Mitochondria: More Than a Powerhouse [transcript]

Written by Christopher Kelly

Oct. 23, 2018

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Christopher:    Hello and welcome to the Nourish Balance Thrive podcast. My name is Christopher Kelly and today I have a very special guest for you. It is none other than Bryan Walsh. Hi, Bryan. Thanks for joining me again today.

Bryan:    Thanks, Chris. It's always great to be here.

Christopher:    I am very excited to talk about the mitochondria but perhaps before we dive into the details of the mitochondria, perhaps, Bryan, you could explain to us why we should care about the mitochondria. At this point, I'm about five years into recording the podcast, I think I might have problem fatigue. There's all these things that I should be caring about. Gluten, I definitely notice was an issue for me and I solved that problem.

    And there was MTHFR and candida and oxalates and lectins and every week you listen to a new podcast and there's this new thing that you've got to worry about. I think I might be getting the point where I'm starting to get fatigue, problem fatigue. Can you explain to me and to my audience why we should care about the mitochondria?

Bryan:    Well, I don't know that this is the answer you're initially looking for. I don't know that people should care about it but it's something that if dysfunctional causes, I guess, global or systemic issues in somebody. So, what I don't want to do is what we've talked about before, is talk about this subject and have people freak out and say -- Well, here's a good example. Actually, I'll take a step back.

    The reason why I started to explore this is the same reason that I explore anything, is because there are conversations in the industry being had about a topic like vitamin D or adrenal fatigue or detoxification or a variety of things and either something doesn't entirely match up for me from what I'm hearing or there's some debate as to if something is good or bad or whatever.

    So, I started looking into this. The reason why is because this phrase, mitochondrial dysfunction, has been tossed around so much. Because of that and the supplement industry, a number of companies have mitochondrial support formula, whatever its fancy name is, mito magic or whatever it might be. Because of this newfound understanding of the role that the mitochondria might play with certain things, and because even conventional medicine says that mitochondrial dysfunction is associated with some 200 chronic diseases or something like that, it's this thing that probably existed for a while but it came to the forefront. People are having discussions about it.

    And so I said, all right, what is this? What really is mitochondrial dysfunction? Do I need to be considering this or caring about this in myself or my patients? Is it as simple as just giving the mito magic, mito supreme, whatever formula is out there to improve somebody's function, health and well-being? But really fatigue is a big thing when it comes to mitochondria because of its production of ATP which we'll talk about.

    But that's how this all started. Where I land with this is where I land with everything, I suppose. Mitochondrial dysfunction is real. However, as we like to do in this industry, we'll say things like everybody is acidic or everybody has inflammation or everybody has too many free radicals. That's just simply not true. Not everybody is inflamed. Some people do and there's different types of inflammation.

    Some people have mitochondrial dysfunctions or sub-optimal mitochondrial function and in those people it will absolutely cause pretty significant health consequences that may not be diagnosed for a really long time. In fact, there was one paper that said the average -- and this is mitochondrial disease now. This is not just mitochondrial dysfunction from a functional perspective.

    But that individuals with mitochondrial disease see an average of 8.19 physicians before getting adequately diagnosed. So, should we be concerned about the mitochondria? Yes and no. It's a really important organelle. It's not the only organelle. Other organelles have just as many important functions as the mitochondria. But it's something that, as practitioners and just as people, if we are interested in optimal health, we need to consider it because, as we'll talk about, it does so much more than just make energy. It has a number of other functions and, if dysfunctional, will cause health issues that might not go diagnosed for quite some time.

Christopher:    Can you talk about the functions of the mitochondria? Even I've heard of that saying the mitochondria, they are the power house of the cell. That's where all the ATP comes from and ATP is the energy currency of the cell. If you want more energy then you should care about mitochondria. I think that's broadly true but the mitochondria do so much more than that. Can you talk about some of the functions of the mitochondria?

Bryan:    Yeah. Well, research has a bunch of emerging roles. That power house of the cell incidentally is a phrase that came about in 1957 and my hope is that we've learned quite a bit more about the mitochondria since then. Its most well-established, and in many cases, only function that people know about is as producing ATP. It makes the energy for which the cell uses to do what that particular cell does.

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    And without ATP then the cell can't do what it does properly. Some of the well-known roles that people may not know about is the mitochondria is the site of heme synthesis to make heme, which is also involved in hemoglobin. It functions with steroid hormone synthesis that all steroid hormones, cortisol, testosterone, estradiol, progesterone, all begins in the mitochondria.

    Some of the newer things that have come out is a very potent intracellular signaling mechanism by releasing things like hydrogen peroxide. It's also involved in calcium signaling regulation. Some of the newer things that are interesting is the mitochondria is involved potently in stem cell differentiation. So, when the stem cell, which can become a variety of other cells does it, the mitochondria is involved with that.

    Some of the things that interest me the most is its role in apoptosis which is, the phrase is programmed cell death which is really interesting, if you take a step back, that the mitochondria not only provides ATP which is essentially life for the cell but it's also involved with death of the cell. In fact, it's thought that it's a major player if not the major player in apoptosis.

    One of my most interesting ones is its role in the immune system. It's emerging in terms of the science. But the mitochondria turns out has a fairly massive role in inflammation, where certain pathogens like bacteria and viruses actually target damage. They seem to target the mitochondria. The mitochondria has things that sort of sense for bacteria and viruses so it's a pretty potent player in the immune system as well.

    It's far more than just the power house of the cell. Again, stem cell differentiation, apoptosis, cell signaling for things like glucose regulation, cell signaling in the production of reactive oxygen species, which are potent cell signalers turns out, and the immune system.

Christopher:    I just realized that you may have elucidated the etiology of adrenal fatigue. I'm thinking that maybe if there's mitochondrial dysfunction in the adrenal glands then you wouldn't be able to produce cortisol. Therefore, the glands are indeed fatigued. Would you agree with that?

Bryan:    Yes. However, I'll just go ahead and say this. If somebody has true mitochondrial dysfunction, it will tend to be systemic, meaning, body wide. And so that individual would have low cortisol but they would also have low sex hormones across the board. Because if it's a guy and the mitochondria aren't working well everywhere then he'll probably have low testosterone as well as probably low thyroid hormone because of the mitochondria's role in that, low cortisol too.

    If somebody has low cortisol, I don't want them to immediately think, "Oh my gosh, I have mitochondrial dysfunction." If somebody has global low, especially steroid hormones, then that's fairly common. I think it's something like 50 somewhat percent of individuals with overt mitochondrial disease have fairly significant endocrine or low hormones.

Christopher:    What are the signs and symptoms would you expect to see in somebody that has mitochondrial dysfunction?

Bryan:    I don't like to just ramble things off. I like things to make sense. When one considers the role of the mitochondria in making ATP or energy, and this gets into a little bit more details, but what cells have a lot of mitochondria versus what cells rely on mitochondria heavily but maybe they don't have quite as many? The most global symptom of all would be fatigue.

    Because if mitochondria is making ATP, if you don't have a lot of ATP then you'll be tired. But there's a lot of different causes of fatigue. Listen, I'm tired. My one and a half year old has decided he doesn't want to sleep through the night very well for the past week and my wife and I -- that has nothing to do with the mitochondria.

    If somebody is tired, you don't immediately think that. But neurological symptoms are fairly common and that can be anything from mood-related issues to cognitive issues. Neurological would also be things like potentially weakness or balance or coordination. The heart will demonstrate mitochondrial dysfunction so people might have arrhythmias, for example. I don't say heart palpitations. It's probably something different.

    A big one is exercise intolerance. And so exercise intolerance is really a fancy term to say you get tired when you exercise sooner than most people would or sooner than you think that you should. It's very real. It has nothing to do with getting tired and willpower and just not doing those last few reps or couple of miles. It's genuinely getting tired before one should get tired. That's a pretty big one.

    Sometimes you can see some hormonal abnormalities in certain people. Hypothyroidism is associated with mitochondrial dysfunction. Hypoglycemia is associated with mitochondrial dysfunction. You might get hearing impairments, some slight hearing loss, for example. But here's the thing, if it's truly global mitochondrial dysfunction, it's not just going to be one thing.

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    It's not just going to be one thing. it's not just going to be somebody that says why don't I hear as well as I used to? Maybe it's the mitochondria. No. Are you tired? Do you have an element of muscle weakness, exercise intolerance, maybe some episodes of hypoglycemia, maybe some neurological down regulation where mood issues, cognitive, everything is just a little bit not working quite as well as you'd expect it to?

    When you start to stack up those -- even some GI issues. I should have added that too. Difficulty swallowing, for example, comes up sometimes, dysmotility issues, constipation or diarrhea. But the more of those that are present then you might start thinking mitochondrial dysfunction.

Christopher:    I was listening to a recent episode of the wonderful STEM-Talk podcast and the interview was with Doug Wallace. He has this, what I thought was a fantastic analogy of the power supply. In mitochondrial dysfunction, you might expect to see the tissue with the highest energy demands fail first in the same as you'd expect the highest demanding appliances to go off in brownout.

    So, the power supply in your house is starting to fail. Which are the appliances that are going to go off first? Well, it's going to be the computer and the refrigerator and then the last thing to go out are the light bulbs. Maybe you would see the same thing in human biology and indeed you do. You do see the tissue with the highest energy demand fail first like the brain and the heart, as you just mentioned.

Bryan:    Brain and the heart.

Christopher:    I also actually happen to be chatting with Dan Pardi who is also a previous podcast guest. He said you can go beyond that and look at the different parts of the brain and then you see the parts of the brain that have the highest energy demands fail first. It's really wonderful analogy. I just wondered whether you had any thoughts on that or whether you agreed with it.

Bryan:    Oh, 100%. It's interesting though. The heart, I guess, pound for pound is loaded with mitochondria and that would make sense. You don't want your heart to lack energy because then it stops beating and survival becomes difficult. But the brain and neurons have considerably less mitochondria than does the heart but the brain and neurons are so reliant on properly functioning mitochondria that if the relatively less mitochondria that they have because their energy needs, like you were saying, then you start to notice neurological symptoms. That's absolutely right. The ones with the highest energy need will typically show symptoms first.

    A great example, the liver. The liver is loaded with mitochondria. But what symptoms will show up in somebody that has mitochondrial dysfunction based on the liver? It's not as energy demanding as the heart, as exercising muscles, or as the brain.

Christopher:    This might be a good time to extend some thanks to you because if it wasn't for your teaching then I probably wouldn't have been able to make head and tail of that podcast interview with Doug Wallace. Thank you for all you do.

Bryan:    Honestly, that's the point of why I do it this way, is because -- we've talked about this before. There's a sense of confidence and, I guess, empowerment when you can listen to a podcast, you can read an article, you can even go into the scientific literature and make sense of a paper. And that just feels good. It feels good to be able to be in a seminar and ask an intelligent question because you actually know what you're talking about or critically evaluate what somebody is saying. I'm glad to hear that. That's a big part of why I try to teach things the way I do.

Christopher:    For me, it doesn't feel good. There's just an absence of frustration. When I first got into this, I try and read something, it will all be Greek, literally in Greek and I wouldn't understand any of it. I listened to a podcast and it was like they were talking another language and I wouldn't really understand what they're saying. Now, I'm getting to the point where I can connect the dots and start to understand how all these pieces fit together, which is wonderful. It just takes a lot of work though. Going back to the Khan Academy and starting with the Organic Chemistry, it was tough. It was like, "Ah, damn. I should have listened in school after all."

Bryan:    Right, right.

Christopher:    I wanted you to talk about some of the signaling roles of the mitochondria. I think this is absolutely fascinating. Can you talk about insulin resistance as cellular antioxidant defense mechanism?

Bryan:    Yeah. This is an area that's emerging. The mitochondria are considered to be involved in cellular signaling and it's not so much that they do it themselves but rather some of the things that they release. One of the big things that's still emerging -- I'm not an early adapter when it comes to science because many times things had been disproven. You and I have talked about that before. Pluto is no longer a planet. The insulin doesn't seem to do it that we thought it did.

    One of the things that happens in terms of signaling-- this also has to do with its ability to sense oxygen, by the way. In the case of insulin resistance, it's thought that the mitochondria might play an initial role in even having skeletal muscle insulin resistance in the first place because if the mitochondria is producing, let's say, too much ATP that with that ATP is going to be a production of -- I'll just use the term free radicals for now. The production of free radicals. One of the most potent ones, and that seems to be the case in all the studies that I've looked at, is hydrogen peroxide.

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    And then when hydrogen peroxide leaks out of the mitochondria and then it ends up being a signal, if you will, for the rest of the cell, that perhaps too much energy is being made in the mitochondria and that perhaps we need to slow down the amount of energy, or I should say energy substrate, in this case glucose, from coming into the cell.

    This is a whole topic, a much bigger topic. But it seems that the mitochondria is one of the major gatekeepers as to whether or not a cell allows glucose in because if too much is happening in the mitochondria, too much ATP is being made, too many reactive oxygen species or free radicals, or in this case, specifically hydrogen peroxide, then hydrogen peroxide leaves the mitochondria and essentially slows down glucose oxidation, slows down the ability for glucose to even enter into the cell in the first place and also increases antioxidants capacity to help deal with the excess free radicals that are being generated from this excess energy that's coming in.

    So, some really interesting theories about mitochondrial dysfunction. Or I shouldn't say it. It's just dysfunction because they're functioning properly, in fact. But that the mitochondria are signaling for the cell to be insulin resistant on purpose until they can deal with all the stuff that's happening on the inside and, therefore, keeping glucose out of the cell inside the bloodstream and then that's when you start to see glucose starting to elevate, A1C maybe elevating. Insulin tends to go up higher because glucose is higher in the blood now and is trying really hard to get glucose in the cell but these cells are so stubborn that they don't want to let glucose in because it's a mess in terms of dealing with that mess first.

Christopher:    Talk about antioxidants. Back in the day when I first got into health and fitness, somebody sent me some antioxidants and they said, "Oh, yeah, this will solve your 8-hydroxy-2-deoxyguanosine problem. You've got oxidative stress as measured in your urine. Take this antioxidant. That will solve that problem." Do you think that's true?

Bryan:    No. No, not at all. I will say I think this whole topic of antioxidants is probably -- you don't have to have me back on -- but a whole show just by itself. Because that's what happened, is I'd say probably a couple of decades ago -- here's the perfect example of what I started out by talking about is mitochondrial dysfunction. Everybody has it. We need to be giving people all these nutrients to help their mitochondria.

    The concept and the understanding of what I'll just simplify by calling free radicals or reactive oxygen species, although that's been highly questioned in the literature that maybe they should be called something else because they're not all reactive, some radicals aren't reactive, some non-reactive radicals. There's too much misinformation out there. It's been overly simplified.

    But that oxidative stress existed. It seemed to cause damage. The quick and easy obvious answer to that was antioxidants because supposedly, at least in vitro, in a test tube or in a Petri dish, antioxidants supposedly contain an extra electron that would donate this electron to these free radicals thereby quenching or scavenging the free radicals, neutralizing them so they didn't cause damage anymore.

    But over the past couple of decades, a few things have happened. One is the use of supplemental antioxidants hasn't really panned out that well in studies to the point that I think it's probably a bad idea for most people to take, I'd say, most antioxidants. I know that's kind of a big statement. But it turns out that, first of all, according to the fairly recent literature, most antioxidants don't scavenge free radicals inside of a cell. That's not their job. There's only one, maybe two, that do, but the rest of them don't do that.

    In fact, some of them act as pro-oxidants. The new theory is that some of these antioxidants actually stimulate antioxidant defense mechanisms inside of a cell, for example, vitamin C might act as a pro-oxidant stimulating these antioxidant response elements, which also are supposedly going to be renamed, and increasing our own antioxidant defenses or, in the case of some of the cool things like sulforaphane or maybe resveratrol, some of those things, they might stimulate other antioxidant defense, endogenous antioxidant defense mechanisms like NRF2, for example.

    I think that we've also oversimplified the whole oxidative stress testing. Here's some functional medicine labs that's supposedly tested but when you look at the literature they basically pick them apart. They say you can't measure oxidative stress that way. And then the bigger question is why is oxidative stress happening in the first place? Is it because of an antioxidant deficiency? Probably not. Is it because of -- It more has to do with what's going on inside the cell, and I can talk about all this, but hypoxia-inducible factor 1 or, like I said, these antioxidant response elements, these transcription factors, and all these things.

    The bottom line is we have way oversimplified this concept of free radicals and antioxidants. I don't think that anybody should be taking an antioxidant formula personally. The studies are clear enough, I think, that might be a bad idea in addition to the fact that I don't think they're doing what we think that they're supposed to be doing.

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    I think that testing is way oversimplified. Yeah, and it's funny because there are some people with some strong words out there about the whole thing about oxidative stress and antioxidant is one of the biggest myths of science that just doesn't seem to die yet. We're pretty wrong on a lot of these things and I would just be careful with some of those concepts.

Christopher:    I've heard you use an analogy which I really enjoyed and I wonder if I could get you to tell it now but I think the first person that I heard present this problem was Ben Goldacre and he talked about, well, these antioxidants, how did they even get where they need to be? Let's say that you do have oxidative stress going on inside of the cell or somewhere. Okay. So, you swallow this capsule. How do you know that the lycopene gets to where it needs to be? Explain to me the molecular mechanism by which that happens? No one can do that.

    I thought maybe at that time it's not understood or I don't understand it. I mean, it obviously works. There's studies showing that when you take lycopene then you can measure lower levels of oxidative stress. So, maybe we just don't -- it's a paradox. It will be discovered later on how the lycopene gets to where it needs to be. You talked about vitamin C. Can you talk about your analogy?

Bryan:    You're going to have to remind me. You've watched my course more recently than I have.

Christopher:    You talked about how imagine you've got a crowded room. Do you remember that one?

Bryan:    Vaguely. Listen, I come up with this stuff on the spot. If I say it once -- I don't watch my own course. I don't remember it. That speaks to -- You can do the actual analogy but that speaks to the point of what I was trying to make scientifically speaking and why antioxidants don't do what they're supposed to do.

    In vitro, in a Petri dish, vitamin C may contain an extra electron that may get donated to a free radical that's lacking electron or really wants it called the nucleophile and electrophile. This is the new terms supposedly for antioxidants and free radicals. But, gosh, it's such an oversimplification to think that if we take vitamin C and it's going to go into the cell that's full of other things that this free radical can react with, thousands of things, proteins, that it can react with, that this little vitamin C is going to raise its hand and be like, "I have the electron. Come over here, nasty free radical, and I'll hand it to you."

    No way. The free radical is going to grab -- and these things happen so fast. The other bit, a little bit more scientifically, is that enzyme catalyzed reactions occur 100,000 times faster than non-enzyme catalyzed reactions. And so if you have a free radical and there are enzymes that can catalyze a reaction relating to it and you have vitamin C that doesn't need an enzyme, what makes people think that vitamin C is going to be the thing that donates its free radical?

    This is just a case of what happens inside the lab is cool and it's interesting but it doesn't necessarily equate to what happens in the body. Like I said, this could be an entire, I think, program by itself and talk about instead of calling them antioxidants, calling them nucleophiles and instead of calling them free radicals, calling them electrophiles, and instead of calling them antioxidant response elements as a transcription factor, calling them electrophile response element.

    The science is there, the discussions are being had in the scientific papers for some reason it's not making its way into the discussions in a clinical realm but suffice it to say that almost everything that we thought we knew about this has been highly questioned. There's some interesting alternative answers. Like you said, lycopene. Lycopene may stimulate endogenous antioxidant defenses and that's how that works instead of just offering an electron as an antioxidant.

Christopher:    I wanted you to talk about some of the markers that you can use on a blood chemistry to assess oxidative stress but before we go there can you just make a concrete -- I realized I've just done it again. When you talk about the mitochondria, suddenly you're talking about oxidative stress. I'm not sure the link is completely concrete in my mind. Why is it that we care about this topic of oxidative stress when we're talking about the mitochondria?

Bryan:    Well, it's because it's a major source of it, I guess, would be the primary reason. I don't know how we're supposed to talk about the mitochondria well in an hour. So, the mitochondria -- I'll just take a step back. For people that can't picture it, it looks like a bean, kind of a jelly bean, I suppose, or some kind of bean. It has two membranes. It has an outer mitochondria. It's like a balloon within a balloon, sort of.

    It has an outer mitochondrial membrane and there's a little space in between called intermembrane space and then there's the second balloon on the inside that has these little twists and turns to it and that's the inner mitochondrial membrane. The inner mitochondrial membrane, there's the components, the proteins and enzymes that make up the electron transport chain. I always joke but, thankfully, scientists aren't real creative when it comes to naming things and the electron transport chain does exactly what it says and that these complexes and enzymes essentially take electrons that were generated from the citric acid cycle or the Krebs cycle and hands them off to one another.

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    And then in that process, the hydrogen ions or protons get pumped from the inner balloon in the matrix of the mitochondria into the intermembrane space, which is the space between the two balloons, and there's so many protons up here. It creates this gradient. And then when the time comes they come rushing through and a whole boatload of ATP is made.

    Oxygen is used in this process. It is actually necessary in order to be able to make this whole process work. The process of utilizing oxygen ends up producing free radicals. That's a bigger topic by itself but it can produce something called superoxide radicals. It can produce eventually hydroxyl radicals which act as free radicals. It also produces this interim piece called hydrogen peroxide that people have heard about. That's the signaling molecule.

    The more ATP -- Well, yeah, I guess we could say that the more ATP is made, the more oxygen is being used, the more oxygen is being used the more free radicals or reactive oxygen species or electrophiles are being produced. The problem is that, in excess, if they're not dealt with appropriately, then they can cause damage and they damage proteins. They can damage lipids when they grab an electron off something, not vitamin C, but they can cause lipid peroxidation and then they get membrane damage or they can cause mutations in DNA, mitochondrial DNA or the cellular DNA. They can cause damage to proteins as well, enzymes. That's the running theory.

Christopher:    We did a whole podcast on this actually. I did one with Megan on how you can use a blood chemistry to assess oxidative stress. I think you're teaching, it pays for itself right there. if you're running a bunch of fancy labs to assess oxidative stress then just knowing about these basic markers on a blood chemistry, that's going to pay for any of your teaching about one test, right?

Bryan:    Easily. Well, that's the whole point. I mean, you know this. You and I go way back and the blood chemistry bit goes way back with us. I was sure a decade ago or whatever that there was more from a blood chemistry test that I wasn't being taught about that we could extract. There had to be more information in the literature that could make me use this -- well, the best test that's available out there. Arguably the least expensive test that's also available out there.

    And, yes, so in the research that I've done, there are three markers that are very well-established -- that's a key point in this -- that are very well-established as markers of potential oxidative stress. And they are bilirubin, GGT or gamma-glutamyl transferase, and uric acid. Of those three, uric acid is, I think, the hardest one to use as a marker of oxidative stress because uric acid either high or low can be caused so many different things, purine intake, catabolism, fructose intake, glucose dysregulation, molybdenum deficiencies. There's so many different things.

    Uric acid is tough. But used in conjunction with those other two, I think, can be helpful. So, uric acid is the most abundant extracellular antioxidant in the body. Just to summarize some of these studies, if uric acid is elevated above a certain level, and someone is not eating a lot of fructose and they're not on a catabolic state or not eating a lot of purines, they don't have gout, they don't have any glucose dysregulation issues like insulin resistance, then it may be that it's because of excess oxidative stress and that the body is trying to produce more uric acid as an antioxidant to deal with that oxidative stress.

    Now, conversely, where it's really interesting is low uric acid is a marker of oxidative stress in that uric acid is essentially being used up as an antioxidant and the oxidative stress side of things is winning, if that makes sense. GGT is used because it is associated loosely with glutathione and the studies are really clear about this. Even a high normal level of GGT within the laboratory reference range is a marker of oxidative stress, can also be a marker of xenobiotic exposure.

    Some studies go so far as to say that it's a marker of glutathione deficiency specifically in the liver, which is really a useful marker. Interestingly, if somebody has xenobiotic exposure there's also a chance that because of that excess xenobiotic exposure, they may be deficient in glutathione as a consequence. So, does it look at xenobiotic exposure? Does it look at potentially glutathione deficiency in the liver? It's hard to really differentiate between the two but that can be marker. It's absolutely a marker of oxidative stress.

    I think my favorite is bilirubin. Bilirubin is also an antioxidant. When I first was, I guess, taught blood chemistry, there was no low end to bilirubin. If it was high it could be some kind of thyroid dysfunction or jaundice or Gilbert's syndrome or all these different things. But there is no low level.

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    It could never be too low. And I'll never forget – I read this stuff all the time. I was in an airport and I came across a study that basically showed that a bilirubin below 0.4, 0.4 or below was associated with all cause mortality. I was like there obviously a low end to a bilirubin because if it's really low then you're not doing real well. So then I started looking into it more and it's a really interesting marker for a variety of reasons, of oxidative stress specifically, potentially lipid peroxidation as a fat soluble antioxidant. So, if bilirubin is low, below 0.4 or below is the range that I use, is pretty solid marker of oxidative stress.

Christopher:    What you're saying is there is no bottom end to the standard reference range?

Bryan:    No. It goes down to 0.0, if you look on it in the lab. I mean, I remember the significant things that happened in the scientific part of my brain. I was in the airport sitting there waiting and I read this. I was like, "What the heck. Wait a minute. What do you mean there's no low end for this?" If you have a 0.1 bilirubin, you have an increased risk for all cause mortality.

    And then I found another study that said the same thing and I thought, well, that's just silly. Bilirubin, if it's low, maybe more of lipid peroxidation as a fat soluble antioxidant. If GGT is high, it might be more glutathione potentially, maybe in the liver, although I think it's a stretch. Uric acid, if it's low, it's sort of global potentially antioxidant, oxidative stress. But if you see low bilirubin, high normal GGT and low uric acid then you're probably looking at fairly significant oxidative stress in somebody.

Christopher:    Talk about what happens to uric acid acutely when there is cold water exposure.

Bryan:    That study, I think – I know which one you're talking about. That's when it went down, is that right?

Christopher:    Yeah, that's right.

Bryan:    Yeah. So, what they did in that one – There's too many studies in my Rolodex [0:31:42] [Indiscernible] in my head. No one uses a Rolodex anymore. What I think in that study is they took healthy – I think they were swimmers. They had to basically jump into a really cold water and they did baseline levels of uric acid. I think it's maybe some oxidative stress markers. But uric acid went down considerably after submersing themselves in cold water. The thought was, because of that extreme cold water exposure, increased free radicals and, therefore, the uric acid that was in the system got used up pretty quickly as an antioxidant. Therefore, it went down. Which is fascinating.

Christopher:    It is fascinating. And it reminds me of some of the things that you said in the 2016 Keto Summit about uric acid and the ketogenic diet. Have you changed – perhaps you'd like to restate what you said there and tell us if you've changed your mind at all since then.

Bryan:    See, how come you ask me this? I forget all the thing I say. I say stuff and I forget about it. No. What's interesting to me about uric acid, what's really interesting, and I think it is yet to be defined, is extra-cellularly uric acid is an antioxidant. There is a couple papers that suggest that intra-cellularly it acts as a pro-oxidant. I'm no keto expert. I don't really care to be. I just dabble and I read a little bit about things, question a bit.

    Without naming any names of keto people, one of them said, yeah, what you see is an initial increase in uric acid when going on a ketogenic diet but then it will tend to normalize after a few weeks and even go down below normal. Now, a lot of times people look at uric acid if elevated as a bad thing because it's associated with gout, because it's associated with fructose consumption or, in cases of diabetes, glucose dysregulation. They basically say lower uric acid is better, which I can see why.

    If somebody goes on a ketogenic diet, uric acid goes up. Maybe it's because they're maybe eating more protein than they did or who knows, more purine in their diet. But uric acid doesn't increase excretion in the urine. So, when it starts to go down, my question is, where is it going? Or some people will say you have more catabolism so maybe you're slightly catabolic state and so you're breaking down DNA and when you break down DNA then uric acid goes up. That's a byproduct of purine breakdown.

    So then the question is, if someone is on a ketogenic diet for a long time, why does uric acid initially go up and then start to drop? If it's not being excreted, if it's not being made more, if you're not in a catabolic state or even if you are, where is it going? If you're not eating more, where the heck is all that uric acid going? Where was it made from? If it's not being excreted, where is it going? It's a concern. There's no basis of this except for my brain.

    Because of the slight PH shift in ketosis, and because uric acid is essentially an organic acid, is to help mitigate the PH shift towards acidity because of the extra ketones being made and uric acid is not being excreted. In fact, ketones will compete with uric acid for excretion in the urine which is why they win and I think uric acid loses but that it goes down so then where is it going?

    My concern is either the body is not making as much, maybe as a protective mechanism and that's cool, but it is an antioxidant. Maybe it's being used up as an antioxidant and that's indicating that ketogenic diet is increasing oxidative stress. I can feel organic tomatoes being thrown at me right now. That's fine.

Christopher:    No. It will be MCT oil or something like that.

[0:35:01]

Bryan:    Yeah, right. Or it's staying inside of cells because if it was in the serum then it might help even further decrease the PH and it's an attempt at buffering the PH. They're just questions. I have no idea. It's purely speculation but it's a very interesting observation. And when you know a couple of things about uric acid, how it's made, how it's excreted, where it goes, then some of it becomes a little bit concerning.

Christopher:    This is what we love about you there, Bryan. You have skin in the game. You are a real doctor seeing patients and you have real concerns and real pressing issues but at the same time you don't really have skin in the research game. You're not like – I won't mention the name of the researcher that you raised questions over. Like you say, there's nothing to disclose with this particular paper. Well, actually, there is something to disclose because your entire career is on the line.

Bryan:    It's based on [0:35:50] [Indiscernible].

Christopher:    Yeah. If there's findings of this experiment disagree with the last three decades of your work then, yeah, you could probably sat on the beach the last 30 years.

Bryan:    Yeah. And just for context, so, you're talking about the course that I made. I was showing a paper that suggested – it was a theoretical paper, I guess, hypothesis – that a ketogenic diet was really helpful for mitochondrial function. It was a really compelling article. But when you look at the author or authors and the fact that they have their entire career riding on a ketogenic diet being helpful but they have no conflict of interest, meaning that they're not getting any money from this, they have a huge conflict of interest in terms of their reputation if they were to publish anything contrary to that support of their 30 years of experience.

    I try not to be dogmatic about anything quite honestly. I don't tell people to take my word for it. I don't like to be too dogmatic about many of these things because it changes. I think having a little humility is a good thing especially in this space.

Christopher:    And it's absolutely not to say that there's something wrong with that paper because of that. It's just something to think about, that's all.

Bryan:    It's inherently biased.

Christopher:    Of course. We better talk about some of the things that might cause mitochondrial dysfunction. Micronutrient deficiency is certainly one of them.

Bryan:    Yeah. If I may, in order to help people, I don't know if we're going to go an hour--

Christopher:    I apologize. Every single question is an entire episode in itself. We do have solutions to that and we'll get to that a little bit later. I mean, if you could possibly summarize some of the micronutrient deficiencies that may cause mitochondrial dysfunction.

Bryan:    I would prefer, if it's okay, to quickly go over what the mitochondria is, how it works, some of the pieces because, I say this, because once you know how it works then you know where dysfunction can occur, if that makes sense. I already mentioned the mitochondria is a bean shaped. It has an inner and outer membrane, the intermembrane space, the matrix on the inside.

    On the inside, there's the citric acid cycle inside the matrix that has to run. When that's running well it makes electrons. When those electrons are made, they're carried over to the electron transport chain I was mentioning before in the inner mitochondrial membrane. Hands down the electrons in the electron transport chain, puts the protons into that little space in between the two balloons creating a huge gradient and then when the times is right it comes rushing through and you make a whole bunch of ATP.

    In addition to that, some reactive oxygen species or reactive species or electrophiles are made in the inner mitochondrial membrane. It's a pretty impermeable membrane. It's pretty tight. And it's because – one of the things is this really cool fat called cardiolipin. It supposedly takes about 20% of a healthy inner mitochondrial membrane. It's not very leaky. This is all going somewhere.

    You have an inner mitochondrial membrane that's supposed to be fairly tight and things are not supposed to come through it. You do have certain pores and certain transport proteins that can allow certain things through but it's highly regulated. The outer mitochondrial membrane is far more permeable. Stuff can go in and out of it fairly easily. It does have some transport proteins as well that can transport fairly large or larger, something like 5,000 daltons, size molecules.

    So, when you talk about dysfunction, dysfunction can come from nutrient deficiency because the citric acid cycle and electron transport chain are so highly dependent on nutrients. Without going into super detail on this, you need a whole host of B vitamins, specifically B1 or thiamine, B2 or riboflavin, B3 or niacin, B5 or pantothenic acid. Another one that you probably heard of is a supplement, but your body can make it, called lipoate or lipoic acid. You need certain amount of iron as well as either manganese or magnesium.

    That's all just to run the citric acid cycle. If any of those things are missing, it doesn't work properly. You need vitamin B6 or pyridoxine in order to change amino acids into things that can go into the citric acid cycle. And then in the electron transport chain, you need iron, you need copper, you need coenzyme Q10. What am I missing?

Christopher:    You need carnitine to bring long chain fatty acid.

Bryan:    Well, carnitine -- Yeah, that's kind of a different story. So, technically, I mean, you don't need carnitine if you can just run off glucose.

[0:40:06]

Christopher:    That's true.

Bryan:    Just within the inner mitochondrial, the matrix, the citric acid cycle, electron transport chains, those are the primary things that you need. If you're deficient in some of those things then none of that works right. And when none of that works right, the electron transport chain starts to slow down. And when it starts to slow down, it becomes really inefficient, an inefficient production line.

    When it's not as efficient then some of these reactive species that are being made kind of float off. And now you start to get that cell signaling. That can actually signal when it gets to the immune system. That can trigger inflammation via the nuclear factor kappa beta and a few other things. And oxidative stress can cause damage to the mitochondria. We didn't even talk about mitochondria quality control and mitophagy and apoptosis and all these different things.

    A simple nutrient deficiency can disrupt the basic ATP producing process of the mitochondria leading to pretty significant stuff, like I said, right down to mitochondria, excess oxidative stress. In addition to that, you can have all those nutrients we just talked about but if you can't get rid of the oxidative stress -- I call it oxidative stress. The free radicals or reactive oxygen species that are being made, if you like glutathione, if you lack glutathione precursors like cysteine, if you lack selenium to be able to utilize glutathione with glutathione peroxidase or riboflavin to recycle it or any DPH to recycle it, then you'll have problems.

    Your question essentially was what can cause mitochondrial dysfunction? I'm going to go through a few of these, not in detail. You mentioned nutrient deficiency, so citric acid cycle, electron transport chain. You mentioned a carnitine deficiency. If you can get fatty acids in, in order to undergo beta-oxidation, then that's going to cause mitochondrial dysfunction.

    I mentioned those protons getting pumped into the inner mitochondrial membrane. You can have a leaky inner mitochondrial membrane. When I said it's impermeable and stuff doesn't come through, if you have a leaky inner mitochondrial membrane, you don't make as much ATP and then you start to get mitophagy, apoptosis, cell death, and some problems. You can have, I'll just call it too tight of an inner mitochondrial membrane and a hyper polarized mitochondrial membrane and that causes issues.

    You can have too much or too little mitophagy, too much or too little fission or fusion, infections, viral or bacterial, can cause mitochondrial dysfunction. Toxins. I don't even think we have time to talk about that. Toxins, xenobiotics, the mitochondria are a major target for xenobiotics. So, when you ask what can cause mitochondrial dysfunction? Viral infections, bacterial infections, xenobiotic exposure, nutrient deficiencies. There's a whole host of things.

    This is why -- I'll go back to saying what I did, is you can't just have a mitochondrial support protocol. Why is somebody's mitochondria dysfunctional in the first place? It's not going to necessarily be fixed by a bottle that has some B vitamins, come CoQ10, some creatine and some ribose in it.

Christopher:    It sounds like we're talking about something very specific, and we are, but when you get into the causes and the solutions and you start to understand the process then you realize that you're just talking about all of the things. Obviously, a protocol could never work.

Bryan:    True.

Christopher:    I really wanted to ask you about why or how the mitochondria might be a target for bacterial infection?

Bryan:    This is an interesting theory. What is fairly well established is that the mitochondria is absolutely a target for certain bacterial infections as well as certain, not all, viral infections. In fact, there's an interesting paper that even says do the mitochondria have its own immune system in the first place, which is it was a hypothesis paper but really fascinating to consider some of the implications of that.

    The theory is, and I recently read a paper that said that this theory is not true although it's one paper compared to many papers suggesting this is a theory, is that the mitochondria evolved from two billion years ago, that a eukaryotic cell engulfed a bacteria. There's a lot of things that point to this as a strong possibility, the fact that it's a double membrane, for example, the size, the fact that the mitochondria has some of its own DNA that makes its own proteins essentially which is rest of the cell can't make.

    The way that it undergoes things like fission and fusion. So, really interesting theory. But if it were a microbe originally then it would make some sense from a survival perspective that it was able to sense if another invading bacteria or microbe, like a virus, interestingly enough, parasites, but a bacteria or a virus might be invading or potentially threatening its survival and, therefore, has certain things that can respond to that accordingly, if that makes sense. I'm not sure if that's where you're going with that but that's the running theory as to why it seems to--

[0:45:01]

    And again, the papers, you saw them. These papers basically say that viruses and bacteria hijack the mitochondria and that the mitochondria is the target for these two different microbes. And getting back into the dysfunction area, how this cause dysfunction, some of them open up the inner mitochondrial membrane. Some of them disrupt the electron transport chain. Some of them disrupt the citric acid cycle. Some of them allow calcium to go rushing in which totally screws things up.

    Again, when you know the physiology of it then it's really easy to understand how dysfunction occurs. And it's interesting because these papers take a specific virus and say how it causes mitochondrial dysfunction and then, therefore, how it hijacks the cell, the cell becomes dysfunctional and causes an immune response.

Christopher:    You did an entire podcast with Tommy on how environmental pollutants might be affecting our health. The Walsh Detox protocol is now an integral part of the Nourish Balance Thrive Elite Performance Program where we work with clients one on one. Can you talk about how environmental pollutants might be affecting mitochondrial function?

Bryan:    Here's the deal. It's the same thing. It depends on the xenobiotic or the pollutant that you're talking about. And the research is pretty well done in this area as well. There is, I think, at least one or two papers that basically said that the mitochondria is a target of xenobiotic exposure or pollutants. Once again, when one knows how the thing is supposed to work in some detail then you can go through and say -- Like arsenic. "Arsenic disrupts the citric acid cycle. I see how it causes mitochondrial dysfunction."

    Or if you see that phthalates or bisphenol or whatever it might be, organochlorine increases permeability of the inner mitochondrial membrane and then it allows the protons to come through, you don't make ATP, targeted for mitophagy, apoptosis, the whole thing, inflammation. So then you can see. There's such a wide range of xenobiotics and different environmental pollutants, many of them, and drugs too by the way, they target the mitochondria in a very specific region ultimately causing mitochondrial dysfunction and all the things that we've talked about.

    But, yeah, the reality is, and you saw some of the papers that I highlighted, I'm hard pressed to find a xenobiotic or toxin that doesn't negatively impact the mitochondria in some way.

Christopher:    Yeah. I will, of course, cite some of those papers in the show notes for this episode. You also cited a really interesting paper, 35% of all pharmaceuticals cause dysfunction. I mean, at this point, everybody knows about HMG-CoA reductase inhibitors and statins but that's not the only drug that can cause mitochondrial dysfunction, right?

Bryan:    Gosh, no. Oh my gosh. No. In fact, that speaks to why -- I don't really, I don't have much of an agenda except that I really want to help people. I told you, what happens is I'll read papers and I'll think to myself why have I never heard this anywhere? People need to know this. Because conversations are being had in the scientific literature that are not making its way to the general public or to clinicians or to medical doctors.

    There are enough papers that are written about the truly detrimental effect. They're looking at at least 30% of all pharmaceuticals, and I'll list out some of the, not specifics, but classes of them. They are known to cause mitochondrial dysfunction. That is absolutely something somebody needs to know. So that if they're feeling -- and it's not just fatigue or exercise intolerance but if they're just not feeling well, to look at their drug that they are taking. To know this information, and then to look up and to see if their drug causes potentially mitochondrial -- That's important information for some patients somewhere, I think, to know.

    So, anyhow, basically every class of medications have been shown, not all medications, but most classes like analgesics, antibiotics, anti-psychotics, anti-epileptic or seizure medications. I think a couple of the hypolipidemic ones or cholesterol lowering ones and some of the anti-diabetic drugs or glucose lowering ones. But 30% is a lot. In most classes of drugs, there are some that cause mitochondrial dysfunction.

Christopher:    Well, let's talk about some of the interventions. First of all, I wanted to ask you about this general idea that perhaps I've had myself but I probably borrowed it from someone else at some point in time reading books and whatnot, and the idea is that many modern diseases are caused by the absence of stress to which we are well-adapted.

    I mean, things like exercise, fasting, cold exposure, hot exposure, those types of stresses. It seems like the absence of those things does seem to cause chronic disease. When I looked at your interventions, it would seem that those things seem to feature quite heavily. Would you agree with that statement?

Bryan:    1000%. I did include a couple of papers in that course that basically speak to that very thing.

[0:50:00]

    It's ironic that the very things that got you and I here, meaning, that our ancestors were able to survive for that long so that you and I could be here, are the very things that we've gotten rid of. We had exposure to a certain amount of extremes. It's like the bell curve. If we get too far in any direction then it's problematic. But we had to deal with temperature extremes before hitting an air conditioning. Now, if we get a little bit too hot we just flip on the AC and it takes care of it for us. If we're too cold, same thing. We can just flip on the heater.

    There was times where we couldn't eat as much and now we have this chronic availability of all foods everywhere from all over the planet and all seasons at our local grocery store. Exercise. We had to move. We had to move. It was life. Now, we don't even have to. The thing that cracks me up along those lines is that there are researchers that are looking at things like curcumin, sulforaphane, resveratrol and all these things to mimic the effect of exercise and of being in a sauna and of fasting because we're too lazy to exercise.

    We desire comfort too much to be hungry. We thermal regulate using external means. They're saying resveratrol might be an exercise mimetic. What does that mean? There is no exercise mimetic. You can never replace what it is to actually exercise when you think about the mechanical stresses that are taking place, all those other things. It just shows you how lazy we truly are, is that we're looking for things that people can take as a supplement to mimic all these things.

    But listen, absolutely, all the things that got us to where we are today are no longer there anymore and we don't have to adapt anything. And you look at the state of health in the majority of people, we need -- We don't need any more psychological stress, for god's sake. But we do need some of this physical stress that help us to get us from an evolutionary perspective even here today.

Christopher:    As the vendor of Hormetea which is one of those supplements you talked about, it's exercise in a tea cup, in its defense, I would say that the two things are not mutually exercise. I can have a cup of Hormetea and then go for bike ride afterwards. They don't necessarily replace.

Bryan:    Well, there's clinical utility for these things 1000% but to say -- these research papers are almost saying that it's a replacement. You can't replace them. If you want to exercise, jump into the sauna and then have a cup of your tea, it might even augment the benefits somewhat. I would propose that it probably does. The point I was making is like the sheer -- Laziness really has what brought us to it. We didn't like to sweat or to shiver and so we have heating and air conditioning. We don't like to get up out of our chairs so we have a remote control for our TV.

    All these things have come out of a certain amount of discomfort that we weren't willing to put up with. Inventions are blessing and a curse in some ways. But to suggest that these things can be replacement, even for a sauna I've seen, is a little bit silly, I think, in my opinion. But it really speaks to the laziness of people. No, no, no. They have clinical application and the research is too clear on some of those things.

Christopher:    I think, more than laziness, it speaks to environmental mismatches. The desire to stay warm or keep cool may have served some evolutionary advantage in the past but now we don't need to do that.

Bryan:    We don't even try.

Christopher:    No, we don't even try. I really enjoy -- there's a book that I think people might enjoy. It's called Why Buddhism is True by Robert Wright. In that book, he talks about how to take these feelings head on and feel the nature of them. I find that really, really helpful. You may find yourself learning to love being cold and hot and hungry and all these things that we're supposed to hate.

Bryan:    I mean, this speaks to a bigger thing but if you look around -- I mean, I really think that most people aren't real happy. You only know happiness when you know unhappiness. You only know comfort when you're uncomfortable. To do a fast, you're hungry, and it's a little bit uncomfortable but then when you get to eat, man, it's good.

    Being in a sauna that's as hot as you can tolerate, it's not comfortable. If you're in the sauna that's really hot and you're really, and you just went -- and after you exercise, it feels great but it's not comfortable. But when you get out and that feeling of the fan, or whatever it is. Discomfort allows you to even experience comfort in the first place. I think we need to be uncomfortable to even appreciate comfort. I totally agree with that.

Christopher:    That's great. One thing I'm a little bit fuzzy on is -- I said it. I put in my statement there that we're well adapted to. So, we seem to handle exercise really well. Why is that not true of some of these environmental pollutants, so the pharmaceuticals? Why are those not hormetic stressors? Why don't my mitochondria get bigger and better and more abundant when I get exposure to arsenic or something like that? Do you know why that is?

[0:55:02]

Bryan:    Well, the short answer is no but I can speculate. One is that they're too new. The reality is if we have enough mild exposure to these things, that perhaps in the future generations, that they are getting stronger in the sense that it's weeding out the mitochondrially deficit that can't survive these things. I don't necessarily agree with it but the adage of the strong and Darwin and the survival of the fittest and some of those things, there's not enough time that has gone by to see if we can't evolve and adapt to these things.

    The problem is, as is the case even with exercise, is if it's too much. If it's too much then it just blows out the system and there's really no adapting to that, at least right then and there. Listen, I mean, you know how I feel about xenobiotics and I think that they're really problematic for a lot of people but in multiple generations, will we adapt to these things?

    Part of it though too, in that it's a big question, is that they're synthetic and it's something that theoretically the body has never had exposure to ever in the history of modern humankind, that it's not a recognizable molecule necessarily that we have adapted along with the evolution of the world and that they're relatively new. We might be adapting to them, who knows? But it would have to be in the right amount, similar to exercise at the right amount or thermal regulation or saunas in the right amount or calories.

    Calorie restriction in severe is starvation and causes death. That's not very good from an evolutionary perspective. But in the right amount perhaps we are going to be able to adapt. I don't mean that you should go out and spray yourself down with glyphosate to see if your future generations will therefore be stronger. But it's an unknown question. I don't know the answer to it myself. But maybe we are. We are fairly adaptive organisms. I just don't know if it's too strong for us to adapt to or maybe just more time needed to elapse.

Christopher:    And maybe it's a question of allostatic load. You've got something that's exposed to thousands of these chemicals and at the same time they're not doing well in other areas. I think I can cite a study that Tommy wrote about in our highlights email series where they gave resveratrol to people that already had insulin resistance type II diabetes and they got worse. It's like you took somebody that was already under too much stress and then you added another stressor and they got worse.

Bryan:    Totally. It's about the proper amount. That's the thing. I mean, people say, is exercise a stress? Well, yeah, but to whom are you saying? To what person? What type of exercise? What volume? What intensity? What duration? All those different things. They're all technically stressors. That's a perfect example. That's a perfect example that you can't say exercise is inherently good for everybody because in some people that might be, even the smallest amount--

    Sauna is a perfect example too. You can get someone that can only last for two minutes on a hot sauna because it's too much of a stressor versus somebody else might be able to last for half an hour. The appropriately applied stress in the right amount, that is the benefit.

Christopher:    Can you talk about some of the dietary interventions that you think might be helpful for mitochondrial function?

Bryan:    Yeah. Well, I'm going to change what you said. It's not what I think is helpful. I really try to limit my own opinions on things and go into the literature as much as possible. In the literature, and none of these should be surprising, but there's some suggestion that a ketogenic diet may be helpful for certain, depending on who wrote it, for certain aspects of mitochondrial dysfunction.

    For example, ketogenic diet has been shown to possibly benefit people that have a complex I deficiency or defect in the electron transport chain. Low carb, similarly, it doesn't have to be a ketognic, might be helpful. One of the most promising ones, I think, is just simply calorie restriction which I realize for much of your audience isn't very novel or new or exciting.

    Calorie restriction, along with time-restricted feeding, will tend to improve metabolic flexibility when it comes to the mitochondria but calorie restriction -- we didn't talk about all this. Calorie restriction in the right amount has been shown to reduce oxidative stress. We didn't talk about fission, infusion and mitophagy and mitogenesis but positively augments all of those things. It has to be nutrient dense. You have to have enough nutrients to even run the mitochondria.

    Here's a problem that I see. It's people that will do calorie restriction and/or time-restricted feeding but they're not getting enough nutrients in the calories that they are eating. I think that's a huge problem. It has to be nutrient dense.

Christopher:    Right. So, Bulletproof coffee, drinking olive oil, that sort of thing, probably are not going to work so great.

Bryan:    In the interim, potentially, but long term, no. That's great. But then you create nutrient deficiencies and then all of a sudden your mitochondria aren't going to be able to work as well.

Christopher:    Can you talk about therapeutic uncoupling?

Bryan:    I would love to. In fact, for an hour. All of this stuff is really cool. Some things get me going a little bit more than others. This thought of therapeutic uncoupling is pretty awesome.

[1:00:01]

    To do so, I'll go backwards again. Going back to just normal function, the inner mitochondrial membrane, the one that's relatively impermeable, it has cardiolipin, it has electron transport chain, it makes the ATP, also has a number of what are called uncoupling proteins. This is the bit that I never heard. I've been to courses on the mitochondria a while ago and I can tell you that none of this is talked about. This is 5% of probably what's in my courses in these things.

    All this other stuff is out there but I haven't really heard about it very much. Citric acid cycle generates electrons. Electrons get handed to the electron transport chain. When they pass these electrons down, they take these protons and you shove it up in between the two balloon spaces, the intermembrane space. Now, I said before that when the time is right, it comes rushing through the ATP synthase or complex V and makes a whole boatload of ATP.

    But it turns out, it has to be in an optimum. You can have too many or too little protons in the intermembrane space which ends up being -- it's kind of like an over inflated or under inflated bike tire. If you have too many -- it's a hyperpolarized membrane. By the way, a hyperpolarized membrane is associated with a number of different chronic conditions, some neurodegenerative diseases, fatty liver, things like diabetes, insulin resistance, some cardiovascular issues.

    That's when the bike tire is too inflated. What's happening is you need a little bit of the pressure out. To let a little bit of the pressure out in a hyperpolarized mitochondrial inner mitochondria membrane is these uncoupling proteins. Another term is called a protonophore, proton pore basically. These protonophores, these uncoupling proteins, allow some of those hydrogen ions that were stuffed inside of that space, in the intermembrane space, back into the matrix.

    Now, just to be clear about all this, there's also a depolarized membrane where you don't have enough hydrogen ions out there and you don't make enough ATP. This is why there's no such thing as a mitochondrial protocol because if you have a hyperpolarized membrane and I have a depolarized membrane, you have two entirely different things going on. We'll both have a dysfunctional mitochondria but we have entirely different things. And you incidentally will benefit from this concept of therapeutic uncoupling. So, allow me to tell this really quick story about DNP.

Christopher:    Oh, yeah, that's great.

Bryan:    Dinitrophenol, 2,4-Dinitrophenol or DNP -- people that had been on the bodybuilding role would know of this. This was a chemical, if you will, that was used in French munitions. It's like 40% or something like that. It was used in their ammunition during World War I. So, that was a while ago. I think what they observed was the munition's employees were probably losing weight, quite honestly, is what happened.

    But because of this, they started doing some experiments and DNP is a potent mitochondrial -- this is my favorite topic. I love this topic of uncoupling. Anyhow, it's a potent mitochondrial uncoupler. If you could picture like a horizontal wall and -- no, let's just say it's the scale, the balance scale. So, on the one scale you have ATP synthesis. On the other scale, you have protons being allowed into the matrix. This has to be in balance.

    You can't have too much ATP production and you don't want to have too many protons leaking through via uncoupling channels or mechanisms. When they go through and they make ATP, it turns out it's energy. When they come through in the protonophores, the uncoupling proteins, it turns out as heat. Or thermogenesis. It turns out as heat.

    So, you need a little bit of both. If you don't make ATP, you're screwed. It turns out, this chronic conditions, they're making too much ATP and there's not enough being let through and they may benefit from this therapeutic uncoupling but DNP, used in World War I, it seems like a magic drug, quite honestly but it had one problem. That problem was fatalities.

    DNP, if you follow this, is an uncoupler. What happens is it uncouples, I think it's a slightly acidic lipophilic -- I forget exactly. But it allows protons through in the inner mitochondrial membrane, and in so doing generates heat and increases the metabolic rate. And here's what this early studies done in the 30s found. It sounds magic. When used in the right dose, you, if you were taking this, would experience a little bit of warmth, maybe a little bit of sweating.

    Your metabolic rate would go up about 20% to 30% within the first hour of taking it and stay elevated for about 24 hours. You didn't excrete any extra nitrogen in your urine so you weren't catabolic. Any weight loss that you had was purely from fat. And supposedly like a 100,000 people used DNP for weight loss and obesity around 1930, mid 1930s. It has an extremely tight therapeutic window that if you exceed that -- and what happened was physicians started using this. They didn't know how to dose. People were dying and then DNP was banned in 1938.

[1:05:04]

    It's still, I mean, potentially available. I don't recommend using it but when you talk about those mechanisms when used properly was kind of magical. Interestingly, in some recent studies, they're revisiting DNP, which is banned, but available, I suppose, for research purposes. They're looking at it in this idea of therapeutic uncoupling.

    Just to quickly summarize, there was a mouse study where diabetes and fatty liver was reversed by using -- it was a sustained release, time-controlled DNP. They're looking DNP and therapeutic uncoupling. I say DNP because it's the most potent uncoupler that they know. There's a couple of interesting and anthelmintic drug, anti-parasatic drug that is an uncoupler. There are some other ones that are--

    DNP is the gold standard for uncoupling. They're looking at this therapeutic uncoupling, potentially using DNP, for neurodegenerative diseases, for things like diabetes and fatty liver, as a cardioprotective mechanism. And so it seems that many of the chronic conditions -- this is summarizing some of the things that we've talked about -- that many of these chronic diseases of modern times, diabetes and heart disease and neurodegenerative diseases, are characterized by a hyperpolarized inner mitochondrial membrane where we're making too much ATP, and as we already talked about, too many oxidative stress, reactive oxygen species, free radicals, electrophiles.

    And that there may be some benefit to this therapeutic and taking -- and they always look for drugs in science. What kind of drugs can we develop that can cause uncoupling safer than DNP did with its therapeutic, really tight therapeutic window and very quick toxicity and death? The initial studies are really, really compelling.

    So then, of course, then the question is what can we do potentially naturally? And that's not as well studied but I'll just give you -- I don't hide actually much of anything. I believe that life is too short and you have to be transparent and honest with people. I don't want to divulge too much. This is just a really, really compelling area for me and I'm going to give you a quick example.

    Curcumin, it turns out, is far more potent than DNP at mitochondrial uncoupling. Even at a lower dose than DNP. So, DNP is the gold standard. Everybody knows DNP is a mitochondrial uncoupler since the 30s, even before they even knew how the mitochondria really worked. But curcumin is an even more potent mitochondrial uncoupler than DNP even at lower doses.

    However, and here's the thing, here's the rub, the dose required -- so, let's say, to be a mitochondrial uncoupler you have to get about 25 micrograms of curcumin inside of a cell. The studies looking at the bioavailability of all the nano particle, liposomal micellized different forms of curcumin, to get that level of curcumin into the cell, you need 25,000 nanograms per milliliter in the blood.

    The problem is most of the studies looking at the best most bioavailable forms of curcumin is usually in the neighborhood of about 100 nanograms per milliliter. We need to get that to 25,000 nanograms per milliliter to get that amount of curcumin inside of the cell to potentially act as an uncoupler. Anyhow, there's going to be a big search, I think, for some natural compounds that might be used as an uncoupling agent for the mitochondria for all these conditions of modern times.

Christopher:    As you were speaking I realize I've got the perfect analogy for the uncoupling protein. It is, of course, a clutch. I saw Professor Richard Feinman, who is also a previous podcast guest, present on his research on uncoupling proteins in cancer. And he presented this cartoon that is available on the web. I'll link it in the show notes. It's a fantastic cartoon. I believe it's been drawn by his wife.

    It's of Richard sitting on what looks like a tractor and then the uncoupling protein is the clutch. You think about it. You engage the clutch. You disengage the engine from the wheels that are causing motion. And so what are you then? You will generate a lot of heat, a lot of noise, but you don't go anywhere. You're not making any ATP. Actually, the German word for clutch, I won't try and pronounce it, but it's spelled K-U-P-P-L-U-N-G. it's the German word for clutch is coupling or looks like that, anyway.

Bryan:    Interesting. The trick is balance. Not everybody would benefit from mitochondrial uncoupling but there's a number of conditions that seem, in the modern ones, that seems like it might. If you uncouple too much you don't make ATP and that's a problem. If you don't do any uncoupling then that's also a problem.

[1:09:59]

    But it seems that what we might be suffering from is a lack of uncoupling and, therefore, there may be some clinical benefit for certain people to try to do, use therapeutic uncoupling.

Christopher:    Well, Bryan, I feel like I've milked you long enough for everything you know on the mitochondria. I know that we're really just scratching the surface here. Quite often people email me and they ask me how did you what you did? How did you transition from being a computer programmer at a hedge fund into health and fitness and start NBT? How did you even have the knowledge to start working with clients?

    The answer is I did Bryan's courses. They're available at Metabolic Fitness Pro. That's mostly all you need to do, which I think is quite incredible. If people want to know more about the mitochondria, why they're important, the symptoms, the test that you can use to assess mitochondrial function, the things that you can do for the people that you're working with, I would highly recommend Bryan's new course.

    It's Bryan standing in front of a white board for over 16 hours, which is one of my favorite things to watch. It's become a familiar sound in our living room. I think even my four-year old daughter knows who you are, Bryan. He's become that familiar. It's absolutely fantastic. I really enjoy that. One of the things I enjoyed the most was you talking about organic acids.

    When you started talking about the Great Plains organic acids test, I was like, "Yes, finally, Bryan is talking about organic acids." I've been waiting for years for this moment. I know you're just scratching the surface on that test but still it's a start and I'm really, really excited about that. I'm not sure I did a very good job of summarizing your course. Would you like to tell us about your course?

Bryan:    Well, you said it. I mean, I'd rather what your take on it was. It's called Everything You Wanted to Know About the Mitochondria because it's not everything there is to know about it. It's everything you want to know about it from a clinical perspective. As with anything, I try to take people through the journey. So, what is it? How does it function properly in the first place? Why is this thing called the electron transport chain and how does it work and the mitochondrial permeability transition pore?

    So, just all the pieces. And to even the lay person, if they're watching, they pay attention, they might have to rewind it a couple of times, but that they understand how it works. Because then when you know how it works the dysfunction becomes really easy. I talk about -- I forget how many hours it was -- but this whole antioxidant thing and how, what we're doing is probably wrong and the new terminology and I flash upon how many papers throughout this whole course showing people where I got this information from, talking about how to assess the mitochondria, signs and symptoms to look for, what tests.

    And again, going to the science, what does the science actually say? There's a lot of people saying, well, here's how you test the mitochondria and it's wrong, according to what the greatest researchers on this topic are actually saying. Like you said, it's 16 hours, which is one of the longest courses, advanced courses I've ever done. That's a lot but my goal was to live up to the name and everything you ever wanted to know about it. Yeah, I don't know if that's summary.

    Everything from what it is to how it works to what can go wrong to how to assess for it to what to do, therapeutic mitophagy, therapeutic uncoupling, what the studies show, the vitamin K-vitamin C thing, some really cool stuff in there, how the viruses and bacteria affect, how it's involved in the immune system, basically. So that when you're done you don't have a whole lot of questions left.

Christopher:    I think the greatest testimonial to the course, actually, is that email that you shared with me from Eric Hinkle. I read it very carefully and the thing that really struck me about that email from Eric was the depth of the investigation that he had obviously done for his client. It was mind-blowing. Who's doing that? You go and see a busy primary care doctor in Santa Cruz, they are not doing that level of investigation.

    And it's not that they can't do it. It's just that they don't have time to do it. They're just frazzled and burned out and seven-minute appointments and all of that. And then you look and see what Eric is doing. I tried to find out who Eric was. I Googled his name. I couldn't even find a website. I don't know what type of practitioner he is. But, man, I want that guy on my team.

Bryan:    Well, it was an example of somebody that really took the information and used it. Here's the thing -- and this is not being really humble about this -- potentially able to help that client in a way that he wasn't able to before. If you go back to what I said in the beginning, mitochondrial diseased patient will see an average of eight practitioners before being diagnosed. What about people with mitochondrial dysfunction, that it's not an overt disease that something's going wrong? I mean, how many years will pass before somebody identifies what's actually going on? And in people that identified, it's a game changer. They can change these people's life.

Christopher:    I think it's just a matter of time before I hear from somebody who, "Oh, my husband has chronic fatigue syndrome. We've seen 17 doctors in the UK and I did Bryan's mito course and we tried this, this, and that and, sure enough, it worked." I can't say that I've heard from that person yet but I feel like it's only a matter of time before I hear from them.

[1:15:03]

Bryan:    I'll give you a quick tip too. If exercise intolerance existed early on in life, that's a real quick potential mitochondrial issue.

Christopher:    Yeah, absolutely. Okay. So, tell people where they can find the course.

Bryan:    No, you said it. So, metabolicfitnesspro.com. Just go to courses and advanced modules and it should be there. I was going to say too that you and I go back aways and your listeners mean a lot to me. For people that purchased this course, for seven days from when this is published or posted, I'm going to do something that I've never, truly never done before and I may never do again depending on how it goes.

    For anybody that buys the mitochondrial course in the seven days after this podcast is posted, then I'm going to do four weekly Q&A calls, I guess, Zoom calls recorded but people can be on where anything and everything that somebody wants to ask, whether it's about the course or about labs or about case studies or just about anything, that they will get to be on the email list for about a month and we'll see how it goes. But make myself 1000% available to people's questions and answers for people that buy within seven days.

Christopher:    That's amazing. I will, of course, link the course in the show notes. Tell me though, for people who have already bought the course -- I think I found out about the course early because I bought one of your previous metabolic fitness pro training courses, and so I got an email. I bought the course. I didn't get a discount on it. I paid for it and did it and I really enjoyed it. Will I get access to that workshop that you just mentioned?

Bryan:    Maybe. I'll have to think about it. The benefit was for people -- that was for customers only. I will consider that. That's putting me on the spot, you realize. I will consider that.

Christopher:    Okay. Well, this has been fantastic, Bryan. Is there anything else that you'd want people to know about?

Bryan:    Probably, but no. I think that's good for now.

Christopher:    Okay.

Bryan:    Just to be happy. Happy is what you have because life is good.

Christopher:    It's not very difficult for me at the moment. I've got a six-month old boy. He's just the most amazing thing in the world. And my daughter, my four-year-old daughter is also a constant source of happiness. It's not very difficult for me to be happy.

Bryan:    No. Kids make it easy.

Christopher:    Exactly. Well, thank you so much, Bryan. This has been fantastic.

Bryan:    Great. Thanks, Chris.

[1:17:22]    End of Audio

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