An Examination of Popular "Diets" -- Avoid Them All

June 30, 2013, 2:25 pm

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Some of the dietary practices that are currently promoted have the inconvenience of producing some of the effects that these practices are being undertaken to check in the first place—namely cortisol and estrogen. 

If any person were so persuaded to do so, he or she should bear in mind that a deficiency of calories, carbohydrate, salt, calcium, and excessive amounts of histamine, choline, and prostaglandins are some of the factors that activate both cortisol and estrogen. 

I’ve written about stress and the reasons for keeping it as low as possible.  Refer back to those for context for this post.  But briefly, the stress hormones—cortisol, adrenalin, noradrenalin, growth hormone, glucagon, and some others—are all catabolic and estrogenic.  When they persist in the blood too long or excessively, irreversible degenerative processes are set in motion that affect all aspects and all levels of the body.

First and foremost, a deficiency of glucose—in the cell and blood—potently activates the stress metabolism, operating centrally by way of the hypothalamic-pituitary-adrenal axis.  At the same time, the stress metabolism decreases the output of thyroid hormones: Indeed, it’s been repeatedly observed that thyroid hormone output and adrenal cortex activity share an inverse relationship.

Glucagon and growth hormone are increasingly secreted by the pancreas and pituitary gland in response to a deficiency of glucose. (Overexertion, exposure to cold, trauma, and emotional arousal also stimulate the secretion of these hormones, reinforcing the designation of these hormones as “stress hormones.”)  These hormones liberate free fatty acids, which do not simply stimulate fatty acid oxidation, but also stick to proteins, diffuse in and out of cells, disrupt the structure of cellular water and their associated proteins, and activate inflammatory pathways in fat, white blood cells, etc.

The catecholamines, adrenalin and noradrenaline, can temporarily elevate glucose levels, but they also inhibit the secretion of insulin, promoting the wasteful conversion of amino acids to glucose and glucose to lactic acid.  Lactic acid increases the acidity near the cells that produce it, and this local decrease in pH favors the protonated form of acids, including free fatty acids, in which form they are more likely to enter cells from the blood, potentiating their toxicity.  Keeping these stress hormones as low as possible permits the efficient oxidative metabolism of glucose.

Some stressed people quickly respond by shifting their “autonomic nervous system” away from sympathetic dominance and more toward parasympathetic dominance, of which choline is the grandee transmitter.  Choline acutely stimulates the secretion of insulin, aggravating hypoglycemia, thereby contributing to the exaggerated swings in blood glucose levels.

Recently, I was asked a question on Facebook about agents for diarrhea, and I remembered offhand that anti-histamines, as a side effect, are also anti-cholinergic, which decrease gastrointestinal motility and secretion so as to help with diarrhea.

The so-called first generation anti-histamines, notably diphenhydramine or Benadryl, can be supportive in times of stress by buffering against hypoglycemia—both by blocking choline, which, once again, stimulates insulin secretion, and histamine, thereby activating uncoupling proteins in the pancreas.  Because pantothenic acid (vitamin B5) and riboflavin (vitamin B2) are needed by insulin-degrading enzyme (or insulinase) to break down insulin, a deficiency of pantothenic acid or riboflavin could therefore cause insulin to persist in the blood, aggravating hypoglycemia, too.

Parenthetically, in haste, I forgot to mention the role of anti-histamines in acne in my previous post.  It turns out that histamine receptors are expressed in keratinocytes and that topically applied diphenhydramine reduces stratum corneum lipids and the production of squalene by sebocytes in culture.¹

A high protein diet, as in the Paleo diet, leads to a persistent elevation of the stress hormones, mainly glucagon, adrenalin, and cortisol.  The resulting free amino acids (namely tryptophan, phenylalanine, tyrosine, and leucine) and free fatty acids, inhibit the uptake of T₃ into cells and into the central nervous system by way of the blood brain barrier.² Diets such as these are promoted to be anti-inflammatory and beneficial for metabolism and weight loss, but nothing could be more wrong; they are proinflammatory and anti-metabolic in every sense.

People talk about sugar as if it is a drug, affecting the brain in a way that cocaine does.  Be that as it may, consider for a moment that practically all body changes are made known to the hypothalamus and the hypothalamus governs much of the endocrine system and immune system, in which many (real) functional disorders are thought to originate.  But these functional disorders are really problems of the hypothalamus, rather than problems of the immune system, endocrine system, or whatever.  Know also that there exists a connection between the cerebral cortex and the hypothalamus, and this connection underlies the physiological effects of psychological stress, such as mental conflict.  What has been the effect of telling people to avoid certain foods like sugar and to fight their natural cravings for such?  Or of telling people that they have (imaginary) disorders with no basis in anything?

A decrease in ATP generation tends to reinforce itself, in part, by inhibiting the uptake of thyroxin, T₄, into cells, which is an energy dependent process.  In the liver, free fatty acids inhibit the uptake of T₄ and this is, I think, the major cause of the deficiency of T₃ in diabetes and low-carbohydrate and Palo dieters, as much of the conversion of T₄ to T₃ (about 60 percent) occurs in the liver.

As to the brain, when the energy charge decreases, neurons become hyperexciteble.  The inability to generate adequate amounts of ATP keeps neurons partially depolarized, which, by allowing calcium to flow into the cell from the blood in droves, increases the neuron’s likelihood of becoming “excited” upon stimulation.   And, the inability to regulate the uptake of calcium into pre-synaptic nerve terminals leads to the inappropriate release of transmitters, which are then available to act on, and to stimulate, their target cells excessively.  Epilepsy, seizure, psychosis are some neurological conditions affected negatively by a deficiency of energy, for which pharmaceutical companies have taken advantage of and developed drugs that target said conditions somewhat rationally.

In the heart, a deficiency of ATP depresses left ventricular functioning, as there is less energy available for robust contractions and complete relaxations.  The impaired contraction also increases the ventricular blood volume so as to impose an increase in pressure on the left side of the heart.   Less blood is pumped for every beat of the heart as a result (reduced stroke volume).  Moreover, the increased resistance to flow in the blood vessels due to the deficiency of energy (or oxygen) adds further to the stress on the heart.  Anything that increases the oxidative metabolism of glucose (of which there are some agents currently in the pipeline) appears to increase the heart’s viability and the chances of survival in patients with heart failure and arrhythmia. 

The addition of magnesium, by sparing ATP, and fructose (or sucrose), by decreasing the cell’s redox potential and by stimulating respiration, can quickly reverse these pathological cellular events.  More generally, a deficiency of energy, acidosis, and hypoxia can be corrected with some supportive care that includes some of the B vitamins, insulin, bicarbonate, and sugar.  Estrogencould apparently aggravate all these problems by interfering with oxygen use.

Persistent hyperglycemia and hypertension are two prominent signs that a person is operating on high levels of stress hormones, due to cortisol and aldosterone, respectively.   An increased susceptibility to infections, gastric ulcers, and eventually, diabetes and cardiovascular disease are others.

Avoiding starvation, high protein, low-carbohydrate, and salt-restricted diets keep the aromatase enzyme, aldosterone, and cortisol in check. (Seems obvious, right?) Prostaglandins and histamine are activators of cyclic AMP-dependent protein kinase and thus aromatase, so NSAIDs and diphenhydramine can help to balance excess estrogen levels.

Hydroxylated flavones—apigenin, chrysin, and quercetin—inhibit the final rate-limiting step in cortisol synthesis, cytochrome P450 1B1.³ However, quercetin is known to induce the aromatase enzyme, while apigenin, as well as naringenin, inhibit the aromatase enzyme.  I mention aromatase here to point out the fact that aromatase is activated by stress, like cortisol, aldosterone, glucagon, etc., are.  Finding fruits and vegetables that contain the desirable balance of these flavonoids has been thus far elusive.

There is some indirect evidence that caffeine has anti-estrogenic effects and the organic acids in coffee inhibit the regeneration of cortisol in tissues.⁴ In men, cortisol increases the expression of aromatase and estrogen, and estrogen, in turn, activates the enzyme that regenerates cortisol—the same enzyme that is inhibited by coffee.

I have to go, but I will delve into some of the even more annoying ideas that are bandied about as fact on the Internet.  For now, suffice it to say that if you read about or try a diet the goes against your base instincts (believe it or not, even telling you to eat despite not being hungry), run the other way while waving your hands in the air and screaming.

REFERENCES

1.       Pelle, E. et al. Identification of histamine receptors and reduction of squalene levels by an antihistamine in sebocytes. The Journal of investigative dermatology128, 1280–5 (2008).

2.       Hennemann, G. et al. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocrine reviews22, 451–76 (2001).

3.       Cheng, L.-C. & Li, L.-A. Flavonoids exhibit diverse effects on CYP11B1 expression and cortisol synthesis. Toxicology and applied pharmacology258, 343–50 (2012).

4.       Atanasov, A. G. et al. Coffee inhibits the reactivation of glucocorticoids by 11beta-hydroxysteroid dehydrogenase type 1: a glucocorticoid connection in the anti-diabetic action of coffee? FEBS letters580, 4081–5 (2006).

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Brain Food

July 4, 2013, 3:25 pm

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"Fish is brain food," is what I would hear in college from a roommate of mine who was seriously into his health.  He believed this so much that he would eat a piece of fatty fish before exams, and would urge me to do the same.  I was interested in health at the time, too, so I tried it.  Maybe I just didn't do it right or for long enough because I found that my friend's pre-exam ritual was a bad one, as was his reasoning for doing so, which was a physiological impossibility.

There is an ever-present belief that if a food contains a substance that is found in a particular body part, it follows inevitably that said food is beneficial for said body part.  I think this is what people really mean when they say that fish is brain food.  The meat of fish and the brain both contain phosphorus, and before the hype about omega-3 fatty acids, phosphorus was thought to be the reason why fish was good for the brain.  Fish is actually a modest source of phosphorus, as there are many other foods that contain significantly more, and phosphorus is now known to be a minor element of brain tissue.

The physiology of the brain is complex, and it is, for all intents and purposes, the most sensitive to changes in energy availability--some areas of the brain more than others.  Some structural support is needed in the form of a phospholipid called lecithin and some of the B vitamins are needed to support oxidative phosphorylation, a deficiency of which will cause mental inefficiency, dullness, sleepiness, insanity, etc.  And adequate blood flow to the brain is also needed to supply nutrients—Including glucose and oxygen.

The extent of the brain’s sensitivity to fluctuations in energy availability, I think, is illustrated by studies in which people fasted for weeks to months.  Because the brain would waste away the slowest of all the organs, hardly any brain tissue would be lost at the end of such fasts.  Is it, then, any wonder that mental functioning at the end of these fasts was normal, nay better, in almost all cases?  To support fasts as long as these, the metabolism would have to decrease and the stress hormones would have to be secreted and maintained at high levels to convert the body's proteins to glucose and to mobilize fatty acids to convert to ketone bodies, which the brain would then use as an additional fuel source.  

I remember reading about Upton Sinclair, a social activist and card-carrying faster, who fasted, off and on, for a period of 6 weeks, in which he lost 25 pounds and wrote an entire play, one of his best and most creative works.  So deeply affected following on the heels of this experience, Sinclair was struck with the idea that the best poetry had yet to be written, and it would remain this way until poets cared enough to be prepared to feed their work with their own flesh.

The brain needs a continuous supply of food but it doesn't need huge amounts of it or all at once.  If this were so, our mental capacity would increase proportionately with the amount of food we ate. (A friend of mine, Heath Kurra, made the point that if this were true, the idea that meat eating led to bigger brains and greater intelligence would have a firmer basis in reality.)

Strictly speaking, realize that excess fat tissue, the product of eating more than what your metabolism can support is not necessarily benign and that health and strength usually return as soon as this excess is eliminated.  Because some people do, I'll mention that we should not express disapproval at the fact that fat is being lost, but rather look upon it as a sign of returning health.

Before I leave this train of thought, know that "excess" in this case is relative and there is no uniformly agreed upon objective standard as to what constitutes a healthy weight.  Be that as it may, if you have hypertension or diabetes, conditions that are inextricably associated with obesity, there's a high likelihood that the body fat you carry is excessive.

Given the adverse physiological changes that take place during a long fast, I've been racking my brain thinking about how these fasts were so effective as a cure for a long list of conditions.  A reduction of inflammation and body fat were undoubtedly at play, but, and this is the main objection to this practice I have, lean tissue would be reduced more than fat tissue, and some organs, like the thymus, wouldn’t fare as well as the brain.  Further, upon the completion of a fast, the metabolism would reset at a lower level from where it was before the fast, in part because of the loss of lean tissue, so that less food would be required for weight maintenance.  But I digress.

The main element of fish that is now purported to improve brain health are the long-chain omega-3 fatty acids.  Long-chain omega-3 fatty acids have a wide-range of drug-like actions in the body, but their main effects, including their famous triglyceride-lowering effect, appear to be carried out specifically by their breakdown products, that is, reactive carbonyl compounds, which can stick to proteins and to other biological molecules to form advanced lipoxidation end products (ALE), thereby impacting the functioning of the entire cell.

More generally, fatty acids make cells resistant to the hormone insulin and as a result, amino acids and glucose are wastefully converted to lactic acid, and the resulting local acidity allows more fatty acids to enter cells.^1,2 These fatty acids can disrupt the cell, partly by decreasing the acidity of the carboxylic acid groups of proteins so as to favor the destabilization of intracellular proteins and the release of potassium and uptake of sodium and calcium, with a subsequent increase in density and decrease in viscosity. Unsaturated fatty acids are more thorough disrupters in this regard than saturated fatty acids are because unsaturated fatty acids also form fewer hydrophobic interactions with each other and are generally stronger acids.³ As cells accumulate increasingly more fat, these disruptive effects become increasingly more problematic. (For an easy-to-read explanation on the basics of cell physiology, read this.) Long-range, yet fundamental, biological effects such as these are hardly ever considered.

Fatty acids are able to slightly polarize the cell's water, as hydrogen bonds begin to form between water molecules and fatty acids, causing further hydrogen bonding among other water molecules.  The interaction between fatty acids and water, in turn, governs the way in which these now explicitly hydrated fatty acids interact with other proteins, or "receptors," and the way in which these proteins interact with other biological molecules.  Modeling of aqueous solutions should always consider the interactions with water, which is different from bulk water and anything but a continuum.  Investigations in the 1930s by Gortner et al., showed this to be the case, as they found that cellular water to which sucrose was added was less resistant to freezing compared to bulk water, indicating some inherent property of cellular water was resisting the dissolution of sucrose.⁴ This idea, however, was pretty much abandoned once the membrane-pump theory was widely accepted in the 1940s.

(Gilbert Ling later made the membrane pump theory untenable, showing that frog muscles without membrane pumps accumulate potassium and exclude sodium, just like cells with intact membranes do, and red blood cells with intact membranes and membrane pumps but without cytoplasmic proteins couldn’t move potassium and sodium against their concentration gradients.)

I think the mistaken idea that fish oil reduces insulin resistance in humans reinforces its unfavorable energetic effects.^5–7 I’ve mentioned before that upon stimulation, PUFA are liberated into the cell and this is accompanied by the depletion of ATP through its conversion to cAMP, which, in turn, activates the aromatase enzyme that converts androgens to estrogens—interfering with the use of oxygen.  Certain prostaglandins promote the deposition of collagen by fibroblasts so as to increase the diffusional distance that oxygen has to traverse to reach cells, aggravating the cell’s deficiency of oxygen.  A deficiency of oxygen, in turn, promotes the accumulation of lipids inside cells by decreasing the breakdown of the protein portion of LDL particles, which is required to prevent the deposition and accumulation of lipids inside cells.

In addition to its effect on the cell’s viscosity, described above, the decrease in ATP accelerates lipid peroxidation processes, including the breakdown of free PUFA to lipid hydroperoxides, lipid hydroxides, unsaturated aldehydes, epoxyhydroxy acids, etc.  Many of these lipid peroxidation products are involved in age-related brain degenerative diseases, such as Alzheimer’s.^8–10

I’ll eat fish occasionally as I think fish is a very good source of B vitamins, some minerals, and protein. (Trader Joe’s has a canned salmon product that is near completely devoid of fat, which I’ve been eating.)  But believing as I do, I don’t have any weird delusions that eating it will make me smarter or whatever.  And taking it as a supplement is no better.  It would be a perversion of facts to think otherwise.  The fact that some of the currently used drugs to treat conditions such as epilepsy and hypertension are incidentally showing to be protective against the neurodegenerative diseases speaks to a different paradigm of neurodegenerative diseases—a paradigm that has no place for the use of cholinergics and fish oil.

REFERENCES

1.       Kamp, F. & Hamilton, J. A. pH gradients across phospholipid membranes caused by fast flip-flop of un-ionized fatty acids. Proceedings of the National Academy of Sciences of the United States of America89, 11367–70 (1992).

2.       Hamilton, J. A. Transport of fatty acids across membranes by the diffusion mechanism. Prostaglandins, leukotrienes, and essential fatty acids60, 291–7

3.       Kanicky, J. R. & Shah, D. O. Effect of degree, type, and position of unsaturation on the pKa of long-chain fatty acids. Journal of colloid and interface science256, 201–7 (2002).

4.       Gortner, R. A. & Gortner, W. A. THE CRYOSCOPIC METHOD FOR THE DETERMINATION OF “BOUND WATER”. The Journal of general physiology17, 327–39 (1934).

5.       Lopez-Huertas, E. The effect of EPA and DHA on metabolic syndrome patients: a systematic review of randomised controlled trials. The British journal of nutrition107 Suppl, S185–94 (2012).

6.       Falco, M., Castro, A. de C. de O. & Silveira, E. A. [Nutritional therapy in metabolic changes in individuals with HIV/AIDS]. Revista de saúde pública46, 737–46 (2012).

7.       Akinkuolie, A. O., Ngwa, J. S., Meigs, J. B. & Djoussé, L. Omega-3 polyunsaturated fatty acid and insulin sensitivity: a meta-analysis of randomized controlled trials. Clinical nutrition (Edinburgh, Scotland)30, 702–7 (2011).

8.       Chia, L. S., Thompson, J. E. & Moscarello, M. A. X-ray diffraction evidence for myelin disorder in brain from humans with Alzheimer’s disease. Biochimica et biophysica acta775, 308–12 (1984).

9.       Smith, D. G., Cappai, R. & Barnham, K. J. The redox chemistry of the Alzheimer’s disease amyloid beta peptide. Biochimica et biophysica acta1768, 1976–90 (2007).

10.     Palmer, A. M. & Burns, M. A. Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer’s disease. Brain research645, 338–42 (1994).

11.     Lutz, O., Vrachopoulou, M. & Groves, M. J. Use of the Walden Product to evaluate the effect of amino acids on water structure. The Journal of pharmacy and pharmacology46, 698–703 (1994).

Rethinking our Diets -- 80/10/10 and Fruitarianism

October 8, 2013, 6:20 pm

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Although I have a rule for myself to not read consumer books about diet or health, despite not having much free time of late, I couldn’t resist the opportunity to speed-read through 80/10/10 by Dr. Douglas Graham recently.

I wasn’t able to see what all the fuss was about, knowing perfectly well how popular 80/10/10 is becoming.  There was but not one thing specifically insightful or interesting to report here.  Instead, despite what’s said by Dr. Graham to the contrary, I found the book to be a rehashing of what natural hygienists (like Dr. Emmet Densmore) had put forth in the past – only presented in a way to support the idea that humans had evolved to thrive on a vegan diet, mainly of fruit and, on average, no more than 10 percent of calories from fat and protein and no less than 80 percent of calories from carbohydrate.

But that’s not the purpose of this post; that is, to point out the errors, oversights, and half-truths in 80/10/10– of which there are many.  It is instead to urge a recalibration of how we should think about diets and the arguments that are put forth for them, so as to avoid the financial, emotional, and bodily harm already incurred by those who were in desperate need of help, and so willing to try anything.

But what are the most optimal foods, let alone diet?  From my own experiences and observations, you’ll never know for sure until you test them on yourself.  Further, it’s important to know that all fruits are not created equal, and we aren’t permitted to deduce that just because a food is a fruit – and not an animal product, grain, starch, or whatever else – that said fruit is the healthiest option of all for every person, in every situation.

Herd mentality, however, is the M.O. of diet movements, in which certain beliefs, like the ones above, get belched out from one member’s mouth to another, repeatedly, absent of understanding or reflection on the matter.  Among contemporary fruitarians, beliefs like:

• “Plant protein is superior to animal protein.”
• “Plants can supply all of a person’s protein requirements to thrive.”
• “Eating meat causes cancer, diabetes, heart disease, osteoporosis, acidosis.”
• “Because omnivores develop B12 deficiencies, too, the fact that B12 deficiencies develop in vegans cannot be used as an argument against vegan diets.”

Suffice it to say for now, none of these statements are true and in some cases the opposite is true (e.g., osteoporosis results from replacing animal protein with vegetable protein).  Anyone who says otherwise is utterly ignorant of all the data that exist on the topic. 

Although making the case for fruit being the most natural food for man does have validity – more so than does meat eating in my opinion – eating a gut-busting 12 bananas in one shot or chomping away on a jaw-cramping 2 heads of romaine lettuce in a salad are some of the least natural and most unusual of all things passed off as natural and healthy I have ever come across.

I mention this not by way of criticism, but because there are people who do appear to do well on 80/10/10 and fruitarianism long-term; that is, for a few years and sometimes even for decades (and I do not see why they would lie about this).  I merely mean that the assumption that a diet works if a person does well on it does not allow for the following:

• Whereabouts a person was in the continuum of health before embarking on the diet.
• The placebo effect.¹    
• All the other times when the diet might fail. 
• The possibility that another diet may have been more effective for a person.

It’s easy to be lured into this diet and lifestyle – especially if you watch one case after another of the dramatic transformational stories on YouTube, of which, actually, there aren’t thatmany cases.  Unfortunately, presented in this way they tend to have the most dramatic impact on us.  The realities, however, fall short of the claims and promises.  Just read about the cases in which the diet abysmally failed (like here).  Again, I ask, what did the diet and lifestyle look like before 80/10/10? 

Imposing a diet on others, just because it has worked for you, is a tactic employed by the loudest and most prominent leaders of diet movements – 80/10/10 is no exception.  In fact, 80/10/10 is probably the most egregious and glaring example of this.  Testimonials (i.e., “look at how well the diet worked for me”) do not count as proof that a diet will work for every person who tries it. 

By the same illogical token, I wouldn’t resist taking the occasion to say that my grandpa, who eats very limited amounts of fruit but doeseat meat and other animal-derived foods, to me, looks way healthier and more youthful than Dr. Graham does, who is about 20 years his junior.

Of course, I would like to see averages– of the people who succeed on the diet and the people who don’t.  Putting to rest, once and for all, whether certain people have much better, or even worse, responses to the diet.  This would be very easy to do.  Until then, the diet cannot be perceived as the panacea that we are led, or forced, to believe it is, by people who have no real education or training in nutrition or science whatsoever. 

Notwithstanding all this, there are 5 aspects of 80/10/10 (and, in general, fruitarianism) that I thought were worthy of listing here.  Having said all that’s occurred to me, and knowing that my readers would be served by a practical list of suggestions, I think the following is an appropriate place to end this post.

1. Simplifying your diet (and trimming the fat from other aspects of your life).  After all, fruitarianism eradicates all food groups but two, champions mono-meals, and discourages the use of supplements (with the exception of maybe vitamin B12).  The idea that a person needs massive amounts of protein, vitamins, minerals, antioxidants, and so forth at every meal and every day is, without a doubt, a weird and unnatural one.  Suffice it to say for now it’s not necessary in my estimation.
2. Eradicating the irrational and unsubstantiated fear of sugar, fruit, and carbohydrate (although the explanation as to why high carbohydrate diets and sugar are not harmful is voiced quite inaccurately in Dr. Graham’s book).
3. Learning to tune into your body’s cravings – namely for sugar, salt, and more food – and not suppressing them or feeling guilty for giving in to them.
4. At least recognizing the differences and at most systematically drawing comparisons between fruit and starches.
5. The importance of maintaining physical fitness and good sleep hygiene practices.

¹In other words, the simple act of adopting a new diet and lifestyle could have activated, or primed, self-healing mechanisms (for real).

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On a personal note, it looks like my pup’s days are coming to an end.  He was the most disobedient dog and tough as nails on the outside, but on the inside, shy and unconfident with an intense fear of abandonment and I never gave up on him.  I was so lucky to find a picture that taken on the first day I got him.

My Guest Post for 180 Degree Health

October 30, 2013, 6:55 pm

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Hey guys, 

My first guest post for Matt Stone's site went live today.  Here is a direct link:

Gram Negative Bacteria and Obesity 

If you don't know, Matt, who I've been in communication with for a few months now, runs a really interesting site where there's no dogma or rigid mindedness allowed.  Matt is open-minded, highly eager to continuously learn, and not afraid to make mistakes along the way, while owning up to them when he does.  So I deem myself honored to be able to contribute to his site.  

All the best, 

Andrew

Diet Dogma Rears Ugly Head Again: Become a Fat Burner, Eat Your Own Crap, and Live Longer

November 5, 2013, 2:13 am

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Holding my dog up against my chest moments before he had peacefully taken his last few breaths this past Saturday evening, I thought about how cold his hands and feet were; how slow his heart beat and breathing were; and just how much he had shrunk and atrophied.  Of course, these are all the consequences of aging, a topic that I try to avoid thinking about as all get out because thinking about aging inevitably leads to an inner dialogue about your own mortality, or the mortality of those close to you. 

Lo and behold, there is a great amount of money spent on all the things that could potentially delay the aging process and the advent of the diseases associated with it – including, but by far not limited to, hormone replacement therapy and massive vitamin supplementation.  Unfortunately, this desire to push back Father Time has spawned and perpetuated some pretty awful ideas which have no basis in any reasonable level of evidence. 

One such idea, actually a few related ideas that I’ll roll into one idea here, is to limit the amount of glucose our cells burn over the course of a lifetime, so as to turn on a primitive stress response mechanism called autophagy, a process whereby cells degrade and recycle their dysfunctional components in the face of nutrient depleted conditions.  Unfortunately, this necessarily entails burning proportionately more fatty acids for fuel (or what’s called being “fat adapted” in horribly egregious articles filled with wishful thinking like this one) and turning down thyroid functioning, or the rate at which we live, adaptations that are directly at odds with reaching our full potential as human beings.

Mainly, the physiological changes which I am most interested in are the increased secretion of ACTH, insulin, and beta-endorphins (anandamides and2-araichdonylglycerol [derived from arachidonic acid]) and decreased secretion and tissue responsiveness to the thyroid hormones– all of which are disease-promoting in excess, while incidentally predisposing to weight gain.  ACTH is a subject that deserves its own post.  Ditto for the beta-endorphins.  The discussion herein will center on the thyroid hormone, especially since I’m highly motivated at this moment to avoid all quibbling over insignificant details and minutiae at all costs.

Maintaining tissue responsiveness to hormones is, I believe, a key factor in slowing down the aging process.  Consider Progeria, a syndrome famous for producing an apparent accelerated aging in children.  Progeria is characterized by a massive reduction in the responsiveness of cells to all hormones – a defect thought to drive the degenerative conditions that appear in children with the condition.

 

A cell’s responsiveness to hormones is most sensitive when the stress hormones, free amino acids, and free fatty acids in the blood are low. For example, a deficiency of growth hormone, a stress hormone secreted by the pituitary gland, leads to an inflated sensitivity to the hormone insulin in adulthood.¹

Next, consider for a moment people who diet often.  Despite having normal lab tests these people will experience all the signs and symptoms of hypothyroidism.  This paradox indicates a reduced sensitivity of tissues to the thyroid hormones, brought about by the stress of under-eating.  In point of fact, the uptake of thyroid hormones into the central nervous system is impaired by high levels of the stress hormones, free amino acids, and free fatty acids.² In the central nervous system, the thyroid hormones, in conjunction with the sex hormones, are not only essential for brain development, but also for brain growth, repair, and maintenance in adulthood.³

A low carbohydrate diet, another self-imposed stressor, not only impairs the ability of cells to uptake thyroid hormone, but also hampers the conversion of T₄ (pro-hormone) to T₃ (active hormone) in the body or directs the conversion of T4 to reverse T₃ (inactive hormone), rather than T₃.  These conversion problems could alternatively explain the pattern of having normal lab tests and hypothyroid signs and symptoms.⁴ In the pituitary gland, for example, anything that inhibits the production of T₃ from T₄ disinhibits the release of TSH, resulting in the following pattern: ↑ TSH, ↑ T₄, and ↓ T₃.⁵

The thyroid hormones are the principle regulators of all the things concerned with metabolism, including the process of tissue repair and renewal.  Because the thyroid hormone both facilitates the release of glucose from the liver and stimulates the uptake and oxidation of glucose in the tissues outside the liver (thereby working antagonistically and synergistically with insulin, respectively) there’s really no surprise here.⁶ In fact, even topically applied active thyroid hormone accelerates wound healing and repair following injury.⁷

But in so turning up the metabolism by way of the thyroid and supplying nutrient replete conditions to cells, are we not incidentally shutting off the mysterious and magical powers of autophagy?

Another feature of Progeria, which animal models of Progeria and the like have unexpectedly found, is an increase in autophagy – an effect touted as highly desirable among Paleo, low-carbohydrate, and caloric restriction advocates.  The molecular mechanisms are not well understood, but it does help to explain, to me at least, why chronic dieters look so haggard and the opposite of healthy, vibrant, and attractive; sometimes, as if death has warmed over.  Simply put, autophagy is an adaptive response to metabolic stress that when chronically activated drives premature aging by inducing catabolic processes that outpace the renewal ability of cells.⁸ An increased oxidization of fat in preference to glucose is a key feature underlying this downward metabolic shift, as well as an impairment of mitochondrial respiration and a decline in ATP levels. 

As an aside, the fact that Internet diet gurus had made a claim – which probably led to undue misery – about their diets based on a study in a roundworm should piss you off.

The positiveassociation between resting metabolic rate and maximum lifespan may suggest two things.  The first is that without having to call upon the mysterious and magical powers of autophagy, a high resting metabolic rate accelerates cell protection and repair mechanisms by way of enhanced protein synthesis.  The second is that the thyroid hormones are efficiently acting on their target tissues on which they activate the uncoupling proteins, thereby diffusing the reductive stress imposed on cells (by for instance a sluggish metabolism) to discourage the formation of reactive oxygen species and oxidative stress.

Patented, synthetic thyroid hormone products are on their way to the market pending approval by the FDA and, from the outside looking in, they seem to be highly effective for all the conditions for which a deficiency of thyroid hormone directly cause, from easy fat gain to heart disease.  They also would eradicate the uncertainties associated with glandular products and the cardiovascular side effects associated with the synthetic products because thyroid hormones, to be effective, only really require identical big and bulky groups attached to each of their two tyrosine amino acid residues to restrict movement around the bond which holds these two tyrosine amino acid residues together via an ether linkage. (I wanted to blog about this in the past but I was 99.97% sure it would interest no one.) 

Whether we like it or not, autophagy will occur in all of our cells.  It is a primitive form of protection that allows cells to dispose of misfolded proteins, misassembled protein complexes, damaged mitochondria, and so forth.  There is absolutely no need or reason to force it to occur artificially with special diets – especially so if you’re already healthy.  Undue misery is sure to follow from this self-imposed deprivation.  Interestingly, all the conditions that bring about autophagy are at odds with the conditions that maximize our potential as organisms, and this entails the thyroid hormone and oxidation of glucose for fuel.  I think it’s time for us to toss the idea of diet-induced autophagy into the pile with the other worthless dogmas that have done little more than leave the landscape of diet and nutrition understanding in disarray. 

REFERENCES

1.       Bartke, A., Sun, L. Y. & Longo, V. Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol. Rev.93, 571–98 (2013).

2.       Hennemann, G. et al. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr. Rev.22,451–76 (2001).

3.       Correia, H. R., Balseiro, S. C. & de Areia, M. L. Are genes of human intelligence related to the metabolism of thyroid and steroids hormones? - endocrine changes may explain human evolution and higher intelligence. Med. Hypotheses65,1016–23 (2005).

4.       Araujo, R. L. et al. High-fat diet increases thyrotropin and oxygen consumption without altering circulating 3,5,3’-triiodothyronine (T3) and thyroxine in rats: the role of iodothyronine deiodinases, reverse T3 production, and whole-body fat oxidation. Endocrinology151, 3460–9 (2010).

5.       Larsen, P. R., Dick, T. E., Markovitz, B. P., Kaplan, M. M. & Gard, T. G. Inhibition of intrapituitary thyroxine to 3.5.3’-triiodothyronine conversion prevents the acute suppression of thyrotropin release by thyroxine in hypothyroid rats. J. Clin. Invest.64, 117–28 (1979).

6.       Brenta, G. Why can insulin resistance be a natural consequence of thyroid dysfunction? J. Thyroid Res.2011, 152850 (2011).

7.       Safer, J. D., Crawford, T. M. & Holick, M. F. Topical thyroid hormone accelerates wound healing in mice. Endocrinology146, 4425–30 (2005).

8.       Mariño, G. et al. Premature aging in mice activates a systemic metabolic response involving autophagy induction. Hum. Mol. Genet.17,2196–211 (2008).

Preserving Brain Function: Principles, Pitfalls, and Practical Conclusions

November 18, 2013, 9:30 am

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INTRODUCTION

I recently had the opportunity to attend a physician-only-lecture at a hospital about the use of ketogenic diets for the treatment of epilepsy in children.  If you at least casually follow the discourse on this dietary approach on the interwebz, especially with regard to the interest of effecting cures, you’d probably think that not only should all children with epilepsy be placed on a ketogenic diet, but that failing to do so amounts to nothing less than egregious malpractice; another failure of the medical profession to employ the best treatments available because of the inherent evils of pharmaceutical companies and of patent medicine.

The truth is, although there are a myriad of proposed mechanisms as far as how ketogenic diets work (review articles have been rapidly accumulating in many different medical publications) no one can really say one way or the other, and to suggest otherwise points to an utter lack of thoroughness in reading of the literature on the topic, a bias in the interpretation of said literature, or both.

I say this in part by way of criticism and disgust, and in part because I know how complex neuropsychobiology and neuropharmacology (and related disciplines) are and have always been owing mainly, in my estimation, to the lack of experimental methods sophisticated enough to draw definitive conclusions; in particular, the inability to convert correlational data derived from such experimentation to proof of cause and effect.  What is clear, however, is that there is an energy deficiency in various neurological disorders including epilepsy; that is to say, a deficiency of glucose and oxygen, the primary substrates by which cells of the nervous system generate energy, which is evidenced by a respiratory quotient[*]that stabilizes at 1.0 therein.

Therefore, the most parsimonious explanation for why ketogenic diets work, when they do, is that the ketone bodies so generated are supplying neurons (and glial cells) with energy, which would normally be provided by glucose, thereby preventing these cells from literally succumbing to the demands placed on them, by all the stressors they have to deal with on a moment to moment basis.  Why then do children with epilepsy develop energy deficiency problems?  Or stated another way, why do they lose the ability to generate energy by way of the oxidative metabolism of glucose, in which carbon dioxide, rather than lactic acid, is produced?  This is a question too complex and speculative to have a discussion on for this audience and for the space I’ve allotted myself here.  Just know for now that this mismatch, between energy reserves and energy demands, represents the essence of the problem.

I’m fully aware of the fact that my post thus far, five paragraphs in, lacks a thesis of any kind whatsoever.  Annoying, I know.  I also know readers in particular appreciate a neat list of recommendations based on a solid foundation of evidence that should have been presented in the body of the article.

But rather than do that, because of the speculative nature of the subject matter, I want to finish up this post by doing two things.  The first is to describe, in the simplest way possible, the way in which the brain should work, especially with regard to energy and stress. The second is to have a general discussion of a few, in my estimation, means to preserve and optimize this system, based on the preceding theoretical discussion. 

By endeavoring to focus on mechanisms (which is the best we could do at this point if we wish to avoid overstating any point) you should see why the focus on particular foods (e.g. the sweet potato) or painting ourselves into a corner by restricting our diets to only those foods that have been deemed “evolutionarily-approved” (whatever that exactly means), is not only utterly silly, but also arbitrary and fatally flawed.

ENERGY DEMANDS VS. ENERGY RESERVES

Energy problems should be expected to manifest in the brain first and most notably because the brain, per unit weight, is the most voracious consumer of energy, namely glucose, of all the organs in the body. (The brain represents merely 2 percent of the body’s total weight yet accounts for 15 percent of the body’s total energy expenditure.) So when a deficiency of energy does occur, the brain and associated structures, which coordinate processes as diverse as memory, learning, mood, and behavior, are impacted quite notably.

One reason as to why the ketogenic diet may ‘work’ is that ketone bodies have a sedative effect in the brain, like the neurotransmitters gamma-aminobutyric acid (GABA) and gamma-hydroxybutyric acid (GHB), thereby protectively reducing the energy demands so as to prevent cells from literally overworking themselves to the point of malfunction and death.

What first got me thinking about the similarities between GABA, GHB, and ketone bodies was an internship I had at one of the major poison control centers in the U.S., where it was drilled into the interns by the medical director that valproic acid (brand name Depakene), a drug used for seizures and structurally similar to both GABA and ketone bodies, would when taken in excess cause ammonia to accumulate to toxic levels in the blood (for which carnitine would be given as an antidote.) Suffice it to say here, the fact that the toxic accumulation of ammonia is a side effect of valproic acid reinforces the idea that the ketone bodies and valproic acid are acting in the ways that GABA normally would in the brain.

In the brain, under normal circumstances GABA derives from glucose by way of the highly prevalent brain amino acid glutamate.  In the absence or improper use of glucose, valproic acid, or ketone bodies – those compounds that are structurally similar to GABA – are probably ‘filling in’ for the glucose-derived GABA that, for whatever reason, is missing.[†]The synthesis of GABA is intimately tied to the oxidative metabolism of glucose, which entails the use of enzymes found exclusively in the brain.

In all, valproic acid mimics the effects of GABA, and the ketone bodies are probably acting in a similar yet more basic way, owing to their structural similarity.[‡]The not-so-rigid dichotomy between the excitatory and the inhibitory systems in the brain is thusly shifted to favor the latter system, whereby the flow of electrical signals through various brain pathways defensively becomes depressed.  Lowering the energy charge in the cell (i.e. depleting ATP) has a similar effect, activating the enzymes that synthesize GABA from glucose and depleting brain dopamine (evidenced by elevated dopamine turnover rates when GABA is introduced exogenously in relatively large amounts).  These enzymes are dependent on vitamin B6, a deficiency of which predisposes to seizures in children and adults. 

In healthy and young people, this system should kick in in the face of prolonged or excessive stress, which rapidly depletes energy stores in the brain.  Healthy and young people should also be more resilient to ‘running out’ of energy, owing partly to the efficiency by which the glucocorticoid system operates in their bodies since the glucocorticoids, in excess, interfere with the storage of glucose in brain cells.[§]  The turnover of GABA is many times higher than that of other neurotransmitters, such as acetylcholine and dopamine, suggesting that the brain has many homeostatic mechanisms in place to maintain GABA concentrations within a certain physiological range under a wide range of external conditions.

SUMMARY/CONCLUSIONS

1. To me, like the use of synthetic glucocorticoid products, ketogenic diets, as of now, is nothing more than a last-ditch effort when all other means fail.  Merely a symptomatic solution, there are probably long-term consequences associated with having this system chronically active and in overdrive.  I’ve heard mentioned offhand by a Paleo blogger that high fat diets relieve anxiety in rats by way of GABA, apparently without reading the study that was linked to support this claim.  Some of the beneficial effects of these diets can be attributed to the surge in glucose brought about by the stress hormones, temporarily relieving the energy stress caused by the deficiency of glucose, so as to prevent the irreversible degradation of brain structural material that would otherwise supply that energy, as well as GABA.  At the same time, owing to their purported sedative and inhibitory effects in the brain, the ketone bodies themselves are neuroprotective.  However, the ketone bodies incidentally block the oxidative metabolism of glucose.

2. Vitamin B6 is a cofactor (tightly bound) of two enzymes: one involved in the synthesis of glucose-derived glutamate and one that makes GABA from glutamate.  A deficiency of vitamin B6 decreases its concentrations in the cells that make GABA, favoring the inactive state of the two vitamin B6-dependent enzymes involved in making GABA.  In point of fact, a diet deficient in vitamin B6 in children and adults can lead to seizures that respond dramatically to treatments that include the vitamin.[**]

3. The amino acids taurine and glycine have similar receptor interaction patterns as GABA.  As such, taurine and glycine induce 'inhibitory' effects in the regions of the brain where they are active.  Animal studies show that chronically low intake of these amino acids, or their precursors, could lead to irreversible degenerative changes in the brain, eyes, and spinal cord.

4. The rationale behind the use of pharmaceutical anti-depressants (i.e. stimulants) stems largely from experiments in which correlations are made between levels of certain neurotransmitters in the brain (or their metabolites in the blood and urine) and the ability of animals to which stressors are imposed, to cope and to avoid developing conditioned helplessness, where the animals simply give up and fail to perform effective avoidance responses to subsequent stressors.

Whether these measured neurotransmitters are, in fact, the cause of depression – a condition that is already poorly defined – is uncertain, as, if you recall, the wherewithal currently available to study these relationships lack the requisite sophistication.

However, as I’ve stated before, animals permitted to develop effective means to cope with stressors have lower levels of anxiety, which, in turn, make then more effective at coping with stressors.  GABA, and probably the ketone bodies and valproic acid, helps individuals cope more effectively with various stressors, in part by reducing anxiety, without adding to the energy stress like the anti-depressants, which now bear the black box warning, the most serious of all warnings, alerting clinicians and patients of an increased risk of suicidal thoughts and behaviors in children and young adults.  Cortisol levels are also lower in animals with effective coping mechanisms.  To put things in more concrete terms, the ability to turn fears and worries into plans and actions soften all of the energy problems described above and help to preserve brain functioning. 

5. The rapidity with which learning is acquired I think reflects how efficiently the systems in the brain and the body ‘work’ to maintain energy availability and the delicate balance among dopamine, serotonin, cortisol, noradrenalin and GABA.

The distinction, however, between learning and simple arousal and stimulation should be made and recognized, especially when interpreting experiments designed to study the ins and outs of learning.  Suffice it to say here, reducing anxiety and employing effective coping techniques facilitates the acquisition of the biochemical and physical changes in the brain that are thought to signify learning.  Learning implies adaptability to changes in the environment, the capacity for which, according to Han Selye and others, determines our susceptibility to disease, aging, and death.

6. Maintaining steady blood glucose levels helps to prevent the drastic changes in glucose availability to the brain, of which merely transient interruptions can cause harm.  I’ve found through my own experimentation that small, mixed meals spaced out equally throughout the day are superior to large, intermittent meals.

Dear reader,

From hereon out, I’ll be writing for Matt Stone’s site, 180degreehealth, somewhat regularly as a site author, so some of my future articles will be posted there, not here.  I’ll be sure to let you know each time one of my posts go live over there.

Happy Thanksgiving,

Andrew

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[*]A respiratory quotient of 1.0 indicates pure glucose use in relation to protein and fat.

[†]Glucose can be converted to GABA, but ketone bodies and fatty acids can’t.

[‡]Because I was asked once already (email), and because its’ probably on the minds of readers now, I’ll mention here so as to dodge answering the same question that as a supplement, GABA is probably useless, as GABA, being highly charged, is unlikely to cross into the brain from the blood, and very little GABA is found outside the central nervous system.

[§]The primary glucocorticoid secreted by the adrenal cortices is hydrocortisone, or cortisol.

[**]Since there are many other vitamin B6-dependent enzymes in the brain, we can’t say for sure that the improvements seen upon the addition of vitamin B6 are due to effects on the GABA system only.   

Formulate Your Own Supplements

November 27, 2013, 11:25 pm

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Generally, I don’t take supplements.  But when I do, I buy them in their pure, powdered form and encapsulate them myself. 

A supplement company does the same thing, only on a larger scale.  It acquires pure, powdered supplements from one of the few supplement manufacturers and packages them into dosage units (e.g. capsules or tablets).  Then, it bottles those dosage units into containers that bear the name of its company, before selling them, at a premium, to wholesalers and retailers.

Not only is doing it on your own cheaper, but it also allows you, the user, to decide on the type of dilutant[*]to use, as well as to avoid certain excipients that may be necessary on a large production scale, but unnecessary (and possibly allergenic) for making supplements at home for your own use.  You also get to create your own unique mixtures of supplements, and to vary the proportions of the supplements in those mixtures – handy for self-experimentation purposes.[†]And, lest the requirement for comprehensiveness be disregarded, some powdered supplements taste awful, so encapsulating them automatically gets around this taste factor.

Here I’ll show you how to make your own supplement capsules, without a capsule-making machine.  You’ll need a digital scale that is sensitive enough to weigh in 100 mg increments;[‡]empty gelatin capsules; and, of course, the powdered supplement (and possibly a dilutant) you wish to encapsulate.

STEPS

1. Determine the number of capsules you wish to fill and the total amount of powdered supplement needed.

As an example, I will formulate 30 capsules, each containing 10 mg of vitamin B6.  Therefore, in total, I will need 300 mg of (pure) vitamin B6 powder (30 x 10).

2. Choose the right capsule size.

There are eight sizes of gelatin capsules available for human use, from 5 (the smallest) to 000 (the largest), with each capsule size providing a range of volume capacity that is dependent on the characteristics (e.g. density) of the powdered supplement.  The smallest possible capsule size should be selected because larger capsules are harder to swallow and require more dilutant.

There are two methods available in the literature to determine the appropriate capsule.  I’ll only describe one of them here: the rule of 6.  The rule of 6 is simple.  It entails subtracting the capsule size (column 2) from 6 (column 1), which yields the fill weight of the capsule in grains (column 3).  Column 4 represents column 3 in milligrams (1 grain = 65 mg).

Sixes	Capsule size	Fill weight (grains)	Fill weight (mg)
6	0	6	390
6	1	5	325
6	2	4	260
6	3	3	195
6	4	2	130
6	5	1	65

3. Calculate the amount of dilutant needed.

Since each of my vitamin B6 capsules contains 10 mg, the smallest possible capsule size is 5, whose total fill weight is 65 milligrams.  Thus, each capsule requires 55 mg of dilutant to fill out the rest of the capsule’s volume.  In total, 1,650 mg of dilutantis needed (55 x 30) for the entire ‘recipe.’

4. Using your digital scale, weigh out the total amounts of the powdered supplement and the dilutant.

For my vitamin B6 capsules, I will weigh out 300 mg of (pure) vitamin B6 powder and 1,650 mg of dilutant.  The dilutant I typically use is powdered sugar.  However, you could use any other dilutant, as long as it is extremely fine in texture. (You’ll see why in the last step.) 

 

5. Mix the powdered supplement and the dilutant together thoroughly. (I use a mortar and pestle.) 

6. Fill the capsules.

First, place the thoroughly mixed powder in a heap onto a clean flat surface.  Then, after separating the body of the capsule from the cap, take the body and tap it, open side down, on the deepest part of the heap until the body of the capsule is packed as much as possible with the powdered mixture. (If the supplement and dilutant are not powdered finely into nearly dust, they won’t pack into the body of the capsule.)  Finally, place the cap back onto the body and repeat the process with the remaining empty capsules.[§]

REFERENCE

Zatz, J.L., & Teixeira, M. G. (2005). Pharmaceutical Calculations (4th ed., pp. 441-445). New Jersey: John Wiley  & Sons, Inc.

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[*] An inert powder (I use powdered sugar) that is added if there is not enough encapsulated material to fill the full volume of a capsule.  Also, if the dosage for the entire recipe is so small, such that it falls below the minimal weighable ability of your digital scale, then a dilutant can be employed to perform a trituration, an elegant process in which a powdered supplement is intimately dispersed with a dilutant.  I won’t describe triturations in this post.

[†] In my opinion, this is one of the greatest advantages of formulating on your own.  Supplement companies almost always stuff excessive amounts of supplements into each dosage unit and create the most nonsensical blends of those supplements.

[‡] You can get one cheaply on eBay, for instance.

[§] It's important to point out that only the body of the capsule should be filled so as to comply with the calculation for the amount of dilutant needed; the cap is used only to retain the powder in the body.

My Guest Post for 180 Degree Health Newsletter

December 31, 2013, 9:09 pm

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Dear reader,

My guest post for Matt Stone’s January newsletter has just gone live.  You can get to it from here.  One of my main purposes for writing about physical attractiveness was to create awareness, generate interest, and initiate a dialogue on the topic – a topic that I think most people have at least thought about, but rarely in an organized or practical way.  By no means is the article meant to be final.  It is merely a starting point for as much continuing investigation as you have the urge and time for.  Please don’t hesitate to share your comments on the forums attached to the newsletter over there; I look forward to reading them. 

                               

Happy New Year!

Andrew

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Straight Talk on Fats, Metabolism, and Body Temperature

February 6, 2014, 5:27 am

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It’s popular to talk about certain foods that stimulate thermogenesis, or heat production, as a means to aid in weight loss – the most fashionable of which is probably coconut oil.   While that’s all good and desirable, the heat generated upon eating makes a relatively small contribution when compared to all the heat generated by all the reactions in the body, including the process of keeping the gut in a state of continuous readiness to digest and assimilate the next meal. 

All metabolic processes in the body generate heat.  In other words, metabolism is unavoidably heat-generating.  The minimum amount of heat generation is set by the resting metabolic rate,[*] which is, in turn, set by the thyroid hormone, among other ancillary factors.  The heat generated from eating – directly related to the energy costs of digesting, absorbing, and converting the myriad of components of food into their appropriate storage forms – adds to the heat generated by the resting metabolic rate.  As far as diet-related heat generation is concerned, of all the macronutrients, protein has the greatest effect.  Carbohydrate has a lesser effect than protein, and fat has a negligible effect.  

Eating can also activate uncoupling proteins, whose function is to process nutrients for heat rather than energy in the mitochondria.  Although the extent to which this adds to heat generation is probably minor, the intensity with which these uncoupling proteins generate heat is governed and fine-tuned by hormones, in particular thyroid hormone and noradrenalin.¹ Uncoupling helps to decrease oxidative stress, while maintaining a high rate of ATP generation – an example of a substrate cycle in which a substance (in this case a proton gradient across the inner mitochondrial membrane) is generated and subsequently dissipated, in a reverse reaction using different enzymes, wasting energy in the process.²  

Although fat has a negligible effect in terms of increasing heat generation after eating, it does play an important role in regulating body temperature, as one of the myriad of reactions mentioned above not involved with eating.  This reaction, in which fat is used to generate heat, is another example of a substrate cycle.  In essence, triacylglycerol, composed of 3 fatty acids and 1 glycerol, is broken down (lipolysis) and the fatty acids subsequently released are taken back up by the releasing fat cell and esterified into triacylglycerol therein.[†]  This process, lipolysis and esterification, constitutes one substrate cycle, and the heat generated from the reactions in said cycle plays an even greater role in regulating body temperature than the physical role of fat as an insulator!  Like the uncoupling proteins, this substrate cycle is regulated by thyroid hormone and noradrenaline.

At least on the order of days, weeks, or even months, the addition of a particular food into a person’s diet in the absence of other changes will probably not have a significant effect in terms of changing a person’s body fat and weight.  A case in point is MCT oil, which has been promoted hard for its ability to aid in weight loss.  The results of clinical studies in which MCT oil was put up against a different oil and weight changes were tracked over time have been overwhelmingly unimpressive to say the least.  Yet, a value to which it is not legitimately entitled continues to be placed on MCT oil by the likes of Dave Asprey and the atrocity that is the Bulletproof Diet.

However, the effects of changing the composition of the fats in a person’s diet are not as ineffectual as I may have indicated above.  Interesting are the experiments in which behavioral changes are observed upon changing the fatty acid composition of the diet of an animal kept in captivity.  Lizards, for instance, will become more active at night and prefer to spend more time in colder places so their bodies become colder by increasing the PUFA in their diets; on the other hand, reducing the PUFA in their diets will elicit the opposite behavior.  For what it’s worth, perhaps nothing to you, I’ve always had a low tolerance to heat – the slightest increase in temperature would make me break out in a sweat, and make my nose stuffy and ears bright red.  But since reducing the fat and increasing the sugar in my diet (effectively reducing the PUFA in my body), my tolerance to heat has improved and I layer up more than I used to as the ambient temperature goes down.

                                                                                           

Of course, there is a ceiling on the degree to which the metabolic rate can be increased, being limited by the risk of overheating from running things so quickly, among other things.  But the main factor that limits a person’s metabolic rate is the availability of oxygen. 

Oxygen decreases the reliance on non-oxidative metabolism, and, merely by the law of mass action, leads to more energy generation and less fat storage.  I suppose exercise, by strengthening the heart and respiratory system – and therefore blood circulation and lung ventilation – would help to increase the efficiency of the delivery of oxygen to tissues.  However, exercise need not be heavy and exhaustive to be effective, only regular and consistent.  Isotonic movements, in which tension is applied and work is accomplished, is probably less stressful than isometric movements, in which no work is performed but much heat is generated.[‡]  The great force and resistance involved in isometric movements tends to compress blood vessels to where blood perfusion becomes greatly reduced so as to create a significant degree of tissue hypoxia, resulting in a greater reliance on non-oxidative metabolism and higher levels of lactate.  Bulging muscles may look good (I guess?) but they appear to come at a price.

But other stressors can decrease the availability of oxygen to tissues, in part by increasing the use of fat for fuel.  More glucose is used non-oxidatively as a result, which, in turn, depletes glycogen and increases lactate and acidity.  As it happens, this stress-induced oxygen depletion is usually offset because the increase in acidity and lactate increases the efficiency with which oxygen moves from the blood to tissues by way of the Bohr effect and the increase in 2,3-diphosphoglycerate (2,3-DPG) within red blood cells.  The ratio of pyruvate to lactate is one of the best indicators as to the extent of oxidative versus non-oxidative metabolism.

A healthy and robust metabolism implies low levels of the stress hormones.   Limiting the stress hormones limits the use of fat for fuel and the production of lactate and ensures the efficient turnover of ATP.  As it happens, ATP, bearing a high density of negative charge, binds and keeps noradrenalin, positively charged under physiological conditions, inside storage ‘bubbles’ inside cells, regulating their release.[§] (The fact that both ATP and noradrenalin are involved in pain transmission further serves to explain their co-localization inside cells.) The carbon dioxide and heat generated as by products of metabolism both increase the delivery of oxygen to tissues, like lactate does, and, stated above, more oxygen means more energy generation and less fat storage.  The oxidative metabolism of glucose generates the most heat, carbon dioxide, and ATP.

The capacity to use the increased oxygen is limited by the availability of all the B vitamins, including thiamin, riboflavin, niacin, pantothenic acid, and others.  A regular and adequate supply of these vitamins improves the reserve and capacity of the Krebs cycle and respiratory chain.  The active thyroid hormone, T₃, stimulates all the reactions involved in the oxidative metabolism of glucose, increasing the requirement for all the B vitamins.  The ingestion of simple carbohydrate also increases the requirement for the B vitamins, in particular thiamin.³

If the body temperature cannot be kept up naturally, the next best option is to keep warm artificially as to keep all the chemical processes in the body operating as fast as they would at higher temperatures.  Trapped air is particularly important to conserve heat in cold ambient temperatures.  Therefore insulation, which for us means clothing, is an important factor determining the amount of heat lost from the body.  The thickness, in particular, as well as the looseness and color of the clothing determines how effective it is as an insulator. 

Questions I get a lot relate to digestion and the simplest thing to do with problems concerned with digestion is to increase the body temperature as high as to what’s tolerable.  Not only is digestion, and therefore the extraction of nutrients, slower at lower temperatures, but parasites and bacteria also have a greater chance of breaking through the gut lining to cause serious infections at those temperatures.  To make matters worse, the activity of the immune system decreases as the temperature decreases, so the likelihood of mounting an effective immune response to the pathogens that do get into the body decreases, too.[**]  Within narrow limits, the temperature at which the body ‘sets’ is determined by the composition of the fats in a person’s diet: the most protective fats are the ones that are the most saturated.

The percentage of PUFA in tissues limits the rate of energy expenditure.  One reason for this is that at higher temperatures, the spontaneous oxidation of PUFA – therefore the production toxins – increases as the temperature increases.  Since reading about hibernation as it relates to PUFA in HLAF, I’ve been thinking more and more about this idea.  Lo and behold, squirrels, professional hibernators, must carefully eat just the right amount and kinds of nuts and seeds in order to store enough PUFA in their tissues for a successful hibernation through the winter, but not so much as to disrupt hibernation from the excessive production of toxic PUFA oxidation products.

Although obesity in humans is associated with a shorter lifespan, in wild animals there is no such association, unless they are domesticated and deliberately fattened by humans.  Obviously a multifactorial and complex matter, the saturation index and therefore the fat composition of the diet, is one factor that may explain these associations.⁴

log (maximum lifespan years)

Combined with the observation that a higher (resting) energy expenditure is generally associated with a longer lifespan^5,6 we are beginning to move even further away from the idea that fat is merely an inert sink in to which surplus nutrients are converted and stored until they are needed elsewhere in the body. 

The formation of fat from carbohydrate is an extremely inefficient process – only by eating carbohydrate in incredible amounts over long periods of time will a person begin to create and accumulate fat made from carbohydrate.⁷ The conversion of carbohydrate to fat is simply a highly energy-consuming process and the activity of the fat synthesizing enzymes is not nearly as active as they are in other animals, like birds and rodents.  So the most efficient way to change the fat composition of the body is by adjusting the fat composition of the diet.  Butter, cocoa butter, tallow, and suet are among some of the most saturated and stable fats currently known.  Good quality chocolate is unusually high in the commonest saturated fats in mammals: palmitate and stearate.  Shifting the diet to include more of these fats and less of more unsaturated fats is sufficient to bring about the positive changes discussed up to now.

Regarding lab tests to assess the state of a person’s metabolism, unless the person is experienced interpreting those tests, tests aren’t as important or informative as signs and symptoms are.

For instance, and because I received this question recently, blood levels of histamine are useless because, as it happens, histamine is concentrated locally.  So regardless of normal, or even low, levels of histamine in the blood, a person could still be exposed to high amounts of histamine (and would benefit from an anti-histaminic agent – my personal favorites being meclizine and diphenhydramine.)

Furthermore, having normal blood glucose levels, as deemed by the “establishment,” does not as a matter of course imply that there is a normal use of glucose by cells.  So despite normal blood glucose levels, it would be impossible to rule out the existence of a deficit in energy production resulting from the inadequate oxidative metabolism of glucose.  By the same token, high blood glucose levels do not necessarily spell gloom and doom; in fact, it could mean quite the opposite.  If cells are burning glucose intensely, for instance, certain hormones are released that in turn stimulate the liver to make more glucose in order to keep up with the increased demands for glucose.  A case in point is exercise, during which glucose levels increase at the same time muscles are vigorously burning glucose.

In cases such as these, a doctor may have no choice but to declare a clean bill of health when the patient feels anything but.  Or, even worse, they may result in treatments that are 180 degrees off the mark.  I’ve read too many cases like the one in which a person was declared to have diabetes and was treated with drugs that, in one way or another, decrease blood glucose levels despite the fact that the person’s symptoms did not line up with that diagnosis all along. 

I say all this to say that blood tests are not foolproof in that when interpreting them, it should be remembered that biological markers are dynamic in nature, and one test result merely represent a snapshot in time.  In many cases, a proper diagnosis isn’t possible in the absence of multiple tests under different conditions, such as when the patient is sick versus well.  Given the complexity of diseases and the variability among people, arriving at an accurate diagnosis is an art as much as it is a science, guided by intuition as much as by years of experience and practice.  Sometimes, the response to an empirical treatment is used to make a diagnosis.

Of all the signs and symptoms, monitoring the axillary body temperature every morning will yield the biggest bang for your buck.  The temperature to aim for is about 98° F.  The body temperature, in conjunction with improvements in other non-specific signs and symptoms (e.g. fatigue, apathy, drowsiness, mental depression) and general well-being should be used to guide treatment decisions.  Exercise, including isotonic contractions, improves cardiopulmonary fitness, and therefore the delivery of oxygen, and increases musculature and bone density – both of which increase the resting metabolic rate and the capacity for heat regulation.  Small meals consisting of sugar and protein throughout the day helps to keep the blood sugar up and the stress hormones down.  Since the conversion of carbohydrate to fat is so inefficient, adding small amounts of fat in the diet – in particular good quality chocolate, butter, tallow, and suet – is protective.

REFERENCES

1.       Hernández, A. & Obregón, M. J. Triiodothyronine amplifies the adrenergic stimulation of uncoupling protein expression in rat brown adipocytes. Am. J. Physiol. Endocrinol. Metab.278, E769–77 (2000).

2.       Brand, M. D. Uncoupling to survive? The role of mitochondrial inefficiency in ageing. Exp. Gerontol.35,811–20 (2000).

3.       Lonsdale, D. A review of the biochemistry, metabolism and clinical benefits of thiamin(e) and its derivatives. Evid. Based. Complement. Alternat. Med.3, 49–59 (2006).

4.       Pamplona, R. et al. Mitochondrial membrane peroxidizability index is inversely related to maximum life span in mammals. J. Lipid Res.39, 1989–94 (1998).

5.       Speakman, J. R. et al. Uncoupled and surviving: individual mice with high metabolism have greater mitochondrial uncoupling and live longer. Aging Cell3, 87–95 (2004).

6.       Speakman, J. R., Selman, C., McLaren, J. S. & Harper, E. J. Living fast, dying when? The link between aging and energetics. J. Nutr.132, 1583S–97S (2002).

7.       Acheson, K. J. et al. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am. J. Clin. Nutr.48, 240–7 (1988).

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[*] The metabolism required to maintain life.

[†] Because glycerol is not taken back up into fat cells as efficiently as glucose is, for every round of this substrate cycle, glucose is taken up from the blood and converted to glycerol in fat cells.

[‡] Imagine straining at stool while on the toilet as an example of an isometric movement.

[§] Noradrenalin bears a positive charge under physiological conditions because the acidity (pKa) of its amine groups is less than the acidity inside cells.  So, more noradrenalin’s amine groups are protonated, and therefore positively charged, under physiological conditions, allowing them to form salt linkages with negatively charged ATP molecules.

[**] Fats also alter the immune system directly.  For instance, omega-3 fatty acids suppress the immune system, decreasing the resistance to infections and wound healing; on the other hand, saturated fats do not suppress the immune system in the same way.