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Energy Metabolism Governs Everything
That was not an exaggeration. Everything.
Last year around this time I wrote What I’m Doing for Allergies, which included an extensive protocol based on biochemical reasoning and some randomized controlled trials, which reduced my allergies by 80-90%.
This year, I am not doing anything for allergies.
Why? Because the spike of tree pollen that usually drives the onset of my seasonal allergies occurred by complete coincidence two days before I started phase II of my biochemical optimization, wherein I added riboflavin to my biotin supplementation. For those two days, my allergies came with their usual onslaught. I did not want to change my diet or supplements in any way, as that would interfere with the interpretation of my highly controlled experiments. So, I simply dealt with it by rinsing my nose with a neti pot, washing my eyes in warm water, taking a shower, and changing my clothes, every single time I came in from the outdoors.
And then I added riboflavin. Boom. Gone.
The allergies just disappeared two days after they arrived.
I was not adding riboflavin to help my allergies. I was adding it to treat a rare genetic defect I am heterozygous for that causes a riboflavin-responsive respiratory chain disorder.
I will be writing about my experience with high-dose biotin in phase 1 soon, after I finish analyzing all my data. I will write up my experience with riboflavin in phase II once I am finished with phase II. I am currently a month into it.
Subsequently, I found that spending hours hiking in the forest during the peak of tree pollen season could generate minor allergy symptoms, and that this seemed to create some residual minor allergy in the week following. However, I currently spend many hours a day outside in the city, it is still peak tree pollen season, I do not use a neti pot, do not change my clothes, do not take a shower just because I was outside, do not take any supplements for allergies, and I am simply allergy-free.
Fixing my energy metabolism has proven to be radically more effective and radically simpler in its eradication of my allergies than focusing on treating the allergies themselves.
Because energy metabolism governs everything, and allergies are no exception.
In the May Live Q&A, we discussed how a problem in the respiratory chain could cause autoimmunity. In this particular case, low ATP compromised the absorption and distribution of minerals, including zinc, and compromised the oxidation of NADH to NAD+. The person also has a genetic impairment in the zinc-dependent enzyme acetaldehyde dehydrogenase, which is responsible for the second step in vitamin A activation. This results in a triple-hit against vitamin A activation — one genetic, one from zinc deficiency, and one from a high NADH/NAD+ ratio — and results in low retinoic acid levels regardless of the supply of vitamin A. Improving the supply of vitamin A can help, but it cannot fully repair the situation and eventually will lead to vitamin A toxicity symptoms from an accumulation of retinyl esters before the vitamin A deficiency symptoms are ever fully resolved. Since retinoic acid prevents autoimmunity, the energy metabolism impairment causes an autoimmune condition.
This clip will be released for free later this week.
It is not necessary to be able to map out the exact biochemical details of how any particular impairment in energy metabolism manifests in any particular clinical condition. This is because energy contains primacy over everything and this is true because of the laws of physics, which trump every other particularity of biology.
The simplest way to view this is as follows:
The cellular utilization of energy dictates whether things go wrong or right, and how wrong or right they go.
All other genetic and environmental factors, including nutrients, toxins, and stress, come together to dictate what in particular goes wrong or right.
As a general rule, this means that the most root-cause actionable item from among several actionable items will always be the one that impacts energy metabolism, and this should always take the primacy of action.
However, there are two exceptions:
One is an outright emergency. For example, if you have a screwdriver stuck in your eye, the most important priority is to take it out as safely and painlessly as possible. Nevertheless, if you have a 10% impairment in your rate of energy production, you will be slightly more likely to get a screwdriver in your eye as a result of impaired neuromuscular coordination and even with otherwise good nutrition you will have a slower rate of healing that will increase the risk of scar tissue. Thus, even here energy metabolism is relevant.
The other is a chronic condition caused by a dramatic impairment in a particular biological process that is dramatically more severe than any impairment in energy metabolism.
Take, for example, a “complete” penetrance version of cystic fibrosis. Most cystic fibrosis genes have an average of 71.3% penetrance, meaning almost 30% of the people who have the genes do not develop the disease. However, some extremely rare versions have apparent 100% penetrance. My guess is with a larger sample it is less than 100%, but let’s take this at face value.
Cystic fibrosis is a defect in an ATP-dependent transporter that leads to clinical effects as a result of excessively thick mucous. The main endogenous defense against excessively thick mucous is glutathione, which is synthesized using energy in the form of magnesium-ATP, and which is recycled using energy derived from glucose in the pentose phosphate pathway. Thus, for someone with a 71.3% prevalence cystic fibrosis gene, their supply of ATP and the activity of their pentose phosphate pathway is very likely to modify their risk. For someone with an extremely rare “complete” penetrance gene, their ability to decrease their risk by working on energy metabolism will be far lower.
However, I do not trust the “complete” effects of any gene ever since I learned of a child with an inexorably “lethal” holocarboxylase synthetase mutation kept alive with 1.2 grams of biotin per day, described in When High-Dose Biotin is Truly Needed.
Now, you could also point out that if those impacted by the “normal” 71.3%-prevalence cystic fibrosis genes had a genetic or nutritional impairment in glutathione synthesis, this would also modify their disease risk. This is consistent with the fact that oral or inhaled glutathione provides some modest benefit to cystic fibrosis patients. My point, though, is that if there is a defect in energy metabolism, this will compromise the synthesis and recycling of glutathione as well as the function of the specific transporter whose impairment is the “single cause” of the disease, and will exert greater influence than a more specific impairment in glutathione synthesis.
In most non-emergency cases, someone is likely to have some impairment in their energy metabolism, since healthy energy metabolism requires all of the B vitamins, all of the electrolytes, iron, copper, and sulfur, is impaired by diabetes, hypothyroidism, and hypoadrenalism, and is impaired by hundreds of different genetic defects that are each rare on their own, but for which carrier status — which typically confers 50% of the biochemical defect — is collectively common. I would argue that in nearly all of these cases, more will be gained from fixing energy metabolism than from working on the specific thing gone wrong, and in nearly all cases energy metabolism should be worked on first.
The reason this principle is so universal is because of the laws of physics.
The Laws of Thermodynamics
There are four principle laws of thermodynamics, and we are concerned mostly with the second. These are the four:
The zeroeth law of thermodynamics essentially states that all heat is fungible; that is, all heat has the same quantitative characteristics and is fully interchangeable. This makes the math discussed in all the other laws make sense.
The first law of thermodynamics essentially restates the law of conservation of energy in thermodynamic terms. Energy can be transformed, but it can be neither created nor destroyed.
The second law of thermodynamics states that any closed system will, over time, reach the maximum state of entropy possible for a given amount of internal energy, and that only an input of energy can reverse the tendency toward entropy. Entropy can most intuitively be described as disorder, where this refers to the random mixing of things according to their probability distributions. From this we can conclude that there is a universal imperative toward greater and greater disorder, and the only defense against this disorder is energy.
The third law of thermodynamics states that the entropy of a system approaches zero as its temperature approaches absolute zero.
The Extremely Limited Application of the First Law
Since humans would be long dead before they ever reached absolute zero, and since the zeroeth law is mainly an enabler of the mathematics used in the other laws, it is really the first and second laws that have some application to health.
However, the first law is limited to being a justification for the CICO truism. That is, calories in must equal calories out if you are to remain weight-stable, after discounting the weight attributable to water and other things containing low amounts of energy or types of energy that are not usable by biochemical pathways, and after accounting for the different mass-to-energy ratios of fat mass and different types of lean mass.
This has relatively little utility except to act as a check against magical thinking. For example, if you went keto and lived off fat-bombs that exceeded the amount of energy you burned or lost in your urine, and got fat, the first law of thermodynamics and its implied CICO truism could allow you to make sense of this and modify your diet to lose weight.
In short, there is very little health utility to the first law.
The Universal Primacy of the Second Law
By contrast, the second law of thermodynamics is the ultimate arbiter of everything that happens in the universe.
The universe is a closed system, and the first law states that its energy remains constant, so the second law implies that its entropy is always increasing towards its maximal state.
If the first law were not true, the second law would not mean that entropy must always increase, because the universe could increase its energy to defend against entropy. However, the first law is true, so the second law holds that because there is no increase of energy to be found, the entropy of the universe always increases until it reaches its maximum.
However, a human being is a system connected to her surroundings, where the sum of the human being and her surroundings equals the universe. The human can decrease her entropy so long as she 1) takes in new energy and 2) increases the entropy of her surroundings. This allows the universe to comply with the second law of thermodynamics.
In broad strokes, we do this by 1) eating food, and 2) evolving heat into the atmosphere, since heat is the most disordered form of energy. Thus, we arrogate energy unto ourselves, and we deload entropy into the atmosphere. We then use energy to do the work of creating order around us, making civilizations in our own image, where we make low-entropy societies that release even more heat into the atmosphere.
All life and health are most centrally defined by being high-energy, low-entropy states. When you lose maximum energy and obtain maximum entropy, you die. When you lose only a little energy and obtain only a little entropy, you get somewhere between less healthy and sick.
As explained in Lesson 1 of my Energy Metabolism class, Thermodynamics, Energy, and Order, this is why a 150-pound human will eat 2000 pounds of food in a year. We are constantly offloading heat to make the entropy of our surroundings increase more than the order we create within our body, so that we comply with the second law of thermodynamics.
What Does a High-Entropy Human Look Like?
Entropy is statistical disorder, or random mixing of things along probability distributions.
What would your face look like if it were higher in entropy? Your ears would not be in a position that best suited hearing; they would be anywhere, such as on your cheek or inside your eye. Your mouth would not necessarily be connected to your throat. It might be on top of your head, or beneath your chin. And so on.
Thankfully, resistance to change is also a feature of everything in the universe, and this is quantified by the activation energy imposed on any given change. This is described in Lesson 2 of my Energy Metabolism course, Activation Energy and Enzymes.
That activation energy can be supplied by, for example, abrupt force delivered to the face. Indeed, blunt trauma could move our facial features around in undesirable ways. However, we would long be dead if we suffered sufficient trauma to arrange our face into a random probability distribution.
However, let us consider some random mixing that we are more likely to witness:
A high-energy, low-entropy state is one where we can win a race or a powerlifting competition while awake and sleep well at night. A low-energy, high-entropy state mixes these two things together and we are wired and tired.
A high-energy, low-entropy state is one where our immune system attacks pathogens, removes things that don’t belong, and leaves alone that which should be left alone. A low-energy, high-entropy state mixes these things together and we get sick often, we have allergies and autoimmune disease, and we fail to clear cancerous tissue.
A high-energy, low-entropy state allows us to maximally contract our muscles when contraction is needed, and fully relax our muscles when it is not. A low-energy, high-entropy state mixes these together and results in fatigue and muscle tension, or the rigidity, tremors, and slow movements of Parkinsonism.
A high-energy, low-entropy state allows us to build lean tissue and avoid excess fat. A low-energy, high-entropy state mixes these together and makes us skinny-fat.
If the only thing going wrong were a decrease in cellular energy, we would see every conceivable problem manifesting equally. But that is never the case. Even in someone who is homozygous for a specific, severe defect in mitochondrial energy metabolism, their clinical presentation will look unique as a result of the many variations in their other genes, in their nutritional status, in their exposure to toxins, and in the stresses and traumas that they have experienced.
Far more often than that, we have a unique mix of many of these problems, alongside a unique mix of assets. In the balance of those, we may wind up rather sick or amazingly healthy. What remains relatively constant across people will be that a strategy based on optimizing energy metabolism will have the highest probability of moving the needle in whichever way one wishes to move it.
For example, someone who took home silver may happen to be heterozygous for a defect in pyruvate dehydrogenase deficiency, and may have intuitively gone keto to help take home silver. In that case, high-dose thiamin might help them take home the gold. This hypothetical person was never high-entropy. But becoming lower-entropy by optimizing energy metabolism allowed them to take home the gold.
Someone with genetic, nutritional, or lifestyle factors that predispose them to a high rate of clotting is going to tend toward a high-clotting state, not a random mix of high-clotting and low-clotting states. Nevertheless, a high-energy, low-entropy state would allow them to protect most of their tissues from the higher rate of clotting, and to divert that characteristic into a higher rate of wound healing. A low-energy, high-entropy state would put that person at a greater risk of pathological thromboses.
Someone with genetic, nutritional, or lifestyle factors that predispose them to cancer will be most at risk for whatever cancer they are predisposed to. A low-energy, high-entropy state will not make them randomly spotted with often-benign, sometimes malignant tumors all over their body; or make their hair, their muscles, and their tumors all equally likely to grow. However, it will make their cells less universally differentiate into the proper cell type, and thus more likely to become cancerous, and it will make their immune systems less discriminatory against cancerous tissue, and thus less likely to remove it. Thus, the low-energy, high-entropy state drives the predisposition toward the specific cancer to “activate.”
It is not necessary to map out the mechanistic details of all of these. It is simply the case that there are no biological laws, but that all biological processes are epiphenomena of the laws of physics. The random mixing of chemicals and biochemicals will lead to the random mixing of the epiphenomena that they generate.
I gave above the specific example of how a respiratory chain disorder could lead to autoimmunity:
This is a result of NADH and NAD+ randomly mixing and of ATP and ADP randomly mixing.
That is, the second law of thermodynamics holds that in the absence of an energy input, NADH and NAD+ must become randomly distributed amongst themselves, and ATP and ADP must become randomly distributed amongst themselves.
This creates two relevant secondary phenomena: zinc becomes randomly distributed instead of concentrated inside the human and delivered to the correct enzyme; and the forms of vitamin A — retinol, retinal, and retinoic acid — become randomly distributed, rather than forming a directional activation of the vitamin A that favors retinoic acid.
These secondary phenomena then lead to tertiary phenomena: low retinoic acid compromises the differentiation of immune cells. Rather than becoming the cells that are most beneficial to have, they become a more random mix of cells, and this takes away the rhythmic rise and fall of myeloid-derived suppressor cells during infection, and takes away the normal suppression of Th17 cells under all conditions.
These tertiary phenomena then lead to quarternary phenomena: the immune system fails to heavily discriminate against that which is a pathogen to be killed, that which are things that should be removed, and that which should be tolerated and even built up as the host. In the chaos that ensues, you get autoimmunity.
It will always be the case that random mixing of the underlying principles leads to random mixing of the epiphenomena. And while it is not the case that all order is desirable, it is the case that all health and all life is a form of order, and that decreasing order and increasing random mixing will always be contrary to health and life.
Thus, there will always be a way to trace low energy and high entropy at the most basic chemical level to a state of dysfunction, but the particular path this tracing takes will be shaped by the unique synergy of the person’s genetics, nutrition, lifestyle, and exposure to toxins and stresses.
How to Optimize Energy Metabolism
Energy metabolism has several components:
The neurological and hormonal regulation of energy distribution. Long-term abundance is signaled by leptin, short-term abundance by insulin, some stress by cortisol and adrenaline, and other stress by inflammatory signals. The brain makes a calculation of how much energy is at hand, and what the imminent and predictable future demands on that energy are, and decides how much can be spent. This emphasizes the importance of healthy body composition, and healthy stress management. Copper, vitamin C, zinc, tyrosine, glycine, and iodine are important nutrients that form components of this neurohormonal control.
The biochemical infrastructure of energy metabolism includes the protein, carbohydrate, and fat that we burn for energy, the micronutrients that are cofactors in energy metabolism, and the proteins and other compounds that we synthesize to make energy metabolism happen. The micronutrients most closely involved in energy metabolism are all of the B vitamins, all of the electrolytes (sodium, potassium, calcium, magnesium, and phosphate), iron, copper, and sulfur. Antioxidant nutrients (protein, vitamin C, vitamin E, zinc, copper, selenium, iron, and manganese) are needed to protect the biochemical infrastructure of energy metabolism.
Idiosyncratic genetic impairments in energy metabolism that are rare as individual diagnosable diseases are likely to be common as heterozygous partial biochemical impairments. My suspicion is that it is very common to have one or a few “carrier status” mutations that do not lead to disease, but do form idiosyncratic bottlenecks in energy metabolism.
I believe that healthy body composition and stress management, together with adequate micronutrients, are likely to take care of the lion’s share of diabetes, thyroid disorders, and adrenal disorders.
However, I also believe that “diabetes” is an epiphenomenon of heterogeneously disordered energy metabolism, where the common contributions are overweight and obesity, and perhaps dysfunctional aspects of our environment (pollution, indoor living, artificial lighting, and so on).
But if I am right about the idiosyncratic genetic impairments in energy metabolism, this is the “missing link” that makes diabetes or overweight more difficult to solve than can be done easily with the low-hanging fruit of good health in many people.
For example, I have already shown you data in Self-Experiments in the Biochemically Unoptimized State that chronic use of dextrose powder lowers my fasting glucose. Improved fasting glucose on a higher-carb diet appears to happen to a lot of people but is the opposite of what happens to the group means in randomized controlled trials. I will show you data in the next two installments that high-dose biotin on its own, without supplemental riboflavin, can send me into the pre-diabetic range, which is contrary to the randomized controlled trials of high-dose biotin for diabetes that I analyzed in When High-Dose Biotin Is Truly Needed. I will also offer you a seamlessly coherent mechanistic explanation of exactly why this happens as a result of my heterozygous mutations in biotin recycling, biotin activation of enzymes, and the riboflavin-responsive enzyme ACAD9 that is responsible for both fatty acid oxidation and the construction of at least one or two of the mitochondrial respiratory chain complexes.
The low-hanging fruit of weight loss, or more data-intensive calorie management if necessary, can be used to optimize body composition.
Spiritual traditions, gratitude journaling, using imagination for sufficient hope instead of excessive worry, meditation, nature walks, healthy breathing, good sleep-related practices, healthy social and familial relationships, proper schedule management, and being honest about what you are capable of handling to yourself and others are all good ways to manage stress.
Of course, nutrition and idiosyncratic impairments in energy metabolism can make everything above easier or harder. When I write about phase II of my biochemical optimization, I will describe how riboflavin, presumably by treating my heterozygous ACAD9 deficiency, spontaneously rewired my brain from a negative outlook to a positive outlook.
My resources for managing micronutrients are these:
The Vitamins and Minerals 101 Cliff Notes, all the major practical points about micronutrients I’ve learned over my career for what was less than a cup of coffee when they were first released and is currently less than what a nice tip to barista would be. Free to Masterpass members here.
Testing Nutritional Status: The Ultimate Cheat Sheet is my complete system for using signs, symptoms, dietary analysis, and lab work, to manage micronutrient status. Free to Masterpass members here.
The best comprehensive screening for nutritional testing is as follows:
The best comprehensive screening for idiosyncratic bottlenecks in energy metabolism is as follows:
For comprehensive analysis of biochemical data, sign up for BioOptHealth.Com. Make sure to click “waitlist me” if there are no times available for calls.