semidehydroascorbic acid radical is formed.

Ascorbate free radical reacts poorly with oxygen, and thus, will not create a superoxide. Instead two semidehydroascorbate radicals will react and form one ascorbate and one dehydroascorbate. With the help of glutathione, dehydroxyascorbate is converted back to ascorbate. The presence of glutathione is crucial since it spares ascorbate and improves antioxidant capacity of blood. Without it dehydroxyascorbate could not convert back to ascorbate. L-ascorbate is a weak sugar acid structurally related to glucose which naturally occurs either attached to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate. In humans, vitamin C is essential to a healthy diet as well as being a highly effective antioxidant, acting to lessen oxidative stress; a substrate for ascorbate peroxidase; and an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for important enzymes:

Ascorbic acid performs numerous physiological functions in human body. These functions include the synthesis of collagen, carnitine and neurotransmitters, the synthesis and catabolism of tyrosine and the metabolism of microsome. Ascorbate acts as a reducing agent (i.e. electron donor, anti-oxidant) in the above-described syntheses, maintaining iron and copper atoms in their reduced states. Vitamin C acts as an electron donor for eight different enzymes: * Three participate in collagen hydroxylation.These reactions add hydroxyl groups to the amino acids proline or lysine in the collagen molecule via prolyl hydroxylase and lysyl hydroxylase, both requiring vitamin C as a cofactor. Hydroxylation allows the collagen molecule to assume its triple helix structure and making vitamin C essential to the development and maintenance of scar tissue, blood vessels, and cartilage. 2 are necessary for synthesis of carnitine.Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation. * The remaining three have the following functions in common but do not always do this: dopamine beta hydroxylase participates in the biosynthesis of norepinephrine from dopamine.another enzyme adds amide groups to peptide hormones, greatly increasing their stability. one modulates tyrosine metabolism.


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