Iron

Comments on the Possible Role of Metals Including Iron in Progressive Supranuclear Palsy

by Ron Ritch

It is widely known that iron can be difficult to remove from the body and in some cases can directly cause serious illness. It is often "stored" in bodily tissue such as that of the brain.

The presence of stored iron or/and other metals in the body can limit the effectiveness of the antioxidants that the body normally produces to fight oxidization. The result is a greater likelihood of a condition similar to "rust" in which the body destroys parts of itself. This distruction can exist anywhere in the body but the most likely area for damage is in the brain itself.

It is known from pathology examinations of the brains of verified cases of Progressive Supranuclear Palsy that the brain tissues often contained high levels of iron. Not enough research has been conducted to discover whether this high iron content can contribute to the cause and progression of the disease but it seems reasonable to assume that it can.

One of the many diseases in the same family as Progressive Supranuclear Palsy is Huntington's disease.

In May 1999 a report was published that stated researchers had verified that those with Huntington's disease had increased basal ganglia iron levels.

Here is the abstract:

One wonders it this might not pertain to Progressive Supranuclear Palsy too and whether the same study should not be made with this disease.

Since the main effect of too much iron would be to limit the effectiveness of naturally occuring antioxidants which would lead to brain tissue destruction, we need to ask how to at least control this action.

The increased use of foods rich in antioxidants along with the avoidance of environmental and lifestyle dangers will do a great deal to lessen the likelihood of acquiring degenerative diseases from this source, they may also slow the disease progress.

It would also seem that the use of readily available antioxidant supplements would help the situation however there is another problem standing in the way.

The brain gets its nourishment from the bloodstream across a "brain-blood" barrier. Most medications and antioxidants cannot cross this barrier because of their molecular size but other substances such as amino acids and the nourishment the brain uses cross this barrier easily.

In general the various generally available supplemental antioxidants do enter the bloodstream and do circulate elsewhere in the body, but little or none of the benefit can get to the brain.

Thus, if tissue in the brain is being destroyed by oxidization, the progress of this process will probably be little affected.

What is needed are strong antioxidants that can cross the blood-brain barrier and be given as part of a patient's daily nourishment. Such substances would help the body to heal itself and would do more to help the patient than any of the very limited benefit medications now being tried.

These substances would have few side-effects and could slow or perhaps even halt the progression of diseases such as Parkinson's and Progressive Supranuclear Palsy.

Until such answers are available we can do a few things. First is to try to limit additional iron in the diet. This isn't easy.

It means eating more vegetables and fruits in the diet and to stop cooking in iron utensils.

Any supplemental vitamins or minerals should not include iron in their formula.

It means becoming aware that many many foods are supplemented with iron even though there is little evidence that additional iron is required in the normal diet. Especially rich are items made with "enriched" flours and cereals.

We have become convinced that "women need extra iron" - this is usually not so. And we have been told to eat our oatmeal and get our days iron.

This excess of iron in the diet has become dangerous to all.

©Copyright 1999, Ron Ritch

Dietary Iron Supplements - Use or Not to Use?

Nutrition Today

James R. Connor
John L. Beard

June 1997 - The ancient Arabs, Chinese, Egyptians, Greeks, and Romans knew of the benefits of additional iron in their diets and provided extra liver to soldiers after battles to speed up their recovery. Throughout the 1800s, iron deficiency anemia, known as "chlorosis," was suspected to be related to diet. Finally, in 1895, Bunge accurately described the anemia of chlorosis in terms of nutritional iron deficiency.

Although we now know much more about the essentiality of iron to prevent nutrient deficiency states, there is growing concern that too much iron in our diets may be related to certain diseases like cancer, cardiovascular disease, and certain neurologic diseases. Diabetes could also be involved; before the discovery of insulin, individuals with hemochromatosis (HC), an iron overload disease, died in a diabetic coma. Many of the diseases associated with iron overload occur predominantly in the aged population.

Although body iron accumulation occurs in the elderly, many aging individuals believe that nutritional supplementation is an appropriate way to prevent some of the decline in biologic processes associated with aging.^[1] Many people begin iron supplementation as they near midlife and continue into old age.

Although some form of nutritional support is essential for some individuals with limitations in their physical condition because of chronic illness or disease, the clear health benefits of using iron supplements over consuming a mixed diet is still hotly debated. Consumption of the major food groups, with special emphasis on five servings of fruits and vegetables, plenty of grains and legumes, and decreased fat consumption, can go a long way toward the provision of good nutrition.^[2]

On the other hand, strong evidence indicates that increased intake of extra calcium for prevention of osteoporosis, extra vitamin C and E for prevention of cardiovascular disease, and plenty of vitamin A for optimal immune functioning is beneficial in preventing the onset and, perhaps, progression of chronic disease.^[1,3]

Public health nutritionists have focused more on how much of the population is at risk of iron depletion and are, thus, more concerned with iron status adequacy and prevalence of depleted iron stores than they are with iron supplementation in normal iron states.

Iron deficiency can be defined as that moment in time when body stores of iron, ferritin and hemosiderin, become depleted of iron and a restriction of supply of iron to various tissues becomes apparent.^[4] Conceptually, the process of depletion of iron stores can occur rapidly or very slowly and is dependent on the balance between iron intake and iron requirements. The absorption and loss of iron are balanced in individuals who have normal iron status and are free of disease. We finely regulate the exact amount of iron absorbed to match the amount we lose in feces, urine, and sweat. When dietary intakes are insufficient to meet daily tissue needs, iron must be mobilized from storage sites in cells.

Historically, we view iron intakes as sufficient if they prevent deficiency states.^[5] Thus, an intake of 15-18 mg/day is sufficient to meet our daily requirements and prevent deficiency states.

In the United States, the mean iron intake of individuals beyond the age of 51 years is approximately 12 mg/day, with a slightly higher intake of 13-15 mg/day in men and a slightly lower intake, 10-11 ma/day, in women.^[6] Although many elderly have intakes above the Recommended Daily Allowance (RDA), a significant portion have intakes below the RDA, particularly those with low incomes, impaired functional status, and very advanced age, and sometimes those in institutions.^[7]

Attempts to alleviate iron deficiency through food fortification and diet supplementation have been largely successful in the United States. Dietary supplementation of iron can be helpful in specific populations at risk for iron deficiency, but this approach is limited by dosage requirements and potential side effects, both of which lead to noncompliance.

Side effects of iron supplementation at high doses ([is less than] 200 mg Fe) include gastrointestinal distress and constipation. Level of education, gender, demographic location, motivation of healthcare providers, and other factors all seem to affect who takes supplements and how often.^[8] To combat iron deficiency in the general population, the United States began fortification of food with iron in the 1940s. The Food and Drug Administration has since upwardly revised standards for iron enrichment of cereal products and has issued guidelines for fortification of infant formulas. These actions have prompted much debate about potential iron overloading in people with adequate iron status.

Meats and grains are the primary sources of iron in American diets. Iron derived from meat plays an especially powerful role; it is better absorbed than any other form of iron normally present in the diet. The average percentage of iron absorption from the American diet is likely less than 10% and perhaps closer to 7% of dietary intake. The absorption of heme iron from meat is much better and can increase to 40% if the individual has a low iron status.^[4] Thus, food choices on a daily basis have a large impact on the amount of iron absorbed by the gut after a given meal.

Meat consumption is decreased in elderly populations, and as a result, only about 22% of dietary iron is derived from meat for men aged 75 and older.^[9] This number declined to about 17% when women over the age of 75 were examined.^[10] The decrease in meat consumption (and, consequently, iron intake) by the elderly is likely the result of many factors, including a response to public health campaigns to reduce fat intake, especially saturated fat intake, to reduce risk of cardiovascular disease.

Iron Intake and the Elderly

Information on iron supplement use in the elderly is limited, but many studies suggest that between 30% and 70% of older adults use supplements.^[11,12] Some scientists argue that total iron intake does not differ much between those who take iron supplements and those who do not.^[13] These comparisons, however, simply group users of all supplements together and compare them with those who do not use any supplements. Hence, the specific effect of an iron supplement per se in aging populations is still debated and requires additional study.

Nonetheless, any total intake of iron in excess of daily need will result in the accumulation of iron in the body because we have a limited capacity to excrete excess iron. This excess iron needs to be stored; the storage "account" is in the form of iron crystallized within the center of a protein shell called "ferritin."

Iron requirements in aging individuals are regulated differently than in the young because there is no longer growth or menstrual cycle losses. The exact rate of loss of iron from aging individuals is difficult to determine. Iron is lost primarily through skin, feces, and urine, but early studies by Finch^[14] demonstrated that individuals between 57 and 84 years of age lose iron at around 0.6 mg/day compared with younger menstruating women, who lose iron at around 1.2 mg/day.

Clinical conditions that occur more frequently in the elderly promote blood loss and, consequently, an increase in iron loss include hemorrhage, worm infestation, peptic gastric or anastomotic ulceration, ulcerative colitis, colonic neoplasia, and aspirin-induced bleeding. In addition to these conditions, a significant amount of iron (210-240 mg Fe/ unit, ie, one pint) can be lost with regular blood donation. However, regular blood donation results in more efficient absorption of iron from supplements in blood donors compared with nondonors.^[15]

Iron Metabolism

A long-term negative iron balance (losses [is less than] intake) leads to a decrease in the amount of iron in the storage protein, ferritin, and iron deficiency results. Several well-known consequences of iron deficiency occur after the depletion of iron stores, including decline in hemoglobin concentration (anemia), decrease in the size and volume of new red blood cells, reduced muscle myoglobin, and reduced amounts of iron-containing enzymes and proteins within cells in most organs.

It is not uncommon for anemic people to complain about being tired all the time, to experience malaise, to be very sensitive to the cold, and to experience what is now know as restless legs syndrome (RLS).^[16] Many of these symptoms can be explained by the effects of the poor iron status of thyroid hormones, cellular energy metabolism, and perhaps neural functioning.^[17] Iron supplements at very modest levels can provide a prompt benefit in many cases.

Assessment of Iron Status

The nutritional iron status of humans can range from iron overload to iron-deficiency anemia. Historically, many different methods have been used to assess the iron status of an individual, including dietary intake, hematocrit (total cell density in blood), hemoglobin (iron-dependent oxygen carrying protein in blood), mean cellular hemoglobin, mean cell volume, erythrocyte mean index, free erythrocyte protoporphyrin, bone marrow iron stain, serum iron, total serum iron binding capacity, serum transferrin, transferrin saturation, serum ferritin, and most recently, the serum concentration of a portion of the transferrin receptor (TfR). This latter method appears to be the best predictor of iron deficiency, and serum ferritin appears to be the best indicator of tissue iron stores.

A long-term negative iron balance eventually leads to the depletion of the storage iron pool, and plasma ferritin concentrations drop dramatically. To date, the most realistic tool in a nonclinical setting for assessment of the size of the storage pool is the measurement of serum or plasma ferritin concentrations. In the range of 20-300 mg/L, each milligram per liter represents 10 mg of storage iron. But, plasma ferritin concentrations can increase dramatically with both acute and chronic inflammations, vitamin B12 deficiency, folic acid deficiency, and many diseases.^[4]

Thus, it is difficult in many elderly to easily diagnose poor iron status before the individual actually runs out of storage iron and becomes anemic. Some healthcare providers have adopted the approach of preventive supplementation of iron for this very reason. The measurement of ferritin is not yet a routine diagnostic test in all clinics, so special efforts need to be extended to monitor storage iron before its possible depletion.

Hemoglobin concentrations, another frequent measurement taken to indicate iron status, are also altered by polycythemia, dehydration, cigarette smoking, chronic inflammation, chronic infection, hemorrhage, protein-energy malnutrition, vitamin B12 deficiency, folic acid deficiency, and hemoglo-binopathies. Thus, considerable information about nutritional and health status is needed apart from hemoglobin determination if the specific interest is iron status.

Once the storage iron pool is depleted because of a prolonged or acute negative iron balance, the transferrin saturation declines, and less-than-adequate iron is available to tissues for essential body function. The end result of this phase is tissue iron deficiency and anemia.^[4] The newest measurement available for the measurement of iron status is the measurement of the concentration of plasma transferrin receptor (TfR). This measurement has diagnostic value for the assessment of iron deficiency anemia and ineffective production of red cells.^[18,19]

The amount of TfR in circulation has been shown to increase even in mild iron deficiency. Measuring the plasma concentration of TfR is better than measuring ferritin because the TfR plasma concentration level is unaffected by inflammation, thus giving a more accurate picture of the iron status of aging individuals, in whom inflammatory diseases are a common occurrence.

Iron and Disease

The balance between normal iron levels and low or high iron is delicate, and chronic alterations in this balance can result in severe health consequences.

Many diseases can be related to body iron status, including cancer, immune function, heart disease, and neurologic disorders.^[20] A major issue for iron and disease is the relationship between iron and oxidative damage. To generate energy from oxygen, a transitional metal (iron is the most abundant transition metal in the body) must be present to accept and donate electrons in the energy producing process. This interaction between oxygen and iron is tightly regulated and confined to specific compartments within a cell; however, iron retains its ability to accept and donate electrons regardless of its cellular location, and oxygen maintains its attraction for accepting electrons. The consequence of this interaction between iron and oxygen is the formation of oxygen radicals.

Oxygen radicals are highly toxic, highly reactive chemical species of oxygen that can damage proteins, lipids, and even DNA. Thus, although the body has intricate mechanisms for sequestering iron within proteins (ferritin) or detoxifying reactive oxygen species, oxidative stress to cells can still occur. Indeed, according to one theory, the aging process results from an accumulation of oxidative cellular and molecular damage over time.

Oxidatively damaged or modified proteins do not function effectively. Oxidatively damaged DNA does not produce faithful copies of itself during cell division and can lead to genetic mutations that can cause cell death or even cancer (see below). As mentioned, cells have numerous methods for protecting themselves from iron-induced oxidative damage, but these methods can be overwhelmed. Ingestion of antioxidants, such as vitamins E and C, may help.

Brain Disorders Associated with Iron Levels

Iron is required by the brain and all other organs for normal activity; however, because the brain has the highest metabolic rate of any organ, it requires high levels of iron and oxygen. The brain also has areas specialized for function (eg, movement, sensation, hearing, etc.), and these areas have their own metabolic and iron requirements.

Consequently, iron must be shuttled to specific parts of the brain not only in adequate amounts, but also in a timely fashion. Most areas of the brain involved in functions directly related to movement contain relatively high amounts of iron. Indeed, one of these areas (basal ganglia) has a concentration of iron similar to that found in the liver. The liver is traditionally considered the iron storage organ in the body; perhaps the brain can compete for this distinction.

Some unique functions for iron in the brain include the synthesis of the neurochemicals dopamine and serotonin, which are known as transmitters because they transmit communications between two nerve cells. Iron is also required for the synthesis of myelin, the lipid-rich substance that wraps around the nerve processes (axons) in the brain, providing insulation to prevent "shorting" of electrical signals passing from nerve cell to nerve cell.

Iron deficiency and brain dysfunction

Iron deficiency during early development is well known as a cause of cognitive and motor impairments that can persist throughout life, even though plasma iron levels return to normal with the return of normal iron nutriture. Scientists believe there is a window of opportunity during development for reversing iron deficiency-associated brain disorders, and studies are currently underway in our laboratories to identify this window of sensitivity.

In adults, iron deficiency is usually considered to be less likely associated with neurologic dysfunction unless the individual suffers from chronic anemia.

However, in recent years, the specific neurologic disorder, RLS has been shown to be associated with iron deficiency.^[16] RLS is characterized by an irresistible urge to move the legs (relieved by movement), and the severity of symptoms of RLS patients are inversely correlated to serum ferritin levels. RLS affects 5%-8% of the population, but 30% of the individuals with iron deficiency are affected. The incidence of RLS is increased in the elderly population.

Individuals with RLS improve with treatment with dopaminergic agents; as mentioned earlier, iron is absolutely required for the synthesis of dopamine in the brain. Thus, the connection between iron deficiency, dopamine agents, and RLS has a biologic basis.

Excess iron and brain dysfunction

Iron accumulates in the brain with normal aging. The reason for this accumulation is not clear. If the proteins responsible for detoxifying iron also increase in the brain with age, then the age-associated accumulation of iron may not be damaging.

In Alzheimer's disease (AD), however, iron accumulates in the brain without the benefit of an increase in the protective proteins. Consequently, cells in the brain in AD patients have increased vulnerability to oxidative stress. In AD brains, there may also be a direct connection between iron accumulation and amyloid plaques, the hallmark characteristic microscopic changes identified by a core of amyloid surrounded by clusters of iron-rich cells. Iron may have direct effects on the production of amyloid by cells in the brain and may also directly influence the deposition of amyloid in the AD brains.^[21]

In a very interesting but controversial study, an iron chelator was used to abate cognitive decline in AD patients.^[22] One of the controversies associated with this study was that the effect reported was attributed to chelation of aluminum instead of iron. Additional studies are required to clarify these interesting results.

Parkinson's disease (PD) is another common neurologic disorder in which iron accumulation in a specific brain region likely plays a role. PD occurs as a result of degeneration of dopamine-containing cells in the substantia nigra (a specific brain region). This area of the brain is an iron-rich area.

One hypothesis for the cause of PD is that the iron accumulation in the affected brain region promotes oxidative injury to the nerve cells, and they die.

Antioxidant therapies in PD patients are currently under investigation. Vitamin E did not delay the development of disability in patients with PD, but vitamin E does not penetrate into the brain quickly, and in the PD patients, it was not clear that the ingested vitamin E had increased the brain vitamin E concentrations.^[23] Deprenyl does delay the development of clinical disability in PD and may work through a mechanism that increases protective agents against oxidative stress.

Multiple sclerosis (MS) is the prototype of demyelinating diseases. Myelin is the target of the disease agent in MS. As explained above, iron is absolutely required for the synthesis of myelin, the lipid-rich substance surrounding nerve axons. Indeed, the brain cells that make myelin contain most of the iron in the brain. Thus, decreased availability of iron would be expected to be associated with a loss of myelin. The iron stores in the cells that make myelin may protect against loss of brain myelin in adults with iron deficiency, but this mechanism has not been studied.

Abnormal iron accumulation has been shown in brains of MS patients and may contribute to the disease process. In an animal model of demyelinating disease used to mimic some aspects of MS, the symptoms and clinical pathology normally associated with the disease can be reduced with iron chelation and with antioxidants.^[24]

Most stroke studies have focused on the association of iron with oxidative damage. Iron leaks from the blood into the brain during and after the stroke. When this iron mixes with oxygen in the cells or when blood once again flows into the area (reperfusion injury), oxidative damage occurs.

To directly test the idea that iron may be involved in exacerbating stroke damage, animal models were necessary. Gerbils, a good model for human stroke, were fed a low-iron diet (but not to the point of anemia) to lower their brain iron concentration. These animals had less brain swelling after stroke than did those animals on normal diets. It was determined that the brain concentration of iron was an important factor in the amount of damage associated with the stroke. Furthermore animals given a single dose of an iron chelator just before stroke had less brain damage.

Of course, it is not possible to know when a person will have a stroke, so it is not possible to inject an iron chelator just before the event. The data clearly show a connection between iron and stroke damage, however. Therapeutic agents aimed at decreasing iron or oxygen radicals induced by iron/oxygen interaction are under development.^[25]

Iron and Cancer

Pathologic iron storage disorders, such as HC, are associated with an increased incidence of cancer, particularly liver cancer. With treatment for the excess iron, the incidence of cancer in HC patients returns to normal ranges. A marker of elevated iron in the body is increased ferritin (normally an iron storage protein in cells) in the blood, and increased blood ferritin levels are associated with head, neck, and breast cancers.

Occupational exposure to iron and smoking (tobacco has high levels of iron) are risk factors for lung cancer. All rapidly growing cells have a high iron requirement, and cancer cells, with their rapid, unregulated growth, are no exception.

Inhibition of iron uptake can decrease proliferation of cancer cells.^[26] Studies have shown that tumors grow more slowly in mice on iron-restricted diets.^[27] More epidemiologic studies examining iron status and cancer are necessary because the current level of information does not permit unequivocal conclusions.

Hepatitis B virus carriers who develop liver cancer have higher iron stores than those who do not develop cancer.^[26] Iron depleted women have a lower risk of lung cancer, whereas women with high iron intake developed colon cancer at a higher rate than normal.

A recent National Health and Nutrition Examination Survey reported that saturation of iron binding proteins in blood in men was associated with higher incidence of cancer. The same is true for women, but the saturation levels had to be much higher.^[28] In cancer patients, low iron levels in blood and decreased iron absorption by the gut may be mechanisms by which the body tries to decrease the amount of iron available to the tumor cells (see Iron and the Immune System below).

A possible mechanism by which iron could be involved in altering normal cells to become cancerous is by damaging DNA. Iron is required for DNA synthesis and can be found in the nucleus of the cell with the DNA. However, when iron is not properly bound to proteins, it can cause damage to DNA, and damaged DNA could increase the probability that a cell will "transform" into a cancerous cell. The cancer therapeutic agent, bleomycin, actually takes advantage of the iron in the nucleus and interacts with the iron to damage the DNA into such small pieces that the cancer cell dies.

Iron and the Immune System

Iron status and immune function

Immune system function generally declines with age. The study of the role of iron in the immune system has been complicated by the obvious fact that while in the process of an immune response, most people are ill. Thus, careful studies in which illness can be controlled are required to truly understand whether or not iron can directly affect immune system function. For this reason, much of our information on iron and immune system interaction has come from studies on iron-deficient animals or from cells that are removed from the blood and then studied outside the body. These studies indicate that iron is required for the proliferation of lymphocytes (the killer cells) in the immune system and for production of antibodies by these cells. Also, neutrophils, the cells in the blood responsible for killing bacteria, have impaired function if iron is not readily available.

Scientists consider the protein transferrin to be the key component of iron function in the immune system. Transferrin transports iron through the blood and into most cells. Normally, transferrin is 30% saturated with iron. In iron deficiency, the percentage of transferrin saturated with iron is markedly decreased. Subsequently, iron is not delivered to cells in the amounts necessary to either support proliferation to mount an immune response or to provide sufficient energy for antibody production. The cells themselves are capable of normal function--iron deficiency does not alter the cells, if they get sufficient iron supplies.

The results of studies on iron overload and the immune system are frequently contradictory. It appears that individual cells, when iron overloaded, have impaired function (de, antibody production, proliferation in response to stimulation).

Iron withholding defense

A second component of the relationship between iron and immune system function is the remarkable response of the body in relation to infections. Microbes (fungi, bacteria) have a high iron requirement and have developed numerous mechanisms and strategies for obtaining iron from their hosts during infection. Indeed, within the various groups of microbes, the level of virulence directly correlates with the ability of the microbes to acquire iron. Our bodies have also developed strategies for keeping iron from the infectious agents once they have invaded the body. These strategies have been classified as "the iron-withholding defense system."^[29] Some of these strategies are discussed below.

In every body fluid except urine, we have two iron binding proteins, transferrin and lactoferrin. Interestingly, and perhaps not coincidentally, the urinary tract is most frequently the site of infectious disease episodes that require medical attention. Lactoferrin and transferrin are proteins that bind iron and serve to withhold it from pathogenic microorganisms. The level of iron saturation of transferrin may have prognostic values in infections. The more saturated transferrin is with iron, the less capable it is of providing protection from infection.

An early response by the body faced with infection is to decrease the amount of iron associated with transferrin by keeping the iron in cells that serve as storage sites for iron. These cells then withhold the iron from the invading microorganisms. The result of iron-withholding is a decrease in plasma iron levels (a complication for immune system function studies noted above). This response is well established^[30] and is known as the "hypoferremia of infection." Ironically, if a patient's blood iron levels are evaluated during the time of an infection, the patient could be mislabeled as "iron-deficient," and iron supplementation could be proposed, which would neutralize the body's own attempts at battling the infection. This is another reason that transferrin receptor levels should be monitored in patients when iron status is being monitored. As mentioned earlier, serum ferritin levels are likely to be affected as part of the disease response.

Finally, another response by the body to infection is fever. Early studies in rabbits demonstrated that their ability to survive an infection was associated with both a rise in temperature and a lowering of plasma iron. The ability of bacteria to grow in elevated temperatures has been shown to be directly related to their ability to acquire iron. It is thought that fever increases the metabolic activity and, consequently, the iron requirement of bacteria. If the increased iron demands are not met, and generally they are not easily met, then the bacteria die.

Iron and Heart Disease

Congestive heart failure, a characteristic of hereditary HC, is prevented by chelation therapy or phlebotomy. HC, of course, is a disease state and represents one end of the spectrum in iron accumulation.

A 1992 prospective study^[31] of Finnish men established that an elevated serum level of ferritin was a significant risk factor for acute myocardial infarction (AMI). The results of this study are consistent with a 1972 report that serum ferritin levels are positively correlated with heart disease.^[32] Elevations in serum ferritin can be (but are not always) reflective of high levels of stored iron in the body. Menses in young adult women has been reported to at least partly explain why women are generally at lower risk for heart disease than men.

Indeed, a Framingham study showed that premenopausal hysterectomy eliminated the protection against heart disease.^[33] Estrogen replacement therapy alone does not decrease the risk of heart disease in women or men. Most studies on iron and heart disease focus on excess iron. Epidemiologic studies have revealed that where iron deficiency is prevalent in a population, there is a low prevalence of heart disease. Obviously, the heart requires a constant supply of iron for normal function, but there is nothing to indicate that a balanced diet will not provide sufficient iron for normal heart activity.

One other area where increased iron has been considered to increase cardiovascular problems has been in association with atherogenicity of low-density lipoprotein (LDL) associated cholesterol. Earlier, we mentioned how oxidatively damaged proteins function poorly or not at all. Iron can cause oxidative damage to LDL, causing LDL to be rapidly cleared from plasma.

Although at first glance, rapid removal of LDL from plasma may appear to be a positive effect, the rapid uptake appears to present problems for the endothelial cells surrounding the blood vessel. It is also thought that incomplete oxidative damage to LDL may render it less functional but also less likely to be cleared from the plasma. Iron itself can be found within atherosclerotic lesions. Antioxidant therapeutic strategies in the treatment of coronary heart disease is an exciting area for research.

Conclusion

There is little reason to support a general need for iron supplementation in the diet at any age. Because the elderly have even fewer means of excreting excess iron than the nonaged population, iron supplementation in the absence of clinical iron deficiency is not recommended.

Although the elderly have the option of blood donation as a means of iron removal, current estimates are that elderly individuals, even when they are taking iron supplements, should not donate blood more than two or three times per year.^[34]

The difficulty in ascertaining tissue iron storage in elderly through direct analysis of blood iron levels or serum ferritin does not warrant iron supplementation as a preventive measure. Detection of transferrin receptor levels in blood should be considered the method of choice for determining tissue iron status. Behavior is not a determining factor in the decision to use iron supplements because both iron-deficient and iron-overloaded individuals are likely to be lethargic and to report low energy.

Perhaps this article and review of supplementation pros and cons should conclude with a new interpretation of an old saying: "It is better to wear out than to rust out;" don't expose your system to more iron than it needs.

James R. Connor, Ph. D., is Professor of Neuroscience and Anatomy and Director of the George M. Leader Family Laboratory for Alzheimer's Disease Research at the Milton S. Hershey Medical Center/Pennsylvania State University Dr. Connor is also a member of the Nutrition Graduate Program at Penn State. He is a member of the editorial board for the Journal of the National Scientific Advisory Council of the American Federation of Aging Research.

John L. Beard, Ph.D., is a Professor of Nutrition at Pennsylvania State University and a member of the Graduate Program in Neuroscience and Anatomy. He is a member of the editorial boards for both the American Journal of Nutrition and has served as a consultant to the Institute of Medicine, National Academy of Science. His research for the last 15 years has focused on the functional consequences of iron deficiency as it occurs in early life or in aging individuals.

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