Thursday, September 29, 2011

Iron, Oxidation, Inflammation, and Aging

In my Ancestral Health Presentation I discussed the idea that nutritional diseases fall into two categories, excess and deficiency.

When we compare recently observed hunter-gatherers with members of modern affluent nations, we see important differences between the two groups in general nutritional status throughout life.  Hunter-gatherers have very low body fat levels incomparison to modern people, which reflects the fact that from birth they have a low fat intake relative to fat expenditure

As the rapid sales of nutritional supplements in the U.S. shows, we tend to worry a lot about deficiencies.  From an evolutionary psychology standpoint, we might have this predisposition toward thinking that our problems are due to deficiency of something because our ancestors were more likely to develop dietary deficiencies than dietary excesses.

In the ancestral environment, food was more scarce than in modern nations, and it took more energy to get that food, a situation favoring deficiency (low nutrient availability plus high nutrient expenditure).  In our modern environment, we have a high availability of nutrients and do not need to expend much to get those nutrients, a situation favoring development of excesses. 

Worldwide, iron deficiency is the most common nutrient deficiency, occurring mainly in developing nations (low food/iron availability) and among children and menstruating women (high iron demand).

But in modern nations, a growing body of evidence suggests that excessive iron intake and retention promotes chronic degenerative diseases.

Iron and Oxidation

In human metabolism, iron play a critical role, as part of hemoglobin and myoglobin, in the promotion of mitochondrial  oxidation reactions that sustain the process of life.  The oxidation process inevitably produces peroxide and superoxide radicals.  These radicals themselves are comparatively non-toxic, and cells have evolved means of dealing with them [1].  However, when these oxide radicals react with unbound or poorly bound iron, they generate much more damaging hydroxyl radicals.

According to Chinese medical theory, we classify anything that acts like fire as relatively yang.  Fire consumes by oxidation and produces heat and light.  Oxidation fuels the normal process of transformation (growth and development, or aging); acceleration of oxidation accelerates transformation (growth, development, aging).  For example, a log left to age will gradually oxidize and turn to ashes; subjecting the log to fire just accelerates the transformation from log to ash.

Indeed, Ou et al have proposed that, on a biological level, the concepts of yang and yin correspond, in part, respectively, to oxidation (yang) and antioxidation (yin).  They found that traditional Chinese herbal medicines classified as yin tonics (used to nourish yin or promote water-like, cool, moist aspects of the body) have, on average, six times more antioxidant activity and polyphenolic contents than herbals classified traditionally as yang tonics (used to fortify yang or promote fire-like, hot, dry aspects of the body).

Since iron supports oxidation, iron deficiency reduces rates of cellular oxidation, and results in a more yin condition:  the iron-deficient person feels cold, fatigued, and weak, and suffers from pallor and cognitive impairment, a weakening of the light of the mind.  Its like the inner fire has died down.  Returning iron sufficiency restores the heat, energy, strength, color (reddish) and mental function, all signs of a fire burning more brightly.

Chinese medical theory predicts that an excess of a yang factor like iron would result in excessive 'fire' in the body, which Western medicine calls in-flamm-ation, the "flamm" simply meaning 'flame,' i.e. fire.   Exposing any tissue of the body to chronic in-flame-ation--low level fire-- results in scarring and hardening.

In "Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases," [2] Douglass Kell reviews an impressive body of evidence indicating

(i) that it is this combination of poorly liganded iron species, coupled to the natural production of ROSs, that is especially damaging, (ii) that the role of iron has received far less attention than has the general concept of ROSs, albeit the large literature that we review, and (iii) that this basic combination underpins a great many (and often similar) physiological changes leading to a variety of disease manifestations, and in particular those where the development of the disease is manifestly progressive and degenerative.

Kell's paper reviews evidence linking excess, unbound, or poorly bound iron to the following disorders:

Preeclamsia
Diabetes type 2, insulin resistance, and metabolic syndrome
Hypertension
Cardiovascular disease (heart failure, stroke, and atherosclerosis)
Alzheimer's, Parkinson's, and other neurodegenerative diseases
Amyotrophic lateral sclerosis (ALS, Lou Gerhig's)
Rheumatoid arthritis
Lupus
Asthma
Inflammatory bowel disease
Psoriasis
Gout
Age-related macular degeneration
Frailty
Aging
Chronic obstructive pulmonary disease
Cancer

I have also found studies linking elevated body iron to PCOS [3] and Multiple Sclerosis [4].

Kell notes that many natural plant food compounds act to bind iron or block iron uptake:

Even though elements of the 'Mediterranean' diet that are considered to be beneficial are usually assumed to be so on the basis of their antioxidant capabilities (but cf. [1820]), many of the polyphenolic compounds (e.g. flavones, isoflavones, stilbenes, flavanones, catechins (flavan-3-ols), chalcones, tannins and anthocyanidins) [1821-1828] so implicated may also act to chelate iron as well [1073,1829-1843]. This is reasonable given that many of these polyphenols and flavonoid compounds [1821,1844-1853] have groups such as the catechol moiety that are part of the known iron-binding elements of microbial siderophores. Examples include flavones such as quercetin [914,1813,1829,1854-1864], rutin [1829,1857,1858,1865,1866], baicalin [1860,1867], curcumin [1813,1868-1872], kolaviron [1873], flavonol [1874], floranol [1875], xanthones such as mangiferin [1876-1879], morin [1876], catechins [1073,1807,1838,1854,1880,1881] and theaflavins [1882], as well as procyanidins [1835,1883] and melatonin [1628,1884-1887].

In addition to the phenols and flavonoids, dietary tannins (tea, coffee, nuts, vegetables) phytates (seeds, nuts, grains, beans), calcium, phosphorus, dairy products, and reduce iron uptake.

On the other hand, dietary factors that increase iron availability include:

Dietary meat, poultry, and fish:  All enhance iron absorption via the MFP factor, which promotes absorption of iron from non-animal foods eaten with the animal product.  Meat, fish and poultry also provide the most bioavailable heme iron, of which the body consistently absorbs about 23 percent, up to ten times more than from non-animal sources.  Red meat generally provides the greatest level of iron as well.

Dietary acids:  Vitamin C and other dietary acids (e.g. those found in sodas) increase the availability of dietary iron.

Hunter-Gatherers and Iron

In my Ancestral Health Presentation, I argued that hunter-gatherers and modern people differ in some very important contextual aspects.  The following slide from my presentation summarizes my observations:



To summarize the table, in comparison to modern people, hunter-gatherers live in an environment with a low food availability and a high energy expense required to get that food.  This combination results in lifelong caloric restriction and low body fat levels in the hunter-gatherer.  

Hunter-gatherers also consume many unrefined plant foods and herbs that contain polyphenols, flavonoids, tannins, and fiber,  all of which so-called 'antinutrients' reduce iron uptake and bind iron to reduce its availability for reaction with peroxide and superoxide.  Finally, they have many other factors causing blood and iron loss, including parasites, insects, and injuries.

This environment is similar to that of our primate ancestors.  Hence, I would surmise that human metabolism is adapted to an environment with a high intake of 'antinutrients,' a low dietary iron availability and a condition of borderline iron deficiency.

In such an environment, meat, particularly red meat, with its highly available iron, may serve as a medicine.

In contrast, people in modern affluent nations inhabit an environment with a low intake of 'antinutrients' (due to emphasis on refined plant foods), a high food iron availability and comparatively few drains on body iron stores.

Even many menstruating women have less iron loss in modern nations due to use of birth control methods.

Thus, modern people have a tendency to accumulate excess iron.

Comparing Nations and Diets

In The Iron Factor of Aging, Francesco S. Facchini discusses the relationship between iron and chronic diseases at length.  After a thorough review of the evidence linking iron to inflammation, disease, and aging, he notes that when we look at modern nations, people who have diets with a lower iron availability also have lower rates of chronic inflammatory, autoimmune, and degenerative diseases.  These include the Mediterranean and Asian nations where tea, wine, cheese, legumes, vegetables, and fruits provide the 'antinutrients' reducing iron availability, and people either consume less red meat and more white meat (fish and poultry, lower in iron) or nearly vegetarian diets.

This perspective raises the possibility that fish consumption sometimes correlates with reduced risks of degenerative diseases not because it provides some essential nutrient (e.g. fish oils) but because people eating fish instead of land animal meat will have a lower intake of iron.

Also, vegetarian diets have a lower iron availability, and also associate with lower risks of chronic degenerative diseases.

The modern diet provides more iron by route of red meat and iron-enriched foods consumed in combination with highly acidic foods or beverages or vitamin C supplements. 

Context

Iron nutrition provides a good example of how context can modify the effect of a food.   The French eat more red meat than the Japanese, and they have a higher risk of cardiovascular disease, but not as high as in the U.S.

The Japanese eat vegetables, rice, fish, and soy products, and drink tea.  They typically eat no red meat.  Their vegetables, soy, and tea all reduce iron availability, while nothing in their typical diet is a rich source of bioavailable iron.  They live long lives with a low incidence of chronic degenerative diseases. 

The French eat meat with vegetables, fruits, dairy, and wine, all of which reduce iron availability.  In contrast, Americans eat meat with bread made from iron-enriched flour, hardly any vegetables,  and typically drink either acidic soda or low-polyphenol beer.

The typical French meal would not provide as much iron as the typical American meal.  The typical French man or woman would have less stored iron and this may explain why he or she has a lower risk of cardiovascular disease.

Men vs. Women

Historically, U.S. men have higher risks of cardiovascular diseases than U.S. women, until women pass menopause.  This means women have lower risk when they have monthly losses of iron through menstruation, and their risk rises when they stop losing iron.

In general, in modernized nations, women have a greater life expectancy than men.  This means women age more slowly, and this may occur because premenopausal women lose iron every month, resulting in a lower iron status, and a lower level of hydroxyl radical formation, during much of their lives.

However, the iron hypothesis predicts that women who reduce menstrual blood losses by birth control methods without compensating by reducing dietary iron availability will have an increased risk of iron-related diseases. 

Men can reduce their iron stores by regularly consuming 'antinutrients' and giving blood.







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