Energy, Fatigue and the Gut with Ari Whitten

Welcome to The Perfect Stool: Understanding and Healing the Gut Microbiome. This is your host, Lindsey Parsons. And today I'm talking with Ari Whitten, founder of the Energy Blueprint, energy and fatigue specialist, and bestselling author. He's been studying nutrition and holistic health for more than 2 decades, has a Bachelor of Science from San Diego State University in kinesiology with a specialization in fitness nutrition. Nutrition and health. In addition, he recently completed the 3 years of coursework for his PhD in clinical psychology. Ari is a tireless researcher who has obsessively devoted the last 20 years of his life to the pursuit of being on the cutting edge of the science on health and energy enhancement. But before our conversation, if you haven't yet followed or subscribed to the show, be sure to do so. And if you want to get transcripts of the podcast, pop over to my website, HighDesertHealthCoaching.com, and sign up for my newsletter. You'll also get my free ebooklet, Finding Your Root Cause Through Stool and Organic Acids Testing, when you sign up.. And if you haven't yet done my quiz on which stool test would help you get to the root cause of your issues, you can find a link in the show notes and take that. Now on to the show. Welcome to the podcast, Ari.

Thank you so much for having me. It's a pleasure to be here.

Yeah, thank you so much for coming on. So you first caught my eye when I saw a conference presentation where you were debunking the concept of adrenal fatigue after an extensive study of the literature. And we can get back to talking about that at the end, but first, Since you're the energy and mitochondria expert, why don't we start by talking about what the mitochondria are and how they relate to gut health?

Sure. Okay. So where to begin? It's a big question. So a lot of my work centers around mitochondrial health, and that relates to some extent to the, to the thing you just mentioned about adrenal fatigue in the sense that I spent many years indoctrinated into the adrenal fatigue paradigm and was a big proponent of it and was totally convinced that that was true. And eventually, through looking at the literature on that— and we can talk about this in depth at some point if you, if you'd like— came to an understanding that adrenal fatigue is actually not a thing and is certainly not the central thing in the case of chronic fatigue. And I'm happy to again talk specifics of why I make those claims. They might seem like bold claims to some people listening, given that there are so many people who are promoting the idea that it is adrenal fatigue and that adrenal fatigue is real and that it is the central thing in chronic fatigue and sort of stress-related fatigue and burnout. And then after realizing that, I myself was quite confused because that was in my mind too, the central thing to chronic fatigue. So if it's not, if the science doesn't support adrenal fatigue is the central driver of chronic fatigue, then what the heck is? And it was largely due to the work of Robert Naviaux, who is an MD PhD who runs a lab for mitochondrial medicine at the University of California San Diego, that I started to develop a new paradigm, a new understanding of what is really the thing in our body that is the most upstream, that is actually regulating and controlling human energy levels in the sense of this deciding whether we have low energy and we're chronically fatigued, or whether we have abundant energy like we do as children. And the, the main finding, which is a pretty revolutionary, I think, biology-shaking new paradigm around mitochondria, is that mitochondria have a second role beyond their role in energy production. And for, for over 100 years, we've known about mitochondria. We all learned about them in high school and college biology classes as the powerhouse of the cell. And these are where the majority of our cellular energy comes from. And all of that is, is true. But what is not true is they're kind of talked about in biology courses as these sort of mindless energy generators that just take in carbs and fats and pump out energy in the form of ATP, adenosine triphosphate. And they are in fact energy generators, but they're far from mindless. It turns out that mitochondria are, in the words of Dr. Robert Naviaux, the central hub of the wheel of metabolism. They are basically like the canaries in the coal mine in our body. They are the most upstream, most sensitive organ in our body that is responsible for sensing signals from the environment about what's going on in the environment, what's going on in the body, and responding to those signals by coordinating metabolic and immune responses and energy responses to that. And, and basically deciding whether or not the mitochondria are going to operate in energy mode or defense mode, or as Dr. Robert Naviaux calls it, peacetime metabolism or wartime metabolism. And basically what this means, to simplify all of this, is that to the extent that your mitochondria are picking up on threats, on signals that are danger signals, that something is wrong in the body, and they have the ability to sense virtually every type of stressor imaginable, from pathogens like viral infections to psychological stress, to poor nutrition, to signals from the gut, to environmental toxicants, to sleep deprivation, to every type of stressor that you can imagine. They can pick up on those danger signals. And to the extent that they pick up on the— they're picking up on the presence of danger signals, they turn down the dial on energy production and shift resources towards cellular defense. So mitochondria are not just mindless energy generators that take in carbs and fats and pump out energy. They are exquisitely sensitive environmental sensors that are actually regulating human energy levels and deciding whether or not we should produce abundant energy or very little energy and shift resources towards cellular defense. And that is fundamentally the central thing. While, while there are many processes that in one way or another relate to energy levels— there are brain processes, there are neurotransmitters, there are hormones, there are all kinds of biochemical processes that indirectly, one way or another, impact on energy. The central most important thing is that our mitochondria are fundamentally regulating whether we have abundant energy or very little energy as a direct reflection of the degree to which they are sensing danger being present in the body.

Interesting. Okay, so tell me a story of how someone starts with a gut infection and this, impacts the mitochondria? Like, what's the, what's the sort of cascade of events?

Yeah, so there could be a number of potential events as far as how this plays out, but let's frame it this way. There are 3 central findings that are very common in people with chronic fatigue, especially chronic fatigue syndrome, as it relates to gut health. There's low microbial diversity in the gut, there's high endotoxin levels, endotoxin-producing or containing bacteria, bacterial species, and there's very low production of short-chain fatty acids and urolithins. So the bacterial species that are responsible for that are in short supply. So there is, in other words, a disturbance in the, in the gut microbiome. Now, that gut microbiome shift to, you could say, although these terms are kind of antiquated now, uh, you could say a bad or non-optimal microbial balance in that gut microbiome can occur for a variety of reasons that I'm sure you've talked about extensively on this podcast. Of course, poor nutrition, psychological stress, circadian rhythm and sleep disruption, environmental toxicants, antibiotic use and other drugs. Can all affect the microbiome diversity and balance. Poor nutrition is, of course, a major one for a huge portion of the population that's eating Standard American Diet or Standard Western Diet. So these kinds of microbial disturbances are widespread. And as a result of an imbalance in the gut microbiome, you can get a degradation of the mucous lining and you can get an increase in gut permeability. Once you have an increase in gut permeability, you, you then necessarily are going to experience a variety of problems. You're going to have undigested food particles that are now entering bloodstream. You're going to have higher levels of endotoxin from those endotoxin-containing bacteria in the gut leaking into the bloodstream, and the result of those things leads to a chronic low-level immune activation and low-grade inflammation response. Now, that, that response then ties back into what I was telling you about mitochondria before, which is the very presence of elevated levels of cytokines, inflammatory cytokines, is actually a danger signal. It is interpreted by mitochondria, is one of the key signals that mitochondria interpret as, uh-oh, there's danger present. We better shift out of peacetime metabolism into wartime metabolism. And that leads to mitochondria turning down the dial on energy production. So there's a very direct link between higher levels of inflammation, inflammatory cytokines, and low energy levels. And of course, anything that goes on in the gut that leads to low-grade inflammation, whether it's poor nutrition or antibiotic use or whatever the source was that led to poor microbiome balance, gut permeability, that is now being translated directly into poor mitochondrial function and mitochondrial shutdown and fatigue as a result, you know, basically being mediated by inflammation primarily.

So you're talking about endotoxins and low butyrate and essentially leaky gut. So I'm thinking about proteobacteria overgrowth and gram-negative bacteria and LPS. So can you talk a little bit about that?

Um, it— I, you know, the, the, the specific species of bacteria that have been seen in the context of chronic, chronic fatigue syndrome, there's a few things that have been known. There's not a huge abundance of scientific literature. We know that they have low levels of bifidobacteria and low levels of lactobacilli in the gut. Yes, we know that they have higher levels of bacteroides and proteobacteria. We also know there's actually some studies that have shown in people with chronic fatigue syndrome very exaggerated immune responses to endotoxins in the blood, which is indicative of them being exposed to high levels of, of endotoxin chronically as a result of this combination of factors. Beyond that, I'm not aware of any other specific research linking very specific species of bacteria to chronic fatigue in particular.

Okay.

But, but I—

but when you talk about endotoxin, that's coming exclusively from gram-negative bacteria that produce lipopolysaccharides, right?

Right.

Okay. So You know, how do lipopolysaccharides impact us?

So lipopolysaccharides do a couple of things. One is we know that, that what's called endotoxemia, which is basically high levels of LPS entering the bloodstream as a result of gut permeability, are linked with all kinds of metabolic dysfunction. This has been linked with neurological disease, cardiovascular disease, obesity, diabetes, fatty liver, and it's been linked with mitochondrial dysfunction directly. So the LPS does two things. It creates an immune and inflammatory response, which again, those signals are sensed by mitochondria and result in mitochondrial shutdown. And the LPS is also directly toxic to mitochondria and actually will damage mitochondria and cause mitochondrial dysfunction. So there's a couple different mechanisms by which that takes place.

And so I know there's a difference between, so, you know, like you can see on certain lab tests that I use, You can see when the mitochondria aren't working and producing very much energy, but then you can also see when they've completely collapsed. So can you talk about the difference between that?

You know, mitochondrial testing is challenging. There's a few different ways that we can test for mitochondria, mitochondrial function. You can do organic acid tests. There's a test called the mitoswab test. You can, depending on I mean, in research settings, they can do certain kinds of tests that are not widely available at the consumer level, or even at the— even available to doctors to test their patients. You can test for nutrient deficiencies. For example, carnitine deficiencies and CoQ10 deficiencies have been linked with chronic fatigue, and there's, there's, there's research where they've actually been able to identify those, those deficiencies. You can do that indirectly with organic acid testing. And, and so that can give some insight into that as well. But that kind of testing is limited in the sense that one, it, it's, it picks up more on mitochondrial dysfunction than it does, which is more like damp physical damage to the mitochondria and dysfunctioning mitochondria more so than it does mitochondrial shutdown. And to give you a, you know, clear distinction of the difference between those two things. If I am healthy today, as I am, but next week I have COVID or I have a flu or some kind of viral respiratory infection, I may have severe fatigue for a few days. And as I recently had COVID a couple of weeks ago, and in the context of that severe fatigue, that happens as a result of that acute viral infection, I don't have widespread mitochondrial dysfunction and damage throughout my body, but I do have mitochondrial shutdown. So there's a distinction between those two things. And I, I would argue that many of the tests are, are much better at picking up mitochondrial dysfunction than shutdown. Now there's one more critical aspect of this One of the types of testing that is done in certain research settings, but is not widely available to consumers, but I would argue is really important, is actually muscle biopsies. They stick a big hollow needle into your muscle, usually your quadricep muscle. They pull out a chunk of tissue and they look at it under a microscope. And we know from that kind of research, when they pull out those muscle biopsies from 20-year-olds, 30-year-olds, 40-year-olds, 60-year-olds, and 70-year-olds, there are massive differences in the number of mitochondria per cell. So we know that on average, the typical 70-year-old has about half of the number of mitochondria per cell that a young adult does. And the mitochondria that are present only have about 50% of the energy-producing capacity of a young person. So those are things that won't be picked up on things like the mito, mito swab test or the organic acids test. Or, you know, there's also another test out of, uh, from some chronic fatigue researchers out of the UK called the ATP profile test. You're not going to find those kinds of results without doing a muscle biopsy. Now, I should mention also that, you know, for people maybe who heard what I just said, they might think, oh my gosh, this is terrible news that we lose so much of our mitochondria as a result of, you know, as a result of aging, basically. But we also know that when we look at 70-year-olds who are lifelong exercisers, and athletes, that they actually have the same mitochondrial capacity as a young person. So the loss of mitochondrial capacity is actually not a normal product of the aging process per se. It is actually the result of loss of hormetic stress in the modern lifestyle, lack of, of metabolic stress, exercise, and other types of hormetic stressors, which is a whole topic we could go into if you want. But Anyway, to get back to answering your question, mitochondrial tests like organic acid tests, mitoswab tests are fine. They're useful, but they definitely don't tell the full picture of mitochondrial health.

Okay. And yeah, no, so, so the hormetic stressor, did you do a long video about hormetic stressors?

Oh yeah, many.

Okay. Maybe it was yours. I can't even remember because it was one of these videos that I saw way before I got into this stuff professionally. But I remember it pretty distinctly about all the different hormetic stressors that can help develop your mitochondria and increase your mitochondria. So yeah, let's talk a little bit about that.

Yeah, that sounds like me. I remember 10 years ago when I used to say the word hormesis and hormetic stress to a lot of my friends who are functional medicine doctors, and they used to give me a funny look. They'd never heard of the word and they didn't know what the hell I was talking about. And I thought I was crazy. And now everybody is aware of hormetic stress, which I'm both happy about and not happy about. Happy about it in the sense that it's important and people should know it. And at the same time, I kind of enjoyed it being my unique shtick that no one else was talking about. But yeah, so the importance of this to mitochondria basically is what I was just explaining. It's important to understand that our mitochondria, the health of our mitochondria and the physical size of our mitochondria and the number of mitochondria that we have per cell are all critically dependent on the degree to which we are engaging in hormetic stress in our lifestyle. Hormetic stress is transient metabolic stress that stimulates adaptations in the body that, that confer greater resistance to a broad range of other stressors. And ultimately that translates into a number of beneficial adaptations that help lower our risk of numerous different diseases, all the major killers like cardiovascular disease and cancer and neurological disease and many others, and also make us more resilient in the face of stress. And by virtue of the adaptations that they're stimulating at the mitochondrial level, which is really the sort of the central thing going on in hormetic stress. We, we build our cellular engine, we build our energy-producing capacity at the cellular level. And this is the difference between somebody who has a big, strong, healthy cellular engine or a very weak one. Do you have a moped engine in your cells or do you have a Ferrari engine? That is entirely dependent on the degree to which you are regularly engaging in hormetic stress and hormetic stressors. To be specific, I mentioned exercise, exer— there's many different subtypes of exercise. So resistance exercise, steady-state endurance exercise, and then high-intensity interval training and sprint interval training. And all of these really are distinct categories that have their their own unique sort of fingerprint of adaptations that they're stimulating that are different from one another. Other types of hormetic stressors are heat and cold, fasting, hypoxia, low oxygen states, so breath-holding practices. There's different types of chemical hormetic stressors. There are things like methylene blue, for example. And then there's xenohormetic stressors. Actually, I'll also mention light, different kinds of light therapy like red and near-infrared light, as well as ultraviolet light are hormetic stressors. And there's xenohormetic stressors or xenohormetans, which are phytochemicals sometimes referred to as exercise mimetics because they stimulate some of the same hormetic pathways as exercise does. And certain phytochemicals like sulforaphane and curcumin and resveratrol and pterostilbene and, and many others act as hormetic stressors as well. So all of these, right, regularly engaging in some variety of the hormetic stressors that I just mentioned is not just optimal for mitochondrial health, it, it is actually necessary to maintain mitochondria in the same way that If you break a bone, you break an arm or a leg and you get a cast on that arm or the leg. And then 8 weeks later you get the cast off, you look down at your arm or your leg and you'll know this if this has ever happened to you or if it's happened to a child or a friend of yours. You look down at your arm or your leg, it's half the size as the other one. And that happens, that atrophy, that loss of that muscle tissue happens because The body is ruthless about getting rid of any tissue, especially energetically costly tissue that is not needed for survival. So as soon as your muscle is immobilized in a cast, the body goes, oh, I guess we don't need that for survival anymore. Let's get rid of it. And that cutting down of that muscle tissue to half the size as the other limb happens literally in the span of 2 months. Now, that same exact process, that same exact principle is happening internally at the cellular level, at the mitochondrial level, where if you are not using your mitochondria, if you're not challenging them and stimulating them through hormetic stress, they atrophy. They literally shrink and shrivel and die off, and you lose your mitochondria as a result of the body basically sensing that they're not needed. Because you live a typical modern lifestyle that is largely devoid of hormetic stress. So this is— this aspect of loss of mitochondria is, in my mind, one of the, the biggest contributors to the modern disease epidemic. And it's something that is, in my opinion, hugely— is little known and hugely underappreciated within within the natural health and functional medicine communities that are just not talking about the difference between a body that is full of big, strong, robust mitochondria or a body that's lost 50 or 75% of its energy-producing capacity. There is a massive difference. This is a central driver of chronic disease and especially chronic fatigue.

Excuse this brief interruption, but I wanted to remind you that if you've been struggling with IBS, IBD, reflux, gastritis, SIBO, dysbiosis, Candida, diarrhea, constipation, and all that gut health stuff, that's my specialty. So I work with clients not just here in Tucson, Arizona, where I live, but also virtually on video chat. And I offer single appointments as well as a 5-session gut health program for people with tougher gut health issues. Or mental health or autoimmune challenges that go along with that, who likely require testing and longer-term follow-up, as well as 12-week programs for weight loss. If you think that a 5-session or longer course of health coaching might help you meet your health goals, you can set up a free 30-minute breakthrough session with me to talk about what you've been going through, and I'll listen and hear if it sounds like I have something in my toolkit that you haven't already tried and let you know if I think that health coaching would be appropriate for you. You can find a link for that in the show notes, and I hope to hear from you. So if someone is suffering from chronic fatigue or fatigue of any type, would you first start with some gut testing to see if that was a factor? Like, what's the first step in, in reversing it?

Not everybody with chronic fatigue has gut issues, so it is, it is certainly the case that a subset of people with chronic fatigue has gut issues. And it's certainly the case that a certain subset of people with chronic fatigue, their primary number one issue, causal issue, is a gut problem that then caused that fatigue. And that's, you can say that's the primary cause of their issue. But it's certainly the case that there are lots of people running around with low energy levels, or not running around, I should say walking around, or laying around or lying in bed. Yeah, exactly. Who have really no significant gut problems at all. And I shouldn't maybe go quite to that extreme because as soon as other systems of the body dysfunction, you're likely to have at least some degree of gut dysfunction. But I would only start with gut, you know, a gut-specific intervention in the case of someone who is really like, has very clear gut-related symptoms. They're complaining of abdominal, you know, GI distress, abdominal pain, bloating, digestive difficulties, or fatigue after meals specifically. In cases like that, I would certainly, you know, start with, with trying to address gut health.

Okay. And then after you've addressed— so assuming gut health, I probably the same root causes as everything else in functional medicine, right? Your toxins, your molds, your— these types of things are root cause issues. Are there, are there others that I'm not thinking about?

Yeah, certainly. Um, poor nutrition is a major cause. Circadian rhythm disruption and sleep disruption, I would say that, and, and, and poor nutrition and psychological stress are probably the 3 most common contributors to chronic fatigue. When you're talking chronic fatigue syndrome specifically, which is differentiated from sort of a more general state of chronic fatigue, basically just by severity. And by it's there, there are no blood tests or any other tests that can tell you if you have chronic fatigue syndrome. It's based on symptoms and specifically the presence of a severe fatigue lasting 6 months or longer and the presence of something called post-exertional malaise, which is a symptom that after any sort of physical exertion, people might be really exhausted for 2 or 3 days following that. Exactly. And so if, if you're in that state, you can say you have chronic fatigue syndrome. Uh, but in more general states of fatigue that are way more common, that affect, you know, 50 to 100 times more people than chronic fatigue syndrome, you're, you're looking at more, more things like poor nutrition, circadian rhythm disruption, and sleep deprivation, low-level sleep deprivation, and psychological stress and lack of hormetic stress as the biggest contributors to that.

Yeah. One of my basic questions when I am interviewing new clients is, how do you feel after you exercise? And if they say, I feel energized, I'm like, okay, good. Yeah. So is there any distinction between the types of gut dysbiosis and how they most impact energy, like Candida versus parasites or H. pylori or just general bacterial dysbiosis or SIBO?

You know, we just don't have the research to make those kinds of determinations. So where, where somebody has gut-specific issues, you know, they, they need to work with a gut specialist like yourself to resolve that. But as far as, you know, an established body of research linked like with that level of specificity linking specific kinds of gut issues with chronic fatigue, that, that research just doesn't exist as of right now.

Okay, fair enough. So let's get back to the whole adrenal fatigue question and, and tell me a little bit more about what they used to think that was and, and what you found in your research. Yeah. Okay.

So just a general overview of what adrenal fatigue, what the adrenal fatigue hypothesis is. Basically, the idea is that our adrenal glands are glands that are involved in the stress response, and they produce a hormone called cortisol, which is produced in response to stress and has a variety of functions, but is involved in, for example, like the release of blood sugar from the liver and from the muscles to help regulate blood sugar levels in response to stress. Uh, it has other roles like anti-inflammatory effects and various other things. And that gets very complex when we talk about it in chronic picture. But the gist of it is it's a hormone that is important in the stress response. And the idea was that with adrenal fatigue is that with chronic— sort of that, that system is meant for acute stress. And with chronic stress, it eventually taxes the adrenal glands and taxes them and taxes them and taxes them. Over a very long period of time chronically. And as a result of that, they get worn out and they stop producing enough cortisol to meet the body's demands. The more— there are several versions of this. Some people say there's 8 phases or 7 phases. Some people say there's 3 phases. There's various models that have been put out there, uh, I should mention, none of which have been scientifically validated, but they are impressive looking. When you look at these fancy models, they seem very sciency. And the idea is that there's an acute phase where stress sort of taxes the adrenals excessively. Then you have high cortisol levels. Then you go back down, you start to go down, and then maybe at some point you're in a middle phase where your cortisol levels are technically like maybe within a normal range. And then, but that's just a phase. It's like phase 2 adrenal fatigue. And then you're headed further down into phase 3 adrenal burnout, at which point you have low cortisol levels. All of this sounds reasonably logical and plausible. Uh, the, the problem with it is that it's completely unsupported by the scientific literature. And what I'm saying is actually not a radical position. It only is perceived to be a radical position in some alternative health circles, but actually within— and I should mention, I'm aligned with the natural health and functional medicine movements, but this is one area where I feel they've gotten things wrong historically. If you look within conventional medicine among endocrinologists, there's a huge body that represents 14,000 endocrinologists MDs. These are hormone specialists, and they came out many years ago and said— this is— I'm going off the top of my head, but it's almost a direct quote— there is no evidence to support the idea that the adrenal glands get worn out as a result of chronic stress of any type, resulting in low cortisol levels and resulting in many common symptoms like fatigue. They literally said there is no evidence to support this theory. And ironically, I got interested in exploring the research on this because I was so pissed off by conventional medicine brushing off adrenal fatigue. I was absolutely convinced that adrenal fatigue was a real thing, and I wanted to stick it to them. And my plan was basically to go into the scientific literature and then compile all the research showing that it is legitimate and science-based. And then I was going to write a book basically on the scientific basis of adrenal fatigue. And what I found when I started to explore that, that issue, the research on that topic was something that shocked me because I had read thousands of articles and books written by people I really respected talking about adrenal fatigue. So of course, I was absolutely convinced it was totally real. But the first big red flag was that I went on PubMed and typed in adrenal fatigue to, to find any research that has been done on that medical condition. Because if you, if you do that with any medical condition, I, even the most obscure random medical condition you can find, like some rare genetic disorder or something that affects 2 out of every 100 million people, You're— if you type that in, you're going to find at least dozens, if not hundreds or thousands of studies. You type in adrenal fatigue, you find almost nothing. So that first was, was quite confusing, quite, um, shocking to me. Why, why, why is there no research on this medical condition whatsoever? So then it took me a while to even figure out how to find any research that would be relevant to evaluating the adrenal fatigue hypothesis. And eventually— and I'm kind of, I'm condensing about a year of my life that I dedicated to this topic into a 5-minute segment here— but eventually, after several weeks of kind of digging around, I started to find bodies of research that did exist that were relevant to this. So there are several other fatigue syndromes that are largely synonymous with the basic idea of adrenal fatigue, only without positing that it's specifically the adrenals and cortisol that are causing it, that, that do exist, that are accepted medical conditions. So one is called clinical burnout, one is called burnout syndrome, one's called vital exhaustion, one is called stress-related exhaustion disorder. And there's also, of course, chronic fatigue syndrome that's in this mix as well. And when I started to look up those terms and HPA axis or cortisol, then I started to find bodies of literature. And in fact, there's, there's been dozens of studies that have, that have tested adrenal function, cortisol levels, and HPA axis function more broadly, hypothalamic-pituitary-adrenal axis function in people with these accepted kinds of fatigue syndromes. And the majority of those studies, and they've been done for over 25 years all over the world. So the majority of those studies, basically, I would say 90% of them, basically just take people with that fatigue syndrome, whether it's chronic fatigue syndrome or stress-related exhaustion disorder or burnout syndrome or whatever. And they analyze their cortisol levels and adrenal function, or do other tests like dexamethasone suppression test to assess, uh, HPA axis function more broadly in the people with the fatigue syndrome. And they compare it to demographic-matched people without fatigue. Same age and sex and gender and controlling for smoking and exercise habits and all these other kinds of things. So the vast majority of the tests basically do that. And over the last 25 years, there have been 59 individual studies by researchers all over the world that have done these kinds of tests. There's another 20 literature reviews, systematic reviews, which is considered the highest level of scientific evidence, uh, that has been done on a lot of these specific subcategories that I mentioned. So for example, researchers will do a systematic review on all the studies looking at cortisol levels in people specifically with chronic fatigue syndrome, or specifically with burnout syndrome, or specifically with stress-related exhaustion disorder. So there's 20 of those, but of the 59 individual studies Here's how they break down. 15 of them gave evidence for lower morning cortisol levels in the group with fatigue compared to those without fatigue. Okay. And, and this isn't even abnormal cortisol levels. We're still within the range of normal on average, but it's slightly lower than the group that was healthy. Another 11 of those 59 studies found the opposite finding, slightly higher cortisol levels associated with the fatigue syndrome. And 33 of the 59 studies found no detectable difference whatsoever in cortisol levels between the group with fatigue and those without. So the, of this body of evidence, this is what I was left with after I spent a year of my life digging into the research and analyzing all these studies, um, I was left with a body of evidence where the bulk of the research clearly is indicating there is no discernible HPA axis function or cortisol abnormality that is even present in people with chronic fatigue, let alone, let alone any sort of scientific case that is compelling to believe that that is the central cause of those symptoms.

But isn't it possible that some people's chronic fatigue or fatigue could be caused by adrenal-related issues and some people's not, and therefore it comes out in the wash in a study because some might be mitochondria-related?

Sure. So for example, you can have Addison's disease and in the context of Addison's disease, one of the symptoms will be fatigue. So there are, there are many different conditions that, that one could have that will cause fatigue. And there's, there is a very small portion of people who have Addison's disease and that is the central cause of their chronic fatigue. It is also possible to have HPA axis dysfunction. That is, it is a real thing. Like HPA axis dysfunction does exist.. And it is possible to have totally dysregulated cortisol levels or even chronically low cortisol levels. If it's very low cortisol levels, it's probably Addison's disease, but it is, it is absolutely possible to have that. It is also the case that this is present based on 25 years of studies from all over the world. It's, this is present to such a small degree in such a small subset of the people who, of, of the bulk of the people who have chronic fatigue. That it is clearly not any kind of central feature of chronic fatigue, but it is, it is the case that it can be a contributor to fatigue in a small subset of people.

Okay. So that's good to know that, that, that there's still some, that it could be playing a role for some people because I do sometimes test people's adrenals personally, just because, you know, if they tell me they're drinking tons of coffee or they're having trouble sleeping or they wake up and they feel like they're still asleep. For a couple of hours, that's when I think, okay, there may be some dysregulation here. So what could you or would you do in cases like that?

So I would say that it's really important to still understand paradigmatically what is going on here, because what you don't want to do is say, well, because HPA axis is a thing, I still believe in adrenal fatigue. And yes, this adrenal fatigue thing still is going on in some subset of people. So one other aspect of research that I, that I spent a lot of time analyzing is the question of, does chronic stress result in low cortisol levels? So if we look at people under various kinds of extreme chronic stress, for very long periods of time, do they have low cortisol levels? Now, on average, if, if you were to compare people who have years or decades-long chronic psychological stress, for example, and compare them to people with less psychological stress, what you would expect to find, if the adrenal fatigue hypothesis had any legitimacy whatsoever, is that on average, the people under chronic years or decades-long stress should have at the very least slightly lower cortisol levels on average, based on the fact that at least some subset of those people will have adrenal fatigue or adrenal burnout, right? This is, this is basically science 101. Now, those studies exist. There are huge bodies of literature that have examined relationship of chronic stressors of all kinds of types, from numerous different kinds of psychological stress, relationship stress, financial stress, job stress. They've looked at physical stressors like physical over-exercise, overtraining syndrome in athletes. They've looked at metabolic stressors, chronic cigarette smoking, chronic alcoholism. They've looked at all kinds of like— Even, even you could say in many natural health functional medicine models, they'll look at allostatic mode. So like, they'll even consider a disease state to be a chronic stressor. Like somebody who has obesity and diabetes, that is a metabolic stressor. Clearly, the high blood sugar levels, chronic hyperglycemia, and high blood lipids and metabolic syndrome is itself a type of metabolic stress that we know causes lots of cell damage. So we can look at any type of stressor that you can think of, and we can analyze the people with the, the most chronic, most severe version of that. They've even broken it down into, are you a heavy cigarette smoker or a light cigarette smoker? Are you a heavy drinker or are you a light drinker versus a non-drinker, right? Those studies exist, and what those studies find, pretty much without exception, every type of stressor that you can think of, the people with the chronic stress actually have on average slightly higher cortisol levels. That body of evidence, and it's a huge body of evidence, gives no support whatsoever to the idea that adrenal fatigue is a real thing, to the idea that there is ever a point where chronic stress is wearing out the adrenal's capacity to produce cortisol. Now, so, so given that, we then need to ask, well then why is there a subset of people who do seem to have low cortisol levels or at least low morning cortisol levels? And I'll tell you one thing that is, that is very strongly supported in the literature as far as a major cause of that. And it's simply two things. One, circadian rhythm and sleep disruption, and two, being a night owl chronotype. There are studies where they've simply looked at normal, healthy people, not even people with any disease state or fatigue or anything like that, just normal, healthy people. You're either a morning person or a morning chronotype, I should say, or a night owl chronotype. And when they look at cortisol levels in those two different chronotypes, they find that typically the night owls have about half of the morning cortisol levels. Of a morning person. This is no small effect. This is a massive effect. Um, and again, these are people without fatigue, without any symptoms. But if that night owl walked into the office of somebody who is an adrenal fatigue proponent, they would walk out with a diagnosis of adrenal fatigue, and they would be told the whole narrative about how chronic stress has worn out their adrenal's capacity to produce enough cortisol. And that whole narrative is completely unsupported by the scientific evidence, But we do know that things like circadian rhythm and sleep deprivation and being simply being a night owl do have a massive impact on, on your levels of cortisol. And there are a number of other potential causes of that as well. Certain prescription drugs can lower cortisol levels or toxins can lower it. But yeah, anyway, that's a bit of a digression.

Okay. No, that was really interesting and amazingly detailed and articulate. So thank you. So what about secretory IgA? Any relationship between that and the adrenals?

I would say that's outside of, of the literature that I looked at, so I, I can't speak to that.

Okay, because I do, I, I do certainly hear from some of my mentors, you know, the idea that high stress can lead to a decrease in secretory IgA, which is your gut mucosal immune system and therefore lead to gut infections.

Yeah, that's true.

Yeah.

I'm not aware of a link with adrenal function specifically, but I do know that chronic stress absolutely lowers secretory IgA.

Right. So the adrenals may not be the mediating factor, but either way, the stress can lead to that.

Yeah. Yeah, I don't know about how those things relate. I mean, it's possible that chronically elevated cortisol levels, which does occur with chronic stress, that that could certainly impact on secretory IgA. It impacts on a number of things. I mean, chronically elevated cortisol levels are not good for a big variety of reasons, immune function and gut permeability, and they— there's, you know, neurological function. There's a lot of negative effects from that.

Right.

Right.

Okay. So I know that you sell some supplements that are designed to help people bring up their energy or increase their mitochondria as well as for immune and brain support. So can you tell me a little bit about those? Sure.

So I have sort of two flag— three flagship formulas, I would say. One is a mitochondrial-specific formula and it's called Energenesis. One is a brain-specific formula. It's meant largely for mood support, and cognitive support and long-term brain health as distinct from like a short-acting nootropic that's full of lots of stimulants that you might get a short-term burst boost from, but is actually hurting you in the long run. And, and then I have a comprehensive multivitamin and multi-mineral supplement with actually real clinically effective dosages of those vitamins and minerals in the optimal form, for example, methylated B vitamins extracted from whole foods, along with a number of superfoods like spirulina and chlorella and things like that. So the mitochondrial formula has lots of good ingredients. It has sort of all the classic mitochondrial support ingredients that you might find recommended by a functional medicine practitioner, things like acetyl-L-carnitine and, and creatine and alpha-lipoic acid and CoQ10 and things like that. And magnesium. And it also has a variety of other really great compounds that are not typically recommended. So things like astaxanthin, which is a carotenoid pigment that comes from algae, that is, this is actually what gives salmon its pink color. Also what gives flamingos its pink color. This is a carotenoid that has a unique chemical structure to it, and it actually embeds itself in mitochondrial membranes where it stabilizes them and protects them from damage. It actually embeds itself across mitochondrial membranes, so both the outer and inner membrane. So really unique, hugely beneficial compound supported by lots of research. And another compound I'll mention is Shoden ashwagandha. And Shoden ashwagandha has a whole bunch of research showing that it improves sleep quality, improves resilience to, to stress and reduces anxiety levels. Increases energy levels in people with chronic fatigue. It's the most potent ashwagandha extract in terms of withanolides. Another compound that's in there is ellagic acid. And this is an interesting one that relates to gut health in the gut microbiome— sorry, the gut mitochondria axis, in the sense that ellagic acid is this compound that's found in significant quantities only in a few found in really minute quantities in a lot of different berries and things like that, but it's rich especially in pomegranate and chestnuts. And this ellagic acid is metabolized by certain bacteria in the, in the gut into a compound called urolithin A. And urolithin A, it turns out, is pretty much the most powerful promoter of mitophagy ever discovered. Mitophagy is basically like a quality control process of our mitochondria. Process where the body sort of identifies dysfunctional mitochondria and targets them for breakdown so that only the healthy mitochondria are reproducing and cloning themselves. And you're, you're only rebuilding healthy mitochondria and getting rid of the bad ones. Super important process, especially for preventing cancer and also of course chronic fatigue. So this urolithin A that comes from ellagic acid is critically important for doing that.

Let me stop for just a second because I was actually looking at a urolithin A supplement yesterday because I was reading an article that linked to it and I noticed it's not cheap. I think there's only one out there and it was like $200 for a bottle.

Exactly. Yeah. I've been trying to get it in one of my formulas for a long time now. It's been unavailable, but I think just a couple of weeks ago, my supplier let me know that they found a source for it. So it's just now becoming available. I think previously it was patented and only held by one company and they weren't releasing it to other supplement formulators. But it's interesting in the sense that there is research on supplementing directly with urolithin A and it's, it's pretty impressive research. The distinction between that and ellagic acid is not totally clear. As of right now, in the sense that it is possible that— well, let me put it this way. I looked into research to figure out what specific bacterial species is responsible for converting ellagic acid into urolithin A. And there's actually a study that I was able to find where they identified the specific bacterial species, and it was a really obscure species. I don't even remember what the name of it was because it's It's so uncommon. I've never heard of this species anywhere else. Now, having said that, so that sort of brings up the question of, well, maybe some people don't have that bacterial species and therefore can't convert ellagic acid into urolithin A. Nevertheless, I asked Kiran Krishnan, who's a friend of mine, who's a sort of world-renowned gut expert.

Microbiome Labs.

Yes. I asked him his thoughts on that and he kind of brushed it off and said, you know, the gut is, is pretty redundant. It's probably not just one species that does this. And there's probably many species that, that do this. He didn't seem to be particularly worried about the idea that someone might not have the capability to produce urolithin A. So yeah, it's, it's not totally clear if there would be a unique benefit of supplementing urolithin A over ellagic acid. I guess if, if it is the case that some people, some subset of people don't convert ellagic acid into urolithin A well, then they would benefit more from direct urolithin A supplementation. So yeah, those are a couple, a few compounds in Energenesis. And then I'll mention one more, which is a patented phospholipid extract called NT Factor. Phospholipid, and this has a ton of amazing research on it. I think this has got to be the most underrated and little-known supplement within the functional medicine community that, that has a ton of amazing research on it that people just don't even know about. And there's a great paper by a researcher named Garth Nicholson called Lipid Replacement Therapy, where they have studied this NT factor phospholipid compound in the context of numerous different kinds of chronic fatigue. Chronic fatigue syndrome, there's several studies, obesity-related chronic fatigue, aging-associated chronic fatigue, just, you know, people who have fatigue in old age and other types of chronic fatigue like Gulf War illness and things like that. And across the board, every study that's been done on this has shown at least 25%, if not closer to 45%, increases in energy levels between 4 to 12 weeks of just using this one compound. So it's a pretty amazing compound. It's been shown also in people in older age to restore their mitochondrial health, mitochondrial function to that of healthy 29-year-olds.

What's it called again?

It's called NT Factor.

Okay.

And yeah, so that's, that's an amazing compound that the, and the literature review from Garth Nicholson is called Lipid Replacement Therapy. Basically, these are our cell membranes and mitochondrial membranes are made of phospholipids. And these phospholipids have the ability to get across the gut intact and actually are get transported into the cells and into the mitochondria where they are into the membranes and mitochondria where they replace damaged phospholipids in membranes of mitochondria, helping basically to repair damage to those membranes and helping to mitochondria to function better. So yeah, anyway, that's a, that's a sort of small sampling of some of the compounds in my formulas.

Cool. Well, we're running out of time, so give me quickly what the other supplements are that you have, and then I'll just link to them in the show notes.

Okay. So Ultra Brain is a brain-specific formula. Again, mood support, anti-depression, anti-anxiety, as well as cognitive support and long-term brain health. It's stimulant-free. Energenesis, the mitochondrial formula, is also stimulant-free, and it has a number of great compounds in it supported by scientific research. So Rhodiola rosea is one that most people will have heard of, of course, but I think most people don't necessarily know how impressive the research is on Rhodiola rosea. There's research in, in the context of people with stress-related burnout and chronic fatigue that just that one compound alone can cut levels of fatigue in half. In some studies, they've shown it in as little as 7 days, which is, I mean, so impressive that it actually makes me skeptical. But there's several, there's several studies where they've shown that. There's a lion's mane extract, dual extract of alcohol and water extract. So it's got basically a broad spectrum of activity. All the different active components of Lion's Mane are in there. Lion's Mane, of course, has many different brain-boosting effects. It boosts levels of BDNF, brain-derived neurotrophic factor, in the brain. It's been shown to reduce levels of anxiety and depression by about 30 to 40% in span of 8 weeks in people with anxiety disorders, in people with major depression. There's a number of herbs in here that are, that have been shown to support long-term brain health, things like ginkgo biloba and bacopa monnieri. It's got acetyl-L-carnitine. It's got saffron. Saffron is another hugely underrated compound. There's—

well, I, I'm gonna have to stop you because I, I do have to wrap it up in a, in a minute or so.

Yeah.

But I'm sure that you've got all of the information on all of the ingredients on your website, right?

Yes, of course. Yeah. So the website is theenergyblueprint.com.

Okay. So I will, I will link to that in the show notes. And then just the name of the third formula, the immune formula.

Yeah, I have another immune formula called Immungenesis.

Okay.

Yeah.

Great. Well, I will have to link to those in the show notes, but people can go on the website and investigate them all. So this was super interesting and detailed and I loved it. So Thank you so much for coming on and sharing about all your research with us.

Yeah, thanks so much for having me, Lindsey. It was a pleasure.

Awesome conversation. Ari really does his stuff when it comes to energy and the research around it, so I'm glad he was able to come share that with us. If you'd like to connect with me online, you can follow my High Desert Health Facebook page, join my gut healing Facebook group, or join my newsletter list at highdeserthealthcoaching.com, as well as find me on Twitter, Instagram, and Pinterest. And of course, I'm always on YouTube as well, just the, uh, audio of my podcast. And links for those are all in the show notes. Thanks for joining me today. And here's wishing you all the perfect stool.