Friday, January 27, 2012

Mitochondrial Dysfunction

(Unlike the other posts I changed the reference count to reset at each sub-heading to make this post easier to edit)

Mitochondrial Dysfunction as a Mechanism of Disease 

There are many chronic diseases.  Some of them can be the result of similar mechanisms.  A perfect example of this are the autoimmune diseases, which share the common mechanism of autoimmunity, but manifest in remarkably different ways.  Another mechanism that can produce a wide variety of chronic diseases is mitochondrial dysfunction. 

Mitochondrial dysfunction is a potential mechanism behind many metabolic, age-related, neurodegenerative and psychiatric diseases or health conditions such as: aging [1], age-related macular degeneration [2], Alzheimer’s disease [3], amyotrophic lateral sclerosis [4], atherosclerosis [5], autism [6], bipolar disorder [7], cancer [8], cataracts [2], chronic fatigue syndrome [9], diabetic cardiomyopathy [10], nephropathy [11], neuropathy [12] and retinopathy [2], endothelial dysfunction [5], epilepsy [13], fibromyalgia [14], hearing loss [15], Huntington’s disease [16], hypertension [5], insulin resistance [17], major depressive disorder [7], male infertility [18], migraines [19], multiple sclerosis (?) [20], non-alcoholic fatty liver disease [21], obesity [22], Parkinson’s disease [23], schizophrenia [7] and type 2 diabetes [24]. 

Diseases and health condition stemming from mitochondrial dysfunction tend to occur in the brain, heart, liver and muscle.  A possible reason is that these parts of the body require a lot of aerobic metabolism and are therefore more dependent on their mitochondria. 

"Chronic mitochondrial oxidative stress on the peripheral tissues subsequently damages the retina, vascular endothelial cells, peripheral neurons, and the nephrons, leading to the clinical sequelae of end-stage diabetes. Thus chronic mitochondrial dysfunction can explain all of the features of type II diabetes, and is thus the likely cause of the disease" [1]

Mitochondria and Respiration 

A mitochondrion is an organelle within our cells.  Endosymbiosis is the theory to explain how some aerobic bacteria were engulfed by eukaryotic cells, but instead of being digested the bacteria became part of the eukaryotic cell.  Mitochondria have many bacterial features and their own separate DNA (mtDNA). 

The primary role of mitochondria is to generate most of our energy by aerobic respiration.  Mitochondria are also involved in detoxification and cellular signalling related to apoptosis and energy status. 

In the cytosol glucose is split from a 6 carbon molecule to a 3 carbon molecule called pyruvate.  Under anaerobic conditions (such as in intense exercise) pyruvate is fermented to lactate*.  The process from glucose to lactate can generate ATP quickly, but only a very small amount.  Under aerobic conditions pyruvate enters the mitochondria and helps form acetyl-CoA. 

Fatty acids are broken down in the mitochondria, two carbons at a time, each couple helps form another acetyl-CoA.  Acetyl-CoA donates 2 carbons to the citric acid cycle, which removes the carbons, generating a little more ATP and attaching the carbons to oxygen to form CO2.  Meanwhile the electrons from the hydrogen atoms are bound to electron carriers.  The electron carriers pass their electrons along the electron transport chain, which releases energy to pumps protons across the inner mitochondrial membrane.  Eventually there’s a lot of potential energy from lots of protons one side of the membrane and lots of electrons on the other side.  An enzyme called ATP synthase opens the gates causing protons to pair up with electrons to form hydrogen, which then bind with oxygen to form H2O.  As the protons flow through ATP synthase they release the potential energy, which ATP synthase uses to create lots of ATP.  Most ATP is generated this way.  (What the electron transport chain does is called oxidative phosphorylation (OXPHOS)) 

* Animals and bacteria ferment pyruvate to lactate.  Plants and fungi ferment pyruvate to ethanol. 

The Role of Mitochondrial Dysfunction in Chronic Disease 

The process of breaking down carbohydrates and fat into carbon dioxide and water doesn’t always work perfectly.  Sometimes hydrogen peroxide (H2O2) is formed instead of water or superoxide (O2-) is formed by an electron binding to oxygen (O2) (a process called reduction) too soon.  Hydrogen peroxide and superoxide are two common reactive oxygen species (ROS).  ROS are involved in cellular signalling, but also steal electrons (a process called oxidation) from proteins, DNA and PUFA (lipid peroxidation), which damages cells and is called oxidative stress. 

To protect against ROS we have antioxidant enzymes such as superoxide dismutase (to convert superoxide to hydrogen peroxide), glutathione peroxidase and catalase (both convert hydrogen peroxide to water). 

If the antioxidant defences are overwhelmed these ROS are free to cause oxidative stress.  The mitochondria are most vulnerable due to their close proximity.  ROS inhibit ATP production and can damage mtDNA, leading to mutations*.  This initiates a positive feedback cycle whereby mutations in mtDNA compromise mitochondrial function, slow down the electron transport chain and lead to more ROS, more oxidative stress and more mutations [1]. 

Mitochondria generate roughly 90% of the endogenous ROS so mitochondrial ROS have a great capacity to cause damage [1].  Hydrogen peroxide and superoxide are less damaging than other oxidants but can from very damaging compounds.  Hydrogen peroxide can bind with metal ions to form a hydroxyl radical (OH-) and superoxide can combine with nitric oxide (NO) to form peroxynitrite (ONO2).  Mitochondrial ROS can increase pro-inflammatory cytokines [2] and insulin resistance [3]

Mitochondria can initiate apoptosis in response to energy deficiency, oxidative stress and elevated intracellular calcium ions (Ca2+), all of which can be a result of mitochondrial dysfunction.  Apoptosis and energy deficiency in a cluster of cells responsible for a specific function can result in chronic diseases such as: the pancreatic beta cells in type 2 diabetes**, the substantia nigra neurons in Parkinson’s disease and the diabetic '-opathies' (cardiomyopathy, neuropathy, nephropathy and retinopathy) [1].  The increase in calcium ions may lead to excitotoxity [4]

Mitochondrial dysfunction is strongly associated with and can cause endoplasmic reticulum (ER) stress and vice versa [5].  The ER is an organelle involved in the synthesis and folding of proteins (putting the protein in the right shape), the synthesis of lipids and steroid hormones, and more.  Protein unfolding occurs during ER stress as an adaptive mechanism, although prolonged ER stress will initiate apoptosis.  Prolonged ER stress stimulates the release of protein-tyrosine phosphatase 1B (PTP1B), which inhibits the signal transduction of leptin, leading to leptin resistance and obesity [6].  PTP1B also increases insulin resistance, gluconeogenesis, triglycerides and cholesterol [7] and promotes tumour growth [8]


Symptoms of these diseases and health conditions appear when the function and/or number of cells drop below a minimum threshold needed for normal functioning.  Mitochondrial dysfunction is major factor behind many progressive, degenerative diseases which usually manifest later in later life and can be described as accelerated aging.  More generally, mitochondrial dysfunction is also related to many aspects of aging and I think it is a main factor driving the aging process [1]

I've done some blog posts on mitochondrial dysfunction and obesity, cancer, cardiovascular disease, type 2 diabetes, Parkinson's disease and Alzheimer's disease

* Unlike nuclear DNA, mitochondrial DNA cannot be repaired [9] 

** Type 1 and type 2 diabetes involve a loss of pancreatic beta cell function (inadequate insulin released).  Gestational diabetes is different, in that there's no pancreatic damage (and there's rarely any glucose in the urine - what 'diabetes mellitus' means), just a higher level of insulin resistance to divert nutrients to the foetus, and so perhaps it should be called gestational insulin resistance instead.

*** There are many theories of why menopause exists, though the most basic purpose is to stop women reproducing.  Only mothers pass their mtDNA to their children. and menopause only affects women.  It's possible that menopause exists to stop women reproducing at an age when the body assumes there would be too many age-related mtDNA mutations, in order to prevent those mtDNA mutations from being passed on to their children.  It's well known that children from older mothers have a greater risk of certain diseases, so perhaps menopause is the body just drawing a line in the sand.  Menopause seems inevitable, so this is just an academic speculation 

Causes of Mitochondrial Dysfunction 

Causes of mitochondrial dysfunction tend to involve oxidative stress.  These can include: alcohol [1], excess calories [2], glucocorticoids [3], homocysteine [4], iron overload [5], lipopolysaccharides [6], nutrient deficiencies [7], pro-inflammatory cytokines [8], smoking [9], and statins* [10]. 

The efficiency of calories to ATP is determined by how coupled* the mitochondria are.  If mitochondria are tightly coupled then calories are efficiently converted to ATP and generate less heat, but excess calories will increase the production of ROS by slowing down the electron transport chain, allowing more opportunity for electrons to reduce O2 to superoxide.  Loosely coupled mitochondria are adaptations to cold climates as calories are less efficiently converted to ATP, but generate more heat (thermogenesis) and excess calories don’t increase the production of ROS as much.  People with tightly coupled mitochondria are at a much greater risk of mitochondrial dysfunction with excess calories [2]. 

Nutrient deficiencies in CoQ10 [10], glutathione [11], carnitine [12], taurine [13] or zinc [14] may lead to mitochondrial dysfunction.  Deficiencies in other nutrients that can act as mitochondrial antioxidants and/or support mitochondrial function may also lead to increased oxidative stress and mitochondrial dysfunction.  Nutrients important for mitochondria include: 

  • Glutathione and selenium to synthesise glutathione peroxidase.
  • Manganese to synthesise superoxide dismutase in the mitochondria (zinc and copper help synthesise superoxide dismutase elsewhere in the body)
  • Vitamins B2, B5, B6 and B7, iron, copper and zinc to synthesise heme in the mitochondria.  Heme is part of catalase and of complex IV in the electron transport chain to reduce ROS [15] 
  • FAD+ from riboflavin (B2), NAD+ from niacin (B3) and CoQ10 are electron carriers in the electron transport chain.  Also acetyl-CoA is derived from vitamin B5
  • CoQ10 [10], PQQ [16], lipoic acid [17], carnitine [18] carnosine [19], creatine [20], taurine [21], vitamin C and E are mitochondrial antioxidants and many have other functions as well

You can look where to find some of these nutrients on my nutrient database and check out this post for some of the others.  The general pattern is that animal foods and vegetables are the best sources.  The amino acid derivatives and CoQ10 are almost exclusively found in meats, which is logical because the muscle and organs contain many mitochondria.  Eat mitochondria to support your own.

* To lower cholesterol statins also block CoQ10 synthesis.  Mitochondrial dysfunction can follow from CoQ10 depletion and may explain some of their side effects such as an increased risk of diabetes and myopathy. 

** Tightly coupled mitochondria are more efficient at pumping protons into the inner mitochondrial membrane and also more efficient at using those protons as they go through ATP synthase to generate ATP [2]. 

*** Environmental toxins such as dioxins [22], heavy metal toxicity (aluminium [23] and mercury [24]), herbicides [25], pesticides [26] and welding fumes [27] can also have a role in mitochondrial dysfunction. 

Mitochondrial Biogenesis 

If mitochondrial numbers and/or function is low then a way to correct this is to increase mitochondrial biogenesis - the growth of new mitochondria.  AMP-activated protein kinase (AMPK) is an energy sensor that is released in response to low cellular energy (a high AMP:ATP ratio), it also increases mitophagy (autophagy of mitochondria) [1], glucose transport and fatty acid oxidation [2].  AMPK inreases PGC-1α, a protein that is largely responsible for mitochondrial biogenesis.  PGC-1α also increases fatty acid oxidation, oxidative phosphorylation, insulin sensitivity and energy expenditure [3]. 

Exercise* [4], ketogenic diets [5], fasting [6], calorie restriction [7], cold exposure [8] and non-ketogenic low carb diets [9] increase AMPK.  All of these signal energy scarcity, so are somewhat stressful for the body and may antagonise thyroid function is large amounts.  More is not always better. 

Active thyroid hormone (T3) [10], BCAAs [11], butyric acid [12], PQQ [13], and a combination of lipoic acid and carnitine [14] increase PGC-1α (perhaps through AMPK independent mechanisms?).  This list is comprised of generally health promoting molecules 

* Based on the studies in an MDA post: endurance and HIIT (30 sprint, 240 off) increases MB, resistance enhances MB from endurance, but resistance alone may not and walking does not increase MB.  My guess it that whatever gets you breathing hardest will increase MB the most.  High doses of vitamin C supplementation (1000 mg daily) reduces exercise induced mitochondrial biogenesis [14].

Summary 

Mitochondrial dysfunction is a mechanism behind many metabolic, age-related, neurodegenerative and psychiatric diseases or health conditions. It can be caused by an excess of calories, nutrient deficiencies and various means of oxidative stress.  Mitochondrial dysfunction is a vicious cycle whereby oxidative stress damages mtDNA, leading to worse mitochondrial function and more oxidative stress.  Many nutrients that support mitochondrial function are found in meats and vegetables. A diet rich in these nutrients and measures that increase mitochondrial biogenesis and reduce oxidative stress will help prevent, and may reverse, mitochondrial dysfunction and other related diseases.

Further Reading:
(1) A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

Sunday, January 22, 2012

DGA 2011 - Grains

2.3 Grain (cereal) foods (mostly wholegrain)

Wholegrains

Key nutrients in wholegrain foods include carbohydrate (starch), protein, dietary fibre, B group vitamins, vitamin E, iron, zinc, magnesium and phosphorus. Other protective components are fermentable carbohydrates, oligosaccharides, flavonoids, phenolics, phytoestrogens, lignans, protease inhibitors, saponins and selenium [36, 37].

Wholegrains aren’t as nutrient dense as the guidelines make them out to be.  As a group they aren’t a great source of B vitamins, having no B12, inadequate riboflavin and folate [1], the biotin in grains and their form of vitamin B6, pyridoxine glucoside, have poor bioavailability relative to animal-based foods [2].  Pellagra is caused by niacin deficiency and associated with high intakes of corn, yet corn has sufficient niacin on paper, which suggests the niacin in corn at least has poor bioavailability, perhaps from dietary lectins in corn damaging the intestinal microvilli [2].  Wholegrains generally have insufficient vitamin E and all have insufficient selenium except for wheat and rye (which also depends on the soil) [1].  The minerals that wholegrains appear to be rich in on paper (iron, zinc, magnesium and phosphorus) have their bioavailability reduced by high concentrations of phytic acid [3] [4] [5].

The recommended amount of protein to reduce chronic disease risk is 15-25% of total calories [6].  Wholegrains are very average sources of protein.  They are roughly 15% protein by calories [1] (the lower limit) and they have many factors which compromise the protein quality.  Grains have an unbalanced amino acid profile being low in the essential amino acid lysine and high in proline and glutamine.  There are a family of storage proteins in grains called prolamines (gliadin, zein, etc), named because they are rich in proline and glutamine.  Prolamines are difficult to digest and therefore can cause allergic reactions in people with a genetic predisposition, intestinal permeability and a poorly regulated immune system.

Speaking of intestinal permeability, gluten is a peptide in gliadin and increases intestinal permeability by stimulating the release of zonulin (which loosens the tight junctions) in both coeliacs and non-coeliacs [7] [8].  Intestinal permeability causes poor nutrient absorption, inflammation and can lead to autoimmune disease [2] [7] [8].  Saponins increase intestinal permeability [9] and tend to be found in the pseudo-grains like chia, amaranth, quinoa and buckwheat.  Another thing that increases intestinal permeability is dietary lectins, especially those in wheat and corn.  Lectins increase intestinal permeability by damaging villi and shortening microvilli.  Lectins can over arouse the immune system, setting the scene for autoimmunity [10].  Wheat germ agglutinin and corn lectin can also transport bacteria throughout the bloodstream as they can bind to glucosamine, a glycoprotein found in enterocytes and bacterial cell walls [11].  WGA has a binding affinity for insulin receptors, which can lead to excessive insulin release and an increased risk of cancer [12].

Finally these difficult to digest and problematic prolamines and lectins are made even more resistant to the digestive process by protease inhibitors and phytic acid by blocking the action of the digestive enzymes protease, pepsin and trypsin [2].  With the protein in wholegrains being so poorly bioavailable and such a poor quality it is likely people would be compelled to overeat calories and gain some weight on the grain-based western diet in order to satisfy protein needs [13].  Wholegrains are not a good source of protein.

The oligosaccharides likely refers to the inulin (a fructan) in wheat.  Inulin is a poorly absorbed sugar that can be fermented by pathogenic bacteria, leading to gut dysbiosis and small intestinal bacterial overgrowth [14].  This too can lead to intestinal permeability and release endotoxins such as lipopolysaccharides into the bloodstream [15].  Lignans are phytoestrogens and the subject of phytoestrogens is covered in response to the previous section, although the quantities of lignans in grains shouldn’t be as bad as the isoflavones in soy.

Research and Recommendations

Research supporting wholegrain consumption may be misleading.  Clinical trials may include wholegrains as part of an overall diet and lifestyle intervention or by comparing a group eating wholegrains to a group eating refined grains.  It’s not surprising that the wholegrain group has better health outcomes, there is little doubt that wholegrains are healthier than refined grains, but unfortunately all these studies show is that either the overall intervention works or that wholegrains are healthier than refined grains.  Epidemiological studies may find similar outcomes, that people who eat wholegrains tend to be healthier, which is what one would expect from the clinical trials when they replaced refined grains with wholegrains.  Epidemiological studies may also be confounded by health conscious people being more likely to eat wholegrains in response to previous dietary guidelines.  The question though is not whether wholegrains are healthier than refined grains, but instead are wholegrains healthy in their own right?  Does adding of wholegrains to our diets improve our health?  Or are they cheap source of calories, a mediocre food, potentially problematic and something we may as well be without?  These are the questions that need to be answered.

Even if those questions have not been answered, the dietary guidelines should at least be consistent with the conclusions of the studies it cites.  The dietary guidelines recommend six servings of mostly wholegrain cereals per day, yet this is more than what the studies suggest is ideal.

“The protective effect was noted with between 1–3 serves per day of wholegrain foods (predominantly oats).”

“The evidence supports three serves per day of wholegrain foods conferring between 21-42% reduction in risk of type 2 diabetes.”

“There is evidence of a probable association between consumption of 3–5 serves per day of grain (cereal) foods (mainly wholegrain) and reduced risk of weight gain”

“There is recent evidence suggesting that consumption of 1-3 serves of cereals high in dietary fibre per day is associated with reduced risk of colorectal cancer in adults”

Above are the studies on which the dietary guidelines have found support for wholegrain consumption.  The number of servings are 1-3, 3, 3-5 and 1-3.  That averages out at roughly 3 serves per day.  However, the dietary guidelines recommend 6 serves of grains per day, which is above all the ranges and double the average that find a reduced risk of disease.  If the dietary guidelines wish to be consistent with the research it cites, the recommended number of serves of grains per day should be 3 serves of wholegrains and no serves of refined grains.

The guidelines are currently recommending six serves, but to make most of them wholegrain.  ‘Most’ does not mean ‘all’, in other words refined grains are getting a free pass, one could even say that refined grains are being recommended in these guidelines, alongside and equal to proper food like fruit and meat.  None of the research cited found any evidence of refined grains improving health or suggested their consumption.  Refined grains are low in almost all micronutrients, except the ones they may be fortified with.  If much of the nutrient density comes from fortification how is that different from eating junk food then taking a supplement.  The dietary guidelines are supposed to be recommending consumption of whole foods.  I don’t consider refined or enriched grains a whole food.

“these Guidelines make recommendations based only on whole foods”

Not only do the dietary guidelines give refined grains a free pass, but they may also end up in wholegrain foods.  The definition of wholegrain foods is for it to contain only 25% wholegrain.  That means up to 75% of a wholegrain product could be made from refined grains.

“In this review, the most commonly used definition was found to be that of Jacobs et al. (1998) [235] who defined wholegrain foods as those containing 25% or more of wholegrains”

In an attempt to eat healthy, people may buy ‘wholegrain’ products with 50% wholegrains (I’m being generous).  They then treat themselves to 2 serves of refined grains for their efforts.  They think refined grains can’t be that bad if the guidelines aren’t explicitly saying not to eat them.  Not like saturated fat.  (Never mind that the excess carbohydrate from the grains will be converted to palmitic acid (16:0).  Or that SFA are negatively associated with LDL oxidation, atherosclerosis and not associated with CVD).  Anyway our health conscious person eats 2 serves of whole grains, 4 serves of refined grains and thinks they are eating healthily.  That has to change.

Conclusion

In this section the dietary guidelines have lowered their standards.  They are recommending excessive consumption of cereal grains, a food group with mediocre nutrition and potential health problems due to antinutrients such as their potent lectins and gluten.  Most of the scientific evidence simply suggests wholegrains are healthier than refined grains and interventions that include wholegrains are successful.  The dietary guidelines recommend six servings of grains (mostly wholegrain), despite the cited studies only recommending three serves of wholegrains and no refined grains.  The guidelines should not be giving a free pass to refined grains.  Instead such a nutrient poor food group, responsible for no good health outcomes (and presumably negative ones), should be considered an extra.

If the guidelines want this food group to maintain six servings, then what should happen is for starchy vegetables, mature legumes, nuts and seeds to be removed from their other groups and placed into the group with wholegrains, which could now be called ‘starches and seeds’.  These foods can be grouped together as they have a similar nutritional profile.

Instead of recommending: eat six serves of grain (cereal) foods (mostly wholegrain).  What should be recommended instead is to: eat three serves of wholegrains, or: six serves of a combination of starchy vegetables, wholegrains, mature legumes, nuts and/or seeds.

Sunday, January 15, 2012

DGA 2011 - Fruit, Vegetables and Legumes

2.2 Plenty of vegetables, including different types and colours, and legumes/beans, and eat fruit

Mature Legumes

“As a group, these foods are nutrient dense, relatively low in energy (kilojoules) and are good sources of minerals and vitamins (such as magnesium, vitamin C and folate), dietary fibre and a range of phytochemicals including carotenoids.”

Vegetables, fruit and legumes (beans are legumes) have been grouped together in the dietary guidelines because they are said to share many of the nutrients and other compounds listed above.  This is the case with immature legumes (green beans, snow peas, and green peas), but not true of mature legumes (black beans, chickpeas, kidney beans, lentils, peanuts and soy beans).  This can be illustrated by following graphs, plotted from data in [1].

The values on the x-axis are 23 different essential micronutrients.  The y-axis value is the median value of a food group based on the percentage of the NRV amount of a given nutrient in 8700 kJ worth of a food, divided by the NRV (for men) for the nutrient.  Nutrient dense foods should have values greater than 100 in most nutrients.

1. Calcium
2. Iron
3. Magnesium
4. Phosphorus
5. Potassium
6. Sodium
7. Zinc
8. Copper
9. Manganese
10. Selenium
11. Vitamin C
12. Thiamine
13. Riboflavin
14. Niacin
15. Vitamin B5
16. Vitamin B6
17. Folate
18. Choline
19. Vitamin B12
20. Vitamin A
21. Vitamin E
22. Vitamin D
23. Vitamin K1



Non-starchy vegetables and immature legumes are very similar nutritionally.  Both food groups are low in energy density and are in many nutrients.  For the most part they have roughly similar quantities of each nutrient.  This may be because when we eat immature legumes we eat more of the plant (vegetable) and less of the seed.  Immature legumes definitely belong in this category alongside of vegetables.


Mature legumes on the other hand are among the most energy dense foods and low in nutrient density relative to calories.  Many nutrients fall below the critical 100 line for mature legumes.  Unlike non-starchy vegetables and immature legumes, mature legumes don’t contain adequate calcium, riboflavin, niacin, pantothenic acid, choline, and vitamins A, C, E and K1.  Seeing as mature legumes are only adequate sources in 3 of the 13 vitamins, whereas non-starchy vegetables and immature legumes are adequate in 11 of the 13, it is misleading to describe mature legumes as being a good source of vitamins (sugary fruits are adequate sources in 7 of the 13 vitamins).  This is because when we eat mature legumes we are eating the seed and seeds foods (grains, mature legumes, nuts and seeds) tend to have high energy density, low energy density and deficits in the vitamins listed above.  Many minerals in seed foods have reduced bioavailability due to a number of antinutrients such as phytic acid.  This was discussed in the previous dietary guidelines.

“…non-haem iron absorption is inhibited by phytates, polyphenols (for example, tannins) and calcium.” [2]

“Zinc found in animal products, crustaceans and molluscs is more readily absorbed than zinc found in plant foods. In contrast, legumes and unrefined cereals contain phytates that reduce zinc absorption” [2]

The previous dietary guidelines showed that Australians on average, particularly women, had low to marginal intakes of iron and zinc (the minerals most affected by phytic acid) and some had deficiencies in these nutrients [2].  Despite this, the current dietary guidelines recommend consumption of phytate rich foods.

Phytic acid alone strongly chelates calcium [3], iron [4], zinc [4], magnesium [5], is a matrix of phosphorus (representing ~80% of the total phosphorus) [6], prevents absorption of all those minerals and blocks the digestive enzymes pepsin, amylase and trypsin [7].  The combination of phytic acid reducing the absorption and retention of nitrogen (protein), calcium and phosphorus results in weaker bones [3].  High fibre diets prevent vitamin D reabsorption [8], it’s possible that fibre is a proxy for phytic acid, which is responsible for this effect too.

All plants have a number of antinutrients and other toxics but seed foods such as matured legumes tend to have more and what they have tend to be more potent.  The lectins in mature legumes, such as phytohaemagglutinin in the kidney bean family, soybean lectin and peanut lectin, influence the intestine structure and function negatively, leading to intestinal permeability, autoimmunity and poor nutrient absorption (other potent lectins include wheat germ agglutinin and corn lectin) [9].  Canavanine is an amino acid found in some legumes that is structurally similar to arginine and induces toxicity when incorporated into proteins in place of arginine.  Saponins are found in some legumes (also nightshades) and bind to the intestine wall, increasing intestinal permeability and poor nutrient absorption, especially fats, fat soluble vitamins and cholesterol.  (Saponins are revered for their cholesterol lowering effect, but they do more harm than good).  Cyanogenic glycosides are found in some legumes (also some root vegetables and other seed foods) and are a storage form of cyanide, which can be metabolised into hydrogen cyanide, which is toxic at low doses and can cause dysfunction in the central nervous system, respiratory failure and cardiac arrest.  Tannins are found in legumes (also the skins of some fruit) and increase intestinal permeability, inhibit trypsin and amylase and reduce the absorption of iron and vitamin B12 [10].  When plants don’t want their seeds to be eaten, to ensure reproductive success, we should expect a number of toxic antipredation mechanisms.

More evidence that matured legumes shouldn’t be in this category comes from the lack of health benefits associated with them.  The guidelines have cited a number of studies that have found fruit and vegetables tend to promote health and are associated with better health.  The research concerning legumes only amounts to soy reducing LDL cholesterol and a possible association with less colorectal cancer.

“Recent evidence suggests that consumption of soy foods is associated with reduced total cholesterol and LDL cholesterol levels, as markers for coronary heart disease risk (Grade C, Section 7.4 in Evidence Report [14]) [180].”

Just because soy reduces LDL-C doesn’t necessarily mean it would reduce coronary heart disease.  If a study found such a result, it would have been included.

“Evidence suggests that consuming legumes is associated with reduced risk of colorectal cancer (Grade C, Section 7.3 in Evidence Report [14]) [184-188]. However, in one study the effect was only significant for women [187], as also seen in the recent analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) database [189]. However no evidence of an association between consumption of legumes and colorectal cancer was described in the WCRF report [42].”

The association between legumes and lower rates of colorectal cancer doesn’t appear very strong.  In the event that legumes do reduce colorectal cancer, this would likely be from soluble fibre being fermented by bacteria, which then release butyric acid and butyric acid nourishes the epithelial cells of the colon.  If this is the case soluble fibre can also be sourced from fruit and vegetables, both of which have a greater nutrient density and more positive health outcomes.

Some of the mechanisms used to explain the good health outcomes of fruit, vegetables and legumes do not apply to mature legumes.  The components listed include:-

Vitamins (especially vitamins A, C, E and folate): Mature legumes are mediocre sources of many vitamins and poor sources of, vitamin A, C and E [1].

Minerals (especially potassium and magnesium): Mature legumes are good sources of potassium, manganese and magnesium though whether they are a good source of other minerals, such as phosphorus and zinc, is questionable due to the high concentrations of phytic acid

Carotenoids: Mature legumes are poor sources of carotenoids such as vitamin A precursors, lycopene, lutein and zeaxanthin [1].

Bioflavonoids (anthocyanins and flavonols): Anthocyanins are used in nature as an antioxidant during photosynthesis and also fruits use them to attract pollinators.  Seeds don’t undergo photosynthesis nor do they encourage predation (quite the opposite), so it’s unlikely that as seeds, for mature legumes to be rich in anthocyanins.

Dietary fibre and resistant starch: Mature legumes are source of dietary fibre and resistant starch.  Yet overall legumes do not seem to reduce colorectal cancer.

Low energy density: This doesn’t apply to mature legumes as they tend to have an energy density of 1350-1550 kJ per 100 grams, which is among the highest of all whole food groups.  Soybeans and peanuts have an even higher energy density at 1,866 and 2,374 kJ per 100 grams respectively [1].

Low in sodium: All whole foods except dairy, eggs, shellfish and offal are low in sodium [1].  This is not a unique quality.

Low in saturated fat: Saturated fat is not associated with cardiovascular disease [11].  A study cited in the guidelines found that fats improved the TC:HDL ratio relative to carbohydrates [12].  Mature legumes are high in carbohydrates and replacing vegetables with mature legumes will increase the carbohydrate content of the diet.  So consumption of mature legumes will likely result in an increased TC:HDL ratio, triglycerides and a higher proportion of atherogenic small, dense LDL particles.  Carbohydrate intake is also associated with atherosclerosis [13].

Phytoestrogens and isoflavones (see below):
 
Isoflavones

“These reviews suggest the isoflavone in soy foods may have a role in cholesterol reduction, improved vascular health, preservation of bone-mineral density [209] and anti-oestrogenic, anti-proliferative, pro-apoptotic, anti-oxidative and anti-inflammatory processes [210].”

Both studies report that isoflavones in soy:

“…have stimulatory effects in low-estrogen environments, and that in high-estrogen environments, they block the effects of estrogen.”

The guidelines only mention the anti-oestrogenic effect, but not the pro-oestrogenic effect in low-oestrogen environments.  As a male I would be cautious to eat soy foods because one low-oestrogen environment is the male body.  The isoflavones in the soybeans are antipredation mechanisms, designed to make the males of the species sterile [14] and succeed in making a variety of animals sterile [15].  Not only are we bombarded by xenoestrogens (substances that have estrogenic activity) in the environment such as bisphenol A (plastics) [16], but the dietary guidelines recommend an even greater oestrogen load for men.

Men who consumed 2 serves of soy food had 41 million sperm/ml less than men who did not consume soy foods [17].  56g of soy protein decreased testosterone in men by 19% after 28 days [18].  Female monkeys on soy protein had a lower adrenal weight suggestive of androgen deficiency and hypercortisolemia [19].  All isoflavones are associated with breast cancer in women [20].  Soy isoflavones are goitrogenic, extra iodine is needed to compensate [21].  Early exposure to genistein (an isoflavones in soy) reduces testosterone long term in male rats, which may overarouse the immune system, increasing the risk of autoimmune diseases [22].  Testosterone:oestriadol was 13% lower and the free androgen index was 7% lower in the tofu group than the lean meat group.  These factors can increase the risk of prostate cancer [23].  Bioflavanoids such as genistein cleave DNA strands resulting in childhood leukimia [24].

That being said, all foods seem to have some isoflavones, but it is the concentration in soy foods, roughly 1,000 times greater, that is responsible for those effects and makes me cautious.  Surely those studies and that number is concerning.  See the table below, sourced from data in [25].

Food
Total isoflavones (mg/100g)
Fruit
<0.10
Vegetables
<0.10
Non-soy breakfast cereals
<0.10
Nuts (except pistachio nuts)
<0.10
Extra virgin olive oil
0.04
Whole eggs
0.05
Other legumes
<1.00
Pistachio nuts
3.63
Soybeans (depending on preparation)
12.50-48.95
Red clover
21.00
Natto
82.29

Before soy products and isoflavones are recommended to the public the science should be conclusive that these ‘foods’ will cause no health problems.  This investigation should be carried out by independent scientists who do not have a vested commercial or political interest in the result.  You wouldn’t recommend that men should take oestrogen tablets, so you shouldn’t recommend soy and isoflavones either with the current evidence.

Conclusion

Fruit and vegetables are widely regarded to be healthy as they are nutrient dense foods.  The inclusion of mature legumes into this category is somewhat misplaced.  Immature legumes are very nutritionally similar to non-starchy vegetables and should be included, but it’s likely that most Australians consider these foods – green beans, snow peas and green peas – to be vegetables anyway.  The legumes that don’t belong in this category are the mature ones.  Mature legumes are energy dense, low in nutrients and have little to no health benefits to speak of.  Mature legumes (especially soy) also contain many potent and toxic antinutrients.  One of the antinutrients is the isoflavones in soy (and clover).  Isoflavones have pro-estrogenic effects in low oestrogen environments such as men.  They cause sex hormone imbalances, thyroid suppression and may cause certain cancers.  All plant foods have antinutrients and other toxins, it is just that mature legumes have more and what they do have is more potent.  The recommendation to eat plenty of mature legumes will displace the more nutrient dense foods in the diet such as vegetables and immature legumes.

Instead of recommending: eat plenty of vegetables, including different types and colours, and legumes/beans, and eat fruit.  What should be recommended instead is: to eat plenty of vegetables, including different types and colours, and eat fruit.