January 3, 2007: by Bill Sardi
Animal experiments provide evidence for the iron overload theory of aging.
A research experiment conducted at the University of Texas Health Science center in San Antonio, Texas, is telling. The level of oxidation in various organs of mice was measured at 6, 12, and 24 months of age. The more food these animals consumed, the greater the accumulation of iron in their tissues, and the greater the amount of oxidation (aging) in these tissues. The accumulation of iron in these animals did not appear till full growth had been achieved, or after 355 days. After that time, iron in the liver increased by 140 percent and in the kidneys by 44 percent. The greatest buildup of iron in these animals with advancing age was measured in the liver and brain. Dietary restriction markedly reduces oxidation and iron levels in tissues
Fruit flies (Drosophila melanogaster), because of their short life span (a few weeks), are often utilized in research studies because they can be used to quickly evaluate anti-aging strategies. Two compelling experiments were conducted in fruit flies to determine the role of iron in aging.
In the first experiment, it was found that iron accumulates in fruit flies throughout life. The rate of iron accumulation was found to be proportional to the rate of aging in this species and “may be the initiator of senescence,” said researchers.
In the second experiment, the life span of male fruit flies was found to be proportional to the iron content in the diet. The same is true for mice and humans. Furthermore, the total body iron count in fruit flies correlates with the total calcium load. The inclusion of tea extracts in the diet of fruit flies was found to inhibit the ageing-related accumulation of iron and to prolong their life span by as much as 21.4%. Researchers concluded that iron accumulation is a significant factor contributing to senescence.
Iron plays a predominant role in virtually every disease. For example:
All age-related brain diseases (Huntington’s, Alzheimer’s, Parkinson’s) are caused by the release of fee iron in brain tissues.
Old cells have 10-fold more iron content than young cells. As cells age, they accumulate iron-generated cellular debris called lipofuscin (age pigment), which clogs the cell and impairs cellular functions. Iron chelators are proposed to retard or erase lipofuscin (lie-poh-fus-kin).
Francesco Facchini is a leading researcher on the role of iron, aging and disease. His research reveals that restriction of iron from the diet slows the progression of diabetic-induced kidney disease better than protein restriction. Survival rates nearly double by restricting iron in diabetics with kidney problems.
The provision of an iron-poor diet to adults with blood vessel disease (atherosclerosis), even though they had normal iron levels as measured by blood testing, results in significant reductions in blood pressure, triglycerides, total and LDL cholesterol, blood sugar and blood-clotting factors. This positive effect is less beneficial in premenopausal females who already control iron via menstruation.
There is a great deal of research on the role of insulin and aging. Researchers at the Massachusetts General Hospital have discovered a gene used by worms to regulate how much it eats and how fat it becomes, as well as controls how long it lives, is a gene strikingly similar to the gene for the insulin receptor, the factor that permits insulin to enter cells.
In research conducted at Brown University, when the signaling from insulin-like proteins is reduced it results in increased life span among worms, fruit flies and rodents. In virtually all species, the slowing down of insulin production, or blockage of its signals to cells, can slow aging.
Insulin, required by cells to burn sugar, often cannot enter cells due to a problem called insulin resistance. The problem appears to be age related. The removal of iron by blood-letting to near deficiency levels normalizes liver enzymes and brings about a 40-55 percent improvement in insulin concentrations.
In another study researchers compared the efficiency of insulin to dispose of glucose (sugar) among meat eaters. Meat provides a readily absorbable form of dietary iron. All of the subjects in the study were lean, healthy and had no insulin metabolism problems. When iron levels were depleted among meat eaters there was a 40 percent improvement in their ability to dispose of glucose/sugar. Iron load is critically important in the control of insulin and sugars in the body.
Evidence is accumulating that free-radical production is increased in patients with iron overload, which can result in DNA damage and malignancies. Although blood-letting is effective at removing excessive iron, chelation (removal) therapy is required in many patients with iron overload.
Surprisingly, iron exerts control over calcium in many ways. Low molecular weight iron, known as ferric lactate, is very effective at inducing calcification in soft tissues. When low molecular weight iron is injected into animals, heart tissue shows a very high increase in calcium influx.
Iron also exerts control over calcium at the cellular level. The uncontrolled influx of calcium is the most common way of inducing cell death. Low-molecular weight iron complexes (ferric lactate) induce calcium deposition in the liver, resulting in cell death.
An interesting experiment at the University of Utah appears to demonstrate the over-riding dominance that iron plays in calcium deposition in bones. As estrogen levels decline in menopausal women, calcium is lost from bones, resulting in a condition called osteoporosis. Female rats whose ovaries had been removed, and thus produced lower amounts of estrogen (some is still produced in adrenal glands and fatty cells), which replicates the menopausal state of women, were given an iron chelator (remover) to prevent iron accumulation. As excess iron was chelated out of the body, there was a slowing in the loss of bone mass. Reduction of iron accumulation in post-menopausal females may avert osteoporosis.
Mark Mattson PhD, of the Sanders-Brown Research Center on Aging at the University of Kentucky, has conducted experiments to show how beta amyloid, the toxic molecule that accumulates in brain with advancing age, and is associated with Alzheimer’s disease, adversely alters the regulation of iron and calcium in the brain. In one experiment Dr. Mattson incubated iron nails in water, albumin or beta amyloid. The amount of iron lost from the nails placed in beta amyloid was double that of nails placed in water or albumin. Water is known to rust nails, but beta amyloid hastened rusting more than water. This experiment was performed to demonstrate the destructive role of iron in brain aging.
Decline in iron content of nails placed in water,
beta amyloid (Aβ) or albumin (BSA).
Dr. Mattson also reports that beta amyloid destabilizes brain cells (neurons) so they can no longer regulated intra-cellular calcium levels. Beta amyloid compromises the ability of the neurons to reduce intracellular calcium levels to normal limits.
It is interesting that many popular health practices counter iron over-mineralization. Physical exercise, even a walking program, reduces iron stores. Drinking tea with meals inhibits iron absorption from foods. An aspirin tablet causes a slight amount of blood loss, which results in iron loss. Calorie restriction or fasting obviously results in reduced iron intake. Calcium is widely believed to be a healthy dietary supplement, and it inhibits iron absorption.
Other metallic metals also accumulate in the body with advancing age during the adult years. The human body holds about 72 milligrams of copper. Copper overload disease is called Wilson’s disease. Iron overload is called hemochromatosis. Both maladies result in liver problems, systemic heart and blood vessel disease and shortened lifespan.
Wilson’s disease may serve as an interesting model of aging in regards to this essential mineral. The age of onset of copper overload (Wilson’s disease) varies from age 12 to 40 years. Apparently during the growing years when copper is needed for growth, the disease does not emanate. But over time, copper accumulates, usually in the liver where it is stored, or the brain, where it may be released, causing symptoms that prompt a visit to the doctor. Buildup of copper in the liver increases mortality rates. If left untreated, most Wilson’s disease patients would succumb at an early age to this disorder.
Under normal conditions iron and copper are bound to transport proteins (ferritin and ceruloplasmin respectively) and do not cause “rust” or tissue damage in the body. But under certain conditions they can be set free to damage tissues, induce DNA mutations and raise cholesterol.
The p53 tumor suppressor gene is frequently studied in models of cancer and aging. Investigators at the National Cancer Institute have found that iron and copper cause mutations in this gene, rendering it useless in the fight against cancer.
If rats are a reliable model of brain aging, supplemental metals in the diet such as iron or copper may accelerate brain aging, according to a report published by researchers at McGill University in Montreal.
Three groups of rats were compared in this study. Group 1 consumed rat chow at will. Group 2 consumed a 40% reduced-calorie diet that would provide less metallic minerals. Group 3 consumed a calorie-restricted diet with added minerals.
After 22 months, brain tissue from the three groups of rats was analyzed. Dietary restriction did NOT reduce the number of aging deposits in brain tissues compared to rats fed a normal diet, though reduced calories did reduce the number of aging brain deposits compared to the group that consumed restricted calories but received supplemental minerals.
The accumulation of aging deposits in the brain tissues of these animals was not accelerated during youth.
This is a key study to understanding aging because it underscores the importance of limited minerals rather than limited calories in the control of aging.
Scientists believe the “curtailment of dietary trace metals” or “metal chelation (removal) therapy” may have a beneficial effect on slowing the rate of brain aging.
Experiments with monkeys ranging in age from 4 to 32 years show that as iron accumulates in the striatum and substantia nigra portions of the brain with advancing age, the balance and coordination (motor function) of these animals declines. The decline in motor function caused by iron exceeded the rate of decline caused simply by aging.
Researchers at McGill University in Montreal report that oxidation, induced by deposition of iron in brain tissues, leads to mitochondrial insufficiency in brain cells which produces a degenerative central nervous system that is incongruent with and cannot be separated from brain aging. (The mitochondria are small organs within living cells that produce cellular energy.)
When metallic mineral levels in biological fluids were evaluated in 60 subjects with Alzheimer’s disease, the most significant result was a strong relationship between blood calcium and iron levels and the severity of mental impairment.
The provision of iron and copper solely from the diet, rather than dietary supplements in full-grown males and postmenopausal females, may be wise. While foods fortified with high amounts of iron and copper may be beneficial for growing children, they may not be appropriate for adults.
The hormonal theory of aging rests upon the gradual decline in the secretion of hormones which results in aging and decline in function and elevated mortality.
Estrogen, the predominant sex hormone in females, exerts considerable control over metallic metals in the body.
For example, cardiovascular disease (CVD) is the leading cause of death in the United States. The incidence of CVD is lower in premenopausal women than in men; however, CVD risk in postmenopausal women is 3.4 times that in premenopausal women. These differences in risk may be partially related to increases in excess body iron. Iron stores increase with age in both men and women, paralleling the rise in CVD risk.
Estrogen releases metallic minerals from storage proteins to help grow babies. However, when the childbearing years are completed, estrogen releases minerals that have no target recipient (onboard baby). Even though ovaries may cease production of estrogen in menopause, the adrenals and fatty cells continue to produce estrogen. Once metallic metals like copper, cobalt, nickel, lead, mercury, tin, and chromium are released by estrogen from their storage and transport proteins, they can stimulate the growth of breast tumor cells via their ability to activate the estrogen receptor, the gateway for estrogen to enter cells. The rate of breast cancer rises significantly in postmenopause, concurrent with the accumulation and release of iron.