Iron Overload, Perturbed Redox Balance, and Meddling Serotonin

 
 
"Blood donors on average have superior health, but it's important to have good nutrition, because other nutrients are lost too."

—Ray Peat, PhD

Iron is a very basic anti-respiratory factor, inhibiting the last crucial step of oxidative mitochondrial metabolism, cytochrome c oxidase.[1] Iron tends to accumulate with age in both sexes,[2] but to a lesser degree in women due to the menstrual cycle. However, this "iron advantage"—which may help explain the increased longevity of females—is lost at menopause. 

A major landmark in aging for a female (similar to baldness in males), menopause is associated with the rapid accumulation of iron.[3] While it has become ingrained in the medical zeitgeist that menopause is the result of an "estrogen deficiency," estrogen appears to increase with age[4]. Because the topic is semi-confusing, it's worth noting that blood levels of estrogen don't necessarily reflect tissue levels of estrogen.[5,6]

Moreover, the amount of prolactin—a hormone increased by estrogen[7]—tends to become excessive around menopause.[8] Both estrogen and prolactin suppress thyroid function,[9,10] and inhibit mitochondrial respiration—transitioning cells to an alternative "stress" metabolism.[11,12] 

Iron Overload & REDOX BALANCE

A fundamental problem with iron overload is the perturbed red(uction)ox(idation) balance that it creates and reinforces.

For example, cells get their energy from electrons derived from molecules such as sugar, fat, and protein. "Flowing" through the cell from protein to protein, electrons are eventually vacuumed into the loving arms of oxygen—the ultimate electron acceptor.

In a larger context, a body producing "efficient" respiratory energy (i.e., glucose to carbon dioxide) is in a highly oxidized "charged" state with few free electrons.[13]

  • Oxidation - The loss of electrons.
  • Reduction - The gain of electrons.

When the ability to use oxygen has been interfered with, for example when the thyroid is suppressed and carbon dioxide is deficient, the flow of electrons "backs up" and leaks out of the mitochondria. These free highly reactive electrons tend to cause many unfavorable oxidative processes in the body (i.e. oxidative stress).

Moreover, a deficiency of oxygen requires the cell to find an alternative electron sink, as the increased reliance on glycolytic (or fermentation) metabolism forms far more electron carrying reduced NADH than oxidized NAD+.

The synthesis of fatty acids can serve as an alternative electron sink,[14] however, this poses many challenges for the metabolism, including the release of free iron,[15] which can greatly interfere with the functioning of the liver.[16,17] 

The over-reliance on this "inefficient" janky fatty acid metabolism has been spun as a desirable trait by some health authorities, although, considering reductive excess is involved in just about every health problem (i.e., mitochondrial dysfunction), the idea seems highly dubious. 

Excess Iron & Meddling Serotonin

Constantly modifying the cellular redox balance is the adaptive "stress" substances cortisol, estrogen, prolactin, and serotonin. By inhibiting oxidative metabolism, iron increases the reliance on these substances overtime, and due to a variety of factors in the environment, their functions tend to be less "adaptive" and more "destructive." 

The process for synthesizing new fat as an alternative electron sink also provides the required cofactors for the conversion of tryptophan into serotonin by the enzyme, tryptophan hydroxylase.[18] 

You might ask why "reductive stress" would lead to the creation of more serotonin. Well, I don't know either, but it might because serotonin powerfully suppresses the metabolism, allowing the organism to go further on less.[19,20] 

Excess serotonin is involved in many problems, including irritable bowel syndrome (IBS), Crohn's disease, and coeliac disease.[21] Similarly, iron overload (and hemochromatosis) tends to result in digestive impairment. The anti-serotonin drug, ondansetron, "relieves some of the most intrusive symptoms of IBS".[22] Similarly, regular phlebotomy can reduce many symptoms associated with iron excess.[23]

Carbon dioxide is probably the basic factor regulating serotonin by keeping it in the blood platelets and mast cells. And carbon dioxide is produced under the direction of good thyroid function—the single factor directing the harmonious renewal of the entire organism. Serotonin—by working in the opposite direction of thyroid hormone—slows the the metabolism (e.g., the temperature and resting pulse), similar to hibernation in other animals.[24,25] 

A decreased rate of metabolism, combined with an excess of iron, seems particularly dangerous. If the diet has contained a disproportionate amount of polyunsaturated fats to saturated fats, the increased liberation of fatty acids into the blood by the lipolytic "stress" substances would further increase the synthesis of estrogen and serotonin. For example, a derivative product of the unsaturated fats, prostaglandin E2, increases the activity of the aromatase enzyme, which converts testosterone into estrogen, and unsaturated free fatty acids tend to displace tryptophan off albumin, it's carrier protein, for synthesis into serotonin. Moreover, free fatty acids, the prostaglandins, and iron increase the rate of lipid peroxidation, contributing to the further decline of the mitochondria, depleting vitamin E, and in general, disturbing the balance between "quick growth" and "efficient renewal."

In all, it's fairly simple to see how this is a self-sustaining vicious cycle in the presence of low thyroid function, an excess of unsaturated fats, and iron, which has been detailed by Dr. Raymond Peat over the past several decades. 

Should you, the reader, THUMP YOUR VEIN IN ANTICIPATION OF BLOOD DONATION?

I don't know.

I've been giving blood a few times a year for the last couple of years because, well, I ate an all-meat diet for two fucking years

A few anecdotal observations I've noticed from intermittent blood donation is the complete elimination of the infamous "stuffy nose," some brands of milk that would have bothered me previously are no longer an issue, and the presence of corkscrew hairs on the trunks of my legs (something I first experienced when going zero-carb) are gone (iron excess destroys vitamin C).[26]

For what's it's worth, I asked Dr. Peat about good tests to evaluate the iron burden in 2012 and he replied:

I think the copper/iron ratio is under hormonal-developmental control, and I have never seen an attempt to use ceruloplasmin to guide nutrition. Regular good light exposure is probably important for preventing the displacement of copper by iron. —Raymond Peat, PhD

Although, Dr. Peat did mention more recently that an iron saturation level below 25% was protective against cancer, which appears to jive with the limited amount of data I've seen on the subject.

References

  1. Britton, R.S. Metal-induced hepatotoxicity. Semin Liver Dis. 1996 Feb;16(1):3-12. “Both iron and copper overload impair hepatic mitochondrial respiration, primarily through a decrease in cytochrome c oxidase activity.”
  2. Lauffer, L.B. Iron and Human Disease. (Book) 1992
  3. Gang, L. et al. Age-associated iron accumulation in bone: Implications for postmenopausal osteoporosis and a new target for prevention and treatment by chelation. BioMetals (2006) 19:245–251. “Based on these observations, we hypothesized that the age-associated accumulation of iron in skeletal tissues of postmenopausal women may have an important role in the pathogenesis of osteoporosis.” “Our findings add further support to the some- what controversial theory that age-associated iron accumulations in tissues increases the risks of diseases such as atherosclerosis, cancer, diabetes and dementia.” “Because aging is often accompanied by cancer, atherosclerosis, dementia and osteoporosis, our findings with others suggest that age-associated iron accumulation may, in return, be one of con- tributing factors for aging. Moreover, our findings may lead to new therapeutic approaches to address a number of aging diseases that are or may be associated with iron accumulation and iron associated oxidative damage.”  
  4. Santoro, N. et al. Characterization of reproductive hormonal dynamics in the perimenopause. J Clin Endocrinol Metab. 1996 Apr;81(4):1495-501. “We conclude that altered ovarian function in the perimenopause can be observed as early as age 43 yr and include hyperestrogenism, hypergonadotropism, and decreased luteal phase progesterone excretion. These hormonal alterations may well be responsible for the increased gynecological morbidity that characterizes this period of life.”
  5. Batra, S. et al. Interrelations between plasma and tissue concentrations of 17 beta-oestradiol and progesterone during human pregnancy. Clin Endocrinol (Oxf). 1979 Dec;11(6):603-10. “The general conclusion to be drawn from the present study is the lack of correspondence between the plasma concentrations and the tissue concentrations of female sex steroids during pregnancy.”
  6. Vermeulen-Meiners, C. et al. The endogenous concentration of estradiol and estrone in normal human postmenopausal endometrium. J Steroid Biochem. 1984 Nov;21(5):607-12. “The results from the tissue levels of both steroids showed large variations and there was no significant correlation with their plasma levels. The mean E2 concentration in tissue was 420 pg/g, 50 times higher than in plasma and the E1 concentration of 270 pg/g was 9 times higher. The E2/E1 ratio in tissue of 1.6, was higher than the corresponding E2/E1 ratio in plasma, being 0.3.”
  7. Constance R. Martin. Endocrine Physiology. 1985 “Estrogens augment prolactin secretion in several ways.” “Estrogens also promote prolactin secretion, and that hormone exerts some growth-hormone like actions." “The adrenal glands of female rats are larger than those of males. This may result in part from estrogen stimulation of both prolactin and ACTH secretion.“ “Estrogen levels undergo substantial changes during the course of ovarian cycles. The steroids are potent stimulants for prolactin release, and corresponding changes in plasma prolactin have been described. “
  8. Metka, M. The role of prolactin in the menopause. Maturitas. 1994 Dec;20(2-3):151-4. “Consequently, we divided the patients into four groups: group one formed by women with normal hPRL levels (O-20 ng/ml), group two with hPRL-values from 20-40 @ml, group three consisted of women with hyperprolactinemia with levels from 40 ng/ml, and group four consisted of women with hPRL levels of more than 100 ng/ml.” “The serum prolactin levels of the screening in 2322 women resulted in a hyperprolactinemea with values in excess of 40 rig/ml in 139 patients, of which 23 women had hPRL levels of more than 100 ng/ml. These patients were further examined with a computer tomography scanner at a neurosurgical department. A total of 993 women displayed levels between 20 and 40 ng/ml whilst the majority of patients (n = 1167) were within the standard range.” [“Normal levels” of prolactin in this study are high levels of prolactin.]
  9. Vandorpe, G. and Kuhn, E.R. Estradiol-17P Silastic Implants in Female Rana ridibunda Depress Thyroid Hormone Concentrations in Plasma and the in Vitro 5’-Monodeiodination Activity of Kidney Homogenates. General and Comparitive Endocrinology 76, 341-345 (1989). "After E, treatment, there is a twofold decrease in plasma T4, and the 5’-D activity is two times lower. These two factors could contribute to the fivefold decrease of the plasma T3, concentration."
  10. Strizhkov, V.V. [Metabolism of thyroid gland cells as affected by prolactin and emotional-physical stress]. Probl Endokrinol (Mosk). 1991 Sep-Oct;37(5):54-8. "A conclusion has been made that one of the most important mechanisms of the adaptive effect of PRL is its ability to suppress thyroid function, thus decreasing the metabolism level, which results in reduction of oxygen consumption and improves body tolerance to stress."
  11. Spätling, L. et al. Influence of prolactin on metabolism and energy production in perfused corpus luteum bearing bovine ovaries. Arch Gynecol. 1982;231(4):263-7. "Under the influence of PRL anaerobic glucose metabolism was stimulated by 40.5% and oxidative phosphorylation was inhibited. Energy production from aerobic glucose metabolism rose by only 0.25%. Unlike PRL, Human Menopausal Gonadotropin (hMG) and Human Chorionic Gonadotropin (hCG) stimulated aerobic metabolism. This may indicate that PRL is the "older" hormone in phylleogenetic terms."
  12. Gross. Reproductive cycle biochemistry. Fertility & Sterility 12(3), 245-260, 1961. "The maintenance of an environment conducive to anaerobic metabolism--which may involve the maintenance of an adequate supply of the substances that permit anaerobiosis...seems to depend primarily upon the action of estrogen.” "Glycolytic metabolism gradually increases throughout the proliferative phases of the cycle, reaching a maximum coincident with the ovulation phase, when estrogen is at a peak. Following this, glycolysis decreases, the respiratory mechanisms being more active during the secretory phase. Eschbach and Negelein showed the metabolism of the infantile mouse uterus to be less anaerobic than that of the adult. If estrogen is administered, however, there is a 98 per cent increase in glycolytic mechanisms.” "The effect of the progestational steroids may be such as to interfere with the biochemical pattern required for support of this anaerobic environment.”
  13. Albert Szent-Györgyi. The Living State: With Observations on Cancer. (1972)
  14. Patra, K.C. et al. The pentose phosphate pathway and cancer. Trends Biochem Sci. 2014 Aug;39(8):347-54. doi: 10.1016/j.tibs.2014.06.005. Epub 2014 Jul 15. “…but also provides NADPH, which is required for both the synthesis of fatty acids and cell survival under stress conditions”
  15. Ling, W. NAD+/NADH and NADP+/NADPH in cellular functions and cell death: regulation and biological consequences. Antioxid Redox Signal. 2008 Feb;10(2):179-206. “Future investigation into the metabolism and biological functions of NAD and NADP may expose fundamental properties of life, and suggest new strategies for treating diseases and slowing the aging process.” “Seemingly paradoxically, excessive intracellular NADH can produce ‘reductive stress’, which may result from its capacity to induce release of ferrous iron from ferritin resulting in increased oxidative damage.”
  16. Bonkovsky, H.L. et al. Iron-induced liver injury. Clin Liver Dis. 2000 May;4(2):409-29, vi-vii. “The liver is a principal target for iron toxicity because it is chiefly responsible for taking up and storing excessive amounts of iron.”
  17. Asare, G.A., et al. Hepatocellular carcinoma caused by iron overload: a possible mechanism of direct hepatocarcinogenicity. Toxicology. 2006 Feb 15;219(1-3):41-52. Epub 2005 Dec 6. “Our findings are compatible with the hypothesis that the direct hepatocarcinogenic effect of free iron is mediated by the generation of oxygen reactive species and oxidative damage that are mutagenic and carcinogenic.”
  18. Constance R. Martin. Endocrine Physiology. 1985. “Tryptophan is rapidly converted to 5-Hydroxytryptophan (5-HTP). This step, which can be rate limiting for the production of serotonin, is catalyzed by the tryptophan hydroxylase that is present in the mitochondria of the pinealocytes. Pteridine, ferrous iron, and NADPH are required cofactors.”
  19. Scwhark, W.S. and Keesey, R.R. Thyroid hormone control of serotonin in developing rat brain. Res Commun Chem Pathol Pharmacol. 1975 Jan;10(1):37-50. "Experimental cretinism, induced by daily propylthiouracil treatment starting at birth, caused increased serotonin levels in all brain regions studied.” "The data suggest that thyroid hormone may exert an important regulatory influence on serotonin metabolism in the developing brain."
  20. Henley WN, Koehnle TJ. Thyroid hormones and the treatment of depression: an examination of basic hormonal actions in the mature mammalian brain. Synapse 1997 Sep;27(1):36-44."In spite of a large clinical literature, little is known about the mechanism by which thyroid hormones elevate mood. The lack of mechanistic insight reflects, in large part, a longstanding bias that the mature mammalian central nervous system is not an important target site for thyroid hormones." "This paper offers the hypothesis that the thyroid hormones influence affective state via postreceptor mechanisms that facilitate signal transduction pathways in the adult mammalian brain. This influence is generalizable to widely recognized targets of antidepressant therapies such as noradrenergic and serotonergic neurotransmission.”
  21. Spiller, R. Serotonin, inflammation, and IBS: fitting the jigsaw together? J Pediatr Gastroenterol Nutr. 2007 Dec;45 Suppl 2:S115-9. "Clinical conditions with an inflammatory basis, such as coeliac and Crohn disease, also are characterised by excess postprandial serotonin release. Several studies report evidence of low-grade inflammation in IBS with diarrhoea. However, reliable markers of low-grade inflammation that may predict response to serotonin antagonists or other anti-inflammatory agents remain a goal for future research."
  22. Garsed, K. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014 Oct;63(10):1617-25. doi: 10.1136/gutjnl-2013-305989. Epub 2013 Dec 12. "Ondansetron relieves some of the most intrusive symptoms of IBS-D, namely loose stools, frequency and urgency."
  23. Andrews, N.C. Disorders of iron metabolism. N Engl J Med. 1999 Dec 23;341(26):1986-95.
  24. Stafford, D.C. The influence of the neurohumor serotonin on hibernation in the golden-mantled ground squirrel, Citellus lateralis. Comp Biochem Physiol A Comp Physiol. 1971 Feb 1;38(2):239-50.
  25. Selye, H. Textbook of Endocrinology. 1947. "Hibernation ["winter-sleep"] is a coma-like condition which develops in certain animals, during the winter season, under the influence of cold and the lack of food. Many invertebrates, amphibia, reptiles and some (exceptional) fish, spend the winter in a condition of immobility, during which their metabolism falls to very low levels. It is only in this manner that they can resist the hardships of the cold season." "Thyroidectomy delays while thyroid hormone treatment accelerates the awakening of hibernating animals. This effect of the hormone is probably due tot he stimulation of the metabolism." "All other vital processes [during hibernation] decrease considerably, thus the body temperature may fall in the urchin to +15C and in certain bats even below 0C. In the urchin and respiration rate, which is normal about 50/min., falls to as bout 1/min., while the pulse rate decreases from the normal of 300/min. to 2-3/min." "During hibernation, in such animals as the hamster, squirrel, etc. the thyroid undergoes profound atrophy, comparable in severity to that caused by hypophysectomy. The resulting decrease in thyroid-hormone production is essential for winter-sleep, since thyroid hormone administration awakens animals from this condition."
  26. Wapnick, A.A. et al. Effects of Iron Overload on Ascorbic Acid Metabolism. Br Med J. 1968 Sep 21; 3(5620): 704–707. "Studies of the ascorbic acid status in two subjects with idiopathic haemochromatosis and in 12 with transfusional siderosis showed that all had decreased levels of white cell ascorbic acid. The urinary excretion of ascorbic acid was also diminished in those subjects in whom such measurements were made. The administration of ascorbic acid was followed by only a small rise in the urinary ascorbic acid output, while the oxalic acid levels (measured in two subjects) showed a significant rise. These findings resemble those described in siderotic Bantu, and support the thesis that increased iron stores lead to irreversible oxidation of some of the available ascorbic acid.