Ok, this is long, but interesting (I think).
I was cautious about using copper supplements because I read that diabetics can have high levels of copper. I wrote Dr. Loren Pickart, a biochemist & leading reseacher on copper peptides. He has given me permission to post this.
There is a great deal of confusion in this area. 30 years ago, it was thought that copper caused many diseases. But by the 1990s, it was found that copper supplements would cure or correct many of these diseases. Plasma copper and ceruloplasmin were used to determine copper levels but were not useful because they are increased by inflammation and disease, and may be falsely high.
Also, may studies use free copper ion and not peptide or protein bound copper. For example, free copper oxidizes low density lipoproteins. GHK-copper blocks the oxidation of low density lipoproteins. There is essential no free ionic copper in the human body. It is all bound the GHK or proteins.
As for diabetes, additional supplemental copper reduces many of the biochemical problems associated with diabetes like excessive tissue oxidation and protein damaging glycations.
Metabolism. 2008 Sep;57(9):1253-61.
Oxidative stress in Cohen diabetic rat model by high-sucrose, low-copper diet: inducing pancreatic damage and diabetes.
Ryu S, Ornoy A, Samuni A, Zangen S, Kohen R.
Department of Anatomy and Cell Biology, Laboratory of Teratology, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
Increased oxidative stress contributes to the development and progression of both types of diabetes mellitus (DM) and its complications. In the Cohen diabetic (CD) rats, a known genetic model of nutritionally induced type 2 DM, a high-sucrose, low-copper diet (HSD) induces within 4 weeks DM in the sensitive (CDs) rats but not in the resistant (CDr) rats. To assess the possible involvement of oxidative stress in the induction of DM, we studied the effect of HSD on the tissue levels of antioxidants and the extent of oxidative injuries in these animals in comparison with the regular outbred strain of nondiabetic Sabra rats. The specific aims were to investigate, at the onset of HSD-induced DM, (1) the extent of oxidative injury, as reflected by levels of malondialdehyde and protein carbonyl groups; (2) the overall antioxidant capacities to cope with increased oxidative stress; and (3) the modification of oxidative damage biomarkers in various tissues of CDr, CDs, and Sabra rats. Female CDs, CDr, and Sabra rats were fed regular diet or HSD for 4 to 5 weeks; and several parameters of oxidative injuries and antioxidant levels were determined. Changes in the levels of nonenzymatic low-molecular weight antioxidants (LMWAs) were measured by cyclic voltammetry and oxygen radical absorbance capacity. The activities of the antioxidant enzymes superoxide dismutase and catalase were measured. Oxidative damage was evaluated by measuring lipid peroxidation and protein oxidation. (1) In all animals fed HSD, the levels of LMWAs were decreased in most organs, although not plasma. (2) A significant difference was consistently found in antioxidant enzymes' activities in the pancreas of HSD-fed CDs rats, but not in other tissues. (3) The activities of superoxide dismutase and catalase and the levels of malondialdehyde and protein carbonyl group increased, whereas the levels of LMWAs decreased, in the pancreas of HSD-fed CDs rats. In the CD rats that develop DM when fed HSD, the pancreas showed susceptibility to oxidative stress-induced injuries. Thus, enhanced oxidative stress seems to play a role in the pathogenesis of DM in this strain.
Environ Health Perspect. 2007 July; 115(7): A341–A342.
Copper Deficiency, Lead, and Paraoxonase
Leslie M. Klevay
University of North Dakota, School of Medicine and Health Sciences, Grand Forks, North Dakota, E-mail: firstname.lastname@example.org
Li et al. (2006) measured paraoxonase 1 (PON1) in workers and found an inverse association between lead exposure and enzyme activity. This observation compliments some epidemiology and related experiments with animals, because low paraoxonase activity is associated with diabetes mellitus, familial hypercholesterolemia, ischemic heart disease, and metabolic syndrome (Klevay 2004). Paraoxonase, although studied most extensively because of its ability to detoxify organophosphate insecticides (James 2006; van Himbergen et al. 2006), has drawn increasing attention because it hydrolyzes homocysteine thiolactone, a vascular toxin that inhibits copper enzymes (Klevay 2006).
Lead intoxication has many manifestations (Fischbein 1998), lesser-known of which is induction of copper deficiency (Klauder and Petering 1977). Rats deficient in copper have an approximately 28% decrease in paraoxonase activity (Klevay 2004). These observations are consonant with the decrease in superoxide dismutase (SOD) associated with occupational exposure to lead (Ito et al. 1985) because this enzyme also depends on adequate copper nutriture for activity (Linder and Goode 1980; Owen 1981). Thus, SOD is an index of copper nutriture in humans (Uauy et al. 1985).
Li et al. (2006) stated that “the mechanism by which heavy metals inhibit serum PON1 activity is still not clear.” It seems likely that lead interferes with copper utilization in the workers, leading to low copper nutritional status (Li et al. 2006). Low copper status has been related to a large variety of adverse cardiovascular phenomena in both animals and people; in this context, the most important are hypercholesterolemia, hypertension, and impaired oxidative defense (Klevay 2000, 2002).
Are there unpublished copper data on the workers, or can they be reexamined to test this copper hypothesis? Plasma copper and ceruloplasmin are not likely to be useful because they are increased by inflammation (Pepys 1996) and may be falsely high. Extracellular SOD may be helpful because it is sensitive to low copper status (Johnson et al. 2005), and low values have been associated with atherosclerosis in humans (Landmesser et al. 2000; Wang et al. 1998).
Can Copper Status Affect Aging?
Author/s: Judy Mcbride
Could a marginal intake of the essential element copper contribute to the aging process? ARS physiologist Jack T. Saari thinks that's a strong possibility--based on rat studies, along with a good bit of indirect evidence.
Saari and a colleague, chemist Gwen Dahlen, at the Grand Forks Human Nutrition Research Center in North Dakota wanted to see if copper deficiency spurs sugar molecules to attach to proteins. The process--nonenzymatic glycosylation, or protein glycation for short--is a spontaneous binding of sugar to protein without the aid of enzymes. It is thought to cause much of the tissue damage in people with diabetes. And it increases in all of us as we age, Saari says.
Tiny sugar molecules attached to a huge protein molecule may be likened to fleas on a dog. But the attached sugars can be more than annoying; they can be deadly to the protein. That's because their free ends tend to hook up to other proteins or other sites on the same protein, forming cross-links. These cross-links bend the protein out of shape so that it no longer functions properly. The useless protein soon gets degraded and hauled off for recycling or disposal.
In the early 1980s, Saari's colleague, Leslie M. Klevay, M.D., reported that copper-deficient rats had glycated hemoglobin--the oxygen-carrying molecule in red blood cells. Klevay heads the Mineral Nutrient Requirements Unit at Grand Forks.
Saari says this and more recent indirect evidence led him to look for a connection between copper deficiency and protein glycation.
Two pieces of indirect evidence come from studies at ARS' Beltsville (Maryland) Human Nutrition Research Center, as well as Saari's laboratory. Rats fed copper-deficient diets have high blood sugar, says Saari. This raises the odds for glycation.
"Their condition is like type-II diabetes," says Meira Fields, who conducted the Beltsville studies. Unlike Saari, Fields finds that the copper-deficient rats exhibit high blood sugar only when their diets are high in sugar--either fructose or sucrose. This sugar-laden diet also causes the rats to secrete less insulin, she says, which is needed to move sugar out of the blood and into the cells to serve as fuel.
What's more, Fields' studies have repeatedly shown that rats suffer the most tissue damage from this diet when the sugar is fructose. Saari notes that in the test tube, fructose is a better glycator than glucose.
Two more pieces of indirect evidence come from Saari's own studies. He reduced the symptoms of copper deficiency--such as an enlarged heart--by two different treatments. First, he fed the rats only a portion of the food they would normally eat. This kept blood glucose levels low, he says, reducing the chance of glycation. Second, he treated the rats with a chemical--aminoguanidine--known to block advanced glycation or cross-linking of sugars. And it worked.
Armed with this evidence, Saari and Dahlen designed a study to look directly for increases in protein glycation. The results bore out their suspicions. Both the early and advanced stages of protein glycation increased significantly in the rats fed a copper-deficient diet.
One sensitive indicator of advanced glycation is a measure of the proteins that it has rendered ineffective. This indicator was at least six times higher in the copper-deficient rats. It was nearly undetectable in the control rats, he says, noting that Dahlen made this very delicate analysis possible by refining an existing analytical method. They published their findings in the April 1999 issue of the Journal of Nutritional Biochemistry.
Treating the rats with aminoguanidine did not reduce cross-linking in this study as it did in the earlier one, says Saari, probably because the dosage was too low. So he and Dahlen did a follow-up Study using a higher dosage. The earliest results available at this writing are showing a reduction in glycation caused by copper deficiency.
Copper Intake Lags
Humans consume more copper than rats do. But the average copper content of diets in the United States, Canada, Great Britain, and Belgium still falls below the U.S.-suggested intake range of 1.5 to 3 milligrams per day.
Klevay, a physician, pulled together data from the chemical analyses of 849 diets in the four countries. He says they show that 61 percent contained less than 1.5 mg of copper daily, and nearly a third of the diets provided less than 1 mg.
"That's in the range that has proved insufficient for both men and women in controlled dietary experiments," he says.
Vegetarian diets had more copper than nonvegetarian diets. That's because nuts, seeds, mushrooms, whole grains, and legumes--such as soybeans, peas, chickpeas, lentils, and peanuts--are good sources of the mineral. The richest sources of copper are animal--oysters, crabs, and liver--which are not common in the daily diet.
Estimated copper intake in the United States, based on USDA's latest nationwide food consumption survey, averages 1.2 mg/day for all individuals--below the 1.5 mg suggested minimum. The estimates show men averaging just the minimum 1.5 mg/day, while women average only 1 mg/day.
Saari speculates that years of eating a diet low in the mineral may be a factor contributing to the age-related decline in tissue function from increasing protein glycation.
"It's a low-grade phenomenon," he says. "It's not like diabetes where blood glucose stays high after an overnight fast." Instead, he says, blood glucose peaks higher than normal after a meal--increasing glycation--but it doesn't stick around. "The only way you know this increase is happening is through a glucose tolerance test or a test of glycated hemoglobin."
The early stage of glycation--when the sugar first attaches to the protein--is reversible. As blood sugar drops, the sugar can detach. Once the cross-links are formed, however, they don't come apart, Saari says. So far, he has looked only at glycation of hemoglobin and serum proteins. But it can also happen to structural proteins that form tissues.
Copper and Oxidation
The most accepted theory of aging holds that it results from cumulative damage to tissues by oxygen free radicals. These radicals are generated during normal metabolism and delivered by environmental pollution. Saari says his thesis fits hand in glove with the oxidation theory because glycation appears to increase oxidation.
According to reports in the diabetes literature, both free and attached sugar molecules can convert the benign oxygen molecule into a free radical. What's more, glycated proteins are more vulnerable to oxidation.
Copper is important to the body's defense against oxidation through a copper-containing enzyme--superoxide dismutase, or SOD. Saari notes that SOD activity reportedly decreases with aging, while oxidative damage increases.
Over the long term, a low copper intake could plausibly weaken this inherent antioxidant defense, slightly elevate blood sugar, and increase attachment of sugar to proteins--all of which tend to increase oxidative damage.
This research is part of Human Nutrition Requirements, Food Composition, and Intake, an ARS National Program described at http://www.nps.ars.usda. gov/programs/appvs.htm.
Jack T. Saari and Leslie M. Klevay are at the USDA-ARS Grand Forks Human Nutrition Research Center, P O. Box 9034, University Station, Grand Forks, ND 58202; phone (701) 795-8353, fax (701) 795-8395, e-mail jsaari@gfhnrc. ars.usda.gov.
Copper's Protective and Anti-Aging Actions
Copper is an essential metal and the intake of copper at reasonable levels should improve your health. The generally recommended dosages per day of copper range from 1 to 3 milligrams daily, however, recent human studies suggest that 4 to 7 milligrams of supplemental copper daily might greatly reduce the rates of some degenerative diseases.
Copper deficiency in animals causes increased cellular oxidation, increased cancer, increased cardiovascular risk, more atherosclerosis, higher LDL-cholesterol, decreased HDL-cholesterol, more lipid oxidation, aortic aneurysms, osteoarthritis, rheumatoid arthritis, osteoporosis, chronic conditions involving bone and connective tissue, brain defects in newborn, obesity, graying of hair, increased sensitivity to pain and lower brain enkephalins, accelerated development of Alzheimer's disease, obesity, and reproductive problems. See more below.
In humans, copper deficiency is associated with all of the above plus depression, impaired brain function, and general fatigue.
Some copper recommendations are based on the recommended zinc dietary levels, and maintaining what these nutritionists feels is a proper zinc to copper ratio. Other recent studies in humans found that supplementation with 3 to 6 milligrams of copper daily had positive actions such as reducing damaging cellular oxidation and lowering cholesterol and LDL levels, while increasing HDL levels. See more below.
Metabolically Active Copper
In the body, copper moves between cuprous (copper 1 or Cu 1+) form and the cupric (copper 2 or Cu 2+) form. The majority of the body's copper is in the Copper 2 form. The copper type that induces tissue regeneration and skin repair is copper 2. Copper 2 is also what is called the body's copper called is called "metabolically active copper".
Only a very small fraction, less that 1% of the body's copper, is called metabolically active copper and this fraction is exchanged between the various tissues of the body as needed. This metabolically active fraction is bound to either amino acids, peptides, or proteins. This fraction is high in healthy people but diminishes in persons with inflammatory diseases such as arthritis.
Most of the body's copper is bound into proteins where it plays an important role in biological activities such as anti-oxidant effects, energy generation, tissue regeneration and so forth.
Confusion Over Blood Copper and Disease States
Blood serum copper is about 5% metabolically active copper; the other 95% being in the anti-oxidant protein ceruloplasmin. During many diseases and stress conditions, the body increases ceruloplasmin levels as a protective anti-oxidant mechanism. Because metabolically active copper is technically difficult to measure, most studies of copper and disease states reported only the total blood serum copper. This has caused much confusion and often has led to false conclusions as to the role of copper in disease states.
For example, total blood plasma copper is elevated in diseases such as cancer, heart disease, and arthritis but this increase is due to increased ceruloplasmin in the blood. Some misinformed persons have interpreted this increase in blood copper to indicate that high copper causes these conditions and diseases. But when copper supplements are given to animals or humans, the additional dietary copper has been found to lower carcinogenesis and tumor growth, inhibit the development of cardiovascular problems, and reverse many arthritic effects. See more below.
Should Dietary Copper Intake be Raised to Reduce Major Diseases?
Some experts on copper are of the opinion that copper intake should be raised. Copper deficiency diseases are virtually the same as the pattern of major diseases in the USA. This suggests that some of these diseases may be partially due to inadequate copper in our diet.
Copper toxicity is a rarity and most experts consider a daily intake of 10 milligrams to be safe. However, since copper and zinc compete for uptake in the body, a high copper intake reduces zinc absorption, and, conversely, a high zinc intake reduces copper uptake. Thus, a balance should be maintained between these to metals. Most commonly, nutritionists recommend a ratio of 7 parts by weight zinc to one part copper.
There Are No Adequate Studies on Toxic Levels of Copper in Water
This is how the toxic level of copper in water was determined. A group of nurses had a party after which a number became ill. It was felt that the illness may have been due to the water they used. The water was analyzed and had a high level of copper. So this amount of copper in the water was divided by 4 and called the toxic level of copper in water. Whether the copper in the water caused the illness is still unknown.
When excess copper is ingested, within a range of 10 to 25 milligrams per day, the superfluous copper is excreted by the liver into the bile and copper balance is maintained.
The one condition where copper intake must be restricted is Wilson's disease, a rare genetic condition that affects 1,600 persons in the USA.
Anti-oxidant Actions of Copper and Dietary Intake
The copper-containing protein, copper,zinc-superoxide dismutase (or CuZnSOD) is the primary anti-oxidant defense in the human body. Higher levels of CuZnSOD are a primary factor in longer lifespans in animals.
However, because copper 2 is usually in short supply in the human body, CuZnSOD has only about 50% of its needed copper (zinc supplies are usually adequate), and this markedly reduces CuZnSOD's anti-oxidant powers and is another reason why more dietary copper would be beneficial. Harris (Department of Biochemistry and Biophysics, Texas A&M University) pointed out that while copper,zinc superoxide dismutase requires two, copper and zinc, only copper, seems to regulate the expression of functional anti-oxidant activity. Restricting dietary copper quickly impairs the catalytic function CuZnSOD in numerous tissues. However, when diets are supplemented with copper, the CuZnSOD activity is quickly restored. (Harris ED, J Nutr, 1992, pp 636-40)
Under some biochemical circumstances, such as after traumatic tissue injury, copper (as well as other metals) can reverse its normal anti-oxidant role and cause damaging cellular oxidation. This has led some benighted amateur nutritionists to propose restricting dietary copper to reduce damaging oxidation in the body. But, controlled animals studies have found the opposite to be true: a reduced copper intake actually increases deleterious cellular oxidation and promotes a wide variety of the types of degenerative diseases associated with aging. On the other hand, a higher dietary copper intake in animals reduces overall damaging cellular oxidation.
It is true that there are damaging oxidative reaction in the human body. What is the answer to reduce destructive oxidation? First, do not worry too much about metal intake. People living in certain high mountain valleys of the world such as the Hunza area of Pakistan, the Vilcabamba area of Equador, the Caucasus of Georgia, Northwest Tibet, and Titicaca region in the Peruvian Andes, eat very different diets but all drink water with a very high mineral content (hard water from glaciers) but the lifespan and health of the elderly in these regions is exceptional high. In contrast, regions with low mineral water (soft water) are characterized by high rates of cancer and heart disease.
One analysis of drinking water in the Hunza valley found a zinc to copper ratio of 1.8. This far lower than the normally recommended ratio of 7.0 and also suggests a higher intake of copper might be beneficial.
Daily Fruit Juice Reduces Lipid Peroxidation by 75%
Also, to reduce damaging cellular oxidation in your body, use other anti-oxidants such as coenzyme-Q10, alpha lipoic acid, vitamin E isomers, and melatonin. These help protect the polyunsaturated fats in cellular membranes.
Copper May Reduce Some Cancers
The Center for Disease Control states that "Copper has not been shown to cause cancer in people or animals". The International Agency for Research on Cancer has determined that copper is not classifiable as to human carcinogenicity. Added copper complexes reduce spontaneous colon cancer in rats and, when administered to tumor-bearing rats, slow the rate of tumor growth. In cell culture, copper complexes cause some types of cancer cells to revert to non-cancerous growth patterns.
In 1912, cancer patients in Germany were treated for facial epithelioma with a a blend of copper chloride and lecithin with some success. In 1913, researchers at at the University of Liverpool reported injections of a copper salt degenerated carcinomas transplanted into mice.
John R. J. Sorenson (University of Arkansas for Medical Sciences, College of Pharmacy) and colleagues treated rats with solid tumors with various copper complexes (such as copper salicylate) with SOD activity and this decreased tumor growth and increased survival rates in rats. These copper complexes did not kill cancer cells but often caused them to revert to the growth patterns of normal (differentiated) cells. (Sorenson, Prog Med Chem 1989; 26: 506-507) Sorenson also found that numerous copper complexes with SOD activity prevented or retarded the spontaneous development of cancers in mice and possessed anticancer, anti-carcinogenic, and anti-mutagenic effects both in vitro and in vivo. (Sorenson (ed.), Biology of Copper Complexes. Humana Press, Clifton, NJ. 1987)
The serum level of copper is often elevated in animals and humans with cancer (Inutsuka and Araki, Cancer 1978; 42: 626; Willingham and Sorenson, Tr Elem Med 1986; 3: 139-140.) It appears that this elevation of serum copper that occurs as a part of the body's response to the cancer, rather than its cause. Most tumor cells have decreased CuZnSOD activity compared to normal cells, and it has been suggested that the elevation in serum copper is a physiological response designed to activate CuZnSOD or other copper enzymes in cancer cells to inhibit their growth. (Oberley and Buettner, Cancer Res 1979; 39: 1141).
Colon cancer is the second most deadly cancer in the USA. When rats were fed low copper diets, they had a higher incidence of carcinogen-induced colon cancers compared with rats fed a high copper diet. (DiSilvestro, Greenson, Liao, Proc Soc Exp Biol Med 1992; 201: 94-99).
Also, APC is a gene known to suppress the formation of tumors and this gene is altered early on during colon cancer development. Familial adenomatous polyposis is a disease that has been linked to mutation changes in the APC gene. Individuals possessing these mutations develop numerous intestinal polyps (precancerous lesions) at an early age. A species of mice (Min or multiple intestinal neoplasia) have a mutation similar to the human gene (APC) that causes intestinal polyps and colon cancer. A study reported in 2001 by nutritionist Cindy D. Davis at the Human Nutrition Research Center (Grand Forks, N.D.) found that, when Min mice were fed a copper deficient diet (20% of normal level), they developed a significantly higher small intestine tumor incidence and a significantly higher small intestine tumor mass than mice fed adequate dietary copper. The low copper also decreased the expression of various protein kinase C isozymes, a series of proteins involved in the signal transduction pathway within the cell, thus upsetting normal cell regulation. Dr. Davis says these results have implications because 80% of the people in the USA do not ingest adequate amounts of copper.
Another study of copper deficiency in animals by Narayanan, Fitch and Levenson found that copper stimulates the production of the tumor-suppressor protein p53. This protein inhibits the growth of tumors in the body. (Narayanan, Fitch and Levenson, Dept. of Nutrition, Florida State U., Tallahassee, FL in The Journal of Nutrition, May 2001)
Copper and Cardiovascular Disease
Humans and animal studies demonstrate that copper deficiency increases the plasma cholesterol and LDL-cholesterol while decreasing HDL-cholesterol, thus increasing the cardiovascular disease risk. (Klevay, Inman, Johnson, et al, Metabolism 1984; 33: 1112-1118. Klevay, Med Hypothesis 1987; 24: 111-119; Klevay, Med Hypothesis 1987; 24: 111-119).
Klevay theorized that a metabolic imbalance between zinc and copper, but more a copper deficiency than zinc excess, is a major factor in the genesis of coronary heart disease. (Klevay, Lack of a recommended dietary allowance for copper may be hazardous to your health. Journal of the American College of Nutrition. 1998; volume 17: pages 322-326) Other investigators found that copper complexes also can minimize damage to the aorta and heart muscle following myocardial infarction.
Severe copper deficiency results in heart abnormalities and damage (cardiomyopathy) in some animals. (Institute of Medicine. Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academy Press. 2001: pages 7-1-27)
A multicenter placebo-controlled study found copper supplementation with 3 or 6 mg/day increased the resistance of red blood cells to damaging oxidation indicating that relatively high intakes of copper do not increase the susceptibility of LDL or red blood cells to oxidation. (Rock, et al. The effect of copper supplementation on red blood cell oxidizability and plasma antioxidants in middle-aged healthy volunteers. Free Radical Biology and Medicine. 2000; volume 28: pages 324-329; Turley, et al. Copper supplementation in humans does not affect the susceptibility of low density lipoprotein to in vitro induced oxidation. Free Radical Biology and Medicine. 2000; volume 29: pages 1129-1134)
Rats on a copper deficient diet had a decrease in aortic integrity that produces eventual aneurysm. (Greene, et al, J Surg Res 1987; 42: 503-512)
Immune System Function
A medical publication in 1867 reported that, during the cholera epidemics in Paris of 1832, 1849 and 1852, copper workers did not develop cholera. Another observation was that persons with Menke's disease died from frequent and severe infections due to an inadequate immune response. Menke's is an inherited disease causing defective copper absorption and severe copper deficiency. (Percival, Copper and Immunity. American Journal of Clinical Nutrition. 1998; volume 67: pages 1064S-1068S; Failla and Hopkins, Is low copper status immunosuppressive? Nutrition Reviews. 1998; volume 56: pages S59-S64)
Studies with animals demonstrated that animals deficient in copper had an increased susceptibility to bacterial pathogens such as Salmonella and Listeria. (Bala and Failla, Proc Natl Acad Sci USA 1992; 89: 6794-6797) A study of 11 infants with copper deficiency found that the ability of their white blood cells to engulf pathogens increased after one month of copper supplementation (Heresi, et al. Phagocytosis and immunoglobulin levels in hypocupremic children. Nutrition Research. 1985; volume 5: pages 1327-1334) A study of adult men on a low-copper diet (0.66 mg copper/day for 24 days , then 0.38 mg/day for another 40 days) showed a decreased ability of mononuclear cells to respond to antigens. (Kelley, et al. Effects of low-copper diets on human immune response. American Journal of Clinical Nutrition. 1995; volume 62: pages 412-6.) Abnormally low numbers of white blood cells is a clinical indicator of copper deficiency in humans and functioning of macrophages decreases in even marginally copper deficient rats . (Babu and M.L. Failla, J Nutr 1990; 120: 1700-1709)
Some studies have suggested that immune function and neutrophil activity is more sensitive to low dietary copper than standard measures of copper status. Immune impairment can be detected by one week after the start of a diet low or marginal in copper; conversely, the addition of adequate copper rapidly reverses the immune suppression within one week. Copper deficiency also reduced DNA synthesis in activated T-cells but this is also quickly reversible after copper supplementation. (Bala and Failla, Proc Natl Acad Sci USA 1992; 89: 6794-6797)
It has been suggested that, because the immune system is very sensitive the changes in the body's copper status, it may be possible to set a scientific RDA (Recommended Daily Allowance) for copper by giving persons graded amounts of dietary copper and then determining the optimal copper dosage for optimal immune function. (Babu and Failla, J Nutr 1990; 120: 1700-1709)
Copper, Inflammation, and Arthritis
Studies of rheumatoid arthritis and copper exemplify the paradoxes that have so confused research on copper and its effects on various diseases.
In 1885, the French physician, Luton, used copper acetate to treat arthritic patients. He made a salve of hog's lard and 30% neutral copper acetate for application to the skin over affected joints. He also had his patients take pills containing 10 mg. of copper acetate per day.
In 1939, the German physician, Werner Hangarter, wrote that Finnish copper miners remained free of arthritis while they worked in the mining industry. This was notable since rheumatism was widespread in Finland. This finding led Finnish medical researchers to treat patients with a mixture of copper chloride and sodium salicylate. They reported treatment successes in patients suffering from rheumatic fever, rheumatoid arthritis, neck and back problems, and sciatica.
Between 1940 and 1970, studies of persons with rheumatoid arthritis found them to have higher than normal serum copper levels. Similar results were found in other various inflammatory diseases in man and animals. (Lewis, Agents and Actions 1984; 15: 513-519) Yet, in seeming contradiction, copper complexes were successfully used in the treatment of numerous conditions characterized by arthritic changes and inflammation. (Sorenson and Hangarter, Inflammation 1977; 2: 217-238). But this use of copper complexes was superseded by the development of anti-inflammatory steroids and aspirin-like nonsteroidal anti-inflammatory drugs in the treatment of these conditions.
Subsequent researchers examined this paradoxical role of copper, and they concluded that increase in serum copper is a physiological response to inflammation, rather than a cause of inflammation. (Sorenson, J Pharm Pharmac 1977; 2: 450-452) The rise in serum copper is due to an elevation of the protein ceruloplasmin in serum, but ceruloplasmin has strong anti-inflammatory activity and tends to counteract the inflammatory state. (Frieden, Clin Physiol Biochem 1986; 4: 11-19) Further research established that copper deficiency increased the severity of experimentally-induced inflammation. (Sorenson and Kishore, Tr Elem Med 1984; 1: 93)
Professor John R. J. Sorenson (University of Arkansas for Medical Sciences, College of Pharmacy) has led the scientific work on the use of copper complexes to treat patients with arthritic and other chronic degenerative diseases. He has found that the copper complexes of over 140 anti-inflammatory agents, such as aspirin and ibuprofen, for example, to be far more active than these compounds without copper. Copper aspirinate has been shown to be more effective in the treatment of rheumatoid arthritis than aspirin alone. It also has been shown to prevent or even cure the ulceration of the stomach often associated with aspirin therapy. Sorenson has reviewed a wide variety of of copper complexes that have potent anti-inflammatory activity when administered to humans or animals; his review is 110 pages long and with a bibliography of 736 references. (Sorenson, Prog Med Chem 1989; 26: 437-568)
Copper and Osteoporosis
200 years ago, the German physician Rademacher established that copper supplements speeded the healing of broken bones in patients. (Dollwet and Sorenson, Tr Elem in Med 1985; 2: 80) In the years that have followed, compelling evidence has established a vital role for copper in the biosynthesis of bone and connective tissues and their maintenance.
Inadequate dietary copper causes osteoporosis in numerous animal species and humans. (Dollwet and Sorenson, Biol Tr Elem Res 1988; 18: 39-48) Copper deficiency is associated with scoliosis, skeletal abnormalities, and increased susceptibility to fractures. (Worthington and Shambaugh, J Manipulative Physiol Ther 1993; 16: 169-173) Danks. Copper Deficiency in Humans. In: "Biological Roles of Copper." CIBA Foundation Symposium-79. Exerpta Medica, Amsterdam, 1980. p. 209) Inadequate dietary copper lowers bone calcium levels. (Strause, P. Hegenauer, R.C. Saltman, et al, J Nutr 1986; 116: 135)
One study of elderly persons found a decreased loss of bone mineral density from the lumbar spine after copper supplementation of 3 milligram daily for 2 years (Conlan, et al. Serum copper levels in elderly patients with femoral neck fractures. Age and Aging. 1990; volume 19: pages 212-214)
Healthy adult males on a low copper intake of 0.7 milligrams daily for 6 weeks exhibited an increased rate of bone resorption (breakdown). (Baker. et al. Effect of dietary copper intakes on biochemical markers of bone metabolism in healthy adult males. European Journal of Clinical Nutrition. 1999; volume 53: pages 408-412)
Copper and DHEA
DHEA (dehydroepiandrosterone) is a key hormone that produces mainly secondary hormones and counter's the damaging actions of cortisol during stress. It is widely used as a dietary supplement to help prevent deleterious changes with age. Klevay and Christopherson found that copper deficiency in rats decreased DHEA in serum by approximately 50%. The authors suggest that eating a diet higher in copper will increase the DHEA level in the body. (Klevay and Christopherson, Society Of Experimental Biological Medicine Proceedings, 1999)
Copper and Pregnancy
In the 1930's at a sheep station in Western Australia many newborn lambs were uncoordinated, had difficulty standing, and died. Later, it was determined that the pregnant sheep were pastured on land that produced grass with a very low copper content. This herbage did not provide enough copper for normal development of the lambs' nervous system and the brain.
Recent research at the USDA's Grand Forks Human Nutrition Research Center found that even marginal copper deficiency in pregnant rats produces brain damage and neurological defects in their offspring. The newborn rats have structural abnormalities in the areas of the brain involved in learning and memory and responsible for coordination and movement. These produced further behavioral changes and the young rats lack the normal "startle" reflex to unexpected noises. This deficit permanently affected the young rats and could not be correct by diets higher in copper.
During pregnancy, a sufficient copper intake is essential for normal neurological development of the fetus. Tom Johnson, Ph.D., lead author of the study said “A reserve of copper is built up in the liver during fetal development that helps satisfy the requirement of the newborn for copper. Thus, adequate copper intake during pregnancy is important to ensure the fetus acquires sufficient copper to fill this reserve. However, for the health of the mother, she should have a copper intake of 1.5-3.0 mg/d postpartum and during lactation.”
Small deficits in dietary copper produce substantial changes in fetal brain enzymes. Protein kinase C (PKC) is a copper-dependent enzyme that is crucial in the development of the nervous system. The PKC levels were measured in the brains of rat pups whose mothers had been fed a copper-deficient diet during and for a few weeks after pregnancy. The diet was defined as 1 mcg/d for one group and 2 mcg/d for a second group of rats (one third of the recommended copper), while the control group received sufficient dietary copper. While PKC levels rose in all the rat groups during the three weeks after birth, the increase was only half as much in the group whose moms got 1 mcg/d, and 25% less in the 2mcg/d group. Moreover, at 2 mcg/d, one form of PKC was off by 50% in the cerebellum, which happens to be the control center for motor function and muscle coordination.
Another study from the University of California at Davis reported that that copper deficiency during pregnancy can result in “Numerous gross structural and biochemical abnormalities,” which seem to arise as the copper deficiency reduces free radical defense mechanisms, connective tissue metabolism and energy production. The same researchers found that copper is better absorbed from breast milk than from infant formula. (Lonnerdal B., Copper nutrition during infancy and childhood. Am J Clin Nutr 1998 May;67(5 Suppl):1046S-1053S.)
Pregnant women (and others) can obtain copper from supplements and seafood, oysters, liver, nuts and seeds, beans, whole-grained bread, cocoa, chocolate.
Anticonvulsant Activities of Copper Complexes
The brain contains more copper than any other organ of the body except the liver, where copper is stored for use elsewhere. This fact suggests that copper plays a role in brain functions. With reports of seizures in animals and humans following the protracted consumption of copper-deficient diets, it was reasoned that copper has a role to play in the prevention of seizures. It was subsequently discovered that organic compounds that are not themselves anti-convulsants exhibit anticonvulsant activity when complexed with copper. Further, it was found that copper complexes of all anti-epileptic drugs are more effective and less toxic than their parent drugs. ( J.R.J. Sorenson, Prog Med Chem 1989; 26: 437-568.)