A couple of my recent articles have been devoted to the topic of iron and its involvement in many disease states and in aging itself. (See Iron the primary driver of aging?, and Iron accelerates aging.)
In the course of my research on this topic, I came across a number of papers written by Eugene D. Weinberg, PhD, formerly of Indiana University, and now retired. (His academic page at Indiana.) Dr. Weinberg is the author of over 140 scientific papers concerned with the physiology and biochemistry of trace metals, especially iron, and their roles in microbiology and in human physiology and pathology.
I got in touch with Dr. Weinberg and asked him if I could put a few questions to him, to which he consented. He is, as I mentioned, now retired, and is in fact 93 years old. As he is an eminent authority in this area with a distinguished career, I’m grateful to Dr. Weinberg for answering my questions.
P. D. Mangan: Given that the current literature seems equivocal, what would you say is the current status of the iron hypothesis, especially as regarding cardiovascular disease? A few epidemiological studies found little to no connection; might there be methodological or other reasons for this?
Eugene D. Weinberg: During the past half century, scores of studies from countries throughout the world have reported that iron hearts are not strong; they are weak. The most iron susceptible component appears to be the ventricular cardiomyocyte. For example, among transfusion dependent thalassemic major children, cardiac complications account for the greatest amount of mortality. (These patients become iron loaded because each transfused unit of blood contains 200-250 mg iron.) (See ref 81 of Metallomics paper.) The few epidemiologic studies that reported no association between iron and cardiac damage were flawed in various ways. Researchers, no matter how inherently honest, can inadvertently bias their results in the direction they expect or desire. [The references to which Dr. Weinberg refers are Iron overload following red blood cell transfusion and its impact on disease severity, and Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation. – PDM]
PDM: The body and in fact virtually all organisms strive to keep iron under tight control, since, like oxygen, it is both necessary for life and a highly reactive element capable of doing damage. In humans, the main iron control mechanism is the protein ferritin, which binds iron tightly so that it cannot react with cellular structures, including proteins and lipids. Free iron appears to be more dangerous to health than that bound to ferritin. What factors might cause the dysregulation of iron and the release of its free form?
EDW: The primary (probably the only) function of ferritin is to CONTAIN or SEQUESTER iron but not to store it for future use. When excessive iron is ingested, injected, inhaled, or decompartmentalized, additional ferritin is promptly synthesized to capture the toxic metal. As the person becomes increasingly iron loaded, the ferritin molecules that have captured iron are deposited in non-traditional organs such as skin. I am not aware of any reports that ferritin might release its captured iron. During episodes of inflammation, prompt synthesis of additional ferritin occurs in order to clean up the inflamed area of iron to prevent growth of microbial invaders and/or of cancer cells.
PDM: Calorie restriction is the most efficient way to extend lifespan in laboratory animals, and it also leads to far less iron accumulation. Do you think that less iron may be the cause, or part of the cause, of the CR effect on longevity?
EDW: The extension of lifespan by caloric restriction definitely is associated with suppression of excessive ingested iron. (Sadly, commercial pet food contains a serious excess quantity of iron.) [Good to know. Something to be watched if you want your pets to live a long, healthy life.- PDM]
PDM: If an intervention increases the median lifespan of a set of lab animals, it’s usually because the intervention prevents some particular disease. If it increases maximum lifespan, it may be considered to have genuinely retarded aging. The fact that iron is linked to so many diseases, that aging increases the rate of disease, and that iron accumulates with age, suggests that lowering iron may be a true anti-aging measure. Do you think this is true?
EDW: Lowering excess iron is strongly associated with longevity. For example, NHANES III reported that at age 60, the mean ferritin for U.S. men was 150 ng/ml, whereas at age 90, the loss of iron loaded persons resulted in a mean of 80 ng/ml (ref 111 in Metallomics paper). Also see Table 5, ref 110, in Metallomics paper).
[Reference 11 is, Association of age, sex, and race with body iron stores in adults: Analysis of NHANES III data.(PDF) Another very interesting idea I learned from this paper is that racial differences in health could be due to iron; at all ages, black men have higher iron stores than white men. Reference 110 is, Elevated Serum Transferrin Saturation and Mortality, which contains the following figure (not sure if this is the one Dr. Weinberg meant). – PDM]
PDM: Recent research has shown that aspirin lowers the rate of many cancers. (See for example, Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.) Could this be related to bleeding and therefore less iron accumulation?
EDW: Aspirin is a fine iron chelator which explains its help in longevity and lowered inflammation (Ref 83 in Metallomics paper). [The reference is Faecal Blood Loss Associated with Aspirin and Pentoxifylline, Given Alone and in Combination. After two weeks of four daily aspirin (total 1300 mg, compare to low-dose aspirin at 80 mg), the subjects were losing nearly 20 ml of blood a day via intestinal bleeding. See also Aspirin increases lifespan.- PDM]
PDM: Can iron fortification of food be linked to the obesity epidemic?
EDW: Iron has been linked to the obesity epidemic (ref 72 & 73 in Metallomics paper). I do not know the mechanism. [References: Serum Ferritin Is Associated With Visceral Fat Area and Subcutaneous Fat Area; Association between Iron Status and Lipid Peroxidation in Obese and Non-Obese Women. – PDM]
PDM: Is the link between iron and disease graded, or is there a threshold?
EDW: Probably the link between excessive iron and disease is gradual but much more quantitative work is needed on this matter.
PDM: You note in one of your papers that senescent cells accumulate 10 times as much iron as normal cells. A recent study showed that quercetin, which is a strong iron chelator, kills some senescent cells. (See my post on quercetin and how it kills senescent cells.) Might there be an iron connection?
EDW: Quercetin, curcumin and many other natural products are good iron chelators. Numerous studies have reported that the pharmacologic mechanism of their action is iron chelation.
PDM: Do you personally do anything to keep your iron stores at a low level?
EDW: After my wife completed menopause, she began donating blood to Red Cross. She has now given 110 pints (thus discarding over 27 grams of iron) and, at 87, is quite healthy. I take a 200 mg aspirin tablet daily plus 10 mg calcium channel blocker (amlodipine). The latter lowers blood pressure and suppresses iron uptake into cells. (Iron enters cells thru calcium channels.) My ferritin is 43 ng/ml. I could probably further lower my ferritin if I gave up ingesting cereals that are adulterated by highly excessive quantities of iron by the food processors. Note also that FDA requires food processors to add high amounts of iron to flour, corn meal, farina and rice.
[Wow, Dr. Weinberg’s wife has given 110 pints of blood! If she started at age 50, that’s close to three donations a year for the past 37 years. She 87 and healthy, no arguing with that. – PDM]
My thanks to Dr. Eugene Weinberg for taking the time to answer my questions. On a somewhat related note, Dr. Weinberg is a sterling example of why anti-aging is so important. He has a wealth of knowledge and talent, and is 93. The fact that he is well past the age when most men are gone means that his knowledge and talent are still available to society.