45 replies to this topic

[nameless]

Greatly accelerated dose-responsive cognitive decline was seen with copper supplementation. Se my first post. So obviously not safe up to 7 mg/day. From my first post where the link to the source is:

"Among persons whose diets were high in saturated and trans fats, higher copper intake was associated with a faster rate of cognitive decline. In multiple-adjusted mixed models, the difference in rates for persons in the highest (median, 2.75 mg/d) vs lowest (median, 0.88 mg/d) quintiles of total copper intake was –6.14 standardized units per year (P<.001) or the equivalent of 19 more years of age. There was also a marginally statistically significant association (P = .07) with the highest quintile of food intake of copper (median, 1.51 mg/d) and a strong dose-response association with higher copper dose in vitamin supplements. Copper intake was not associated with cognitive change among persons whose diets were not high in these fats"

Ah, yeah. That study doesn't necessarily prove AOR is incorrect in their statement that 7mg doesn't increase free radicals, although it certainly does lean to the theory that high copper = bad brains. Especially if lots of saturated fats are included in diet. Have you found any reference to zinc status in that above study? I'm curious if adequate zinc was included in their diets.

Correct, chelated minerals have much higher bioavailability so more is aborbed. But this occurs more slowly which causes less free elemental metal not bound to proteins. A temporary effect after intake but can still be damaging. Chelated minerals are similar to minerals more slowly absorbed from food which we are adopted for. Unlike copper tubing and supplement pills which are new creations.

Also, if you read the links regarding Ferrochel it is claimed that the chelated iron is not absorbed if body iron stores are full. Unlike elemental iron.

So they claim that chelated minerals aren't absorbed by the body, once the body stores are full? I never heard of this before, so I am a bit skeptical. It's like saying a person could consume megadoses of calcium, magnesium, zinc without it causing health issues, so long as it's chelated with glycinate.

Copper citrate is a chelate too, by the way. I should also add I'm not pro-copper, or saying people should megadose on the stuff. But I don't see how by improving copper absorption via a chelate, you'd avoid any issues from consuming too much copper. It'd be the same (or worse) as diet high in copper, or drinking lots of water from copper pipes.

[Blue]

Ah, yeah. That study doesn't necessarily prove AOR is incorrect in their statement that 7mg doesn't increase free radicals, although it certainly does lean to the theory that high copper = bad brains. Especially if lots of saturated fats are included in diet. Have you found any reference to zinc status in that above study? I'm curious if adequate zinc was included in their diets.

So they claim that chelated minerals aren't absorbed by the body, once the body stores are full? I never heard of this before, so I am a bit skeptical. It's like saying a person could consume megadoses of calcium, magnesium, zinc without it causing health issues, so long as it's chelated with glycinate.

Copper citrate is a chelate too, by the way. I should also add I'm not pro-copper, or saying people should megadose on the stuff. But I don't see how by improving copper absorption via a chelate, you'd avoid any issues from consuming too much copper. It'd be the same (or worse) as diet high in copper, or drinking lots of water from copper pipes.

They state that Ferrochel do is toxic in very high does but at much higher doses as compared to elemental iron. Especially if considering that much more is absorbed if iron deficient. The FDA has given it GRAS (generally regarded as safe) status unlike any other iron form.

You get a temporary spike in free ions with tap water or supplements due to the liver and serum binding proteins being overwhelmed by the temporarily very high copper concentrations. This can (hopefully) be avoided by chelation releasing the copper more slowly so the liver and the proteins can bind the copper before it reaches the brain.

Edited by Blue, 06 July 2009 - 07:32 PM.

[Blue]

Copper citrate is a chelate too.

No. It is a salt.

[nameless]

No. It is a salt.

Yep. Chelated with a salt instead of an amino acid. Although I admit I don't know the rate at which free elemental copper is released from a citrate vs an amino acid chelate.

Edited by nameless, 06 July 2009 - 08:04 PM.

[Blue]

Yep. Chelated with a salt instead of an amino acid.

A chelate requires the metal to bind to the ligand at two places. Making it electrically neutral and prevents easy interactions with other substances. A salt is very different.

Edited by Blue, 06 July 2009 - 08:11 PM.

[nameless]

A chelate requires the metal to bind to the ligand at two places. Making it electrically neutral and prevents easy interactions with other substances. A salt is very different.

My mistake then. I've read that citrates and various organic acids can form chelates with minerals in various articles, but perhaps they were wrong or used the term loosely, or I misunderstood.

I'm still not sure if it matters, in regard to copper toxicity/problems, but I suppose if absorption of elemental copper differs significantly, then maybe.

[Blue]

I'm still not sure if it matters, in regard to copper toxicity/problems, but I suppose if absorption of elemental copper differs significantly, then maybe.

Agree that replacing elemental metals is chelated ones is problematic. Almost all studies are done on salts. I have seen one rat study suggesting copper glycinate is 3 times more bioavailable than several copper salts. Suggesting that one should only take 1/3 as much to achieve the same effect. But a single rat study seems very uncertain grounds for a long-term supplementation.

Similary, would chelation stop the cogntive decline seen with copper supplementation? Maybe, but no one knows before a study is done. So I prefer to not take any copper at all since get the more than the RDA from food alone. There was also some weaker assocation with high copper intake in general which points against supplementation.

Edited by Blue, 06 July 2009 - 08:42 PM.

[Blue]

Another prospective serum copper study. Differs from the others in suggesting an u-shape for mortality:
"To investigate the association of serum copper and zinc with mortality from cancer and cardiovascular disease, the authors performed a case-control analysis of data obtained in a Dutch prospective follow-up study. Cancer (n = 64) and cardiovascular disease (n = 62) deaths and their matched controls were taken from a cohort of 10,532 persons examined in 1975–1978. Trace elements were measured in baseline serum samples, which had been stored during the six to nine years of follow-up. The adjusted risk of death from cancer and cardiovascular disease was about four times higher for subjects in the highest serum copper quintile (>1.43 mg/liter) compared with those with normal levels. The excess mortality observed in subjects with low copper status suggests a U-shaped relation. No significant change in the risk of death from cancer and cardiovascular disease was found for subjects with low or high baseline levels of serum zinc. However, a protective effect of a high zinc status on the risk of cancer and cardiovascular disease is compatible with the data. For definitive conclusions, analysis of larger prospective data sets is recommended."
http://aje.oxfordjou...tract/128/2/352

A serum and dietary copper study:
"There are conflicting data on the associations between copper and glycemia, plasma lipids, and atherosclerotic diseases. Copper has both pro-oxidant and antioxidant effects. We performed a cross-sectional analysis to investigate the associations between dietary copper intake and metabolic variables and serum high-sensitivity C-reactive protein (hs-CRP) in asymptomatic subjects from a population-based cohort (n = 1197) and between serum copper concentration and markers of oxidative stress, including plasma nitrotyrosine (NT) and total antioxidant status (TAS), hs-CRP, and metabolic variables in a subgroup of men from this cohort (n = 231). In all subjects, diastolic blood pressure and circulating glucose, uric acid, and total and LDL-cholesterol concentrations significantly decreased, whereas the hs-CRP concentration increased, from the lowest to the highest tertile of copper intake. In the male subgroup, glucose and total and LDL-cholesterol and TAS decreased, whereas hs-CRP and NT concentrations increased from the lowest to the highest tertile of serum copper concentration. In multiple regression models, dietary copper intake was inversely associated with diastolic blood pressure (P = 0.002), fasting glucose (P < 0.001), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), and uric acid (P < 0.001) and was directly associated with the hs-CRP concentration (P < 0.001). Serum copper concentrations were inversely associated with glucose (P < 0.001), total cholesterol (P < 0.001), LDL-cholesterol (P < 0.001), and TAS (P < 0.001) and were directly associated with hs-CRP (P < 0.001) and NT concentrations (P < 0.001). Marginal copper deficiency is associated with an unfavorable metabolic pattern, but copper supplementation might not be recommended in view of its association with inflammation and markers of oxidative stress."
http://jn.nutrition....tract/138/2/305

So rather strange pattern. Higher dietary and serum copper improves many variables except crp and and markers of oxidative stress which worsen. How to resolve this? Maybe a significant proportion of the population have a subclinical copper deficiency which worsen many variables? Yet at the same a too high copper intake produces inflammation, maybe from prooxidant activity as free copper, which in the long term increases many causes of mortality? Which would as I suggested earlier may imply that optimal range for copper intake may be very narrow.

Edited by Blue, 14 July 2009 - 08:28 PM.

[nameless]

Thanks for the studies.

I'm still not sure what to make of serum copper. If it rises due to inflammation alone, I don't know if the studies are measuring true copper status or some other inflammatory disease/problem.

The dietary study is interesting, yet sorta weird. Low seems bad, high seems bad (but for different reasons)... and they didn't apparently check zinc status in that study, so we can't tell if high copper depleted zinc either.

Some other copper weirdness I've run across as to Alzheimer's and copper:

Copper Damages Protein That Defends Against Alzheimer's
http://www.scienceda...71107074329.htm

-- There are different ways to measure copper in the blood, and indeed, there is some research linking low levels of copper to Alzheimer's, while there is other research linking high levels of copper to the disease."

Intake Of Dietary Copper Helps Alzheimer's Patients
http://www.scienceda...51004084327.htm

-- Lower levels of copper have been reported in the brain of AßPP transgenic mice and post-mortem in AD patients

Edited by nameless, 14 July 2009 - 11:13 PM.

[Blue]

Thanks for the studies.

The result of the copper supplementation in your last link was later published.
"Disturbed copper (Cu) homeostasis may be associated with the pathological processes in Alzheimer’s disease (AD). In the present report, we evaluated the efficacy of oral Cu supplementation in the treatment of AD in a prospective, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild AD for 12 months. Sixty-eight subjects were randomized. The treatment was well-tolerated. There were however no significant differences in primary outcome measures (Alzheimer’s Disease Assessment Scale, Cognitive subscale, Mini Mental Status Examination) between the verum [Cu-(II)-orotate-dihydrate; 8 mg Cu daily] and the placebo group. Despite a number of findings supporting the hypothesis of environmental Cu modulating AD, our results demonstrate that oral Cu intake has neither a detrimental nor a promoting effect on the progression of AD."
http://www.springerl...811g1j5w140jl8/

Which contradicts the study in my first post which found a strong effect from copper supplementation. Due to longer time in that study (6 years v. 1 year)? But 8 mg is a high dose although from an unusual source, Cu-(II)-orotate-dihydrate. A chelate?

Another human study:
"We assessed levels of copper, iron, zinc, transferrin, ceruloplasmin, peroxides, total antioxidant capacity, free copper, and apolipoprotein E genotype in 81 patients with mild or moderate AD... ...free copper was the only predictor of a more severe decline"
http://www.neurology...bstract/72/1/50

[stephen_b]

Copper and Cardiovascular Disease at the Whole Health Source blog. I found it a persuasive argument for copper deficiency harming the cardiovascular system.

[e Volution]

Copper and Cardiovascular Disease at the Whole Health Source blog. I found it a persuasive argument for copper deficiency harming the cardiovascular system.

Everything he says is persuasive; he's the MR of Paleo! Someone show me a single flaw of logic or reasoning (or facts!) in anything he has written.

But I think Blue is not arguing against deficiency, just that it looks like the margin of error for copper is very small. I am also very sceptical now when I see anti high-fat and high-saturated-fat thrown in there a long with it (as is in the studies in OP).

[neogenic]

Thoughts?

Copper and Cardiovascular Disease
via Whole Health Source by Stephan on 4/8/10

In 1942, Dr. H. W. Bennetts dissected 21 cattle known to have died of "falling disease". This was the name given to the sudden, inexplicable death that struck herds of cattle in certain regions of Australia. Dr. Bennett believed the disease was linked to copper deficiency. He found that 19 of the 21 cattle had abnormal hearts, showing atrophy and abnormal connective tissue infiltration (fibrosis) of the heart muscle (1).

In 1963, Dr. W. F. Coulson and colleagues found that 22 of 33 experimental copper-deficient pigs died of cardiovascular disease. 11 of 33 died of coronary heart disease, the quintessential modern human cardiovascular disease. Pigs on a severely copper-deficient diet showed weakened and ruptured arteries (aneurysms), while moderately deficient pigs "survived with scarred vessels but demonstrated a tendency toward premature atherosclerosis" including foam cell accumulation (2). Also in 1963, Dr. C. R. Ball and colleagues published a paper describing blood clots in the heart and coronary arteries, heart muscle degeneration, ventricular calcification and early death in mice fed a lard-rich diet (3).

This is where Dr. Leslie M. Klevay enters the story. Dr. Klevay suspected that Ball's mice had suffered from copper deficiency, and decided to test the hypothesis. He replicated Ball's experiment to the letter, using the same strain of mice and the same diet. Like Ball, he observed abnormal clotting in the heart, degeneration and enlargement of the heart muscle, and early death. He also showed by electrocardiogram that the hearts of the copper-deficient mice were often contracting abnormally (arrhythmia).

But then the coup de grace: he prevented these symptoms by supplementing the drinking water of a second group of mice with copper (4). In the words of Dr. Klevay: "copper was an antidote to fat intoxication" (5). I believe this was his tongue-in-cheek way of saying that the symptoms had been misdiagnosed by Ball as due to dietary fat, when in fact they were due to a lack of copper.

Since this time, a number of papers have been published on the relationship between copper intake and cardiovascular disease in animals, including several showing that copper supplementation prevents atherosclerosis in one of the most commonly used animal models of cardiovascular disease (6, 7, 8). Copper supplementation also corrects abnormal heart enlargement-- called hypertrophic cardiomyopathy-- and heart failure due to high blood pressure in mice (9).

For more than three decades, Dr. Klevay has been a champion of the copper deficiency theory of cardiovascular disease. According to him, copper deficiency is the only single intervention that has caused the full spectrum of human cardiovascular disease in animals, including:
Heart attacks (myocardial infarction)
Blood clots in the coronary arteries and heart
Fibrous atherosclerosis including smooth muscle proliferation
Unstable blood vessel plaque
Foam cell accumulation and fatty streaks
Calcification of heart tissues
Aneurysms (ruptured vessels)
Abnormal electrocardiograms
High cholesterol
High blood pressure
If this theory is so important, why have most people never heard of it? I believe there are at least three reasons. The first is that the emergence of the copper deficiency theory coincided with the rise of the diet-heart hypothesis, whereby saturated fat causes heart attacks by raising blood cholesterol. Bolstered by some encouraging findings and zealous personalities, this theory took the Western medical world by storm, for decades dominating all other theories in the medical literature and public health efforts. My opinions on the diet-heart hypothesis aside, the two theories are not mutually exclusive.

The second reason you may not have heard of the theory is due to a lab assay called copper-mediated LDL oxidation. Researchers take LDL particles (from blood, the same ones the doctor measures as part of a cholesterol test) and expose them to a high concentration of copper in a test tube. Free copper ions are oxidants, and the researchers then measure the amount of time it takes the LDL to oxidize. I find this assay tiresome, because studies have shown that the amount of time it takes copper to oxidize LDL in a test tube doesn't predict how much oxidized LDL you'll actually find in the bloodstream of the person you took the LDL from (10, 11).

In other words, it's an assay that has little bearing on real life. But researchers like it because for some odd reason, feeding a person saturated fat causes their LDL to be oxidized more rapidly by copper in a test tube, even though that's not the case in the actual bloodstream (12). Guess which result got emphasized?

The fact that copper is such an efficient oxidant has led some researchers to propose that copper oxidizes LDL in human blood, and therefore dietary copper may contribute to heart disease (oxidized LDL is a central player in heart disease-- read more here). The problem with this theory is that there are virtually zero free copper ions in human serum. Then there's the fact that supplementing humans with copper actually reduces the susceptibility of red blood cells to oxidation (by copper in a test tube, unfortunately), which is difficult to reconcile with the idea that dietary copper increases oxidative stress in the blood (13).

The third reason you may never have heard of the theory is more problematic. Several studies have found that a higher level copper in the blood correlates with a higher risk of heart attack (14, 15). At this point, I could hang up my hat, and declare the animal experiments irrelevant to humans. But let's dig deeper.

Nutrient status is sometimes a slippery thing to measure. As it turns out, serum copper isn't a good marker of copper status. In a 4-month trial of copper depletion in humans, blood copper stayed stable, while the activity of copper-dependent enzymes in the blood declined (16). These include the important copper-dependent antioxidant, superoxide dismutase. As a side note, lysyl oxidase is another copper-dependent enzyme that cross-links the important structural proteins collagen and elastin in the artery wall, potentially explaining some of the vascular consequences of copper deficiency. Clotting factor VIII increased dramatically during copper depletion, perhaps predicting an increased tendency to clot. Even more troubling, three of the 12 women developed heart problems during the trial, which the authors felt was unusual:
We observed a significant increase over control values in the number of ventricular premature discharges (VPDs) in three women after 21, 63, and 91 d of consuming the low-copper diet; one was subsequently diagnosed as having a second-degree heart block.
In another human copper restriction trial, 11 weeks of modest copper restriction coincided with heart trouble in 4 out of 23 subjects, including one heart attack (17):
In the history of conducting numerous human studies at the Beltsville Human Nutrition Research Center involving participation by 337 subjects, there had previously been no instances of any health problem related to heart function. During the 11 wk of the present study in which the copper density of the diets fed the subjects was reduced from the pretest level of 0.57 mg/ 1000 kcal to 0.36 mg/1000 kcal, 4 out of 23 subjects were diagnosed as having heart-related abnormalities.
The other reason to be skeptical of the association between blood copper and heart attack risk is that inflammation increases copper in the blood (18, 19). Blood copper level correlates strongly with the marker of inflammation C-reactive protein (CRP) in humans, yet substantially increasing copper intake doesn't increase CRP (20, 21). This suggests that elevated blood copper is likely a symptom of inflammation, rather than its cause, and presents an explanation for the association between blood copper level and heart attack risk.

Only a few studies have looked at the relationship between more accurate markers of copper status and cardiovascular disease in humans. Leukocyte copper status, a marker of tissue status, is lower in people with cardiovascular disease (22, 23). People who die of heart attacks generally have less copper in their hearts than people who die of other causes, although this could be an effect rather than a cause of the heart attack (24). Overall, I find the human data lacking. I'd like to see more studies examining liver copper status in relation to cardiovascular disease, as the liver is the main storage organ for copper.

According to a 2001 study, the majority of Americans may have copper intakes below the USDA recommended daily allowance (25), many substantially so. This problem is exacerbated by the fact that copper levels in food have declined in industrial nations over the course of the 20th century, something I'll discuss in the next post.

[jazzcat]

Overall, I find the human data lacking. I'd like to see more studies examining liver copper status in relation to cardiovascular disease, as the liver is the main storage organ for copper.

I would like to see more info on cu def in humans. My understanding is that they know in animals (ruminants mainly) that molybdenum levels play a role in copper toxicity and def. Mo is needed for cu utilization and therefore storage of cu in the liver. There are cu-mo ratios for ruminants that seem pretty broad. I haven't seen anything about cu-mo ratios for humans. Mo may be the best way to reduce cu toxicity and is probably critical for chronic cu def.

But there doesn't seem to be enough info on cu bioavailability because biounavaiable cu isn't diagnosed as often as it should be.

There is some indication that Wilson's and perhaps even Menke's may be about mo (or mo's relationship to cu). I think more needs to be known about this relationship and cu bioavailability esp. since it may be involved in those extreme and rare genetic conditins. Because that means that relationship is relevant (though to a lesser extent) to cu issues in somewhat healthy people without genetic conditions. I don't know that narrow range is the issue so much as why cu can be problematic (either too high or def.); but definitely tricky to balance.

[Lufega]

Overall, I find the human data lacking. I'd like to see more studies examining liver copper status in relation to cardiovascular disease, as the liver is the main storage organ for copper..

I found this study to be very compelling. My GF's grandma has this same problem. Naturally, her Doctor has her on statins. I'm going to try and persuade the family to start her on 1.5 mg copper twice a day.

Dietary copper supplementation reverses hypertrophic cardiomyopathy induced by chronic pressure overload in mice

Sustained pressure overload causes cardiac hypertrophy and the transition to heart failure. We show here that dietary supplementation with physiologically relevant levels of copper (Cu) reverses preestablished hypertrophic cardiomyopathy caused by pressure overload induced by ascending aortic constriction in a mouse model. The reversal occurs in the continued presence of pressure overload. Sustained pressure overload leads to decreases in cardiac Cu and vascular endothelial growth factor (VEGF) levels along with suppression of myocardial angiogenesis. Cu supplementation replenishes cardiac Cu, increases VEGF, and promotes angiogenesis. Systemic administration of anti-VEGF antibody blunts Cu regression of hypertrophic cardiomyopathy. In cultured human cardiomyocytes, Cu chelation blocks insulin-like growth factor (IGF)-1– or Cu-stimulated VEGF expression, which is relieved by addition of excess Cu. Both IGF-1 and Cu activate hypoxia-inducible factor (HIF)-1𝛂 and HIF-1𝛂 gene silencing blocks IGF-1– or Cu-stimulated VEGF expression. HIF-1𝛂 coimmunoprecipitates with a Cu chaperone for superoxide dismutase-1 (CCS), and gene silencing of CCS, but not superoxide dismutase-1, prevents IGF-1– or Cu-induced HIF-1𝛂 activation and VEGF expression. Therefore, dietary Cu supplementation improves the condition of hypertrophic cardiomyopathy at least in part through CCS-mediated HIF-1𝛂 activation of VEGF expression and angiogenesis.

http://www.ncbi.nlm..../jem2040657.pdf

Edited by Lufega, 10 February 2011 - 05:19 PM.

[kilgoretrout]

http://journals.lww....p;type=abstract[/b]

Blue,
Your source came to the conclusion that copper was only bad when there was a shortage of magnesium or zinc.---The risk of copper was much smaller when there was sufficient zinc or magnesium. Maybe the problem is not too much copper, but not enough of something else.

From Your Link
"Conclusions: High serum copper, low serum magnesium, and concomitance of low serum zinc with high serum copper or low serum magnesium contribute to an increased mortality risk in middle-aged men."

A little more nuance from Relentless Improvement "Balanced Zinc-to-Copper ratios. Getting too much of either of these nutrients creates a functional deficiency in the other". The advice from them is to take your copper and zinc in balanced amounts and avoid trouble.

Good points.

Random neophyte, non-physician, non-biochem-researcher Googlers acting like Pretend Doctors imagining that they know the proper full meaning of things by reading a few abstracts of highly technical studies totally beyond their non-existent areas of professional "expertise", then coming out with grand proclamation of their conclusions ("Throw Away Your Copper Supplements!")... making all sorts of asinine alarmist assertions/warnings that they are TOTALLY UNQUALIFIED to make... more of these types here than at any other website I've ever seen. I think it stems from some ego thing or something. Which is to be expected I suppose of a forum devoted to living forever. Lots of great info here, but come ON, quit with the amateur "I'm a biomedical researcher in my free time" shtick. Google does not increase your IQ or experience or training or turn you into some expert. LOL. Sorry if this offends anyone, but as they say on those Saturday Night Live news segment commentaries from time to time "I Mean, Really!"

Edited by kilgoretrout, 11 February 2011 - 12:37 AM.