Can Copper Status Affect Aging?
Searching for possible functional consequences of glycation--the attaching of
sugar molecules to protein--physiologist Jack Saari measures heart performance
and blood pressure in a copper-deficient laboratory rat.
Could a marginal intake of the essential element copper contribute to the
aging process? ARS physiologist Jack T.
Saari thinks that's a strong possibilitybased 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 processnonenzymatic
glycosylation, or protein glycation for shortis 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,
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
In the early 1980s, Saari's colleague, Leslie M. Klevay, M.D., reported that
copper-deficient rats had glycated hemoglobinthe oxygen-carrying molecule
in red blood cells. Klevay heads the Mineral Nutrient Requirements Unit at
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 sugareither 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 deficiencysuch as an enlarged
heartby 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
chemicalaminoguanidineknown to block advanced glycation or
cross-linking of sugars. And it worked.
Technician Peter Leary performs a test to detrmine the degree of glycation of
hemoglobin in blood drawn from copper-deficient rats.
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
"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 legumessuch as soybeans, peas,
chickpeas, lentils, and peanutsare good sources of the mineral. The
richest sources of copper are animaloysters, crabs, and liverwhich
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
individualsbelow 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 mealincreasing
glycationbut 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
The early stage of glycationwhen the sugar first attaches to the
proteinis 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 enzymesuperoxide 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 proteinsall of which tend to increase oxidative damage.By
Judy McBride, Agricultural
Research Service Information Staff.
This research is part of Human Nutrition Requirements, Food Composition,
and Intake, an ARS National Program described at
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.
"Can Copper Status Affect Aging?" was published in the
August 1999 issue of Agricultural