Antioxidants: The Evidence
Here's an Introduction to Research into the
Effects of Antioxidants on Mental Health
Infections irritate us - they inflame the body. Gasoline, poison ivy and other irritating substances all make us red, make us itch, make us burn. The body's own immune system causes inflammation when it's doing its job.
This article summarizes the peer-reviewed evidence base on the effects antioxidants have on mental health. For more about antioxidants and how to use them, click here.
When tissues are inflamed fluid spills out of blood vessels and into the space between cells where cellular debris is already piling up. If we could look closely enough at this cellular sludge we'd notice tiny molecules darting energetically in and out, sucking and chewing away at the mess. These are free radicals, tiny assemblages of atoms with an unbalanced electrical charge. This makes everything else very electrochemically attractive to them. They need fresh electrons to satisfy their electrochemical cravings, targeting our cells and tissues.
As free radicals steal electrons wherever they can they leave their targets corroded, electrically unbalanced themselves. A free radical electron-stealing corrosive chain reaction is set in motion. When this happens to oil or cheese we call it going rancid. When it happens to us we call it aging.
Free radicals are an irreducible waste product of our own cells' respiration. We also absorb them from cigarette smoke, air pollution, just about any fried food (unless one is obsessively careful about one's oils.) Whenever we produce or encounter them, they begin their corrosive vampiric dance.
Anti-oxidants are the weapon of choice. Antioxidants soak up free radicals like sponges soaking up dirty water,1 like cops filling a paddy wagon with thieves.
Anti-oxidants keep our bodies from going rancid like a piece of cheese left forgotten on the kitchen counter overnight. Antioxidants run a sting operation. They work by being more electro-chemically attractive to the free radicals than our bodies' fats, proteins and tissues are. Antioxidants specialize. Some work better in fats (vits A, E, carotenoids, Co-Q10), others in water (vit C, bioflavonoids, glutathione, selenium.) The fat-beat antioxidants (A&E et al) protect our cell walls, our membranes, the tiny organelles inside each cell that make the cell work (nucleus, mitochondria, etc.) The water-beat antioxidants (C et al) protect the watery environment inside and between our cells.
Antioxidants work all together as a team. Antioxidants recharge each other; by accepting electrons they reduce each other. (Reduce is the opposite of oxidize.) A reduced antioxidant is now refreshed and can go out and soak up more free radicals. Vitamin C is one of the most powerful rechargers. If antioxidants are beat cops Vitamin C is the county jail.
If oxidization is rusting, then reduction is polishing something and shining it up again. Or getting troublemakers off the street into paddywagons (E, carotenoids, alpha-lipoic acid, etc.) then carting them off to jail (vitamin C) so the streets are safe again.
But there's more to this story. By soaking up free radicals and shining up the biochemical environment in our bodies, antioxidants make DNA transcription possible. Remember that DNA makes proteins, and proteins run the body (neurotransmitters, enzymes, hormones, the physical structure, the works.) DNA does this first by transcribing itself to RNA; the RNA then attracts and lines the amino acids up in the right order to make the protein. This only happens in a cellular environment clean of free radicals.2,3,4 By soaking up free radicals and cleaning up the environment, antioxidants help the regulation and expression of our genetic inheritance. Antioxidants create the right atmosphere for our bodies to do business.
Water-soluble anti-oxidants soak up up free radicals in the space inside and between the cells.
- Vitamin C (ascorbic acid, sodium ascorbate, Esther-C)
Fat soluble anti-oxidants protect cell walls and the boundaries of organelles within cells; they also protect fatty organs like the brain and liver. They protect fragile Essential Fatty Acids from being destroyed before they can be used. The body stores them easily, and so overdoses are possible:
- Vitamin A (better taken as beta-carotene.)
- Vitamin E
- Co-enzyme Q-10.
There are many other anti-oxidants; all of which work together as a team. They'll soak up free radicals and then pass them on to other anti-oxidants, most notably Vitamin C, which can recharge the others. Two notable others:
- alpha-lipoic acid
- super-oxide dismutase
In most mammals vitamin C is the most abundant antioxidant. Most mammals' bodies can turn blood sugar (glucose) into vitamin C and back again. Higher primates (including our remote ancestors) underwent a genetic mutation 40 million years ago and haven't been able to make vitamin C since.
So humans need to get all our vitamin C from food. Some scientists think that the loss of our ability to make Vitamin C long ago may have caused homo sapiens' rapid evolution into modern man.5,6 Most other mammals make generous amounts of vitamin C in their own bodies. Goats for example make 13,000 mg of ascorbate daily and much more when they're stressed.7 If they were the size of your average 154 pound human, they'd be making 17,000 mg/day.
White blood cells eat foreign proteins for a living. They do it by making hydrogen peroxide. Vitamin C combines with the peroxide to kill the bacteria. "Unless the WBCs are totally saturated with ascorbic acid, they are like soldiers without bullets," says William Philpott.8 Vitamin C also helps oxidize the nucleic acid of invading viruses, inactivating them.
Vitamin C protects mammals from toxic substances.9,10 It pulls lead, mercury, copper and other substances out of our tissues.11,12,13 We need vitamin C to change cholesterol into bile acids so we can get rid of it.14,15
Our bodies use vitamin C to help turn lysine and proline into elastin and collagen, two substances our bodies use to make connective tissue strong. Arteries, ligaments, cartilage, skin . . . all need plenty of vitamin C to be built.16 Udo Erasmus has a great line about this in Fats that Heal Fats that Kill. He says that vitamin C is the glue that holds us together. Without vitamin C we'd dissolve into a puddle of cells on the floor.
That's what scurvy is, actually. The fibrous tissues dissolve out of artery walls until they're so weak that blood leaks out into the tissues and we start bruising too easily.
Vitamin C recharges other anti-oxidants. When molecules of vitamin E, A, alpha-lipoic acid, glutathione, super-oxide dismutase have done their job and soaked up some free radicals, they can find a vitamin C molecule and transfer their load to it. Vitamin C protects and escorts B vitamins and other essential molecules safely to their jobs.
Apparently, loss of our ability to make vitamin C didn't dampen our appetites for the simple carbohydrates from which our remote ancestors made it. Today the sugar in our blood lowers the activity of any vitamin C we do have because sugar and Vit C both compete for the same transport mechanisms.
Bioflavonoids are one family of plant pigments that give fruits, vegetables and flowers their color. A cup of brightly-colored tea or berries can contain dozens of these powerful health-enhancing compounds.
Bioflavonoids are antioxidants, anti-histamines and anti-inflammatories (AAA). They help vitamin C get absorbed in the G.I. tract and since they're also good at collaring free radicals, they leave more vitamin C available for resupplying the immune system, building body structure and cleaning us up. Allergies cause inflammation, and allergic reactions in brain tissue have been associated with a wide variety of emotional and cognitive disorders, notably attention deficits and depression. Their AAA action make bioflavonoids prime allergy-fighters.17,18
There's too many to list. We'll look at a few important ones here, Quercetin, Pycnogenol and Resveratrol:
Quercetin is a bioflavonoid found in red wine, grapefruit, onions, apples, and black tea and in lesser amounts in leafy green vegetables and beans. As an antioxidant it's anti-inflammatory and useful in allergic conditions19 such as rheumatoid arthritis20 and the brain allergies just mentioned. It increases calming neurotransmitters21 and inhibits the breakdown of excitatory ones22 as the body's changing needs require. Quercetin also reduces the breakdown of estrogens, contributing to women's emotional equilibrium.23
Pycnogenol is not a single substance; it's a mix of over 40 different bioflavonoid antioxidants made from the bark of Pinus Martima, the European coastal pine. Pycnogenol is one of the strongest antioxidants known.24 It's so strong that it can recharge all other antioxidants, accepting the electrons they've absorbed as they do their jobs. It even "renews" vitamin C, the usual final stop for free radicals. Vitamin E, glutathione and other antioxidants are also recharged by pycnogenol. If Vitamin C is the county jail pcynogenol is the federal pen.
As a bioflavonoid, Pycnogenol is anti-inflammatory.25,26 One short-term trial showed Pcynogenol just as effective as Ritalin in treating ADHD.27,28 It may help prevent Alzheimer's.29 Pycnogenol can increase production of nitric oxide (NO), a neurotransmitter that in the right amounts turns our genes on and off, relaxes our arteries, allowing better brain cell nutrition and improvements in cognitive function (our ability to think.)23,30 Pycnogenol can also destroy excess nitric oxide; a good thing because excess NO can restrict blood flow and increase inflammation, adding to our chances of getting arthritis, colitis and cancer.
Pycnogenol has been found to have beneficial effects for PMS, asthma and smokers.31 It also works with vitamin E to reduce the stickiness of platelets, the cells that clot our blood. When platelets are less sticky they tend not to glue themselves to the insides of artery walls (atherosclerosis) or to each other (blood clots: heart attacks, strokes.)32
Resveratrol (Grape extract)
Resveratrol is a bioflavonoid phytoestrogen, which means that it's a substance found in plants that mimics human female hormones. It's found primarily in red wine and grape juice, with concord grapes having the most. Although there's been concern about cancer and estrogen, plant estrogens in moderate amounts actually prevent tumors.33
Moderate red wine intake has been found to have a protective effect against dementia and Alzheimer's.34 It's anti-inflammatory35 and helps build the synaptic connections involved in learning and memory.36,37 Reservatrol has been used as part of a prescription for helping ADD patients have better energy, focus and impulse control.38
Sticking to the inside of each of our cell membranes are a whole forest of glutathione molecules. They stand sentry there to catch any free radicals that sneak through our cell walls' antioxidant defenses and stop them before they can get deeper into the cytoplasm.39 Glutathione is recharged by vitamin C if there's enough C around, so it can be used over and over again.
Glutathione is versatile. It's critical to glucose metabolism: Glucose Tolerance Factor (GTF) is made up of chromium, vitamin B3 and glutathione.40 Glutathione removes heavy metals like mercury, lead and cobalt from the body.41,42,43 The brain is particularly reliant on glutathione. Being mostly fat, brain tissue is unusually susceptible to free-radical attack. Nitric oxide, a critical neurotransmitter that in the right amounts relaxes arteries and improves brain blood flow, easily becomes excessive when allergies overstimulate immunity. Too much nitric oxide is very toxic to the brain.44 Glutathione is one of the best anti-oxidants for absorbing excess nitric oxide45,46,47 before it does harm.
The liver, kidney, spleen and pancreas have the highest concentrations of glutathione, as do the eyes.48 We tend to make less and less glutathione as we get older.49 If we want to increase our glutathione levels, the least expensive way is to take l-Cysteine.
Some people prefer N-acetyl-cysteine (NAC.) NAC is an intermediate step in the conversion of l-cysteine to glutathione. It has a reputation for being more effective than l-cysteine, but this is probably not true except in cases of infection by retroviruses (notably HIV) which can interfere with the conversion of cysteine to NAC and glutathione.50,51,52
Selenium is an antioxidant mineral most famous for its association with lowered cancer rates.53,54 It increases the production of glutathione, the detoxifying antioxidant just covered. One study demonstrated a relationship between supplemented selenium and lowered levels of lipofuscin in older people.55 Lipofuscin is oxidized spoiled proteins and fats that, when a lack of vitamin E causes them to accumulate in the skin, create brown "age spots." The same lipofuscin also accumulates in the brain, crowding and eventually choking brain cells.56
Isolated selenium atoms are poisons like many other metals; they only become useful when incorporated into proteins or other molecules. One family of selenium-containing molecules (glutathione peroxidases) repairs damaged cell membranes, while another (glutathione S-transferases) repairs damaged DNA and prevents mutations.57 Selenium also appears to be involved in helping the immune system destroy invading viruses.58,59
There are eight different selenium-containing proteins in brain tissue, but work is just beginning on their functions.60 A number of studies have shown a relationship between low selenium levels and mood issues.61 At least one type of thyroid hormone needs selenium to function.62 Not all selenium supplements are equally useful, though. The most bioavailable selenium is found in high-selenium yeast (aka: selenized yeast.)63 It's a good idea to make sure one is getting extra selenium - western countries have soil that's notoriously poor in selenium and getting poorer all the time.64
Vitamin A is a fat soluble vitamin. This means the body can store it, which also means we can get too much.
Vitamin A is critical for healthy epithelial tissue: the lungs, skin, the gastro-intestinal tract, the urinary tract. Most neurological research done to date has been limited to its role in dark adaption in the eye - not enough vitamin A gives us night blindness. There isn't a lot of research probing the effects of vitamin A on cognition or behavior. One recent study did relate vitamin A loss to a loss of synaptic plasticity - the mechanism by which we learn and remember - in the memory center of the brain (the hippocampus.)65 Another found significantly lower Vitamin A in the blood of Alzheimer's patients.66
Most of us make our vitamin A from beta-carotene, the yellow pigment in carrots and yellow cheese. Some people with liver disease (alcholics, hepatitis) may have difficulty making vitamin A from beta-carotene. These people should consult with a physician and with supervision supplement their vitamin A.
Just like the bioflavonoids, there's a wide variety of carotenoids. Like bioflavonoids carotenoids give their own bright colors to our fruits and vegetables. We'll look at a few important carotenoids: the beta-carotene that makes carrots and yellow cheese orange, the lycopene that makes tomatoes red, the lutein that makes corn and marigolds yellow.
Carotenoids are most at home in fatty tissues. They protect cell walls and are attracted to fat deposits and fatty organs like the brain. Researchers are in the early stages of exploring the role of fat-preserving antioxidants like lycopene67 which seems to have a dopamine-protecting effect, at least under some circumstances.68 Lycopene also protects against DNA damage. Lycopene is found in tomatoes, watermelon and many plant oils. Zeaxanthin, another carotenoid, converts light to nerve signals in the eye (it's a photoreceptor.)69 Zeaxanthin is found in corn. Lutein is another carotenoid that protects the delicate light-transducing cells (rods) made from zeaxanthin.70
By far the best investigated carotenoid is beta-carotene. It's well-established that there's an association between lowered levels of antioxidants and mental decline71,72,73 but the exact mechanisms involved remain undefined.74 Still, it makes sense that fat-protecting beta-carotene and the rest of the carotenoids would have a protective effect on the fatty brain. One study showed that fortifying the morning biscuits of 115 schoolchildren with iron, iodine and beta-carotene produced measurable improvements in their cognitive functioning,75 another showed beta-carotene produced measurable improvement in memory in the very elderly.76
Vitamin A is made from beta-carotene. A related carotenoid, alpha-carotene, appears to have its own neuro-protective effects independent of those of beta-carotene, especially against cancer.77,78 Alpha- and beta-carotene are different isomers of carotene - that is, they are the same molecules but twisted in different directions.
Vitamin E was discovered in 1923. It is the main fat-soluble anti-oxidant. It protects cell membranes and fatty organs like the liver, kidneys and brain. Vitamin C recharges vitamin E: the two work together as a team.79
Vitamins E and C together have also been found to strengthen arteries, the immune system and the brain's ability to think (cognition.)80,81 Vitamin E can protect the brain from age-related cognitive declines.82,83 In addition to its overall fatty-cell neuro-protective effects, vitamin E keeps amyloid plaques from oxidizing and killing off hippocampal neurons, leading to Alzheimers.84,85
Vitamin E in nature occurs in eight different forms: four tocopherols (alpha, beta, gamma and delta) and four tocotrienols. Most food in nature contains a variety of vitamin E forms. Synthetic vitamin E is dl-alpha-tocopherol (the closest natural form is d-alpha-tocopherol.) The synthetic form (dl-) contains eight stereoisomers, only one of which works like natural d-alpha-tocopherol. The others can't be used by the body86 Most people prefer natural, d-alpha-tocopherol to the synthetic dl-alpha-tocopherol.
Some forms of vitamin E may have special protective effects on the brain that the others don't have. Too much glutamate, an excitatory neurotransmitter, can damage neurons. Tocotrienols were much more effective in protecting nerve cells from excess levels of glutamate than alpha-tocopherol.87
Co-enzyme Q-10 (ubiquinone) is an antioxidant that's also an essential part of the process the body uses to make energy. The brain uses lots of energy so it's not surprising that studies suggest that increasing CoQ-10 levels can improve brain function.88,89 Ataxia, a progressive loss of motor co-ordination and difficulty in speech (a neurological disease that resembles being very drunk) is associated with a Co-enzyme Q-10 deficiency.90 Low blood levels of CoQ-10 have been found with Lewy Body disease, an Alzheimer's-like syndrome where people lose their memory, language, their ability to reason and to judge distances.91 CoQ-10 can also lessen Parkinsons' symptoms in some cases.92
In Alzheimer's itself Coenzyme Q-10 levels are increased, perhaps to help protect the brain from unusually high free radical activity rotting the fatty brain tissue.93 CoQ-levels appear to rise and fall in such a sensitive response to free radical (and other oxidizing) activity that they've been proposed as a quick way to measure just how much oxidative stress an organism has.94
Alpha-lipoic acid is a special anti-oxidant in that it can easily migrate back and forth between fat and water. In addition to soaking up free radicals it also chelates (combines with) iron and copper and helps carry excesses of both elements and toxic cadmium out of the body.95,96 It's also special in that like, CoQ-10, it serves an important role in the mitochondrial production of energy while also being an important defense against free radicals and other oxidizers.97 It seems to do this particularly well in the brain.98
When we eat sugar or high-glycemic index carbohydrates (donuts, pastries and chips come to mind) it becomes a high priority for the body to keep blood sugar from rising too high. It does this by secreting insulin, which forces sugar (and large amino acids) into the cells. As we get older, sometimes the cells get tired of letting insulin push them around; they refuse to accept more sugar in spite of high insulin levels. This creates adult-onset diabetes (Type II) where the cells stop listening to insulin. Alpha-lipoic acid helps cells respond to insulin again.99,100
One of the reasons it's so important for the body to control high levels of blood sugar is that sugar is very sticky, like glue. Excessive sugar in the blood sticks to protein and fat molecules, glycating them. This is similar is some ways to what happens when we "brown" a sugar dessert.
When excess sugar glycates and sticks to protein or fat molecules it makes them useless for the body's purposes. Alpha-lipoic acid protects against glycation.101 It especially protects the mitochondrial DNA from glycation and oxidation.102 This is important because mitochondrial DNA runs the energy-generating processes of the cell.
Alpha-lipoic acid is known primarily as good prevention/treatment for diabetic neuropathy103,104 When too much glycation has occurred to the neurons in the hands and feet they tingle and go numb. Sometimes they hurt. Alpha-lipoic acid also protects neurons in the brain from the same fate.105,106
1. I'm oversimplifying just a little bit here. Not all oxidation reactions are free radical reactions.
2. Gohil, K., Packer, L. 2002. Bioflavonoid-rich botanical extracts show antioxidant and gene regulatory activity. Annals of the New York Academy of Science. 957:70-77.
3. Cho, K.J., Yun, C.H., Packer L., Chung A.S. 2001. Inhibition mechanisms of bioflavonoids extracted from the bark of Pinum maritima on the expression of proinflammatory cytokines. Annals of the New York Academy of Science. 928:141-156.
4. Packer, Lester, interview with Richard Passwater. 2000. Whole Foods Magazine. Feb.
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8. Philpott, William and Kalita, Dwight. 2000. Brain Allergies: the Psychonutrient and Magnetic Connections. Los Angeles: Keats. 100.
9. Altuntas, I. et al. 2002. The effects of organophosphate insecticide methidathion on lipid peroxidation and anti-oxidant enzymes in rat erythrocytes: role of vitamins E and C. Human and Experimental Toxicology. 21(12):681-685.
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11. Hill, C.H.1980. Interactions of vitamin C with lead and mercury. Annals of the New York Acadamy of Science. 355:262-266.
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17. Sato, M., et al. 1997. Quercetin, a bioflavonoid, inhibits the induction of interleukin 8 and monocyte chemoattractant protein-1 expression by tumor necrosis factor-alpha in cultured human synovial cells. Journal of Rheumatology. 24(9):1680-1684.
18. Ogasawara, H. et al. 1985. Effect of selected flavonoids on histamine release and hydrogen peroxide generation by human leukocytes. Journal of Allergy and Clinical Immunology. 75:184.
19. Ogasawara, H., et al. 1986. The role of hydrogen peroxide in basophil histamine release and the effect of selected flavonoids. The Journal of Allergy and Clinical Immunology. 78(2):321-328.
20. Sato, M. Ibid.
21. Blardi, P., et al. 1999. Stimulation of endogenous adenosine release by oral administration of quercetin and resvertrol in man. Drugs Under Experimental and Clinical Research. 25(2-3). 105-110.
22. Walle, T., Eaton E.A., Walle U.K. 1995. Quercetin, a potent and specific inhibitor of the human P-form phenosulfotransferase. Biochemical Pharmacology. 50(5): 731-734.
23. Otake, Y. 2000. Quercetin and resveratrol potently reduce estrogen sulfotransferase activity in normal human mammary epithelial cells. The Journal of Steroid Biochemistry and Molecular Biology. 73(5):265-270.
24. Passwater, R. 1999. Antioxidant cocktail update part (2): lesser known antioxidants are very important; interview with Dr. Lester Packer. Whole Foods Magazine. November.
25. Rohdewald, P. 2002. A review of the french maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. International Journal of Clinical Pharmacology and Therapeutics. 40(4): 158-168.
26. Cho, K.J., Packer, L. et al. 2001. Inhibition mechanisms of bioflavonoids extracted from the bark of pinus martimia on the expression of proinflammatory cytokines. Annals of the New York Academy of Science. 928:141-156.
27. Tenenbaum, S., et al. 2002. An experimental comparison of pycnogenol and methylphenidate in adults with attention-deficit/hyperactivity disorder (ADHD). Journal of Attention Disorders. 6(2); 49-60.
28. How about that placebo, hunh? And who was giving it?
29. Peng, Q.L., et al. 2002. Pycnogenol protects neurons from amyloid-beta peptide-induced apoptosis. Brain Research. Molecular Brain Research. 104(1): 55-65.
30. Gohil, K., Packer, L. 2002. Bioflavonoid-rich botanical extracts show antioxidant and gene regulatory activity. Annals of the New York Academy of Science. 957:70-77.
31. Rohdewald, P. 2002. A review of the french maritime pine bark extract (pycnogenol), a herbal medication with a diverse pharmacology. International Journal of Clinical Pharmacology and Therapeutics. 40(4):158-168.
32. Passwater, R., 2000. Antioxidant recommendations, Part 3: what the studies show; interview with Denham Harman, M.D. Whole Foods Magazine. Sept.
33. Stewart, J.R. et al. 1999. Resveratrol preferentially inhibits protein kinase C-catalyze phosphorylation of a cofactor-independent, arginine-rich protein substrate by a novel mechanism. Biochemistry. 38(40):13244-13251.
34. Draczynskia-Lusiak, B., Doung A., Sun A.Y. 1998. Oxidized lipoproteins may play a role in neuronal cell death in Alzheimer disease. Molecular and Chemical Neuropathology. 33(2):139-148.
35. Lombard, J. and Germano, C. 2000. The Brain Wellness Plan. New York: Kensington. 83.
36. Tredici, G. et al. 1999. Resveratrol, map kinases and neuronal cells: might wine be a neuroprotectant? Drugs Under Experimental and Clinical Research. 25(2-3):99-103.
38. Amen, Daniel. 1998. Change Your Brain, Change Your Life. New York: Times Books. 149.
39. Erasmus, Udo. 1993. Fats that Heal Fats that Kill. Burnaby, BC: Alive Books. 60.
40. Erasmus, Ibid. 342.
41. Billatori, N. , Clarkson, T. W. 1982. Developmental changes in the biliary excretion of methylmercury and glutathione. Science. 216(2):61-62, 1982.
42. Domingo, J. L. and Llobet, J. M. 1984. The action of L-cysteine in acute cobalt chloride intoxication. Revista Espanola de Fisiologia. 40:231-236.
43. Hsu, J. M. 1981. Lead toxicity as related to glutathione metabolism. Journal of Nutrition. 111(1):26-33.
44. Petit, J.F. et al. 1996. Protection by glutathione against the antiproliferative effects of nitric oxide. Biochemical Pharmacology. 52(2):205-212.
45. Hogg, N. 1996. The role of glutathione in the transport and catabolism of nitric oxide. FEBS Letters. 382(3): 223-228.
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47. Walker, M.W. et al. 1995. Nitric oxide-induced cytotoxicity: involvement of cellular resistance to oxidative stress and the role of glutathione in protection. Pediatric Research. 37(1):41-49.
48. Braverman, Eric. 1987. The Healing Nutrients Within. New Canaan: Keats. 98.
49. Hazelton, G. A. and Lang, C. A. 1980. Glutathione contents of tissues in the aging mouse. Biochemical Journal. 188(1):25-30.
50. Buhl, Roland, et al., 1989. Systemic glutathione deficiency in symptom-free HIV- seropositive individuals. The Lancet. 2(8675):1294-1298.
51. Smith, C. V., et al., 1990. Glutathione concentrations in plasma and blood are markedly decreased in HIV-infected children. International Conference on AIDS. 6(2):368
52. Eck, Hans-Peter, et al. 1991. Metabolic disorder as early consequence of Simian immunodeficiency virus infection in Rhesus macaques. Lancet. 338:346-7.
53. Clark, L.C., et al. 1996. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: A randomized controlled trial. Journal of the American Medical Association. 276(24):1957-1963.
54. Passwater, R.A. and Olson, D.M. Method and Composition to Reduce Cancer Incidence, U. S. Patent 6,090,414
55. Clausen, J., Nielsen, S.A., Kristensen, M. 1989. Biochemical and clinical effects of an antioxidant supplementation of geriatric patients. A double blind study. Biological Trace Element Research. 20(1-2):135-151.
56. Erasmus, Udo. Ibid. 140-141.
57. Passwater, R. 2001. Selenium and cancer. Whole Foods Magazine. May.
58. Kiremidjian-Schumacher, L. et al., 1992. Regulation of cellular immune response by selenium. Biological Trace Element Research. 33:23-35.
59. Turner, R.J., Finch, J.M. 1991. Selenium and the immune response. The Proceedings of the Nutrition Society. 50:275-285.
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62. Holben, D.H., Smith, A.M. 1999. The diverse role of selenium within selenoproteins: a review. Journal of the American Dietetic Association. 99(7):836-843..
63. Passwater, R. Ibid..
64. Rayman, M.P. 2000. The importance of selenium to human health. Lancet. 356(9225):233-241..
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72. Riedel, W.J., Jorissen, B.L. 1998. Nutrients, age and cognitive function. Current Opinion in Clinical Nutrition and Metabolic Care. 1(6):579-585..
73. Foy, C.J. et al. 1999. Plasma chain-breaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease. QJM. 91(1):39-45..
74. Gonzalez-Gross, M. et al. 2001. Nutrition and cognitive impairment in the elderly. British Journal of Nutrition. 86(3):313-321..
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