Miscellaneous Micronutrient Supplements

by Ben Best

1. FOLIC ACID
2. VITAMIN B₁₂
3. VITAMIN B₆
4. TMG
5. ZINC
6. MAGNESIUM
7. IODINE
8. NIACIN
9. VITAMIN K
10. VITAMIN D
11. CENTROPHENOXINE/DMAE

[Many of the uncited facts below come from MODERN NUTRITION IN HEALTH AND DISEASE by M.E.Shils,et.al, Editors (Eighth Edition, 1994) and TOXICOLOGY LETTERS 102-103:5-18 (1998)]

RDA = Recommended Daily Allowance based on preventing acute nutrient deficiency disease conditions rather than based on amounts producing optimum health.

I. FOLIC ACID

Folic acid (folate) was so-named because it was discovered in the leafy vegetable spinach. Yeast, liver and fresh green vegetables are particularly good sources of folate. Cooking and food processing (such as canning) can destroy nearly all of the folic acid. Pernicious anemia due to folic acid or Vitamin B₁₂ deficiency can be completely cured by folic acid, but is more safely cured by Vitamin B₁₂.

The form of folic acid that circulates in the blood stream is 5−methytetrahydrofolate (5−MTHF). 5−MTHF enhances endothelial cell (cells that line blood vessels walls) nitric oxide synthetase activity, increasing nitric oxide production and reducing production of damaging superoxide free radicals in blood vessels [CIRCULATION; Antoniades,C; 114(11):1193-1201 (2006)].

Folic acid is necessary for the methylation of uracil to thymine. Without this methylation, uracil rather than thymine may be incorporated into DNA — which can lead to chromosome breaks during DNA repair [PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES (USA); Blount,BC; 94(7):3290-3295 (1997)]. Supplementation with folic acid above the RDA levels minimizes chromosome breaks. Similarly, ingestion of less than 50% of the RDA of Vitamins B₆ and B₁₂ causes high levels of uracil incorporation in DNA and consequent chromosome breaks [MUTATION RESEARCH; Ames,BN; 475(1-2):7-20 (2001)].

Rat hippocampal cells cultured in a folic acid deficient medium showed 8 times the rate of cell death as rat hippocampal cells cultured in a control medium, and cell death due to the amyloid-beta (Aß) peptide (Alzheimer's Disease) toxicity was more than double in the folic acid deficient medium. Amyloid transgenic mice showed similar effects on a folic acid deficient diet. Neuron death was attributed to impaired DNA repair [THE JOURNAL OF NEUROSCIENCE; Kruman,II; 22(5):1752-1762 (2002)]. An epidemiological study of elderly (mean age 74) humans showed that over a four year period high plasma homocysteine and low plasma folate were independently associated with an approximate doubling of risk for both Alzheimer's Disease and all-cause dementia [THE AMERICAN JOURNAL OF CLINICAL NUTRITION; 82(3):636-643 (2005)].

Folic acid deficiency increases accumulation of homocysteine, which can cause neurological defects in the fetus of a pregnant woman. Homocysteine also damages endothelial cells and is thus implicated in cardiovascular disease. Homocysteine promotes atherosclerosis through fibrin deposition, oxidant stress, cytokine release, inflammation and other mechanisms [AMERICAN JOURNAL OF CLINICAL NUTRITION; McCully,KS; 86(suppl):1563S-1568S (2007)]. Although elevated plasma homocysteine in epidemiological studies is associated with elevated cardiovascular disease, and although plasma homocysteine can be lowered by folate, Vitamin B₆ and Vitamin B₁₂ supplementation, clinical trials have failed to demonstrate reduced cardiovascular disease through reduction of homocysteine by folate or other vitamin supplementation [FRONTIERS IN BIOSCIENCES; Lin,C; 14:3836-3845 (2009)].

However, a double-blind study in which patients with vascular disease or diabetes were given a combination of folic acid along with Vitamins B₆ & B₁₂ or a placebo for 5 years showed a 20% lowering of homocysteine, but no reduction in cardiovascular death as compared to placebo [NEW ENGLAND JOURNAL OF MEDICINE; 354(15):1567-1577 (2006)]. A similar 40 month study of myocardial infarction patients showed a 27% reduction in plasma homocysteine, but no reduction (and possibly a small increase) in risk of cardiovascular death compared to placebo [NEW ENGLAND JOURNAL OF MEDICINE; 354(15):1578-1588 (2006)]. Vitamin B therapy may be interfering with methylation [CARDIOVASCULAR TOXICOLOGY; Joseph,J; 9(2):53-63 (2009)].

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II. VITAMIN B₁₂

Vitamin B₁₂ has a very large and complex chemical structure having cobalt as the central ion. Like folic acid, Vitamin B₁₂ is particularly critical for DNA synthesis. Vitamin B₁₂ regenerates folic acid, and adequate amounts of folic acid can completely eliminate the pernicious anemia associated with Vitamin B₁₂ deficiency. But even in the presence of adequate folic acid, Vitamin B₁₂ deficiency can result in neuropathies (myelin damage) leading to fatigue and depression. The neuropathies can affect the peripheral nerves, spinal cord, and cerebral cortex. The cerebral syndromes include memory loss, dementia and even psychosis [BRITISH MEDICAL BULLETIN; Weir,DG; 55(3):669-682 (1999)]. It is therefore dangerous to treat pernicious anemia with folic acid without assuring that there is no Vitamin B₁₂ deficiency. Defective gastric intrinsic factor can cause B₁₂ deficiency because intrinic factor is essential for Vitamin B₁₂ absorption from the gut into the bloodstream. Vitamin B₁₂ has been shown to improve memory in studies with women [JOURNAL OF NUTRITION; Bryan,J; 132(6):1345-1356 (2002)]. A study of non-demented healthy elderly subjects who were not Vitamin B₁₂-deficient showed that those with the lowest serum Vitamin B₁₂ had the greatest brain volume loss over a 5-year period [NEUROLOGY; Vogiatgzoglou,A; 71(11):826-832 (2008)].

Hypothyroid patients have been found to have reduced serum Vitamin B₁₂ and elevated homocysteine (a cardiovascular risk factor). Treatment with thyroid hormone has lowered serum homocysteine, but also lowered serum Vitamin B₁₂ [ENDOCRINE JOURNAL; Orzechowska-Pawilojc,A; 54(3):471-476 (2007)].

As with folic acid, Vitamin B₁₂ is necessary for uracil to be methylated to thymine. Again, supplementation with Vitamin B₁₂ above the RDA will minimize chromosome breakage. Homocysteine also accumulates with Vitamin B₁₂ deficiency because Vitamin B₁₂ is require to methylate homocysteine to methionine — making Vitamin B₁₂ deficiency a risk factor for heart disease. A four-year randomized, double-blind, placebo-controlled clinical trial supplementing stroke patients with folic acid 2 milligrams, Vitamin B₆ 25 milligrams, and Vitamin B₁₂ 500 micrograms showed significant reduction in plasma homocysteine, but no significant improvement in endothelial function [BMC CARDIOVASCULAR DISORDERS; Potter,K; 8:24 (2008)].

The adult daily requirement for Vitamin B₁₂ is 2 to 3 micrograms. The major dietary source of Vitamin B₁₂ is meat (especially liver and shellfish) and dairy products. In nature, only bacteria can synthesize Vitamin B₁₂. Cyanocobalamin, a synthetic form of Vitamin B₁₂, is converted to physiologically active forms of Vitamin B₁₂ in the body. Vegans (persons eating no meat or dairy products) are frequently deficient in Vitamin B₁₂, but symptoms can be slow to develop because Vitamin B₁₂ is well-conserved by the body. A number of substances including metformin, nicotine, and potassium chloride supplements can block Vitamin B₁₂ absorption.

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III. VITAMIN B₆

Pyridoxine	Pyridoxal	Pyridoxamine

 

pyridoxal−5'−phosphate

Vitamin B₆ is a name applied to three related (enzymatically interconvertible) chemicals: pyridoxine, pyridoxal, and pyridoxamine. The primary biologically active form of the vitamin in human metabolism is a phosphate of pyridoxal: pyridoxal−5'−phosphate (PLP). PLP acts as a coenzyme in the synthesis of several neurotransmitters (serotonin, dopamine, norepinephrine, GABA), as a coenzyme for the synthesis of heme (a component of hemoglobin) and single-carbon metabolism involved in nucleic acid synthesis. PLP is a coenzyme in all transamination reactions.

Severe Vitamin B₆ deficiency is rare, but mild deficiency is common. Severe deficiency results in neurological symptoms such as irritability, confusion, anemia, inflammation, EEG abnormalities, and ulcers in the mouth. Milk & meat are common sources, but some plant foods (bananas, soybeans, peanut butter, orange juice and brans of wheat, corn or rice) have Vitamin B₆. The minimun Recommended Daily Requirement (RDA) for adults is 1.3 milligrams — less for children, more for elderly people as well as pregnant or breast-feeding women. The amount of Vitamin B₆ required increases with increased dietary protein, probably because of the role of PLP in amino acid metabolism. Two milligrams daily would be a safe minimum for all adults. Some vegetarians should consider taking supplements. Excessive pyridoxine can cause painful sensory neuropathy so 100 milligrams daily is the recommended maximum for adults (30 milligrams daily is the maximum for young children).

Anti-glycation comparison

Homocysteine is an intermediate in metabolism of the amino acid methionine. Increased serum homocysteine is a risk factor for cardiovascular disease. Homocysteine levels can be reduced by conversion of homocysteine to the amino acid cysteine with Vitamin B₆ (PLP) as a cofactor, or conversion of homocysteine back to methionine with folic acid & Vitamin B₁₂ as cofactors.

Vitamin B₆ deficiency is associated with immune system deficiency (reduced lymphocytes and interleukin−2 production) [AMERICAN JOURNAL OF CLINICAL NUTRITION; Meydani,SN; 53(5):1275-1280 (1991)]. Vitamin B₆ has been shown to improve memory in studies with women [JOURNAL OF NUTRITION; Bryan,J; 132(6):1345-1356 (2002)]. PLP protects proteins from glycation [JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY; Nakamura,S; 16(1):144-150 (2005)] and PLP prevents lipid glycation more effectively than other common anti-glycation agents [JOURNAL OF LIPID RESEARCH; Higuchi,O; 47(5):964-974 (2006)]. Lipid glycation of LDL cholesterol increases the LDL oxidation associated with atherosclerosis [ATHEROSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY; Ravandi,A; 20(2):467-477 (2007)].

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IV. TMG

TMG (TriMethylGlycine, betaine) converts homocysteine to methionine in the liver, whereas folate-dependent remethylation of homocysteine takes place in all cells. Methionine can combine with ATP to form S-AdenosylMethinine (SAMe, methinine-adenosine), the principal source of methyl groups in the body. Both high and low levels of methionine can increase serum homosysteine levels [ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY; Holm,PI; 25(2):379-385 (2005)]. Methylation is essential for DNA & RNA synthesis. Much of the SAMe in the liver is converted to the water-phase antioxidant glutathione. Six grams of TMG daily for three months reduced plasma homocysteine levels by 9% in 22 obese subjects [AMERICAN JOURNAL OF CLINICAL NUTRITION; Schwab,U; 76(5):961-967 (2002)]. TMG decreases plasma homocysteine more in patients with high plasma homocysteine than in healthy volunteers [ARCHIVES OF INTERNAL MEDICINE; Brouwer,IA; 160(16):2546-2547 (2000)]. Because TMG helps reduce homocysteine, it could protect against heart disease — but see the sections above on folic acid and Vitamin B₁₂.

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V. ZINC

Zinc Finger

Zinc is an essential component of many enzymes and proteins, including the anti-oxidant enzyme Cu/Zn-SOD (SuperOxide Dismutase) and p53 tumor-suppressor protein. So-called zinc fingers are loops of 12 or 13 amino acids (residues) centered on zinc which is bound to pairs of Cysteine (C) or Histidine (H) residues. Zinc fingers are found on steroid receptors and transcription factors (enabling the factors to bind to DNA). Two zinc fingers are found in the DNA-binding domain of the DNA-repair enzyme PARP — Poly (ADP-Ribose) Polymerase.

Zinc deficiency can lead to impairment of many hormones, including thyroid, corticosterone, growth hormone and sex hormones. Insulin output can be reduced while there is an increase in insulin resistance. Zinc can counteract the inhibition of DNA synthesis by the toxic, carcinogenic metal cadmium [NUCLEIC ACID RESEARCH; Nocentini,S; 15(10):4211-4225 (1987)].

The immune system is severely impaired by zinc deficiency, due to both reduction in cell division rate and reduced Cu/Zn-SOD. The thymus & spleen are smaller, and lymphoid tissues show more reduced mass than other tissues. The functions of lymphocytes, neutrophils and natural killer (NK) cells are all impaired. Diabetic patients are often supplemented with zinc to improve immune function.

A randomized, double-blind, placebo-controlled study of human victims of common cold showed that lozenges of 13.3 milligrams of zinc acetate taken every 2-3 hours while awake reduced the overall duration of the cold from about 7 days to 4 days, while also decreasing the severity of cold symptoms (cough, nasal discharge, muscle aches). The beneficial effects of zinc were attributed to antioxidant action and modulation of proinflammatory cytokine release [THE JOURNAL OF INFECTIOUS DISEASES; Prasad,AS; 197(6):795-802 (2008)].

Shellfish and red meats are rich sources of zinc. Nearly 80% of zinc is lost in making flour from wheat during the milling process. Phytate in whole grains binds to zinc thereby aggrevating the risk of zinc deficiency for vegetarians.

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VI. MAGNESIUM

Magnesium depletion results in defective parathyroid hormone secretion and activity. Magnesium depletion is also associated with anxiety disorders, migraine, depression, insomnia, elevated serum lipids, high blood pressure, and reduced immunity. Magnesium depletion causes depletion of calcium and potassium, which is responsible for some of the symptoms. Excess magnesium results in electrocardiogram irregularities and central nervous system depression. Severe magnesium toxicity can cause coma and cardiac arrest.

Increasing magnesium can relax smooth muscle and reduce blood pressure. Coronary artery disease patients given 325 milligrams of magnesium daily showed improved endothelial cell function and reduced exercise-induced angina [CIRCULATION; Shechter,M; 102(19):2353-2358 (2000)]. Evidence for the use of magnesium to prevent artrial fibrillation is not definitive [HEALTH TECHNOLOGY ASSESSMENT; Shepherd,J; 12(28) (2008)]. Low magnesium is associated with age-related diseases and low magnesium can induce cellular senescence in endothelial cells [MAGNESIUM RESEARCH; Killilea,DW; 21(2):77-82 (2008)].

Depending mainly on body size, the human requirement for magnesium is estimated to be between 300 to 400 milligrams per day. The average person in the United States does not get this much magnesium. Diabetes and osmotic diuretic drugs can deplete magnesium. Because magnesium (Mg²⁺) is the coordinating ion in chlorophyll, green vegetables are a good dietary source. Nuts, notably cashews and almonds, are good sources of magnesium. Magnesium sulfate (epsom salts) has been used as a supplement, but the laxative effect can result in diarrhea if too much is ingested.

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VII. IODINE

Iodine deficiency has been called the world's leading cause of intellectual deficiency [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Hollowell,JG; 83(10):3401-3408 (1998)]. Iodine deficiency during pregnancy can lead to a form of irreversible hypothyroid mental retardation known as cretinism. Studies of iodine deficiency in children have estimated a loss of at least six IQ points [ENDOCRINE REVIEWS; Zimmerman,MB; 30(4):376-408 (2009)].

The primary nutritional use of iodine by the human body is for synthesis of thyroid hormones by the thyroid gland in response to TSH (Thyroid Stimulating Hormone) secreted by the anterior pituitary gland. Thyroid hormones regulate metabolism and development (particularly of the brain). In adults with low iodine intake, TSH blood levels become elevated, which stimulates thyroid gland growth, while thyroid hormone remains low. An enlarged thyroid gland is termed goiter. Symptoms of hypothyroidism include fatigue, weight gain, cold intolerance, depression and impaired mental function. Excessive dietary iodine can cause hyperthyroidism.

Iodine is highly concentrated in oceans and depleted in mountainous areas. Because the Japanese eat seaweed (kelp) and much seafood, the average Japanese person consumes hundreds of times more iodine daily than the average North American [THYROID; Nagataki,S; 18(6):667-668 (2008)]. Not surprisingly, the addition of iodine to salt for dietary supplementation was begun in mountainous Switzerland in the 1920s. FDA guidelines for iodized salt provide 150 micrograms per half teaspoonful of salt. Most salt used in processed foods is not iodized.

Daily recommended iodine intake is 90-120 micrograms daily for children and 150 micrograms daily for adults. Pregnant and breast-feeding women are advised to take 200 micrograms daily. A number of foods can interfere with iodine uptake, including broccoli, cauliflower, linseed, lima beans and sweet potatoes [ENDOCRINE REVIEWS; Zimmerman,MB; 30(4):376-408 (2009)]. Because of declining salt consumption and increasing vegetarianism, iodine levels in Americans have been declining [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Hollowell,JG; 83(10):3401-3408 (1998)]. Increasing iodine intake when selenium is deficient can lead to autoimmune disease due to insufficient selenium-based anti-oxidant enzymes in the thyroid to protect against the iodine [JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION; Hoption Cann; 25(1):1-11 (2006)]. Thyroid control of thyroid hormone production and release prevent even very high quantities of ingested iodine from increasing serum thyroid hormone levels [JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM; Theodoropoulou,A; 92(1):212-214 (2007)]. Selenium supplementation should be an adjunct to iodine supplementation, but excess iodine should nonetheless be avoided because of the potential for thyroid damage and resultant hypothyroidism. A Japanese study of reversible hypothyroid patients found that iodine restriction (avoiding foods such as seaweed products) led to a 50% decrease in serum TSH within one week for those who had no antithyroid antibodies, whereas the same decrease took over two weeks for those with antibodies or who had elevated TSH associated with pregnancy [CLINICAL ENDOCRINOLOGY; Sato,K; 45(5):519-528 (1996)].

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VIII. NIACIN

NIACIN	NIACINAMIDE

Niacin and its amide, niacinamide, are called vitamers, because both equivalently act as a vitamin. The terms nicotinic acid and nicotinamide are also used for the vitamers. "Niacin" is also a generic term describing both vitamers together.

Niacin can be synthesized from tryptophan, but tryptophan is an essential amino acid that cannot be synthesized. An intake of 60 mg of tryptophan might result in one mg of niacin, because most tryptophan is used by the body for protein maintenance. Riboflavin (Vitamin B₂) and pyridoxine (Vitamin B₆) are essential cofactors in synthesizing niacin from tryptophan. The niacin-deficiency disease pellagra was first recognized in 1735 by a Spanish physician among people living on corn (maise), a vegetable that is low in both niacin and tryptophan. It wasn't discovered until 1937 that niacin could cure pellagra. The RDA (Recommended Daily Allowance) of 13-20 mg per day is based on the amount required to prevent pellagra. High doses of niacin are often avoided because of the skin flushing that it causes.

A dose of 1.5 to 3 grams of niacin per day can lower LDL cholesterol and elevate HDL cholesterol. Niacin increases apolipoprotein B (the primary lipoprotein of LDL cholesterol) degredation in the liver and inhibits triglyceride synthesis. By inhibiting liver removal of apolipoprotein a−1 (the primary lipoprotein of HDL cholesterol) from the circulation, niacin increases serum HDL half-life [AMERICAN JOURNAL OF CARDIOLOGY; Kamanna,VS; 101(Suppl):20B-26B (2008)].

Niacin forms the core of the nucleotide coenzyme NAD (Nicotinamide Adenine Dinucleotide) and it phosphate coenzyme NADP. NAD and NADP are essential for energy production, electron transport and antioxidant function through hydrogen acceptance (NADH & NADPH) and donation. NAD+ is required by the DNA-repair enzyme PARP — Poly (ADP-Ribose) Polymerase. Niacin doses equivalent in a human to 3 to 6 grams per day in rats have been shown to elevate PARP, NAD+ and reduce cancer susceptibility in a dose-dependent manner [JOURNAL OF NUTRITION; Boyonoski,N; 132(1):115-120 (2002)].

An observational study of over 6,000 people 65 years of age and older found that compared to people in the lowest fifth of niacin intake, those with higher intake had between 20% to 50% the risk of getting Alzheimer's Disease. This result was after adjustment for age, sex, race, education, ApoE type and intake of vitamins E & C as well as beta-carotene. The effect was specific to niacin, as opposed to the other B vitamins [JOURNAL OF NEUROLOGY, NEUROSURGERY, AND PSYCHIATRY; Morris,MC; 75(8):1093-1099 (2004)].

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IX. VITAMIN K

Vitamin K is a lipid soluble (hydrophobic) vitamin which is important for blood coagulation, bone integrity (opposes osteoporosis) [PROCEEDINGS OF THE NUTRITION SOCIETY; Bugel, S; 62:839-843 (2003)] and blood vessel health (reduce vascular calcification) [JOURNAL OF NUTRITION; Geleijnse, JM; 134:3100-3105 (2004) and ARCHIVES OF INTERNAL MEDICINE; Cockayne,S; 166(12):1256-1261 2006)]. Vitamin K deficiency disease associated with fatal hemoorhage was discovered in 1929, resulting in its name (K for "Koagulation" — German). Vitamin K₁ (phylloquinone) is found in many green vegetables, whereas Vitamin K₂ (menaquinone) is found in organ meats, eggs & cheese — and is normally produced by intestinal bacteria. The common denominator of Vitamin K chemical function is the carboxylation of glutamate residues of proteins to form calcium-binding sites.

The isoprenoid side chains of Vitamin K₂ (menaquinone) are designated MK−n, where "n" specifies the number of isoprenoid side chains. The MK−4 form of Vitamin K₂ is very rapidly absorbed, but only remains in the bloodstream for a few hours. The higher menaquinones are more hydrophobic, and have longer half-lives. The bioavailability of MK−7 is 2.5 times better than Vitamin K₁ over a 24−hour period, and 6 times better over a 96−hour period [BLOOD; Schurgers,LJ; 109(8):3279-3283 (2007)].

A three-year randomized, placebo-controlled study of Vitamin K₁ supplementation (500 micrograms daily) in men & women aged 60 to 80 showed a reduction in the progression of insulin resistance in men taking the supplements, but the benefit was not seen for women [DIABETES CARE; Yoshida,M; 31(11):2092-2096 (2008)].

Persons taking Vitamin E supplements are cautioned that Vitamin E can antagonize Vitamin K
[see the comments near the bottom of Vitamin E (Tocopherols and Tocotrienols)].

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X. VITAMIN D

Vitamin D2	Vitamin D3

UVB forms Vitamin D3

 

Vitamin D maintains serum calcium and phosphorous to support bone formation & maintenance, and other metabolic needs. Vitamin D (cholecalciferol, Vitamin D₃ and ergocalciferol, Vitamin D₂) is manufactured in the skin in response to sunlight (UltraViolet B, UVB). Vitamin D deficiency was rare prior to industrialization in Europe, after which the Vitamin D deficiency disease rickets began to appear increasingly in urban centers. Cod liver oil came to be used in as a folklore remedy for rickets in the eighteenth century. In 1920 Vitamin D was isolated in cod liver oil. In the 1930s Vitamin D fortification of milk became a common practice in Europe. Only a few foods (egg yolk, fatty fish, and fish liver) are rich in Vitamin D. Avoidance of solar radiation (including use of sunscreens) to prevent skin cancer and skin wrinkling also limits the amount of Vitamin D formed in the skin by sunlight.

Recently Vitamin D in doses larger than those required to prevent rickets has been shown to have a variety of other health benefits. In response to microbial infections, Vitamin D₃ induces genes that promote innate immunity [THE JOURNAL OF CLINICAL INVESTIGATION; Schauber,J; 117(3):803-810 (2007)]. As a negative regulator of renin synthesis, Vitamin D₃ can reduce high blood pressure [JOURNAL OF STEROID BIOCHEMISTRY & MOLECULAR BIOLOGY; Qiao,G; 96(1):59-66 (2005)]. Vitamin D can suppress a number of autoimmune diseases (including rheumatoid arthritis and type 1 diabetes) so long as calcium intake is adequate [THE FASEB JOURNAL; Deluca,HF; 15(14):2579-2585 (2001)]. Vitamin D₃ may inhibit production of the pro-inflammatory cytokine Tumor Necrosis Factor−alpha (TNF−α) [EUROPEAN JOURNAL OF IMMUNOLOGY; Zhu,Y; 35(1):217-224 (2005)]. Doses of 800 IU Vitamin D₃ with 1,200 mg calcium daily has reduced hip fractures in elderly women by 42%, and lowered the risk of type 2 diabetesby a third, whereas lower does have not shown these effects [THE NEW ENGLAND JOURNAL OF MEDICINE; Holick,MF; 357(3):266-281 (2007)]. Vitamin D₃ (1,100 IU daily) with calcium (1,400-1,500 mg daily) was shown to substantially reduce all-cancer risk in a study of postmenopausal women [AMERICAN JOURNAL OF CLINICAL NUTRITION; Lappe,JM; 85(6):1586-1591 (2007)]. Vitamin D₃ induces expression of cystatin D, leading to tumor suppression of colon cancer [THE JOURNAL OF CLINICAL INVESTIGATION; Alvarez-Diaz,S; 119(8):2343-2358 (2009)].

Serum Vitamin D tends to be about half as high in winter months as it is in summer months — and reduced sun exposure has been correlated with many forms of cancer [ANTICANCER RESEARCH; Peterlik,M; 26(4A):2581-2588 (2006)]. Vitamin D₂, the form of Vitamin D usually found in vitamin supplements, is only about one-third as potent as Vitamin D₃. Excess Vitamin D can be toxic, leading to calcification of organs and soft tissues as well as kidney stones. But a review of human clinical trial data concluded that the limit of tolerable intake should be revised upward from 2,000 IU (50 micrograms) daily to 10,000 IU (250 micrograms) daily [AMERICAN JOURNAL OF CLINICAL NUTRITION; Hathcock,JN; 85(1):6-18 (2007)]. Retinol (Vitamin A) antagonizes calciferol (Vitamin D), decreasing serum calcium and increasing serum phosphorus by an unknown mechanism [JOURNAL OF NUTRITION; Rohde,CM; 135(7):1647-1652 (2005)], which means that more Vitamin D intake is required to compensate for the effects of Vitamin A. Vegans who avoid consuming fish and dairy products are advised to supplement with Vitamin D₃.

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XI. CENTROPHENOXINE/DMAE

Centrophenoxine (Lucidril) & DMAE (DiMethylAminoEthanol) function to protect against free-radical oxidation. DMAE (which is found in high concentrations in sardines & anchovies) is claimed to facilitate production of the neurotransmitter acetylcholine (as is phospatidyl choline). Because acetylcholine (primarily from the nucleus of Meynert in the basal forebrain) acts as a neurotransmitter to stimulate the hippocampus, memory function can be improved somewhat by substances that facilitate acetylcholine production — particularly in Alzheimer's Disease patients. No cholinergic agonists have been successful in simulating this effect, but some acetylcholinesterase (acetylcholine-destroying enzyme) antagonists like tacrine have been.

DMAE is metabolized in the brain to form phosphatidyl-DMAE which becomes incorporated in nerve cell membranes where it is highly protective against hydroxyl free-radical damage. Loss of permeability of cell membranes with aging is correlated with dehydration, declining enzyme activity and increasing lipofuscin accumulation. This is most serious in the brain & heart because the cells in these tissues are non-dividing.

Centrophenoxine is an ester (carboxyl-linked dimer, ie, two molecules linked to a C=O group by a -O- connection) of p-chlorophenoxyacetic acid and DMAE. Centrophenoxine crosses the blood-brain barrier (BBB) much more effectively than DMAE alone, and once across the BBB the DMAE can be released by hydrolysis. Some early studies claimed that centrophenoxine reverses lipofuscin concentration in the frontal cortex and hippocampus in treated mice (lipofuscin concentration normally increases particularly dramatically in the CA3 cells of the hippocampus). Although there is evidence that centrophenoxine can significantly reduce the rate of lipofuscin accumulation, a more recent study concluded that already-formed lipofuscin cannot be eliminated [JOURNAL OF ANTI-AGING MEDICINE; Terman, A; 2(3):265-273 (1999)].

Procaine (an ingredient of Gerovital, GH-3) is broken-down in the body into para-aminobenzoic acid (PABA, sometimes called a B-vitamin) and DEAE (DiEthylAminoEthanol), which may function similarly to DMAE.

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