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
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
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
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
This research is part of Human Nutrition Requirements, Food Composition,
and Intake, an ARS National Program described at http://www.nps.ars.usda.
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.
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