NAD/NADH Ratio - The One Metabolic Cause To Rule Them All

Discussion in 'Science' started by haidut, Sep 27, 2017.

  1. haidut

    haidut Member

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    Yes, there is a congestion and it is called excessive glycolysis and not enough Krebs cycle activity or electron transport chain (ETC) activity. I mentioned this a few times in the Danny Roddy podcasts. Carbs go through glycolysis and generate pyruvate. In the process existing NAD in the body is reduced to NADH. So, at the end of glycolysis there is a buildup of both pyruvate and NADH. If the enzyme pyruvate dehydrogenase (PDH, Pyruvate dehydrogenase - Wikipedia), which is downregulated in virtually all diseases/hypothyroidism/cancer, is not working well then the body is stuck and since it needs its NAD to continue operating at all it will have to oxidize that excess NADH back to NAD somehow. In normal metabolism the oxidants are quinones and ultimately oxygen. But in anaerobic glycolysis there is no oxygen so the body will use pyruvate as the emergency oxidizing agent. So, the enzyme LDH will oxidize NADH back to NAD using pyruvate as the oxidant and this will generate NAD and lactate. In cancer, this process occurs even when oxygen is present and it called excessive aerobic glycolysis. Giving niacinamide will raise NAD and the total NAD+NADH pool because new NAD will be generated from niacinamide. This helps as the activity of PDH depends on the NAD/NADH ratio (as well as thiamine and magnesium). So far it has not been shown that raising the total pool of NAD+NAH by supplying extra niacinamide is a bad thing. To the contrary, the body always needs nucleotides and niacinamide also inhibits SIRT1 and fatty acid oxidation, which are all good things. But if you don't want to consume extra niacinamide and raise the total pool then you need other oxidizing agents to avoid LDH getting activated and generating lactate. Quinones like vitamin K2 and emodin, and especially methylene blue (MB) are all oxidizing agents that can oxidize NADH back to NAD even if there is an issue like cancer. So, with quinones/MB you can avoid the excessive lactate buildup and can raise the NAD/NADH ratio even in cases of excessive aerobic glycolysis. If the NAD/NADH ratio is raised, and assuming there is no thiamine/magnesium deficiency the enzyme PDH will resume working. Quite a bit of work has been done on cancer, diatebes and other metabolic diseases to see if there is an actual damage to PDH in those conditions and the answer so far is a resounding NO. So, PDH is simply downregulated and can be upregulated by raising the NAD/NADH ratio and/or supplying extra thiamine. As a side note, the case with thiamine is especially interesting as it also inhibits the enzyme PDK just like the anti-cancer drug DCA does. In addition, MB can help the electrons from food bypass complex I, II, and III of the mitochondrial electron transport chain in case they are not working properly and if this was not good enough MB can also activate the last complex (IV) also known as cytochrome C oxidase (which Peat has written about extensively) in cases where it is being blocked by things like NO or PUFA. Very few other chemicals can match MB in its systemically pro-metabolic effects. Thyroid (T3) is one of them and progesterone is another. DHEA, niacinamide, pregnenolone, magnesium, etc are next in the metabolic ladder. Thus, it becomes immediately clear why Peat writes about all of these chemicals in pretty much every newsletter.
    Furthermore, the importance of high NAD/NADH ratio does not stop with glycolysis ad pyruvate. NAD is also needed in the Krebs cycle, so a high NAD/NADH ratio contributed to high activity of the Krebs cycle. NAD is consumes (reduced) and NADH relesed in the following Krebs cycle steps: oxidation of malate to oxaloacetate, oxidation of isocitrate to alpha-ketoglutarate, and oxidation of alpha-ketoglutarate to Succinyl-CoA. Why is high activity of the Krebs cycle important? Because high activity of Krebs cycle or ETC inhibits glycolysis. So, in a cancer cell where glycolysis is excessive and Krebs/ETC activity is low this is how you get these cells to revert to normal - by inhibiting this excessive glycolysis. As long as glycolysis is excessive and lactate is overproduced the cell will continue growing and dividing. Also, it is the Krebs cycle where CO2 is being generated and since CO2 also inhibits lactate formation it is another important reason to keep Krebs cycle activity high.
    In summary, a combination of MB, niacinamide, thiamine, and biotin can be a very powerful pro-metabolic stack which should benefit virtually all conditions. Thyroid (T3) may also be needed in the most extremely deranged cases but the stack should provide noticeable benefit to the vast majority of people. I mention biotin because biotin is another chemical that can help the buildup of pyruvate bypass the PDH and enter the Krebs cycle, which also avoids overactivation of LDH. Biotin activates (Effects of biotin on pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and markers for glucose and lipid homeostasis in type... - PubMed - NCBI) the enzyme pyruvate decarboxylase (PDC, Pyruvate decarboxylase - Wikipedia) which can convert pyruvate to oxaloacetate and this allows metabolism to continue on to the Krebs cycle. PDC is the alternaive to PDH if it is not working or downregulated for some reason but given that they both have same cofactors, it is uncommon to have one of them working well and the other one not. The cofactors for PDC are also thiamine and magnesium, so you immediately see why it is important to have thiamine and magnesium in sufficient quantities - both PDH and PDC depend on them as cofactors.
    I may be oversimplifying it a bit but I think this is a good illustration of quite a few of Ray's points and one of this depends on studies - i.e. as Gbolduev likes to say this is standard biochemistry written in every book and makes it immediately clear what Pest is all about and why it works.

    Hey @Travis, @Such_Saturation and @aguilaroja - please review and keep me honest here if I made any mistakes. Thanks in advance.
     
  2. Peatful

    Peatful Member

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    This is quite helpful. Very helpful actually.
    Thank you for taking the time to educate.
     
  3. Makrosky

    Makrosky Member

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    Thanks haidut!!! I think this single post can be extracted from here to create a new thread? It will be more accessible for people looking for this info so they (we) don't ask for it afain and again. Also lots of fellas in the forum are gonna miss this. I can do that if you want, or @charlie can do it?
     
  4. OP
    haidut

    haidut Member

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    By all means, feel free to move it wherever you want. And I can expand on this on and on and on. Estrogen stimulates glycolysis but inhibits PDH. It also stimulates fatty acid oxidation (FAO), which further drives down carbohydrate metabolism (through the Randle cycle) and thus increases lactate. NO, serotonin, prolactin, PTH, cortisol, adrenaline, etc all pretty much do the same. This is not studies, this is standard biochemistry. The only disagreement between Peat and the mainstream is whether the metabolic derangements are the RESULT or CAUSE of the various conditions people endure. This debate has ranged on for more than 100 years and only recently has mainstream medicine started to change course towards Peat. Those metabolic derangements are the CAUSE of diseases and the genetic mutations only come later.
    The Warburg Effect drives oncogenesis: researchers at Lawrence Berkeley National Lab and in Japan show cancer really does have a sweet tooth • r/science
    The Warburg Effect drives oncogenesis: researchers at Lawrence Berkeley National Lab and in Japan show cancer really does have a sweet tooth • r/science

    "...There's been a long running debate over whether or not the well known Warburg Effect is a result of genetic transformation of cells into a malignant state or whether the Warburg Effect is a key driver of the transition. The debate may now be beginning to be over. What's very interesting that in the paper, many of the authors' findings are clearly dependent on 3D culture. Many pathways and proteins such as mTOR, AMPK, and HIFs that have long been studied in cancer are shown to be not important players in inducing oncogenic signaling by increased glucose uptake and metabolism in 3D culture. The authors provide very concrete evidence that increase aerobic glycolysis transforms cells into cancer phenotypes. Simply taking away glucose consumption, as the authors show, can revert cancerous cells back into phentotypes with more organized structure; conversely, the authors are also able to show that healthy cells can be transformed into malignant phenotypes by just increasing glucose uptake alone. Furthermore, this ability to transform phenotypes of cancer cells via glucose metabolism manipulation is not dependent on arresting cell proliferation."
     
  5. Makrosky

    Makrosky Member

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    Haidut what would be a good title for a thread of these last two posts of you? "On NAD/NADH ratio" ? A good title for people who looks for this kind of info on the future.
     
  6. Such_Saturation

    Such_Saturation Member

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    I really fail to see how this is not enough to treat a person. But people keep taking Ray Peat's qualitative reasonings, assuming the quantities, and using that to "correct" him. Haidut do you think in a sick person, ketogenesis can have both negatives and positives? And what is the net of those?
     
  7. Xisca

    Xisca Member

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    citric cycle is better known than NAD NADH

    and we never say that fats and protein enter the citric cycle, not only glucose!
    Why focus on sugar?
    So I was thinking the same as Burt...
    All?
     
  8. Amazoniac

    Amazoniac Member

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    This is excellent!
    What happens when there's something else getting in the way of proper flow and you insist on substances that increase the ratio? Wouldn't the excess be overall congestive? I'm not diminishing their value because I benefit from some of them beyond belief and those are questions that I keep asking myself, but you can find reports, and quite frequently within the forum, where people suppressed their metabolism with pro-metabolic substances, yet insisting and keep suppressing further. In other words, with a simple approach, why some many people are not stuck in georgiolysis? There has to be more to the story or else I'm missing the how.

    Zeus' metabolic priming
     
  9. OP
    haidut

    haidut Member

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    Ketones are strong GABA agnists. That is why they help in seizure disorders. I would say that as an emergency fuel they could be good but I would not try to stay in ketosis by default. Ultimately, any extended (and systemic, not just in muscle) fat burning is a signal for the organism that the environment is suboptimal, so adaptations are made accordingly. Fatty acids of any type, but especially PUFA interfere with insulin and thyroid signalling.
     
  10. OP
    haidut

    haidut Member

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    Yes, all sans bacterial infections where antibiotics may be needed but for those niacinamide, progesterone, DHEA, MB and aspirin, have been shown to help.
     
  11. OP
    haidut

    haidut Member

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    Maybe "The one metabolic cause to rule them all" but feel free to name it something simpler if you want. I will add to that thread and modify as needed. There are other substances that inhibit excessive glycolysis. DCA is one of them, and Peat said this:
    Mitochondria and mortality
    "...Heart failure, shock, and other problems involving excess lactic acid can be treated "successfully" by poisoning glycolysis with dichloroacetic acid, reducing the production of lactic acid, increasing the oxidation of glucose, and increasing cellular ATP concentration. Thyroid, vitamin B1, biotin, etc., do the same."

    Some Krebs cycle intermediates also stimulate its activity and some of them suppress excessive glycolysis. However, others do not and can even be dangerous. Citric acid is VERY dangerous intermediate as not only does it not suppress excessive glycolysis but it increass fatty acid synthesis and promoted tumor growth. Succinic acid is a VERY beneficial one because it stimulated the activity of the cycle, inhibits excessive glycolysis, and in higher doses acts just like the drug Mildronate - i.e. suppresses the enzyme BBOX, which synthesizes carnitine. So, succinic acid is a fatty acid oxidation inhibitor in higher doses. The effective concentration (IC50) is about 70uM/L, which can be achieved with 250mg - 300mg dose. This matches Ray's recommendations of 250mg twice a day when somebody asked him about supplementing with it. I will post more on that down the road and even have a supplement with succinic acid ready.
    Insulin, calcium, fructose and palmitic acid stimulate PDH but ATP inhibits it. So, ATP production should not be too high and some of the energy from food should be "wasted" as heat - i.e. mild uncoupling of metabolism is better than completely efficient synthesis of ATP.
     
  12. OP
    haidut

    haidut Member

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    Excess of what would be congestive? If there is a congestion, I would check for infection. Chronic infection of bacterial origin can prevent thyroid from working and can accumulate NADH.
     
  13. OP
    haidut

    haidut Member

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    Because fat oxidation systemically (aside from inside muscle at rest) is not optimal for health. It is absolutely vital for tumor growth and suppresses glucose oxidation through Randle cycle. Glucose is the preferred fuel in healthy organisms, and muscles burn fat at rest. That changes in exertion and disease and that is why fatty acid oxidation inhibitors are therapeutic and can even serve as doping agents (e.g. Sharapova and Mildronate).
     
  14. Xisca

    Xisca Member

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    I have found something I like and easy to read about the citric cycle and the organic acids that can detect the defects
    http://www.functionalmedicine.net/pdf/Insider's Guide_37.pdf

    Adipate, Suberate, and Ethylmalonate are all functional markers for deficiency of carnitine Carnitine is needed to move fatty acids into the mitochondria where they are converted toenergy using vitamin B2. When insufficient levels of carnitine or vitamin B2 slow down this process, other parts of the cellular machinery take over and make adipate and suberate. A similar block in another pathway causes high ethylmalonate. Since most of your body’s energy is produced from the burning of fatty acids, your muscles and brain suffer when this cellular energy pathway is blocked. Anything that interferes with the normal fatty acid oxidation may reveal high levels of these metabolites. Rule out environmental toxin exposure, excessive aspirin use.

    Lactate is the principal product of glucose metabolism in skeletal muscle and is a major player in anaerobic energy production and gluconeogenesis. High levels are commonly associated with coenzyme Q10, biotin and lipoic acid deficiencies. The following should be ruled in or out to determine the underlying reason why lactic acid is elevated: overwhelming infection, hypoxia, high intake of acetaminophen, increased consumption of alcohol, cocaine, increased iron levels, drug side effects (metformin). Rule out diabetes. High lactate can cause muscle cramping, fatigue and brain fog.
    If HIGH Consider supplementing with CoQ10, Vitamin B1, B2, B3, B5, Lipoic acid and Biotin.

    Suspect lipoic acid deficiency when the combination of lactate and pyruvate are high. Many studies have shown that lipoic acid is helpful in treating diabetes and for assisting the liver with removing toxins from the body.
    @Fisherman94
     
  15. tara

    tara Member

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    I'm thinking this would not apply when the root causes of the conditions involve nutrient deficiencies. For instance, if:
    - adequate nutrition is not available
    - undereating in the influence of culture or eating disorder
    - malnourishment because the quality /balance of food available or chosen is poor
    - the digestive system is damaged or vulnerable in ways that make absorption and use of the adequate nutrition difficult
    - maybe also there might be situations because of chronic stress activations - a special area of expertise for you - functioning of the digestive system is not given the bodily resource it needs to make use of the nutrition to support a stronger metabolism?
     
  16. Amazoniac

    Amazoniac Member

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    You believe that infections are treatable by forcing an oxidative state, right? Since everything is interdependent, whether you're depleted by an infection or malnutrition, by boosting metabolism with those substances, if you're not able to restore flow in enough time, it will only serve to deplete you even more. As this happens, and you keep insisting on supplying nutrients, there will be an excess of them because they can't be used, which goes against the idea of keeping things moving and leaving nothing attractive behind. Maybe I'm wrong.

    gbolduev believes that there's no such thing as maladaptation and you believe that people should get out of a suppressed state as soon as possible, even if that means using crutches, and it doesn't matter much if it was a proper response or not. Correct?

    What's the reason why you think that higher doses of niacinamide are usually needed to restore activity?
     
  17. Amazoniac

    Amazoniac Member

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    I think that the best guide after all is appetite: it will tell you if you're boosting the metabolism the right way.
     
  18. OP
    haidut

    haidut Member

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    No, I believe that in certain states like serious bacterial infection you'd better get treated with antibiotic. The niacinamide, aspirin, MB, etc benefits for infection are just a bonus and adding ore of them should be supportive but again if you have an infection and it is treatable by antibiotics then I think its wise to treat it.
     
  19. Regina

    Regina Member

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    Epic post(s) haidut! Do you have a daily target for how many magnesium mg's? Thank you.
     
  20. Travis

    Travis Member

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    Nice post. It's nice to see the Warburg Effect given context. And you brought-up pyruvate decarboxylase.
    And this makes me want to rant about the Breslow Mechanism. This is just a minor detail in the grand scheme of things, but it's important in that it highlights how false paradigms can have inertia; there's serious reluctance to change it despite obvious errors. Authoritarianism plays an important role; especially when considering things that cannot even be seen directly – like molecules. Explanations printed in the shiniest books are usually considered to be the truth.

    Doctor Alan J. Knell's 1970 doctroral dissertation† provides a 144-page β-slap of Breslow's mechanism for how exactly this enzyme works – for how thiamine removes carbon dioxide from pyruvate.
    And he goes into great detail on all of his points.

    The Breslow Mechanism in rarely drawn with the entire thiamine molecule. This is done partly to save space and time; but also, the rest of the thiamine molecule actually gets in the way if you try to do this. Knell mentioned in point (a) that it was impossible to build models ― Honestly, it's impossible to even draw.
    breslow.png
    And you would think that Breslow intermediate #3 would be practically irreversible, since this is a carbon-carbon double bond. Knell mentions that "attempts to prepare the pyruvate adduct itself were unsuccessful." So intermediate #2 might not have ever been made, anywhere. Not even inside the enzyme. And even if it had, #3 wouldn't easily be converted back to thiamine like it needs to be. Instead, Knell does one better:
    knell1.png
    The active coenzyme is actually though to be thiamine's isomer, xantho-thiamine.
    knell2.png
    Pyruvate is drawn here with partial charges; the ketone is polarized as usual. The sulfur nucleophilicly-attacks the carbonyl carbon of pyruvate. There is absolutely nothing unusual about such an interaction; this happens all of the time.

    knell3.png
    The σ-bond is free to rotate. [S-linked-pyruvate shown migrating towards pyrimidine rings]
    knell4.png
    It forms a transient bond as electrons are drawn through the heterocycle by the positively-charged histidine* side-chains of the enzyme. There are two of them in close proximity to the pyrimidine rings. (Electrons need to be removed from pyruvate to decarboxlate it to acetyl-.) The ring structure is electronically-conjugated with an extensive π-bond system, so electrons are free to move through it. Conjugated double-bond systems are much more conductive than saturated carbon chains with sigma bonds. Graphite is a semiconductor (~10⁻⁵Ωm) while diamond is not (~10¹¹Ωm). They are both pure carbon.

    Another nice thing about this is that you end with an S-linked acetyl group, which is how they're usually shuttled around in the body by coenzyme A and others. It could be thought of as S-acetylthiamine, which transfers to CoA (forming acetyl-CoA) through the second complex (E2) of pyruvate decarboxylase by an enzyme-linked lipoic acid prosthetic group(s). This process also directly involves sulfur atoms; lipoic acid's ring opens to create primary thiols, and these are what bond with the acetyl group in transit to CoA.
    Since Knell's paper other interesting things have appeared, and completely overlooked, which support him. Take this 1998 X-ray crystallographic study done on pyruvate decarboxylase and thiamine:
    thiamine1.png
    It shows an open-ring configuration; this is similar to the Knell configuration. The C2 carbon, Breslow's magic carbon that attacks pyruvate, between the nitrogen and sulfur of the thiazole ring is
    conspicuously absent. Thiamine cannot possible function in the way that Breslow imagined without the C2 carbon. It is so essential to Breslow's mechanism that it may-as-well be called the Breslow Carbon. The authors seem a bit puzzled by this:
    Since X-rays were used to image the enzyme – and the thiamine molecule – the researchers just brushed-this-off as radiation damage.

    And as late as 2009, the same thing was imaged by and entirely different research group of chemists. They were imaging a different enzyme, but this too was a thiamine-dependent decarboxylase
    thiamine2.png (click to embiggen)
    Again: No electron density where the elusive Breslow carbon should be, but they don't seem to be bothered by this.
    Ronald Breslow was president of the American Chemical Society, so most people are careful not to offend him by telling him he's wrong. But he probably is wrong. Alan Knell's explanation is much more theoretically plausible, and is more in accord with experimental observations. This reminds me of Gilbert Ling.

    The Breslow Mechanism should should be treated accordingly by being placed next to the membrane pump, the George Wald theory of retinal phototransduction, and the Huxley Crossbridge Theory folders in the filing cabinet; under the section marked "Unicorns."

    Unicorn Folder
    Dean, Robert B. "Theories of electrolyte equilibrium in muscle." Biol. Symp. Vol. 3. 1941.
    Wald, George, Paul K. Brown, and Ian R. Gibbons. "The problem of visual excitation." JOSA 53.1 (1963): 20-35.
    Huxley, Andrew F., and Ro M. Simmons. "Proposed mechanism of force generation in striated muscle." Nature 233.5321 (1971): 533-538.
    Breslow, Ronald. "On the mechanism of thiamine action. IV. 1 Evidence from studies on model systems." Journal of the American Chemical Society 80.14 (1958): 3719-3726.

    It's a minor detail, but is highlights a major problem in science. All of the textbooks beat to the same drum, they all have this mechanism; and they all basically just plagiarize each-other. It seems as thought once a wrong idea actually becomes firmly established it will not be corrected by the same people who had created it, or had accepted it, for fear of embarrassment.


    *Histidine414 and Histidine114 (see Dobritzsch‡)
    *To save space, the squiggly line depicts the pyrophosphate side-chain of thiamine pyrophosphate.
    †Knell, Alan John. Thiamine: a study of its chemistry, biochemistry and mechanism of action. Diss. University of Warwick, 1970.
    ‡Dobritzsch, Doreen, et al. "High Resolution Crystal Structure of Pyruvate Decarboxylase from Zymomonas mobilis." Journal of Biological Chemistry 273.32 (1998): 20196-20204.
    §Chakraborty, Sumit, et al. "Detection and time course of formation of major thiamin diphosphate-bound covalent intermediates..." Biochemistry 48.5 (2009): 981-994.
     
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