Iron is a mineral that’s essential to human health and life. Your body uses iron to generate the protein hemoglobin, which red blood cells use to carry oxygen from the lungs throughout the body, as well as the protein myoglobin, which provides oxygen to muscles. The body requires a careful balance of iron in just the right amounts: In studies, iron has presented as one of the few micronutrients that shows a pronounced U-shaped dose-benefit-response curve within a relatively narrow range of intakes or blood levels. This means that both too much and too little iron is harmful to your health. In this article, we explore ways of walking this tightrope to maximize long-term health through optimal iron intake.
Under normal circumstances, iron is so precious that nature did not come up with an active mechanism for the excretion of this metal. Bleeding and cell shedding are the major ways in which the body loses iron and modulates uptake. While iron is utilized by many enzymes, it is nonetheless dangerous to the body under certain circumstances. Unbound or free iron can catalyze oxidative stress and DNA damage through the so-called Fenton reaction.
As a rule of thumb, men and postmenopausal women want to lower their body iron stores, whereas menstruating women and athletes need to exercise caution. Everyone should get regularly tested to avoid deficiency and excess. The target goal for ferritin should be around 30-80 ug/L. If you suffer from brain fog or fatigue, however, it is worth trying iron supplementation, as this is the most common and debilitating symptom that is responsive to supplementation. In this context, it is worth noting that vitamin C can promote absorption of non-heme iron (Heffernan et al. 2017), and calcium supplements may somewhat impair the absorption of iron when taken at the same time (Abioye et al. 2021).
Less invasive and more pleasant ways of lowering iron are limiting dietary intake of this metal or increasing intake of natural iron chelators. One can, for example, avoid foods rich in bioavailable heme iron, in particular red meat like lamb, pork, beef, or veal, and instead consume a plant-based diet, as these are associated with lower ferritin levels (Haider et al. 2018).
Iron is an essential nutrient, but like all nutrients, it’s possible to have too much of it. If your doctor finds that you have excess iron, the treatment may involve a simple blood donation, an adjustment in your diet, or other measures. On the other hand, supplementation may be indicated in cases where iron is too low. By leveling out iron stores in the body at optimal amounts, you will be better equipped to live healthier for longer — something that all of us strive to achieve.
Iron is a mineral that’s essential to human health and life. Your body uses iron to generate the protein hemoglobin, which red blood cells use to carry oxygen from the lungs throughout the body, as well as the protein myoglobin, which provides oxygen to muscles. The body requires a careful balance of iron in just the right amounts: In studies, iron has presented as one of the few micronutrients that shows a pronounced U-shaped dose-benefit-response curve within a relatively narrow range of intakes or blood levels. This means both too much and too little iron is harmful to your health. In this article, we will explore ways of walking this tightrope to maximize long-term health through optimal iron intakes.
The bad news is that we cannot measure free iron in tissues and inside cells, where it is likely causing damage to biomolecules through the Fenton reaction. The good news is that the blood markers we have are nonetheless quite useful. As long as we can exclude inflammation, ferritin is the best overall marker of iron status. The so-called normal range for ferritin is gender-dependent, since menstruating women have lower “normal” levels. Typical levels are in the range of 11 to 307 ug/L for women and 24 to 336 ug/L for men (Mayo Clinic).
Basic Iron Biology
Under normal circumstances, iron is so precious that nature did not come up with an active mechanism for the excretion of this metal. Bleeding and cell shedding are the major ways in which the body loses iron and modulates uptake.
Most of the iron from our diet is absorbed in the upper part of the small intestine. Heme iron is absorbed more efficiently because intestinal cells have dedicated transporters for this type of iron.
Generally speaking, once absorbed by intestinal cells, iron first enters the lysosome from where it is released into the cell interior. This intracellular iron is then quickly bound by the iron storage protein ferritin or incorporated into various enzymes and proteins. Major iron-containing proteins include hemoglobin and myoglobin, where iron helps to bind and carry oxygen, cytochromes involved in mitochondrial respiration and drug metabolism, as well as many others.
Most of the absorbed iron then passes through the intestinal cells, which export it via a channel-forming protein called ferroportin and package it into the transport protein transferrin. Cells and tissues that require iron use transferrin receptors to take up the required amount of this metal. Although all cells need iron, the major iron-utilizing tissues are the bone marrow, which produce red blood cells; the liver, which senses and stores iron; muscle; and, presumably, cancer cells.
When body iron stores are high, the liver produces a small peptide hormone called hepcidin that reduces iron export by intestinal cells. Thus, absorbed iron becomes trapped in these cells and is eventually lost when the cells are shed.
While iron is utilized by many enzymes, it is nonetheless dangerous to the body under certain circumstances. Unbound or free iron can catalyze oxidative stress and DNA damage through the so-called Fenton reaction.
Iron and Aging
Iron metabolism evolved many thousands of years ago during a time when access to meat was irregular and blood losses due to vigorous activity and accidents were common. Hence human iron metabolism is optimized for the efficient storage of iron, improving reproductive performance of young individuals at the cost of optimal long-term health (this is a form of “antagonistic pleiotropy”). Given this, it should come as no surprise that iron can accelerate aging.
It has long been speculated that lower tissue iron stores contribute to the longer lifespans (and fewer cardiovascular events) seen in women (through menstruation), vegetarians, vegans, and blood donors. While plausible, it is impossible to make a fair comparison because blood donors are healthier than non-donors, women are different from men, and vegetarian diets are not just low in bioavailable iron, but also high in phytonutrients. Therefore, in this article, we will focus on stronger and more direct evidence from human and animal studies.
Iron accumulation is a conserved marker of tissue aging between different species. Iron is increased in senescent cells (Masaldan et al. 2018) and fibrotic tissues (Maus et al. 2022). It accumulates in the liver, heart, kidney, and fat depots of mice (Alves 2021). It also accumulates in human substantia nigra, where it is linked to Parkinson’s disease, as well as muscle, where it may promote sarcopenia (Picca et al. 2019), an age-related loss of skeletal muscle mass and strength. Long-lived mice, such as those subjected to caloric-restriction, have attenuated iron accumulation in the liver, kidney, and brain during aging (Cook and Yu 1998).
Experimental reduction of iron is beneficial. Iron lowering is usually achieved with drugs or nutraceuticals that are able to bind iron, reduce absorption and block ROS formation via the Fenton reaction. This is called iron chelation, and such chelators extend the lifespan of nematode worms (Klang et al. 2014) and reduce cardiac cell death in aging rats (Arvapalli et al. 2010). The lifespan extension effects of tea polyphenols (e.g., epigallocatechin gallate, EGCG) in flies are also partly attributed to iron chelation, as are the effects of curcumin and of several other substances (Mangan et al. 2021, Massie 1985).
Iron is central in many age-related pathways. Iron promotes protein aggregation (Klang et al. 2014), DNA damage (Melidou et al. 2005), the formation of the aging pigment lipofuscin (Brunk and Terman 2002), cell death through apoptosis and an iron- specific type of cell death called ferroptosis (Zheng et al. 2021, ref2). In contrast, iron chelation decreases mTOR signaling, at least in cancer cells (Shang 2020);, stimulates mitophagy (Hara et al. 2020); and limits inflammation (Di Paola et al. 2022). High levels of iron, as measured by plasma ferritin, are associated with shorter telomere length (Liu et al. 2019), and the pro-longevity transcription factor Nrf2 increases the expression of iron-binding proteins called ferritins (Galaris et al. 2019).
Several studies using a novel genetic method called Mendelian randomization support the notion that high iron levels are also harmful in humans. In this new approach, researchers measure the genetically predicted iron levels and correlate this with health outcomes. In 2020, one such study found that higher genetically predicted serum iron was associated with shorter lifespans in the UK Biobank cohort (Timmers et al. 2020). Soon afterwards, this finding was confirmed and extended in a different cohort, showing that both high serum iron and transferrin saturation are associated with increased all-cause mortality (Moksnes et al. 2022). Finally, this was followed by a meta-analysis of over 1 million participants that added ferritin to the trifecta of risk factors (Daghlasa and Gill 2021). With this study, all three clinically relevant markers of iron metabolism — ferritin, transferrin saturation, and iron levels — have now been associated with genetically predicted mortality or longevity.
Heme is a particularly toxic form of iron. Intakes of dietary heme, often found in red and processed meats, are clearly associated with diabetes (Shahinfar et al. 2022), cardiovascular disease mortality (Han, Guan et al. 2020), and multiple cancers (Fonseca-Nunes et al. 2014) in observational studies. By themselves, observational studies are considered moderate to weak evidence. However, in this case we have support from multiple other study designs. Again, using Mendelian randomization, it was shown that haptoglobin, which binds free hemoglobin to prevent the release of toxic heme, is associated with longevity (Perrot et al. 2021). This seems to be a conserved anti-aging mechanism because longer-lived mammals have consistently higher haptoglobin and hemopexin mRNA levels in the liver compared with shorter-lived ones (Fushan et al. 2015).
Measuring Iron Status and Iron Deficiency
The bad news is that we cannot measure free iron in tissues and inside cells, where it is likely causing damage to biomolecules through the Fenton reaction. The good news is that the blood markers we have are nonetheless quite useful.
As long as we can exclude inflammation, ferritin is the best overall marker of iron status. The so-called normal range for ferritin is gender-dependent, since menstruating women have lower “normal” levels. Typical levels are in the range of 11 to 307 ug/L for women and 24 to 336 ug/L for men (Mayo Clinic). Keep in mind that ferritin is measured in units of either ng/mL or ug/L, which are equivalent. Both normal and optimal are hard to define. In the Copenhagen City Heart Study, any elevated ferritin level showed a linear relationship with mortality (Ellervik et al. 2014). Similarly, in a recent meta-analysis, any ferritin level was associated with metabolic syndrome (Zhang et al. 2021).
Although less sensitive to changes in iron metabolism, it is also worth paying attention to total iron levels in blood (normal range: 10 to 30 umol/L), transferrin saturation (normal range: 20% to 50%), and hemoglobin levels (normal range: 11.6 to 15 g/dL for women and 13.2 to 16.6 for men). These will usually only decrease with severe deficiency or anemia (Mt. Sinai).
Ultimately, fatigue is the most common symptom of non-anaemic iron deficiency. In the general population, ferritin levels >30 ug/L and absence of symptoms can be used to rule out deficiency (Balendran and Forsyth 2021). However, in the presence of symptoms, especially in older people or women, ferritin levels as high as 100 ug/L can be associated with deficiency, albeit rarely (Sopp 2018).
The Most Successful Cancer-Prevention Trial You Never Heard Of
The iron (Fe) and atherosclerosis (FeAST) study was originally designed to test whether iron lowering through phlebotomy, also known as bloodletting, would prevent cardiovascular disease. It did not — except perhaps in the youngest participants (Zacharski et al. 2007). What the authors found, however, was even more amazing and unexpected than what they had hoped for.
Around 1,300 older men (67 years of age) with iron parameters in the normal range were randomized to receive bloodletting treatment or no intervention. Their ferritin levels declined from around 120 to 80 ng/mL, followed by a 37% lower risk of developing a new cancer, and survival in those who did develop cancer was around twice what it was in the control group (Zacharski et al. 2008). In further analyses, the authors found that higher compliance with bloodletting and lower ferritin levels were associated with larger benefits, consistent with an optimal ferritin range as low as 12–50 ng/mL (note that we do not recommend this range; continue reading).
Although the FeAST trial is large and well-designed, there remain many open questions and issues that have limited its impact. The study specifically tested iron lowering in older men, so we do not know if this treatment would work in women or younger men. The study was primarily designed to test the effects on cardiovascular disease. It was impossible to blind the participants to the treatment they received, and the benefits of iron reduction emerged within six months, which is unusually quick. Counterintuitively, ferritin levels at baseline were also not associated with cancer. Nevertheless, this is one of the most important and promising cancer-prevention trials ever published.
How to Lower Body Iron Stores Safely? And How Much?
In the clinic, doctors often prescribe the iron chelator deferoxamine, deferiprone, or deferasirox to reduce iron uptake in patients with extreme iron overload, e.g., due to hemochromatosis. Although deferiprone is being studied as a treatment for age-related Parkinson’s disease, in the FairPark II study, it is a dangerous and potentially mutagenic drug.
Another option to lower blood iron levels is phlebotomy, as was done in the FeAST trial, but this therapy is still experimental. An alternative to phlebotomy is blood donation, which has the altruistic side-effect of saving lives. Recent studies suggest that simply diluting the blood of aged mice reduces neuroinflammation and senescence in the brain, leading to better cognition (Mehdipour et al. 2021). Thus plasma donation might reap some of the same anti-aging benefits without jeopardizing iron stores.
This is relevant because we do not know the lowest safe level for ferritin. The FeAST study showed no obvious side effects of iron lowering, but it is not clear if they monitored for subtle effects like fatigue. As a rule of thumb, men and postmenopausal women want to lower their body iron stores, whereas menstruating women and athletes need to exercise caution. Everyone should get regularly tested to avoid deficiency and excess! The target goal for ferritin should be around 30-80 ug/L.
Although potentially unpleasant, mild iron deficiency does not seem to be associated with large reductions in physical performance (Houstan et al. 2018, Burden et al. 2015) or considerably worse health outcomes in the general population (Mayo Clinic). If you suffer from brain fog or fatigue, however, it is worth trying iron supplementation, as this is the most common and debilitating symptom that is responsive to supplementation. In this context, it is worth noting that vitamin C can promote absorption of non-heme iron (Heffernan et al. 2017), and calcium supplements may somewhat impair the absorption of iron when taken at the same time (Abioye et al. 2021).
Less invasive and more pleasant ways of lowering iron are limiting dietary intake of this metal or increasing intake of natural iron chelators. One can, for example, avoid foods rich in bioavailable heme iron, in particular red meat like lamb, pork, beef, or veal, and instead consume a plant-based diet, as these are associated with lower ferritin levels (Haider et al. 2018).
Indeed, most natural iron chelators are found in plants and belong to the flavonoids (Wang et al. 2021, Orisakwe et al. 2020). This includes curcumin found in turmeric (Thephinlap et al. 2009); epigallocatechin gallate (EGCG; Koonyosying et al. 2019), a major polyphenol found in green tea; and silybin found in milk thistle (Reisi et al. 2022). While these natural iron chelators may not be as potent as clinically used chelators, they are safer and may be sufficient to limit iron absorption in healthy people.
Less widely known flavonoid chelators include baicalin, apigenin, luteolin, quercetin, and myricetin (Wang et al. 2021). Several of these can improve healthspan or lifespan of nematode worms, a common preclinical model of aging (Mangan et al. 2021).
The most significant non-flavonoid chelators are perhaps phytic acid (e.g., IP6; Petry et al. 2010) found in legumes, grains, nuts, and tannic acids (Jaramillo et al. 2015) found in tea and chocolate, among other foods.
Even though polyphenols seem to reduce serum iron, they do not affect hemoglobin concentrations negatively, probably through a stimulatory effect on iron utilization for erythropoiesis (Xu, Zhang, Liu 2021).
Conclusion
Iron is an essential nutrient, but like all nutrients, it’s possible to have too much of it. If your doctor finds that you have excess iron, the treatment may involve a simple blood donation, an adjustment in your diet, or other measures. On the other hand, supplementation may be indicated in cases where iron is too low. By leveling out iron stores in the body at optimal amounts, you will be better equipped to live Younger For Longer™ — something that all of us strive to achieve.
References
Iron and Aging
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Iron accumulation drives fibrosis, senescence, and the senescence-associated secretory phenotype
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bioRxiv 2022.07.29.501953
Measuring Iron Status and Iron Deficiency
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The Most Successful Cancer Prevention Trial You Never Heard Of
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How to Lower Body Iron Stores
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The Regulation of Dietary Iron Bioavailability by Vitamin C: A Systematic Review and Meta-Analysis
Proceedings of the Nutrition Society , Volume 76 , Issue OCE4: Summer Meeting, 10–12 July 2017, Improving Nutrition in Metropolitan Areas , 2017 , E182
DOI: https://doi.org/10.1017/S0029665117003445
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Reviews
Alves, Francesca M., et al. “Age-related changes in skeletal muscle iron homeostasis.” The Journals of Gerontology: Series A (2022).
Chen, William J., George P. Kung, and Jaya P. Gnana-Prakasam. “Role of Iron in Aging Related Diseases.” Antioxidants 11.5 (2022): 865.
Guo, Qianqian, et al. “The Role of Iron in Cancer Progression.” Frontiers in Oncology 11 (2021).
Zeidan, Rola S., et al. “Iron homeostasis and organismal aging.” Ageing Research Reviews 72 (2021): 101510.
Mangan, Dennis. “Iron: An underrated factor in aging.” Aging (Albany NY) 13.19 (2021): 23407.
