The Masterjohn Q&A Files

You can ask your question anonymously in text, but you can also ask it publicly, and you can even get "on stage" and share your mic, web cam, or screen with everyone.

330: Is Whole Food Vitamin C Really Different?

Question: Is whole food vitamin C superior to natural because it is part of a tyrosinase complex?

Short Answer: Vitamin C is nearly ubiquitously distributed in plant tissues, and is never bound to any enzyme as a structural complex. Vitamin C promotes absorption of iron from plant foods, inhibits copper absorption, and de-loads copper from ceruloplasmin, which may play a role in distributing copper to tissues. Vitamin C is not capable of destroying ceruloplasmin. These functions follow directly from vitamin C as an electron donor and there is no evidence whatsoever that whole food vitamin C behaves differently in these respects than synthetic vitamin C. However, daily needs in most contexts are 2-400 milligrams of vitamin C per day, which is below the dose shown to potentially cause problems with copper. Getting this from whole foods or whole food supplements is better than using synthetic vitamin C because it avoids GMO corn and Chinese synthetics and provides a host of other beneficial constituents alongside the vitamin C.

329: What's the Deal With Seed Oils?

Question: What Is the Real Issue With Seed Oils?

Short Answer: The main issue with seed oils is that they present an oxidative liability. They do not acutely cause oxidative stress, but their polyunsaturated fatty acids (PUFAs) are more vulnerable than any other macronutrient to oxidative damage. Oxidative stress can increase because of nutrient deficiencies, toxins, infections, other sources of inflammation, alcohol, or smoking, and it will inevitably increase as a function of aging. As oxidative stress increases, more PUFAs in the tissues mean more damage. At least 0.6 milligrams of vitamin E should be gotten per gram of PUFA in the diet, but vitamin E cannot fully protect against PUFA, so their intake should be moderated to the very low levels needed, as obtained by eating fatty fish once or twice a week, eating eggs daily, and eating 4-8 ounces of liver per week. Additional secondary problems with them include residual solvents and heat damage prior to intake, but the main issue is that we do not want to increase our tissue PUFA content more than needed.

328: Is Hair Mineral Testing Useful?

Question: How useful is hair trace mineral analysis (HTMA) for nutritional testing?

Short Answer: Hair trace mineral analysis is included as an optional add-on in the comprehensive nutritional screening from Testing Nutritional Status: The Ultimate Cheat Sheet, because it can capture data for some ultra-trace minerals for which there are no better-validated tests, and it might capture a pattern that might not be picked up as quickly with blood work, such as a mineral transport issue. However, its utility is limited by the fact that hair mineral content is not well validated as a test for any specific mineral, is generally anti-validated when there is enough science on a mineral (such as zinc, where hair zinc does not go down in deficiency), and should not be used as a central piece of data without corroboration from other more well-validated tests, which exist for most of the nutrients.

327: How to Find the Root Cause of Autoimmunity?

Question: How do we find the root cause of an autoimmune condition? One example considered where the root cause is energy metabolism.

Short Answer: Autoimmune conditions are likely driven by deficiencies of vitamins A and D, which contribute to post-infectious autoimmunity by compromising the rhythmic rise and fall of myeloid-derived suppressor cells (MDSCs), and to autoimmunity regardless of infections through impaired suppression of Th17 helper T cells. More broadly, infections and tissue damage are the most likely drivers of autoimmunity onset. However, energy metabolism governs everything through the second law of thermodynamics, which holds that energy must be used to prevent everything from randomly mixing, and this includes randomly mixing the immune defense against pathogens with immune attacks on the host. In this example, we discuss how a respiratory chain disorder would compromise absorption and distribution of zinc and compromise the oxidation of NADH to NAD+, and how both of these would interact with a genetic impairment in acetaldehyde dehydrogenase to prevent the activation of vitamin A to retinoic acid. Autoimmunity thus results as one of many symptoms of vitamin A deficiency driven not by lack of vitamin A, but rather by impaired activation of vitamin A, secondary to impaired energy metabolism. 

326: Why Would Vitamin C cause muscle pain, joint pain, and brain fog?

Question: Why Would Vitamin C Cause Joint Pain, Muscle Pain, and Brain Fog?

Short Answer: Acutely, vitamin C would likely cause these effects by generating oxalate, which could cause crystals that lead to muscle and joint pain, and could cut energy metabolism in half, leading to brain fog. This vulnerability could result from deficiencies of any of the B vitamins, any of the electrolytes, or of iron, copper, or sulfur; from diabetes, low adrenals, or hypothyroidism; or from any of the hundreds of genetic defects in energy metabolism, only one of which is glucose 6-phosphate dehydrogenase deficiency; or any one of a huge number of toxins that impair energy metabolism. Chronically, vitamin C may increase the harms of iron overload or contribute to copper deficiency. The main ways to manage these latter issues are to take vitamin C away from meals, to maintain good copper status through proper dietary intake, and to treat iron overload with phlebotomy.

325: Can NAC hurt your gut health?

Question: Can NAC Hurt Gut Health When Used to Disrupt Biofilms?

Short Answer: N-acetylcysteine or NAC can be used at a dose of 600 to 2,400 milligrams per day for 5-10 days to disrupt biofilms and make it easier for antimicrobials to kill bacteria. Animal studies suggest that acute doses up to 6 grams do not deplete mucus or cause ulceration, but that an acute dose of 17.5 grams can deplete mucus and cause ulcers within two hours. Human studies suggest that 10 grams per day can be used for 24 weeks with fewer than 1 in 6 people complaining of gastrointestinal side effects. Yet, chronic use of NAC will thin the mucus, disrupt the biofilms used by normal healthy microbiota, and possibly deliver excessive sulfur to certain components of the microbiome. Therefore, I would not use it except for specific, targeted reasons, and I would not use it at a dose higher than needed or for a duration longer than needed.

324: How can I protect against oxalates?

Question: How can I protect against oxalates

Short Answer: Getting 300-400 mg calcium between food and supplements at each meal will minimize oxalate absorption. Maintaining postprandial urine pH in the 6.4-6.8 range by getting 3-5 grams of potassium per day from food or from organic acid salts such as potassium citrate will prevent its crystallization in the kidney. Reducing dietary oxalate will prevent any possible damage in the gut.

323: Why Should Postprandial Glucose Be Kept Under 140 mg/dL?

Question: Why should postprandial blood glucose be kept under 140 milligrams per deciliter?

Short Answer: When blood glucose rises above 140 mg/dL, this is the approximate point at which it spills into the polyol pathway at a greater-than-normal rate, which represents a suboptimal state of metabolism that is likely to hurt antioxidant status and compromise detoxification pathways as well as the recycling of vitamin K and folate. It must be kept in mind that a healthy person will adapt to glycemic loads they consume regularly. Thus, a one-time spike above 140 mg/dL should never be used to conclude anything whatsoever. Only repeated spikes above this level with repeated consumption of the same glycemic load over several days to several weeks should be used as a cause for concern.

322: What is the relationship between copper and estrogen?

Question: What is the relationship between copper and estrogen?

Short Answer: Estrogen moves copper from the mother’s bloodstream to the fetus during pregnancy. Its action at the intestines is poorly understood but I believe estrogen and progesterone interact to promote intestinal copper absorption. Maintaining pregnancy-level hormones while not pregnant poses a risk of promoting too much absorption of copper from food without transferring it to a growing baby. Copper status should be monitored when using supplemental hormones to avoid copper toxicity.

321: How to slow or reverse graying of hair?

Question: How to slow greying of hairs and potentially reverse it?

Short Answer: What works for any given individual will likely be to find the weakest link and fix it, from among the following systems: the signaling of energy abundance (body fat, insulin sensitivity, thyroid hormone, adequate protein, individualized meeting of carbohydrate needs, good management of psychosocial stress, supporting neuroendocrine signaling with copper, vitamin C, zinc, and glycine, and supporting thyroid function with iodine and selenium); the biochemical infrastructure of energy production (all the B vitamins, iron, copper, sulfur, magnesium, potassium, and managing genetic idiosyncrasies impacting energy metabolism), and antioxidant protection (protein, vitamin C, vitamin E, zinc, copper, selenium, iron, and manganese).

320: How Much Iron Can We Absorb At Once?

Question: How much iron can we absorb at once?

Short Answer: High-dose iron will produce more total absorbed iron, but will also leave more in the gut, which could cause constipation or disturb the gut microbiome. If desperate for quick relief, 200 milligrams per day of iron taken in the morning will work faster than lower doses or the same dose taken in the afternoon. For most people, however, I believe it is best to start with 18 milligrams of iron, and only increase it to 27 or 36 milligrams, or higher, if needed. If it is difficult to raise iron with a supplement, try eating a temporary carnivore diet that includes egg yolks but not whites, or at least try taking your iron with a breakfast that matches this description.

319: What cofactors are needed to synthesize and recycle BH4?

Question: What cofactors are needed to synthesize and recycle BH4?

Short Answer: Zinc, magnesium, potassium, and niacin are the cofactors needed for the synthesis and recycling of BH4. Folate and methylation are not involved, though high-dose folate or folic acid could hypothetically hurt BH4 recycling since both are recycled by dihydrofolate reductase (DHFR).

318: Is It Important to Get Vitamin D Sulfate Specifically From the Sun?

Question: Is it important to get vitamin D sulfate specifically from the sun?

Short Answer: It is important to get morning outdoor sunlight as close to every day as possible for your circadian rhythm, and to get some exposure to unprotected sunlight during the day when UV is available, but at doses less than needed to cause reddening, and it is equally important to always avoid burning. There are many reasons for this, and the cholesterol sulfate hypothesis — to which the vitamin D sulfate hypothesis is peripheral — is an interesting and worthy hypothesis but should not be the final arbiter of your sun exposure habits.

317: If I have a hereditary weakness in breaking down branched-chain amino acids, what cofactors do I need to consider, and do I need to restrict my protein when losing weight?

Question: If a person has a hereditary weakness for Branched Chain Amino Acid Catabolism would this impact the type of diet they might choose to loose weight? Should they limit protein if it will increase their need for nutrients like Biotin?What are all the possible cofactors we should consider supplementing to support Leucine catabolism?

Short Answer: Metabolizing branched-chain amino acids requires all B vitamins except folate, calcium, magnesium, potassium, and chloride. If you have a genetic impairment in this pathway, then reducing branched-chain amino acid intake and doubling down on cofactors is important during weight loss because the pathway will be stressed more in the catabolic state.

316: How do I consume omega-3 without hurting my omega-6 status?

Question: If I don’t want to hurt my omega 6 status through my omega 3 intake, how do I do that? Is it simply a question of taking them at separate times? Or is it a question of dose? And if it is a question of dose, how do I know when to start eating fish and taking my omega 3 supplement again?

Short Answer: How they are combined in meals is not important, but it is important not to have too much EPA in cell membranes relative to arachidonic acid, and this is driven by cumulative intake over years. For someone who has consumed too much EPA for many years, the best approach is to eat liver and egg yolks for arachidonic acid while getting omega-3s from a DHA supplement and not from fish, fish oil, or fish liver oil.

315: Can plant foods and their phytochemicals be used to reduce arterial plaque?

Question: Can plant foods and their phytochemicals be used to reduce arterial plaque?

Short Answer: Yes, but if you don’t have specific intolerances to plant compounds the best thing to do is simply aim to meet your vitamin and mineral targets from a diet rich in fruits, vegetables, herbs, and spices, rather than trying to use specific plant compounds from specific studies in any specific amount.

314: What to Do About Twitching

Question: What can be done about twitching?

Short Answer: Most twitching will be driven by glutamate/GABA balance or acetylcholine regulation, and the most likely nutritional issues are any of the electrolytes or any factor that influences energy metabolism. The best way to address it is to consider the conditions that influence it and then trial and error your way through each potential nutritional issue in order of which ones make the most sense for your individual case first.

313: Vitamin K2 and Undercarboxylated Osteocalcin

Question: If undercarboxylated osteocalcin has health benefits, and vitamin K2 decreases it, what does that mean for K2 supplementation?

Short Answer: Vitamin K2 helps secure osteocalcin in bone matrix, where it is decarboxylated and released as an endocrine hormone in response to certain stimuli. When released, it acts to optimize insulin secretion, insulin sensitivity, fuel use during exercise, and male testosterone.

312: Phosphatidylcholine and TMAO

Short Answer: On a scale of one to ten, my concern about TMAO and cardiovascular disease is a three. There are thousands of things that should be given equal weight as potential contributors to heart disease, but TMAO gets the most attention because the Cleveland Clinic has an incredible PR machine to spread their research, which serves to bolster their financial interest in marketing the test. That said, it is not a universal necessity to supplement with phosphatidylcholine. If you are concerned about your TMAO, you can try substituting trimethylglycine (TMG), and ultimately judge the value of each supplement by whether it is helping you in a demonstrable way.

311: Low Blood Sugar on Vegan Keto

Short Answer: Consider how important it is for your ketones to be elevated. Most likely you need to eat more protein, which will lower your ketones. I would aim for a minimum of 0.8 grams per kilogram of ideal bodyweight and consider using 1.2 grams per kilogram of ideal bodyweight. If this does not work, consider all of the nutrients involved in energy metabolism — all of the B vitamins, iron, copper, sulfur, magnesium, potassium — but especially biotin and B6 for their disproportionate role in gluconeogenesis. If the protein you need to normalize your blood sugar does reduce your ketones to a level that are not giving you the benefits you are looking for, you could consider raising them with exogenous ketones.

310: Brain Fog on Calcium, Vitamin D, or K2

Short Answer: Most likely by decreasing serum phosphorus. The solution is to balance these nutrients with vitamin A and phosphorus.

309: Why Plasma Zinc is the Best Marker of Zinc Status

Short Answer: Plasma zinc is the single most important marker of zinc status. Urine zinc may decline faster in deficiency. Hair zinc increases with supplementation but does not decrease in deficiency. Plasma zinc is decreased by inflammation, oxidative stress, the ovulatory and luteal phases of the menstrual cycle, probably pregnancy and oral contraceptive use, and any kind of stress that leads to an adrenal output. If plasma zinc declines despite supplementation, corroborate that this reflects zinc status by showing normal hair zinc and low urine zinc. Use symptoms as the ultimate arbiter of whether zinc supplementation is helping.

308: Glutathione Intolerance: Getting to the Bottom of It

Short Answer: It could be byproducts of any of the three amino acids that make up the glutathione molecule, which include the individual amino acids, ammonia, hydrogen sulfide, sulfite, and propionyl CoA, or it could be microbial metabolites of glutathione produced in the gut. The full answer contains seven hypothesis-driven tests that can be done at home to determine the cause.

307: Statins Vs. Sulfur for Heart Disease

Short Answer: From the trials, statins seem to reduce heart disease risk and total mortality, but it is impossible to separate this from conflicts of interest and industry funding. There are plausible mechanisms by which they may hurt mitochondrial function and promote soft tissue calcification. Dietary sulfur appears to lower cholesterol. While Lester Morrison showed 1500 milligrams per day of chondroitin sulfate could reduce cardiac events 7-fold, this has a theoretical potential to hurt the microbiome. My preferred way of getting sulfur is 1.2-1.8 grams per kilogram bodyweight of total non-collagen protein, with an emphasis on animal protein.

306: Why would someone not tolerate methyl donors even if they need them?

Short Answer: I believe most methyl donor intolerances are a result of deficiencies in the glycine buffer system, which requires glycine, vitamin A, fasting (glucagon), androgens, riboflavin, unmethylated folate (THF), and iron. No one should expect to tolerate 30 milligrams of folate, however, and there is almost never a reason to use doses that high.

305: Does whey protein hurt the kidneys or otherwise hurt our health?

Short Answer: The main problem with too much protein, particularly animal protein, is that acidity may hurt the bones and increase the risk of calcium oxalate kidney stones, but this can be obviated by balancing it with organic acids, which have bicarbonate-sparing effects that are alkalinizing. The best index of the organic acid content of foods is the potassium content. This balance can be achieved with 750 to 1500 milligrams of potassium for every 100 grams of protein. This is not specific to whey protein. Other than allergies, none of the claimed harms of whey protein are convincing.

304: Does glucose handling in the brain decline with age? And if so, does this serve as a rationale to supplement with MCT oil to prevent cognitive decline?

Short Answer: Energy metabolism in general declines across the body with aging, but energy metabolism seems to stay healthy enough in the brain in people who do not experience cognitive decline. Cognitive decline does appear to be driven by decreases in brain energy metabolism, but these are not best described as a specific impairment in glucose handling. MCT oil can be modestly beneficial and a ketogenic diet can probably be somewhat more beneficial in people who have cognitive decline from any type. There is no evidence to support using it as a preventative. For prevention, I believe we should focus on aerobic fitness, nutrients required for healthy energy metabolism and antioxidant defense, and maintaining metabolic health with a healthy body composition and a healthy physical activity routine that includes the proper spread of a portfolio of different types of exercise.

303: Why is an IV more hydrating than salted water?

Short Answer: If it can’t be explained by the dose of salt, it may be that the salt is not being absorbed orally. Glucose, starch, or simply a meal consumed alongside the salted water may help with this.

302: How to Increase or Decrease SHBG?

Short Answer: SHBG is increased by adiponectin (vitamin K2, insulin sensitivity), thyroid hormone, fasting physiology (AMPK, fat oxidation), and estrogen (especially estrone), while it is decreased by insulin resistance, obesity, the fed state and carbohydrate-dominant physiology, androgens, and polyunsaturated fat.

301: Protein and Longevity

Short Answer: While protein restriction may have value in people with established cancer or kidney disease, cycling robustly between fasting and feeding states is likely to provide all the value that restriction of protein or calories might otherwise provide, and a high protein intake supports bone mass, muscle mass, and the detoxification of carcinogens, all of which are important to longevity.

300: Why do my urinary B6 markers say I'm deficient if I'm supplementing and my plasma levels are high-normal?

Short answer: Low or low-normal alkaline phosphatase may raise the plasma B6 level over the cellular level. Tryptophan metabolites in urine reflect the B6 requirement for the kynurenine pathway, and this requirement increases with more estrogen, more inflammation, or a higher protein intake.

299: The 3 Phases of Fasting: And How to Get Kicked Out of Each One

Short answer: 4-6 hours after a meal the small intestine is emptied and the insulin-to-glucagon ratio declines; 25 hours after, hepatic glycogen is emptied; 5 days later the brain is adapted to ketones and gluconeogenesis reaches its minimal level. Moving from one to the other cannot occur with a small piece of signaling like the bite of an apple. It requires the preponderance of signaling.

298: Will reishi, turmeric, or curcumin tank my testosterone?

Short answer: Probably not. Animal studies showing a difference use huge doses in an unrealistic context. Human studies show they don’t at doses used. Human effect on PSA is vulnerable to regression to the mean and thoroughly unconvincing.

297: What if my A1C says I'm diabetic but my CGM says I'm fine?

Short answer: Trust the CGM. HbA1c is confounded by red blood cell turnover and fructosamine 3-kinase activity.

296: Reversing Fatty Liver: How Long Does It Take?

Short answer: You should be able to see changes on imaging within a few weeks if your approach is working well, but ultimately this is entirely dependent on how negative your “delta fatty liver = (fat in) - ((fat out) + (fat burned))” equation is.

295: What's the difference between 25(OH)D and 1,25(OH)2D when it comes to the VDR?

Short answer: 25(OH)D is 1000 times weaker at activating the VDR than 1,25(OH)D, but 1000 times more abundant. This is why I advocate measuring both, and ultimately believe we need to create a calculated index of “biological vitamin D activity” from them.

294: If glutathione whitens your skin, is that good or bad?

Short Answer: Measure this against whether it increases your likelihood of burning. If it does, it’s probably a bad thing, but if it doesn’t, or if it lowers your risk of burning, that’s a good thing.

293: Vitamin D supplements, testing, and interactions with the vaccine.

Short Answer: Vaccination shouldn’t change the vitamin D requirement. Quarterly testing makes sense for someone who has never tested before or who wants to make sure they stay in range during COVID, but generally testing yearly around the mid-point of seasonality for you, once you know your variation, is plenty.

292: BH4 vs tyrosine for low neurotransmitters and a high phenylalanine-to-tyrosine ratio.

Short Answer: BH4 is expensive and requires very high doses, so if the problem is modest it can much more easily be solved by taking tyrosine.

291: Does TMG have to be taken in the fasting state?

Short Answer: While the body will tend to use TMG for methylation in the fasting state, it is normally found in food, so you should be able to absorb it with meals and hold on to it for later use, much as we do with folate.

290: Is urinary mycotoxin testing useful for indoor mold exposure?

Short Answer: When I had a serious case of indoor mold-induced illness, I tested my urine and my apartment dust for mycotoxins. Both were high, but the classes of toxins were totally different between the two, making me think the mycotoxins in my urine came from food rather than my apartment. Symptoms going away when outside of the apartment was a far more useful clue, so I think you should consider the cost of a vacation, the cost of mycotoxins, and assume you get more information out of taking the vacation, and then decide which to do.

289: Ferritin sky-high without hemochromatosis?

Short Answer: Even if genetics and other bloodwork don’t look like hemochromatosis, sky-high ferritin justifies trying to lower it with blood donation or phlebotomy if inflammation markers are low. If this doesn’t work, oxidative stress should be investigated.

288: Will the booster shot be worth it?

Short Answer: If optimizing for efficacy, the booster shot will likely be worth it for Pfizer, whereas other vaccines don’t have clear evidence of declining efficacy yet. If optimizing for safety, one should be skeptical of the booster since a 3-dose regiment hasn’t been tested in clinical trials.

287: How to use carbs and glycine for sleep.

Short Answer: To get adequate raw material for melatonin synthesis in the brain, carbs can come any time of day and are best if high-glycemic. To suppress brain histamine levels, carbs in the evening, with low protein and relatively low fat, is best. From among protein, collagen is best at night for the glycine.

286: What are the downsides to taking prescription calcitriol for bones?

Short Answer: It requires more frequent dosing and has some risk of hypercalcemia, and it would be best to make sure you have adequate D and magnesium and aren’t overdoing anything that could deplete D, such as other fat-soluble vitamins, first.

285: Does quinolinate sometimes indicate niacin or inflammation instead of B6?

Short Answer: B6 cannot be ruled out, though inflammation and estrogen could also be involved. While it is possibly a regulated means of increasing excitatory effects of quinolinate, it makes sense to assume it may respond to B6.

284: Why would 5,000 IU vitamin D cause tooth sensitivity?

Short Answer: While it is unclear, it could relate to vitamin K depletion, hypercalcemia, or compensation in acid-base balance. First and foremost, use the full testing algorithm in Testing Nutritional Status: The Ultimate Cheat Sheet (available at https://chrismasterjohnphd.com/cheatsheet) rather than just testing 25(OH)D to determine deficiency.

283: What’s the best and most affordable diet for a hungry teenage boy?

Short Answer: A half a gram to a gram of protein per pound of bodyweight, no more than 20-40 grams of that from protein powder, and whole foods supplying the targets for vitamins and minerals, erring on the side of overshooting them. Lentils and other legumes as primary carb foods and supply a portion of protein, and adjusting quality of meat to what you can afford, can help with budgeting.

282: Why would MCV be elevated if MMA and FIGlu are normal?

Short Answer: If the cause is nutritional, FIGlu cannot rule out folate deficiency as a cause because it reflects tetrahydrofolate rather than methylene-THF. So, increasing the dose of folate or switching from methylfolate to folinic acid could be tried. Otherwise the most likely  nutritional solution would be copper.

281: How to further explore slightly high coronary calcium and Lp(a) and borderline high LDL-P?

Short answer: If inflammatory markers are low and Lp(a) is proportionally more elevated than LDL-P, then blood lipids probably account for part of the calcification, while factors impacting LDL oxidation come next and those impacting calcification directly come after that. For the latter two, the oxidative stress and calcium sections of the Cheat Sheet should be consulted.

280: Is blackstrap molasses toxic because of AGEs?

Short answer: The science behind dietary AGEs being bad for us is very poor-quality. While food that is treated to excessively high heat, such as fried food, should not be the major portion of our diet, dietary tables of AGEs in foods are not accurate and dietary AGEs are probably not a major source of AGEs within our bodies. Blackstrap molasses should be seen as a sweetener that is better than refined sugar and can be an important source of minerals.

279: Why can the sodium-potassium pump work backwards?

Short answer: The second law of thermodynamics means that concentrations of specific chemicals or positive or negative charges will always "want" to disperse and randomly mix in their environment, making concentrations of ions such as sodium or potassium a form of potential energy. While the pump normally uses energy from ATP to invest into creating those concentrations, if ATP levels are low and sodium and potassium are already highly concentrated on opposite sides of the cell membrane, their potential energy can be released by mixing across the membrane, and can be used to synthesize ATP.

278: If What can I take to improve my memory?

Short answer: Alpha-GPC, ginkgo biloba, lion's mane, and a comprehensive analysis of your nutrient status as outlined in Testing Nutritional Status: The Ultimate Cheat Sheet to see if anything is missing.

277: If you have high ferritin, are there any downsides to blood donation?

Short answer: When trying to stop the early progression of insulin resistance, it is best to use a combination of strength, power and muscle building, fat loss, and high-intensity exercise in 20-second to one-minute bouts; to institute a rhythmic fasting-feeding cycle; and not to use berberine or metformin unless absolutely needed. One good way to integrate these is to use an "earn your carbs" approach to tie your carb rewards to specific physical activity goals.

276: What type and how much psyllium to lower LDL-cholesterol?

Short answer: When trying to stop the early progression of insulin resistance, it is best to use a combination of strength, power and muscle building, fat loss, and high-intensity exercise in 20-second to one-minute bouts; to institute a rhythmic fasting-feeding cycle; and not to use berberine or metformin unless absolutely needed. One good way to integrate these is to use an "earn your carbs" approach to tie your carb rewards to specific physical activity goals.

275: What is the most sustainable way to implement carb cycling?

Short answer: When trying to stop the early progression of insulin resistance, it is best to use a combination of strength, power and muscle building, fat loss, and high-intensity exercise in 20-second to one-minute bouts; to institute a rhythmic fasting-feeding cycle; and not to use berberine or metformin unless absolutely needed. One good way to integrate these is to use an "earn your carbs" approach to tie your carb rewards to specific physical activity goals.

274: Do fat and carbs differ in how much energy they yield?

273: Should green tea be taken with meals and can it hurt nutrient absorption?

272: Why does methylfolate act as the off-switch for the glycine buffer system?

271: How to get by on poor sleep?

270: Across what timeframe should we diversify foods?

269: Nutrition For Bone Healing

268: What tests to use for protein status?

267: Is nicotinamide riboside hydrogen malate as good as NR for fasting?

266: Would high-dose thiamin cause imbalances with other B vitamins?

265: Why does B12 damaged by nitrous oxide require megadosed folic acid rather than normal levels of folate?

264: Nutrition, Metformin, and Respiratory Chain Disorders

263: Why do some paleo advocates and functional medicine practitioners recommend low-calcium diets?

262: How should you program the temperature on an Ooler or Eight Sleep?

The way that I do it is, if I wake up feeling cold, I want to program it to increase the temperature at that time point so that I do not wake up cold. So, I would say, generally speaking, you want it as cold as it can be starting, that does not interfere with your sleep, and you want it as cold as can be in the middle of the night, that does not wake you up. So, I think that's going to be very different for each person, and I think whatever temperature prevents you from waking up cold, is the one you want.

261: Is it useful to measure HVA, VMA, and 5-HIAA?

I find them useful in a very limited context. The limitation of their usefulness is basically that you can't really tell if something is high or low because of production or degradation.

260: What nutrients require insulin to get into cells?

Magnesium phosphorus and potassium are the big ones that are going to have poor uptake in response to insulin.

259: What are the top whole food supplements to take?

I mean, that's kind of too general a question, especially for end of the AMA rapid-fire. I don't make blanket supplements suggestions, but in the likes of Oystermax, an organ mix or liver supplement from Ancestral or from Paleovalley, although their organ mix is a sold out, and nutritional yeast, I think are great components of a natural, DIY, whole food multivitamin.

258: Could iron deficiency create a complex 1 disorder?

If you're iron deficient and you have blood work that looks like a complex 1 block, and you feel like you have an energy metabolism disorder, then, while it is possible you have a genetic complex 1 deficiency, it's also possible you have an iron deficiency that is not playing out in your CBC or your thyroid panel that is impacting your energy metabolism.

257: How to get more sulfate if you have sulfite issues?

If you're not converting sulfite to sulfate, that should be a molybdenum deficiency. If it's not a molybdenum deficiency it's probably a gut microbiota problem. Could be a sulfite oxidase enzyme deficiency, of course, but I think it would be much more common that you have sulfate metabolizing bacteria in the intestines, then that you have a sulfite oxidase genetic deficiency. Although, you can never rule out a modest impairment in that enzyme, that would not be diagnosed with anything. So, it can't be ruled out. But I do you think it's going to be much more common that someone has a sulfur intolerance that's driven by gut microbiota.

256: If you're eating oysters, do you need to eat liver too?

And I think oysters are more reliably a source of zinc relative to copper and relative to liver. And liver is much more consistently a source of copper relative to zinc and relative to oysters. And so I stand by what I said in terms of taking into account the variation in different species of oyster, in different oceans and different batches of oyster products, but Oystermax does batch testing.

255: Lipoic acid: does it need to be the R form?

Lipoic acid can help with blood sugar and it is an antioxidant. I would always use R-Lipoic acid. I would never use the racemic mixture of alpha-lipoic acid because the R form is the biologically active one. And I think it might be the case that you can just take a higher dose, but why mess around with the possibility that some isomer that doesn't belong in your body and isn't found in food, isn't going to interfere with the function of the R form. So I would just take R- Lipoic acid for any purpose at all.

254: How much fruit is it safe to eat at once?

I don't really agree with that premise and that premise might be sensible at really high fructose intake, but I don't think many people are going to hit that by eating fruit, unless they're on a fruitarian diet. I think if you're eating 1, 2, 3 servings of fruit at a time, you're probably not going to seriously hit that mark, but that depends on your energy metabolism and the rest of your diet. So I think the metric to look at that would be your uric acid levels. If your uric acid levels are high, you are eating a lot of fruit at one sitting.

253: Should I supplement NAC if cysteine, taurine, and sulfate are low?

You can supplement NAC, but you probably just need more animal protein. Although a vegan could supplement NAC instead of animal protein. If your homocysteine is on the high side, then you definitely want to increase methionine in order to increase SAMe to increase the breakdown of homocysteine.

252: Iron deficiency without anemia?

I would just say that I would be wary of iron deficiency, even if it's not causing anemia, because iron plays roles in energy metabolism, detoxification, and thyroid metabolism separate from anemia. But the things that are easiest to test are thyroid panel and CBC. So if your thyroid panel and your CBC look great, you probably aren't truly iron deficient, but I would also measure it against symptoms. So for example, if you have unexplained fatigue and you feel much better when you get more iron in your diet, I would interpret that as iron deficiency, that probably is just most sensitively affecting the electron transport chain if it's not showing up in a CBC or a thyroid panel.

251: How to Calculate the Amount of a Nutrient in a Complex

So this is how to know what percent of something in a complex form gives you what percent of the nutrient of interest, if you ever want to calculate it yourself. So what you want to do, let's say you want to know what percent of Alpha-GPC is choline. What you want to do is say Alpha-GPC, molar mass and Google gives it to you right here, 257.221. And then you want to say choline molar mass 104.1708 and so you want to take this number, the nutrient of interest, and you want to divide it by this number, the dose of the complex form. And then you would get 0.404985. So to carry it out to two digits that rounds down to 0.4. Alpha-GPC is 40% choline. And if you want to find amount of choline in Alpha-GPC, you take the dose of Alpha-GPC and you multiply it by 0.4. Or if you want to be highly specific, you multiply it by this number and you can do the exact same thing for magnesium glycinate, iron bisglycinate, et cetera.

250: Eggs, Choline Bisulfate, and TMAO

If you really want to know what eggs are doing to your TMAO, then I'm pretty sure Cleveland Clinic has a TMAO blood test, and that would be the best way to do it. Yeah, the Cleveland heart lab has a TMAO blood test, so you could test your response to this. If you didn't want to test, then if you assumed the worst case scenario, I would say you could probably just eat two eggs at a time and you would not raise your TMAO that much, but if you do test TMAO, you can probably show that you might be able to get away with eating six eggs at a time and not raise your TMAO that much.

But the thing is, I don't think you're going to get the same response from six eggs at a time as in that study, as you would get from eating two eggs separated and spread out from the day. And the reason is I think the TMAO is mostly generated from the choline that does not get absorbed in the small intestine, going to the colon, being available to the microbiome. So if you lower the dose of eggs and spread them out, then you should be able to kind of totally head off significant TMAO generation.

249: Floxed: How to Recover From Cipro

And a lot of these things probably have nothing to do with hydration, but are a direct result, or rather not direct, but a secondary indirect result of the failure of mitochondrial energy metabolism. So, I have been doing some limited research on Cipro and brainstorming some educated guesswork around recovering mitochondrial energy metabolism health. And there are multiple hypotheses around Cipro toxicity mechanisms, but the bulk of the thought is in damaging mitochondrial DNA and basically just leading to defective mitochondria. And so it seems to me like the best strategies around regaining health after Cipro toxicity, and this is all educated guesswork, none of this is tested in randomized controlled trials, and I'm not a medical doctor, and this is not medical advice, but it seems like the most promising hypotheses would be around promoting mitophagy and mitochondrial biogenesis. And so probably whatever you can do to maximize the depth of your cycling in the fast and fed states is probably the most promising thing you can do for mitochondrial turnover.

248: If you correct a deficiency too fast, can you make it worse?

I think the answer is no. And I definitely don't think that happens, and I've never seen anything to suggest that happens.

247: If my methionine is high, do I need to worry about betaine?

If your methionine is on the higher side then it's probably the case that you don't really have an issue with recycling homocysteine to methionine. TMG's role in methylation is to support the recycling of homocysteine methionine. So if your methionine levels are on the high side of normal then you probably don't need TMG, but I'm also not sure what you mean by methylation issues.

246: How do I eat to protect my joints?

From a nutritional perspective I think it's more a matter of hitting nutritional adequacy across the board. One thing that you can do that is, that's been tested is 15 grams of collagen or gelatin with a little bit of vitamin C taken a half-hour before your workouts will improve collagen synthesis in your joints. Protein and carbohydrates is one, but also sulfur is very important as a constituent of those, and manganese is very important as a cofactor for the enzymatic production of those things. It's probably not a bad idea to consume things that are in joints, and that's sort of whole foods way to do that would be to either, well, the crude way to do it is chew the joints of chickens and stuff like that.

245: Why do glycine and salt help with sleep?

The glycine is probably working primarily by acting as an inhibitory neurotransmitter and lowering core body temperature to promote faster falling asleep and deeper sleep achieved. And then on the salt. The salt is going to stimulate antidiuretic hormone or vasopressin, which is really a mechanism to regulate the concentration of solutes in the blood, and make sure your electrolyte and fluid balance is proper. And so glycine's getting you a deeper sleep. Salt is preventing you from having to pee, and the two of those make you less likely to wake up for that purpose.

244: Will lowering my PTH with calcium reverse my atherosclerosis?

And so you will definitely be removing a major source of calcification risk if you suppress your PTH down into the bottom half of the reference range. And generally, I don't know exactly where the point of maximal suppression is, and I suspect that it's different between different people.

So what I would do is, however you're approaching that with vitamin D, calcium, et cetera. Try something, re-measure it, try tweaking the dose upwards and see if it keeps going down and find the point of maximal suppression. And if you do that it's hard to say where the difference is between not getting worse and reversing.

But I think that will certainly... To the degree that you can reverse it I think that would be, definitely be an important thing to do in order to get reversal, and so I would hope so. And I think there's good reason to hope for that.

243: How long does it take environment to change gene expression, epigenetics, and genetics?

Well, generally speaking, environment mediates, I mean, it depends what you mean by environment mediating, right? So environment mediates changes in gene expression through epigenetics, but gene expression is not SNPs. SNPs are produced through mutations in the heritable genome, and then by environment changing, do you mean the production of the mutation that is the SNP for the first time? Or do you mean the change in the proportion of the population?

242: What does it mean if you're helped by SAMe?

It could indicate that, or it could indicate that they have an impairment in the conversion of methionine to SAMe, which could be mediated by low magnesium status, low ATP status, or a poorly functioning MAT, methionine adenosyltransferase gene.

241: Why would glutathione cause a headache?

Probably sulfur intolerance. I'm guessing that's conversion to sulfite in the gut or something like that. Or production of hydrogen sulfide gas in normal metabolism leading to vasodilation.

240: Can antioxidants increase homocysteine?

An underappreciated reason that homocysteine could be backed up is because you have good antioxidant status.

239: Why is methylfolate the off-switch for the glycine buffer system?

The reason is that generally in the fed state, you have lots of incoming methionine. And so you have an excess of SAMe in the fed state. In the fasting state, you have no incoming methyl groups from diet, and therefore the fasted state is the low-methylation state. So fed state, high methylation state, fasted state, low methylation state. You basically shut off MTHFR in the fed state, because in the fed state, which is a high methylation state, the incoming methionine makes you not need any MTHFR activity.

238: Potassium supplements for salt-sensitive high blood pressure?

So it's best to get potassium from food, if you can. And you want to go through all the medical and health contraindications for potassium supplementation. If you take potassium supplements in doses higher than 100 milligrams, especially if you're going to take high-dose potassium, that is not well-mixed into a meal. Those include diabetes and NSAIDs, especially including potassium-sparing diuretics, but there's a big list of contraindicated medications.

237: Can a high-protein diet hurt nitric oxide and raise blood pressure?

The people with OTC gene do have higher blood pressure because of lower nitric oxide. And they have a problem eating too much protein, but the protein is a problem, because they can exceed the capacity of the urea cycle and generate more ammonia. Whereas the OTC gene being low is what's driving the low nitric oxide to lower arginine production. So you are seeing the combination of this person should not eat too much protein. This person has low nitric oxide, high blood pressure, but I don't think it's the protein that's causing that. I think it's just low arginine synthesis due to low citrulline synthesis. And so they should supplement citrulline to improve their blood pressure. And they probably shouldn't eat too much protein, but I don't think that too much protein is going to be the thing that drives the high blood pressure.

236: General supplement recommendations for a physically active male in his 30s

I don't make general supplement recommendations. My recommendation for anyone would be do a dietary analysis. See what you're not getting from your diet. Either make up for that with foods or with supplements. If the foods are impractical, do nutritional status testing where it makes sense. Comprehensively, if you have enough financial resources or just where it makes sense based on signs and symptoms, fill in more gaps with supplements on an as needed basis.

235: For how long does methionine from a meal support methylation?

What I can say much more easily is that methionine is going to effectively run out as the fasting state emerges. Methionine has many fates, right? And so if it all goes into the methylation pool, it's going to be quickly either used for methylation or broken down in the CBS pathway. You are not going to save methionine for the fasting state.

234: Could collagen hurt absorption of iron from iron bisglycinate?

Yes, because the iron bisglycinate is probably going to be absorbed through glycine transporters rather than iron transporters.

233: Combining carbs and fat, LDL-C, calcification, and atherosclerosis

Generally speaking, if someone is overweight and hyperglycemic, then they're probably going to get a lot of benefit from trying to separate their carbs and fat, whereas if someone has amazing body composition and a totally healthy blood glucose level while they're eating a mixed diet, then I think it's kind of pointless. I would say that for blood lipids, generally, if macronutrients are going to affect your blood lipids, that's probably involving your fasting blood lipids, which is what's usually measured. If changing your macronutrients around is going to affect those, I think it's probably going to be in the context of some level of insulin resistance or overweightness, really insulin resistance or it would just be one of several ways to get there with carbohydrates generally pumping the sort of VLDL production and triglyceride content.

232: Could low-normal phosphorus be from my calcium intake?

Given that your calcium is coming from milk and yogurt and Traditional Foods Market brand whole bone meal to get your calcium, you're definitely consuming plenty of phosphorus, and so I don't think your dietary phosphorus is off. I wouldn't really worry about the phosphorus being low in that range. It's not low, it's on the low end of the range. I think the PTH being suppressed to 18 is great. I think the calcium doing that is great. I think that the calcium did that, even when all your calcium sources were balanced by phosphorus, sounds really good because phosphorus would do the opposite.

231: Exercising in the fasted state

The answer is necessarily subjective because the cut-off between a fasted state and a fed state is arbitrary. It's not like there's an on switch or an off switch for the fasting-feeding cycle. There's just tens of thousands of things happening that cluster together in different ratios and proportions that proportionally shift in one or another direction, depending on how much food you've eaten and how recently.

230: What does an upregulated GGT gene do to glutathione status?

Well, if you assume that whatever the genetic test told you is actually happening as increased GGT activity, then what it should do is break down blood glutathione and help the breakdown products get into the cell to increase intracellular glutathione. I think as to what it does to glutathione status measured in the blood, I don't know. Because on the one hand, it's probably going to break down glutathione in the blood. But in general, if you're improving glutathione status inside the cell in the liver, you're going to increase the export of glutathione.

229: A question on urinary lactate, pyruvate, and Krebs Cycle metabolites

When the NAD+ sensitive steps of the citric acid cycle are being inhibited,  that could be hypoxia, it could be high-intensity exercise, it could be taking metformin or berberine, it could be having a complex 1 disorder, and of course, I would sort of measure this against symptoms. So if you feel great, I wouldn't overinterpret this. But if you have something that feels like messed up energy metabolism, then I think it's best correlated with a deficiency in the respiratory chain, whether that's driven by oxygen, by increased demand, through high-intensity exercise, through taking complex 1 inhibitors like metformin or berberine, or through having a genetic complex 1 disorder. Thiamine is possible but if it's thiamine deficiency, then you should also see elevations in alanine as well. So I would get a plasma amino acids test, and then you could also look at the thiamine level in the blood and you could look at... HDRI has an erythrocyte transketolase activity test, and it's listed as ETKA on their requisition form.

228: High-dose EPA, triglycerides, and general health

It's definitely the case that high dose EPA lowers triglyceride levels in people with high triglycerides. And it does that by interfering with carbohydrate signaling. So carbohydrate signaling, part through glucose itself, and part through insulin, increases triglyceride synthesis and in insulin resistant people, generally the average person with insulin resistance has an amplification of that pathway and is actually hypersensitive to it while being resistant to glucose handling part of the pathway. So blood glucose and blood triglycerides increase. And if you take high-dose EPA, you will interfere with the signaling and you will lower the triglycerides.

227: Are there any downsides to eating lots of nuts and seeds?

I would mainly be looking at phytate and PUFA, and on the PUFA front, that's polyunsaturated fatty acids, on the PUFA front, I'm not in the extreme minimize it at all costs camp, but I am in the camp of, don't really overdo it beyond what you need to get your nutrients in. So I would look at the contribution of nuts and seeds to your micronutrient intake, and if you're flying real high on the pattern of nutrients that are in the nuts and seeds way more than you need of those types of nutrients, and I think I would cut back on that. And I would be a little bit concerned about the PUFA intake, whereas if you're not hitting your magnesium target, unless you eat the nuts and seeds, then I have a very different view of that.

226: Low cystine & sulfate, mid-range methionine, high homocysteine: what to do?

My default position on this would be, you probably don't have a problem recycling homocysteine to methionine. And that might explain why, I'm assuming this is in the fasting state, your homocysteine is only slightly elevated. Now, if you mean by slightly elevated, if you mean slightly elevated outside of the lab's reference range, then that's very elevated. And so I would look at that a little bit differently, but especially when paired with the low cystine and sulfate levels, it sounds like you have a low rate of the transsulfuration pathway or the CBS enzyme, which is the first step in that pathway, which takes homocysteine down to cysteine, which then can be metabolized to sulfate.

225: Is TMG a good source of glycine?

And so glycine is a methyl buffer. So it's not the default that one extra methyl group from TMG is going to make one molecule of glycine get lost, but generally if you put TMG into the system, you're going to lose methyl groups and you're going to wind up with probably the dimethylglycine going into the mitochondrion. Maybe that improves your glycine status, but I'm not so sure about that and I wouldn't rely on it. So I would just treat them completely differently.

224: Zonulin: what nutrients to look at if it's high?

I think of that from my perspective, which is much more focused on nutrients and biochemistry, I'm thinking especially if you have the ION panel, which kind of takes apart my end of the spectrum, actually I would look at arachidonic acid levels because arachidonic acid in the gut is associated with lymphoid tissue, is metabolized to prostaglandin E2, which promotes immune tolerance.

223: My iron won't go up even though I'm supplementing

The top things that I would think of would be riboflavin and copper, plus inhibitors of iron absorption. So generally speaking, plant foods are strong iron absorption inhibitors. Generally, you're going to have organic acids that promote iron absorption in proportion to the amount of potassium in the vegetables that you eat, although it's also the case that polyphenols will tend to correlate. And polyphenols inhibit iron absorption, so I'm of the opinion that you shouldn't eat plant foods at the meal that you're trying to get your iron in if you have trouble getting your iron up.

222: Vitamin K and Clotting Risk When Not on Anticoagulants

There's essentially not a trade-off because if you're not on vitamin K antagonist anticoagulants; in theory, there shouldn't be any effect of vitamin K supplements on clotting at all. The one caveat to that is that you might be relatively vitamin K deficient now and not realize it. So it is within possibility that you're not meeting your own personal vitamin K requirement to maximize clotting, but that's very, very unlikely because in population studies, almost no one falls into this category. But if that were true, then essentially, vitamin K supplementation would bring you up to a normal level of clotting, which may or may not affect the cardiologist's assessment of whether you should be on anticoagulants. 

221: Do some people do well on ketosis because they have defective glucose metabolism?

I doubt that that's the majority of people that feel good in ketosis, but certainly people with GLUT1 defects need to be on a low-glycemic index diet at least, if not a keto diet in order to not have seizures, and that's the best example of what would fit with that. People who do poorly with glucose, maybe in more moderate ways are going to do better on fat.

220: What to do when different folate markers don’t line up

You know, if you have high figlu on the NutrEval, which is Formiminoglutamic acid, which rises when there is Tetrahydrofolate THF, unmethylated folate, to metabolize figlu, and in that case, I would be thinking about maybe you have a B12 deficiency that is leading to the trapping of folate as the methylfolate form, so that THF isn't regenerated for that reaction. So I would absolutely never use figlu as the only marker of folate. I would look at serum folate and red blood cell folate always as the first markers of folate. So in this case, I would look at your serum folate and your red blood cell folate.

So before I would get folate injections, I would be looking at all those markers to see whether there's a coherent story between all of them that are agreeing that your folate status is low despite supplements, versus a divergence story between them that is telling me that one form of folate is the one that's missing rather than a total folate.

219: Can sulforaphane hurt the thyroid?

What I can say is that sulforaphane does generate thiocyanate ions, which do inhibit uptake of iodine into the thyroid and mammary glands. Although that is a matter of the ratio between isothiocyanate, or between thiocyanate ions and iodine. And so in principle, most uses of sulforaphane, in the context of adequate iodine shouldn't be an issue. I believe at some dose you're going to run into a problem with balancing with iodine, especially in people who have marginal iodine status, but I don't have any studies to back up what point that is. But I have seen cases of people where they got brain fog when they were taking sulforaphane and it went away when they took iodine.

218: Are the PUFAs in phosphatidylcholine supplements a concern?

I don't think so. I think that you're looking at fairly low levels of PUFAs in there, but the way that I see it is yes, we want to restrict PUFA beyond what's needed, but what's needed is defined by what do we need to get our essential nutrients in.

217: Is dairy safe for overmethylators?

There's so little methylcobalamin in milk that I think that it is totally insignificant with regards to methyl groups, coming into the methylation cycle. Generally, if you're experiencing over-methylation symptoms from methylcobalamin or methylfolate, I think the big issue is partly that you don't have enough glycine in the system, very likely, and partly that your body is over-accustomed to low methyl supply and putting more suddenly into it leading into the system being adapted to a different state than the one you're putting into it. But if you find it is, you're reacting to dairy, I would be very surprised if it was the methylcobalamin, but if you're very convinced of that, then titrate up slowly with the dairy.

216: Should different macronutrients be eaten at different times of day?

No, I don't agree with the principle. I think you want protein spaced out at every meal. And that's because your efficiency in extracting protein for muscle synthesis is limited in any given hour or any given unit time. And so you need a lot more protein if you're going to put all your protein in one meal, then you are not going to get optimal body composition results from that. Body composition plays into every other metabolic thing we care about. If I were to shift protein around in emphasis, I would put protein bias towards the morning and biased away from night. And that would be on the basis that protein is the basis for every single neurotransmitter involved in wakefulness.

215: Is it OK to take two milligrams a day of MK-4?

Two milligrams, I don't have major safety concerns over, but I would prefer for most people who aren't dealing with a clinical soft-tissue calcification issue take more like 200 micrograms. 

214: How to feel great on a poor night’s sleep?

I would say get rid of the poor night's sleep. And so that's go through the checklist of two to four hours of blue light blocking before bed, up to two to four hour, depending on your needs, psychological winding down routine, in which you clear everything off your to-do list, everything off your problem-solving list, focus on a paperback fiction, TV, video games, movies, et cetera. Deal with all those things first, because I don't think there is any magical one-off cure for poor night's sleep.

And then if cold exposure helps, then that tells me that boosting norepinephrine is what's helping. So how do you boost norepinephrine? There's a lot of micronutrients involved in norepinephrine synthesis. So vitamin C, copper, salt, lots of things come into play, antioxidants that is. Cold exposure, maca root, coffee are probably the biggest things that you could use.

213: What supplements should be taken by someone on PPIs?

I would first consider what you should do to get off the PPI. And so PPIs Are targeting stomach acid. And so I would first and foremost be thinking of excess histamine might be leading to excess stomach acid.

You should probably try to eat a higher-protein diet, unless you're getting negative consequences from poor protein digestion. But if you're poorly digesting your protein, you are going to need more protein to nourish yourself. So I would think a higher protein diet and a multivitamin would really be the best things because there's too many nutrients whose absorption is going to be compromised by that. And then I don't really consider myself a gut specialist, but I would read up on what other people who are specializing in the gut are saying about how to compensate for PPI's with the microbiome, because I would think that would also come into play. 

212: Could methylglyoxal be causing elevated fasting glucose in low-carbers?

Yes. I did my doctoral dissertation on methylglyoxal so I've covered it in a lot of different contexts, and the basic story is we know that diabetics have high methylglyoxal levels. We know that diabetics have high methylglyoxal-derived advanced glycation endproducts. And we know that this is true even when they're treated. Now that raises the question, does diabetes cause methylglyoxal to increase, or does methylglyoxal cause diabetes? And the answer is both. 

211: Is it important to hit the AI for total omega-6?

I think it's totally normal to not meet the AI for Omega-6 and to exceed the AI for Omega-3. Question is really, if you have systemic inflammation going on, you frame this as, should I strive to at least meet the AI for Omega-6 if I have chronic disease/inflammation? Well, if you have chronic disease/inflammation, you might be depleting your Omega-6, which means depleting arachidonic acid, which means you might need more arachidonic acid. If your arachidonic acid levels look good, you shouldn't worry at all about meeting the AI for linoleate as far as I'm concerned.

210: How 30 minutes on the elliptical helps my head and neck tension

So what the elliptical does is, it doesn't do a whole lot for moving my neck one way or another, but it does a lot for moving my thoracic spine and my shoulders through a pretty defined range of motion, not full range of motion going like this is, but it's a lot of movement through a considerable amount of that range of motion, and I think it's sufficient to give my thoracic spine and my shoulders a lot of circulation of fluid that nourishes the joints and keeps things moving.

My experience with this is that 30 minutes on an elliptical three to five days a week, cause improvement. Five days or more cause very marked improvement, three days a week is more like maintenance, and below three days a week... If I had to simplify it, five days a week, 30 minutes a day on the elliptical causes improvement that just gets better week, after week, after week. Three days of 30 minutes on the elliptical per week will maintain whatever improvement I've gotten from doing five days a week, and less than three days a week will cause a regression.

209: Why does it take time to be fat-adapted when our body already knows how to burn fat?

So the body does need time to get fat-adapted because yeah, the body knows how to burn fat, but fat adaptation is not about the body knowing how to burn fat, it's about the body increasing the expression of enzymes involved in burning fat. So everything that you do in the body requires enzymes. Enzymes are proteins that need to be made. It's going to increase enzymes involved in fat digestion and metabolism if you've been eating fat, and because it's expensive to do that, it's going to cut back on them if you haven't been eating fat. 

208: What should someone with FH eat if they also have prediabetes?

So first of all, it's a separable component of the diet so you need a low-saturated fat, low-cholesterol diet without necessarily eating a low-fat diet. Then second of all, the effect of that on blood lipids is dependent on the healthfulness of your insulin pathway. And so over time, that's something where you can play the balance between those two things and as you improve your blood glucose handling, you can fit in more carbohydrates to have a fuller dietary effect.

For managing blood glucose, and I don't think it's a good idea to condemn all carbohydrates as a means of managing that. I think the best thing would be to get a continuous glucose monitor or a regular glucose monitor. If you're using a regular glucose monitor, use 30 minute, one hour, two hour, three hour, four hour time intervals after a meal and collect a baseline before a meal and look at how do different starches that you don't have an immunological response to... so you don't have to test grains because you don't tolerate them, but other foods that are rich in starches, whether it's carrots, or potatoes, or sweet potatoes, or whatever it is.

207: How should I take zinc if it makes me nauseous?

As far as I know, there's no relationship between the nausea and zinc deficiency. I could be wrong, maybe there's research on it I haven't seen or it could be not researched but I don't think there's a connection. My guess would be that that is either related to her ionizing it faster in the GI tract than you, or something else related to her nausea impulse that might be nutritional, it might be genetic, it might be male/female.

You could test out whether a little bit of bone broth or orange juice, or what have you with it buffers that enough to stop the nausea, and if it doesn't, I would just try to take it with a phytate-free meal. And by a phytate-free meal, I mean, a meal that doesn't have any whole grains, nuts, seeds, or legumes.

206: Can familial hypercholesterolemia be managed without statins?

I think there's the general perspective that there's no point in having LDL-C be any higher than 50; therefore, since it doesn't matter, let's provide a sufficient margin of error where we're real confident that getting it down to 100 is great and so why not get it down to 50? If there is any extra protection we get it and we don't lose it.

So my point of view would be, I would personally rather use a more conservative target of lowering down to 100 or so where the confidence is actually really high, because I'm not convinced by the lack of confidence that there's no neurological downside to pushing it twice as low as that. So that's my general perspective and if this were me, and it'll never be because I can't for the life of me get my total cholesterol above 160, but if it were me I'd be lowering my dose on that out of precaution on the other side.

205: Is this a biotin deficiency?

Beta-hydroxyisovaleric acid is well-established to be the most sensitive marker of biotin status. And actually typically it's done after leucine challenge, which is, no one does that. And so, generally in my experience, the way they have the reference ranges set on that should, on the ones that do have it, so the ION panel has it, the Genova panel has it, and the way they set the reference ranges, I think it works without the leucine challenge. But, I prefer the Genova ION panel because it has more, I just had a spreadsheet made up of the different markers that I wanted and the ones that were on the different organic acid panels and the ION panel has the most that line up with what, what I was looking for.

204: Why do vitamin E requirements stay elevated for four years when we stop eating PUFA?

None of this really proves that long-term vitamin E status is compromised, and that will make the clinical effect of PUFA be net negative after four or five years. But it does show you that the general relationship between the fact that you get more vitamin E when you eat PUFA oils, right? Because in the plant, the plant doesn't have this turnover problem, the plant makes vitamin E whenever it wants. And it has a certain amount of PUFA for some purpose, and it loads it up and so the plant has the amount of vitamin E that is needed to protect those under those conditions. So the question is, does a person, a human being, eating that oil also benefit from that relationship between vitamin E and PUFA that the safflower plant made? The answer to that is controversial.

Important note: In the video, a graph was shown that showed adipose linoleate is cleared in about one year rather than four. This was from an animal study. On page 30 in the PDF and 546 in the journal of this reference:

https://www.sciencedirect.com/science/article/abs/pii/0079683271900358

… it can be seen that it takes about 50 months (approximately 4 years) for adipose linoleate to bottom out in a human switched from corn oil to beef fat.

203: How long should our fasting windows be?

I think someone who eats three meals a day and no snacking is doing a form of intermittent fasting that most people aren't doing. And I don't even have a basis for believing whether that is superior, inferior, or the same as one meal a day in a 20 hour, four-hour feeding window. And so I think it's very clear that you want to cycle through the fed and fasted states. I think exactly how you do that is all trial and error and anecdotal accumulation of anecdotes and experiences at this point.

202: What is the value of third party genetic reports?

There are very, very few genes where we have really good information on how they impact nutritional requirements, but we have many, many, many genes where we have decent information on what they do mechanistically and where we can speculate things that might be helpful. So genome analysis is very useful as a brainstorming mechanism. And of course, there's genome sequencing in a clinical context to identify rare metabolic diseases, a totally different thing. That's obviously useful for where it's been defined as being useful, but doing a 23andMe analysis and submitting it to a report is useful for brainstorming and potentially generating some explanations for things that you observed.

And I think Self-Decode did a really good job in distilling, first of all, taking a lot of conflicting polymorphisms and distilling them into a net result. And then, second of all, distilling some actionable principles. Third of all, noting where they're brainstorming and providing references to give some reasonable level of confidence of exactly.

201: What is the value of the oxidized phospholipids test?

It's interesting to measure, but we don't have real strong data on its correlation to disease risk.  And we also don't really know how much it reflects the oxidation of lipoproteins in the subendothelial space, which is what matters.

200: Can NADH supplements cram more NADH into the system?

The NADH will be hydrolyzed to something along the lines of nicotinamide riboside, it will be absorbed and it will act like nicotinamide riboside does, which will increase the amount of nicotinamide stored in the liver for release to the tissues. And that will help increase their NADH levels.

199: How to avoid losing nutrients in fat thrown out from an organ meat blend

I don't think you're going to lose that many nutrients because the 25% fat, 75% lean ground beef mixed with those organs, most of that fat is coming from the marbling of the beef. That's not coming from the organ meats. Most of the nutrients in the organ meats, and they're not in marbled fat they're in cells and stuff.

198: How to manage the zinc-to-copper ratio?

I don't agree with using the zinc/copper ratio in testing. So it is the case that zinc and copper need to be in a very loose range of ratios. So you don't want your dietary zinc to be more than 15 times your dietary copper, and you don't want your dietary zinc to be less than two times your dietary copper. But other than that, you're really looking at them individually, and you're looking at, do I have enough zinc? Do I have enough copper? Do I have signs of zinc deficiency? Do I have signs of copper deficiency? Do I have signs of too much of one or the other? Much more than you're looking at the ratio.

197: Milk thistle, sulforaphane, and blood donation for iron overload

If it's an uptrend, you probably want to do something about it. Someone in that situation could try the Nrf2 stimulators, like milk thistle and sulforaphane. But if it is a genuine uptrend in early stage iron overload, that might be a situation that giving blood once a year would be the best solution.

196: Why would methylated vitamins increase pain sensitization?

I'm not sure. Just to throw out some random threads that may or may not be of use. I think methylation in some people is going to lead to increased synthesis of dopamine. But in general, the effect is going to be to decrease the tonic pool of dopamine. There's going to be some degree to which it decreases other neuro-transmitters. And it's possible that if, particularly, if glycine is not stabilized, that you're going to lose the inhibitory effect of glycine and that you might also lose the effect of ambient glycine in coactivating NMDA receptors. Now off the top of my head, I would think that you would want the glycine there to support.

195: Why would ferritin and B12 increase on a low-calorie keto diet?

Ferritin is very strongly influenced by inflammation, oxidative stress. And so if the iron status is not changing and the ferritin is going up and then down, to me that suggests that oxidative stress or inflammation is increasing in the hypocaloric state. I was thinking maybe there's more PUFAs and stronger favoring of oxidative stress when there's more PUFAs released from adipose tissue during the hypercaloric during a hypocaloric state. 

So, all the PUFAs are being metabolized in the liver. And so there's probably oxidative stress increasing in the liver specifically in the hypocaloric diet, because the fatty acids are all being biased towards lipolysis from adipose tissue straight to the liver for beta-oxidation. And I think that's dramatically increasing the oxidative burden on the liver and there's short term damage being done in the liver that's increasing the B12 and ferritin levels.

194: Why are polyunsaturated fats more easily burned for energy than saturated fats?

I don't know in detail the mechanism, but I do know that it's been shown in human cells and in live animal experiments. And it presumably is related to the affinity of the enzyme for the fatty acid. And that's not something that's biochemically difficult. It's normal if there are enzymes that work with any fatty acid, for them to have different affinities for some fatty acids versus others.

193: Why zinc deficiency causes resistance to thyroid and sex hormones and vitamins A and D

The answer to that is because the, because all of those things carry out their gene expression function by binding to nuclear receptors. And all of the nuclear receptors to DNA using zinc finger motifs. Zinc finger motif means that in the nuclear receptor, there's a zinc ion that coordinates the primary structure of the protein, which is a long string of amino acids into a finger shape.

192: Which nutrients do we need every single day?

I would say that the top ones to be concerned about from a have-to-get-it-today perspective would be zinc and B12. And both of those have absorption caps that are fairly tight, but B12 is the number one concern.

You want to pay decent attention to the zinc rule, and you do want to make sure that your B vitamins are getting in on most of those other B vitamins you could probably, as long as you're hitting the daily average on the weekly basis, that's good.

191: What nutrients does a collegiate swimmer need to look out for?

Mainly calories would be absolute number one. Number two would be carbohydrate. So I do think that people can fuel athletic capabilities on low-carb diets, but you might want to look at stress hormones and sex hormones, because sometimes fueling athletic performance on a low-carb diet comes at the expense of elevated stress hormones, which could mess with thyroid hormones and sex hormones. I think those two things, the calories and carbs would be the top risk for potential hypothalamic amenorrhea. That would trump everything else, completely. Higher energy demands are going to demand more B vitamins. And that's generally going to be probably most B-vitamins besides B12 and folate. Although B-12 and folate are peripherally involved in energy metabolism, the other B vitamins are more directly involved.

190: Is extended fasting the best choice for weight loss when low-carb doesn’t work?

If someone's on low-carb diet, they're not losing weight, they're not sustaining the caloric deficit at food intake that's satisfying them. So I would try helping the protein and doing something maybe cyclical keto on top of that before I would do an extended fast.

189: MK-4 vs MK-7: Vitamin K2 Showdown

My default here is that a healthy diet would always have a mix of all of them. And although it's hard to justify a reason for having K1 specifically if you also have MK-7, the justification for having MK-4 is somewhat speculative. I wouldn't say speculative, but it's at kind of the theoretical level. So basically, MK-4 is not very good at supporting blood clotting, but MK-7 and K1 are. And we know that from human trials. And so we can at least say, you shouldn't only get MK-4, because it's not very good at supporting blood clotting.

As default, get your K1 from veggies and then try to get a mix of MK-4 and MK-7, that totals up to 2-400 micrograms per day for the people who are just talking about one to 200 micrograms for general people, that can come from food if you eat those foods and supplement if you don't.

188: How should someone balance a vitamin D of 80 ng/mL with other nutrients?

Let's say the idea is to maintain someone on a lifelong level of 80 nanograms per milliliter. Maybe four times the first year, two times the second year, once the third year and then every few years thereafter, I would measure the urinary calcium and make sure that that level is not associated with hypercalciuria in that person. Because if it is, I think you're putting that person at an increased risk of kidney stones if nothing else. And then I would say that person wants to get at least 200 micrograms of vitamin K2. My default would be to say 10,000 IU of vitamin A, just off of the fact that I feel like you're basically doubling the normal amount of vitamin D in someone who is 80 nanograms per milliliter.

187: Can MTHFR cause ADHD?

So, methylation will reduce the background level of tonic dopamine. And make you more mentally flexible. And a lack of methylation will generally lead to a higher level of background dopamine and make you not as mentally flexible. So, I really don't think that the ADHD is solely a consequence of MTHFR. Low methylation state and glycine wasting is probably playing into some of the aggravating factors, particularly glycine wasting.

186: MTHFR, Depression, Irritability, and Anxiety

So, if someone has an MTHFR snip, they don't have enough methylfolate. And so if they're treating it with methylfolate, the methylfolate causes the depression, irritability, and anxiety, then that's one thing. Whereas, if they have the MTHFR snip, they're not doing anything about it and they have depression, irritability, anxiety, that's another thing. So, if they're not doing anything about it and they have those problems, then it's probably from under-methylation. If they're supplementing methylfolate and that's causing the depression, irritability and anxiety, then my guess is that that is a temporary transient over-methylation state. That is a result of the body being adapted to a low methylfolate state and suddenly switching to a high methylfolate state. And I think the key to getting through that is to take small doses of the methylfolate and equilibrate to the lowest dose.

185: Why you have to multiply labeled phosphatidylcholine by 15%

Yes. If a lecithin product states the phosphatidylcholine content and you want to know the choline content, multiply by 15%.

184: Is liver OK to eat if raw or if blended in a Vitamix?

So, the blending might hurt some really sensitive stuff. There's a lot of glutathione in liver. It might hurt some of the glutathione. I think the majority of the vitamins are going to be okay. And the minerals in general will be fine. And I think it's important to note that, if it makes the difference between whether you eat the liver or not, then it's much more important to eat the liver that you like. My personal choice during times when I've wanted raw liver, my rule has always been that if it's frozen for two weeks or longer, it's safe to eat. And it's also from a clean and trusted source.

183: If total carnitine is low, should I supplement?

Supplementation does increase the acylcarnitine fraction and total carnitine to near normal levels. But I'm not clear about whether it's worth worrying about. So, if the total carnitine is low, but the free carnitine is normal, then total carnitine is low because the acylcarnitines are low. I wouldn't be too worried about the acylcarnitines being low. I would be very worried if the acylcarnitines were very high and overwhelming the total pool of carnitine, 'cause that would suggest a metabolic problem.

182: Isn’t taking copper with zinc self-defeating?

No. So, the competition between their absorption is not that bad. And if it was bad, everyone would be deficient in both of them because all foods that contain one, contain the other.

181: Insulin resistance from fat invading muscle cells?

I think increased free fatty acids in the blood. That's going to be a normal reaction to dietary fat and I think that if you have increased fatty acids than increased glucose, that you have more energy to dispose off. And if you have more energy to dispose of, and you don't dispose off the energy, then that's going to cause insulin resistance.

180: How do carbonated water, magnesium, and potassium affect pH?

If you drink carbonated water, the CO2 is going to give up hydrogen ions to become carbonic acid, which is going to give up hydrogen ions to become bicarbonate. So making bicarbonate from CO2 is acidic taking bicarbonate is alkaline. So the thing you have to keep in mind here is that the reason bicarbonate is alkaline is because it makes CO2.

179: What’s the difference between the NADH/NAD+ and the NADPH/NADH ratios?

So the NADH to NAD ratio and the NAD pH to NADP plus ratio are things that are having real consequences as ratios and biochemistry that are dictating what's going on in our body. The NAD pH to NADH ratio is physiologically irrelevant, but is used as a biomarker of niacin status. So if you look at a biochemistry textbook, that's telling you how things work in the body you're going to see constant references to the NADH to NAD ratio or the NAD pH NADP plus ratio. And you're never going to see any reference to the NAD pH to NADH ratio.

178: What if my ferritin is low, but other iron markers are normal?

I would first see whether getting more iron in your diet raises your transparent saturation or your iron saturation higher than 40%. If it does, then I wouldn't push it but if it doesn't or if your transparent saturation is significantly below 30%, then I think there's room to try to increase iron further.

If pushing iron up isn't the answer, I would try something like milk thistle or sulforaphane, things that are designed to promote gene expression for detoxification are antioxidant defense such as milk thistle and sulforaphane are generally also going to raise ferritin because ferritin is part of the protective response.

177: Menstrual Migraines, Pregnancy, and HRT

What I think is happening is the estrogen is probably suppressing DAO when it's higher, but because it's staying suppressed, there's compensation that's happening for it to help minimize the histamine level. Whereas when the estrogen is cyclical, it's suppressing DAO when the body hasn't made any adaptations to low DAO. And that's sort of like sometimes women will get very strong problems with histamine coming off of a pregnancy because the DAO has been so high so long that all the other adaptations that you would have in other ways of breaking down histamine or down-regulating histamine receptors or whatever else, have all been... There's been no need for them. And so your body is maximally accustomed to DAO doing all the work for you.

176: How do I know if biotin deficiency is causing my hair loss and fungal rashes?

The plasma or serum biotin level is not a good marker of biotin status because it's not very sensitive. And so, if you're in the bottom 10% of it, I would definitely take that as a red flag that you might have biotin deficiency, the best test for biotin, well, the gold standard for biotin deficiency is beta-hydroxyisovalerate in the urine after a leucine challenge. I don't know how you'd get anyone to give you that, but the next best thing is to get a urinary organic acid test that has as beta-Hydroxyisovaleric acid on it and I know that the Genova ION panel, which is the one I usually prefer has that, but a lot of other ones do too. So I, if you get one, I would just check and see whether the beta-hydroxyisovalerate is on the list of analytes.

175: How do you know if skin problems are from zinc deficiency?

I would measure plasma zinc and if the plasma zinc, the sweet spot is around 120. If the plasma zinc is in the 70 to 90 range, that's borderline and if it's below 70, that's very clearly potentially related to skin problems. I think you have your answer right there. If your zinc's at 120, your skin problems, are not due to the zinc deficiency.

174: Anxiety, Neurotransmitters, and Nutrition

So there's a few trans neurotransmitters that are particularly relevant. Histamine is a key anxiety neurotransmitter. Another neuro-transmitter that's relevant is dopamine and I don't see dopamine as primarily actually causing baseline anxiety.

Measurement of neuro-transmitters is very difficult but you can get some hints and make some inferences. I would say the Genova methylation panel and the Genova ION panel plus sporty would give you more than enough to probe this stuff.

173: What are the best ways to stabilize blood sugar?

I would definitely be trying to lower the glucose response. And what I would do in such a situation would be to run a series of experiments on the type of carbohydrate, as well as the amount of carbohydrate, as well as the context of the meal to see. I would use that as the maximum and so define the carbohydrate load of the specific foods that you can tolerate within that range, and then once you have that, then you can experiment with other things like what happens if I add Apple cider vinegar to this regiment, what happens if I add whey protein, which can also help, what happens if I add glycine, which can also help.

The test is a great hint at what might be happening. But at the end of the day, what matters is what happens when you eat the meal you always eat.

172: What are the best natural ways to lower cholesterol?

The top things that I would think of to lower cholesterol levels are number one, I'd get thyroid status thoroughly checked out. Number two, I would consider experimenting with a diet low in saturated fat or diet low in cholesterol to see how responsive your levels are to those things. Number three, I would experiment with some fiber supplements.  Number four, for people who are overweight, then normalizing body composition is an issue. Number five, I wouldn't use pantothenic acid. I would try pantethine.

171: Does high B12 mean it’s not getting into the cell?

The right way to address that would be to measure serum or urine or both methylmalonic acid MMA, and that's a functional marker that's very specific to B12. If B12 was not getting into the cell, then methylmalonic acid is going to be high.

170: What range of folate and homocysteine are good for MTHFR?

So 18 to 22 nanograms per milliliter for serum folate and then for homocysteine, I would say seven to nine, I think eight is right smack in the middle and it's fine. No harm in getting down to five, if you can get there but I wouldn't, if you're in the seven to nine range, I wouldn't worry about it.

169: Do Ketogenic Diets Lower Glutathione?

And so what a ketogenic diet does is put you in a low insulin to glucagon ratio longterm and the insulin to glucagon ratio is what is used for the body to perceive whether it has enough energy to invest in making glutathione. And so the reason the liver's glutathione is going to go down on a ketogenic diet is because you're in the fasting state.

Glutathione synthesis is a fed state process. It's something that goes down in the fasting state and up in the fed state period. And so if you're using a diet that is mimicking the fasting state and is allowing you to carry out fasting state physiology for a longer period of time than you would be able to go on zero calories, then you're going to mimic the fasting state. And the fasting state is characterized by lower glutathione synthesis. And that's the end of it.

168: Why do I have a high LDL-C when my diet is on point?

Generally in the presence of insulin sensitivity, more carbohydrates, less fat will lower LDL, but in the presence of insulin resistance, more carbohydrate will sometimes raise LDL.

And if the LDL is only a little bit out of range and the HDL is good, I wouldn't worry too much about it. If the total to HDL cholesterol ratio is under four, especially if it's close to 2.0 or underneath that, then I would be worrying about all the elements a little bit out of the range. But I would look at coconut oil, reducing it, body composition, normalizing insulin sensitivity, optimizing it. And if all those things are done, substituting some more carbohydrate, less fat may help.

167: Can protein replete glycogen on a low-carb diet?

Yes, it's possible. And I don't know exactly what the dosing is, but I think it's totally possible. It comes at the risk, I don't want to say risk, but at the downside of creating a lot more ammonia. But I think it's quite possible. I think it was Master Nutrition, Energy Metabolism, Lesson 17, it was the one on the evidence around low-carb and athletic performance. And if you look at the studies suggesting low-carb does not compromise athletic performance, the diets are much higher protein than the diets that suggest that it does compromise athletic performance for glycogen levels. And so, I think on a low-carb diet protein is going to probably be a very critical determinant of glycogen levels.

166: Creatine: do the benefits outweigh the risks for a mid-30s male?

I think that there are borderline no risks to creatine supplementation. I know some people get bloated from it that usually passes. Anecdotally, some people get insomnia. I think if nutrients are balanced and you just stick with it, that'll go away. There's speculation that it could aggravate male pattern baldness, but there's no good evidence of it.

165: How important are MAT1A SNPs to methylation?

These in principle, could reduce the activation of methionine, but I don't know that there are any studies that have looked at whether that's the case. And so, just because a SNP isn't a gene doesn't mean that it reduces the activity of that gene. In fact, it doesn't mean it does anything even to the protein sequence of a gene because a lot of SNPs don't affect the protein sequence.

164: How to increase red blood cell magnesium content?

Well, the first thing you want to do is look at your serum levels. And if your serum levels are low, you want to look at your urinary levels. And if your serum levels are not low or especially, if your serum are high, then you want to focus on promoting magnesium absorbed into the cell.

If your serum levels are low, then you probably don't want to focus on that, you want to focus on magnesium intake or retention or absorption. If you're focusing on getting it into the cells, you're looking at insulin sensitivity, insulin stimulation, vitamin B6 and salt. For urinary loss, you're looking at anything that causes too much urinary output, stress. And if you still can't find the answer, you might want to start looking at certain genetic polymorphisms.

163: Why would ferritin rise on a low-carb diet when iron status is stable?

Well, they sound copper deficient because copper is needed to mobilize iron out of ferritin. Copper is most abundant in plant foods, except that it's also very rich in liver. And it's pretty decent in a number of shellfish, but on a low carb, steak and cheese diet, not only are you deficient in copper, but you are also now pushing your zinc levels up, which will lower your copper absorption. Low white blood cells is, first thing that I'm going to look at is copper levels, especially if the neutrophils are low. And that would very easily explain rise in ferritin.

162: What are the best practices for nutrient absorption?

Large meals and fat soluble vitamins. Large meals are the ally of fat soluble vitamin absorption. Fat absorption from poor fat digestion, is the enemy of not only the absorption of fat soluble nutrients, but also the absorption positively charged minerals. There might a few of them missing, but those are the ones that really stand out to me as big nutrient absorption issues.

I wouldn't micromanage these things, but if it is an eminent view where there is a problem to fix, that's when I start thinking a lot about them. But certainly there are more details in the vitamins and minerals 101 course, and what I have gone through right here.

161: What’s the best prenatal nutrition?

The things that sort of stick out to me are, you don't want to be Vitamin A deficient or Vitamin A toxic, so you're right in the middle of the range. You really don't want to be deficient in anything. Everyone knows about folic iron which is really important, but there's not really a good nutritional status test for choline. Biotin is very important. One third of mothers spontaneously become biotin deficient from pregnancy. And so I think that you want to be at least getting the RGA for biotin. DUS test of biotin status, is beta-hydroxyisovaleric acid, which is found on a blood panel but it is kind of pricey, but is the best. I think all of the nutrients are important, but I would single out those as being the most important to look at.

160: Supplement Timing and Food Combining for Zinc?

So for zinc and food, the main issue is that, my guess is that a carnivore meat based meal would probably enhance zinc absorption, but that's never really been tested. There's some controversy in the field over whether you should take zinc on an empty stomach or not. So my position is basically like if it's practical for me to take the zinc on an empty stomach, do an empty stomach. And if it's not practical for you to take the zinc on an empty stomach, do it on a phytate free meal - no whole grains, nuts seeds or legumes.

159: How to approach chronic joint pain?

So the movement must target the joints that are affected. And you definitely want like 30 minutes a day of just moderate movement, even walking would be great. But then you also want movement aimed at actually supporting the muscles and the proper joint motions and stuff like that. And so that's where weight lifting comes in. And then you definitely want some guidance from a physical therapist who works with athletes at a minimum to guide the form on the weightlifting movements to make sure they're supportive of the joints instead of making them worse. And then eat a nutritious diet and look for inflammatory foods and try to cut them out and see if that improves it.

158: How should I break a 36-hour fast?

The two things that I would think about are your digestion, it's probably going to take a little bit of time to ramp itself up. I don't think you're going to do any harm by eating things that are difficult to digest, probably not great for your microbiome, but probably something that would just adapt to you. And so I would take that very subjectively. In your experience, what types of things do you have trouble digesting from when you stop a fast? But I think it's going to be fairly common to feel like some things just don't digest this well when you come off at 36 hour fast than you otherwise would. I think that's very subjective. My main concern from a health perspective would be feeding syndrome. So generally when you're fasting, you lose phosphorus because the phosphorus is associated with carbohydrate metabolism and your glycogen levels have been depleted.

157: What are optimal levels of B12?

So there's a paper called the Pathophysiology of Elevated Vitamin B12 in clinical practice that PM Schoenfeld, another Masterpass member, had given me. And this paper is very interesting because it identifies a bunch of things that high B12 can be an indicator of, not a causal factor in but an indicator of problems. And it also disputes the low end of the range. So according to this paper, we really want B12 levels above 400 picograms per milliliter, which is 295 picomoles per liter. I believe picograms per liter is what most people's lab results come in. And that's like double what most labs are using for low levels at least at the time this paper was written. I believe it's like 1400 is where their cutoff flies for potentially indicating problems.

156: Are GABA or methylation support useful for panic attacks?

I think anything that increases GABA activity is probably going to slow down anxiety and panic. I think that's clear just from the drugs that are used to treat an anxiety, or panic disorder. Xanax is used for that purpose. So I do think that working on nutritional support around GABA makes sense, but I also would look at histamine, because histamine is an alertness signal, but I think in very excessive amounts histamine is a panic signal.

GABA might help move focus from one thing to another. And methylating dopamine is needed to provide mental flexibility so that you don't get stuck on anxiety producing thought patterns and emotional patterns. And histamine just is a general stimulant of anxiety beyond a certain threshold. So I think those would be the key areas to focus on if that helps. 

155: Is increasing reactive oxygen species a good strategy for appetite control?

Is that going to cause satiety in the brain? Maybe. I haven't studied that. I think Stephan Guyenet would be a great person to talk to about that. It wouldn't surprise me in the sense that if you want to shut down energy coming into the cell, why wouldn't you also want, at some bigger level, to shut down energy input into the body? I guess that makes sense. But I've mostly studied this in the case of outside the brain, peripherally, what is it doing? And what it's doing in adipose tissue or in skeletal muscle is it's shutting down glucose uptake, leading to hyperglycemia, and it's shutting down fatty acid uptake into the mitochondria leading to elevated free fatty acid levels, all of which are generally harmful to the body. Now this is an adaptively desirable thing because, let's say you have a trillion cells.

154: What’s the best way to increase ferritin?

If you're taking an iron chelate supplement then you should probably take it with a carnivore meal. Vitamin C and a few other ones, folate, are not really vegan nutrients but they're very plant-oriented nutrients in terms of what's the thing you're probably going to add to your diet that's going to help. And so I really feel like if I had iron deficiency anemia, I would probably just spend four weeks on a carnivore diet that was rich in red meat and if I really wanted to just pick a simple dietary plan, go all in on it.

153: What to eat for a 35-year-old vegan woman with hypothyroidism and low zinc levels?

I think a vegan with poor zinc levels should supplement with zinc. You know, it's one thing if you have a vegan whose diet just happens to provide good zinc status, despite the fact that their diet is dramatically lower in total zinc than an omnivore who eats a lot of red meat or seafood, particularly oysters, and that the bioavailability of zinc from those foods is dramatically less.

So a vegan probably needs twice as much zinc as an omnivore needs because of the inhibitory effect of phytate and the beneficial effect on zinc absorption by the amino acid composition of most animal proteins.

152: Are the concerns about cyanocobalamin exaggerated?

I'm not sure what people have said about the dangers. I know that I have been a critic of cyanocobalamin relative to other forms of B12 and then, other people may have used something I said maybe in an exaggerated way. And then there might be just much marketing that I haven't actually been exposed to where people have come up with their own marketing claims around other forms of B12.

So my opinion is basically as follows: number one, the amount of cyanide that would be released from taking even high doses of cyanocobalamin is very small. And so I don't think taking cyanocobalamin is dangerous in any context that I can think of so that's number one. But number two, one of our mechanisms for detoxifying cyanide, and it's not the only mechanism, but it's one of the key mechanisms is to join the cyanide, to cobalamin, to pee it out in the urine.

151: What’s a better nasal spray, Sterimar or povidone-iodine?

It's hard to say. So the Povidone-iodine obviously has some contraindications and it has contraindications mostly because it's been so commonly used in a medical setting and therefore has so much known about its safety and risk profile and I don't have any particular reason to think that the Sterimar is unsafe in any context. And I used it a lot. The only thing I can say anecdotally is I've used the Povidone-iodine intra nasally, and I've used the Sterimar spray intra nasally. And I feel like 0.5% Povidone-iodine is really powerful in wiping out anything we have going on in the nose.

150: Do postmenopausal women need to worry about iron overload?

Generally, it's not men who are necessarily predisposed to iron buildup. It’s men with some genetic predisposition to that, so maybe less than 10% of men. But yeah, postmenopausal women with the same genetics will, like men, be vulnerable to that. When you stop menstruating, you essentially become like a man in terms of your ability to accumulate iron.

149: Should NAC supplementation be pulsed?

So, yes, boost glutathione. It might bring glutathione down. It's speculative that you could pulse it to avoid that. But even supplementing oral glutathione for 6 months was shown to not affect glutathione production. And certainly, oral glutathione is going to have more of a negative feedback loop than a glutathione precursor. So, I am not too worried about it.

148: Why would my threonine levels be low?

The two things I can think of are increased gluconeogenesis and increased conversion of methylglyoxal, both of which I would expect to be driven by a low carbohydrate diet. Then of course, it could also be not enough protein consumption. But if it's why threonine is being metabolized, I'm gonna be thinking of a low carbohydrate diet.

147: What’s the best alcohol to microdose?

I prefer red wine on a taste, and tradition, and aesthetic basis. Just for background, I think  Half a drink to a drink a day is probably the net maximal benefit for alcohol and that can be averaged. It doesn’t have to be every day. And that’s the main thing.

146: What’s the best nutrition for panic and anxiety?

Methylation is overwhelmingly important. I do think that other factors impacting dopamine can be relevant in the sense that the main way that methylation regulates mental rigidity is through decreasing the pool of tonic dopamine, which favors mental flexibility. And so, you can also favor mental flexibility by increasing the activity of dopamine receptors that mediate the basic response dopamine. 

145: What determines the absorption of nutrients?

This is a gigantic question because what determines the absorption of any given nutrient is independent for that nutrient. And so, it’s different for every nutrient. And we just don't have that level of data to drive modeling of absorption of other nutrients in an accurate way.

144: Do low serine levels require IV supplements?

You're probably just depleting serine through the CBS pathway and just eat more protein and consider supplementing glycine or collagen along with it. I don't see why that would require IV supplements.

143: How to fix high iron and calcium, low copper and magnesium, without blood donation?

Your only options for decreasing iron levels are to eat a low meat vegetarian diet high in vegetables, nuts, seeds, and whole grains. That's probably your best bet.

But the thing is, a very vegetable rich diet is gonna be pretty high in copper. And it's going to be high in iron too, but it's gonna be very poorly absorbable iron. And you know, especially if you eat a lot of whole grains, nuts, seeds, and legumes, you can get a lot of phytate. When doing that, you should probably supplement with zinc. You could consider supplementing with copper. The preferred copper for me would be liver or liver capsules, which I think provide copper way out sized to the iron that they provide. I think that's your best option when you don't have giving blood as an option to get rid of iron. If needed, you can do supplemental phytate, but I would use that as a last resort rather than a first one. 

142: How much time should separate my zinc supplements and nut consumption?

So, phytate primarily inhibits absorption of zinc and iron. I think you're gonna have a much lower probability of zinc encountering phytate if you take the zinc 2 hours after eating the phytate than if you take the zinc while you eat the phytate. But you know, if you're trying to be maximally conscientious, 3 hours after the meal.

141: What’s the safe use of an iodine nasal spray?

So, the iodine in the food and supplement guide for the coronavirus most recent version, I included iodine as a nasal spray. It's very important to look at the percentages. And so, 0.5% is the concentration recommended and that means that if you get a 10% solution, which is the most common one, you want to dilute it down 20-fold, which means taking one part of the 10% solution 19 parts water. If you have a different percentage starting solution, you wanna dilute it differently. And it's critically important that you dilute it properly. And so, you should have someone double check your work if you're doing your own math or triple check your work because higher concentrations can cause damage to the nasal tissue. But in terms of how often what I recommend doing is using it as a before and after in potential exposures.

140: Why would ferritin be extremely high when transferrin saturation is low?

Ferritin as a potential indicator of iron overload should not be anywhere near the level that was set to try to rule in biopsy provable hemochromatosis that is just a profoundly negligent approach to setting the range for ferritin. Now, I think part of what has stopped, you know— This mostly is a problem of the binary diagnostic mindset of conventional medicine. So, I'm not saying that this mindset is not useful. It is tremendously useful, but too many people confuse it for a reality when in fact it is a reality distortion filter meant to more efficiently triage people through various treatments or nontreatments.

It may be inflammation as you very well tried to feather out. And if it's not that, it's probably oxidative stress. So, I’m not gonna say that’s the only other thing it could be. And for the record, you cannot rule out hemochromatosis genetics with 23andMe or any other genetic test by anyone because there are a small percentage of hemochromatosis genetics that are not in the HFE genes and no one has a panel for them. And so, it’s improbable that it’s hemochromatosis based on 23andMe. You can’t rule it out, but I would say it’s probably not hemochromatosis because his iron is low. And so, you know, I'm highly suspicious of oxidative stress, which also upregulates ferritin. If you have Testing Nutritional Status: The Ultimate Cheat Sheet, I would measure everything in the oxidative stress section.

139: Can carnitine be used for fatty liver instead of choline?

The role of choline and the role of carnitine have nothing to do with one another. Choline is going to help move fat out of the liver. Carnitine is going to help fat get into the mitochondria to be burned for energy. So, first of all, I think one thing that’s important to note is that you're gonna get more bang for the buck by fixing the things that are wrong rather than pulling on levers that are working perfectly fine.

138: Is it OK to drink a pint of Gerolsteiner mineral water a day?

It’s significantly less than a bottle. I guess conceivably if you're also drinking a lot of milk, or eating a lot of cheese, or supplementing with calcium, or taking bone meal powder, I guess you can get too much calcium. I wouldn’t really worry about it from 1 pint. I do think that the main concern with carbonated beverages of any type is that you have too much acid running over your teeth a lot. So, I think it's wise to drink this in a way that tends to bypass your teeth. You can do it more effectively if you use a straw, but I think you can manipulate the bottle in your mouth to kind of pour it beyond your teeth, which I think is a good thing to do. Probably the best thing that you can do for that is before you brush your teeth, make sure that you swish with water or baking soda. 

137: Cataracts: what are the roles of methylglyoxal and polyols?

Is the polyol pathway activation and methylglyoxal independent causes of cataract formation or are they related to one another? And the answer is a little bit of both. You know, if independent means unrelated, then they’re related. Not independent. But they are independent in the sense that you could have more of one. You know, you could do something that increases one and not the other or at least disproportionately increases one versus the other. So, the polyol pathway, I think the best way to describe that is under conditions of severe hyperglycemia where you have too much sugar to be disposed of in the normal routes. You can use the sugar to synthesize polyols.

Glutathione is needed, among other things, to detoxify methylglyoxal. And methylglyoxal causes cataracts. Now, that's not to say that there aren’t other things going on. I mean, certainly glutathione is also needed to defend against oxidative stress. But then again, this might not be the only way that oxidative stress contributes to cataracts, but oxidative stress increases methylglyoxal generation in part by decreasing the activity of glyceraldehyde 3-phosphate dehydrogenase or GAPDH, which is the enzyme within glycolysis that is responsible for clearing what are known as triose phosphates.

136: Is the sugar in Life Extension Enhanced Zinc Acetate lozenges a problem?

In that kind of protocol attuned to the progress of the potential cold, I find no alternative is more effective than the zinc acetate lozenges. And so, therefore, I'm willing to consume 40 or 60 grams of sugar for like 1 day or 2 days and then have it taper off granted— I might have a totally different attitude if I had diabetes. But from a cost-benefit analysis, I don't think consuming 40 grams of sugar once for a healthy person is going to cause any permanent damage. It's not the ideal thing, but the problem is that all the alternative zinc lozenges have generally involved factors that decrease the zinc ionization in the mouth.

135: If I use SAMe for depression, what do I need for nutritional balance?

Nutrition wise, I think the most important thing would be to make sure that you have an adequate glycine status. And you know, I don't know what your background is in terms of other issues, but the glycine buffer system, which is how you buffer excess methyl groups, which is what you would have if you take a large bolus of SAMe.

Other nutritional concern would be having enough molybdenum. Generally, you're gonna have enough with 100 mcg a day. If you're eating liver once a week, you probably have enough, but there's no harm in taking like 500 mcg a day, so not really a problem if you want to supplement there just to make sure it's not an issue.

134: Should I take iron every day or use alternate day dosing?

o, according to this abstract, in iron depleted women without anemia, oral iron supplements induce an increase in serum hepcidin that persist for 24 hours, decreasing iron absorption from supplements given later on the same or next day. Consequently, iron absorption from supplements is highest if iron is given on alternate days.

Bringing this back to a practical level, is it easier for you to maintain a habit of every day dosing or is it easier for you to maintain a habit of every other day dosing? Because I know for myself by far and away, the easiest thing for me to do is to have a little turntable inside my cabinet of everything I’m gonna take in the morning just take it all. The more complicated things get, the more you need a list or you need an app that reminds you to take it every other day.

When I wake up in the morning half the time I am not going to remember whether I took it the day before or not. So, I'm gonna have to keep track of that somehow. It's just so much more practical to take something every day at the same time than it is to try to impose more complicated dosing on it that I would want to be much more convinced that there is a real effect before I was going to bother with that greater difficulty of sustaining the habit.

133: Should I spread my collagen out across my meals?

I'm not sure what the best dosing is given that it hasn't actually been studied fully, but I believe that it was estimated that in the people who have the highest collagen waste during collagen turnover that they can run short of glycine about 60 grams a day whereas I believe the more conservative estimate of glycine requirements based on people that turnover collagen much more efficiently.

I would say that as a general rule, you should assume that you want something spread out as much as possible rather than the reverse if you don't have the data showing that it’s okay or better to have it all at once because wherever there is data or wherever there is a plausible rationale, it's almost always the case that it's better to have it spread out.

132: Where should I buy my chicken products?

You may have local options. And a good place to look for local options would be eatwild.com. I’m assuming it’s still up. That was a great database and probably still is a great database of pasture-raised products of any type. Not just chicken. And then of course, there are the mail order companies that I have exclusive discounts with inside the Masterpass program, most of which sell chicken products.

So, White Oak Pastures, North Star Bison who focuses on bison but I believe they have chicken also. And U.S. Wellness whereas chicken might not be their main thing, I’m pretty sure they have chicken. Generally those companies, even if they don’t advertise themselves as mainly being about chicken, they usually will have some chicken.

131: Why would blood glucose go up on a low-carb diet?

When you're adapted to low insulin levels with lower GLUT expression, but you want to get glucose into muscle, you're going to need higher blood glucose levels to do it.

I think elevated blood glucose is sufficiently known to be pathological that it would be unwise to assume the sort of more generous interpretation of that as a physiological response. I think it would be a much better approach to do what you need to do to get your blood glucose levels into the healthy range. Otherwise, I think it's quite a gamble to presume innocence of that elevated blood glucose. 

130: Why do thyroid levels drop on a low-carb diet?

So insulin and leptin are both positive regulators of thyroid hormone, production, and conversion. And generally I do think there's probably a larger effect from thyroid production than peripheral conversion. I'm not too sure about that, but insulin does directly regulate thyroid. It has TSH-like effects on the thyroid gland. It doesn't replicate all of TSH's effects, but it does replicate a portion of them. So basically, more or less, have like TSH amplification with insulin.

129: Is hydrogen sulfide produced in the gut a bad thing, and what to do about it?

I agree that most people that have this problem have some kind of deranged sulfur metabolism, but I don't see why that makes it a physiological adaptation rather than a pathological condition. The correlation is probably a direct result of the predominance of sulfur-metabolizing bacteria in the gut, which is a bad thing that is actually causing the derangement of sulfur metabolism.

Well, you could go the antibiotic route. And I think metronidozole, and let me see if I can dig this up quickly because I have done a lot of research on this issue for one of my clients. Okay. So from the research I was looking at, metronidozole is very effective against sulfur-metabolizing bacteria. But isn't that reliably delivered to the stool and maybe could be used as an enema. But I think generally, it is used. And then I think there's one other one that's sometimes used. I forgot what the other one is. I think it's... Okay. I can't find it. Anyway, you can go the antibiotic route under the guidance of a prescribing specialist.

128: What if low-carb makes me wake up to pee?

I would start by looking at your blood sugar. So I do think it's possible that if your blood sugar. Second of all, it's stimulated by salt. So salt at night might help. Third of all, in order to make it you need copper, vitamin C, and zinc. And then, fourth of all, you need, going past that, I also suggest trying to get deeper sleep. You might want to look at the quality of your sleep. So, I do think generally carbs help people get better sleep, but I do think that a ketogenic diet elevates GABA. And so I think there's a subset of people who would get better and deeper sleep on keto because of the increased brain GABA. 

127: How does someone get arachidonic acid and choline without eggs and liver?

So apart from liver and egg yolks, I think that it is very difficult to get enough arachidonic acid from food. Yes, GLA might help, but there's actually arachiodonic acid supplements. And for the vegans out there, I don't know if the production process is strictly vegan, but they are derived from a specific mushroom and you can get them on Amazon. So I think supplementing with arachidonic acid is probably the most direct way to do that. And then evening primrose or a barrage oil could help provide precursors to arachidonic acid.

126: Nutritional suggestions for SI joint pain and sulfur sensitivity?

So apart from liver and egg yolks, I think that it is very difficult to get enough arachidonic acid from food. Yes, GLA might help, but there's actually arachiodonic acid supplements. And for the vegans out there, I don't know if the production process is strictly vegan, but they are derived from a specific mushroom and you can get them on Amazon. So I think supplementing with arachidonic acid is probably the most direct way to do that. And then evening primrose or a barrage oil could help provide precursors to arachidonic acid.

125: If it’s easier to store fat than to convert carbs to fat, why is it easier to lose weight on low-carb?

It's easier to store dietary fat as fat than it is to store dietary carbs. Why is it easier to lose weight on the keto diet than a higher carb diet assuming isocaloric? Well, I think there's an assumption that's not necessarily true there, but the ease with which you store something as fat is not really related to weight loss. So I think that's part of why that is true, or part of why there seems to be a conflict there. So the implication of the fact that it is easier to store dietary fat as fat than it is to store carbs as fat is that when you eat too many calories from carbs, you will have a lot more fat that is stored as fat because the carbs displaced their use for energy.

124: Long-term shortness of breath after COVID-19: do I need iron?

I don't think there's any evidence that iron fuels COVID-19. And it's pretty clear that the systemic inflammation is driving dysregulation of iron in a way that hurts oxygen delivery. So it's very clear that low oxygen delivery is a major feature of COVID. And I think probably the bulk of that is due to clotting, but also inflammation. And if you look at the CRP levels in COVID, like going up to the hundreds. Normally, you want it below one. Your CRP is two or three, we say you've got a problem with inflammation.

In COVID, these problems are largely driven by CRP levels that are in serious excess of 150. And so that and the IL-6 are driving iron into ferritin at the expense of hemoglobin. If your iron is low that in itself will compromise hemoglobin and therefore compromise the delivery of the already scarce oxygen driven by the clotting. And so the last thing that you want is an iron deficiency that you're not fixing. So yeah, I would say no two ways about it. You absolutely want to fix your iron deficiency.

123: Are liposomal supplements really superior?

I doubt it. So I think the evidence indicates that liposomes don't survive digestion unless they are pegylated, which means that they have polyethylene glycol that's attached to the liposome to protect them from digestion. There are a number of other such modifications that can be made, but I don't think that applies to most liposomal things on the market. So I'm generally very skeptical of the claims that liposomal will offer superior delivery, particularly if they're not being specifically designed to survive digestion, which most are not.

122: Why would I develop shortness of breath on a carnivore diet?

That can happen in scurvy. So given that vitamin C is one of the higher-risk nutrients on a carnivore diet, that would be the first thing that I would look at. I'm glad it was short-lived. I think it's possible that there are vitamin C-sparing effects of a carnivore diet, but they take a little while to kick in. So as you transition, you had a temporary scurvy and then you had adaptations that mitigated that. Certainly it could be many other things, but without doubt, I would look at vitamin C first and given that it was short-lived, I think that's great. But I think that you should still do some nutritional testing to make sure that you're not in a marginal position on some of those possible things.

121: Is it possible to meet all your nutritional needs on a carnivore diet?

So the short answer to this question is yes, but the longer answer to this question, as I just went through, is it's quite complicated. 

I've said it with respect to carnivore diets. I think it's good to look at nutrition, kind of like an economic portfolio. If you are very, very expert, you can know what you're doing in limiting the asset classes you include in your portfolio. So, really know what you're doing. You can do carnivore or vegan, you can do it right or you can know whether you're not the right person to do either of those things. But, if you're not super expert and you're not willing to say, "Okay, this type of portfolio isn't going to work for me and my risk level," the best thing to do is to diversify. And you don't just diversify by eating different types of animal food. You diversify your asset classes. So just like no smart person who's not a massive expert should put all their retirement account into real estate. It's just much more robust to error to diversify your nutritional portfolio by eating a diverse number of animal foods, diversifying across the animal parts, nose to tail, diversifying across the species and doing the same thing with plant foods and thereby diversifying across plant and animal.

120: Why are medium-chain fatty acids ketogenic even in the presence of carbs?

It's all about the ratio. We know for a fact that MCT oil is ketogenic even in the presence of pasta, period, end of story. So, the question here is, biochemically, why is it happening? Well, they go into the mitochondria, even in the presence of insulin and a buildup of acetyl CoA over the incoming oxaloacetate. A high acetyl CoA-to-oxaloacetate ratio generates ketones.

So the question is that basically this question is why isn't there enough oxaloacetate? So generally insulin is going to favor the burning of carbs. And so generally when you have a large input of carbs, you have production of oxaloacetate, but the metabolic conditions are favoring you burning it for energy, not you producing oxaloacetate. And I think it's just a matter of the ratio and the speed at which things come in. And so if the MCTs are coming into the mitochondrion fast enough, and they're exceeding the rate at which oxaloacetate is produced, which is a likely scenario given that A, production of oxaloacetate from pyruvate is quantitatively minor anyway, and then B, in the presence of carbs stimulating insulin, you're going to get the pyruvate even more preferentially burned for energy.

119: What measurement of magnesium status is best to use for arrhythmias?

I assume by "measure" you mean a measurement of nutritional status, in which case I think you want to look at the serum level. think that if you're trying to fix a problem with the serum level, you probably at some point want to look at the red blood cell level and the urine level. One of the ways that magnesium could impact the arrhythmias would be through influencing other minerals, and so I would not recommend just looking at magnesium on its own. You definitely have to look at the calcium levels, the sodium levels, the potassium levels, and those would be the big four.

118: Is subclinical thiamine deficiency a contributor to many diseases?

So in terms of like in terms of subclinical deficiency, is it common, does it exist? It is hard to answer because, as usual, most of the data that's clear is on severe deficiencies, but there are some studies. I wouldn't say that there's a huge body of literature. There are some studies suggesting that even if you take a group of people who have some blood sugar issues and they are not thiamine deficient by classical standards, you can give them a hundred milligrams of thiamine hydrochloride a day and their blood sugar improves. So I think that's pretty good evidence that there is widespread subclinical thiamine deficiency. A lot of nutrition scientists and policymakers would object to using the word deficiency in that context.

But the way that I see it is if you do a study and you show that blood sugar improves with a hundred milligrams of thiamine, unless you have a hypothesis about why a hundred milligrams of thiamine hydrochloride would be acting pharmacologically rather than nutritionally. And by that, I mean having some different effect at a higher than normal level, a supraphysiological level, that activates some biochemical pathway that is never activated at normal nutritional levels that could be obtained from food.

117: Should a female focus on lowering DHT to avoid pattern baldness?

Carrie: DHT is only one of the alpha metabolites. If you just do it in serum, that's usually what everyone test, but there are some other big ones, androsterone, and 5 alpha-androstanediol is another big one that you can test in your intestine. DHT maybe low in women, but I'll see the androsterone be really elevated which is more common in women I see. In which case, yes, you can decrease testosterone, but you need to get yourself sort of off the 5 alpha pathway.

That's when you're looking at one, lifestyle, so decreasing stress, looking at your insulin, but then supplemental. This is where you're looking at the things like saw palmetto, stinging nettle root, Pygeum africanum, EGCG from green tea, reishi mushrooms, zinc. Those things help reduce the 5 alpha effect to reduce the male pattern baldness effect. That's usually what I see. You can't reduce the testosterone, but really it's the pathway. It's going down. You're probably just missing the metabolite that's causing the problem.

116: Is there an optimum number of meals or insulin spikes per day for optimizing thyroid function?

Assuming that you're controlling for the level of insulin sensitivity on the thyroid gland -- I guess if I had to throw out a wild guess, the free fatty acid concentration is probably mostly relevant when the free fatty acid levels are really high. It's probably not the case that you want to just like -- it's probably -- I don't know. If you go a long time without eating food or you eat like very high fat, very low carb acutely, in that context it's probably when the free fatty acid levels are getting the highest. If you're spreading your meals out more, you're probably never going to have as big of a peak. Or you're spreading your carbohydrate out more, you might have slightly elevated free fatty acids that never actually cross the threshold for that to matter. But I still think the dominant things for insulin on the thyroid is mostly just going to be an average cumulative thing. I don't think that the number of spikes is going to drive that. 

115: What can be done to reverse hypothyroidism other than taking thyroid medicine?

Chris: I'll throw in a couple things. If you just look at the nutrients needed to make thyroid hormone, you're looking at enough protein in addition to enough iodine. But then also the production of thyroid hormone is a very, very dirty process that requires an enormous amount of antioxidant support. Selenium is very important. But also, if you're looking at antioxidant protection, you're looking at not just things that we think of as dietary antioxidants. But you're looking at protein, zinc, iron, copper, manganese in addition to selenium. You're looking at vitamin C, vitamin E and a whole bunch, sort of a Pandora's box that you're opening up.

I think that probably the things that stand out the most are protein, iodine and selenium, but really you have a pretty big network of supportive nutrients in the background. Of course, everything I just said assumes that you're missing something that you need to make thyroid hormone, which is not necessarily the case, but I covered part of it. 

114: Why would a woman have no cycle? Why would a woman have an anovulatory cycle?

Carrie: Remember, cortisol is very, very, very potent in the brain. If the body perceives itself is under stress, whether it's physical, mental, emotional, environmental, it doesn't matter, then reproduction is not its primary focus anymore. I had been thinking this for a long time. I didn't know how to eloquently say it and then she said it on stage one day. She said, "Ladies, whether you want to or not, I'm sorry, but you were put here to reproduce. Biology is what you do."

Now obviously not all women do and a lot of women, in fact, are trying to avoid it, but that's what the body is set up for. When you were under a lot of stress and under body fat, under body weight falls in that category, then your brain says, "This is a stressor. This is not a good time to get pregnant. I'm going to take away her ovulation and/or I'm going to make her cycle late and/or I'm going to take her cycle away completely all together."

113: What to do about premenstrual water retention?

Chris: I looked at a really good paper that showed that in women who had water retention symptoms with PMS, the main difference in their hormones was that they weren't clearing progesterone as fast from their ovulation-related peak. I was discussing this with a different friend who had found that she would consistently get water retention in response to using progesterone creams.

Carrie: A big reason, that we are protected up to the point and then we go through menopause and we'd lose all that estrogen. A man's production of estrogen and a postmenopausal woman's production of estrogen.

112: Dietary nutritional advice for breast cancer prevention and thoughts on HRT?

Carrie: Well, that's probably better for you when it comes to like nutrient ratios and stuff. But I will say working for an estrogen lab, we're looking at phase one and phase two detoxification and what we're trying to assess with estrogen. Men and women, we make estrogen, and then we detox our estrogen. We go through phase one detoxification. Well, it becomes a reactive oxygen species essentially. Then we quickly neutralize it. Our body has these systems in place to protect us. 

111: What are causes for night sweats in men?

Carrie: Oh. Well, it can be hormonal just like it can be for women. I test all the same hormones in men. I check their thyroid with night sweats. I definitely even check the same thing. I check cortisol and I do norepinephrine markers with night sweats. This is also assuming that I don't suspect cancer because night sweats can be a key note, especially in men, night sweats can be a key note for cancers, and so I want to make sure I'm not suspicious of that. But it's to say for women, blood sugar issues, hormone issues, cortisol issues and making sure you're not sleeping in an extra hot room because men can get their night sweats from being overheated just like women can, sort of those basic things too.

110: With an ovary removed, when should I think about increasing progesterone or estrogen?

Carrie: You may actually need more progesterone. Like I was saying in the very beginning of this, that progesterone actually turns into that neurosteroid allopregnanolone, which can cross the blood-brain barrier and bind itself to GABA and affect sleep. It's very calming, obviously relaxing. It's GABA.

Carrie: Obviously, there are other things that affect sleep too. If your norepinephrine is going up at night, if you got blood sugar issues, if your cortisol is going up at night -- and norepinephrine is a big trigger for hot flashes for women, especially night sweats. It's one of its symptoms. Women think it's hot flashes and night sweats from hormones and really it's from norepinephrine. Getting stress under control, winding down at night, those things, if you're on any kind of adrenal support, nourishing adrenal as opposed to stimulating adrenal can be really helpful also.

109: Why do I wake up early every morning when I’m depressed?

Carrie: Now, with depression, it's heavily studied if you have an elevated or excessive cortisol awakening response, meaning you go higher, your spike is higher and more dramatic than the average bear, then your risk for morning depression is much higher. The reason for that as we've already touched upon with estrogen and the serotonin versus kynurenine pathway because high excessive glucocorticoids or cortisol can also upregulate the pathway away from serotonin and down towards kynurenine.

If you wake up with excessive amounts of cortisol, for whatever reason, you're stressed out, you're anticipating your day, you wake up in pain, you wake up with inflammation, something startled you awake, your kid is throwing up, it can increase your risk for morning depression because it pushes all that excessive cortisol, pushes your tryptophan away from serotonin and down towards kynurenine.

108: How does the body make hormones and what nutrients and foods do they need to do this?

Carrie: Now, as far as nutrients go, like I said, cholesterol is the backbone to all of your hormones. Much like the gentleman who said earlier his cholesterol was quite low, it can impact the way and the amount of hormones that you make. The lower your cholesterol is, the tougher time you can have to make hormones. But the more cholesterol you make doesn't necessarily mean you're going to have mass amounts of hormones. It's a very tightly controlled system. 

107: Should someone with low testosterone go back on testosterone replacement therapy or wait it out?

Carrie: Men have luteinizing hormone just like women do. It comes from the brain. It's what stimulates the testes to make testosterone. If you have low LH, then I know it's a brain problem, not necessarily a testicular problem. If your LH is normal, it's not in the brain.

Chris: If the question is how long should he wait, waiting is probably not going to give you any more answers than it was giving you for the last five years. Waiting probably isn't going to raise your testosterone. If you have one measurement that it's 100 in the morning and 45 in the night, you don't really know if it's increasing, like maybe six months ago it was 50. If you wanted to wait, what I would do is do some follow-up testing to see if it's actually changing over time. But if it's been flattened out for five years, I don't think it's going anywhere. But if it's been going up ten nanograms per deciliter every three months for the last five years, then you probably could wait it out. But without knowing that, there's no data indicating that waiting is a good strategy here, it sounds like.

106: What to do about low libido after a LEEP procedure?

Carrie: With the LEEP procedure, so like I was saying, basically it's kind of like a hot knife through butter. They cut away a portion of the cervix. And it depends. Sometimes it's a little portion and sometimes they do what they call like a full big slider right across the face of the cervix. If you remember, for those of you who maybe never seen a cervix, it's shaped like a doughnut. Literally, your cervix is this tiny little pink doughnut and has a hole in the middle and the hole leads up into your uterus.

For a lot of women, there's a lot of nerve sensation there so it does greatly affect orgasms. Other women don't have it. There's probably women listening who were like, "Mine is not sensitive at all. Is that normal?" Yup, totally normal. Every woman is different. For her though in particular, she did have a lot of nerve sensation there on the cervix.

105: Would a seasonally low vitamin D intake and high calcium intake cause soft tissue calcification?

Chris: The end of this question is would the calcium simply be excreted due to the low vitamin D levels. Your vitamin D level being low, the first thing that's going to do and the major thing that's going to do is it's going to lower your calcium absorption. You would have more calcium excreted in the feces as a result of not absorbing it if your vitamin D level is low. However, a high enough calcium intake is going to more than compensate for that. It depends how low it is. If you live in northern Michigan and you're not supplementing with vitamin D in the winter, but you're outdoors a lot, your vitamin D is probably not going like rickets level low. It's probably dipping a bit. A calcium intake of 2,000 milligrams is so high that you're probably absorbing at least enough calcium

104: Question on Iodine, Fatigue, and Detox Reactions

Carrie: Remember, iodine belongs to the halogen family and other halogens can bind onto your PT or tyrosine. I have had this before where patients would take iodine and the iodine will push off the fluoride and the chloride and the bromide off of the tyrosine, and so it binds on and now you have essentially a detox reaction. People will say, "I get headaches. I've broken out in rashes. I'm really tired." Because the other halogens have come off the tyrosine and are now floating around your system.

I believe in iodine. I'm not sold yet on iodine testing. I feel like there are so many rules of thoughts. But if I use iodine, I warn people of that, of the detox reaction.

Chris: What are all the normal things you do for a Herxheimer reaction?

Carrie: Wait a minute. Obviously lots of water, exercise, binders, so like fiber and charcoal or zeolite or whatever you're doing to bind this stuff up, clay, those supplements with that sort of stuff in it. Saunas are really good, sweating, dry skin brushing to try to help move it through your body while staying on the iodine. You want the iodine to bind to the tyrosine and not the halogen to rebind because you stopped taking it, which is going to rebind to your tyrosine. I've seen it take up to a couple weeks, depending how halogen toxic that you are.

103: How to lower Sex Hormone-Binding Globulin (SHBG)?

Carrie: SHBG is like bane of my existence. I have no idea how to get SBHG down once it's up. Boy, I actually talk to practitioners about this all the time to figure that out. I would agree that supplements that for SHBG, it's very hit or miss, Tongkat being one of them, DHEA being the other. There are two other ones, stinging nettles and Avena oats. There's like very mild, very weak research about lowering SHBG with nettles and then with Avena. Again, it's like hit or miss. How to get that SHBG down? Well, also remember, SHBG binds estrogen as well. Although he said his estrogen is low. Actually low, but relative.

102: Why does estrogen regulate tryptophan metabolism

I think that it's basically the body trying to make sure that the baby has enough niacin because chronic estrogen exposure would occur during pregnancy. When I was doing my niacin research, one thing that I found is that women seem to need more total niacin than men, but they seem to be better at making niacin from protein. What's really interesting is that the studies that were done that were used to make the RDA, there weren't comparisons in men and women, but two of the studies were men and two studies were in women. The standard deviations, meaning how much variation there was person to person, in how much niacin that they needed to normalize what they were looking at was way bigger in men than it was in women.

101: Insomnia is different between people who are and aren't on HRT?

Carrie: Yes, sort of. If it's strictly a hormone issue, if she says, "I've never had insomnia. I turned 45 and I got insomnia. And, oh, by the way, I'm also having irregular periods and hot flashes and night sweats and all this stuff," I find that going on HRT generally resolves their insomnia.

If they've had insomnia their whole life and, by the way, they're having hormonal issues as well or they're perimenopausal, going on HRT may or may not help their insomnia because their insomnia may be induced by, of course, other things; cortisol, blood sugar, parasites, hypothyroidism, hyperthyroidism. Then I find that it's much more systemic as opposed to just the women who say to me, "I turned 40 and can't sleep," or "I turned 56 and I can't sleep." I'm like, "Oh, perimenopause."

100: The use of pregnenolone to manage perimenopausal symptoms, particularly insomnia.

Carrie: Well, so here's the thing about pregnenolone. Oral or sublingual, so if you've got drops or little tables you suck on. Pregnenolone and progesterone, when they go through first pass, so you swallow them and then you go through first pass, they turn into other metabolites. One is called allo, which is short for allopregnanolone. Allo binds to your GABA receptors in your brain. Allo can cross the blood-brain barrier, binds to GABA. GABA, of course, is your calming, relaxing, everything is going to be okay hormone. Pregnenolone, oral pregnenolone and oral progesterone actually work on the anxiety and on the insomnia from a GABA point of view.

099: Guidance on what time of day it is best to take T4 and/or T3?

Carrie: It actually depends if you're taking immediate release T4 or T3 especially or sustained release because T4 has a much longer half-life which is why we traditionally say to take it in the morning since it helps with energy and metabolism and all those things. Although I do know some people choose to take their T4 at night before bed. But T3 has a very short half-life, and so what I'm finding is some practitioners are now doing what's called a sustained release T3. They take their T3 and it helps sustain longer throughout the day, or they will take their T3 twice. They'll take it in the morning and then they'll sort of take it again in the mid-afternoon.

Now, if you're taking a combination T4/T3 such as Armour or Nature-Throid, you can't get the sustained part. I do know some people who will take their Armour or their Nature-Throid in the morning, and then they will take in additional dose of T3 in the early afternoon like an extra, whatever it is, 2.5 or 5 micrograms of T3.

098: A rant on why many people use “MTHFR” to slap a label on their health problems.

I put MTHFR in quotes because I meant it the way that people mean when they say, "I have MTHFR." Everyone has MTHFR. What people mean by that is they have these MTHFR polymorphisms. What I meant by that title is that there's a very compelling—It's not totally airtight. It's not completely proven. There's a very compelling argument that the low activity of the C677T polymorphism in MTHFR is exclusively a result of mediocre riboflavin concentrations. That's what I meant by just your MTHFR in quotes means the polymorphism, the result of the polymorphism. Just riboflavin means that the enzyme activity is only lower as a result of that polymorphism because of the mediocre riboflavin concentrations.

To them, MTHFR doesn't mean the rate of the MTHFR enzyme. It's a general label for all their health problems that they put Band-Aid solutions on like these tedious distinctions between these different forms of B vitamins and stuff like that that in a healthy well-balanced system don't matter.

If people are hypersensitive to little distinctions in the type of B vitamins they’re taking like this, their problem is not just MTHFR. Their problem might be related to methylation. They probably have mineral deficiencies, or other genetic polymorphisms, or other health problems, thyroid-adrenal stuff that are causing that. The reason that MTHFR isn't simply about riboflavin for those people versus the well-controlled studies of showing that riboflavin supplementation specifically lowers homocysteine 40%, specifically in people with MTHFR C677T homozygous, specifically with poor riboflavin status.

When you're out there saying that overmethylators can't tolerate methylcobalamin or they get terrible reactions to this, you're slapping overmethylator label on someone whose problem is that they just don't have a rational strategy for dealing with their MTHFR. Because no one is an overmethylator or an undermethylator, unless it's a collection of symptoms of a poorly managed methylation system.

097: Are there safety concerns in supplementing cyanocobalamin rather methylcobalamin in those with MTHFR polymorphisms?

If you're concerned about methylation-related issues, you would want to be careful with methylcobalamin supplementation in a way that you would not need to be careful about hydroxocobalamin supplementation. If you don't have a specific methylation-related goal, then I think hydroxocobalamin is the default because that's the sort of like metabolically neutral B12 in that it's not predisposed to any particular system, and it's not going to affect any system in a specific way apart from just being nutritional B12.

Then the second thing is “if you had MTHFR, is it dangerous to supplement with cyanocobalamin?” It doesn't matter. I don't think MTHFR has anything to do with methylcobalamin really.

If you don't have malabsorption of everything else, you should look at the specific causes of B12 malabsorption, which are pernicious anemia and gastritis, including subclinical gastritis driven by H. pylori in the stomach.

096: What about pyroluria and measuring kryptopyrroles?

I think it's fairly harmless to increase zinc and B6 as a test of whether that's true and see if you get results from it. But I wouldn't treat it like a diagnostic value because no one has followed up any science on that disorder in the decades since it's been proposed. Kryptopyrroles are very similar to porphyrins, that LabCorp has a whole series of tests on. I would go to LabCorp's site, go to Test Menu and then search it for porphyrin, and you'll see a bunch of things that come up.

095: How to manage blood levels of omega-3 and omega-6 fatty acids.

I don't specifically want to look at the omega-3-to-omega-6 ratio. The AA/EPA ratio, I do not believe in wanting to get it low enough to prevent inflammation. I don't believe in using it that way. But I do believe that if it were too low, it could cause problems. I don't know what the cutoff would be. But if you're on the low end of normal, then I would think about cutting back your intake of EPA.

094: Can PEMT genetics cause fat malabsorption, mineral deficiencies, and oxalate problems?

PEMT polymorphism is a marker of poor synthesis of phosphatidylcholine. That will impair export of fat from the liver. Low phosphatidylcholine synthesis due to PEMT. I was thinking of it as a direct marker. It's not a direct marker, but it could theoretically impact. This is probably especially true if you have a low phosphatidylcholine intake. Probably eating phosphatidylcholine protects against this. But yeah, low phosphatidylcholine levels in the liver partly as an interaction between low activity in the PEMT enzyme and low intake of phosphatidylcholine from food could cause bile acid issues, which could in turn cause fat malabsorption.

If you have fat malabsorption and you have enough digestion of the fat to release the free fatty acids from triglycerides, but you don't have enough absorption of those fatty acids, the fatty acids will bind calcium. They won't bind oxalate, they can't. Binding the calcium will lower the calcium absorption, and it will also prevent the calcium from binding oxalate. Calcium binding oxalate is what prevents oxalate absorption, so yes, I would think that would increase oxalate absorption.

093: Could an elevated BUN indicate protein malabsorption and low stomach acid?

I find it almost certainly the case that a slightly high BUN would never be a useful marker of low stomach acid and would never be a good marker of poor protein digestion. If you want to know if you have poor protein digestion, measure the protein in your stool. Get a GI stool test that looks at what you're not absorbing. That's how you test that.

The reason that this sounds nuts to me is maybe you are allowing the protein to ferment in your gut and generate urea from the microbes that you're absorbing, like maybe. But where does most of the urea come from that's in your blood? It comes from the urea cycle, which is how you get rid of ammonia. How do you get ammonia in your body that goes into the urea cycle? You digest protein into amino acids, you absorb the amino acids, and then you break them down so that you can either burn them for energy or turn them into glucose or turn them into certain neurotransmitters or whatever, and then you lose ammonia that you put into the urea cycle.

Why wouldn't the urea be a marker of having good digestion? I'm not even sure that we could say it could be an equally useful test of good digestion and bad digestion of protein. I don't know if it's as good a marker of bad digestion of protein as it is of good digestion of protein. But even if it were just as good a marker of bad digestion of protein as it is of good digestion of protein, something that's an equally good marker of two opposites is not a good marker of anything.

092: Are bilirubin and uric acid useful markers of antioxidant defense and oxidative stress? What are better markers?

I think the best marker of oxidative stress in plasma is the cysteine to cystine ratio. Cysteine is the reduced form of the amino acid cysteine. Cystine is the oxidized form. There are good studies at a general population level showing that that is the major specific indicator of oxidative stress that takes place in the plasma.

So, what I would recommend to assess oxidative stress would be Genova's Oxidative Stress 2.0 panel. It does give you the cysteine to cystine ratio.

091: Does it matter what form of B12 you take?

Cyanocobalamin is cheap and there's not really any clear evidence that it's harmful, but I just don't like the idea that it is cobalamin bound to cyanide. It's not found in the food supply. Forming cyanocobalamin and peeing it out is actually one of the main ways you detoxify cyanide.

Hydroxocobalamin is also relatively inexpensive. It's relatively easy to get as injections. It is not an end product of detoxification. It is found in very high concentrations in the food supply. The normal forms of vitamin B12 that you find in the diet from food are hydroxocobalamin and methylcobalamin in milk, and hydroxocobalamin and adenosylcobalamin in meat. Hydroxocobalamin is the most universal food form of cobalamin, and it is always a substantial part of the food supply. I'm pretty sure it's cheaper than methylcobalamin, so I would use intramuscular injections of hydroxocobalamin.

Most B vitamins start their absorption in the stomach and then mostly absorb in the small intestine. In the case of B12, when you're dealing with food, you're absorbing it in the small intestine almost exclusively with intrinsic factor that's produced in your stomach.

090: Is it useful to measure urine pH?

The urine pH is telling you the acid burden that your body has been subjected to. It's telling you, you can make an inference about the compensations that your body has had to engage in. You can also make an inference about the limitations of your body in compensating for that because even your urine pH should be buffered. It's not the case that you put a little bit of acid in the urine and then boom your pH is going to go down. It's the case that your body has a whole bunch of systems to buffer even the urine pH as you excrete acids from your body.

089: Why AGEs and deficient insulin signaling are the main problem in diabetes.

The reason that methylglyoxal, which I did my doctoral dissertation on, the reason that methylglyoxal, which is quantitatively the most important form of advanced glycation end products in diabetics, the reason that it is elevated is not because of hyperglycemia. It's because of deficient insulin signaling.

That is for two reasons. One is that you can derive methylglyoxal from glycolysis. You can derive methylglyoxal from ketogenesis. You can derive methylglyoxal from protein, specifically from the amino acid threonine. Insulin prevents you from making methylglyoxal in the glycolytic pathway no matter how high the glucose level is. Insulin, what it does in glycolysis is at the step where the intermediates spill out to generate methylglyoxal, insulin stimulates that enzyme that sucks the intermediates down.

The role of methylglyoxal starts at the first instance of hyperglycemia to cause the development from an acute first ever instance of hyperglycemia through the pathway of developing diabetes. Then in diabetes, methylglyoxal is overwhelmingly responsible for causing the cardiovascular complications, the complications in the eyes, and the neurological complications of diabetes, cataracts, all of these things. And so I think it's a huge mistake to think that the spiking glucose is the thing going on rather than the deficient insulin signaling.

088: Nutritional recommendations for MTR and MTRR polymorphisms.

If your MTHFR is working fine, then the creatine is much less relevant, and the glycine really isn't that relevant. Glycine is still important for everyone, but it's not specifically relevant because of the genetic variations. With that said, I do think that because some tissues rely more on folate and B12 than they do on choline that there might be some tissues that would benefit from supplementing creatine, so you could play around with it. I supplement creatine, and I don't have any problems. I mean, there's no harm in trying out the creatine.

In my view, there's no blanket recommendation for someone with MTRR polymorphisms. What I say is because in theory you will be bad at repairing B12 when your B12 gets very damaged, you should thoroughly look at your B12 status at least once. Then every time you enter a new health era, you should monitor your B12 status again.

087: Nutrition for children with ADHD.

In adults 100 to 800 milligrams per day has been used in a couple studies showing effects in the brain. One of the things that's going wrong in ADHD is that the brain is not getting dopamine's signal that something is valuable enough to keep paying attention to it. 

I think the drugs that are used to treat ADHD are increasing the tonic level of dopamine in the frontal cortex, and they're increasing the tonic level of dopamine in the basal ganglia. In the frontal cortex, the increased dopamine is basically making more stable mental states. If you focus on something, you will hold on to that better. In the basal ganglia, increasing the tonic dopamine is making it harder for a new thing to grab your attention, which reinforces the fact that you are more focused. Anything that increases dopamine is going to be good.

086: Nutrients important for neuroregeneration

Iron, phosphorus, and sulfate are very important for regenerating nerves. Magnesium. Acetylcholine is a major factor in regeneration of nerves, and so choline is important. If you were to use a supplement, alpha-GPC would be the ideal choline supplement to use because it's superior at generating acetylcholine. Vitamin A and zinc are very important for nerve regeneration. DHA, which is one of the omega-3 fatty acids that you find in fish is very important. Vitamin B6. Possibly GABA supplementation can help. 

085: Advice for what to do after suffering a transient ischemic attack.

A TIA, a transient ischemic attack, is like a mini stroke, but they all kind of fall into the same category where the development of plaque is a very significant part, is the major thing disposing you to having an event like that.

Nutritionally, the major factors in blood pressure are potassium is the biggest one, the salt-to-potassium ratio, not eating too much. Some people are salt-sensitive, some aren't. But the major factor is really the salt-to-potassium ratio. Some of the other minerals like magnesium and calcium are important. But then stress and physical activity are huge in blood pressure as well. Assuming that's under control, the main nutritional factors that you want to pay attention to are things that get the blood lipids under control and then things that get the process of calcification and inflammation under control.

The reason that the lipids are problematic is because they're getting damaged by free radicals and other damaging molecules, so things like vitamin C and E, glutathione, fruits and vegetables supplying polyphenols, all the minerals like zinc, copper, iron, manganese, selenium, all those things are important.

Figuring out whatever the limiting factor is and managing the details is a really big project. There are some simple rules of thumb like getting regular exercise, provided that the doctor okays it. Obviously, with cardiovascular issues, you have to do that, but whatever is safe for him to engage in. If needed, meditation or stress reduction on the blood pressure. And then just cut the junk food out and include a well-balanced diet. 

084: When on a ketogenic diet, it is a problem if ketones are going up to 5 to 6 millimoles per liter?

One of the popular ketogenic advocates was saying that if the ketones are getting above 3, then it's from not eating enough protein. I don't really see it that way. I think that protein will suppress ketogenesis, and so will carbs. Five to 6 millimoles per liter is what you see in therapeutic ketogenic diets.

In terms of how you could bring the ketones down, more carbs or more protein are going to bring them down. Between the two of those, probably protein would be the most important thing to increase as a means of protection against lean mass loss and as a means of keeping neurotransmitters and all the other things that you do with protein healthy. But you could raise the carbs a little bit too. Because remember that your carb demand even on a ketogenic diet is definitely not down to 20 grams of carbs. That's not even feeding your brain on the ketogenic diet.

If you have room to increase carbs, then I think would be great to get the carbs up to at least 30 and then maybe use protein going up to supply the rest of that. Then also pay attention to micronutrients. Do a dietary analysis. If there are certain nutrients that this person is not really getting in that more vegetables would help those micronutrients, then increase the vegetables and the carbs along with them for that purpose. But just on macros alone, I would say go up at least 10 grams on the carbs and go up to, if you can get there, a gram of protein per pound of body weight on the protein, and that will bring the ketones down. 

083: Are there any solutions to getting nauseated from zinc supplements even at low doses and even when the zinc comes as oysters?

With the zinc, my general recommendation is to take zinc on an empty stomach. The thing that is not controversial is that phytate is the principal inhibitor of zinc absorption. Phytate is found in whole grains, nuts, seeds, and legumes. I think there's a very broad agreement across the zinc research community that taking zinc not with a meal that contains whole grains, nuts, seeds, and legumes is going to lead to higher zinc absorption.

If you eat the oyster at the end of a phytate-free meal, is it still making you sick? If so, I don't think that's the zinc. I think it's something else. And your digestive system might not be up to the task of eating oysters right now at this moment. But if at the end of a phytate-free meal if you can fit in one or two oysters and it doesn't make you nauseated at all, then I think that's great. Oysters are probably the ideal zinc supplement if you can get them in. A couple of oysters a day goes a long way to getting your zinc in. 

082: Could low LDL hurt female fertility?

I haven't seen evidence of it, but that would not surprise me at all given that cholesterol is what you make sex hormones from. If you see levels that low, I don't know that it's intrinsically a problem. You kind of want to start looking at what are the reasonable things you could expect to happen from that that affect female fertility? Fat-soluble vitamins could be relevant. Sex hormones could be relevant. I'd start looking at those things.

I doubt that the LDL being that low itself in and of itself is going to be the thing that compromises fertility. This is the thing. Is the LDL low because of really good clearance from the blood, or is it low because of really low production? If it's low because of really low production, then you definitely have problems with fat-soluble vitamin transport. Because if the liver is not making lipoproteins as much, the fat-soluble vitamins are staying trapped in the liver and they're not getting to other tissues that need them.

081: Is it safe to take creatine when nursing?

If you felt fatigued and you took the creatine and all of a sudden that started reversing, then you either felt fatigued because you had low creatine synthesis, or you felt fatigued because you had a methylation problem. Those aren't mutually exclusive. If you're not methylating well, the most sensitive thing that will happen is you'll synthesize less creatine. But I mean it could have gone beyond creatine. It could have been that you're synthesizing less creatine, and you're not regulating your dopamine properly and things like that.

In terms of safety in breastfeeding, I don't think there's any evidence one way or another. It's probably safe because you could get this from meat, and there's no evidence of harm. But if you wanted to be hyper careful, I don't think you need to do this, but if you wanted to be like super, super careful, what I would do is divide the 5 grams over three or four meals evenly on the basis that there are very, very trace amounts of byproducts of high-dose creatine. Five grams will cause extraordinarily tiny amounts of toxins that appear in the urine. I mean, not toxins at the level that we're talking about, but I doubt it's a risk. But if you wanted to be hyper careful, divide the dose up evenly. 

080: Can you explain plant polyphenols and hormesis?

In brief, our detoxification system didn't evolve to handle the toxins of modern society. Modern society invents a new chemical. Our body knows it's a toxin, but it doesn't know it because we were exposed to it for millions of years. It knows it because it has similarity to other toxins. That similarity may be weaker or stronger depending on the toxin.

Now, in the modern society, what do we do? We invented new toxins. By the way, the fruit and vegetable polyphenols, what happens if you just take a bunch of them and you dump them on cells? You kill the cells. What happens when we eat them? Ninety-nine percent of them don't get absorbed. Why? Because the intestinal cells have a detoxification pathway that's just like the liver's.

I think where you cross the line is, what you don't want to do is isolate those things into a pill and megadose them. That's why people, when they ask me about sulforaphane and milk thistle, my view of that is that that's what you do when you can't eat a high volume of unrefined plant foods with five to nine fruits and vegetables. But what you don't want to do is say, "Well, if the bottle says one capsule milk thistle a day is good for me, then ten capsules of milk thistle on top of ten servings of fruits and vegetables is good for me." Then you're in the zone of who knows what that's doing to you.

079: What to do when serum magnesium is high but RBC magnesium is low?

The magnesium in the blood and the hair is high. When you say blood, I'm assuming this is serum or plasma because the RBC magnesium is low. I'm hoping that's not whole blood magnesium in which case it would be hard to separate from the RBC magnesium. But I mean even for whole blood, if the RBC magnesium is low and the blood magnesium is high, then the magnesium that's in the blood that's high is in the serum or plasma, not in the RBCs obviously.

Clearly this means that you're deficient in magnesium transport. You're not deficient in magnesium. So, the last thing that you should do is start blasting high-dose magnesium at that. Because not only is it not going to help, but you basically have two or three times the risk of harm from supplementing high-dose magnesium, because the harm of high-dose magnesium comes when your serum levels go to double the upper limit of the reference range. If your serum level is high, and your RBC is low, and you start blasting.

In other words, you want your serum magnesium to be a little over the top of the upper reference range in order to try to drive magnesium into the red blood cells. But you still need to measure it regularly so that you know that you're not anywhere near twice the top of the upper reference range. Then just do what you can to maximize the other factors. Insulin, salt, and B6 is what I think there.

078: Is there a potential for adverse effects of 5-10 mg of folate for heterozygous MTHFR?

Is there a potential? Yeah. The tolerable upper intake level for folate was set at 1 milligram on the basis that there are rare hypersensitivity syndromes that have caused reactions to 1 milligram or higher. On the basis that in numerous case reports, supplementation of more folate than that has been the factor that appears to precipitate the neurological degeneration in B12 deficient patients. It seems like if you're B12-deficient and you add a megadose of folate, there might be something causal about adding the folate precipitating the B12 deficiency. That makes sense.

077: Is folate unstable in frozen liver or just in frozen veggies?

The answer is folate is stable in frozen liver. It is not stable in frozen greens. 

076: How much vitamin C should I take with collagen?

There's no evidence that you need to take vitamin C with collagen. There is a study by Keith Baar, who showed that 15 grams of gelatin, not collagen, but I suspect the collagen is exactly the same, 15 grams of gelatin but not 5 grams, the dose is important, with 50 milligrams of vitamin C taken before exercise improved collagen synthesis in the tendons. They included 50 milligrams of vitamin C because it's made for collagen synthesis, but they don't show that you needed the vitamin C. They just had the vitamin C in there. I don't know if it even matters in that context whether you need the vitamin C. I also have no reason to think that you need 50 milligrams instead of 10 or that 100 milligrams wouldn't work better because they didn't test the different doses. They tested the different doses of gelatin. I see no reason to think a high dose of collagen is any different in this respect.

075: Are liver capsules as good as eating liver?

Liver pills are mainly for people who are not going to eat liver. That's the first thing. The second thing is, there are advantages to taking the dosing schedule of a little bit of liver every day.

I don't recommend anyone who would otherwise eat liver stop eating liver and take the capsules, but I do recommend the people who won't eat liver take the capsules. I think it's a nice thing to do. If you eat liver but take the capsules anyway, then take that in a lower dose because you eat liver. Like I said, eat one serving of liver once a week or twice a month and take two, three, or four of the capsules instead of six; two, three or four capsules every day. I think that's a happy medium that can have best approximates the best thing which is the 10 to 20 grams of liver a day.

074: Should I take 3 grams of leucine per meal?

Leucine is metabolized into a leucine metabolite that is the signal of protein synthesis. It's the thing that tells your muscles whether they should be synthesizing protein. But do you synthesize more protein when you upregulate all the factors of muscle protein synthesis? Well, that is entirely dependent on the amount of amino acids you have supplied. Think about it this way. Why is leucine used as the marker to determine how much muscle protein to make? Because usually when you get leucine, it's with high-quality protein that has all the other amino acids that you need to make muscle protein.

Now, the question is, is meat better than isolated protein? The research is pointing in the direction that at least some whole foods are just better than protein supplements, number one. Perhaps as a general principle, perhaps whole protein foods are better than protein supplements, number two. Number three, taking leucine or the leucine metabolite that regulates muscle protein synthesis is not going to be better than getting whole proteins even from protein supplements when you get enough protein to provide that leucine because the leucine and its metabolite don't actually achieve peak muscle protein synthesis unless you supply the protein with it. If you supply the protein with it, you do get the leucine.

073: What are your thoughts on root canals?

My suspicion is I wish I could give you a black and white answer. I know that it's not that useful to have an answer that's just nothing but gray zones. But I'm very skeptical of how good root canals are. I'm not so terrified that I'm highly motivated to get the other one taken out even though it probably is the last thing in my life that I should do more research on what to do about. I'm sorry, I can't give you a better answer than that. All I can say is yes, it is justified to be worried about the risks of root canals. I can say this totally unambiguously. What you should absolutely definitely not ever do is make your decisions about something that has any potential to be a root canal situation without a dentist.

The whole point of Price's work was they're serious from whole body health. Price was a pioneer in so many things. This is another one. Now, there's increasing evidence that inflammation in your mouth and decay in your mouth is tied to other diseases. Like periodontitis is tied to heart disease for example. Price was the pioneer of saying that the infections in your mouth are causing other diseases in the rest of your body.

072: What does it mean when histamine intolerance and blood sugar dysregulation occur together?

If his blood sugar is no longer as stable and he has histamine intolerance, then that drug probably interferes with vitamin B6 metabolism. Let me try to take one minute to see if I can find quick information on this. I can't. I can't find it quickly.

My instinct is to say that the drug is affecting vitamin B6 metabolism on the basis that 80% of the vitamin B6 in the body is used for glycogen metabolism in liver, which is the thing that stabilizes your blood sugar between meals. If your blood sugar is not stable between meals any longer, then yeah, it could be a hormonal thing. What it really probably means is that there's something wrong with the liver's ability to store glycogen or to access the glycogen when it's stored because your blood sugar is stabilized between meals exclusively by the liver's glycogen metabolism.

071: If PTH is mid-normal, do I need a calcium supplement?

I'm assuming that by midrange you mean it's 30. If you mean it's 40, then no, you're deficient or you're probably deficient. You need to test how you respond. But what I would say is, it would still be good for you to try increasing that and see if the PTH goes down anymore. Because my baseline for where I suspect that someone's PTH is maximally suppressed is 30. But the evidence that it's maximally suppressed is that it doesn't get suppressed by more calcium and vitamin D. If it goes down in response to calcium and vitamin D, then it wasn't maximally suppressed. Where you want to be is not 30 to 20. It's the point of maximal suppression.

Then the final thing is magnesium deficiency can compromise your ability to make PTH. I don't think that the average person in our society is deficient enough in magnesium for that to be relevant on the basis that population-wide most people have too much PTH. That contributes osteopenia and osteoporosis. But the big caveat here is if you are magnesium-deficient, then that might invalidate most of what I said if you're deficient enough to affect PTH.

If your PTH is around 30 and not higher than that, you're probably fine. But it's good to know your magnesium status because if it's really bad, that could change that interpretation. It's also good to know if adding more calcium suppresses your PTH further, because if it does, that's probably calcium that you need.

070: What to do about sky-high pyroglutamate?

Pyroglutamate, its other name is 5-oxoproline. It is something that is primarily produced when you are synthesizing glutathione, but you do not have enough of the second step in glutathione synthesis to keep up with the first step.

Maybe you need more glycine, but your glycine isn't low enough to cause orders of magnitude higher pyroglutamate. It's almost certainly the case that you have a glutathione synthetase deficiency, unless you have extraordinary levels of oxidative stress. I think that would be easy to test for because I just can't imagine that your glutathione levels -- I guess it's not that easy to test for because if you have a glutathione synthetase defect, you're going to have bad glutathione levels. If you have a tremendous amount of oxidative stress, you're also going to have low glutathione levels. If you have low glutathione levels, that's going to cause a tremendous amount of oxidative stress.

I think if it's not a glutathione synthetase defect, then it becomes a lot harder to figure out what it is because it probably means you have massive oxidative stress from somewhere and there's a lot of things that could cause that. That would be a potential Pandora's box of questions that would come out of that. But definitely the first step would be to look at glutathione synthetase.

069: In hemochromatosis, why would ferritin be low but transferrin saturation high?

Ferritin is your long-term iron storage. Transferrin is your short-term iron storage. The problem with hemochromatosis is that usually in a normal functioning system, there is a hormonal regulatory system that prevents you from absorbing iron from food when you have enough iron that when you have too much iron, shuttle the iron into ferritin which is protective both against pathogens eating the iron to grow and against oxidative stress, which free iron causes, which if you don't know the details about can be thought of as wear and tear on your tissues over time.

In hemochromatosis, normally the way you judge how much iron you have is in the circulating transferrin pool, which is your short-term storage. How full is it? The defect in hemochromatosis is that when the short-term storage, transferrin, starts getting fuller than usual, you don't notice it, so you don't stop absorbing iron from food that makes the transferrin saturation go up even further. But you don't shuttle the iron into ferritin. That makes ferritin lower.

068: Does folic acid act differently in the body than natural folate?

Does folic acid act differently in the body than natural folate?

They don't really. Everything that is said bad about folic acid is sort of true to an extent but has been completely exaggerated in some circles. What happens is you have an enzyme called dihydrofolate reductase, or DHFR. Its purpose is not to metabolize synthetic folic acid obviously because that folic acid molecule doesn't exist in the food supply. Its normal purpose is that every time that you use folate to participate in processes outside of methylation, such as DNA synthesis, you wind up producing dihydrofolate as a byproduct. DHFR recycles that and turns it into tetrahydrofolate, or THF. Tetrahydrofolate is what has the methyl group added to make methylfolate.

The question is, does that synthetic folic acid, we call that unmetabolized folic acid, does that cause harm? There are scientific hypotheses that it might, and it might, but there's no conclusive evidence of that. That's one side of the argument against synthetic folic acid. The other side of the argument is now that you are giving the DHFR enzyme more work, that means that might be detracting from the work that it has in recycling dihydrofolate that came out of the DNA synthesis reactions to make tetrahydrofolate.

067: Can frozen vegetables be trusted for folate?

Can frozen vegetables be trusted for folate?

You absolutely cannot trust frozen vegetables as a source of folate ever. That's because folate is extremely unstable in the freezer, and you have no idea how old the vegetables are. If they were fresh-frozen yesterday, they'd probably have plenty of folate. But if they were fresh-frozen three months ago, they may seem completely fresh and yet they don't have any folate in them.

066: How much spinach, broccoli, and kale is too much?

How much spinach, broccoli, and kale is too much?

The spinach is not a cruciferous vegetable, so it's not really contributing to this problem. It is high in oxalates and so it has its own problem. As long as you're getting calcium with the oxalate, for most people, there are exceptions to this. But if you don't personally have an oxalate issue, meaning a high risk of kidney stones driven by high oxalate levels in your urine or potentially behavioral issues in children some people are tying to oxalates. But if you don't have a specific issue with that, then I think really the only issue with oxalate is you want to make sure that you're consuming calcium in the meal that you're getting it in.

 The spinach has calcium, but it's only about 5% bioavailable so you should basically discount the calcium in the spinach. The kale and broccoli have bioavailable calcium. If you're mixing them together, that's probably a great way to do that, but you might not be hitting 300 milligrams of calcium in a meal. I think if you have a lot of oxalate in a meal, you probably really want to make sure you hit 300 milligrams of calcium in that meal.

065: What can be done nutritionally to specifically improve antiviral immunity?

Certainly, the fat-soluble vitamins, vitamins A and D, both important. Lauric acid as a fat. Coconut oil might be a good fat choice for the fat in your diet. Monolaurin would be a very good choice for a supplement. Lauricidin is the best monolaurin to take, 3 to 10 grams a day. Be careful of your bowel tolerance, spread it out among your meals, and cut back if it starts to loosen your stool.

Elderberry, which has mostly been studied in the context of flu, that probably has good antiviral properties.

Garlic. Garlic appears to require very high doses if you're just taking a garlic extract. If you're taking stabilized allicin, 180 micrograms a day is good. But you could raise the question what if you're missing on some of the other important compounds in the garlic. I'll debate with some of my friends about that, but what's really been tested is 180 micrograms of stabilized allicin.

Then zinc for sure in the immune response is super important.

Then you get back to nutrient density. Although I'd give special importance to vitamins A and D, arachidonic acid just mentioned, zinc and copper, both, and then those supplements. If you're missing any one particular nutrient, then you're going to wind up with a specific vulnerability that will persist until you fix that one nutrient. Thanks, anonymous.

064: Can you give any suggestions for increasing delta-6 desaturase activity?

Can you give any suggestions for increasing delta-6 desaturase activity?

The big governor though is if you have if you have insulin resistance or you have low insulin levels from chronic carbohydrate restriction, that might increase it. But you also look at your inflammation because you might have some of the higher fatty acids being depleted from inflammation or oxidative stress. I mean, more nutrient-dense diet across the board, more carbohydrate, if that doesn't do it, then just maybe take a supplement or increase the liver and egg yolks to the point where the arachidonic acid is normal. Measure your CRP. If that's high, address inflammation.

In the Testing Nutritional Status: The Ultimate Cheat Sheet, I have a big section on oxidative stress. I go through that testing. A starting point might be Genova's Oxidative Stress 2.0 blood panel. But if inflammation and oxidative stress are the things, work on those. If those aren't issues, then more nutrient density across the board, fix any nutrient deficiencies you find, increase carbohydrate if you're on low-carb. If none of those things work, then just increase your arachidonic acid level in your diet.

063: What are the pros and cons of boosting sulforaphane?

Sulforaphane, the nice thing is it promotes detoxification. The bad thing is it raises the need for iodine. I don't know what ratio to take, but you definitely want to make sure that you're getting some kind of iodine into your diet, whether it's through like 200 micrograms of iodine from a kelp powder supplement or you experiment with milligram amounts from a broken up Iodoral tab or whatever. Because I don't know the dose, I'm just going to say work slowly and work your way up. Certainly, if you have any signs of hypothyroidism or you have any brain fog, increase the iodine or decrease the sulforaphane would be my opinion.

062: Is it true that we can’t absorb more than 1.5 grams of creatine at one time?

Is it true that we can’t absorb more than 1.5 grams of creatine at one time?

I don't think that's true. From what I looked at, it looked like the absorption of creatine was really, really good. I don't know if someone was arguing maybe that we don't retain more than that. But I think the retention of your muscles is going to be best with creatine if you take it post-workout and if you take it with carbohydrate to stimulate insulin. But on the whole, I think that the absorption and retention is good enough that it's more a matter of how fast will you get to peak muscular creatine than it is about where you get in the long-term.

061: NMN vs. NR: What’s better? And is TMG necessary?

Question: From your deep dive into nicotinamide riboside and NMN, do you think either is effective, and is one preferred over the other? Do you still recommend taking TMG with NR?

Let me back up a little bit here. These are all different forms of niacin. In the anti-aging community, many people are taking nicotinamide riboside, which is NR, or nicotinamide mononucleotide, which is NMN. The question is, is one of those better than the other? Then he asks me, do I still recommend taking trimethylglycine or TMG with NR because extra niacin depletes methyl groups and TMG is a methyl donor.

I think that in order to get the best NAD response and to tax the methylation system the least, you want to take a smaller dose with every meal rather than taking a higher dose once. I would take like 150 milligrams max at a meal. If you're going to take 450 milligrams, I'd take 150 at each of three meals. If you want to take less than that, you either use the powder or empty half of it out in a capsule. Like take half the capsule, empty it out into your mouth with a meal, 150-milligram capsule to do that. It will give you 75 milligrams. Take that three times a day.

Then there's no good test to really see whether it's doing anything for you. You really have to judge it by your response. Are you getting tangible benefits from it? If so, then I think it's fine to keep it up. But yeah, I would take 100 milligrams of TMG for every 200 milligrams of nicotinamide riboside or nicotinamide mononucleotide. Personally, I wouldn't use the NMN and use the NR because there's more data on it.

060: What to do about cataracts.

"Cataract in one eye becoming noticeable. This eye had a posterior detachment about 11 years ago, which is basically healed. I've been on a low-carb diet for over 40 years. Eat raw cream cheese, eggs, meat and liver. In the past few years, adding fasting and more keto diet. Saw your thoughts about glutathione on the cheat sheet and interview with Wendy Myers. Am I on the right track and what else could I do? Grain intolerant. What testing beyond normal tests might be helpful?"

I believe that cataracts in the eye are largely driven by the glycation of lens proteins. The glycation of lens proteins is largely driven by methylglyoxal, which I did my doctoral dissertation on. In direct contradiction to much of the low-carbohydrate literature, glycation is not all driven by carbs. Methylglyoxal is quantitatively the most important source of advanced glycation end products in the body.

059: If free T3 looks good, why is TSH still a little high? Why hasn't the T3 brought it down enough?

Your thyroid gland makes thyroid hormone. Thyroid hormone increases your metabolic rate and does a lot of related things. Your hypothalamus is governing that by controlling your pituitary, the master endocrine gland, and its secretion of TSH, which is what controls the thyroid gland and makes it make more thyroid hormone.

The way that the feedback occurs is that the circulating T4 is converted to T3 inside the cells of the pituitary. That is what suppresses the production of TSH, which is basically the pituitary monitoring the thyroid hormone levels to know whether the thyroid has done its job. If the pituitary, the master endocrine gland, decides that the thyroid has done its job, it takes down TSH, the signal to make more thyroid hormone.

058: What food supplements and training programs are good for developing muscle mass?

Overwhelmingly, what matters for muscle mass is working out, eating enough protein, and eating enough calories. 

You want to try and hit 10-20 sets per muscle group per week with eat set hitting within 80% of failure. So, if your doing a set of 8 reps but you could have done 20 reps with your chosen weight, that doesn’t count. You would want to pick a weight that you can lift no more than 10 times. Ideally, you’ll do some sets in the 5-rep range, 10-rep range, and 15-rep range. 

For protein, you probably want to be up around 1 gram per pound of body weight or per pound of target body weight. 

Then calories, you do need a caloric excess, but you don't want to get fat. If you know how many calories you need to be weight-stable, I recommend titrating the calories up 100 calories a day and then track your progress if you are gaining waist circumference. I know this is a little bit harder when you're a woman because you're going to have more fluctuations in water weight, but in terms of simple things to do to track your progress, waist circumference is valuable, and looking in the mirror is valuable.

057: Should I manage my total cholesterol of 305 just for my doctor or should I be doing it for my own sake? If so, how should I do it?

Question: Should I manage my total cholesterol of 305 just for my doctor or should I be doing it for my own sake? If so, how should I do it?

You should want to improve your lipid profile for a lot more than to please your doctor.

The only way to have a total cholesterol of 300 or more in most cases is to either have a thyroid disorder or to have a familial hyperlipidemia. We're talking about fasting levels here. You should want to manage your blood lipids for your own sake because people with familial hypercholesterolemia have a dramatically increased risk of having heart disease decades earlier than it becomes normal for the general population. 

I'm not saying it's 100% certain that if you have a cholesterol of 300 you will have heart disease, but you are way disproportionate in risk for that reason. You definitely want to address this for the sake of your health.

I think that if you have weight to lose, that losing weight should be one of the first things that you do to normalize your blood lipids and your inflammation. Being overweight also contributes to elevated free fatty acids, and elevated free fatty acids do raise your blood lipids. That's, in fact, the entire rationale of using high-dose niacin to lower LDL-C is by suppressing free fatty acid release.

This Q&A can also be found as part of a much longer episode, here: https://themasterpass.chrismasterjohnphd.com/products/mastering-nutrition/categories/2811841/posts/9361575

056: Do you have any recommendations on how to get enough calcium on a low-carb, no-dairy diet?

Do you have any recommendations on how to get enough calcium on a low-carb, no-dairy diet?

The bioavailability of calcium from different vegetables is highly dependent on the specific vegetables. 

Cruciferous vegetables have very good bioavailability. It's better than from milk. Spinach has like close to zero bioavailability. It's terrible and you shouldn't even count it. Nuts and seeds have about 20% of the calcium being absorbed. If you compare that to milk --- milk is probably going to be like 30% or 40%. Cruciferous vegetables are going to be like 50% or 55%.

The real problem is the volume. If you look at broccoli or kale and you look at how much volume of those foods do you need to eat in order to get 1000 to 1500 milligrams of calcium a day, which is the target, it's a ridiculously high volume. 

055: What should people with glucose-6-phosphate dehydrogenase deficiency be doing not just about glutathione, but about folate, vitamin K, fatty acids, and neurotransmitters?

G6PD, glucose-6-phosphate dehydrogenase deficiency, is an inborn error of metabolism. It's the most common one in the world. About 8% globally have some impairment in this enzyme. The reason that it's important is because glucose-6-phosphate dehydrogenase is the enzyme that allows you to make NADPH, which is a specific derivative of niacin that's involved in antioxidant defense, detoxification, synthesis of neurotransmitters, and synthesis of nucleotides, which are needed for cell division because they're parts of DNA.

Someone with G6PD deficiency is vulnerable to hemolysis, or the destruction of red blood cells, because of glutathione deficiency. Glutathione reductase uses energy and NADPH, the thing that you can't make, to recycle glutathione. But it also uses riboflavin. So, one of the adaptations that someone with this impairment has to try to protect themselves is for the glutathione reductase enzyme to hog all the riboflavin so that it says, "I don't have enough of the raw material I need to make this happen, so I'm just going to make myself get way better at using what I do have." That's an adaptation to compensate for not being able to make NADPH is just to get way better at using NADPH to recycle glutathione.

054: If my tryptophan is low, and I'm on a low-carb diet, would you recommend 5-HTP supplements or tryptophan supplements or both?

Question: If my tryptophan is low, and I'm on a low-carb diet, would you recommend 5-HTP supplements or tryptophan supplements or both?

There are multiple reasons why tryptophan could be low. It could be that you are not eating enough protein, or it could be that you have a high utilization of the tryptophan. I would look in the test and see if the 5-hydroxyindoleacetate is elevated — because if it is, then that would suggest high serotonin production, and that might explain the low tryptophan.

If that is the case, you may want to look into other explanations. In this particular case, we have talked about high estrogen levels and how they might be one of those things. In which case the root cause is the high estrogen levels and you need to address it at that level.

Repleting the tryptophan maybe isn't necessarily the goal unless you have symptoms that are related to low tryptophan levels. If you're overproducing serotonin, if anything, you might have symptoms that are more related to high serotonin levels. 

053: What to do if signs and symptoms of zinc deficiency persist despite taking 75 mg zinc gluconate per day.

You should do plasma zinc. 

Also you know I kind of wonder whether you're taking that right. So if you're taking 75 milligrams of zinc like at one time then it's not surprising because you're absorbing like seven of those milligrams. The rest you are not. 

To maximize absorption take them on an empty stomach in 10-15 mg which is typically the smallest dose available. 

If you're doing that and the signs, the deficiency persist they're persisting when you're taking that, then it probably isn’t zinc related.

052: What to do about high arsenic.

Question: Is a high value of arsenic a concern?

Yes, arsenic is a toxin. You probably don’t want a lot of it, if it's just a little high it might not cause terrible damage.

051: Are low total omega-6 levels on the ION panel a cause for concern?

Not the total, but if the arachidonic acid levels are low I would look at low arachidonic acid intake, or inflammation, or oxidative stress. It would concern me because arachidonic acid is important to a lot of physiological functions, but I don't care about the total omega-6.

050: What to do when high selenium levels won’t come down, even if you’ve stopped supplementing.

Question: When high selenium does not come down in response dietary efforts and cessation of supplementation, what's going on?

Either there's high levels of selenium in the soil where your food is grown, or you have low methylation because methylation is needed to get rid of excess selenium.

049: When should you take creatine, if you don’t have an MTHFR SNP?

Question: Creatine, when is it recommend that if you don't have the MTHFR SNP that causes methylation problems?

1.) When you want to improve your physique.

2.) When you want to improve your athletic performance.

3.) When you have a rare creatine synthesis disorder.

4.) If you have depression, it might help.

5.) If you have any signs that something else is messing with your methylation even though your genetics don't explain it.

048: When to take tryptophan on a ketogenic diet.

Question: When should tryptophan be taken on a keto diet? Night, day, both?

Presumably you're doing this to try to increase tryptophan getting into the brain. 

The best thing to do is to take it two to three hours away from other protein. 

The second consideration is if you have an allotment of carbs that you concentrate at one time of day, then it would be best to take the tryptophan then. With the caveat being if you’re eating protein with the carbs. In that case it would be best to take it away from the protein + carb meal.

047: Alex Leaf answers a question about creatine non-responders and methylation.

Question: Do you think there are true non-responders to creatine, or do you think that those apparent non-responders have some defects in methylation that makes typical doses of creatine sufficient only for other needs.

Alex: I don't think that methylation is going to be relevant here. When you look at responders and non-responders, the difference seems to be in their ability to uptake creatine into muscle cells from the serum. So, it's very unlikely be related to methylation and it has to probably do with differences in creatine transporter abilities across cell membranes.

046: How to bring up low levels of arachidonic acid.

Question: How do I bring up low levels of arachidonic acid? Should I supplement with 250 milligrams? What brand is there from well-known company?

If you want 250 milligrams of arachidonic acid, eat an egg. I don't know anything about arachidonic acid supplements yet, except that they exist because you can eat eggs and you'll get plenty. Do you want to try the supplement? Well you can, but I don’t think it’s necessary. 

You eat two eggs a day already, so eat four. 

The oxidative stress and inflammation will consume the arachidonic acid, so look at that too.

045: How to interpret the pattern of high citrate, low cis-aconitate, low glutamate, and high glutamine.

The aconitate and citric acid are markers on the citric acid cycle where we metabolize most of our energy. If citric acid is high and isocitric acid is low, (this must be the Great Plains Test which doesn't have isocitrate/cis-aconitate) that would indicate oxidative stress.

In terms of the glutamate being low --- if your glutamate is low and your glutamine is on the high side, then you probably have ammonia generation from somewhere that you're mopping up with glutamate. That would be my guess, but that's another can of worms to open.

044: Nutritional strategies for glucose 6-phosphate dehydrogenase (G6PDH) deficiency.

Question: What are the best ways to optimize glutathione status for someone who has a G6PD deficiency?

Riboflavin was shown to be of benefit for normalizing oxidative stress in people who have glucose 6-phosphate dehydrogenase deficiency.

So for people who don't know what this is G6PD is, glucose 6-phosphate dehydrogenase is an enzyme that you use to take energy from glucose specifically, you can't take it from anything else, and you use it to recycle glutathione which is a master antioxidant of the cell. 

You also need this to support the recycling of vitamin K and folate and you need this for synthesis of neurotransmitters among other things.

What I would usually recommend for glutathione status would be plasma levels of glutathione. I also think LabCorp does whole blood glutathione.

043: How much fatty fish should you eat?

Question: Are there diminishing returns in the amount of fish in a weekly diet? I know you mentioned eating fish about twice a week. I've been trying to eat salmon once a day. Is there an ideal ratio of fish to non-fish protein you should aim for?

There's not a lot of data backing that up and the data we have is pretty poor quality. But I'm of the mind that the diminishing returns come after one or two servings of fatty fish per week. I think if you're talking about white fish it's different. But I am referring to salmon or mackerel — I think once a week or twice a week is good. 

042: How to deal with the fact that blood tests for nutritional status aren’t adapted to children.

There aren't childhood-based ranges that are data-driven. So what if the ranges need to be a little bit different in children?

The approach in the Cheat Sheet is not to rely exclusively on ranges, it's also to look at the diet and lifestyle analysis and to look at signs and symptoms. 

So what you do is you piece together: does the diet and lifestyle analysis, the blood lab, and the signs and symptoms all say deficiency X, too much Y. Then that's very good information and what you do is you intervene on the basis of what seems probable and you monitor the outcome.

041: Matt stone and the “overdeification” of vitamin A.

Question: I just saw an email from Matt Stone referring to the overly deified nutrient vitamin A. Also, a few Weston A. Price Foundation bloggers are starting to spread the word about being sick on a high vitamin A diet. Any thoughts about this and comments about Vitamin A being toxic?

You shouldn't deify any nutrient, right? Any point of view that breaks down the world into good and bad molecules, is a doomed-to-failure point of view because molecules don't have virtues. 

Everything is about context. Too much vitamin A cannot be defined outside of context. Not just what your needs are, not just what your genetics are, not just what your turnover rate is, not just whether you are getting pregnant, but also the presence of other things in the diet. For example, vitamins D, E, and K, which will affect the vitamin A requirement because they all regulate each other's breakdown.

Some people have too much Vitamin A. Some people take more vitamin A than they should. There's dozens of case reports of vitamin A toxicity, but there's no evidence that people at normal intakes who are not supplementing are getting inflammation from consuming dietary levels of vitamin A.

040: Is it ok to mix carbs and fat?

There are a lot of people on the internet that claim the Randle cycle is behind America being fat, since the standard American diet is mixed in fats and carbs. Yet, I feel great on a diet of about 30% protein, 30% fat, and 40% carbs, based on meat, potatoes, fruits, and vegetables. 

The randle cycle addresses why you would have elevated fatty acids or hyperglycemia and hyperinsulinemia due to competition. You're more likely to have circulating energy supplies in your blood due to poor tissue uptake when you're consuming carbs and fats together, and you're more likely to be more dependent on a higher insulin response.

This doesn't mean that mixing them causes diabetes, it just means that there is more substrate competition and that, all else equal, if someone is on the edge of diabetes eating a mixed diet increases the probability that they're going to go over that edge because of the substrate competition contributing to hyperglycemia and the greater insulin requirement than someone who's on a low-carb or low-fat diet.

If you have no evidence of metabolic dysfunction on a mixed diet, then there's no issue.

039: What are “parent essential oils”? Should we get these instead of cold-water fish oils? Response to Brian Peskin’s theory.

Question: Can you explain what parent essential oils are? I was given some articles that seemed to be saying that high-dose cold-water fish oils are damaging to cell membranes and mitochondrial function.

"Parent essential oil" is a term invented by Brian Peskin, who looked at some  data that said it's not clear that supplementing with fish oil is good for you because doing so can cause oxidative stress and cause damage to cells.

That's true because the highly unsaturated oils found in fish oil, as well as in liver and egg yolks, are highly vulnerable to being damaged. This includes the physiologically essential omega-3 fatty acid, DHA, and omega-6 fatty acid, arachidonic acid. 

But that damage comes only when you eat too much. This is where I think Peskin is wrong, because he took that data and concluded that you don’t want to eat any of these oils. Instead, you should eat oils like flaxseed that provide the “parent” fatty acids that your body turns into DHA and arachidonic acid.

But the parent oils are prone to being damaged too, just to a lesser extent. On a gram to gram basis, they are safer, but you need to eat a ton of parent oils to get the physiological requirement for DHA and arachidonic acid. So, on a daily requirement basis, the parent essential oils are going to be way more damaging.

I recommend simply taking a small amount of arachidonic acid and DHA, since then you fulfill your requirements regardless of genetics or the environment or whatever could impede the transformation of parent oils to these physiologically essential oils. High-dose fish oil is ridiculous, and risky, but that doesn’t mean you shouldn’t consume any. 

038: How to use an Oura ring to monitor HRV and optimize recovery and performance.

Question: What are your thoughts on monitoring HRV for optimizing performance?

Measure your HRV every night and you stop exercising entirely to get a baseline. 

You completely stop working out, you don't go “oh no I'm going to lose my muscle mass,” nothing's going to happen for a week or two. And this is the whole foundation of you having good data.

This baseline ensures that you have good starting data that isn’t influenced by anything. 

Now you start working out. You do one workout that's typical, you keep taking your HRV, you may see your HRV plummet. Then you say, how long does it take me to recover on my current diet and lifestyle?

You repeat that, like you don't work out again until it's back up to the plateau level. Then you work out again and you see if you have a repeatable response where there's a certain amount of time on average that's fairly replicable that it takes you to recover your peak HRV after your typical workout. Then when you have that you get on that frequency.

You can then start playing around with factors — like does it matter what type of workout I do? Is my recovery level consistently different when I lift weights at 5 reps per set versus 15 reps per set. Is my recovery time consistently different when I do cardio, or when I do cardio and weights on the same day, or when I play soccer. Then you can start to tailor your recovery time around the specific workouts.

Maybe it takes you two days to recover from one workout and four days recovering from another. Lower body, upper body, if you have a lower body upper body split, does it take me five days to recover the lower body and does it take me three days to recover from upper body?

At that point you can start tweaking diet and lifestyle. Do I recover faster if I eat more carbs? Do I recover faster if I eat food X?  Do it recover faster if I take supplement X?  Always testing one thing at a time and making sure it's replicable before you form a conclusion before you do the next test.

037: Concerns about vitamin A in pregnancy

Question: Why did the FDA have a vitamin A requirement during pregnancy at 8,000 IU, which is much higher than the IOM recommendations in the past?

I have no idea. I do know that the concerns around vitamin A during pregnancy are that in the first weeks of pregnancy, 10,000 IU and higher has been associated with birth defects. That was one prospective study in 1995, which is higher quality than retrospective studies, but still contradicted all the retrospective studies that came to the opposite conclusion. 

So, there's no good consensus on the data, there's just moderately justifiable paranoia about the possibility that you could could cause birth defects. Also, there were like seven or eight letters to the editor about why that study had a bunch of problems with it, like the data just doesn't make sense.

036: Does mixing carbohydrate with fat cause people to get fat because of the Randle cycle?

There's a theory floating around on the internet that mixed diets are more fattening than low-carb or low-fat diets because of the metabolic competition between glucose and fatty acids. 

I don't believe this to be true because, in the context of isocaloric diets, mixed diets don’t seem to be more fattening than low-carb or low-fat diets.

Isocaloric diets are important for understanding physiological cause and effect, but they interfere with the real-life practical understanding of something. We want to use isocaloric science to study the academic question of, physiologically, are carbs and fat more fattening when combined than not combined. But, in real life, people eat more food on a mixed diet than they eat on a low-fat or low-carb diet.

I think someone who says mixed diets are more fattening because of the Randle Cycle is totally misunderstanding this. They are more fattening because of the hyperpalatability factors that Stephan Guyenet has explained. 

Also, they probably are more likely to cause metabolic harm because of what Alex Leaf has explained about the Randle Cycle in his post, “Why you may reconsider buttering your potato” at Superhumanradio. He was arguing that you don't want to put butter on your potato because you have substrate competition between glucose and fatty acids, which makes it more difficult to clear the glucose from your blood and causes a compensatory higher insulin response.

I'm not so insulin-centric that I believe that you necessarily always want to be minimizing your insulin response, and I definitely know that I have friends and colleagues who disagree with me on that, but I just don't view any disease, including type-2 diabetes, as a problem with hyperinsulinemia.

The short of it is that the more you mix carbs and fat in your diet, the more likely you are to overeat. You don't necessarily overeat, but it's way more probable because it's hyperpalatable. The more you mix carbs and fat, the more you don't specialize in one or the other. What's the most efficient thing to do?

If you eat a high-carb, low-fat diet your body specializes in burning carbs, you eat a high-fat, low-carb diet your body specializes in burning fat — and you're not going to do either of those as good if you're eating a mixed diet. Can you do them good enough? Often times, but if you have metabolic problems you might want to try a low-carb or a low-fat diet so you can specialize and be more efficient with your metabolism, because if you have metabolic problems whatever you're doing isn't working for you right now.

035: What to do if gamma-tocopherol levels are low-normal while taking 100 IU/d of alpha-tocopherol.

My initial impression is that there is nothing wrong because I don't care that much about gamma tocopherol. My doctoral research specialized in gamma tocopherol and there is some evidence that gamma tocopherol does some things that alpha tocopherol doesn't do. It’s likely that people who take high-dose alpha tocopherol supplements are suppressing their gamma tocopherol levels.

But you don’t have to be in the middle of the green for gamma tocopherol on the ION test. So if you are taking a 100 IU of alpha tocopherol at the time of test, then stop taking that and replace it with TocoSorb, or take a lower dose. I think a reasonable dose of vitamin E for the average person is 20 IU.

034: What to do if taking biotin and yet beta-hydroxyisovalerate is elevated.

033: B6 deficiency, and a man with high estrogen, what should they do?

Question: For someone who is taking 45 mg of vitamin B6 as P5P but has xanthurenate, kynurenate, and quinolinate high in the urine as markers of vitamin B6 deficiency, and who is a man with high estrogen, what should they do?

If you have xanthurenate and kynurenate spilling into your urine, it means that quinolinate would be building up. Quinolinate is usually the last thing to rise in B6 deficiency. 

Quinolinate is an excitotoxin: it both can cause neurotoxicity like glutamate does and it can also make you hypersensitive to glutamate, effectively giving you a glutamate sensitivity.

You clarified that quinolinate is in the fourth quintile. So you're kind of in the zone quinolinate might be a problem, particularly if you have trouble sleeping, or if you have trouble with anxiety, or you have anything that would be related to glutamate sensitivity, like headaches. 

If you have any of those symptoms, they could be from quinolinate buildup. In that case, I recommend increasing B6. I would titrate it up to 100 mg. I'd be very cautious going higher than that. Don't take any pyridoxine hydrochloride ever.

Second course of action is look at iron and riboflavin levels. If there's any things wrong with those fix them, since they are needed to properly convert tryptophan alongside B6.

Third course of action is to reduce protein intake, if necessary, or search for low tryptophan proteins and focus on those to meet your protein needs. You need at least a few hundred milligrams of tryptophan in your diet to be okay.

032: My take on a person homozygous for the H63D allele of the iron- and hemochromatosis-related HFE gene and blood donation.

Question: For someone who is homozygous for the H63D allele of the iron- and hemochromatosis-related HFE gene, if ferritin is low but transferrin saturation is high, should they still donate blood?

H63D is one of the genes that predisposes to hemochromatosis, a condition of iron overload. Most clinicians who work in this area do not consider the H63D allele to be a concern because it's less severe. With that said, most people who are progressive on the iron research front do believe it's a concern. There is literature showing that people can get clinical hemochromatosis from it and you don't have to get clinically hemochromatosis to be worried about iron overload.

My opinion on this is going to be different than someone who is an expert clinician, but is not immersing themselves deeply in the physiological literature about how this works.

I don't have the skills that they have in triaging and filtering who’s ideal for what treatment and looking at large numbers of people that do one or another treatment and knowing intuitively what happens in those — but what I do have is I have immersed myself very deeply in the physiology.

So the way that I look at this is as follows: iron saturation is an estimate of your transferrin saturation. It's a cheaper way to estimate it than to actually measure transferrin saturation, so it's much more common to get iron saturation.

But let's assume that we're talking about actual transferrin saturation or that iron saturation is a good metric of it. That's your short-term iron storage. Ferritin is your long-term iron storage. The defect in the H63D allele, same for the C282Y allele of the HFE gene, the two moderate and severe hemochromatosis alleles. Allele is a variant of the gene.

In normal physiology what happens is transferrin acts as a gauge of your iron status. The normal physiological levels are between 30 and 40 percent. Now being 41 percent doesn't mean you have a disease, we're not talking about diagnosis here, we're talking about understanding the physiology.

Mechanistically this is designed so that as you go from 30 to 40 percent and especially as you go over 40 percent that communicates the signal to a hormonal system that says you have more iron than you need. So you ramp down iron absorption and you ramp up ferritin. Why do you ramp up ferritin? Because you have more than you need in your short-term storage, so that's when you put it into your long-term storage. Also, because ferritin is a protective response that prevents you from having free iron.

Free iron is bad because it feeds pathogens and it makes infections worse. Free iron is bad because it causes oxidative stress and causes wear and damage on your tissues. And so to avoid free iron you ramp up ferritin while you take down your absorption from food at the same time.

And now is that a problem at all? You could debate that, but if you're just talking, if you're not talking about diagnosis and you're talking about wellness, and you're talking about health management then… What I would want to do myself in that situation is I would first of all not let the ferritin go under 20, and if it's going near there I would be getting a CBC to make sure I'm not making myself anemic.

And so I would not stop donating blood just because the ferritin is going down 60, 50, 40, I would consider it a gray area, it would be my preference to focus on the transferrin saturation and get it consistently under 40%. You get the pinprick to look at your serum iron levels, they're not going to let you donate blood if you're actually in the danger zone of anemia.

So I would get the CBC to be proactive about it.

031: How to lower a resting heart rate in the 80s or 90s.

Question: Thoughts on lowering my resting heart rate. It's often in the high 80s or low 90s once I'm up for the day.

I wish I knew the answer to that. I'd use it for my heart rate. I don't even measure my heart rate because my whole life it's been kind of high. I think breathing and meditation are probably the best things that you can do.

030: How to manage the zinc-to-copper ratio and what to do if zinc and copper are both low-normal when supplementing with 15 mg of zinc and 1 mg of copper.

I don't recommend looking at the zinc-to-copper ratio. Although there are studies correlating health endpoints with the zinc-to-copper ratio, I do not believe that it is a causal factor in disease. 

I believe the zinc-to-copper ratio is often associated with disease because inflammation raises plasma copper and lowers plasma zinc, based on taking zinc up in the cells and mobilizing stored copper out of the liver. You want zinc and copper at the right levels; the ratios are less important. You want both around the middle of the reference range; the bottom of the range is not adequate.

If you are taking a supplement, then the simplest thing to do would be to take it twice per day instead of once per day and to make sure you are taking it on an empty stomach. Up to 50 mg of zinc will not cause nausea on an empty stomach in most people if you take it with a full glass of water.

Some people do have digestive issues when supplementing on an empty stomach, and if you need to take it with food, do not supplement anywhere near phytate, which is the principal inhibitor of zinc absorption and is found in whole grains, nuts, seeds, and legumes.

I recommend Jarrow’s zinc balance, which has the exact ratio that you’re talking about. It’s a convenient way to have the copper in the zinc supplement already. But if you are low in copper, this isn’t an adequate source for two reasons: (1) the amount of copper is too low, and (2) the form of copper isn’t ideal (it has lower bioavailability because it’s not the oxidation state that you get in food).

For a copper supplement, I would want to use food first, and liver capsules if you want a supplement. For foods, check out the tiers of copper-rich foods that I recommend, which includes liver, cocoa powder, and certain mushrooms.

029: What nutrients are needed to break down old, damaged bone and build new, healthy bone?

So you are breaking down bone all the time throughout every second of your life. 

We are always breaking down bone, we are always building up new bone, and if you had any kind of defect in the ability to break down old bone, then you would have problems manifesting elsewhere. 

Bone breakdown is necessary to maintain your serum calcium levels. You would probably be having severe hypocalcemic attacks if you were not breaking down your old bone — and you probably also would have exercise intolerance and/or poor exercise performance as a result of the undercarboxylated osteocalcin released from bone, which acts as a hormone to improve energy utilization during exercise. 

In fact the overwhelming problem in the general population is that people are breaking down too much bone and not building it back up enough. 

So if you just look at the course of someone's life over time when we are young we are building more bone than we're breaking down and that, somewhere around 25 years old depending on male and female — we reach peak bone mass and then we spend the entire rest of our lives declining in bone mass.

I want to emphasize over and over again that it's better to get calcium from food than to get calcium from supplements, but it's better to get calcium from supplements and then not get calcium. 

028: What are my thoughts on detoxing heavy metals?

Question: What are my thoughts on detoxing heavy metals?

My thoughts are first you need to look at how bad the heavy metal is and if it is even at a level that a conventional practitioner would say you have toxicity; for example lead. 

If this is your situation then I don’t feel comfortable advising anyone here, but if your levels are slightly high and you would like to reduce them, then my suggestion would be zinc supplementation on the basis that most heavy metals produce a metallothionein increase. 

Metallothionein is your endogenous chelatior. 

The ability of the heavy metal to provoke that protective response is completely dependent on zinc concentrations inside your cell even across the range of deficiency through normal status through more zinc than you need, and there's no evidence for a threshold or cutoff.

So I think if your zinc status is fine and you boost your zinc status a little, without causing any zinc toxicity, or copper deficiency -- I think that's a very gentle and safe way to reduce your load of heavy metals.

Unless what you're seeing is arsenic, in which case methylation would be my focus because methylation plays a specific role in addressing arsenic. For anyone who hasn't seen that I have a comprehensive methylation resource at chrismasterjohnphd.com/methylation.

027: What to do about elevated morning blood glucose in the mid 90s.

Question: What to do about elevated morning blood glucose in the mid 90s.

I think usually your morning glucose is primarily impacted by your hormones and very rarely impacted by what you ate the night before, unless you are severely glucose intolerant.

So the overwhelming probability is that if your blood glucose is elevated in the morning and mid-90s is not tremendously high; it is most likely cortisol. 

If there are other signs of slipping into pre-diabetes then I might come up with another explanation, but I don't think waking up in the morning and often having mid-90s glucose — with everything else being fine, is likely to be a sign other than cortisol levels. 

It's not necessarily a bad thing because you're supposed to have a cortisol spike in the morning. You may want to look at your cortisol levels over time. The DUTCH test can do that. It happens to look at a lot of other things that I think are useful so that might be my first go-to. 

First you want to know if that's actually the issue. 

If cortisol is out of range then you probably want to look at stress reduction as a first step, and there's some evidence for using phosphatidylserine to lower cortisol. 

026: What to do, in the context of diabetes, if T3 supplementation does not increase heat production?

Question: neither my mother nor myself respond to T3 supplementation (cytomel; up to 140 mcg/d). Body temp remains low and reverse T3 stays normal. Could you discuss the factors that might interfere with thermogenesis in response to T3, and offer considerations how to improve this?

Having normal levels of reverse T3 tells you that the body isn’t deliberately getting rid of the thyroid hormone. High reverse T3 would be a sign that your body just doesn't want the thyroid hormone around.

That doesn't seem to be happening and so that makes me wonder if there could be a problem with taking up the thyroid into the cells. In which case I would expect thyroid hormone levels to be higher in the blood then you would otherwise expect them to be.

Or if there's a problem with the thyroid actually carrying out its functions inside the cell to regulate gene expression. This could be a zinc deficiency issue, since zinc is necessary to allow the thyroid receptor to bind to the DNA. In fact, zinc is necessary for everything that has a nuclear receptor that alters gene expression by binding to a nuclear receptor. This includes receptors for vitamin A and vitamin D, receptors for the sex hormones, and for thyroid hormones; all require zinc to act.

025: What are your top three non-nutrient factors that prevent beta-oxidation or ketogenesis?

Question: "What are your top three non-nutrient factors that prevent someone from entering beta-oxidation or ketogenesis? I mean like sleep disruption."

Top three non-nutrient factors? Unless you are taking a drug that prevents lipolysis, then they aren't non-nutrient. 

The overwhelming things that govern those are carbohydrate and fat intake. You eat more fat, you have more beta-oxidation. You eat less fat, you have less beta-oxidation. You eat less carbohydrate beyond a threshold.

==I don't think sleep disruption is going to do that. Sleep disruption is going to increase your stress hormones — so with sleep disruption, your cortisol is going to spike, and it's going to increase your appetite for junk food —  so you're probably more likely to eat things that are anti-ketogenic when you're sleep-deprived because you're eating more junk food, which has more carbs. You probably are not going to have lower beta-oxidation. You're probably going to have higher oxidation because you're going to eat more fat.

So, yes, sleep disruption will disrupt the appropriate way of handling those things, but I don't think it's going to block ketogenesis or beta-oxidation, except by messing up your appetite.

024: Recommendations for peripheral neuropathy

Question: "Any recommendations for peripheral neuropathy? Testing vitamin B, lion's mane?"

First of all, there is no such thing as vitamin B. I'm not trying to be a nitpick, but there's literally almost a dozen B vitamins, with different tests, that do different things. So, I think it's important to establish a habit of never saying vitamin B because, not to be a grammar nitpick, but I just think it's misleading to think about the concept of vitamin B. 

There are quite a few B vitamin deficiencies that can cause peripheral neuropathy. 

You can also cause peripheral neuropathy by taking vitamin B6 in too high doses, and that's one of the reasons why you have to separate them out because B6 is unique among the other B vitamins in that respect. 

In Testing Nutritional Status: The Ultimate Cheat Sheet; I have an index of signs, and if we go into peripheral neuropathy, I have listed here deficiencies of thiamin, riboflavin, and vitamin E — toxicity of selenium and B6. 

023: How to improve LDL receptor activity.

Question: "If cholesterol, LDL-P, and oxidized LDL are high, the sterol panel is normal, and TGs are great, would you suspect clearance of the particles driven by LDL receptor in the liver is the issue, and what would you recommend to boost LDL-R?"

Yes, it sounds like you should target LDL-R. 

The big regulators of LDL-R function are thyroid hormone, and the amount of cholesterol in the liver cell, and anything that brings bile acids into the feces, and that's generally a high-fiber diet; psyllium husk would be a fiber you could add.

Thyroid hormone is the other piece of that, and that you target with higher carbohydrate intake. Higher carbohydrate intake also acts on PCSK9 to boost LDL receptor activity. 

022: Recommendations on magnesium supplements and dosage

My opinion is that most people shouldn't be supplementing with high doses of magnesium. I think if you're going to supplement with more than 400 milligrams a day, you should be testing your magnesium status, and you should be making decisions on that. I think there's way too many people throwing really high doses of magnesium into their system. 

The topical stuff makes sense if you're absorbing poorly, but hey, maybe you're absorbing poorly because you don't need it, and so I think you really have to judge it against real metrics of results.

So, in terms of types, I would not recommend magnesium oxide for anything. It's poorly absorbed, so maybe you could argue that magnesium oxide is going to help act as a laxative better, but that's not bowel function, that's pharmacologically modulating your bowel transit time. So, I don't think it makes sense to deliberately take a poorly absorbed magnesium to have that effect.

The good sources of magnesium are: magnesium citrate is okay, glycinate is okay, malate is okay, across the board, I genuinely don't believe that the form is that important. It's just that oxides of minerals including magnesium are generally poorly absorbed. There isn’t much difference in the other forms. As always tailor it to the individual. I wouldn't give blanket recommendations there.

021: How to lower your calcium score

Question: "Calcium score, is there a way to treat one's calcium score and get it to zero?"

⇒ No, you don't treat the calcium score. You take the calcium score as indicative of what's going on in atherosclerosis, and you treat that.

020: What do you think of alternative testing like hair mineral analysis or SpectraCell?

I'm against SpectraCell on the basis of, it's not validated. I gave more details in a podcast episode "What Makes a Good Marker of Nutritional Status?" and you can find that at chrismasterjohnphd.com/marker.

Hair mineral analysis; I like hair mineral analysis when there is nothing better and more validated. For a lot of the trace minerals where we don't have good, validated markers of nutritional status, so I think hair mineral analysis is good. I also think hair mineral analysis is good if you don't have the money to do something comprehensive with all the best markers, and you want something that can clue you in when something might be off. So, the nice thing about it is, with less money, you cover all the minerals. The less nice thing about it is, it's not very well validated quantitatively. 

019: How to address edema.

Edema is basically going to be caused by excess salt retention in the body. The reason is that with the exception of very extreme scenarios, your body is going to tightly regulate the sodium concentration of the water in your body, and sodium draws water. 

Now, that's not to say that the cause is eating salt. And there are cases where eating salt might remove edema. But generally salt retention of total water volume is going to be a big factor. In hypothyroidism it becomes I believe at least partly about glycoproteins in those spaces that are holding onto water. 

If it's thyroid-related, you're not really talking about nutritional support, you're talking about fixing your thyroid. Maybe that means nutritional support, but it might mean other things. But the nutrition is aimed at the thyroid, not the edema.

Maybe manganese would help modulate those glycoproteins in hypothyroidism the same way that it does in regulating the stickiness of the arterial wall. I'm totally guessing on that.

Edema in the menstrual cycle is caused by high aldosterone, which is probably caused by high progesterone. I know that everyone in alternative health thinks that progesterone is the good hormone, and estrogen is the bad hormone — but in PMS water retention, I believe progesterone is just accumulating so much that it's spilling into aldosterone. I genuinely don't know what to do about the high progesterone, but about the high aldosterone. Magnesium and B6 have been shown to help with that. I did an episode about that, so I would Google "Masterjohn what to do about menstrual weight gain" for more details on thata. Then I would play around with salt and potassium. So, generally less salt during that time and more potassium in the diet are potentially going to be helpful.

I think the principles are going to be similar elsewhere. It doesn't have to be in the menstrual cycle. You are generally going to find that salt is increasing extracellular water, and potassium is increasing intracellular water, and that's often going to be a factor in edema that can't be tied to thyroid hormone.

This Q&A can also be found as part of a much longer episode, here:https://chrismasterjohnphd.com/podcast/2019/02/09/ask-anything-nutrition-feb-1-2019/ 

018: How do you determine if you’re getting enough protein?

Question: "How do you determine if you're getting enough protein? I heard Dr. Stephen Phinney say, for those on a keto diet, if ketones are greater than 3 on a regular basis, then it's a sign you're not getting enough protein."

First of all, why are you on a ketogenic diet? 

If your purpose is to get the ketones, why wouldn't you want your ketones higher than 3? The ketogenic diet is, regardless of what people are doing it for, it's best tested in terms of epilepsy, and the classical ketogenic diet gets ketone levels up to 3 or 4 millimoles per liter… sometimes higher.

Then the question is, you're not doing it for medical therapy, why are you doing it? 

If you're doing it to lose weight, who cares what your ketones are? 

There's a ton of people out there who are on a "ketogenic diet" who don't care what their ketones are because they're doing it for weight loss, for body composition, or to feel better. If those are what your goals are, your metrics should just be whether you're losing weight, whether you're getting better body composition, or whether you're feeling better. There's no data backing up the fact that you can measure your blood ketones and determine what any of those outcomes are going to be.

That has nothing to do with why you need protein. Yes, too much protein is probably going to lower your ketones. Protein is anti-ketogenic. It's not as anti-ketogenic as carbs are, so I get the kernel of truth that Phinney is getting at. The higher your protein is, the lower your ketones are going to be, and maybe there's some general correlation to be seen across people that the people who tend to have ketones that high tend to not be eating enough protein, but that's a correlation that has nothing to do with the underlying reason of why you eat protein. 

You eat protein because you need protein to optimize your neurotransmitters, you need protein to optimize your metabolism, and you need protein to optimize your body composition. The number one metric that we have on protein intakes and quantifying them is on body composition, and you want a half a gram, to a gram of protein for every pound of target body weight. So, if you're trying to gain muscle, use what you want to have at the end of gaining muscle. If you are overweight, use what your ideal weight would be. And the more you care about your body composition, the more you should aim for the top of that range instead of the bottom. It doesn't matter if you're keto or not.

This Q&A can also be found as part of a much longer episode, here:https://chrismasterjohnphd.com/podcast/2019/02/09/ask-anything-nutrition-feb-1-2019/ 

017: What supplements would you recommend for a ketogenic diet?

Question: What supplements would you recommend for a ketogenic diet? Any concerns with carbs being that low? 

If someone's on a keto diet and they have 80 grams total carbs, the first question I have is where are the carbs coming from? 

That's really going to determine whether the person needs supplements. So, on a keto diet in general and protein, too? If you're eating a lot of fat instead of protein, then you're going to need supplements of the things found in protein foods. If your carbs are all coming from honey, then you're going to need things that are found in vegetables.

==>You just can't tailor nutrient needs based on carb total data alone. 

The biggest things would be make sure you're getting a gram of protein per pound of body weight if your ketones and goals can handle that load of protein. That'll protect you from a lot of nutrient deficiencies right there. Try to cook your proteins in ways that recapture the juices. That will help conserve the electrolytes. 

You also probably want salt and either a lot of low-net carb vegetables, or you're probably going to need more potassium in your diet. Those are the big things that I'd look at.

016: Why would a male have low blood levels of calcium

You either have something wrong with parathyroid hormone governing your calcium levels, in which case you would want to see a doctor about that, or you have a long-going deficiency of related nutrients. 

Not enough calcium and not enough vitamin D should not cause low serum calcium — unless the deficiency has been going on for a very long time and is very bad.

Then again, I don't know what measurement you're referring to. So, maybe the calcium was a tiny bit low, and you remeasure it, and it's not low anymore; it was a fluke. 

But if you're talking about confirmed low serum calcium, then nutritionally, I would look at long-standing severe deficiencies of calcium and vitamin D. I'd follow it up with measurements of PTH and calcitriol to better assess the situation.

015: Can a low-carb diet cause waking up in the middle of the night?

Question: "I keep waking up in the middle of the night and stay awake for hours. Would low carb make it worse?"

It definitely could. 

Your brain will consume 120 grams of carbohydrate every day, just your brain. There's got to be another 30 grams or so that would be used no matter what obligately by red blood cells, certain cells in the testes, the kidney, and the lens of the eye. Then the rest of your body — if you're eating not a ketogenic diet, the rest of your body is not really trying to burn fat, so it's going to burn through carbohydrate.

Low-carb is not the best solution to high fasting glucose. There's a lot of people on low-carb who have high fasting glucose. There's a ton of people who go low-carb and develop high fasting glucose. That’s because a low carb diet alters the hormonal environment in two main ways:

1.) Increases the morning glucagon response. 

2.) Increases adrenal hormones. 

Both of these are early and late-stage adaptations to low glucose supply. 

014: Best formula and dosage of no-carb electrolytes to take at night to optimize sleep, especially after sauna use

Question: "Which brand and dosage of no-carb electrolytes would you take at night to optimize sleep, especially after sauna use?"

I would drink a bottle of Gerolsteiner, and I would add to it 100 milligrams of any kind of magnesium: citrate, glycinate, malate, those three are fine. And I would add to it 400 milligrams of potassium citrate, or bicarbonate if it's an empty stomach.

You say no-carb. Because of the potassium, I personally would take maybe like a teaspoon of honey with this. I would also take some salt. Let's say a half a teaspoon, to a teaspoon of salt with it. The caveat being if you’re sodium sensitive you should be mindful not to overdo it. If you know you don't have a problem with salt and blood pressure, then I would recommend adding the sodium to the mix.

013: Heart palpitations as a result of vitamin K2 supplementation and whether increasing calcium intake could help

Question: "Vitamin K2, MK-4 and MK-7, might have caused prolonged heart palpitations. Upon stopping it, symptoms mostly resolved after a week or so. Does that mean that the body is better off without it? Might increasing calcium intake mitigate this?" 

I would say, the calcium is really interesting. I genuinely hadn't thought of that until you mentioned it. Even though I've heard other people ask this question, I haven't had time to look into it, but you raise a good point.

So, it is conceivable, for example, that your bone density has been very low because you have not had the K2 you needed to get the minerals into the bone. So when you get the K2, you start loading the calcium into the bone, but maybe because your whole body is programmed to assume things were the way they were before you started taking the K2, then it doesn't adapt fast enough to normalize your blood calcium, which, by the way, how do you normalize your blood calcium? You take calcium out of the bone.

Calcium supplements are bad compared to getting enough calcium from food. A huge portion of those people are not getting enough calcium from food, and getting calcium is more important than where it comes from.

This Q&A can also be found as part of a much longer episode, here:https://chrismasterjohnphd.com/podcast/2019/02/09/ask-anything-nutrition-feb-1-2019/

012: Bovine colostrum for those with dairy sensitivities, and what to do about food sensitivities in general

Question, part 1: "Bovine colostrum from New Zealand cows. Yea or nay for those with dairy sensitivities? If nay, what would you recommend instead?"

What is your goal? If you have a dairy sensitivity, your problem could be with casein, with the whey proteins, or with something more specific like certain antibodies. It's very complicated. You're less likely to tolerate colostrum if you have a known dairy sensitivity, but you can't really know without testing the colostrum.

Question, part 2: "to settle a client's overactive immune system down."

What, specifically, about the overactive immune system are we looking at? I would think maybe this is chronic inflammation that's not resolving, and then I'm thinking more about arachidonic acid and DHA.

Question, part 3: "She can take a supplement one time and then the next time it throws her over. Same with food."

Okay, that sounds to me like an oral tolerance issue. When you put something in your mouth, it goes to your gut, and then your immune system decides whether it's safe or whether it's not safe. Your immune system doesn't know anything when you're born; it is more or less a blank slate. You do have predispositions because you have genetics that impact categories of protein fragments that you have the potential to make a decision about, but you are never born having a tolerance or intolerance to something. You are born with very broad genetics that say, “I will make decisions about this category, I can't recognize this category, I will make decisions about this category.”

So, you eat food or take supplements, you put something in your mouth, you swallow it. In your gut, your immune system says, “This might be something important, I'm going to take it back to my home base and decide what to do about it.” That home base is called the gut-associated lymphoid tissue, or GALT. Your immune system is deliberately taking things into that lymph tissue, purposefully taking fragments that are not completely digested for the purpose of making decisions about it.

In the gut, how does it make that decision? Overwhelmingly, there are two pro-tolerance factors. They are prostaglandin E2, which is made from arachidonic acid, the omega-6 fatty acid that's found most abundantly in egg yolks and liver, and that is the direct target of anti-inflammatory drugs, acetaminophen (Tylenol), aspirin, high doses of EPA from fish oil, and probably a lot of herbal anti-inflammatories. They will lower prostaglandin E2, and prostaglandin E2 is critical for oral tolerance in the gut.

011: If your cholesterol is high, how do you avoid having a large burden of oxidized LDL?

Question: If your cholesterol is high, how do you avoid having a large burden of oxidized LDL?

First, normalize your cholesterol. 

And no, I’m not saying that high cholesterol is the cause of heart disease. It's not, but oxidized LDL is, and the number one cause of both high cholesterol and oxidized LDL is not clearing LDL particles from the blood. So, I would never skip over the question of what I can do to get cholesterol in the normal range.

I think the boundaries of the normal range are a little exaggerated. 

When LDL is circulating in the blood, it gets behind the arterial wall, and that's the main site of oxidation. So, the question is, how oxidizing of an environment is that? Also, it gets stuck behind the arterial wall, so the question is, how sticky of an environment it is? 

Because if it gets stuck in the oxidizing environment behind the arterial wall, then that's the very powerful regulator of whether it's going to oxidize.

Then there’s the oxidizing environment. A big part of that is systemic inflammation because if inflammation causes oxidative stress. You should have been looking at inflammation for high cholesterol in the first place. Assume you have that covered. And then antioxidants in general. 

You're looking at protein, selenium, zinc, copper, iron, manganese, vitamin C, vitamin E, glycine… you're looking at so many things in there, so you really got to figure out what the weakest link is in that person and focus on that weakest link. There may be many.

010: The role of the lymphatic system in fat metabolism

Question: "I'm curious about the role of the lymphatic system in fat metabolism, specifically in high-fat, low-carb diets. Is there a biochemical explanation for why improving lymphatic circulation would improve fat metabolism?"

Well, I wouldn't call it biochemical, I'd call it physiological, but yes.

Fat goes from your gut through your lymphatic system to your blood. If your lymphatic circulation is not good, neither is the delivery of your fat to any part of your body. It's as simple as that.

If your lymphatic system is slow, so is your delivery of fat to every organ in your bod

009: The relationship between Lp(a) and cardiovascular disease

Question: "Lp(a) and genetic component with relation to cholesterol and risk of cardiovascular disease."

First, I'm going to be able to give better answers to questions if they're more specific.

But to the question: Everyone seems to think that Lp(a) causes heart disease. I don't believe it.

I don't believe it because the function of Lp(a) is to clean up oxidized LDL particles. It might have other roles, but that's one of the primary ones.

So, we have two possible explanations for the correlation between Lp(a) and heart disease. Either Lp(a) causes heart disease and people with genetically elevated levels have a higher risk of heart disease, or it is correlated simply because people with more oxidized LDL particles (which does cause heart disease) have more Lp(a) to clean them up.

I’ll be recording with Peter Attia on this topic, so I’ll brush up on Lp(a) data beforehand and may change my viewpoint, but this is my view right now. If anyone wants to send me data to look at to revise my view, I'll happily take a look.

008: Could magnesium hydroxide be absorbed via skin and cause hypermagnesemia?

"Can magnesium hydroxide be absorbed via skin?"

I don't know. I genuinely don't know.

"I've been applying milk of magnesia as a deodorant alternative in spray form for a few years now, and it works well, but I'm concerned about I might be hypermagnesemic, as I'm having low pulse, low blood pressure, and frequent bowel movements."

You might be hypermagnesemic. You should measure your magnesium status, for sure.

007: Concerns about long-term bicarbonate supplementation and other suggestions for raising pH

Helen Donnell says, "Your post on urine pH and exercise tolerance was a game-changer for me, but anytime I miss a dose of bicarb, I'm right back to 5. Any long-term concerns with taking bicarb two to three times a day, any suggestions for other ways to get my system pH up?"

Well, I will say in my case that I stopped taking the bicarbonate when I figured out that I had a zinc deficiency. So, for people who don't know the backstory here, Google "Masterjohn urine pH" and you'll probably get that blog post to come up. It's called "How Normalizing My Urine pH Helped Me Love Working Out Again". 

The backstory in brief is, when I was going through the mold and barium toxicity crisis of turn of 2016 into 2017. I got to the point where it would take several days to recover from one workout. I couldn’t afford to be laid out like this

I realized while looking at some lab tests —  a Genova ION Panel —  had some findings that suggested pH imbalance problems. The only thing abnormal in my ION Profile was that my glutamine-to-glutamate ratio. The glutamate was really high, and the glutamine was really low. 

006: Should you be more concerned about overall fat intake or saturated fat intake with familial hypercholesterolemia?

Question: "I have familial hypercholesterolemia, as well as a mutation in my Lp(a). I listened to your 2016 podcast regarding FH and have implemented a low-fat diet and am in the process of fixing thyroid issues. My question is, can you please further explain whether I should be more concerned about overall fat or saturated fat intake?"

To be clear, I am not treating anyone here. I am not a medical practitioner, so I am not treating the disease of familial hypercholesterolemia and this is just educational in nature. 

As a general principle, if I'm thinking about familial hypercholesterolemia —  I would be thinking more about saturated fat, with that said, I would be testing it.

First it depends on the specific saturated fatty acid, but saturated fat relative to other fats raises cholesterol levels. There are people that dispute that, but the data is super clear. This does not mean that everyone should lower their saturated fat intake because most people can probably accommodate that, right? Most people have a working system to regulate their cholesterol levels.

The thing is with the familial hypercholesterolemia, that system is broken, so you become hypersensitive to all the things that do have some effect. You will be hypersensitive to the fact that saturated fat raises cholesterol levels more so than other fats do — but I think it's more to the root of the problem, based on how these things regulate LDL receptor activity, which is what clears cholesterol from your blood and which is what is broken in familial hypercholesterolemia. 

I think a lower-fat, higher-carbohydrate diet is more relevant to the root mechanism. 

How do you test this? So, standard lipid panels are dirt cheap, and it is not hard to convince your doctor to order them. You don't need to get fancy. You don't need the NMR and all that other stuff. I'm not saying it doesn't have its place, but if you want to do dietary tests to see what are the big factors affecting you, you just run these standard tests every couple of months and you pick a diet to go on and stay on it for 4-8 weeks and then see what the results are.

So, you do the low-fat diet where most of your fat comes from coconut, which is the Kitavan diet, where they don't have heart disease. You can try that for 4 or 8 weeks, and then look at your cholesterol levels. Next you do the low-fat diet where most of your fat comes from olive oil, which is a more of a Mediterranean approach. You can try that and see what that does to your cholesterol levels.

You tailor your diet to your own response —  because I can predict what will generally happen, but the individual person is going to have so many different genetic and other factors, that influence what they're responsive to that they just need to test it out.

005: How would you address normal TSH but low T4?

Well, the first thing I'd do is I'd look at your T3. For those of you who aren't familiar with thyroid hormones, TSH tells your thyroid to make thyroid hormone. T4 is the precursor. T3 is the active hormone. 

If your TSH is normal, that means that your pituitary is receiving the proper messages from your thyroid gland.

But if your T4 is low I would ask; is your T3 normal or high? If your T3 is high, then you're probably just converting it very rapidly. If your T3 is low —  then even though your pituitary appears to be receiving the right signals, you're not making enough thyroid hormone.

In fact, it would become unclear whether your pituitary is actually making the right signal because if your T4 and your T3 are low, your TSH should be high because your pituitary should be saying, "wait a second, T4 and T3 are low, so I need to make more of the message, TSH, to tell the thyroid gland to kick into gear."

If T4 and T3 are both on the lowish side and the TSH is normal. I would then look to the pituitary.

In terms of nutritional issues, I think the big things that you're looking at are calories, carbohydrate, and body fat — because the pituitary is overwhelmingly asking the question, do I have enough energy in the short term and the long term to engage in the health-promoting, long-term investments that thyroid hormone governs? 

Those are many, like all the biological peacocking, like making nice hair, and making nice skin, and making things look nice. It’s also protecting your tissues from damage. Then the big, thing is if you're in the right age bracket, is fertility.

So, if your pituitary is not making as much TSH as it should, then that's basically saying your brain perceives that you don't have enough energy on hand, and that means either your body fat's too low, your calories are too low, or your carbs are too low —  because those are the big signals that your brain is going to use.

As mentioned int the Nutrition in Neuroscience series that I did all of these releasing hormones that govern the endocrine system require copper, vitamin C, zinc, and glycine. 

So bottom line is; look at is body fat, calories, and carbs. But the next layer to peel back would be; vitamin C and copper especially, and zinc and glycine in the background.

004: Best clinical way to monitor COMT function if you have already tested for SNPs

"What do you think is the best clinical way to monitor COMT function if you have already tested for SNPs?"

One way you can look at it is through the DUTCH test — which is at dutchtest.com — it's a dried urine hormone testing platform, they have a methylation index that is based on the methylation of estrogen. For example; the main significance of COMT, is related to long-term risk of estrogen-related cancers.  

Acute symptoms are primarily going to manifest in the brain in the relation between COMT and dopamine. 

The higher your COMT activity, the more flexible your brain. 

The lower your COMT activity, the more rigid your brain. 

If your nutrition is straight and you don't have a psychological disorder, that's just a personality trait.

They call this the worrier/warrior, phenotype. 

High COMT activity; you don't worry as much, like a warrior who picks his battles, wins, and repeats. There is nothing to worry about, the only concern is victory.

If you are a low COMT activity; you're not a warrior, you're a worrier. You think about all the possible ways something could go wrong. Instead of moving forward with an image of invincibility, you struggle to move at all, like a deer in the headlights. 

But that's the extremes. Within most of the population, it's just a personality trait. 

So, you really look at, how is your mind operating? If your mind is getting stuck on stuff, low COMT. If your mind is racing around to different things, high COMT. If that's just your personality, don't worry about it. But if it’s starting to interfere with your life, then that’s where it matters. 

Low COMT, focus on methyl donors: B12, folate, choline, betaine, some of the other assisting B vitamins. 

High COMT, focus on  methyl buffers: Glycine. 

003: Supplements that may increase deep sleep

So, deep sleep is, primarily what's going on in deep sleep is that all of your biogenic amines, which are most of the neurotransmitters that you make from protein with the possible except — like depending on how you classify it, you could say ultimately you make melatonin from protein, but it's not a biogenic amine.

Biogenic amines, which are the catecholamines — all are basically shut off. They're probably not zero, zero, but they're almost zero during sleep. Acetylcholine is also shut down during deep sleep, but it pops up during REM sleep.

I really don't think this is a supplement issue. 

First of all, you definitely don't want to be taking anything that has acetylcholinesterase inhibitors at night. 

Non-organic foods have pesticides that are acetylcholinesterase inhibitors. I don't know if that's relevant here dose-wise.

Things that improve cognitive function are often acetylcholinesterase inhibitors. So, gingko biloba is one. I wouldn't take that at night. There are drugs that treat neurological problems, especially Alzheimer's, that are acetylcholinesterase inhibitors; I wouldn't take those at night. 

I'm on the fence about whether you should take choline at night. I think it's most likely fine to eat eggs at night. If you're taking something like alpha-GPC; I'm not sure. You might want to avoid that at night if you find, particularly if you find that when you're tracking your sleep with an Oura ring your REM is higher than normal and your deep sleep is lower than normal. 

But other than that — I would say that methylation support is very important to help lower some of the important biogenic amines. Histamine, for example, is primarily gotten rid of with methylation in the brain and if your histamine levels are high during the day, it might cause anxiety during the night and that could interfere with your deep sleep.

Electrolytes are also super important. Calcium, magnesium, salt and potassium. All these things you need to get straight in order for your sleep cycle to be working right.

If your cortisol is high at night or other factors of anxiety are high at night you might want a targeted supplement there, like phosphatidylserine — the evidence is conflicting, but has been used to lower the stress response. 

I don't think it's a blanket answer to that question. I think it's like figuring out what's the cause of the low deep sleep and working from there.

002: Supplements that may lower anxiety at night and improve heart rate variability during sleep

I don't know enough about the HRV, the heart rate variability, to comment on improving that specifically. Heart rate variability is largely related to recovery from stress. So, I know the Oura ring tracks heart rate variability during sleep. 

The main application that I'm familiar with HRV for is recovery from stress, especially from exercise. So anything that supports recovery — mainly is rest, is going to support that. Getting enough carbohydrates to support your high-intensity exercise is going to be another thing.

In general, nutrient density across the board is going to be supportive of recovery, and enough calories. 

Now, lower anxiety at night before or during sleep I think is a whole different story. 

You might have anxiety because you have not recovered well from your exercise. 

Maybe your cortisol is running high. 

But it could be for totally different reasons, and that's a giant can of worms that I don't think really can be unpacked in an umbrella answer. I think that's kind of something that needs to be very individualized because it requires 10, or 15, or 20 follow-up questions.

But some of the first things that I would think about would be what are you doing to psychologically wind down? The fact is that this is not all about nutrition. It's not all about light hygiene. It's also about psychology. So, is your anxiety at night driven by overthinking? If so, what are you overthinking about? You may need to start a psychological wind down routine if this is your issue. 

And then, there are so many other potential causes of anxiety that you really have to address it on a case-by-case basis, but those are the top things that I think about.

001: What causes low white blood cell count and what can you do about it?

Nutritional causes of low white blood cells and possible solutions?

The absolute first thing that I would always think of when I see low white blood cells is copper. 

So, generally copper deficiency at its most sensitive is going to cause neutropenia; which is low neutrophils, but it can cause low white blood cells across the board. I'm not saying there aren't other things, but that's going to be the number one thing that I jump to first when looking for low white blood cells.