Mitochondria & Brain To Regulate Energy

Ari Whitten, PhD Candidate, CES, PES

Yeah, my pleasure. Thanks for having me.

Kashif Khan

And I think, honestly, of all the things that we’re gonna be talking about, this is one where like, everybody needs to know. Because we all have our days or our weeks or our months where it’s just not going right. And what we think are, my energy or my coffee intake or whatever is not aligned, but really this we’re talking about going right down to the cellular level at the mitochondria. So, how do we look at sort of mitochondria and the brain, and I know this is what you often talk about as the two sources for like, here’s where we gotta start when it comes to fatigue and energy?

Ari Whitten, PhD Candidate, CES, PES

So, the brain piece is, maybe a bit more straightforward. So we’ll start it there. One of the key principles to understand when it comes to how the brain regulates our energy levels is something called sickness behavior. And this is a, are you familiar with that phrase?

Kashif Khan

I’ve heard that, yeah, yeah.

Ari Whitten, PhD Candidate, CES, PES

Okay, So it’s a sort of, a well established phrase. There’s a lot of scientific literature about it. If so someone’s gonna go on PubMed or Google scholar, you can look it up. And it’s basically fatigue and lethargy and lack of motivation and kind of a depressed mood and apathy and those kinds of things and a number of other related symptoms. That happen when the brain is detecting high levels of inflammatory cytokines in the system. Okay, and that can be the result of pathogen and infection like a flu or COVID or something like that. It can also be the result of an injury. So if you got a sprained ankle or… Like my dog, the other day, I came home from surfing and my dog was laying in the driveway and I knew immediately something was wrong. ‘Cause normally she’s running up to the car, like super excited barking, and she was just sitting there looking at me. And I went, oh no, she got hurt. 

And sure enough, she did something to her foot. Nobody was around when it happened, but she I think got it caught in some branches or maybe got stung by a scorpion or something like that. We’re not sure what happened, but she injured a foot somehow. And she was moping around the house all day, just laying there depressed and not wanting to move. And guess what? Those are classic sickness behavior symptoms. Why? Why did her mood change? Her energy levels change? All these things change because she injured her foot. And it’s because the high levels of inflammatory cytokines, were influencing her brain to regulate all these different things that are downstream of that. So, this is why people when they get a flu or they get a severe sickness or COVID, this is why you’re in bed. Or my wife got food poisoning a couple days ago, she’s puking and super high levels of inflammation from all those bacterial toxins entering your bloodstream. Guess what? Laying in bed, fatigue, don’t wanna move, depressed mood, right?

That sickness behavior. And that is happening to some degree in most people, because most of us have ubiquitous things in our lifestyle that are causing elevated levels of inflammatory cytokines. Things like exposure to environmental toxicants, things like not enough sleep, sleep deprivation, things like psychological stress, things like poor diet, and things like being overweight. It turns out just carrying excess body fat, actually produces high levels of inflammatory cytokines all the time. And if your brain is sensing high levels of inflammatory cytokines due to the presence of, high levels of excess body fat, it’s gonna respond to that in much the same way it does, if you have inflammatory cytokine due to food poisoning or COVID or a flu or whatever, or an injury, right? 

So inflammatory cytokines are perceived by the brain in a way where it lowers energy levels. So that’s one key layer of the energy story, that’s important for many people. But the biggest one is mitochondria. And mitochondria are an interesting aspect of this story because on the one hand, it’s very straightforward. Mitochondria are our energy producers, so it makes sense that they should have a big role to play when it comes to our overall energy levels, and they do. However, the story is more complex than most people are aware of. Most people think of mitochondria and the way that we were kind of taught in high school and college biology classes, where it’s like mitochondria are the “powerhouse of the cell.” And we kind of learn to think about them as these sort of mindless energy generators that just take in carbs and fats and pump out ATP, adenosine triphosphate cellular energy. 

And, they do do that, and that their role as the powerhouse of the cell or the energy generator is incredibly important. But it turns out that they have another role, that is as important and that most people have no idea about. And because it’s only been very recently discovered in the last five or 10 years, which is their role as environmental sensors. So it turns out that mitochondria are like canaries in the coal mine. And they are the sensors that are constantly taking samples of what’s going on and around the cell, what’s going on in the bloodstream, and they’re taking samples, testing that environment to determine, is there any danger present? Is there any stressor that we need to be aware of? And as soon as they detect the presence of a significant amount of stressor, they shut energy production down, okay? 

They turn it down and they shift resources into defense mode or what the researcher, the primary researcher who’s responsible for or uncovering most of this, Dr. Robert Naviaux, who runs a lab for mitochondrial medicine, at the University of California, San Diego. He calls it the cell danger response, okay? Or CDR for short. And it turns out basically mitochondria have these dual roles and they are two sides of the same coin. So they’re mutually exclusive, to the extent end that mitochondria are switched into defense mode, because they are detecting the presence of stressors or dangers, they turn down the dial on energy production. So from this paradigm, you can think of your overall energy levels, whether you’re highly energetic, bouncing off the walls, like a little kid, like my five year old and two year old are all day, except for nap time, or you are an older person who’s struggling to get through the day because you don’t have much energy, right? Or you’re somebody who’s debilitated with severe chronic fatigue in bed, you can barely move, barely function, severe brain fog, everything’s kind of shutting down, okay? These are, different places on this spectrum, from mitochondria being unlocked into full on energy mode, to mitochondria being fully shut down into full-blown defense mode.

Kashif Khan

Yeah, and that’s them, because most people, first of all, the way you put it, you made it so easy to understand. ‘Cause I’ve spoken about this before, even within the summit, we had another conversation that touched on this and it’s just so clear and eloquent the way you describe it. Then all of a sudden, if this science is kind of new, meaning that, you know it, some other people know it, people don’t think of the mitochondria in this way, and they’re targeting the energy production only, does that mean that the solutions they’re using, are mismatch are not gonna be helpful, because there’s so much else going on?

Ari Whitten, PhD Candidate, CES, PES

Yeah. Well, here’s maybe an analogy, largely appropriate. Let’s imagine I was hitting your toe with a hammer and I was just smashing it. And every day you wake up and I say, “Kashiv come over here.” And I smash your big toe with a hammer 10 times, okay? And then you’re conceptualizing that problem as, “Man, I really feel pain. “I feel a lot of pain in my toe.” It must be because of, these eicosanoids, and the high levels of inflammatory cytokines and the nociceptors, and they’re triggering this nociception region of my brain, that’s triggering this feeling of pain. So if I just take these pharmaceuticals, these maybe if I take some anti-inflammatories and I can reduce the inflammatory cytokines or I can take some morphine or opioids that decrease the activity of the pain regions of my brain, pain sensing regions of my brain. Boom, problem solved, right? But that’s not actually solving the problem, right? Because, I’m still smashing your toe with a hammer every day, right? To solve the problem, you need to stop me from smashing your toe with a hammer every day, not not to take drugs that cover up your sensation of pain. So–

Kashif Khan

Yeah. I’m asking is where, sorry, go ahead.

Ari Whitten, PhD Candidate, CES, PES

Yeah, so we need to solve problems at the root cause level and figure out what is the real source of this problem and solve it there.

Kashif Khan

Yeah. And this is the misconception of what illness or disease is, because sometimes the root cause in the way you describe, is completely counterintuitive or unrelated to the symptom. So pain, isn’t a disease, pain is your body telling you there’s something wrong need to start investigating, right? But the investigation usually ends like, can you please get rid of the pain?

Ari Whitten, PhD Candidate, CES, PES

Yeah.

Kashif Khan

What’s the point of your body trying to communicate with you? So that’s where, yeah you gotta dive deeper, ’cause ultimately do you want to be managing the pain or eliminating as you’re figuring out what’s actually going on, right?

Ari Whitten, PhD Candidate, CES, PES

Yeah, my brother’s a chiropractor pain specialist. And, he talks about, he likes to give an analogy where he talks about like, you get into car and your check engine light is on, because you haven’t changed the oil in three years. And, the way to solve that problem, isn’t to ask a mechanic to turn off the little light that’s in the sound that’s beeping, that’s saying, check your engine, replace the oil, it’s to replace the oil, and fix the problem.

Kashif Khan

Exactly, yeah. We just need to meet people that are better equipped to understand what that light means.

Ari Whitten, PhD Candidate, CES, PES

Exactly.

Kashif Khan

I guess in just looking at that, the tools that are provided in conventional medicine, I mean their symptom masking tools, how do you then work with somebody that understands, I mean, it’s awesome that you’re sharing this knowledge today, and people will learn a little bit and maybe resonate with, oh, that’s what’s actually going on, right? But in general, the solution is go to the doctor and get a conventional medication. So essentially you’re saying that, that stuff’s not really gonna help you, it’s only gonna mass out the light.

Ari Whitten, PhD Candidate, CES, PES

Yeah, well let’s talk specific. There was a paper published maybe eight years ago, something like that, called “Fatigue and Overview.” And it was a paper published in the “Journal of the American Family Physician.” And it was not an individual study, it was a compilation of the body of research, to form a set of evidence based guidelines, what they’re calling evidence based guidelines, for conventional doctors of how they should treat their patients with fatigue. And basically they said, there’s four treatments, that you can offer your patients with fatigue. One is a recommendation to walk for 30 minutes in day, another one is cognitive behavioral therapy, and then antidepressants, and stimulant pills as needed. 

Those are the four things that conventional medicine offers to treat people with fatigue. And I mean, that’s it. So notice, I didn’t even mention anything about nutrition. Like you could have a patient who goes to a doctor, complaining of chronic fatigue, and that patient may eat nothing but pizza and crispy cream and McDonald’s every day, and that doctor wouldn’t even analyze their diet, or connect the dots to say, “Maybe your diet has something to do with this.” Because it isn’t nutrition isn’t even written about, in their evidence based guidelines. So, and nutrition is obviously one of the biggest contributors to chronic fatigue. One of the other biggest contributors is of course sleep, and circadian rhythm issues, massive contributor. So anyway, conventional medicine doesn’t have much to offer.

Kashif Khan

Even in the food paradigm, like we look at, okay, what am I eating, to the pizza for example, well, I’m Italian and for 10 and 10 generations, this is what my ancestors did, so it should be fine. Yeah, but for 10 generations, they weren’t getting it from Pizza Hut, right? The actual raw ingredients… An example, we have a patient that we were dealing with, who says that, why is it that in Toronto where we are, I can’t eat bread, but in London, England, I have no problem. Because in London, England, the chemical that’s used with the drying agent, to store the wheat and put it in a grain silo during our Canadian winter, is illegal, because it’s so toxic, right? ‘Cause the ability for him to actually clear that toxin there’s a gene called a GSTT1, which literally is a police force on the blood and goes out and binds and finds these toxins, sends ’em to Liberty.

He doesn’t have that gene, missing. GSTT1 is the same thing of the gut. He had one of two copies, so 50% capacity. So all of a sudden, you wonder why, his friends have no problem going and getting a burger and having a piece of white bread, but he just can’t do it. He used to get joint in pain, brain fog and fatigue, right? He was drained whenever he would eat bread. And now you understand what was actually going on. So the other layer that I know you speak of is adrenals, and how that sort of leads to fatigue. So how are we thinking about that right or wrong?

Ari Whitten, PhD Candidate, CES, PES

Mostly wrong. A lot of my mentors in the natural health functional medicine space talked a lot about adrenal fatigue. I kind of grew up reading a ton about it. And I was convinced that the whole thing, was very true and very important. And I was so convinced of that, that at one point, I wanted to write a book on the subject, because I was so irked by the fact that conventional medicine brushes off the whole thing of adrenal fatigue as pseudoscience and nonsense. I was so irked by that, that I said, you know what, I’m gonna stick it to you guys, I’m gonna prove that adrenal fatigue is a real thing, and I’m gonna dig into this literature, and find out the truth, and write a book on it. And, I went on PubMed and I put in adrenal fatigue, and I was first, like the first day I went to try to do this, and I was shocked the fact that almost nothing came up. 

There was literally all almost zero result. And this is, for people who don’t know, this is unusual because, I mean, even if you thought of the most obscure disease that you could imagine, like Klinefelter syndrome or Ehlers-Danlos syndrome, or like just some random, rare genetic disorder, or any obscure disease you can think of. If you go to PubMed or Google Scholar and look it up, you’re likely to find at least dozens, if not hundreds or thousands of studies on it. And so, adrenal fatigue has been around for like 20 years, that people have been talking about this, and, dozens of books have been written about it. There’s a million articles online, a million videos online about it, you’d think that you’d find at least a few dozen studies on it, but Nope, like nothing. So this was kind of odd to me. 

And then to make a very long story short, I ended up spending about a full year of my life, dedicated entirely to digging into the literature on this subject. Because, first of all, there was nothing that comes up with adrenal fatigue, so then I had to figure out, okay, what can I find literature on? What is relevant to this? So then I figured out, okay, what if I look up chronic fatigue syndrome and adrenal function, or cortisol, or HPA axis function, Hypothalamic, pituitary, adrenal function? Oh, now there’s some studies that come up. What are some other names for fatigue syndromes? Oh, it turns out there’s some other names for different kinds of fatigue syndrome. There’s burnout syndrome, There’s clinical burnout. There’s vital exhaustion. There’s stress related exhaustion disorder, right? It turns out there’s all these other names for these burnout or fatigue syndromes, that just don’t go by the name adrenal fatigue. 

And if you look up those, and it took me, summarizing this all in a matter of like 30 seconds, but this took me weeks and weeks to discover, even just one new term that exists. Because you can’t just look for it by name, if you don’t know exists. You have to discover somehow to exist. So I start uncovering all these other terms that have been researched. And there is evidence on stress related exhaustion disorder and cortisol levels, or adrenal function, or HPA axis function and chronic fatigue syndrome and burnout syndrome, and clinical burnout. And so, then I start digging into all that literature and fibromyalgia and all these this. So, it turns out that there was a body of literature, on all these other things, where they’re essentially explicitly looking at the hypothesis of the adrenal fatigue hypothesis. Which is basically for people who don’t know, is basically the idea that cortisol is this really important hormone, that we produce in response to stress. It’s involved in some things related to energy production, like managing blood glucose levels, in response to stress, and things like that, sort of unlocking glycogen from muscles and liver, to be released into the bloodstream. 

So, there’s some logical relationship to energy levels. So, it makes some sense, okay? And the adrenal fatigue idea is that, that system is meant only to respond really to acute stressors, but with chronic stress, it sort of taxes the adrenal glands to produce this hormone cortisol and taxes and taxes and taxes them, and then it just, they sort of wear out and then they’re not able to produce enough cortisol, and then you get fatigue as a result of that. So, the way that you test this hypothesis, to see if it is legitimate is very, very straightforward. Take a group of people with chronic fatigue, and take a group of people of the same ages and gender and body composition and control for all the confounding variables like smoking and exercise habits and yada yada yada, and check if there’s a difference in adrenal function, and cortisol levels, between the people with chronic fatigue and the people who are normal, healthy people. It’s very straightforward. People can try to make this very complex, but, the reality is this is a totally accurate and legitimate way of assessing the validity of this hypothesis. And it turns out that it there’s a whole bunch of studies. 

Dozens of studies, on different chronic fatigue syndromes, burnout, stress related exhaustion disorder, all those ones, I mentioned, chronic fatigue syndrome, et cetera, and where they look at all kinds of different measures of cortisol levels, and they look at it in the saliva, they look in 24 hours. They look at blood levels. They look at what’s called dexamethasone suppression tests and how responsive the HPA axis system is, to certain hormones and how much cortisol is produced. But the majority of them basically, just do as I described before. Take a group of people with fatigue syndrome, take a group of normal, healthy people, see if there’s any difference in cortisol levels or adrenal function. It’s very straightforward. And of the roughly 70 studies, that have been done over the last 25 years, on all of those topics, and keep in mind, I’m condensing about a year of my life here in the span of a few minutes. 

Of the 70 studies that have been done, about 15 of them found slightly lower cortisol levels in the morning, in the people with fatigue, compared to normal, healthy people, about 11 of those studies, found the exact opposite finding where they had slightly higher levels of cor of cortisol in the mornings compared to normal, healthy people. And 33 of the 69 total studies, 59 total studies, excuse me, I’m including literature used. 33 of the 59 studies, the vast majority of them found no discernible difference whatsoever in cortisol levels between people with full blown, chronic fatigue syndrome or burnout syndrome or clinical burnout or stress related exhaustion disorder and normal, healthy people. 

So in other, there’s lots of practitioners out there, naturopaths and other kinds of doctors who are big proponents of adrenal fatigue. If I was to take 100 lab results of cortisol testing, from 100 different people, and put those 100 papers in front of a doctor who is a full proponent and believer in adrenal fatigue. And I said, tell me, which of these 50 people have fatigue and which of these 50 are normal healthy people with no fatigue. They would be as effective at doing that roughly as flipping a coin. That’s their odds of getting it right.

Kashif Khan

Wow, so that’s where, I mean, on one end, when you’re trying to personalize root cause medicine, the anecdotal studies actually are powerful because somebody says, I felt better. So figure out why, right? The clinical studies are typically, we call them evidence based, but really they’re more around safety as opposed to efficacy, right? It’s like around how do you build something to make sure that this thing we have a theory around is safe and is not gonna kill people, right? So the anecdotal studies typically work, but when you have enough anecdotes, that’s when you kinda start to distill, what’s actually, in trends true, which it seems like you’ve done, right? So that’s all from the disease that takes us back to, well, then what was actually going on with these people? They were solving the wrong problem, and what they actually need to solve, well, let’s get back to the mitochondria. So what then, if you’re saying that there’s more going on in the mitochondria than we think, which means that the solutions that we probably have that are conventional, maybe aren’t enough, what should we actually be doing? What is the solution if you think that this is one of the main sources that people should look at?

Ari Whitten, PhD Candidate, CES, PES

Well, the main thing to sort of, to summarize everything I’ve said so far, the main thing to understand is that, the focus on the adrenals has been overblown, and they’re much less important, and cortisol is much, much less important than many people have claimed it is, in the fatigue story. And that trying to focus your efforts on fixing your adrenals is not a good approach. The big thing that you should focus on is your mitochondria. And the thing to understand about mitochondria, is they are the primary regulators of our energy levels. So there are many different mechanisms in the body that are in one way or another involved in some capacity, one capacity or another indirectly with energy production. Like thyroid hormone, testosterone, dopamine, serotonin, GABA, eulexin, insulin, like many, many, many different things that you could make a case for cortisol, that have some relationship to energy production. 

And that’s legitimate. But what is the big thing that’s regulating energy levels? That’s really the most upstream that is deciding whether the body should be producing lots of energy or not a lot of energy. And the main thing that’s doing that is the mitochondria. They are in the words of Dr. Robert Naviaux, the central hub of the wheel of metabolism. And the way that they’re deciding that, again is, to the extent that they are sensing stressors in the environment, okay? Stressors that exceed what I call their resilience threshold. So that exceed their capacity to deal with that stressor. And as soon as you have stressors present that have exceeded the capacity of mitochondria to deal with that stressor while staying in energy mode, if exceeded that resilience threshold, now they’re turning out of energy mode and shifting into defense mode, okay? So there’s two key layers to this story from this way of understanding things. One is the stressors that are present in that individual’s lifestyle and environment, okay? 

So, this is where we identify things like, what does their diet look like? What are their sleep and circadian rhythm habits look like? How much psychological stress are they under? What are their habits with regards to managing that psychological stress? What are their environmental toxicant exposures like? And what are their mitigation strategies? Do they have anything in their lifestyle that’s dealing with these environmental toxicants? Are they going in the sauna? Are they sweating during exercise? Are they drinking pure water? Are they using any sort of… Are they eating vegetables to ramp up detoxification pathways? Using supplements to support, right? All these kinds of things. We look at the stressors in their lifestyle, that’s one layer of the story. And the other key layer of the story is, what’s going on internally at the cellular level, that’s determining their resilience threshold. And that primarily is a function of their mitochondria. Their mitochondrial size and number. So in other words, do you have cells that are filled with lots of mitochondria, that are big and strong mitochondria, or do you have cells filled with, or not even filled with, but that have very few weak shriveled damaged mitochondria and not very many of them, right? 

And the difference between those two things, is vitally important to understand. So let me phrase it this way. We know from research that between the ages of 20 to 70, most people lose about 75% of their mitochondrial capacity. Which is a huge number. So if you’re 70 years old, most people who are 70, have about 25% of the mitochondrial capacity of a young person. Now you might be thinking in response to that, well, that sucks that we lose, that through just the natural aging process, that we lose so much of our mitochondria in our cells. Well, here’s the key, it’s not a natural product of aging. It’s actually the result of lack of hormetic stress in our lifestyle. Hormetic stress is types of stressors that are transient metabolic stressors that stimulate our cells in our mitochondria to grow bigger and stronger. And ultimately create beneficial adaptations that make us more resilient and resistant to a broad range of other stressors and resistant to many diseases and extend our lifespan. 

So it turns out that the reason we know this is not just a natural byproduct of the aging process, is because if you look at 70 year olds, who are engaged in regular exercise, who are lifelong athletes, they do not have 25% of the capacity of a young person, they have roughly the same mitochondrial capacity as a young person. So it turns out this is not a loss of mitochondria. that’s from aging, it’s a loss of mitochondria that’s from lack of hormetic stress built into your lifestyle. And hormetic stressors are things like exercise and all the subtypes of exercise, things like breath holding practices, heat, cold, fasting, different kinds of phytochemicals, and certain kinds of light, UV light, red and near-infrared light, things like that. But certainly exercise heat and cold and breath holding practices and fasting are huge, huge, very, very important hormetic stressors. And in the modern lifestyle, we live basically an anti-hormetic lifestyle. 

We eat a highly processed diet devoid of these hormetic phytochemicals. We’re mostly sedentary. We have very long feeding windows and almost never engage in lengthy fasting. We don’t regularly engage in breath holding types of practice. We are living most of our lives in climate controlled indoor environments, and so we’re not being regularly exposed to the elements of extreme heat and extreme cold. And because of the lack of hormetic stress in our lives, our bodies become weak and our bodies become fragile, and our resilience threshold goes down, because the mitochondria by virtue of not being stimulated or challenged, are literally shriveling up and even dying off. And the way to think about this is, if you’ve ever broken a bone, if you’ve ever broken an arm or a leg, and you had a cast on for six weeks or eight weeks, what happens after you get that cast off? You look down at your arm or your leg, and it’s half the size as of the other one. 

And it’s because those muscles literally shrunk and atrophied to half the size of the other side, in the span of less than two months. So, this same exact process happens internally at the cellular level with our mitochondria. If you don’t challenge them with hormetic stress, they shrink and they shrivel and they die off. And that’s the reason that people lose most of their mitochondrial capacity as they age. And as your mitochondrial capacity shrinks, your resilience threshold goes down and now the stressors of life, your body becomes much more fragile and sensitive, such that stress that you’re exposed to, whether it’s from pathogens, whether it’s from psychological stress, whether it’s from exposure to environmental toxicants, or sleep deprivation or physical overexertion or whatever it is, poor diet, et cetera, you can now overwhelm those mitochondria, much more easily and shift them out of energy mode into the offense mode. And this is why it’s really rare to see a child with chronic fatigue. But it’s pretty common for older people to be fatigued. It’s because of the loss of mitochondria, the loss of the resilience threshold and the fragilizing of the cells, of our bodies at the cellular level, at the mitochondrial level, through loss of hormetic stress, lack of hormetic stress.

Kashif Khan

So the way you described it is, just mirrors so many other things that we know about the body that has lost in terms of its resilience, right? We are not designed to be weak and victims, we designed to fight back, right? And we just don’t know what we’re fighting back against and meaning that if there’s nothing to fight, body says, okay, fine. I’ll just take a break. And the atrophy sits in, just the atrophy at the cellular level, the beautiful way you described it, just takes longer than the muscle. So, it’s really about your body, just like you go rip that muscle and tear it and build it up, everything in your body requires that. And if there’s nothing to fight, what’s the purpose of being strong? So your body will just take a break, right? So for anyone that’s gone beyond this, like, they’re hearing you now today, and they’re already 75 and they didn’t spend the last 75 years training, Is there anything you can do to reverse or mitigate sort of the damage that’s been done?

Ari Whitten, PhD Candidate, CES, PES

Yeah, great question. So, the reverse is also true. So, the body can engage… Just as we can have mitochondrial atrophy, and loss of mitochondria, you can actually, there is a reverse of that process. And we can stimulate the growth of mitochondria, and we can also stimulate a process called mitochondrial biogenesis, the creation of new mitochondria from scratch. And we do that through or hormetic stress. That’s the primary means through which we can grow our mitochondria bigger and stronger and create more of them. So by engaging regularly in a regimen of exercise, various types of exercise, breath holding practices, heat exposure, cold exposure, you don’t have to do all of these, but at least a couple of them regularly, will create widespread adaptations, in different systems of the body that create these beneficial adaptations to grow your mitochondria and create more of them. 

So yes, you can absolutely reverse them. And each one of these types of hormetic stress has its own sort of physiological fingerprint, of the unique adaptations it’s stimulating. Even within the category of exercise, different types of exercise, stimulate adaptations differently in the body. So steady state endurance activities, is different from weight training, is different from high intensity interval training or sprint interval training. And then breath hold practices are different from, heat exposure, are different from cold exposure. So, there are certain universals of how these things operate when they converge on stimulating mitochondrial growth, up regulating the internal antioxidant system, to make you more resilient at the cellular level. But for example, breath holding practices, stimulate unique adaptations with regards to enhancing lung mitochondria. And enhancing the… 

Actually, altering the structural interface, the physical interface between the lungs, and the bloodstream, to be able to extract oxygen more efficiently into the bloodstream. And then you also get unique adaptations for dealing with low oxygen states cells, and the mitochondria become uniquely adapted to low oxygen states, and become hyper efficient extracting oxygen to utilize it, to produce energy. So those adaptations are kind of specific to breath holding practices and are different from let’s say sauna exposure. And sauna exposure gives its own unique profile of the benefits that it creates, which are also amazing and wonderful. So having some variety of different types of hormetic stress can build mitochondria and resilience into your system, in their own unique ways, in different systems of the body.

Kashif Khan

That’s truly awesome to hear, ’cause all of a sudden it’s like you can carry this menu of items that stimulate it in different ways and turn these different dials, but they’re all, ’cause they’re converging to this better version of yourself. So when you think about guys like Wim Hof, and why just can get sick, going out in the cold all the time and doing his breath work, et cetera. You think about these yogis that do their breath work, and they’re 100 years old, look like they’re 35. What we just talked about is you can reverse, mitigate, bring things back. You need bring on the stress and it comes back, energy levels go up, because all of a sudden mitochondria is like populated and dense. You also talked about mitochondria, it’s second job that most people are unaware of, which is that signaling, that environmental signaling. So do you end up with this… It sounds like a compound effect where all of a sudden your sensors are a lot more sensitive and alert and you’re able to, not only the energy levels go up, but your sensorial relationship environmentally is also better and stronger now, because the, the sensors are also more dense?

Ari Whitten, PhD Candidate, CES, PES

It’s an interesting idea. I would frame it differently than that. The way I think of it is that, when your mitochondria are weak, those environmental sensors become hyperactive, hypersensitive.

Kashif Khan

Okay.

Ari Whitten, PhD Candidate, CES, PES

So every little threat becomes overwhelming to them. Let me present like an another way of understanding this. Let’s say we have… Let’s say you and I, imagine we were here together on my property and I’ve got a bunch of big boulders up there on my land, that we need to move, okay? Is it beneficial for us to do it, just you and me, or if we call 10 other guys to help us? Which is gonna be easier, right? Having the 10 other guys, right? So, mitochondria are the same way. So the bigger and stronger the mitochondria are, and the more of them that we have, then accomplishing a given amount of work, let’s say moving these 20 big boulders, from one side of the land to the other, is way easier with more guys, with more mitochondria than it is with fewer mitochondria. So, the way this works at the cellular level is that, hormetic stress, any type of stress, taxes the mitochondria to some extent, okay? 

And when the mitochondria are taxed, they produce lots of free radicals or reactive oxygen species. If they’re being overwhelmed by that stress, they’re producing a toxic amount of free radicals. That actually so much free radicals, that it ends up causing damage in the cell. And the damage being present, all that oxidative stress and oxidative damage that’s occurring, then triggers that cell into defense mode. But let’s imagine that cell was under the same exact amount of stress, but it had twice as many mitochondria to handle that same workload. Now all of those mitochondria, is like having 10 more guys to move the boulders, right? They can now handle of that workload with much greater ease while each individual mitochondria is being taxed much less heavily than in the prior scenario. And by virtue of that, each one of them is now below their threshold of being overwhelmed. And so they don’t end up producing this toxic overwhelming amount of free radicals in oxidative stress, they don’t end up causing the, all this oxidative damage in the cell, and then the cell doesn’t get triggered into defense mode. 

It stays in energy mode in peace time metabolism where it’s pumping out energy instead of shifting into defense mode. So the way I think about it is more that the more mitochondria you have, the bigger and robust your mitochondrial networks are and stronger they are, the less sensitive your body is. The less easily perturbed it is by the stressors of life. The more it can handle the stressors of life with ease without being thrown off. So you can get some exposure to environmental toxicants without being super fatigued from it, or, having brain fog or something like that.

Kashif Khan

That makes a lot of sense. And I can tell you just from my personal experience, I used to be fairly fitted active when I was younger. Like most people, you kind of give up and feel you’re invincible and you stop training. And by my mid thirties I was sick and you name a thing I had it. And then I started training again and I kind of feel like I can’t get sick anymore. Even the common cold, my throat kind of tingles, and by the time I try to figure out what to do about it it’s already gone. And I feel that sense of resilience, you can hit me with whatever it is and I just, yeah, I’m exposed, I’ll get it, but the measure of health is that I can fight it fast.

Ari Whitten, PhD Candidate, CES, PES

Yes, absolutely.

Kashif Khan

So, and I certainly feel that. And it’s kind of like, even when I go to the gym now, before I had to need the energy to get to the gym, now I start and the energy’s there. Like, I could feel like that first, yeah, the first set might be difficult, but it just, everything starts pumping and flowing, right? And it speaks to that kind of training you’re talking about where the mitochondrial load has increased and it’s yeah. It’s all put in perspective, it makes sense now. And this is why you can look at Arnold Schwarzenegger was in his 70s, still training and ripped, ’cause he never stopped. He just kept putting that stress in his body and he’s able to do what the guys, even the young guys around him can’t. So that, it’s awesome to hear. So in terms of specific supplementation, I don’t know if there’s very specific things that you found have worked. I know going to some of the biohacking events and functional medicine conferences, you see a lot of people now more than ever before, touting mitochondrial support, right? But mitochondrial support could mean different things. It could mean relieving oxidation, like the ability what’s happening at the cell. It could be development of mitochondria, the biogenesis you’re talking about. So, what should you be actually striving for? What products do that? I dunno if you have a sense of what people should be doing there.

Ari Whitten, PhD Candidate, CES, PES

Yeah, definitely. So there’s many different mechanisms of things that you can support at the mitochondria level. There’s compounds that you can take that act to help mitochondria grow bigger and stronger to stimulate mitochondrial biogenesis. These fall into the category of xenohormetic, for the most part. So this is a type of hormetic stress, that acts on many of these hormetic stress pathways, but through something called xenohormesis, xeno with an X in the scientific literature, if you were interested in looking it up, and it has a lot to do with plant phytochemicals. So various kinds of anthocyanins and flavanoids and things like that, can act on some of these same hormetic pathways to stimulate mitochondrial growth and biogenesis.

 Things like, curcumin, things like sulforaphane, resveratrol, there’re stilbene gynostemma, ginseng, Rhodiola rosea, and many, many others. Have compounds in them that act as xenohormetic stressors, and stimulate mitochondrial growth and biogenesis. PQQ is another one, that is very, very important for this. Another great thing to support in this regard is, one aspect is just mitochondrial co-factors. So thing like CoQ 10, acetyl-L-carnitine, alpha-lipoic acid, ideally R alpha-lipoic acid, and B vitamins are all hugely important co-factors. Magnesium, very, very important co-factors for mitochondrial energy production. So that that’s more straightforward. That’s one layer that I think most historically, most mitochondrial supplements have focused only on that layer. Where they conceptualize mitochondrial support as a matter of providing co-factors for energy production. An important layer, but definitely not the only layer. So, stimulating hormetic stress through the Xenohormones, you’re providing co-factors. Another layer is stimulating mitophagy. And mitophagy is basically like autophagy, but at the mitochondrial level.

So autophagy is basically the process of breaking down, dysfunctional, worn out, broken cell parts and rebuilding new healthy cell parts. So we do the same thing with our mitochondria and we need to have a quality control process with our mitochondria, such that the defective ones, don’t get the chance to keep on living and potentially divide and create more mitochondria that are from that dysfunctional stock, right? So we need to have this quality control process where we are breaking down and recycling the damaged, broken mitochondria, the ones that are producing too much free radicals and oxidative stress and not producing energy efficiently. We need to get rid of those guys and rebuild new healthy ones. And mitophagy is critically important for that. So there are not many things that have been proven to support mitophagy. But one of the most critical ones is, something called urolithin A. 

And urolithin A comes for… It’s actually a metabolite that bacteria in our gut produce. After digesting something called ellagic acid or ellagic tannins. And this is a compound that is found in some foods, the richest foods in it are pomegranates and chestnuts. So pomegranates, have this compound called ellagic acid when it hits our certain species of gut bacteria, they break it down, they digest it and produce a compound called urolithin A. And urolithin A then goes into our bloodstream, where it is pretty much the most powerful promoter of mitophagy that has ever been discovered. So doing that is another layer of how you do quality control on your mitochondria. Supporting autophagy and mitophagy through adequate fasting windows every night is also incredibly important. And one of the other aspects that I’ll mention is melatonin. Melatonin is the mitochondrial targeted antioxidant. And it is pretty much the most important antioxidant for protecting our mitochondria. Way more important than people realize. 

Most people know of melatonin only in the sort of the sleep story. Melatonin is produced by our pineal gland and it’s a hormone involved in sleep. Many people don’t even know it’s a hormone. They think it’s a, just like a supplement, but it’s a hormone produced in our brain, that’s involved in sleep. Turns out it’s actually much more than that. It’s a vitally important compound for protecting your mitochondria. And your mitochondria need to be bathed in melatonin, in order to function properly and maintain the balance of what’s called redox balance. The balance of oxidants relative to antioxidants. The melatonin is vital to that process. Here’s a layer to the story that most people don’t know. Most of the melatonin produced in our body over 90%, isn’t produced in our pineal gland. It’s produced in our cells by the mitochondria. And one of the primary things, that allows your mitochondria to produce adequate amounts of melatonin, is light. Exposure to near-infrared light in particular. 

Which is something I’ve written a book about, “The Ultimate Guide to Red and Near-Infrared Light Therapy,” near-infrared light, which we get from sun exposure, or you can get from red and infrared light therapy lights, interacts directly at the cellular level and helps the mitochondria basically recharge levels of melatonin. So that’s another critical layer to this story. Sleep and circadian rhythm, absolutely another critical layer to mitochondrial health. And then as far as, I kind of deviated a little bit from supplements here, but melatonins kind of crosses over a little bit. The last thing I’ll mention is, membrane support. There are certain compounds that you can take, that protect mitochondrial membranes, which are very success to the damage from oxidative stress. It protects them from that damage. 

One such compound is called astaxanthin. And astaxanthin is a carotenoid that comes originally from algae, and then it’s concentrated in many other animals up the food chain. It’s what gives shrimp and salmon their pink color, but we can supplement with astaxanthin as well. It’s also, you could take it in the form of salmon row. It’s very concentrated in salmon eggs. So that astaxanthin has a very unique chemical structure that allows it to be embedded in mitochondrial membrane, across the membrane. So most antioxidants either act inside or outside of the cell, vitamin C is water soluble acts outside of the cell. Other things are fat soluble, vitamin E for example, acts primarily inside the cell. Astaxanthin has this unique chemical structure that allows it to embed across the membrane. And stabilize the membrane and protect it from damage. So astaxanthin is really a wonderful compound and there’s been several studies that have shown that it mitochondrial membranes from damage. 

And then the last compound I’ll mention is something called NT factor phospholipids supplements. There’s an amazing paper by a researcher named Garth Nicolson, who wrote a paper called “Lipid Replacement Therapy” that compiles the literature on a whole bunch of studies using phospholipid supplement called NT factor. And basically, it’s forms of phospholipids. These are the same lipids that make up our membranes, our cell membranes, mitochondrial membranes, and things like phosphatidylcholine phosphatidylethanolamine, et cetera. And this supplement has been used in several studies in people with various kinds of chronic fatigue. It’s one thing to have theory of like, oh yeah, this works in so and so pathway, and therefore it should result in this benefit. It’s another thing to actually have hard evidence like, here’s this supplement in people with chronic fatigue, what were their result in terms of their energy levels? 

And we know that in these studies, there’s been, I think at least 10. Where they’ve looked at people with chronic fatigue syndrome, chronic fatigue from aging, chronic fatigue associated with obesity, many other types of chronic fatigue. And they have them take just this supplement, no other interventions, just take NT factors. And within three weeks, four weeks, eight weeks, we see dramatic improvements in energy levels. 30, 40% increases in energy levels just from doing this one thing alone in a month or two. So, and the reason why is that these phospholipids, actually get absorbed into our bloodstream intact and then end up making it all the way into the cell, believe it or not, and into the mitochondria where they can replaced damaged phospholipids and rebuild healthy membranes so that mitochondria can function better.

Kashif Khan

That’s fascinating and, on one end, they’re measuring, okay, energy levels up 30, 40%, but there’s all the other ancillary or side byproduct benefits that they don’t even realize the disease prevention, the resilience, all that thing that’s happening. But, so first of all, like this hour went by, it felt like five minutes. ‘Cause, everything you’re talking about is so incredible and so informative I’m sure people are gonna love what they heard. One last thing I would ask you, so for the people that are obviously gonna be intrigued to understand the mitochondria better after hearing this, there’s one thing to say, “yeah, that sounds like me. “I resonate with like low energy, et cetera.” Are there actual empirical tests that you can do to measure, Like where are you at?

Ari Whitten, PhD Candidate, CES, PES

Not really.

Kashif Khan

Not really, right?

Ari Whitten, PhD Candidate, CES, PES

Not very good ones. There’s a MitoSwab test, where you can kind of swab the inside of your mouth. That might be the best one. There’s been a couple things that have been done in the actual scientific literature to try to assess mitochondrial function. Like they’ve looked at, it in the context of people with chronic fatigue syndrome, measuring mitochondrial capacity in one way or another. Sometimes they measure it in a Petri dish, which is not a great way of doing it. Sometimes they measure other aspects of mitochondrial function. There’s one that’s been developed by researchers in the UK called an ATP profile test, that’s been pretty well validated, in patients with chronic fatigue syndrome. But all of them are imperfect, and all of them are, they’re more built on the model of like trying to determine abnormalities and levels of co-factors. So like, lot of them, might detect, the people with chronic fatigue syndrome, have lower levels of CoQ10, or, this co-factor, that co-factor, it’s not really what we’re like… In the model that I’m presenting here, the cell danger response model, it’s more a matter of mitochondrial shutdown in response to stressors and less a matter of just deficiencies of co-factors or something like that, or–

Kashif Khan

sorry.

Ari Whitten, PhD Candidate, CES, PES

Yeah. So, all those tests are imperfect, but they can give you some indirect insight. I don’t want to bash them so much. Tests that I do like are heart rate variability testing. And I love the BOLT score, which is a very simple test that you can do for free at home body oxygen level test. It’s a way of just doing a very gentle breath hold, and then stopping with your first urge to breathe. If you want, I could guide people through it right now, but I don’t know if we have time. And then the length of time that you hold that, I find correlates very strongly to one’s level of fatigue or energy. And as one improves their BOLT score, it tends to very predictably relate to improvements in energy levels.

Kashif Khan

Sure, yeah, before we go, let’s do it, man. Let’s do the BOLT score right now.

Ari Whitten, PhD Candidate, CES, PES

Cool. Do you wanna bring up, if you can just do a screen share, bring up like, just do a good Google search for online timer, and then we’ll time it. So what we’re gonna do, and I’ll just describe as you’re bringing this up, I’ll describe what we’re gonna do. You’re gonna do a few normal breaths, in and out through the nose, calm, normal breathing. Not deep breathing, not heavy breathing, just normal breathing. And then after a few breaths, you’re just going to exhale out through the nose, a normal exhale. So instead of, doing a full forced exhale, just normal, relaxed, exhale, stop at the end of the exhale. So, in you shouldn’t have all your air forced out, in other words. So a normal exhale, if this is the full exhale, that much, where a normal exhale kinda stops, maybe 60% of the way there, 70% of the way there to a full exhale. Once you do that, you’re just gonna pinch your nose and hold your breath. 

And you’re gonna stop, when you feel the first urge to breathe. The first distinct urge to breathe. This is not a maximal breath hold time test. Meaning you don’t wanna go, go, go and push, push until you can absolutely hold no longer such that at the end of it, you’re going, , and you’re gasping for air. That’s more of a maximal breath hold time test. This is a BOLT score, a body oxygen level test, and it’s done in a much more relaxed way. Normal exhale, pinch the nose, hold, until the first urge to breathe. And then that first urge to breathe should be relatively relaxed. If you’re gasping for air, that means you did it too long, okay? So we’re gonna do three normal breaths, after the exhale on the third breath, we’re gonna pinch the nose. So here we go. One, one more and pinch the nose and hold and go.

Kashif Khan

So we’re obviously living different lives here because, I was done at 17 seconds.

Ari Whitten, PhD Candidate, CES, PES

So basically anything below 20, is considered a sign of breathing dysfunction, or a low BOLT score, okay? So ideally we want to be above 20. And then interestingly, this test was done many, many years ago, and it was sort of quantified among young athletes, I don’t know if they were professional athletes, but maybe college athletes. And they looked at average BOLT score times among, sort of young fit people. And they found that 30 and above was considered optimal. So, that’s what we wanna shoot for. And what we find in a lot of people who are unwell, is BOLT scores of less than 10 seconds.

Kashif Khan

Oh, wow, yeah.

Ari Whitten, PhD Candidate, CES, PES

So this is something that we can improve dramatically by bolstering our mitochondria and particularly through breath hold practices, which is just a wonderful form of hormetic stress. In my opinion, the single fastest and most powerful way to increase energy levels in people with chronic fatigue that I’ve ever found in 25 years of studying natural health. These breath hold practices are just amazing in their capacity to create adaptations at the lungs, and as far as oxygen utilization at the mitochondrial level, that allow us to produce energy much more efficiently. And, what you’ll notice is literally within a few weeks, you’ll start to see that BOLT score going up by a couple seconds, every week and maybe five seconds in some cases and within a month or two, I’ve seen people just make massive improvements, in their energy levels, just by doing these breath hold practices or intermittent hypoxic training. 

I’ve created a new program called Breathing For Energy, with a guy named Patrick McKeown, Who’s the author of “The Oxygen Advantage” one of the most world renowned experts in breathing practices. And so he and I kind of partnered together to produce this program specifically for energy enhancement. And it’s got a lot of his foundational practices and then a whole system of six levels of, six progressive levels of intermittent hypoxic training, breath holding practices, that take you all the way from 10 to 15 second breath hold, to three minutes and beyond. So, it’s an amazing system, we’re getting just phenomenal feedback from people, about how well this works.

Kashif Khan

So if people, I mean, obviously I think minds are gonna be blown after listening to today, but, for those that do want to work with you potentially, is that the best way?

Ari Whitten, PhD Candidate, CES, PES

Yeah, the Breathing For Energy Program is great, I mean, it’s amazing actually. I have an energy blueprint program as well, that’s much more comprehensive like all things, nutrition and lifestyle, from gut health to hormetic stress, to light, to nutrition at like very, very comprehensive. And then I have a supplement line as well. So like a lot of the compounds that I mentioned for mitochondrial health, are in our mitochondrial formula. I have a brain formula as well, and a very comprehensive, really premium, top of the line, multivitamin, multi-mineral, and super-food formula as well. So, yeah.

Kashif Khan

Where do people find all that?

Ari Whitten, PhD Candidate, CES, PES

Yeah, that’s at the energyblueprint.com.

Kashif Khan

Okay. And through there they can also find your programs there?

Ari Whitten, PhD Candidate, CES, PES

Yes.

Kashif Khan

Okay, I might end up enrolling in one of those too, ’cause I gotta get my BOLT score up.

Ari Whitten, PhD Candidate, CES, PES

Yeah, you do.

Kashif Khan

So, this was truly awesome, fascinating, thank you for sharing so much. I’m sure you’re gonna help a lot of people. Again, thank you for coming today.

Ari Whitten, PhD Candidate, CES, PES

Yeah, my pleasure. Thanks so much for having me.