Grow Youthful: How to Slow Your Aging and Enjoy Extraordinary Health
Grow Youthful: How to Slow Your Aging and Enjoy Extraordinary Health

Copper

Copper is a confusing mineral

Health properties of copper

How much copper do you need?

Factors causing copper deficiency

Tests for copper deficiency

Symptoms of copper deficiency

Cuprous versus cupric copper

Copper excess

Food sources of copper

Copper supplementation

Copper enzymes

References

Copper is a confusing mineral

Many health-aware people think that copper is something we get in excess. Doctors and popular health writers warn us about copper accumulation through copper plumbing and cookware. Some even refer to copper as a toxic mineral. However, the reality is that most people are copper-deficient. This is a critical deficiency because copper is one of the most important trace minerals in our diet. Copper is essential for many processes in the body, including the production of most proteins, enzymes and hormones.

Copper deficiency is a primary cause of many modern diseases such as coronary heart disease, stroke, atherosclerosis, inflammation, anaemia, old skin and rapid ageing, fatigue, grey hair, osteo arthritis, rheumatoid arthritis, cancers and many psychological, brain and nervous disorders.

Why is copper deficiency not widely acknowledged and copper not widely supplemented? The answer is that there are several confounding factors:

Health properties of copper

How much copper do you need?

One estimate is that 80% of the population in the USA is copper-deficient. (3) The average American gets 0.9 mg of copper per day, a level that studies show causes severe cardiovascular problems in animals. (95)

The current RDI (Recommended Dietary Intake by the US Food and Drug Administration) for copper is 2 mg per day. (43) Most adults excrete about 1.3 mg of copper per day. If they sweat a lot, they can lose an additional 0.34 mg per day. (59) If you are getting less than 2 mg per day, it is easy to become copper-deficient. (60)

One study (61) concluded that to prevent copper deficiency 2.6 mg per day of copper is required. Most nutritionists recommend a daily copper dosage between 1 and 3 mg. (43) Several scientists who have studied copper and its health benefits take 4 mg daily. Other studies have found that 4-7 mg daily supplemental copper has resulted in benefits such as reducing cellular oxidation damage, lowering LDL cholesterol and raising HDL. (93) This level of copper intake may reduce the risk of many degenerative diseases. (95)

The World Health Organization gives 10 mg per day as the tolerable upper limit of copper intake. Most nutritionists recommend not exceeding 10 mg of copper daily. Remember that copper works synergistically with other minerals and nutrients. Copper needs to be taken in the correct ratio with zinc and other minerals like iron in order to maximise absorption. (107) Most scientists suggest that the ideal ratio of zinc to copper in the diet is 5:1. However I have seen recommendations from popular health writers from as low as 1:1 to as high as 9:1. Ageing and sickness is associated with extreme high or low ratios. (110)

If you are supplementing with large amounts of any copper antagonists, your copper needs will increase. For example, consuming large amounts of vitamin C (>800 mg) or zinc (>15 mg) per day will affect on your copper requirement.

Those with genetic disorders affecting copper metabolism (such as Wilson's disease, Indian childhood cirrhosis) should not supplement copper.

Factors causing copper deficiency

Tests for copper deficiency

Unfortunately there is no easy and reliable test for copper sufficiency or deficiency. Blood, hair, urine and saliva tests for copper are usually unreliable. (51, 88) Hair tests are often misleading, as it is possible to have a high level of copper in the hair while being copper-deficient in the body. The lack of clear and reliable tests of human copper sufficiency make it difficult to determine how much supplemental copper you need for optimum health or to prevent chronic disease.

One of the most reliable tests is a liver biopsy. This is often used by farmers after the slaughter of their animals, but obviously is it not normally used on humans. It does mean that farm experience with feeding and copper supplementation is often valuable for humans.

Copper deficiency doesn't necessarily lower the level of copper-dependent enzymes, so tests for cuproenzyme levels may not be reliable. However, copper deficiency does significantly lower their activity. For example, lysyl oxidase is the main enzyme involved in the cross-linking of collagen and elastin, vital for the strength and flexibility of connective tissue in our skin, blood vessels, bones and other organs. In a copper-deficient person the level of lysyl oxidase looks normal. However, activity of this enzyme can be reduced by more than 50%. (92)

For the above reasons, the most practical quick test available is simply whether you are showing symptoms of copper deficiency. The hallmarks of copper deficiency are connective tissue disorders (prematurely aged, loose and weak skin), heart disease manifested by weak/distended/damaged blood vessels, and osteoporosis.

Symptoms of copper deficiency

Obvious and severe copper deficiency is not common. Marginal, chronic deficiency causing a variety of long-term chronic ailments is more the norm.

Cuprous versus cupric copper

Cuprous copper

In this inorganic, unbound, non-biological form, cuprous copper is not efficiently excreted and can accumulate in the body. (72, 89, 97) This is the toxic form of copper which is not normally found in a healthy human body. Nearly all cuprous copper compounds are colourless when in solution in water. They are easily oxidised and less stable than most other copper compounds. Most of them will not dissolve in pure water, but will dissolve in acidic water.

Examples of cuprous copper compounds include:

Most people get their municipal water through copper pipes. If the copper pipes are in constant use, the build-up of cuprous copper in the water flowing through them is insignificant. However, if the water is slightly acidic and the pipes are not used for many hours or days, then cuprous copper compounds can build up in the water. The presence of other chemicals in the water such as chlorine, for example, may compound the problem.

Another situation in which metallic copper and an acid environment access the human body is with a copper IUD contraceptive device. Copper cookware is yet another situation where acids in food or drink can come into contact with metallic copper. For most people, their tap water is not significantly acid (or alkaline). If you are concerned, the solution is to flush out the pipes before drinking such water. Run the cold tap long enough to flush water from your supply connection (usually by the water meter) to the tap.

Naturally high levels of copper in the sources of municipal water are not common. (89) Water with a copper level of more than 2 mg per litre is usually cloudy or has a blue or green tinge or blue/green particles. You can see the discolouration it if you put a litre of such water in a white bowl or container. If you boil it the water or particles may change colour to brown or black and the particles may float to the surface. If you have this much copper in your water supply, you need to carefully consider how much copper you are getting, and in what form (cuprous or cupric) as there is a risk of copper toxicity. (97)

Cupric copper

In this organic, bound, biological form, cupric copper is more precisely controlled and quickly excreted from the body.

Cupric copper compounds dissolve in pure water, and are blue or blue-green colour in solution. They are more stable than other copper compounds. Cupric copper is the bio-available form of copper, which is essentially non-toxic as any excess is quickly excreted from the body. In its organic cupric form, the liver regulates copper with speed and precision. (61, 62) Bile is the major pathway for the excretion of copper.

In a study, scientists tried to create an elevated level of copper in blood plasma by injecting dogs and healthy human volunteers with high doses of cupric copper. All the excess copper in their blood disappeared within hours. In another study, 50 mg of cupric copper (25 times the RDI) was injected into healthy human volunteers. It completely disappeared from their blood in 4 hours. (64)

In another study, researchers gave healthy adults 4-8 mg of cupric copper a day for 1 to 3 months. This moderately high dosage did not change their copper plasma concentration because copper is so quickly and efficiently excreted. (65, 66)

Simple cupric compounds include:

Copper excess

It is virtually impossible to overdose on copper by eating high-copper foods. However, it is possible to get an excess of copper from cuprous forms of copper.

Copper toxicity is rare. Acute copper poisoning has occurred through the contamination of acidic drinks stored in copper-containing containers. Immediate symptoms of severe copper toxicity include abdominal pain, vomiting and diarrhoea (all of which purge the copper). Over time, copper toxicity can cause liver damage, kidney failure, psychosis, coma, and then death. (96)

In healthy adults, doses of up to 10mg of copper per day have not resulted in liver damage, so this level was set as the World Health Organization's upper limit. Those with genetic disorders affecting copper metabolism (such as Wilson's disease or Indian childhood cirrhosis) may be at risk of copper toxicity at significantly lower copper intake levels.

Copper inhibits or opposes zinc, iron, magnesium, manganese and molybdenum, and vitamin C, folic acid, vitamin B1 and vitamin E. Excess copper may cause low levels of all these minerals and vitamins, but particularly a low level of vitamin C (and all the consequences of insufficient vitamin C). (71, 82) On the other hand, it is possible that your copper levels could be abnormally high if you have abnormally low levels of copper antagonists in your body. Low zinc levels can occur with untreated pyroluria, for example.

Many of the symptoms of excess copper are similar to those of insufficient copper: immune problems, hormone upsets, painful joints, psychosis and upsets to brain function, liver damage. (73, 74, 75, 76, 77, 78, 79, 80, 83, 96)

Estrogen dominance (via xenoestrogens) is associated with copper excess. (69)

Food sources of copper

Broadacre and conventional farming strips the copper content from soil. In addition, the use of superphosphate and nitrogenous fertilisers prevent the uptake of copper. A study showed that the copper content in a variety of foods halved between 1942 and 1966. (95) Since then it has only got worse, so most foods that used to provide copper are now severely deficient. Australian soils were generally copper-deficient to start with, even before modern farming.

The richest food sources of copper are liver and other organ meats, oysters and other shellfish, cacao nibs, cocoa and black chocolate and red meat.

Other foods which may include copper depending on the soils and circumstances include apples, apricot kernels, avocado, bananas, barley, bee pollen, beetroot, blackstrap molasses, brewer's yeast, broccoli, buckwheat, burdock, butter, chicken, chickweed, coconut, dandelion greens, echinacea, eyebright, eggs, fennel, fish, garlic, golden seal, green beans, legumes especially lentils, mushrooms, oats, olives, oranges, parsley, peaches, pork, prunes, radish, raisins, red wine, seaweed, sesame seeds (unhulled), soy beans, split peas, sunflower seeds, tomato puree, tree nuts (mainly cashews, and then brazils), wheat bran, wheat germ.

A high quality traditionally-made red wine is usually rich in organic copper, and may be responsible for the "French paradox" (in addition to its beneficial resveratrol content).

In certain regions well water may be a source of copper, but you first need to ascertain what kind of copper. In Grow Youthful I maintain that the best water of all is the outflow from mountain glaciers or previous glacial regions. This water is rich in a wide variety of health-giving minerals, including copper.

Vegetarians may absorb copper less efficiently than non-vegetarians. A study found that lacto-ovo vegetarians averaged 1.45 mg of copper per day of which 0.48 mg was absorbed. In contrast, the non-vegetarians averaged 0.94 mg of copper per day of which 0.39 mg was absorbed. (67)

Copper supplementation

The best way to get copper is by eating copper-rich foods. If you are pregnant or ill, do not supplement except under your doctor's supervision. Take care to use high quality supplements, and measure quantities carefully.

Symptoms of copper deficiency may be rapidly reversed by copper supplementation. (68) The dose required depends on the problems being treated and the condition of the patient.

Warning: do not apply copper compounds to open cuts, inflamed or very sensitive skin as it may cause irritation and pain. Alternatively, use it very diluted.

Dry skin does not absorb copper very well. Most copper salts do not easily pass through dry skin, but absorption is increased if the skin is damp. Different people may get different results, in particular depending on their skin's acidity. When copper is in contact with the skin, and the skin is not acidic, it forms chelates with components of human sweat and this aids its skin absorption.

Copper is a remedy and a preventative, especially when an ingredient in other medicines. (28)

The most common forms in which copper may be supplemented

Copper gluconate is the most common form in which copper is supplemented. It is less tightly bound than salicylate, so should be used with care and only taken with food. Other amino acid chelates are also used, but gluconate is generally preferred.

Copper salicylate is the most stable form in which to supplement copper, both orally and transdermally. It does not alter liver or blood chemistry as much as other copper compounds do, because it is so stable. (84) Copper salicylate may be directly applied to the skin at the site of the problem - a painful joint, arthritis, skin cancer, ulcer, aged skin or grey hair. To penetrate the skin, it needs to be kept moist for many minutes or longer. After applying the copper salicylate, magnesium oil, aloe vera, MSM or DMSO can also be applied, and then covered with a damp cloth to keep it moist. DMSO is the most effective carrier through the skin.

Copper aspirinate (copper acetyl-salicylic acid, the copper complex of aspirin). This is more effective than normal aspirin, and does not have the harmful side-effects of aspirin, probably because normal aspirin binds to copper in the gut, whereas copper aspirinate provides copper, so there is no deficiency on the gut wall.

Copper ascorbate, which has strong anti-viral properties.

Copper sulphate. Like copper gluconate, it is well utilised but can oxidise if not coated.

Other forms in which copper may be taken include cupric oxide, copper citrate, copper acetate and other copper amino acid chelates. None are as effective as gluconate and salicylate forms.

Copper in drinking water (with the exception of natural mountain mineral water or glacial water) is NOT a good way to supplement copper. One study of rabbits showed that trace amounts of copper in their drinking water harmed their brains. (98) This was confirmed in another study. (99)

Copper bracelets. Another way to supplement copper is with a copper bangle or bracelet, though the amount of copper that you get from a bracelet is relatively low. After years of experience, many people have discovered that copper armbands reduce arthritis and improve both physical and mental health. Copper metal on the skin has a long history of traditional use, with numerous anecdotal reports of effectiveness in the treatment of arthritis and a variety of other ailments, and as a "youthing" supplement.

Copper enzymes

Most symptoms of copper deficiency can be explained by the ineffective activity of one or more copper-dependent enzymes. For instance, lack of pigmentation can be explained by a tyrosinase deficiency, and the defects of collagen and elastin causing abnormalities in the connective tissue and vascular system can be explained by a lysyl oxidase deficiency.

Copper is required to produce more than a dozen important enzymes (cuproenzymes), including: Cytochrome-c oxydase is required for oxidative mitochondrial energy production within cells. It plays a critical role in cellular energy production by the mitochondria creating the ATP energy-storing molecule. (68) This enzyme also breaks down vitamin C. Myelin requires cytochrome c oxidase for its synthesis.

Lysyl oxidase is needed to produce and cross link collagen and elastin for healthy connective tissue in skin, joints and blood vessels. The copper-containing protein copper-zinc superoxide dismutase (CuZnSOD) provides the primary antioxidant defence in the human body. It is a potent antioxidant for protection against free radicals.

Tyrosinase is required to produce the pigment melanin, essential for skin and hair pigmentation. (101)

Ceruloplasmin-ferrosidase, an antioxidant needed by the iron metabolism and for iron transport.

Dopamine hydroxylase and dopamine-beta-monooxygenase, required for the production of hormones such as dopamine, noradrenaline and adrenalin (epinephrine). Dopamine betahydroxylase catalyses the conversion of dopamine into norepinephrine.

Other copper-based enzymes include amine oxidase, lysine-6 oxidase and peptidylglycine monooxygenase. (1)

Your comments about any of your experiences - positive or negative - with your use of copper are welcome at Grow Youthful. I am always curious about your use of and experience with natural remedies, and your feedback is very welcome.

References

1. Camakaris, J, I Voskoboinik, JF Mercer. Molecular mechanisms of copper homeostasis. Biochem Biophys Res Commun 261, no. 2 (1999): 225-32.

2. Saari JT, AM Bode, GM Dahlen. Defects of copper deficiency in rats are modified by dietary treatments that affect glycation. J Nutr 125, no. 12 (1995): 2925-34.

3. Davis CD, WT Johnson. Dietary copper affects azoxymethane-induced intestinal tumor formation and protein kinase C isozyme protein and mRNA expression in colon of rats. J Nutr 132, no. 5 (2002): 1018-25.

4. Sorenson JR, W Hangarter. Treatment of rheumatoid and degenerative diseases with copper complexes: A review with emphasis on copper-salicylate. Inflammation 2, no. 3 (1977): 217-38.

5. Oberley, LW, SW Leuthauser, RF Pasternack, TD Oberley, L Schutt, JR Sorenson. Anticancer activity of metal compounds with superoxide dismutase activity. Agents Actions 15, no. 5-6 (1984):535-8.

6. Greene, FL, LS Lamb, M Barwick, NJ Pappas. Effect of dietary copper on colonic tumor production and aortic integrity in the rat. J Surg Res 42, no. 5 (1987): 503-12.

7. Narayanan, VS, CA Fitch, CW Levenson. Tumor suppressor protein p53 mRNA and subcellular localization are altered by changes in cellular copper in human Hep G2 cells. J Nutr 131, no. 5 (2001): 1427-32.

8. Sorenson JR. Evaluation of copper complexes as potential anti-arthritic drugs. J Pharm Pharmacol 29, no. 7 (1977): 450-2.

9. Dollwet HH, JR Sorenson. Historic uses of copper compounds in medicine. Trace Elements in Medicine 2, no. 2 (1985): 80-87.

10. Sorenson John R. Roles of copper in bone maintenance and healing. Biol Trace Elem Res 18 (1988): 39-48.

11. Sorenson JR, K Ramakrishna, TM Rolniak. Antiulcer activities of D-penicillamine copper complexes. Agents Actions 12, no. 3 (1982): 408-11.

12. Alzuet, G, S Ferrer, J Borras, JR Sorenson. Anticonvulsant properties of copper acetazolamide complexes. J Inorg Biochem 55, no. 2 (1994): 147-51.

13. Morgant, G, NH Dung, JC Daran, B Viossat, X Labouze, M Roch-Arveiller, FT Greenaway, W Cordes, JR Sorenson. Low-temperature crystal structures of tetrakis-mu-3,5-diisopropylsalicylatobis-dimethylformamidodico pper(II) and tetrakis-mu-3,5- diisopropylsalicylatobis-diethyletheratodicopp er(II) and their role in modulating polymorphonuclear leukocyte activity in overcoming seizures. J Inorg Biochem 81, no. 1-2 (2000): 11-22.

14. Lemoine, P, B Viossat, G Morgant, FT Greenaway, A Tomas, NH Dung, JR Sorenson. Synthesis, crystal structure, EPR properties, and anti-convulsant activities of binuclear and mononuclear 1,10-phenanthroline and salicylate ternary copper(II) complexes. J Inorg Biochem 89, no. 1-2 (2002): 18-28.

15. Viossat, B, FT Greenaway, G Morgant, JC Daran, NH Dung, JR Sorenson. Low-temperature (180K) crystal structures of tetrakis-mu-(niflumato)di(aqua)dicopper(II) N,N-dimethylformamide and N,Ndimethylacetamide solvates, their EPR properties, and anticonvulsant activities of these and other ternary binuclear copper(II)niflumate complexes. J Inorg Biochem 99, no. 2 (2005): 355-67.

16. Bhathena, SJ, L Recant, NR Voyles, KI Timmers, S Reiser, JC Jr Smith, AS Powell. Decreased plasma enkephalins in copper deficiency in man. Am J Clin Nutr 43, no. 1 (1986): 42-6.

17. Okuyama, S, S Hashimoto, H Aihara, WM Willingham, JR Sorenson. Copper complexes of nonsteroidal antiinflammatory agents: Analgesic activity and possible opioid receptor activation. Agents Actions 21, no. 1-2 (1987): 130-44.

18. Klevay, LM, DM Christopherson. Copper deficiency halves serum dehydroepiandrosterone in rats. J Trace Elem Med Biol 14, no. 3 (2000): 143-5.

19. Ebbs, JH, FF Tisdall, WA Scott. The influence of prenatal diet on the mother and child. J Nutr 22, no. 5 (1941): 515-26.

20. Morton, MS, PC Elwood, M Abernethy. Trace elements in water and congenital malformations of the central nervous system in south wales. Br J Prev Soc Med 30, no. 1 (1976): 36-9.

21. Keen, CL, JY Uriu-Hare, SN Hawk, MA Jankowski, GP Daston, CL Kwik-Uribe, RB Rucker. Effect of copper deficiency on prenatal development and pregnancy outcome. Am J Clin Nutr 67, no. 5 Suppl (1998): 1003S-11S.

22. Lonnerdal B. Copper nutrition during infancy and childhood. Am J Clin Nutr 67, no. 5 Suppl (1998): 1046S-53S.

23. Hawk, SN, L Lanoue, CL Keen, CL Kwik-Uribe, RB Rucker, JY Uriu-Adams. Copper-deficient rat embryos are characterized by low superoxide dismutase activity and elevated superoxide anions. Biol Reprod 68, no. 3 (2003): 896-903.

24. Penland, JG, JR Prohaska. Abnormal motor function persists following recovery from perinatal copper deficiency in rats. J Nutr 134, no. 8 (2004): 1984-8.

25. Itoh, S, K Ozumi, HW Kim, O Nakagawa, RD McKinney, RJ Folz, IN Zelko, M Ushio-Fukai, T Fukai. Novel mechanism for regulation of extracellular SOD transcription and activity by copper: Role of antioxidant-1. Free Radic Biol Med 46, no. 1 (2009): 95-104.

26. Giampaolo, V, F Luigina, A Conforti, R Milanino. Copper and inflammation. In Inflammatory diseases and copper: The metabolic and therapeutic roles of copper and other essential metalloelements in humans. Edited by JR Sorenson. Clifton, New Jersey: Humana Press, 1982.

27. Hart, EB, H Steenbock, J Waddell, CA Elvehjem. Iron in nutrition. VII. Copper as a supplement to iron for hemoglobin building in the rat. 1928. J Biol Chem 277, no. 34 (2002): e22.

28. Sorenson John R. Inflammatory diseases and copper: The metabolic and therapeutic roles of copper and other essential metalloelements in humans. Experimental biology and medicine. Clifton, New Jersey: Humana Press, 1982.

29. Kremer JM, J Bigaouette. Nutrient intake of patients with rheumatoid arthritis is deficient in pyridoxine, zinc, copper, and magnesium. J Rheumatol 23, no. 6 (1996): 990-4.

30. Conlan D, R Korula, D Tallentire. Serum copper levels in elderly patients with femoral-neck fractures. Age Ageing 19, no. 3 (1990): 212-4.

31. Jonas J, J Burns, EW Abel, MJ Cresswell, JJ Strain, CR Paterson. Impaired mechanical strength of bone in experimental copper deficiency. Ann Nutr Metab 37, no. 5 (1993): 245-52.

32. Baker, A, L Harvey, G Majask-Newman, S Fairweather-Tait, A Flynn, K Cashman. Effect of dietary copper intakes on biochemical markers of bone metabolism in healthy adult males. Eur J Clin Nutr 53, no. 5 (1999): 408-12.

33. Elsherif, L, RV Ortines, JT Saari, YJ Kang. Congestive heart failure in copper-deficient mice. Exp Biol Med (Maywood) 228, no. 7 (2003): 811-7.

34. Cartwright GE, MM Wintrobe. The question of copper deficiency in man. Am J Clin Nutr 15 (1964): 94-110.

35. Klevay LM. Hypertension in rats due to copper deficiency. Nutr Rep Int 35 (1987): 999-1005.

36. Klevay LM, ES Halas. The effects of dietary copper deficiency and psychological stress on blood pressure in rats. Physiol Behav 49, no. 2 (1991): 309-14.

37. Klevay LM, DM Medeiros. Deliberations and evaluations of the approaches, endpoints and paradigms for dietary recommendations about copper. J Nutr 126, no. 9 Suppl (1996): 2419S-26S.

38. Klevay LM. Trace elements, atherosclerosis, and abdominal aneurysms. Ann N Y Acad Sci 800 (1996): 239-42.

39. Klevay LM. Cardiovascular disease from copper deficiency - a history. J Nutr 130, no. 2S Suppl (2000): 489S-92S.

40. Klevay LM. Dietary copper and risk of coronary heart disease. Am J Clin Nutr 71, no. 5 (2000): 1213-4.

41. Klevay LM. Ischemic heart disease as deficiency disease. Cell Mol Biol (Noisy-le-grand) 50, no. 8 (2004): 877-84.

42. Klevay LM, RE Wildman. Meat diets and fragile bones: Inferences about osteoporosis. J Trace Elem Med Biol 16, no. 3 (2002): 149-54.

43. Trumbo, P, AA Yates, S Schlicker, M Poos. Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J Am Diet Assoc 101, no. 3 (2001): 294-301.

44. Rock E, A Mazur, JM O'Connor, MP Bonham, Y Rayssiguier, JJ Strain. The effect of copper supplementation on red blood cell oxidizability and plasma antioxidants in middle-aged healthy volunteers. Free Radic Biol Med 28, no. 3 (2000): 324-9.

45. Prohaska JR, RG Hoffman. Auditory startle response is diminished in rats after recovery from perinatal copper deficiency. J Nutr 126, no. 3 (1996): 618-27.

46. Lutsenko S, A Bhattacharjee, AL Hubbard. Copper handling machinery of the brain. Metallomics 2, no. 9 (2010): 596-608.

47. Klevay LM. Alzheimer's disease as copper deficiency. Med Hypotheses 70, no. 4 (2008): 802-7.

48. Hung, YH, EL Robb, I Volitakis, M Ho, G Evin, QX Li, JG Culvenor, CL Masters, RA Cherny, AI Bush. Paradoxical condensation of copper with elevated beta-amyloid in lipid rafts under cellular copper deficiency conditions: Implications for Alzheimer disease. J Biol Chem 284, no. 33 (2009): 21899-907.

49. Cater, MA, KT McInnes, QX Li, I Volitakis, S La Fontaine, JF Mercer, AI Bush. Intracellular copper deficiency increases amyloid-beta secretion by diverse mechanisms. Biochem J 412, no. 1 (2008): 141-52.

50. Bala S, ML Failla. Copper deficiency reversibly impairs DNA synthesis in activated T lymphocytes by limiting interleukin 2 activity. Proc Natl Acad Sci U S A 89, no. 15 (1992): 6794-7.

51. Bonham M, JM O'Connor, BM Hannigan, JJ Strain. The immune system as a physiological indicator of marginal copper status? Br J Nutr 87, no. 5 (2002): 393-403.

52. Percival SS. Copper and immunity. Am J Clin Nutr 67, no. (5 Suppl) (1998): 1064S-68S.

53. Heresi, G, C Castillo-Duran, C Munoz, M Arevalo, L Schlesinger. Phagocytosis and immunoglobulin levels in hypocupremic infants. Nutrition Research 5, no. 12 (1985): 1327-34.

54. Kelley DS, PA Daudu, PC Taylor, BE Mackey, JR Turnlund. Effects of low-copper diets on human immune response. Am J Clin Nutr 62, no. 2 (1995): 412-6.

55. Babu U, ML Failla. Copper status and function of neutrophils are reversibly depressed in marginally and severely copper-deficient rats. J Nutr 120, no. 12 (1990): 1700-9.

56. Klevay LM. Iron overload can induce mild copper deficiency. J Trace Elem Med Biol 14, no. 4 (2001): 237-40.

57. Frost PA, GB Hubbard, MJ Dammann, CL Snider, CM Moore, VL Hodara, LD Giavedoni, R Rohwer, MC Mahaney, TM Butler, LB Cummins, TJ McDonald, PW Nathanielsz, NE Schlabritz-Loutsevitch. White monkey syndrome in infant baboons (papio species). J Med Primatol 33, no. 4 (2004): 197-213.

58. Klevay LM. Metabolic interactions among dietary choletstrol, copper, and fructose. Am J Physiol Endocrinol Metab 298, no. 1 (2010): E138-9.

59. Jacob, RA, HH Sandstead, JM Munoz, LM Klevay, DB Milne. Whole body surface loss of trace metals in normal males. Am J Clin Nutr 34, no. 7 (1981): 1379-83.

60. Williams DM. Copper deficiency in humans. Semin Hematol 20, no. 2 (1983): 118-28.

61. Chambers A, D Krewski, N Birkett, L Plunkett, R Hertzberg, R Danzeisen, PJ Aggett, TB Starr, S Baker, M Dourson, P Jones, CL Keen, B Meek, R Schoeny, W Slob. An exposure-response curve for copper excess and deficiency. J Toxicol Environ Health B Crit Rev 13, no. 7-8 (2010): 546-78.

62. Cabrera A, E Alonzo, E Sauble, YL Chu, D Nguyen, MC Linder, DS Sato, AZ Mason. Copper binding components of blood plasma and organs, and their responses to influx of large doses of (65)Cu, in the mouse. Biometals 21, no. 5 (2008): 525-43.

63. Boal, AK, AC Rosenzweig. Structural biology of copper trafficking. Chem Rev 109, no. 10 (2009):4760-79.

64. Gubler CJ, ME Lahey, GE Cartwright, MM Wintrobe. Studies on copper metabolism. IX. The transportation of copper in blood. J Clin Invest 32, no. 5 (1953): 405-14.

65. Harvey, LJ, G Majsak-Newman, JR Dainty, DJ Lewis, NJ Langford, HM Crews, SJ Fairweather-Tait. Adaptive responses in men fed low and high-copper diets. Br J Nutr 90, no. 1 (2003): 161-8.

66. Turnlund, JR, WR Keyes, SK Kim, JM Domek. Long-term high copper intake: Effects on copper absorption, retention, and homeostasis in men. Am J Clin Nutr 81, no. 4 (2005): 822-8.

67. Hunt JR, RA Vanderpool. Apparent copper absorption from a vegetarian diet. Am J Clin Nutr 74, no. 6 (2001): 803-7.

68. Uauy, R, M Olivares, M Gonzalez. Essentiality of copper in humans. Am J Clin Nutr 67, no. 5 Suppl (1998): 952S-59S.

69. John R. Lee. What Your Doctor May Not Tell You About Breast Cancer. 2002.

70. Aminoff MJ. Pharmacologic management of Parkinsonism and other movement disorders. In: Katzun BG (editor), Basic & Clinical Pharmacology. Prentice Hall International, London. 1995:419-431.

71. Finley EB et al. Influence of ascorbic acid supplementation on copper status on young adult men. American Journal of Clinical Nutrition, 47:96-101, 1988.

72. Knobeloch L, et al. Gastrointestinal upsets and new copper plumbing - is there a connection? WMJ 1998 Jan 97;1, 9-53.

73. Kivirikko K, et al. Abnormalities in copper metabolism and disturbances in the synthesis of collagen and elastin. Med Biol. 60:45-48, 1982.

74. Adam, M, H Pohunkova, O Cech, J Vachal. A. [The effect of collagenous gel on endoprosthesis anchoring]. Acta Chir Orthop Traumatol Cech 62, no. 6 (1995): 336-42.

75. Adam, M, O Cech, H Pohunkova, J Stehlik, Z Klezl. B. The role of collagen implants containing the tripeptide gly-his-lys in bone healing process. Acta Chir Orthop Traumatol Cech 62, no. 2 (1995): 76-85.

76. Ahmed, MR, SH Basha, D Gopinath, R Muthusamy, R Jayakumar. Initial upregulation of growth factors and inflammatory mediators during nerve regeneration in the presence of cell adhesive peptide-incorporated collagen tubes. J Peripher Nerv Syst 10, no. 1 (2005): 17-30.

77. Ehrlich, HP. Stimulation of skin healing in immunosuppressed rats. Presented at the Symposium on collagen and skin repair Reims, France, Sept 12-13 1991.

78. Huang, PJ, YC Huang, MF Su, TY Yang, JR Huang, CP Jiang. In vitro observations on the influence of copper peptide aids for the led photoirradiation of fibroblast collagen synthesis. Photomed Laser Surg 25, no. 3 (2007): 183-90.

79. Maquart, FX, P Gillery, JC Monboisse, L Pickart, M Laurent, JP Borel. Glycyl-l-histidyl-l-lysine, a triplet from the a2 (I) chain of human type I collagen, stimulates collagen synthesis by fibroblast cultures. Ann N Y Acad Sci 580 (1990): 573-75.

80. Maquart, FX, L Pickart, M Laurent, P Gillery, JC Monboisse, JP Borel. Stimulation of collagen synthesis in fibroblast cultures by the tripeptide-copper complex glycyl-l-histidyl-l-lysine-Cu2+. FEBS Lett 238, no. 2 (1988): 343-6.

81. Van Campen DR. Zinc interference with copper absorption in rats. Journal of Nutrition, 91:473, 1967.

82. Van den Berg, GJ et al. Dietary ascorbic acid lowers the concentration of soluble copper in the small intestinal lumen of rats. Br J Nutr. 71(5):701-707, 1994.

83. Walsh W. Zinc deficiency, metal metabolism and behavioural disorders. A report of the health research institute. March 1996.

84. Bland J. Copper Salicylates and Complexes in Molecular Medicine. Int Clin Nutr Review 4, 3, 130-134, 1984.

85. Sorenson John R. Copper Chelates as possible Active Metabolites in the Antiarthritic and Antiepileptic Drugs. J Applied Nutrition 32, 1&2, 4-25, 1980.

86. Thackeray EW, Sanderson SO, Fox JC, Kumar N. Hepatic iron overload or cirrhosis may occur in acquired copper deficiency and is likely mediated by hypoceruloplasminemia. J Clin Gastroenterol. 2011;45(2):153-158.

87. Ford ES, et al. Serum copper concentration and coronary heart disease among US adults. Am J Epidemiol. 2000;151(12):1182-1188.

88. Bertinato J, Zouzoulas A. Considerations in the development of biomarkers of copper status. J AOAC Int. 2009;92(5):1541-1550.

89. Araya, M, MC McGoldrick, LM Klevay, JJ Strain, P Robson, F Nielsen, M Olivares, F Pizarro, LA Johnson, KA Poirier. Determination of an acute no-observed-adverse-effect level (noael) for copper in water. Regul Toxicol Pharmacol 34, no. 2 (2001): 137-45.

90. Downey, D, WF Larrabee, V Voci, L Pickart. Acceleration of wound healing using glycyl-histidyllysine copper (II). Surg Forum 25 (1985): 573-75.

91. Ernst, B, M Thurnheer, B Schultes. Copper deficiency after gastric bypass surgery. Obesity (Silver Spring) 17, no. 11 (2009): 1980-1.

92. Gacheru, SN, PC Trackman, MA Shah, CY O'Gara, P Spacciapoli, FT Greenaway, HM Kagan. Structural and catalytic properties of copper in lysyl oxidase J Biol Chem 265, no. 31 (1990): 19022-7.

93. Klevay LM. Extra dietary copper inhibits LDL oxidation. Am J Clin Nutr 76, no. 3 (2002): 687-8; author reply 88.

94. Sorenson JR, LS Soderberg, MV Chidambaram, DT de la Rosa, H Salari, K Bond, G.L Kearns, RA Gray, CE Epperson, ML Baker. Bioavailable copper complexes offer a physiologic approach to treatment of chronic diseases. Adv Exp Med Biol 258 (1989): 229-34.

95. Raymond A. Schep. Cardiovascular Disease in the Western World - an Overlooked Risk Factor. Rose Croix Journal, 2014, Vol 10, 72-88.

96. Bremner I. Manifestations of copper excess. Am J Clin Nutr. 1998;67(5 Suppl):1069S-1073S.

97. Fitzgerald DJ. Safety guidelines for copper in water. Am J Clin Nutr. 1998;67(5 Suppl):1098S1102S.

98. Sparks DL, Schreurs BG. Trace amounts of copper in water induce beta-amyloid plaques and learning deficits in a rabbit model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2003;100(19):11065-11069.

99. Kitazawa M, Cheng D, Laferla FM. Chronic copper exposure exacerbates both amyloid and tau pathology and selectively dysregulates cdk5 in a mouse model of AD. J Neurochem. 2009;108(6):1550-1560.

100. G. E. Cartwright, M. M. Wintrobe. Copper Metabolism in Normal Subjects. Am J Clin Nutr April 1964 vol. 14 no. 4 224-232.

101. Fatemi Naieni F et al. Serum iron, zinc, and copper concentration in premature graying of hair. Biological Trace Element Research 2012 Apr;146(1):30-4.

102. Pang Y et al. A longitudinal investigation of aggregate oral intake of copper. Journal of Nutrition 2001 Aug;131(8):2171-6.

103. Reiser S, J.C. Smith Jr., W. Mertz, J.T. Holbrook, D.J. Scholfield, A.S. Powell, W.K. Canfield, J.J. Canary. Indices of copper status in humans consuming a typical American diet containing either fructose or starch. The American Journal of Clinical Nutrition 1985 Aug;42(2):242-51.

104. Reiser S et al. Role of dietary fructose in the enhancement of mortality and biochemical changes associated with copper deficiency in rats. The American Journal of Clinical Nutrition 1983 Aug;38(2):214-22.

105. Dembinski K et al. Three distinct cases of copper deficiency in hospitalized pediatric patients. Clinical Pediatrics 2012 Aug;51(8):759-62.

106. Bastian TW et al. Maternal iron supplementation attenuates the impact of perinatal copper deficiency but does not eliminate hypotriiodothyroninemia nor impaired sensorimotor development. The Journal of Nutritional Biochemistry 2011 Nov;22(11):1084-90.

107. Sandstead HH. Requirements and toxicity of essential trace elements, illustrated by zinc and copper. The American Journal of Clinical Nutrition 1995 Mar;61(3 suppl):621S-624S.

108. O.M. Alarcon , Y. Guerrero, M. Ramirez de Fernandez , I. D'Jesus M. Burguera, J.L. Burguera, M.L. Di Bernardo. Effect of copper supplementation on blood pressure values in patients with stable moderate hypertension. Archives Latinoamericans de Nutrition 53(30)(2003): 271-276.

109. Henry C. Lukasaki, Lelsie M. Klevay, D.B. Milne. Effects of dietary copper on human autonomic cardiovascular function. European Journal of Applied Physiology 58 (1988): 74-80.

110. Andrea Mezzetti, Sante D Pierdomenico, Fabrizio Costantini, Ferdinando Romano, Domenico De Cesare, Franco Cuccurullo, Tiziana Imbastaro, Giuseppe Riario-Sforza, Franco Di Giacomo, Giovanni Zuliani, Renato Fellin. Copper/zinc ratio and systemic oxidant load: effect of aging and aging-related degenerative diseases. Free Radical Biology and Medicine, Volume 25, Issue 6, October 1998, 676-681.