ABSTRACT
Secondary analyses of data from the Age-Related Eye Disease Study (AREDS) revealed that higher calcium intakes were associated with slower progression to age-related macular degeneration (AMD). Earlier, primary analyses had revealed that a supplement containing copper reduced the odds of developing AMD while lengthening life. Because ocular lesions are being reported increasingly in neuropathy from copper deficiency and because higher dietary calcium can have beneficial effects on copper metabolism, it is hypothesized that the association of calcium intakes with better vision was mediated by improved copper utilization of study participants who were eating too little copper. Nutrition surveys reveal that amounts of copper proved insufficient for men and women in controlled studies are readily available to the general population. Observations on eye anatomy of animals deficient in copper and on decreased retinal superoxide dismutase, an enzyme dependent on copper for activity, in people with AMD support this hypothesis. Eradication of AMD will require new approaches based on hypotheses that fail falsification.
INTRODUCTION
Tisdale, et al. did secondary analyses of participants in the Age-Related Eye Disease Study (AREDS) and found that higher dietary and supplementary calcium intakes were associated with lower incidence of progression to late agerelated macular degeneration (AMD). An accompanying editorial suggested that the findings should be viewed as hypothesis-generating.
HYPOTHESIS
It seems quite likely that some of the people in the AREDS were eating too little copper. Those supplemented with copper (and zinc) lived longer (relative risk=0.73) with better vision (odds ratio <0.75). It is hypothesized that the beneficial effects of calcium arose from enhanced copper utilization.
COPPER IN THE WESTERN DIET
Copper in the Western diet has been decreasing at least since the 1930s. Diets containing less copper than amounts proved insufficient (0.65 to 1.02mg/day) for more than 35 men and women, in controlled, depletion experiments, are readily available to the population at large. Some 60 articles tabulated from various medical (but not nutrition) journals summarize data on poor copper status of hundreds of people. In contrast to magnesium, calcium and copper are poorly correlated (r=0.128 vs. 0.849) in chemically analyzed meals. Thus it seems unlikely that benefit of high dietary calcium was from hidden dietary copper. Copper intakes calculated from food tables in nutrition surveys are falsely high (on average, +77%) in comparison to intakes measured by direct, chemical analysis. Whether or not calculated calcium intakes are similarly inaccurate is unknown. It seems reasonable to assume that analytical intakes and calculated intakes are correlated positively.
CALCIUM AND COPPER
Calcium can modify utilization of other dietary elements. Romasz et al. fed rats a wide range of calcium. As dietary calcium increased (from 0.18 to 0.98%), the concentration of copper in liver increased (from 11.0 to 15.1 µg/dry g) though dietary copper was constant. Liver copper is the gold standard for assessing copper nutriture.
COPPER AND THE EYE
The epidemic of neuropathy responsive to copper supplementation may be worldwide; it seems rare enough to be published, but common enough that 10 to 15 cases can be reported from single clinics. It may be as common as the neuropathy from pernicious anemia, which it resembles. Seven separate, peer-reviewed articles briefly mentioning ocular lesions in this neuropathy are collected. Vision of one woman improved from 20/400 to 20/25 with copper supplementation. It was suggested that copper supplementation may have been beneficial in the AREDS. Retinal superoxide dismutase may be decreased in AMD. Among 62 elderly (20-36 years old) rhesus macaques examined for AMD, those with the most drusen had lower superoxide dismutase in erythrocytes; higher plasma thiobarbituric acid reactive substances may indicate these animals were compromised in the ability to metabolize reactive oxygen species.
Superoxide dismutase usually depends on copper for activity. Decreased activity of copper-dependent enzymes is a sign of copper deficiency. Demyelinization characterizes copper deficiency in most animals. Decreased myelination of optic nerves has been found in copper deficient rodents.
TESTING THE HYPOTHESIS
A randomized trial of calcium was thought to be both unlikely and complicated because a large proportion of this elderly population is taking calcium for the prevention of osteoporosis. By the way, copper metabolism also may be involved in osteoporosis. The hypothesis can be tested by reevaluation of some of their data, by more experiments with animals, by measuring copper in liver of people with macular degeneration via autopsy or biopsy and by supplementing patients with copper. These tests can be inexpensive, rapid and specific. It seems likely that a supplementation trial with copper may be done with far fewer subjects than the nearly 5000 studied by the authors. No studies have defined the optimal dose, duration, route and form of copper supplementation to cure deficiency. Dietary supplements containing cupric oxide are not likely to be useful; this salt has been abandoned in animal nutrition because it is utilized poorly. Copper gluconate is the only copper supplement listed by the United States Pharmacopeial Convention for oral use. A supplement of four mg of elemental copper daily may be effective. The daily, tolerable upper intake level from all sources is 10mg for adults.
Consideration of circulating copper is not likely to be useful because normal values are defined poorly and because inflammation increases C-reactive protein and ceruloplasmin. These two proteins are correlated positively in serum. Some standard methods of assessment in people are insensitive. However, low values for plasma or serum copper are diagnostic of deficiency.
pubmed.ncbi.nlm.nih.gov
CHOLESTEROTROPIC AND CUPROTROPIC CHEMICALS
A dozen or so chemicals modify both cholesterol and copper metabolism. Ascorbic acid and cadmium, etc., inhibit copper metabolism and raise cholesterol. Calcium and clofibrate, aspirin, etc., enhance copper and lower cholesterol. Perhaps the doses of dietary cholesterol and fructose in this experiment were too severe to permit fenofibrate to lower cholesterol in a manner similar to clofibrate.
Donaldson et al. fed six groups of female Sprague Dawley rat pups standard diets, standard diets with added quercetin or fenofibrate or these three diets plus 2% added cholesterol and a drinking solution of 20% fructose for 8 weeks. As expected, serum cholesterol was increased in rats consuming cholesterol plus fructose; this diet also increased hepatic macro-steatosis, but the increase was smaller with either quercetin or fenofibrate. A dozen articles have been collected illustrating disrupted copper metabolism in animals fed either cholesterol or fructose since the phenomena was discovered decades ago. It seems likely that the disruption will be greater when cholesterol and fructose are fed together rather than separately. Fructose can increase hepatic triglyceride when dietary copper is adequate; the increase is greater when dietary copper is lower.
Part of the beneficial effect of clofibrate on lipid metabolism is mediated by enhanced copper utilization.6 Fenofibrate did not decrease the serum cholesterol of Donaldson et al.’s animals; perhaps the combination of cholesterol with fructose was too severe. Whether or not quercetin and dietary copper can interact to produce metabolic change is unknown. A dozen or so chemicals modify both cholesterol and copper metabolism. Ascorbic acid, cadmium, fructose, glucose, histidine, sucrose, and zinc inhibit copper utilization and increase serum cholesterol in animals. Calcium, clofibrate (above), aspirin, sodium phytate, and guar (a seed polysaccharide) enhance copper utilization and lower cholesterol. These chemicals vary considerably in their structures. Three are inorganic salts. Several are carbohydrates; small molecules seem harmful and large ones appear to be beneficial. As a class, collectively, they are called cholesterotropic and cuprotropic chemicals. Perhaps the authors will repeat their experiments with an extra group of rats given a substantial copper supplement to determine which of their findings depends on altered copper metabolism. Kuhn suggests that when scientists fail to recognize and control a relevant variable, experiments must be done again. It may be necessary to decrease the concentration of dietary cholesterol and the concentration of fructose in their solution.
The Western diet has been changing. Dietary copper has been decreasing since the 1930s and diets containing less copper than the amounts thought to be required are readily available to the general population. This diet is also high in fructose. It may be worthwhile to test quercetin with rats fed a purified diet free of cholesterol to seek cooperative or interactive effects between these dietary ingredients. Altered copper-fructose metabolism can exacerbate experimental metabolic syndrome and nonalcoholic fatty liver disease.
pubmed.ncbi.nlm.nih.gov
Secondary analyses of data from the Age-Related Eye Disease Study (AREDS) revealed that higher calcium intakes were associated with slower progression to age-related macular degeneration (AMD). Earlier, primary analyses had revealed that a supplement containing copper reduced the odds of developing AMD while lengthening life. Because ocular lesions are being reported increasingly in neuropathy from copper deficiency and because higher dietary calcium can have beneficial effects on copper metabolism, it is hypothesized that the association of calcium intakes with better vision was mediated by improved copper utilization of study participants who were eating too little copper. Nutrition surveys reveal that amounts of copper proved insufficient for men and women in controlled studies are readily available to the general population. Observations on eye anatomy of animals deficient in copper and on decreased retinal superoxide dismutase, an enzyme dependent on copper for activity, in people with AMD support this hypothesis. Eradication of AMD will require new approaches based on hypotheses that fail falsification.
INTRODUCTION
Tisdale, et al. did secondary analyses of participants in the Age-Related Eye Disease Study (AREDS) and found that higher dietary and supplementary calcium intakes were associated with lower incidence of progression to late agerelated macular degeneration (AMD). An accompanying editorial suggested that the findings should be viewed as hypothesis-generating.
HYPOTHESIS
It seems quite likely that some of the people in the AREDS were eating too little copper. Those supplemented with copper (and zinc) lived longer (relative risk=0.73) with better vision (odds ratio <0.75). It is hypothesized that the beneficial effects of calcium arose from enhanced copper utilization.
COPPER IN THE WESTERN DIET
Copper in the Western diet has been decreasing at least since the 1930s. Diets containing less copper than amounts proved insufficient (0.65 to 1.02mg/day) for more than 35 men and women, in controlled, depletion experiments, are readily available to the population at large. Some 60 articles tabulated from various medical (but not nutrition) journals summarize data on poor copper status of hundreds of people. In contrast to magnesium, calcium and copper are poorly correlated (r=0.128 vs. 0.849) in chemically analyzed meals. Thus it seems unlikely that benefit of high dietary calcium was from hidden dietary copper. Copper intakes calculated from food tables in nutrition surveys are falsely high (on average, +77%) in comparison to intakes measured by direct, chemical analysis. Whether or not calculated calcium intakes are similarly inaccurate is unknown. It seems reasonable to assume that analytical intakes and calculated intakes are correlated positively.
CALCIUM AND COPPER
Calcium can modify utilization of other dietary elements. Romasz et al. fed rats a wide range of calcium. As dietary calcium increased (from 0.18 to 0.98%), the concentration of copper in liver increased (from 11.0 to 15.1 µg/dry g) though dietary copper was constant. Liver copper is the gold standard for assessing copper nutriture.
COPPER AND THE EYE
The epidemic of neuropathy responsive to copper supplementation may be worldwide; it seems rare enough to be published, but common enough that 10 to 15 cases can be reported from single clinics. It may be as common as the neuropathy from pernicious anemia, which it resembles. Seven separate, peer-reviewed articles briefly mentioning ocular lesions in this neuropathy are collected. Vision of one woman improved from 20/400 to 20/25 with copper supplementation. It was suggested that copper supplementation may have been beneficial in the AREDS. Retinal superoxide dismutase may be decreased in AMD. Among 62 elderly (20-36 years old) rhesus macaques examined for AMD, those with the most drusen had lower superoxide dismutase in erythrocytes; higher plasma thiobarbituric acid reactive substances may indicate these animals were compromised in the ability to metabolize reactive oxygen species.
Superoxide dismutase usually depends on copper for activity. Decreased activity of copper-dependent enzymes is a sign of copper deficiency. Demyelinization characterizes copper deficiency in most animals. Decreased myelination of optic nerves has been found in copper deficient rodents.
TESTING THE HYPOTHESIS
A randomized trial of calcium was thought to be both unlikely and complicated because a large proportion of this elderly population is taking calcium for the prevention of osteoporosis. By the way, copper metabolism also may be involved in osteoporosis. The hypothesis can be tested by reevaluation of some of their data, by more experiments with animals, by measuring copper in liver of people with macular degeneration via autopsy or biopsy and by supplementing patients with copper. These tests can be inexpensive, rapid and specific. It seems likely that a supplementation trial with copper may be done with far fewer subjects than the nearly 5000 studied by the authors. No studies have defined the optimal dose, duration, route and form of copper supplementation to cure deficiency. Dietary supplements containing cupric oxide are not likely to be useful; this salt has been abandoned in animal nutrition because it is utilized poorly. Copper gluconate is the only copper supplement listed by the United States Pharmacopeial Convention for oral use. A supplement of four mg of elemental copper daily may be effective. The daily, tolerable upper intake level from all sources is 10mg for adults.
Consideration of circulating copper is not likely to be useful because normal values are defined poorly and because inflammation increases C-reactive protein and ceruloplasmin. These two proteins are correlated positively in serum. Some standard methods of assessment in people are insensitive. However, low values for plasma or serum copper are diagnostic of deficiency.
Calcium can delay age-related macular degeneration via enhanced copper metabolism - PubMed
Secondary analyses of data from the Age-Related Eye Disease Study (AREDS) revealed that higher calcium intakes were associated with slower progression to age-related macular degeneration (AMD). Earlier, primary analyses had revealed that a supplement containing copper reduced the odds of...
pubmed.ncbi.nlm.nih.gov
CHOLESTEROTROPIC AND CUPROTROPIC CHEMICALS
A dozen or so chemicals modify both cholesterol and copper metabolism. Ascorbic acid and cadmium, etc., inhibit copper metabolism and raise cholesterol. Calcium and clofibrate, aspirin, etc., enhance copper and lower cholesterol. Perhaps the doses of dietary cholesterol and fructose in this experiment were too severe to permit fenofibrate to lower cholesterol in a manner similar to clofibrate.
Donaldson et al. fed six groups of female Sprague Dawley rat pups standard diets, standard diets with added quercetin or fenofibrate or these three diets plus 2% added cholesterol and a drinking solution of 20% fructose for 8 weeks. As expected, serum cholesterol was increased in rats consuming cholesterol plus fructose; this diet also increased hepatic macro-steatosis, but the increase was smaller with either quercetin or fenofibrate. A dozen articles have been collected illustrating disrupted copper metabolism in animals fed either cholesterol or fructose since the phenomena was discovered decades ago. It seems likely that the disruption will be greater when cholesterol and fructose are fed together rather than separately. Fructose can increase hepatic triglyceride when dietary copper is adequate; the increase is greater when dietary copper is lower.
Part of the beneficial effect of clofibrate on lipid metabolism is mediated by enhanced copper utilization.6 Fenofibrate did not decrease the serum cholesterol of Donaldson et al.’s animals; perhaps the combination of cholesterol with fructose was too severe. Whether or not quercetin and dietary copper can interact to produce metabolic change is unknown. A dozen or so chemicals modify both cholesterol and copper metabolism. Ascorbic acid, cadmium, fructose, glucose, histidine, sucrose, and zinc inhibit copper utilization and increase serum cholesterol in animals. Calcium, clofibrate (above), aspirin, sodium phytate, and guar (a seed polysaccharide) enhance copper utilization and lower cholesterol. These chemicals vary considerably in their structures. Three are inorganic salts. Several are carbohydrates; small molecules seem harmful and large ones appear to be beneficial. As a class, collectively, they are called cholesterotropic and cuprotropic chemicals. Perhaps the authors will repeat their experiments with an extra group of rats given a substantial copper supplement to determine which of their findings depends on altered copper metabolism. Kuhn suggests that when scientists fail to recognize and control a relevant variable, experiments must be done again. It may be necessary to decrease the concentration of dietary cholesterol and the concentration of fructose in their solution.
The Western diet has been changing. Dietary copper has been decreasing since the 1930s and diets containing less copper than the amounts thought to be required are readily available to the general population. This diet is also high in fructose. It may be worthwhile to test quercetin with rats fed a purified diet free of cholesterol to seek cooperative or interactive effects between these dietary ingredients. Altered copper-fructose metabolism can exacerbate experimental metabolic syndrome and nonalcoholic fatty liver disease.
Cholesterotropic and cuprotropic chemicals - PubMed
A dozen or so chemicals modify both cholesterol and copper metabolism. Ascorbic acid and cadmium, etc., inhibit copper metabolism and raise cholesterol. Calcium and clofibrate, etc., enhance copper and lower cholesterol. Perhaps the doses of dietary cholesterol and fructose in this experiment...
pubmed.ncbi.nlm.nih.gov
