Dr. Joel Rosen:
All right, I am super excited to be interviewing Georgi Dinkov a second time. For those of you who know who he is, he doesn’t need a bio. But for those that may not know who Georgie didn’t cough, is, there’s so much to say and so much to get to today. I’m going to abbreviate his bio, but basically, he is a self-taught guy. His interest in health topics continued after he left his job.

While researching aspirin and its effects on the brain circa 2011 11, he stumbled on Ray Pete’s website, and I think that’s what dug down into the bioenergetics field. His ideas on Bennett bioenergetics which is controlled by dietary and environmental factors as the ultimate causal factor in health disease and even aging immediately appealed to Georgia. And since then, he’s been doing research in that field. So Georgia, I’m super excited to get started. Thank you so much for joining us.

Georgi Dinkov:
Thanks for inviting me again. Hopefully, it will be I’ll be useful to your listeners. Oh, yes.

Dr. Joel Rosen:
Listen, I went through that interview several times. And I came up with some great questions for you today. So for those who want to hear the past interview, we got into metabolic flexibility. We’ll leave links there. And Georgie, as I was telling you, before we got started, I walked away with a lot of aha cars that were contrary to what’s being taught. And I’ve gone down the cortisol rabbit hole, if you will.

And even just our conversation when we just had that amazing insight has shifted my perspective. And I wanted to share that. So cortisol is not what we thought it was the truth behind it is it’s a rapidly aging stress hormone. One of the sacred cows or the contrarian thinking is that cortisol is anti-inflammatory when in fact, it’s pro-inflammatory. So maybe in your in your amazing way of bringing difficult concepts into an easy, understandable way. Explain that to the person who thought, well, cortisol is anti-inflammatory, and I take prednisone hydrocortisone, for an anti-inflammatory immune response or suppression, but ultimately, it’s putting more oil on the fire perhaps. So maybe let’s go into that.

Georgi Dinkov:
I think probably the best comparison that I can give you is with opioids, which are widely used for pain management in the medical field, and a lot of people are abusing them for these pain-relieving properties. It’s very well known that basically, if you continue using opioids, you develop tolerance to them, and then it and not only that, you’re going to start needing higher and higher doses to be able to tamp down the same level of pain. But eventually, if you try to wean off or you stop the opioids, there will be a baseline of pain, that’s going to shoot up tremendously. In other words, you’re going to be in a worse position than you started.

And the pathways for the opioids are fairly well known. They increase reluctant histamine and serotonin, and they also increase the expression of an endotoxin receptor known as TLR four. All of these are known to be involved in chronic pain. So while you’re taking opioids back activation of the opioid receptor, which is a receptor that our endogenous opioids known as the better endorphins also activate, yes, you are kind of inhibiting the signals, at least the peripheral signals from for pain to reach the brain and that are kind of registered as a pain signal. But it’s while you’re doing that you’re up-regulating the machinery that causes these pain signals to travel much more rapidly. So as soon as you stop the opioid, you’re in a worse position than where you started. So you kind of like, you know, in a catch-22 or, or actually, once you, once you start, you can stop unless you’re taking care of, you know, kind of like, unless you also take care of reducing these inflammatory mediators that were upregulated while using the opioids.

And most people are not doing that simply because for a lot of, you know, whenever you prescribe opioids for pain, there’s there’s little concern, and now it’s starting to become a concern. However there was little concern about the long-term effects on pain. Now, doctors are starting to find out through various long-term studies that people who are using opioids long-term, end up being worse, right? Their pain starts to become unmanageable. And once they become resistant to the opioids, there’s very little you can do for them.

And maybe the opioids aren’t the kind of like the end stage of pain treatment. In the hospital, they’re usually given to terminal cancer patients, or just in general terminal people just to kind of like ease the transition to them dying. But it’s really like a last resort step. So if patients stop responding to opioids, then there’s very little that the doctor can do for them, or at least that’s that’s what they think. So there wasn’t much of a thought to this process. But now they’re starting to find out that there’s this booming addiction to opioids, they’re saying, Well, what’s going on like, it’s just the pleasure response cannot explain the addiction and the need for using higher high doses. What explains this addiction and the need for higher doses, the development of tolerance, specifically, the tolerance to the pain, easing effects of the opioids, and you know, people keep using more, but the more you use, the more you upregulate, the machinery for inflammation and chronic pain in the future if you were to stop the opioids, and something similar turns out to be working with cortisol as well. So cortisol has an undisputed anti-inflammatory effect, while you’re using it inhibits the release of the inflammatory interleukins, one and six. It also inhibits the release of something called tumor necrosis factor alpha, and the activation of something called nuclear factor kappa B.

And those are like them in combination, they’re basically the, the primary, the primary pathway towards chronic inflammation. Another thing that glucocorticoids do is while you’re taking them, they inhibit the activity of the enzyme cyclooxygenase and lipoxygenase, which are the IS is produce inflammatory mediators known as prostaglandins, or leukotrienes. From the polyunsaturated fatty acids. However, recent studies discovered that while causal or synthetic glucocorticoids are inhibiting the activity of those inflammatory enzymes, they’re simultaneously up-regulating their expression. So basically, just like the opioids, you’re developing tolerance, to the effects of the global credit coach, but the moment you stop using them, now, all of this machinery that responsible that was responsible for producing inflammatory signals, now he works in overdrive, because the cortisol, he’ll build more of that specific machinery.

And I think the essential studies specifically say that cortisol regulates the genetic expression of the cyclooxygenase and lipoxygenase enzymes. And also, cortisol up-regulates the expression of the enzyme tryptophan hydroxylase. And also the history of decarboxylase. So the moment you stop taking the glucocorticoids, you’re gonna be producing more than before more than baseline of the prostaglandins leukotrienes histamine and serotonin and serotonin kind of has like a reputation of being a happy hormone, at least peripherally. Now it’s not a serotonin is anything but it’s a very dangerous profibrotic molecule. There are many drugs that are clinically in clinical currently clinical trials that are blocking one of the serotonin receptors, five HD, to be precise, that have been shown to prevent and even reverse peripheral fibrosis to conditions that were considered incurable. So taking glucocorticoids makes you feel good currently for you know, presently, in the background up-regulates the machinery that will make you a lot worse than you were before you started taking the glucocorticoids as soon as you stop them. So you know, you know, you know, you’re in this situation, we want to start taking the glucocorticoids you can’t stop unless you take measures to inhibit a lot of that machinery that cortisol started up-regulating while you’re taking the glucocorticoid.

And of course, because this is kind of like disparate knowledge not put together politically, not that it isn’t known. I think specific doctors know that that there’s there’s this famous glucocorticoid rebound effect. So doctors are aware that this can happen. They’re just not digging, or at least connected the dots with preclinical research say, Hey, why are my patients becoming worse after I withdraw the corticoids? We don’t we don’t want them on call. recourse because we know, even aside from the APR agent effect of cortisol, we know that corticoids glucocorticoids, chronic use can cause osteoporosis, we know it can cause insulin resistance, we know it can cause diabetes, etc, etc. So I don’t want my patients to be taking glucocorticoids forever. But my immediate concern is that I gave them glucocorticoids for asthma or, you know, maybe COVID, or some other condition that is driven by inflammation. And now I want them to stop because, like I said, I don’t want him to take them forever.

And now they present him with even higher inflammatory biomarkers than before, what’s going on here? What can we do to prevent that? And I think the answer is, well, don’t start using glucocorticoids. To start with, other anti-inflammatory steroids are there, specifically pregnenolone, progesterone, to a degree that dihydrate, and Rostro. But that one can be potentially dangerous because it could convert easily to estrogen. But yeah, really cortisol, just like the opioids, you’re going to pay a very heavy price for using it now, later on, to, you know, it’s like a circle. It’s like a power drill, you’re using the power drill to solve a problem that didn’t require to start with and the power drill did a lot of peripheral damage, that when you stop using the power drill may have a hole and a lot of damage around it that needs to repair it. And if you don’t, the whole wall may start crumbling simply because you destroyed it using a very powerful tool. That’s very nonselective and nonspecific.

Dr. Joel Rosen:
Yeah, it’s a great example. And I wish that were the only example in pharmaceuticals and just in healthcare in general, that if you don’t address the problem or the contributing problems, and you use it as a stop-gap, you still are burdened with the responsibility of figuring out why this is happening in the first place. Georgia, I wanted to talk a little bit more about the cortisol and the impact.

So one of the things that I walked away with is, so many people are thinking about adrenal fatigue and cortisol is low, or cortisol is high. The question I would ask you is whether it doesn’t matter in terms of whether it’s a glucocorticoid genomic signaling problem. I guess the question would come down to what we talked a little bit about this earlier. How do we quantify what’s going on based on testing to be able to determine how to approach solving this without getting on a court is anti catabolic, detrimental drug like that? Yep.

Georgi Dinkov:
So one thing I forgot to mention, I think it feeds great into your question is that I recently found a study because I’ve long suspected that it’s true. But every doctor I talked to said no, cortisol has a very robust negative feedback mechanism. So cortisol is rarely dysregulated, unless you have, let’s say, people with depression, who have cortisol insensitivity, there are so-called nonresponders of the dexamethasone suppression test, and so are people with Cushing’s disease and potentially ectopic Cushing’s Syndrome if they have a cortisol producing tumor similar peripherally. So doctors say these are very rare cases, in the vast majority of cases, cortisol has a very robust negative feedback mechanism. In other words, if your cortisol shoots up beyond where it should be it triggers negative feedback against a corticotropin-releasing hormone, and then ACTH.

And then ultimately, cortisol levels are going to go down. Turns out that this is the central mechanism. And yes, the negative feedback exists, they’re, surprising to me, even though I kind of suspected it. However, I was able to find evidence that peripherally that is not true, not only not true, cortisol, peripherally is a positive feedback mechanism, it stimulates its production. One of the first kind of pieces of evidence that kind of drove me towards that line of thought was that there was a rat study that was an animal study that was looking at maybe four or five years ago, and it showed that you if you take animals and you put them on a fasting diet, basically they do intermittent fasting.

And simultaneously with that you also make them run on a wheel. In other words, imitating you know, endurance exercise in humans, after about four to six weeks. If you stop that regimen, that the rats that the animals had, they become immediately profoundly insulin resistant. And he even by a basic within a week or so of going back to their normal regimen, without any change in calories. The study utilized some of the animals to look at their tissues and whatnot and discovered that while central production of cortisol was within balance, they didn’t have elevated cortisol in the blood, then that strikingly elevated cortisol in peripheral tissues, and specifically, they had very high levels of the cortisol, the rate-limiting cortisol producing enzyme known as 11, beta hydroxy, steroid dehydrogenase type one, and then for the animals that remained alive. The researchers tried to put them on a regular calorie diet, low-fat diet, low carb diet, but nothing worked.

These animals remained diabetic until they were given an anti-cortisol drug known as Are You 46. So it was an indication that cortisol does something peripherally which is not necessarily detectable in red billable tests basically if you have a person there with normal blood cortisol levels where they can be very obese or very insulin resistant and they cannot tolerate sugar, their blood sugar is high. Doctors are accustomed to saying, Well, what’s going on, this shouldn’t be happening, this person’s cortisol and insulin levels are normal.

But if you look into fatty tissue, and this is starting to be done more regularly, biopsy of tissues with of people with type two diabetes, ‘s been several publications already came out showing very high expressions of 11 Beta HSD. One is very high levels of cortisol, at least in the fatty tissue. So the fatty tissue is very insulin resistant, even in the presence of normal cortisol levels in the blood.

So how can we test for that? Well, this cortisol has to go somewhere. So if there’s peripheral production, high peripheral peripheral production of cortisol, and normal, central, right meaning from the adrenals controlled by the brain, this cortisol still has to be excreted and processing power. So I think the Dutch test will be one way to look at that.

And again, emphasize the blood test will most likely not discover this, and multiple 1000s. Probably both tests have been done on people with type two diabetes, they show either normal or slightly elevated blood levels of cortisol, certainly not enough to explain the obesity and the insulin resistance that has been seen in these people. But now that the doctor is trying to do the biopsies of the fatty tissue of these people, they realize the causal is a problem. It’s just not visible on the blood test. So the Dutch test will probably demonstrate it assuming that phase two did detox enzymes, and the phase two system in the liver is working well.

And then the kidneys are working well, because you know, after the liver takes the cortisol from the blood, it attaches either a glucuronic acid or a sulfate group making it more water-soluble. And then if the kidneys are working, well, they’re supposed to uptake it and then you excreted with the urine. Now, unfortunately, we’re in people who have already established type two diabetes, you may not see that because you may not see much change at a distance because the kidneys are already shocked. Kidney Disease is very common in people with type 2 diabetes. But I still think that until the end stages of diabetes type two, we have kidney failure, you shouldn’t be able to seal the Dutch test or dysregulation. In cortisone, you’ll probably see elevated levels of cortisol but lower levels of the five Alpha reduce metabolites of cortisol, which are known to have anti cortisol effect.

And I think the Dutch test specifically has that they’re they’re looking at your regular cortisol and the five off-reduced metabolites. And I think one of the measures that they do is that if the ratio of the regular cortisol to the five Alpha Tetra hydrocortisone is below is above a certain level, they’re saying you’re in a stage of cortisol dominance. So yeah, so one way to catch it is with the Dutch test. And another one would be a tissue biopsy, which is now starting to be been done more often on patients. But I think a lot of people first of all, balk at getting, you know, getting stabbed with needles set of times, and most doctors are probably unwilling to do it because insurance usually doesn’t cover it unless it’s part of some kind of a clinical study. So for most people, I will say a combination of the blood test and the bench test will be good.

And if they can do a cheek swab, that’s another one, but it’s a fairly expensive test, Some labs will introduce a low analysis of hormones if you send them tissue samples and a noninvasive one will be to do a cheek swab. Another one would be if you can test in the nail, and here because the cortisol to get there has to go through the capillary through the capillaries. And we found in we’re finding now that in people with normal cortisol levels, energy grades will be menopausal when we’re when we’re supposed to be in a state of estrogen deficiency. In every single one that we’ve tested. So far, we found out that their estrogen levels at least one of the estrogens is high in hair or nails.

And their cortisol levels are either at the upper limit of normal or above. But in all cases, people with obesity, type two diabetes, or any kind of a chronic condition, have elevated cortisol in hair or nails where at least the ratio of cortisol to the cortisol, steroids such as DHEA. unisex because we produce about the same amount in both genders or cortisol to testosterone ratio, specifically males, is elevated beyond a certain optimal level. So it’s not about so much about the absolute levels of cortisol you’re producing unless you have Cushing syndrome or Christian disease.

It’s more about the ratio of cortisol, which is the diabetic pro-obesity, pro-aging, versus the other steroids which kept up to be anti-cortisol, which is known as the youth hormones and they tend to have anti-diabetic anti-obesity anti-aging events. If you go on Google and type Jeff Bezos testosterone therapy, you will see several doctors have very high profile doctors looking at pictures of Jeff Bezos and Elon Musk and several other high-profile celebrities out there, and some of them openly admit to using testosterone replacement therapy. But the doctor is saying that there are very objective visual biomarkers of these people, at least the resting agent or the or in some cases even kind of aging in worse, there was specifically about Jeff Bezos, who if you look at pictures of him in the late 90s or early 2000s, he looks more aged than he does now.

And more importantly, more feminized than he then he does now. And Jeff Bezos is very famously on testosterone replacement therapy. And I think in several interviews, he basically said that, you know, his cortisol levels were through the roof, which you would expect from somebody running Amazon, right? But that’s what happens. You know, it’s a great example of the pro-aging, hormonal effects of cortisol.

And because cortisol activates the enzyme, aromatase, people with high cortisol also tend to have high estrogen. So also explains the kind of feminization that was seen in Jeff Bezos in the late 90s, to the early 2000s. All of that is being all but reversed. Now, if you look at him right now, he looks like a miniature bodybuilder.

And that’s what you know, several doctors are saying, they haven’t tweeted him. But he’s saying, this cannot be explained by training alone, there’s an obvious dramatic increase in muscle mass and loss of central fatty tissue, meaning around the mid-thigh muscle, I’m sorry, the midsection, and that usually can happen only through some kind of a drastic reduction of cortisol, or at least drastic reduction of the ratio of cortisol to the anti cortisol hormone such as DHEA testosterone in males.

Dr. Joel Rosen:
I hope you’re getting tremendous value from our content, and learning how to slow your rate of aging. I have a really exciting announcement, I’ve just completed the complete age reversing blueprint, User Guide, complete with learning how to not just slow your rate of aging, learn nutritional bioenergetics learning about circadian rhythm entrainment, the six key factors that you need to be aware of learning how to make sure that the environment isn’t accelerating your age-related biomarkers, and of course, mastering your sleep, this course is going to be retailing for $997. But as a gift to you for watching our content and subscribing to our channel, I’m going to be giving this away for free just for a limited time only leave your name and email and I’ll be sure to send you the complete age-reversing blueprint user’s guide right away.

Dr. Joel Rosen:
And that you said a lot there. And I love I want to unpack a little bit of it for, me, and for people who are listening. So I do a lot of Dutch tests. And I realized Georgie that the central mechanism and the peripheral mechanism are on two different pages when I did that test, and I would go okay, well the brain in its attempt to keep the body alive. The prioritization has a different agenda than the the peripheral tissues.

And basically, that’s what you’re saying you have this is communication or at least other genomics going on when the brain is signaling and down-regulating. But all of that is still being released. And you have an enzyme, it’s not just the 11, beta HSD, that converts cortisone to cortisol, but you have the binding proteins, you have heat shock proteins, you have so many compensatory mechanisms, that it’s not as easy as just saying, okay, the brain signals to the adrenals, the adrenal feedback, and that’s it, that’s all, you know, 90%, I read somewhere up to 90% of the dysfunction or the breakdown occurs outside of the adrenals and not the adrenals itself. So it brings new credence in terms of I have adrenal fatigue, or my cortisol is low, or my cortisol is high, it’s not the absolute amount, it’s the relative amount when you’re looking at different angles like you said if you’re looking at an x-ray, you don’t just take the front to back, you need a side, you need an oblique, you need to look at all these different ratios.

And you’re suggesting the Dutch hormone test, ‘s a really good place to start to be able to get a sense of the waters of central feedback and peripheral and getting an understanding. And then you went into discussing potentially doing a longer term, either a hair or nail sample, maybe you can give a little more insight into that. And then of course, what’s what looks at in terms of the blood testing as well and what some of those ratios should look like to get an understanding of, is this a problem for me, I’m rapidly aging and I think my cortisol isn’t I accept the fact that it’s not super low or super high, but how can I get some insight with this? So basically,

Georgi Dinkov:
in a healthy young person, I think the Dutch test in certain like hair and nails will probably have almost a perfect one-to-one correlation because anything that’s produced in excess and reflected in the hair and nails should be excluded or at least shown as being excreted and accessed in the darkness. Now as we’re getting into progressive pathology or increased agents when delivering kidneys are not working so well anymore, then you may start having a discrepancy. So ideally all three tests which are blood, show you the transport mechanism and production of the of the sources right, how well the adrenals work or for the dysfunctional how level the gonads are working, or progesterone, the ovaries. So ideally, you should have all three types of tests the long-term exposure which can be shown by biopsy, or hair or nails, then you have a central production mechanism, which is the blood, the blood levels, then you have the darkness, which is the excretion.

And together basically, this shows you how much you’re producing, where is it going, and how well it’s being deactivated and excreted. Because ultimately, no matter what hormone you’re producing, I will say the only one that you can probably never overdose on is pregnant alone, everything else, at some point, will probably start having some kind of a side effect if it’s not getting properly excreted. And by doing these three tests, you’re going to find out the production of the transport and the disposal. And you know, for, you know, starting with justice, I think it’s a really good idea. But also Okay, you want to talk about like how people can find out.

Dr. Joel Rosen:
So maybe just looking at the ratios you told me okay yet on the blood, on the sort of on the transport side of things, right?

Georgi Dinkov:
So they asked for a blood test, if you go to the doctor and donor, later a blood test. And if all the hormones are in range, you’re probably going to get sent home and said, everything’s fine. Or at least you know, there’s something close to one of the to the Lord, the upper limit, you may get called for a second test. But as we’ve seen, and of quite a few studies being published on both tissue levels, blood levels, and even here in their levels, it’s not so much the absolute levels of a steroid, that matter because that kind of only tells you about the pathology and specific organs producing it. But it’s the ratio of these steroids. So in other words, a lot of people who say they have adrenal fatigue, present with, let’s say, normal, in the first initial stage of fatigue, they present when normal, maybe slightly elevated levels of cortisol, but very low levels of DHEA sulfate.

And then the answer is no, you don’t have adrenal fatigue, because cortisol is produced by the adrenal, so they’re still working, right? It’s What happened is that you are under probably acute stress and acute elevations of cortisol are known to inhibit the enzyme 1720 lays, which is the rate-limiting step for producing DHEA.

So that’s the initial stage of basically, initially, in a young person, when they’re presented with stress they produce called cortisol and DHEA DHEA sulfate, if that stress continues for a week or more, then the levels of DHEA sulfate start to decline, because the cortisol is inhibiting the production of DHEA. If that continues for long, and how long, it really depends on your I don’t know, not I don’t want to say genetics, but basically, the inheritance patterns call well called go to your parents were and how resilient you are and how you’re taking care of yourself that can go on from a few months to years, eventually, you’re going to start seeing quarters will also start to decline.

And that, if it declines, below sufficient levels, you get diagnosed with full-blown Addison’s disease, and then you’re going to need adrenal failure. In other words, you’re going to start needing supplements with cortisol and also the other anti-causal hormones. Very rarely, we see that like unless it’s a person is already in the hospital and very, very sick. So what you want to look at is the ratios, and the unisex ratio, which has been shown so far to be the best long-term predictor of all causes of mortality, and all causes of morbidity. In other words, if you’re going to do one test, and you want to know your long-term risk of disease or dying from any kind of a condition, it’s the cortisol to DHEA ratio or the cortisol to DHEA sulfate ratio. Multiple studies have demonstrated that what you measure in blood hair nails or even tissues, you want the ratio to be in favor of DHEA.

In other words, cortisol to DHEA should be below one. In fact, the below one is not sufficient. You want it to be below point five, because multiple studies demonstrated that after you cross the point by varier, which means you’re getting closer, you’re moving in favor of cortisol, you already start getting diagnoseable pathologies such as insulin resistance, diabetes type view, clinical depression, psychosis, which cortisol can cause in very high amounts, right. But for optimal health, you want it to be no more than point three. And that’s that’s the ratio that we’re seeing in young children already in puberty because the DHEA starts getting overproduced in puberty.

And in general people, people that have not been to the hospital have not had any kind of acute infectious episodes of a serious disease, like pneumonia or anything like that. That’s that’s what you want to see. In a healthy person. There’s a male-specific ratio, which is the cortisol to testosterone. And you want that ratio to be outside below 15. So below 10 is ideal, but it’s very difficult these days simply because the social levels are relentlessly declining. But ideally, you want to be below them. In other words, cortisol to 10, according to testosterone tends to be over 20 Several studies demonstrated the ratio over 20 in males reliably predicts at the very least obesity, and over 30 Every single person tested with this ratio was type 2 diabetic. So once again, we see here that Korzo is the thing that’s driving this pathology, it is testosterone that specifically in males has an anti-cortisol effect in both sexes DHEA is also an anti-glucocorticoid and the receptor level, and inhibiting the enzymatic pathways DHA does inhibit the level of ADHD one and activates 11 bit HSV two which deactivates cortisol. It’s really like a universal anti-cortisol hormone DHEA. So for both genders, cortisol to DHEA cortisol to DHEA sulfate. I specifically for males, cortisol, and testosterone, a recent study demonstrated that you can diagnose post-traumatic stress disorder, just by looking at this ratio of cortisol to testosterone.

And if it was over 20, the male in all likelihood had some kind of a psychiatric disease, specifically post-traumatic stress disorder. So I think it’s a pretty, pretty decent indication that cortisol is not what we want to be elevated, at least in the long run. Yes, it’s a life-saving hormone. But just like all the life-saving hormones, you pay a very heavy price for it. So in other words, your life should not be always in danger. Because if it is, and that’s what cortisol is kind of like keeping alive than your pain, with the pain, the price by having a lot of other enzymatic machinery and structure of your body and the cells disintegrate simply to kind of shift resources towards keeping you alive, because that’s the primary goal. And that’s the role of cortisol. In other words, causing strife is not good, it’s not a very good thing for our health.

Dr. Joel Rosen:
Awesome, awesome information. I you know, I told you, before we started, I was rethinking about doing the Dutch test just because of that very fact, you can do a bloodspot a hair and nail your, you know, a sample and just see those ratios. But I agree with you, if you want to get a complete picture of what’s going on with the sort of with quote unquote, the broken bone, you get as many different angles as you possibly can, which is a good dovetail Georgie into mine, my other sacred cow, or the, the, the, I guess, the nontraditional thought process of inflammation, and how cortisol and just we well, let’s just get into it. So what you talked about last time was part of the problem, with not converting the food we eat, and the air we breathe into H2O, CO2, and ATP is that those electrons don’t make it to the the end terminal.

And then you have this excessive state of reduction, which I had to scratch my head and think, Okay, I’m writing this down, I’m thinking about these reductants or all these hydrogens. So anyways, you could say it more eloquently than me, but maybe explain to the listener, that it’s not so much these reactive oxidative species that are creating the inflammatory milieu or setting up the problem for inflammation, but it’s this excessive state of reduction, where we’re bio energetically not creating ATP, effectively, maybe kind of give us some insight on that. Yep.

Georgi Dinkov:
So basically, for us to be in a good healthy state, we don’t want unpaired electrons floating around in the body, they’re highly reactive, right? And they will probably react with molecular oxygen. And since the electrons in our bodies, the ones that are free-floating, are in the form of hydrogen ions, that usually results in the creation of either the superoxide anion or hydroxyl radical. And, you know, those, these are highly reactive.

And they tend to attack vulnerable molecules. And the most vulnerable ones are polyunsaturated fats. So if you’re in a state with excess electrons, these electrons will create the reactive oxygen species because they have to go somewhere, right? And there are several mechanisms. One of them is the RLs, which is probably the worst way to dispose of them. less dangerous one, but still not optimal is the body uses the excess electrons to synthesize a large amount of citric acid, which should, feed into something called the fatty acid synthase enzyme, and we synthesize fats. So you can look at obesity as a very reliable indicator that the electrons that you’re getting from food are not meeting their proper terminal acceptor, which is oxygen.

And, you know, this leads to a lot of people saying, Well, these people should just not eat that much. You know, they’re they, yes, if the electrons are coming from food, this means they’re eating too many, too much food, too many electrons doesn’t always work like that. I mean, there are plenty of studies showing that you can have a person subsist and even gain weight, and mostly in the form of fat, of course, not muscle gain weight on a very low-calorie diet. One of the best examples in humans is the recent show, which I think at this point has been canceled, it was called The Biggest Loser, what an app name. So they put these these morbidly obese people through a grueling regime of exercise and fasting, and stimulants, such as caffeine and all kinds of other you know, drugs for them to lose weight. Some of them did, right a lot of them didn’t, they just fell is too much stress and dropped out. Some of them did. However, without a single exception, every single one of these people that won the contest was in quote and then went back to their normal life. Within six months. They were not only back to their original weight, they overshot it and by the way, they stayed on a calorically restricted diet. So clearly it’s not only the calories that matter, it’s the calories out that matter, right?

And get in calories out through a stress mechanism such as exercise or fasting. You know, that’s the first tool that we use, but it doesn’t would be a very heavy price. Why? Well, if cortisol up-regulates its synthesis right peripherally, and we’re stressing ourselves, eventually we’re going to end up with higher cortisol than we started with. Cortisol is a very well-known obesogenic effect, even admitted by mainstream clinical medicine. If you get a metro pack, which is very common, like, oral glucocorticoid use for minor inflammation and a clicker ear infection and whatnot, they give a metro pack, which is I think six tablets of basically 2250 milligrams of six Metaline. Cortisol, I think, is basically the so it’s a glucocorticoid. The site, if you look at the side effect brochure, says this should not be used long term, and in more than a month requires special approval by an endocrinologist, why? Well, it dramatically increases your risk of endocrine disorders, including type two diabetes is a resistance, you know, cardiovascular disease, all these all these things. So we know that cortisol causes these things, right? But if we’re overstressing ourselves, to lose those excess electrons, we’re creating the machinery to produce even more cortisol.

And cortisol is known to cause the very thing that we’re using now, cortisol to combat which is obesity, you know, we’re stressing our cells, which means we’re raising our cortisol to lose this extra these extra calories. But in the process, we’re lowering our metabolism disorder. And now with cortisol over-producing itself, it blocks the insulin receptor makes it insulin resistant, it increases the activity of fatty acid synthase, which is going to make you synthesize even more fat. And of course, it shreds muscle terrible outcomes because it’s muscle mass that determines and it’s the ratio of muscle mass to fat mass that determines your long-term health and your basic basal metabolic rate, your resting metabolic rate. And if you’re destroying a muscle mass while simultaneously increasing the fat, it doesn’t matter if you lose all the fat and muscle at the end of the day if you stop, they have a much lower after you’ve exercised and fasted for listen to three months, yes, you lost all of the maybe all of the excess weight. But now you have almost no muscle.

And by the way, you preferentially lose muscle to fat in a ratio of about three to one, because muscle is much easier to break down the fat in fatty tissues not very well innervated and not very well supplied with blood. So for fat breakdown to occur, you need a sufficient supply of mechanical elements such as adrenaline, muscle is very well integrated into the variable blood supply, which means the cortisol, which breaks down muscle is going to do its job very well, but not so much for the fatty tissue. So even while you’re fasting and exercising, you’re losing predominantly muscle. In other words, you’re killing your basal metabolic rate. And let’s say you managed to lose all of that fat and muscle as well.

And then you end up as a skinny person with an extremely low basal metabolic rate. Now, if you try out, if you attempt to go to even half the calories that you were eating before, you will still regain all of that weight simply because now your basal metabolic rate has been shot. And you’re you know, extremely hypo metabolic, I will say, I don’t know if they did this with these, for the Biggest Loser show, I think they did, they said that they were clinically hypothyroid towards the end of this exercise. So basically what happens when you’re stressing yourself is that yes, you will be burning more calories, but at the expense of causing the fat-producing machinery to increase right, you’re also losing your muscle mass.

And then in the end, you’re going to regain all of it, but not the muscle, because the production of muscle tissue depends on muscle protein synthesis, which depends on the metabolic rate. And now you don’t have that so when you regain your weight, you will regain mostly fat. And you’ll be much worse than you started before because presumably, at least before he had some muscle mass, you know, to kind of keep your metabolically active. Now everything that you gain back is fat. So what happens to another thing that causes it or does it block several of the enzymes in this pathway for the electrons from food to oxygen? So cortisol directly inhibits your oxidative phosphorylation metabolism, which means that there’s going to be a buildup of electrons at one or more of these steps, we can think of it as a bus line from start to finish, right?

And the bus let’s say a state has 10 stops, each bus is an electron. So the electron has to pass to at least 10 stops the final stop is where it makes oxygen and creates water. Because the electrons that we get from food, are transported in the body in the form of hydrogen ions. So hydrogen eventually has to meet with oxygen and pre-create water. If cortisol is blocking the movement of these hydrogen ions across one or more of these, let’s say 10 steps, I think there’s more than them, then there’s going to be a build-up of these buses that are, you know, kind of building up some one or more of these stops.

But what happens to these buses for these electrons? Well, two options one, is the less problematic one but still problematic in the long term. Is it used To synthesize fat, so this mass that you’re getting for food is energy that you’re getting for food has to go somewhere, the body cannot simply expel these electrons freely into the air, once they’re inside of you that something has to happen to them.

And the ideal thing is to meet with oxygen, which creates water, which you then excrete. Now, if that doesn’t happen, if there is a blockage somewhere, then the body says, Okay, I have a buildup of electrons, I’m going to start since this is synthesizing some fat, but that process is not very efficient, and it’s slow. It also consumes energy, fat acid synthase, consumes ATP, which would be low if your metabolic rate is already low. So that pathway very quickly starts getting overwhelmed as well.

And really, the only thing that remains is kind of like a, I wouldn’t even call it an option is the only thing that can happen physic physically is that these electrons that are building up, our worst are going to start leaking around the cell from the mitochondria, and combining with molecular oxygen to create the reactive oxygen species. So in other words, the buildup of electrons, in other words, a reductive state is what creates reactive oxygen species.

And I think it’s an unfortunate name because a lot of people when they hear about reactive oxygen species, think it’s because they oxidize too much. No, it’s the exact opposite. It’s because you’re not oxidizing. In other words, you’re not combining efficiently oxygen with these electrons that you’re getting for food. That’s when you get the reactive oxygen species, which the electrons created by attacking the molecular oxygen and creating these highly reactive molecules, which then can wreak havoc not just on the cell structure, but even genomically.

Several of them are known mutagens and carcinogens. For hydroxy. Nan Enel is one of the peroxidative byproducts of polyunsaturated fat and I think the hydroxyl rhotic radical, which is now known to be a mutagen aircraft and carcinogen. malondialdehyde, probably the most widely distributed most common pooper peroxidation byproduct is also a known carcinogen. So basically, by being in a state of excess reduction, in other words, not processing the electrodes properly, you create reactive oxygen species, which then set up the field for creating virtually any disease that we know any chronic disease. I mean, recently study came out that said that COVID-19 is nothing but a cytokine storm triggered by access to a drastic accumulation of reactive oxygen species. So they both were very serious, you know, situations where a pandemic about it, and then driven by reactive oxygen species. In other words, reductive states are very well known that the actual reactive or suspicious are driving diabetes, obesity, heart disease, cancer, all of that you come up with a disease and put it in Google and then followed by RLS, you’re gonna get a plethora of studies describing the driving role of reactive of suspicion, that specific disease, and how do we get there simply by not efficiently oxidizing the food that we ingest.

And many things inhibit this oxidation. It just so happens that the polyunsaturated fats are not only precursors to the inflammatory mediators, not only precursors to the peroxidase in products, which are mutagens, and carcinogens. But by oxidizing fat specifically polyunsaturated fats, they’re inhibiting one of the crucial steps of oxidative phosphorylation is called electron transport chain complex Q.

And, once you you have a block in these two steps that I mentioned in the 10 step that I mentioned, doesn’t matter if it’s one, or like every single one is only one block is sufficient to start having a buildup of electrons, then you start getting a bill to electrons, and oxidizing predominantly fat creates a bottleneck at ATC electric press, Pachinko picks two, and then you start getting a buildup of electrons. In the end, if the buildup is really bad, not only do you get reactive oxygen species got you also start having the electron transport chain flow in reverse. So both the electron transport chain and even the Krebs cycle can flow in reverse. And that is something we’ve we’ve seen so far in every single cancer type that we’ve managed to look at metabolically, they don’t oxidize the nutrients that we give them. They use the nutrients to synthesize more machinery, which is what the cancer cells need to divide and grow. They’re almost always hypoxic, even in the presence of sufficient oxygen, the infamous Warburg so-called Warburg effect.

And now there’s a I would say a field, of oncology, which is starting to think of cancer a nothing but a metabolic disease driven by one or more blocks somewhere in the in the in the in this pathway of electrons to oxygen. Attempts are being made to identify those blocks and remedy them. There’s already a proposal to try to treat cancer with high doses of Coenzyme Q 10, which is the crucial cofactor for electron transport JQ. We’ll see how this goes but he was already identified as a potential roadblock.

And you know, there’s a clinical spirit in being done at Anderson Cancer Center in Texas, and I think they’re going to be administering high dosages of Coenzyme Q 10 To 100 to 2400 milligrams daily to see if they can remove that block. There are several studies with other queens that Have Coenzyme Q in the quinoa, such as methylene blue, vitamin K, or tetracycline antibiotics. Not many people think of them as quinoa, but they are in fact, their their structure is a cleaner molecule. So there are two electron acceptors and one tube. There are several studies with doxycycline, one of the tetracycline antibiotics in humans for breast cancer, a recent study demonstrated that 200 milligrams of doxycycline, which is the type of Queen or daily, fully arrested the progression of triple-negative breast cancer, which is considered the hardest to treat because it does not respond to hormonal therapy. So there’s a lot of evidence that this reductive state is behind many diseases.

And even though the reactive oxygen species get the biggest blame, it’s not only them for us to get to them, what precedes that is the state of building up of electrons. And then the buildup of electrons can lead to a buildup of fatty acids, right? Which is always never good, right? And we don’t want fatty tissue to build up we know it’s metabolically active, and we know it stimulates cancer growth. We know it synthesizes estrogen, more efficiently than other types of tissue. So it’s the whole state of the inefficient pairing of these electrons with oxygen, which is behind the scenes behind every chronic disease that we know.

Dr. Joel Rosen:
Yeah, it’s the body that has a cruel way of letting us know that we’re not doing things properly by up-regulating or down-regulating different enzyme systems. I guess it comes down to Georgia, Georgia, now that we hear about that, and sort of the sky is falling, and I think environmentally between our hydrogenated oils, and our seed oils, and our PUFAs and our high fructose corn syrup, and endocrine disrupters, and so forth and so on.

Not even getting into the iron oxidation and the bioavailability of copper. What do we do about this in terms of, okay, what other biomarkers, I think that’s a good introduction to the anabolic effect of proteins and being anti-catabolic, not having excess amounts of life policies demands by having such a decrease in intake and an increase in output, which we you’ve already just so descriptively explained how that feeds forward and creates more problems, and it’s helping. But with that being said, being in this excessive state of reduction needing oxidants to accept those, though, hydrogens, what biomarkers can give us some insight, into dietary approaches? What do we do about all of this now,

Georgi Dinkov:
I mean, some of the, I guess the best biomarker, or at least the most widely known in the clinical research, literature, is the NAD plus to the NADH ratio. Unfortunately, when you measure it in blood, it’s not always indicative, which is not a great example of why blood tests are not always reliable, in fact, rarely see or at least they mislead you, they give you a picture that does not necessarily represent what’s going on inside the cell. It’s not that they’re wrong, is that they’re useful for specific purposes. But for some reason, because I guess we haven’t had that many of the other tests develop, we’ve come to over-rely on blood tests and try to use them for something that they’re not supposed to, which shows you what’s going on inside of the cell. So inside the cell, you have two types of NAD plus to the NADH ratio, one is in the cytosol, which is outside of the mitochondria.

And the second one is inside of the mitochondria. And it’s the mitochondrial NAD plus the NADH ratio, which gives you an indication of your redox status. Because in the cytosol, NAD H can get oxidized back into NAD plus very effectively, but at a tremendous cost. And so in a cancer cell, where the oxidative phosphorylation is blocked, which means the mitochondrial part, where oxidizing the Krebs cycle and the electron transport chain, the only thing that remains functional is glycolysis. So the final output product of glucose is something called pyruvate.

But during glycolysis, the cell accumulates NADH by using NAD plus, because NAD plus is the oxidizing molecule, and by extracting the electrons from foods specifically from glucose, you produce NADH. So when there’s a buildup of NADH, which is also a drop of NAD plus, the cell desperately needs packets of NAD plus normally in a healthy cell, then what happens in the oxidative phosphorylation part during which NADH gets oxidized back into NAD plus, if that portion is not working, now the cell has a visible buildup of electrons NADH buildup, once the sale deal with the sale knows very well, it’s very dangerous, and he cannot continue to function even glycolysis cannot function without sufficient supply of NAD plus. So the cell says okay, if you’re not mitochondria, if you’re not going to give me back my NAD plus, and I’ve given him NADH. You don’t want to take it. If you’re not going to give me back energy posts. I’m going to synthesize it myself. What can I do? Well, my final output product of glycolysis pyruvate. Pyruvate is an oxidizing molecule. You can accept one electron and in the process Have lactate. So I’m going to use pyruvate, instead of oxygen very inefficient, it can work very well but at a tremendous cost. I’m going to re-oxidize NADH back into NAD plus using pyruvate is the oxygen, but in the process of producing a lot of lactate, and that’s known as the Warburg effect, also known as aerobic glycolysis. So oxygen is there. But for whatever reason the mitochondria are not working the cell is using pyruvate as the oxygen instead of oxygen, and it’s producing all of the lactate.

And for a long time, lactate was thought of as just this benign characteristic of cancer. That is just you know, it can be used to diagnose cancer, right? But aside from, you know, being a metabolite on Aqua metabolite, it wasn’t thought to contribute to cancer itself, not anymore. Lactate has been known for a long time to be the most potent endogenous driver of angiogenesis. So whenever you have a tissue injury, you’re going to have an accumulation of lactate. And this will start to be simply a result of the temporary injury that’s happening in that area there. It’s not only that it turns out that the sales increase their production of lactate to stimulate the formation of blood vessels, which will stimulate wound healing, the same process is overexpressed in cancer.

And, one of the most successful drugs I think it’s been on the market since the 1960s is called Avastin is an angiogenesis inhibitor. It was developed for breast cancer, but now it’s been given for all kinds of cancers, where angiogenesis is thought to contribute to at least the primary tumor growth, and lactate, the overproduction of lactate is a very reliable stimulus. Several reasons that he’s demonstrated that if you inject lactate into tumor-bearing animals, you drastically increase the growth of tumors without doing any other change to the environment or even treatment. So we know that overproduction of lactate is not a good thing. But that’s what happens when you have you know, missing oxidative phosphorylation, and you know, using using pyruvate as as an option. But what this means also means is that cancer cells have a very high NAD plus to the NADH ratio in the cytosol, but very low NAD plus for the NADH ratio in the mitochondria. Now short of doing a biopsy, and even then will be very difficult because you have to get an intact cell, you have to somehow measure the redox state in the cytosol.

And you have to measure the redox state and the mitochondria very, very difficult. You require very tiny little probes and, a very expensive test. So it’s not feasible for most people to test the NAD plus to NADH ratio in the blood, because it may even be very high in cancer patients. After all, they are overproducing NAD plus, but at the expense of lactate. A better ratio is the pyruvate to the lactate ratio. Because Peruana is an oxidant lactate is a reductive they have a direct relationship to NAD plus NADH, and they participate in it’s a bi-directional pathway to thought, so you can measure that in the blood.

That’s usually a pretty good indicator of your redox status inside of the cell because any excess fluid that is locked into the cell cannot be processed directly and gets exported outside of the cell for usage by other tissues. So it says lactate, you know, we know that lactate is overproduced in cancer cells. If you have low pyruvate to lactate ratio, that is you know a good indicator of the redox status it’d be at a certain level. In other words, if that ratio drops too low, it’s probably a good a good biomarker for cancer. Unfortunately, not very specific, because this this test has been done.

And Apurva to lactate ratio is also low in people with severe uncontrolled diabetes. People with severe skin burns, people with trauma like when they get to the ER, people with severe infectious disease. So for example, the people with COVID-19 who ended up in a really poor state even died when they tested their blood, they had very high levels of something called C reactive protein which is a very good biomarker of inflammation and also a very low ratio of pyruvate to lactate. So not very specific for a specific disease, but tells you that something is just metabolically very, very wrong.

Especially if you test it over a couple of days if this ratio does not improve, or is not decent another good indicator could be the acetyl acetate to beta-hydroxybutyrate. Both of these are considered ketones, even though one of them is not ironically beneficial. Roxy butyrate if you go online and read the literature, it says oh yes, this is a ketone overproducing diabetes no is the reduced form of acetyl acetate, which is the actual ketone, and the acetyl acetate benefits Roxy butyrate is another pair of oxidant vs reductive that is a very good indication of your redox status. Another one will be the oxidized to the reduced form of glutathione gssg which is the disulfide form of glutathione.

And then you have GSh which is the Sophie hydro form of glutathione. In the reduced form there is also a very good redox biomarker, so you don’t have to do all of these but one or more of these when you do them together gives a pretty good indication of basically you know where you stand in terms of redox status. Some of the steroids have very similar supporters. No, which is the reduced form the alcohol, and cortisone, which is the ketone, it’s also a very good indicator of the redox status because that enzyme that reduces cortisol and cortisol also uses NADH as an input as an enzyme. So cortisol to cortisone absorbed cortisone to cortisol will be equivalent to pyruvate to lactate ratio, so many different ratios like that, as long as you’re taking a pair that has a direct one-step relationship, and it consumes or consumes reproduces, either NAD plus or NADH is part of the reaction.

Dr. Joel Rosen:
And that’s awesome. So I mean, coupled with what we talked about earlier, and looking at a Dutch test, looking at a blood test, looking at a potentially a hair test, to get an idea on exactly what’s happening. Just to summarize, the redox state we’re looking at is if we’re in this excessive state of reduction, our hydrogens aren’t getting to the end terminal to make energy, potentially, because we have too much fat and too much cortisol dumping glucose into the bloodstream, or just glucose or whatever it is. And that’s causing this excessive state of reductant. Or read the excessive state of reduction, causing,, your oxidants to have to accept those. And then, as a result, your redox status would show a very low relationship between the oxygen and the reduction because

Georgi Dinkov:
intermittent oxygen burrowed, you can think of root as intermittent oxygen, use it you will oxygen, right? But if you can use oxygen, one of the errors will be used, because there’s nothing else to soak in use. Right,

Dr. Joel Rosen:
exactly. Interesting stuff. So I guess the next question to me to you is, is that a lot of people will, again, do these intermittent fast and the concern is, as you said, it turns over the bacteria which creates endotoxins, which ultimately creates more cortisol, which then creates the challenge of the bioenergetics.

And potentially this excessive state of reduction. And being aware of getting the same benefit out of a charcoal or a binder that would bind up those endotoxins, which is typically what’s driving that cortisol aging challenge in the first place is this inflammatory cascade, in this case, endotoxins in the GI tract, but in other cases, these mediators mediate areas that can compete with each other and can’t produce energy effectively, and then ended up having exhaust coming out of the tailpipe. What I wanted to ask you was the relationship with serotonin, because I don’t think a lot of people understand that.

And if you couple that with SSRIs, that creates that to be around longer. How does the serotonin fit into all of this GA, especially with cortisol and energetics and so forth?

Georgi Dinkov:
That’s a great question. And I’ve talked to several psychiatrists about this. They weren’t aware of the relationship between serotonin and cortisol, serotonin is the most potent central controller of cortisol production because serotonin through the five HT to C receptors controls the release of ACTH. So basically, you can create Cushing’s Syndrome if you inject a sufficiently high amount of serotonin into an organism because serotonin will stimulate the synthesis in the release of cortisol.

Conversely, some of the antidepressant drugs that are marketed specifically the drip Prozac, even though it’s an unnecessary drug, show, I would say antidepressant effects slightly better than placebo. The largest trial so far, the meta-analysis shows that it’s not very effective, but the way it does work, it does work in some cases. Unbeknownst to many people, Prozac is a five HD to see antagonist, and five HD to see antagonist and in general, no Selective Serotonin antagonists have been used off-label to treat Cushing’s Syndrome and Cushing’s disease, the drug Cyproheptadine. Some of the older Airgo derivatives such as bromocriptine, Cabergoline, maatregelen, glyceride. Certainly, all of these have several case studies showing that they can treat Cushing’s syndrome.

And the explanation so far has been that they all have the ones that you are antagonists of the five HD juicy receptors. However, aside from the fight, if you have serotonin active in all of these receptors, serotonin will always raise cortisol. So when you take an unnecessary drug, the ones that do work are invariably on a double antagonist or at one or more of the serotonin receptors, usually five HD juicy, and there’s a very good reason for that. We know that cortisol is either upregulated in depression, or people with clinical depression don’t respond to cortisol with sufficient sensitivity. In other words, the infamous dexamethasone suppression test which is used for diagnosing Cushing’s Syndrome Cushing’s disease, or ectopic Cushing’s, which means that if they give you a synthetic glucocorticoid, your endogenous production, of course, should decline because cortisol is the disease Tarik, one is acting at the same glucocorticoid receptors.

And the negative mechanism, which is the central negative feedback mechanism should tell your body to say, Hey, I have plenty of cortisol, even though it’s the synthetic one, stop producing the endogenous one because I don’t want too much, right? Well, in people with depression Cushing syndrome, or question disease, this feedback mechanism is missing. So in other words, for people with clinical depression, the more severe the depression, the less responsive they are to dexamethasone.

The dexamethasone suppression test is now suggested as replacing the entire Beck’s depression scale, and in this course diagnosing checklists, they’re saying, how do we know that you as a patient when we’re giving you the antidepressant? How do we know that you responded? Well, the only tool that psychiatry has so far is very subjective, because it relies on on the patient’s response to a specific checklist.

So patients like other patients don’t want to admit that they’re not feeling better, right? Some patients are ashamed to admit so how do we objectively know that the drug that we’re given is working, several studies have proposed that the restore restoration of the response to the dexamethasone suppression test is a very reliable predictor that you’re coming out of the depression. So if you’re giving an antidepressant and you start responding to them to the maximum to the maximum the DEXA metals or suppression, this then means that your sensitivity to glucocorticoids is increasing, which means you’re probably coming out of the depression and a great great great corroboration of the fact that cortisol causes depression is a recent clinical study with glucocorticoid antagonists are you for a sixth in use a rapid and complete remission of treatment-resistant depression in just 48 hours.

So a very good indication is that cortisol is involved directly in the causal factors of depression. So, even if you if even if you assume that serotonin is the happy hormone, which is a very tenable proposition, if serotonin is the most potent activator of cortisol relea