Iron is a necessary nutrient, and low levels in the diet, faulty absorption, or excessive bleeding can cause low levels of iron, leading to anemia, cognitive deficits, and immune dysfunction. The blood is the major storage organ of iron, containing about 70% of all body stores of it.
On the other hand, excess amounts also cause health problems, as can be seen with the primary example of iron overload, hemochromatosis, a genetic condition that causes the body to absorb too much iron from the diet. Hemochromatosis can lead to cancer, liver failure, and heart disease, and left untreated definitely kills people. The treatment for hemochromatosis is phlebotomy, that is, bloodletting. Getting iron levels down to normal in hemochromatosis allows essentially for the disease to be cured.
Iron in the natural world reacts with oxygen and rusts. Inside the body, it essentially does the same thing, causing high levels of oxidative stress.
The difference in iron levels between men and women has consequences
Men of course die younger than women, and higher rates of heart disease in men is one of the main reasons for this. Men also have higher iron stores than women, a consequence of the fact that premenopausal women lose small amounts of blood every month through menstruation. Since blood is the major iron storage organ, losing blood means losing iron. Post-menopausal women catch up with men in terms of iron stores, and in later life women also catch up in terms of rates of heart disease.
The body tightly regulates the amount of iron that is absorbed from the gut, but other than blood loss, as well as small amounts of iron being lost through sweating, the body has no way to rid itself of excess iron. The reasons for that seem clear enough: in the bad old days, blood loss due to wounds and injuries as well as intestinal parasites was a common occurrence, and dietary sources of iron, mainly meat, were not always plentiful. Therefore there was no need for the body to have a mechanism to rid itself of excess iron. In fact, hemochromatosis is probably around because having only one gene for it gave its carrier an advantage in being able to absorb more iron from food.
Way back in 1981, Jerome Sullivan proposed that the difference in heart disease rates between men and women was due to higher levels of iron in men, which accumulate with age. (Lancet.) Sullivan proposed testing this through therapeutic phlebotomy. Since his hypothesis, much work has confirmed that he was on to something big.
Calorie restriction and aging: Is less protein the cause, or less iron?
As we’ve repeated quite a bit on this blog, calorie restriction is the most robust treatment known for extending the lifespan of experimental animals. It is usually said that restriction of protein is the reason for extended lifespan, since if calories are restricted but protein is not, the lifespan extension is abrogated or does not occur at all.
But meat, the major dietary source of protein, also contains large amounts of iron. Could less iron accumulation be the real reason, or at least part of the reason, why calorie restriction extends lifespan? As it turns out, there’s good evidence that it is.
Consider that inhibition of iron absorption – interestingly, by putting tea in their food – increased the lifespan of Drosophila by >20%. (Mechanisms of Ageing and Development.) The authors of that study say, “It is concluded that iron accumulation is a significant factor contributing to senescence.”
In rats, calorie restriction led to much lower levels of iron with age, and as a result, levels of lipid peroxidation, a measure of oxidative stress, were markedly suppressed. (Mechanisms of Ageing and Development.)
In a paper just out this month, it’s reported that “iron starvation” induces mitophagy and extends the lifespan of C. elegans. (Current Biology.)
Although there a number of other similar animal studies, we’ll add just one more: calorie restriction downregulates iron absorption and leads to less iron accumulation. (Rejuvenation Research.) From this study:
The results suggest that the anti-aging effects of CR might partially lie in its capacity to reduce or avoid age-related iron accumulation in the brain through down-regulating expression of brain hepcidin—the key negative regulator for intracellular iron efflux—and that facilitating the balance of brain iron metabolism may be a promising anti-aging measure.
From all this we see that it is entirely possible that one of the reasons, perhaps even the major reason, that calorie restriction extends lifespan is because it causes less iron to be accumulated with age.
What is the evidence in humans?
In humans, aging leads to decreases in insulin sensitivity and higher levels of fasting blood glucose. These are also characteristic of diabetes. Is there any evidence here that iron accumulation plays a part in these, in both aging and diabetes? Yes.
Medical scientist Francesco Facchini has done much work in this area. He found that in patients with insulin resistance – what he calls “carbohydrate intolerance” – therapeutic phlebotomy such that the patients got to “near iron deficiency” caused an approximately 50% improvement in insulin sensitivity. (Gastroenterology.)
He also found that iron depletion via phlebotomy led to an improvement in cardiovascular risk factors. (Annals of the N.Y. Academy of Sciences.)
Facchini studied lacto-ovo vegetarians – who eat eggs and dairy but not meat – along with a comparison group of meat-eaters, and found that the vegetarians had both lower iron stores and much better insulin sensitivity. To discover whether iron and insulin sensitivity were related, he took six of the meat-eaters, and through phlebotomy dropped their iron stores to the level of the vegetarians; the meat-eaters’ insulin sensitivity increased by 40%. (British Journal of Nutrition.)
Blood donors have lower disease risk, much lower
A different group of researchers looked at a group of blood donors, and carefully matched them with a group of non-donors by age, BMI, waist-to-hip ratio, blood lipids, smoking status, and blood pressure. They found that the donors had increased insulin sensitivity and lower insulin secretion. (Clinical Chemistry.)
Since insulin resistance increases with age, as do iron stores, it can be seen that less iron means less aging.
Another study looked at blood donors compared to non-donors. This was a prospective study; anyone who had donated blood in the 24 months preceding the start of the study was deemed a donor, then they were all followed for an average of 9 years. When adjusted for age, examination years, and all the coronary risk factors they could think of, the donors had an 88% decreased risk of heart attack. (American Journal of Epidemiology.) Awesome, I think.
Of course there are confounding factors to be considered. Blood donors are healthier than non-donors to begin with. That’s why the statistics were adjusted for coronary risk factors. One factor they didn’t adjust for is years of education, a proxy for IQ. Blood donors tend to be not only healthier, but better educated and more civic-minded, so this could skew the results. Nevertheless, there are good physiological reasons for believing that lower iron stores make for better health, so I have no trouble believing that blood donation causes better health.
A randomized controlled study looked at the effect of reducing iron stores via phlebotomy on cancer rates. (Journal of the National Cancer Institute.)It found that those randomized to phlebotomy had a 35% lower cancer rate, a 60% lower rate of cancer mortality, and and a 50% lower rate of all-cause mortality. Proof doesn’t get much better than that.
Iron and cholesterol
When I discussed this issue over on Twitter, one respondent wrote that we should try to be objective here and not make iron into a villain, since we did that with cholesterol, and that ended badly. Not only was cholesterol not a villain, but the prescribed method of avoiding it, low-fat eating, had a major role in the obesity epidemic.
It’s perfectly true that iron is a required nutrient, and in many parts of the world, iron-deficiency anemia is a serious problem. But it tends not to be in the affluent Western world, where dietary sources of iron are readily available, and bleeding from wounds and intestinal parasites is uncommon.
Cholesterol and iron are similar in that the body requires both; but the body makes cholesterol itself, iron no. The body also closely regulates cholesterol levels; if enough is taken via food, then internal production decreases, and vice versa. With iron, the only method the body has to control it is to increase or decrease absorption; there is no way to get rid of it, while cholesterol can be metabolized. It seems clear enough that there’s no physiological advantage to having a high ferritin level; the minimum is good enough.
A further line of evidence: polyphenols
Polyphenols from tea, coffee, chocolate, wine, and berries are known life extenders, and it’s usually thought that most of their benefit comes from activating the cellular energy sensor AMPK, making them essentially calorie-restriction mimetics. It turns out that many of these also bind to iron, rendering it inactive and available for excretion. (Cell Chemistry and Biophysics.) This could be a major component of their health-giving properties. Quercetin, for example, has potent iron-binding capacity. (PLOS One.)
Aspirin is also known to extend lifespan, by lowering cancer rates among other things. It is also known to activate AMPK. It also causes intestinal blood loss, an average of about 5 ml daily. (JAMA.) So iron loss could be one way that aspirin’s health benefits work.
Coffee and tea are also known to have many health benefits, and they both reduce iron absorption from the gut, coffee by ~40%, and tea by 64%, which are large decreases, I think it fair to say. (AJCN.) So again, the health benefits of coffee and tea could be due in part, perhaps major part, to inhibition of iron accumulation.
What to do about excess iron
From Facchini’s studies, we know that any amount of iron over the minimum can be deleterious and promote aging. The test used to determine iron stores is ferritin, the normal range of which for a man is 12 to 300 ng/ml. Facchini phlebotomized his patients down to a level of about 30 – lower than that there may be problems, such as anemia. But even at a level of 70, insulin sensitivity was substantially decreased. So it seems that for anti-aging purposes, we may want a level above 30, but not much.
The major solution to excess iron is bloodletting, which is easily accomplished through blood donation. Donation of 500 cc of blood, which is about the size of a typical blood donation (450 cc in the U.S.) leads to the loss of from 200 to 250 mg of iron. Amazingly, one month after a single 500 cc phlebotomy in healthy blood donors, ferritin levels went from 75 to 38, and in a 2-hour glucose tolerance test, plasma insulin was reduced by 37%, and plasma glucose by 19%.
It appears that not much in the way of blood donation is necessary to obtain real benefit.
If you have a high ferritin level, then more donations may be required. Ferritin testing requires a doctor’s order, but is relatively inexpensive and performed by almost all labs.
Beyond blood donation, inhibition of iron absorption can slow iron accumulation. This can be accomplished by drinking coffee or tea with or within one hour after a meal. The supplement inositol hexaphosphate strongly chelates iron, and can be used to lower iron stores.
It also goes without saying that iron supplements of any kind should not be taken except under a doctor’s supervision and advice.