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Vitamin C, Selenium, Boron, and AMPK

November 2015

By Life Extension

Vitamin C

Vitamin C as an antioxidant: evaluation of its role in disease prevention.

Vitamin C in humans must be ingested for survival. Vitamin C is an electron donor, and this property accounts for all its known functions. As an electron donor, vitamin C is a potent water-soluble antioxidant in humans. Antioxidant effects of vitamin C have been demonstrated in many experiments in vitro. Human diseases such as atherosclerosis and cancer might occur in part from oxidant damage to tissues. Oxidation of lipids, proteins and DNA results in specific oxidation products that can be measured in the laboratory. While these biomarkers of oxidation have been measured in humans, such assays have not yet been validated or standardized, and the relationship of oxidant markers to human disease conditions is not clear. Epidemiological studies show that diets high in fruits and vegetables are associated with lower risk of cardiovascular disease, stroke and cancer, and with increased longevity. Whether these protective effects are directly attributable to vitamin C is not known. Intervention studies with vitamin C have shown no change in markers of oxidation or clinical benefit. Dose concentration studies of vitamin C in healthy people showed a sigmoidal relationship between oral dose and plasma and tissue vitamin C concentrations. Hence, optimal dosing is critical to intervention studies using vitamin C. Ideally, future studies of antioxidant actions of vitamin C should target selected patient groups. These groups should be known to have increased oxidative damage as assessed by a reliable biomarker or should have high morbidity and mortality due to diseases thought to be caused or exacerbated by oxidant damage.

J Am Coll Nutr. 2003 Feb;22(1):18-35

Decreased plasma and tissue levels of vitamin C in a rat model of aging: implications for antioxidative defense.

Aging is an independent risk factor for the development of cardiovascular and many other diseases. The aging process is known to be associated with increased oxidative stress, possibly related to an age-inherent loss of antioxidant capacity. Vitamin C is a major naturally occurring antioxidant. Thus, we investigated its role in a rat model of aging. Vitamin C in plasma and tissues as well as malondialdehyde in the heart were measured in young (6 months old) and old (27-30 months old) F1 (F344 x BN) healthy male rats fed a normal diet. In old rats, vitamin C plasma levels were found to be decreased (p<0.02) as compared with young animals. Furthermore, there was a tissue-specific distribution: in the heart, liver, kidney, lungs, and skeletal muscle, vitamin C decreased with age (p<0.005 to p<0.05), while no significant differences could be observed in the aortic wall and in the brain. Organs of the digestive tract rather showed an increase of vitamin C levels with age. Oxidative stress, determined representatively in the heart by measuring malondialdehyde tissue levels, exhibited an age-dependent increase (p<0.05). A distinct pattern of specific tissue distribution of vitamin C suggests a differential age-associated regulation. As vitamin C decreased concomitantly to an increase in cardiac lipid peroxidation, its supplementation may be useful to prevent age-related oxidative stress and tissue aging.

Biochem Biophys Res Commun. 2003 Apr 4;303(2):483-7

Immune-enhancing role of vitamin C and zinc and effect on clinical conditions.

Vitamin C concentrations in the plasma and leukocytes rapidly decline during infections and stress. Supplementation of vitamin C was found to improve components of the human immune system such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis, and delayed-type hypersensitivity. Vitamin C contributes to maintaining the redox integrity of cells and thereby protects them against reactive oxygen species generated during the respiratory burst and in the inflammatory response. Likewise, zinc undernutrition or deficiency was shown to impair cellular mediators of innate immunity such as phagocytosis, natural killer cell activity, and the generation of oxidative burst. Therefore, both nutrients play important roles in immune function and the modulation of host resistance to infectious agents, reducing the risk, severity, and duration of infectious diseases. This is of special importance in populations in which insufficient intake of these nutrients is prevalent. In the developing world, this is the case in low- and middle-income countries, but also in subpopulations in industrialized countries, e.g. in the elderly. A large number of randomized controlled intervention trials with intakes of up to 1 g of vitamin C and up to 30 mg of zinc are available. These trials document that adequate intakes of vitamin C and zinc ameliorate symptoms and shorten the duration of respiratory tract infections including the common cold. Furthermore, vitamin C and zinc reduce the incidence and improve the outcome of pneumonia, malaria, and diarrhea infections, especially in children in developing countries.

Ann Nutr Metab . 2006;50(2):85-94

Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: a randomized controlled trial.

The early indications of vitamin C deficiency are unremarkable (fatigue, malaise, depression) and may manifest as a reduced desire to be physically active; moreover, hypovitaminosis C may be associated with increased cold duration and severity. This study examined the impact of vitamin C on physical activity and respiratory tract infections during the peak of the cold season. Healthy non-smoking adult men (18-35 years; BMI < 34 kg/m2; plasma vitamin C < 45 µmol/L) received either 1000 mg of vitamin C daily (n = 15) or placebo (n = 13) in a randomized, double-blind, eight-week trial. All participants completed the Wisconsin Upper Respiratory Symptom Survey-21 daily and the Godin Leisure-Time Exercise Questionnaire weekly. In the final two weeks of the trial, the physical activity score rose modestly for the vitamin C group vs. placebo after adjusting for baseline values: +39.6% (95% CI [-4.5,83.7]; p = 0.10). The number of participants reporting cold episodes was 7 and 11 for the vitamin C and placebo groups respectively during the eight-week trial (RR = 0.55; 95% CI [0.33,0.94]; p = 0.04) and cold duration was reduced 59% in the vitamin C versus placebo groups (-3.2 days; 95% CI [-7.0,0.6]; p = 0.06). These data suggest measurable health advantages associated with vitamin C supplementation in a population with adequate-to-low vitamin C status.

Nutrients. 2014 Jul 9;6(7):2572-83

Immunologic modulation by vitamin C in the elderly.

Aging is associated with a decline in both humoral-mediated and cellular-mediated immunity. These aberrations may contribute to morbidity and mortality in the elderly. Since we have previously shown that vitamin C enhances in vitro and in vivo immune functions in young healthy volunteers, we studied the effects of vitamin C on certain immunologic parameters in an elderly population. In vitro lymphocyte proliferation to the mitogen concanavalin-A was significantly less when compared to a young control group. When lymphocytes from the elderly were pre-incubated overnight and cultured in the presence of 10 micrograms/ml of vitamin C, mitogen-stimulated lymphocyte proliferation was similar to that from controls without vitamin C in culture. Having demonstrated significant in vitro immunoenhancement with vitamin C, we next studied the effects of oral ingestion of 2 g of vitamin C daily on certain in vitro and in vivo immunologic parameters in the elderly. When compared with a placebo-treated group, 3 weeks of vitamin C treatment did not effect in vitro mitogen-stimulated lymphocyte proliferation or in vivo reactivity to common skin test antigens. The augmenting effects of in vitro vitamin C suggest that this essential vitamin may be an effective agent in modulating aberrant immunologic functions in the elderly. The clinical significance of these findings requires further study.

Int J Immunopharmacol . 1986;8(2):205-11

Antioxidant activity of vitamin C in iron-overloaded human plasma.

Vitamin C (ascorbic acid, AA) can act as an antioxidant or a pro-oxidant in vitro, depending on the absence or the presence, respectively, of redox-active metal ions. Some adults with iron-overload and some premature infants have potentially redox-active, bleomycin-detectable iron (BDI) in their plasma. Thus, it has been hypothesized that the combination of AA and BDI causes oxidative damage in vivo. We found that plasma of preterm infants contains high levels of AA and F2-isoprostanes, stable lipid peroxidation end products. However, F2-isoprostane levels were not different between those infants with BDI (138 +/- 51 pg/ml, n = 19) and those without (126 +/- 41 pg/ml, n = 10), and the same was true for protein carbonyls, a marker of protein oxidation (0.77 +/- 0.31 and 0.68 +/- 0.13 nmol/mg protein, respectively). Incubation of BDI-containing plasma from preterm infants did not result in detectable lipid hydroperoxide formation (</=10 nM cholesteryl ester hydroperoxides) as long as AA concentrations remained high. Furthermore, when excess iron was added to adult plasma, BDI became detectable, and endogenous AA was rapidly oxidized. Despite this apparent interaction between excess iron and endogenous AA, there was no detectable lipid peroxidation as long as AA was present at >10% of its initial concentration. Finally, when iron was added to plasma devoid of AA, lipid hydroperoxides were formed immediately, whereas endogenous and exogenous AA delayed the onset of iron-induced lipid peroxidation in a dose-dependent manner. These findings demonstrate that in iron-overloaded plasma, AA acts an antioxidant toward lipids. Furthermore, our data do not support the hypothesis that the combination of high plasma concentrations of AA and BDI, or BDI alone, causes oxidative damage to lipids and proteins in vivo.

J Biol Chem. 1997 Jun 20;272(25):15656-60

Rationale and impact of vitamin C in clinical nutrition.

PURPOSE OF REVIEW: The impact of vitamin C on oxidative stress-related diseases is moderate because of its limited oral bioavailability and rapid clearance. Parenteral administration can increase the benefit of vitamin C supplementation as is evident in critically ill patients. The aim here is to assess recent evidence of the clinical benefit and underlying effects of parenteral vitamin C in conditions of oxidative stress. RECENT FINDINGS: In critically ill patients and after severe burns, the rapid restoration of depleted ascorbate levels with high-dose parenteral vitamin C may reduce circulatory shock, fluid requirements and oedema. SUMMARY: Oxidative stress is associated with reduced ascorbate levels. Ascorbate is particularly effective in protecting the vascular endothelium, which is especially vulnerable to oxidative stress. The restoration of ascorbate levels may have therapeutic effects in diseases involving oxidative stress. The rapid replenishment of ascorbate is of special clinical significance in critically ill patients who experience drastic reductions in ascorbate levels, which may be a causal factor in the development of circulatory shock. Supraphysiological levels of ascorbate, which can only be achieved by the parenteral and not by the oral administration of vitamin C, may facilitate the restoration of vascular function in the critically ill patient.

Curr Opin Clin Nutr Metab Care. 2006 Nov;9(6):697-703

Micronutrients at the interface between inflammation and infection—ascorbic acid and calciferol: part 1, general overview with a focus on ascorbic acid.

As elements of the antioxidant system, cofactors of enzymes, components of transcription factors, and epigenetic modulators, micronutrients, such as vitamins and trace elements, influence various metabolic processes that are directly associated with immune functions. Specifically, the vitamins C and D have been shown to have significance immune function. Therefore, the objective of this review is to elucidate interactions between micronutrients and the immune system. In the initial section of this review, we present a general overview of interactions between the immune system and micronutrients, with a focus on the immunobiologically relevant functions of vitamin C. Immune competent cells accumulate vitamin C against a concentration gradient, with a close relationship between vitamin C supply and immune cell activity, especially phagocytosis activity and T-cell function. Accordingly, one of the consequences of vitamin C deficiency is impaired resistance to various pathogens, while an enhanced supply increases antibody activity and infection resistance.

Inflamm Allergy Drug Targets. 2011 Feb;10(1):54-63

Effect of high-dose vitamin C on Epstein-Barr viral infection.

Background Many natural compounds were tested for the ability to suppress viral replication. The present manuscript details an analysis of high dose vitamin C therapy on patients with EBV infection. Material and Methods The data were obtained from the patient history database at the Riordan Clinic. Among people in our database who were treated with intravenous vitamin C (7.5 g to 50 g infusions) between 1997 and 2006, 178 patients showed elevated levels of EBV EA IgG (range 25 to 211 AU) and 40 showed elevated levels of EBV VCA IgM (range 25 to 140 AU). Most of these patients had a diagnosis of chronic fatigue syndrome, with the rest being diagnosed as having mononucleosis, fatigue, or EBV infection. Results Our data provide evidence that high dose intravenous vitamin C therapy has a positive effect on disease duration and reduction of viral antibody levels. Plasma levels of ascorbic acid and vitamin D were correlated with levels of antibodies to EBV. We found an inverse correlation between EBV VCA IgM and vitamin C in plasma in patients with mononucleosis and CFS meaning that patients with high levels of vitamin C tended to have lower levels of antigens in the acute state of disease. In addition, a relation was found between vitamin D levels and EBV EA IgG with lower levels of EBV early antigen IgG for higher levels of vitamin D. Conclusions The clinical study of ascorbic acid and EBV infection showed the reduction in EBV EA IgG and EBV VCA IgM antibody levels over time during IVC therapy that is consistent with observations from the literature that millimolar levels of ascorbate hinder viral infection and replication in vitro.

Med Sci Monit. 2014 May 3;20:725-32