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In this episode, you will learn about the mitochondria and The Energy Blueprint.

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About My Guest

My guest for this episode is Ari Whitten. Ari Whitten, PhD (Cand), CES, PES is the founder of The Energy Blueprint system, a comprehensive lifestyle and supplement program which has helped more than two million people (and counting) experience optimal health, better performance, and more energy. He's also the bestselling author of The Ultimate Guide to Red Light Therapy and the host of the popular The Energy Blueprint Podcast which features the world’s leading natural health experts.  In 2020, Ari was voted #1 Health Influencer by Mindshare, the largest natural and functional medicine community. For more than 25 years, Ari has been dedicated to the study of human health science. He holds a M.S. in Human Nutrition and Functional Medicine, a B.S. in Kinesiology, certifications as a Corrective Exercise Specialist and Performance Enhancement Specialist from the National Academy of Sports Medicine, and he has completed all of the coursework for a Clinical Psychology Ph.D. You can find his podcast, programs, and supplement formulas at TheEnergyBlueprint.com.

Key Takeaways

  • What are the symptoms of mitochondrial dysfunction?
  • What "signals" lead to impairment of the mitochondria?
  • How might supporting the mitochondria need to consider whether or not one is in a Cell Danger Response?
  • What are "zietbegers" and their relevance to brain and body clocks?
  • Can too much protein lead to overactivation of mTOR and potentially be harmful?
  • What role do short-chain fatty acids play in energy production?
  • Can prebiotics and resistant starches be used in those with SIBO?
  • What role might vinegar play in supporting the mitochondria?
  • How might Urolithin A be supportive of the mitochondria?
  • Are niacin derivatives such as NR or NMN proving to be helpful?
  • How might melatonin support the mitochondria?
  • Are the adrenals a key player in fatigue?
  • What role might red light therapy or photobiomodulation have in supporting mitochondria?

Connect With My Guest


Related Resources

Book: Eat for Energy: How to Beat Fatigue, Supercharge Your Mitochondria, and Unlock All-Day Energy

Breathing for Energy Program

The Energy Blueprint Store

Interview Date

June 28, 2022


Transcript Disclaimer: Transcripts are intended to provide optimized access to information contained in the podcast.  They are not a full replacement for the discussion.  Timestamps are provided to facilitate finding portions of the conversation.  Errors and omissions may be present as the transcript is not created by someone familiar with the topics being discussed.  Please Contact Me with any corrections.  


[00:00:01] ANNOUNCER: Welcome to BetterHealthGuy Blogcasts, empowering your better health. And now, here's Scott, your Better Health Guy.

The content of this show is for informational purposes only, and is not intended to diagnose, treat or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. As always, please discuss any potential health related decisions with your own personal medical authority.

[00:00:35] SCOTT: Hello, everyone. And welcome to episode number 168 of the BetterHealthGuy Blogcasts Series. Today's guest is Ari Whitten, and the topic of the show is The Energy Blueprint.

Ari Whitten is the founder of The Energy Blueprint System, a comprehensive lifestyle and supplement program, which has helped more than 2 million people, and counting, experience optimal health, better performance and more energy. He's also the best-selling author of The Ultimate Guide to Red Light Therapy and the host of the popular The Energy Blueprint Podcast, which features the world's leading natural health experts.

In 2020, Ari was voted number one health influencer by Mindshare, the largest natural and functional medicine community. For more than 25 years, Ari has been dedicated to the study of human health science. He holds an MS in Human Nutrition and Functional Medicine, a BS in Kinesiology, certifications as a Corrective Exercise Specialist and Performance Enhancement Specialist from the National Academy of Sports Medicine. And he's completed all of the coursework for a Clinical Psychology Ph.D. You can find his podcast programs and supplement formulas at TheEnergyBlueprint.com.

And now, my interview with Ari Whitten.


[00:01:55] SCOTT: I’m excited today to have Ari Whitten on the podcast to talk about mitochondria and his book, Eat for Energy: How to Beat Fatigue, Supercharge Your Mitochondria, and Unlock All-Day Energy.

Thanks for being here, Ari.

[00:02:07] ARI: Thanks so much for having me, Scott. It's a pleasure.

[00:02:10] SCOTT: Most of my guests have a personal story or journey that led them to doing the work they do today and to the passion they have for helping others. So, what was your personal story that drives you to do what you do today?

[00:02:23] ARI: Well, there's a long and a short version of it. So, the truth is I’ve been studying health science as sort of my singular passion and obsession for over 26 years now since I was about 12 years old. And at that time, it was very much I was an athlete. I was an aspiring bodybuilder. So, my world my, my interests and passions centered around nutrition, and fitness, and performance enhancement, and body composition, muscle gain, fat loss. And that was pretty much my world for about a decade.

And then I went on to do a degree in kinesiology in college and a lot of other training certifications. Becoming a personal trainer and certifications as a corrective exercise specialist. A performance enhancement specialist to work with athletes and things of that nature. And then in my mid-20s, I got mononucleosis, and I got from Epstein-Barr virus. And I got hit quite severely by it for a number of reasons we could dive into if you're interested.

And for about six weeks, I had severe acute illness. And that was a pretty rough road. I had two giant golf balls, white balls of pus in the back of my throat that made it impossible to eat food because it was so painful to chew and swallow anything. So, I was living off broth for about a month. And I lost about 40 pounds in that month. And mostly muscle. Not fat loss. I don't want to make it sound too appealing to people.

But that wasn't really the worst part. The worst part was that, for about a year after that, I was left with pretty debilitating chronic fatigue. And that experience really rocked my world. Because like I said, I had always been an athlete. I had always been fit, and healthy, and strong. Prior to that, I had always been sort of the pinnacle of health and fitness.

And when my energy was taken away from me, this thing that I had always taken for granted, I suddenly got to see firsthand how critical energy is to every aspect of life. Because I watched pretty much everything in my life sort of fall apart, my friendships, my relationship with my girlfriend. I was in school, and I had a job, a hard-manual labor job at the time, and I wasn't able to do any of it. And I wasn't able to pursue my hopes and dreams in life. And everything just kind of was deteriorating right before my eyes. And there was nothing I could do about it.

So, it was that experience that was sort of the catalyst for me to start developing an interest in the topic of energy in particular. And then also, in tandem, with seeking out a lot of conventional medical doctors for help, realizing they basically had nothing to offer. Seeking out a lot of people in the alternative natural health, functional medicine world. And also, while I’m very much a part of that camp and movement and an advocate for it, the truth is that they historically have not had much to offer those with chronic fatigue and have not had a good understanding of it. They're understanding largely centered around adrenal fatigue, which I ended up spending about a year of my life exploring the literature just on that topic alone. We can talk in depth on that topic. I could talk to you for hours just on that one if you wanted to.

But all of those things together, my own personal fatigue with kind of realizing that the different conventional medical and natural health camps didn't have much to offer, that was all sort of the catalyst for me to then switch my obsession to this topic of human energy. What really controls and regulates human energy levels? What is deciding whether we are chronically fatigued or have youthful and abundant levels of energy? And what are all those mechanisms and how do they interplay with one another? So, that's been my obsession for the last decade or so.

[00:06:35] SCOTT: And I think that EBV plays a much larger role in many chronic conditions than what I think people realize. There's been more research coming out recently about its contribution to Multiple Sclerosis.

Let's talk a little bit more about symptoms that one might experience that could clue them into the potential for mitochondrial dysfunction. And then given the number of mitochondria in various tissues in the body is different, how does that predict where these symptoms might first appear?

[00:07:05] ARI: Very good question. Okay. So, let's go big picture first. So, it's important to understand the way that mitochondria are taught about in high school and college biology courses as these sort of mindless energy generators. They are the powerhouse of the cell. They're presented as sort of one of many different organelles over, "Here's the Golgi apparatus. Here's the endoplasmic reticulum. Here's the nucleus. Here's the mitochondria that produces energy." Da-da-da-da-da.

And the truth is that mitochondria are vastly more important than that and they are not mindless energy generators. In the words of Dr. Robert Naviaux, who is a mitochondrial researcher; runs a lab for mitochondrial medicine at the University of California San Diego. He says that mitochondria are the central hub of the wheel of metabolism.

Metabolism, for those listening, it's the sum of all the biochemical processes that are happening in your body. And he's now positioning mitochondria as the central hub of metabolism. In particular, there was a paper that came out from his team of researchers in 2014 called the Cell Danger Response. And I think this is one of the most important papers in the last 100 years of medicine.

And what this paper did was reframe our entire understanding of mitochondria so that they are not just mindless energy generators, but they actually have a second role that is just as important as their role in energy generation. And that is cellular defenders. So, it turns out that mitochondria aren't just these mindless energy generators. They are essentially like the canaries in the coal mine of our body. They're environmental sensors that aren't just taking in carbs and fats and pumping out ATP cellular energy regardless of what's going on and what we're doing. They are actually constantly taking samples of what's going on in the body and asking the question, "Is it safe for us to produce energy?" And that is critically important to understand. Because this reframing of mitochondria positions mitochondria as the most upstream thing that is actually regulating human energy levels.

So, just as you could have a car that has many different aspects to it that are in one way or another important to that car moving down the road. There's an engine block with pistons, and spark plugs, and there's an exhaust system, and a catalytic converter, and there's gasoline, and there's an accelerator pedal, and there's a brake pedal. There's many, many different components that are in one way or another related to the ability of that car to move. The same is true in the human body in terms of there are many different hormones, and neurotransmitters and biochemical processes that are in one way or another related to energy production and energy levels. Hormones like thyroid hormone, and testosterone, and growth hormone, and insulin, and melatonin, and cortisol and all these different things. Neurotransmitters like dopamine, and serotonin, and GABA. And different processes and gene expression that you could talk about in relation to the circadian clock. And inflammation pathways. And AMPK. And mTOR. And you could talk about a million different things that are in one way or another related to this energy story.

But the fundamental thing, the most upstream thing that is actually regulating human energy levels is our mitochondria. And they are doing it in proportion to the degree to which they are sensing threats. So, in other words, these roles of energy generators and cellular defenders are mutually exclusive. And to the extent that they are picking up on danger signals, they are turning down the dial on energy production and shifting into defense mode. Shifting resources towards cellular defense. And that is the fundamental thing that is really controlling human energy levels. It's the extent to which mitochondria are either in energy mode or defense mode.

So, I think that big picture understanding of what mitochondria are and how they regulate energy levels is very important. Now, you asked a very interesting question, which is related to the density of mitochondria in different tissues of the body and how that might relate to symptoms that will show up. Well, there are a few tissues that are really dense in mitochondria, the brain, the heart, the liver and muscle tissue. All of them have a very, very high density of mitochondria, very high numbers of mitochondria per cell in those tissues.

So, when we see patients who start to have either damage to mitochondria, or dysfunction, or shutdown of the mitochondria, and there's a variety of ways that can happen, the main symptoms that tend to show up are, number one, fatigue. Very important. Number two, there tends to be cardiovascular weakness and muscle weakness. Skeletal muscles tend to shift more into anaerobic lactic-acid-producing metabolism more quickly. There tends to be kind of an exercise intolerance. You might get winded. Feel like your heart's pumping fast. Your muscles are burning much quicker. The liver aspect of things may contribute to the liver being more easily overwhelmed by toxicants and having trouble detoxifying. So, you might develop various kinds of sensitivities. And the brain issues will oftentimes start to result in brain fog, difficulty concentrating and things of that nature. Or brain-related fatigue. So, if you do any sort of mentally demanding task for a period of time, like read a book, or play chess, or even drive a car, or something like that, try to pay attention to a lecture, or a podcast, you might find it difficult. Or after doing it for half an hour, an hour, you might feel like you need a nap because you're so tired from that. So, those I would say are the main types of symptoms that tend to show up with mitochondrial damage or dysfunction.

[00:13:44] SCOTT: Thinking about mitochondria as environmental sensors, what are some of the key things then that might impair mitochondrial functioning? Are we talking about environmental toxicants? What about water damaged buildings? What are the things that you consider the top mitochondrial impairers or what you call signals in the book?

[00:14:04] ARI: Yeah. So, it's a great question. It turns out mitochondria can basically sense every type of stressor that you can think of, from environmental toxicants like heavy metals or pesticide residues to they can sense nutrient deficiencies, they can sense the presence of toxic nutrients, they can sense sleep deprivation, psychological stress, you name it. Physical over training from too much exercise or exertion. Pretty much any type of stressor you can think of, mitochondria can sense.

Now, this is not because mitochondria have a receptor for physical over training, and a receptor for mercury, and a receptor for every one of the different hundreds of types of pesticides and other environmental toxicants of thousands environmental toxicants, and a receptor for sleep deprivation, stress signals or something like that. It's because, basically, every type of stressor, whether we're talking about an environmental toxicant, or we're talking about let's say LPS endotoxin leaking from the gut, from bacteria in the gut, due to gut permeability. Not leaking into the bloodstream. To psychological stress. To sleep deprivation. All of those things ultimately get translated into a few different chemical signals in the body. And those tend to be – They tend to get translated either into higher levels of oxidative stress, okay? Higher levels of oxidants or reactive oxygen species, or higher levels of inflammatory cytokines, and/or the presence of direct cellular damage occurring.

So, any of those things – And there tends to be a lot of overlap between them. So, for example, eating a poor diet will tend to cause oxidative stress and higher levels of inflammation, which also translate into cellular damage. So, all of them are occurring in the context of many stressors. But mitochondria can sense those things. They can sense the presence of oxidative stress, higher levels of inflammatory cytokines and cellular damage. And they do have essentially receptors or signaling mechanisms that allow them to sense those things. And by virtue of that, they can sense basically every type of stressor that we're exposed to.

[00:16:41] SCOTT: So, in Bob Naviaux's cell danger response model, it is the extracellular ATP that is the danger signal that really triggers this protective hypometabolic state? And so, in some cases, if we're too aggressive about supporting the mitochondria, the way I think about it, is it's almost like trying to press on the gas pedal when the body's already stomping on the brakes. We also have the scenario then that if we start providing mitochondrial support and production of energy increases, and the body then starts working through a lot of things, detoxification and other things that it couldn't previously do, that that also can be an uncomfortable process. So, how do your recommendations for supporting mitochondria consider the possibility that we might need to do it low and slow and consider some of those signals early on before we get too aggressive with mitochondrial support?

[00:17:34] ARI: Yeah, it's an excellent question. Very sophisticated thought. What I was just mentioning about cellular damage is related to what you're referring to. So, when there is cellular damage, there is a leakage of energy molecules, purinergic molecules like ATP and ADP, out of the cell. They really belong inside of the cell. But when there is damage that occurs to the cell, they leak outside of the cell. They get into the blood. And there are receptors on our cells, purinergic receptors, that sense the presence of those energy molecules.

And by virtue of sensing that, they go, "We're under attack. There's cellular damage occurring." And we know that because there's all these energy molecules leaking out in the bloodstream where they shouldn't be. So, that helps create the signaling cascade to other cells, and tissues, and organs throughout the body that the body is under attack.

This is, for example, how a respiratory tract infection that might be causing cellular damage in the sinuses, and throat, and lungs can translate into the systemic symptom of fatigue when you get COVID, or a flu, or a cold, or something like that, or an Epstein-Barr Virus.

There is a scenario where the body is in this state of the cell danger response and locked into this fatigue mode as a protective adaptive mechanism, as an intelligent mechanism. So, it's important to understand that this is not just a mistake. The body is designed, when it is under attack, to go into that state.

And as a simple example of why, imagine you're in a war zone right now, and let's say you're in Ukraine and the Russians then attack your little town and they throw tear gas in the street or some other kind of poison gas in the street, it would be a terrible mistake to go about your business as usual. Leave the windows of your house open. Say, "Oh, it's a beautiful day outside I think I’ll go for a nice walk outside in the park," right?

What you do in that scenario when you're under attack is you shut the windows down, you close the doors, you lock yourself inside. And that is exactly how cells are designed to behave when they're under attack and how our body is designed to behave. It's also the case that energy production happens when the body perceives itself to be safe. And that is part of this intelligent adaptive mechanism.

So as an example of this, why are you fatigued when you get a flu, or COVID, or Epstein-Barr Virus? Part of it is to make it so you're less likely to go out and expend energy, right? So, if you are sick, the body's trying to divert resources towards fighting off that threat. It doesn't want you to go for a 10-mile jog and then have a bunch of energy exhaustion and tissue that needs to be repaired it. It wants to save all its resources so it can divert it to fending off the threat. And if you have a bunch of energy that's causing you to do a bunch more work, that's just more demand on it in that already stressful high-demand situation.

So, it is important to understand this is an intelligent adaptive response. And this is what your question is getting at, is we don't necessarily want to force the mitochondria out of that state into a high-energy state in that scenario. Now, I don't necessarily think that providing more nutrients. Like, let's say b vitamins or acetyl-L-carnitine, or CoQ10, or alpha-lipoic acid, or d-ribose or something like that is necessarily forcing them out of an intelligent cell danger response.

I don't know if it's even possible to force them out. I would say the closest thing that that there is to that would be using the peptide MOTS-c. There's a peptide called MOTS-c. That's a mitochondrial peptide that kind of signals for energy production at the mitochondrial level and mitochondrial biogenesis and things of that nature.

And I have talked to one world-class peptide expert who has used it with many people with chronic fatigue syndrome with great success. However, he does warn against sort of forcing the engine to rev up in that state. And that's really getting at exactly what you're talking about, is there may be a downside in some context to that.

Again, I don't think necessarily providing sort of some of the mitochondrial supplements is going to force them into a state like that. I think it's just maybe helping bolster their capacity to produce energy in a fairly gentle way. I would be more concerned with one of my favorite topics, one something I think is very important, which is hormetic stress, which is I think vital to engage in to recover and bolster mitochondrial health.

However, when someone is in a full-blown cell danger response, there is a very tight goldilocks zone for what is the appropriate dose and type of hermetic stressor that will create a beneficial effect. And it's very easy when you're working with somebody in that kind of very serious chronic illness and very fragilized state where their mitochondria are really shut down to it's very easy to create a negative effect and overdo it and lead to more symptoms or a negative reaction.

Now, conversely, there is also a subset of people that may be locked in the cell danger response inappropriately. So, the way that Dr. Robert Naviaux talks about this in his work is sort of that sometimes this mechanism sort of malfunctions and the switch kind of stays in the cell danger response position. And even though the acute threat is over, the body has kind of locked itself in that state of physiology.

And in that context, as distinct from a context where let's say somebody's living in a mold-infested house and they're being exposed to the stressor constantly, that stressor is still present. Or they have an active chronic infection or some other. They're an athlete and they're chronically physically over-training. If that stressor is still present, it is appropriate and adaptive for your body to stay in the cell danger response. To stay more shut down.

If that stressor is not actively present that caused it in the first place, I think it is appropriate to use a bit more forceful measures to try to kick the body out of that cell danger response mode. Does that make sense?

[00:24:49] SCOTT: It does. So, what is it that you clinically perceive with your clients when they're in that CDR1 state versus moving into CDR2, CDR3 and eventually out of the cell danger response? What do you see that shifts at that point?

[00:25:04] ARI: I don't know if it's – I don't know if my observations of working with people sort of match up that perfectly with Dr. Robert Naviaux's model of CDR1, 2 and, 3. I think it's an interesting model. But I don't really have much to say on that specific thing. It's hard to sort of lump everybody into a clear pattern that relates to that model.

In the book, you talk about addressing the most common cell danger response triggers using nutrition. What nutritional factors are cell danger response triggers or resolvers in your experience?

[00:25:44] ARI: Okay. Big question. So, perhaps I’ll sort of give an outline of the book, my new book, Eat for Energy, as a way of getting into this. And we can delve into specific topics from there.

So, the first chapter of the book is all about the circadian clock, the circadian rhythm. We have a central circadian clock in the brain primarily responsive to light inputs. And we also have, as a newer scientific discovery, we have peripheral clocks in virtually all the tissues of our body, from our skin, to our liver, to our intestines, to our heart, to our muscles and our hormone-producing glands, they all have their own circadian clocks. And those clocks are primarily responsive to food inputs. And we also want to synchronize the two, the central clock and the peripheral clock.

So, there's a number of ways in which nutrition can either desynchronize those things and cause dysfunction in those mechanisms or that nutritional strategies that you can use to synchronize them and make them work optimally. Again, giving an overview, we can come back to this topic if you want.

And the next chapter is all about body composition. So, the ways in which excess levels of body fat and low levels of muscle mass contribute to mitochondrial shutdown and low energy levels. And how nutrition interplays with body composition.

And the next chapter is all about blood sugar. So, a huge portion of people have chronically high blood sugar levels or spikes into very high levels of blood sugar. And another portion of people have reactive hypoglycemia, low blood sugar levels two to five hours after eating. And many people have both, a combination of the two, largely driven by insulin resistance, which is largely driven by excess levels of body fat that exceed your personal fat threshold. A number of other contributors also matter here to this story. Both high blood sugar and low blood sugar are triggers to mitochondria to switch them into cell danger response.

The next chapter is all about gut health. And the next chapter is all about brain health. And there are specific mechanisms occurring at those levels that directly contribute to mitochondrial shutdown. So, in the context of gut health, I already mentioned, for example, how gut permeability can lead to an increase in LPS, lipopolysaccharide, getting into the mitochondria and triggering the cell danger response. So, that's probably the central mechanism. And that's a very superficial version of that story.

But there are many different ways that gut health, for example, relates to energy levels. And gut health, in turn, very much depends on nutrition, of course. And so, there are many specific things that can go on in one's diet that are either causing dysfunction at the level of the gut or creating optimal function.

[00:29:00] SCOTT: Let's dig in a little bit more to sleep and circadian rhythm optimization. I think that's so critical for health and certainly in the mitochondrial conversation for energy levels. So, what are some of the recommendations that you give your clients to optimize sleep? What are the zeitgebers, as you mentioned them in the book, and their relevance to our brain and body clock?

[00:29:21] ARI: Okay. So, the central clock in the brain is critical for sleep and wake cycles. And the primary zeitgeber – I don't know why circadian rhythm researchers decided to use this weird German word to describe environmental inputs that regulate the circadian clock, but they did. It's kind of a fun word. The primary zeitgeber for the central clock in the brain is light inputs.

The modern world disrupts that central clock in the brain in a couple of very profound and important ways that we now know from a large body of research that's accumulated in the last 15 years that disrupted and dysfunctional circadian rhythm relates – It increases the risk massively for dozens of different diseases, neurological diseases, cancer. In fact, night shift work is the only profession that's a recognized carcinogen. Obesity, diabetes, insulin resistance. It's linked with higher levels of inflammation. It's linked with disrupted hormonal rhythms and many different hormones that are directly tied into the circadian clock. Like, testosterone, and thyroid hormone, and cortisol, and melatonin, and growth hormone, as well as insulin, and a long list of other diseases. And of course, fatigue.

So, when you have a disrupted circadian clock, you are going to have disrupted sleep. And sleep and energy are two sides of the same coin that are linked by your circadian clock. So, we really want that circadian clock to function well if we want all those hormones that I just mentioned to be at optimal levels. As well as a number of other mechanisms, neurotransmitters, like dopamine, and serotonin and GABA, and orexin are all tied into the circadian clock as well. And they relate very much to aspects of mood, and energy, and libido, and motivation, and wakefulness, and cognitive performance. So, all of that depends on circadian rhythm.

Now, we have two really big problems in the modern world. One is that we're not getting enough sunlight during the day, and especially the morning when we should be getting it. And we are getting way too much bright light from artificial light sources in the evening when we shouldn't be getting it. The combination of those two disrupts our circadian rhythm and prevents that system in the central clock in the brain from doing its job of regulating all those hormones and neurotransmitters I just mentioned.

Now, there are a variety of fixes for that. So, just to mention them briefly, but I’ll assume that people have some familiarity with this. Bright light first thing in the morning within the first half an hour of the day is critical. You want at least 10 minutes of bright light. And ideally, a practice of sort of waking up, going outdoors. Hopefully it's somewhere in the hours close to sunrise. And looking at the sun or in the direction of the sun and allowing that sunlight to enter your eyes. Maybe combining it. I like to combine it with some breathing and movement practices. , I’m using that time. I’m not just standing there doing nothing. Go for a walk, something like that.

And you want to get as much bright light as possible during the day. And in the evening, you want to block out and minimize blue wavelengths of light in particular. To some, extent green wavelengths as well. And there are various ways of doing that using incandescent and dim lighting in your home. Switching off the fluorescent and LED lighting in your home, which has, by the way, been shown to suppress melatonin levels by upwards of 70% just being in a home under standard room lighting in modern homes. And that doesn't even account for TV screens, and computers, and cell phones, and things like that.

So, we want to minimize that by wearing blue-blocking glasses, switching the lighting in our homes and our bathroom, before bed in our bedroom and things of that nature. We want to have complete darkness in the bedroom by one way or another using blackout curtains, using an eye mask if blackout curtains are not an option for you. And those are a few of the sort of basic strategies to optimize the central clock.

We also have these peripheral clocks in all the tissues of our body as I mentioned. And the primary zeitgeber for that is nutritional inputs. The key there is that the – There are a few key strategies here. The most important of which is our daily eating window. So, there's been research that's been done by a circadian rhythm researcher named Satchidananda Panda, who is probably the best name of all time for a researcher. It's my favorite one to say. He tracked people's eating habits in a very sophisticated way and found that most Americans consume their food in a window between 14 to 16 hours a day. Over 85% of people consume their window of from their first bite of food to their last bite of food is 14 to 16 hours a day.

And that is problematic in the same way that extending the daylight period via lighting is problematic for the central clock in the brain. So, what I mean, if people aren't following, is there is a natural rhythm to the rise and fall of the sun. And our evolution has wired our circadian clock, has wired our biology, to respond to that rhythm and that timing of the rise and fall of the sun.

What the modern invention, human invention of electricity and man-made lighting, did was extend the daylight hours. And for most people, it extends the daylight hours by several hours. The feeding window, the eating window, should similarly be confined to a certain number of hours per day. And when it is extended out beyond that, we get dysfunction and we get dysregulation of those circadian clocks.

And we know from dozens of animal studies, as well as human studies, that when you take somebody who has a long eating window of let's say 14 to 16 hours a day and you do nothing else, you don't change the food they're eating, you don't change how much they're eating, all you do is change the window of time that they are accessing food.

We see reductions in inflammation, reductions in oxidative stress, improvements in insulin sensitivity, as well as improvements in a number of other parameters, measures of systemic inflammation, sleep quality, energy levels, things of that nature. But if you just consider the reduction, the improvements in insulin sensitivity, the reductions in oxidative stress and the improvements in measures of inflammation, all of those things directly tie into mitochondrial energy production.

So, the more you have poor insulin sensitivity, higher oxidative stress and inflammation, the more the mitochondria are picking up on danger signals, turning down the dial on energy mode and shifting into cellular defense. Ultimately causing you to feel the symptom of fatigue.

How many hours of the day we are eating directly ties into how much energy our mitochondria are producing? And we need to give them adequate time each night where they are not processing and metabolizing food and can go into catabolic processes, can go into autophagy and mitophagy in particular, which are basically breaking down worn out and dysfunctional cell parts and worn out dysfunctional mitochondria and rebuilding healthy ones. And that process needs to happen mainly during the nighttime period. And it needs to be in a fasted state.

So, if you are eating a very long eating window each day like most people are, 14 to 16 hours, you are condensing and confining that fasting window to a very small period of the 24-hour day. And you're also causing this dysregulation of the circadian clocks. You're also doing a few other things, you are suppressing levels of melatonin. You're causing higher levels of insulin resistance and things of that nature. There's a few mechanisms by which it contributes to fatigue.

But the gist of it is that. And we know from, again, these studies where they condense the eating window, you see these widespread improvements in basically every measure of metabolic health. So, the optimal range of where you change your eating window to is somewhere in the neighborhood of six to ten hours a day.

Now, I should say that more, or I should say less is not better necessarily. Doing six hours is not necessarily better than 10 hours. And I would say it's very context-dependent. So, the person who is a relatively fit, healthy athlete probably wants to go more towards 10 hours a day because they have a level of physical activity that will warrant more times feeding during the day. Whereas somebody who's very overweight and sedentary may benefit from going more to the six-hour end of the spectrum. But either way, it should be done slowly. You should not go instantly from a 14-hour window of eating per day to a six-hour window. If you do that all in one day, you will experience some negative side effects, some hypoglycemia, and some fatigue. So, you need to do it slowly over a period of time to help train your body into greater levels of metabolic flexibility where it can tap – It can switch from using the fuels that just came in from the food that you just ate, particularly carbs, to switch into tapping into stored body fat in a seamless way where you don't have hypoglycemia and you don't have a big dip in your energy levels.

[00:40:08] SCOTT: So, extending on that then, thinking about mTOR and AMPK, which is also the autophagy side of things, I want to talk a little bit about your thoughts on protein. So, you do talk in the book about protein. That it can support muscle building. The importance of body composition for mitochondria. So, where do you stand on protein? Do you think that we can get too much? And thus, constantly in that mTOR activation, not getting really into autophagy? And if we can get too much protein, is that animal protein? Or can we also get too much plant protein?

[00:40:41] ARI: Yeah, there's a lot in there. And it's controversial territory. I will say, I think to start with, that I think that there's a lot of over-simplistic notions around mTOR and AMPK, in particular, that have been put out there by many different, mostly, well-meaning diet gurus and health gurus of various types.

In particular, the notion that mTOR is bad, and that when we have too high of mTOR levels, we will drive cancer development and basically speed our demise. Has a grain of truth in it. But is largely misrepresented, okay?

And here's what's really going on. So, first of all, if you look up the relationship of mTOR activation, or IGF1 for that matter. And IGF1 is also oftentimes lumped into this. And this sort of the arguments against animal protein consumption. And that it's pro-cancer development. If you look up the relationships of mTOR activation or IGF1 levels and mortality, all-cause mortality, your risk of dying from any cause, it's actually a U-shaped curve. And what that means is that very high levels of mTOR and IGF1 lead to higher levels of mortality. But they lead to the same high levels of mortality that very low levels do. Very low levels of IGF1 and mTOR.

What this means is, like most things in the body, like, thyroid hormone, and testosterone, and pretty much everything else, there is a goldilocks zone of the optimal range of where you want to be. And too high is bad, and too low is just as bad as too high.

This is where I have a really big issue with many people talking about the subject who just sort of frame, "Oh, mTOR is bad. It's going to drive cancer. You got to avoid mTOR." No. mTOR actually is vital for your body. It is involved in tissue building, tissue healing and regenerating processes. And we need it. And here's how much we need it. You know what else stimulates mTOR really strongly? Exercise.

If you do weight training, it stimulates a big transient rise in mTOR. And we know that weight training is decidedly associated with good health, and resistance to disease, and longevity. So, that tells you there's something else going on in this story that's – With this story of mTOR that it's not as simple as more mTOR is bad.

Now, the real thing that's going on is this is another layer to discussion, things are neither bad nor good. They need to be in the appropriate range. And there needs to be undulation. There needs to be cycling in and out of these different compounds. We don't want to be in a chronically activated mTOR state, where we have chronically high levels of mTOR. We want a spike of mTOR when it's needed. And then we want it to go back down.

This is distinct from basically the typical American who is sedentary on a standard American diet with a feeding window of 14 to 16 hours a day, over-consuming calories, not doing exercise, and eating too much food in general for too long of the day. That is a scenario, legitimately, of too much chronic mTOR activation that will contribute to cancer development and many other diseases.

On the other hand, somebody who's a fit athlete who weight trains for 30 to 60 minutes five, or six, or seven days a week, who is busting their butt doing lots of exercise, dipping into strong AMPK activation with low mTOR levels, and then spiking mTOR and then eating a bunch of protein to help facilitate recovery of those tissues, they have a very intense cycling and undulation between the AMPK activation and the spikes of mTOR activation. As opposed to the chronic AMPK suppression and mTOR activation that we saw with the standard American diet eating sedentary person, okay? Who's eating 14 to 16 hours a day.

So, it's important to understand those nuances. It's not that mTOR is bad. It's that chronically over consuming calories, eating way too many hours for the day, and not spiking AMPK via exercise, that is a bad scenario where you're chronically in mTOR mode. And also suppressing it during the evening time during the fasting window at night while you're sleeping. So, yeah, hopefully that answers the question adequately.

[00:45:57] SCOTT: I like that answer, because I definitely love my protein shake every day. So, that's a good thing. Short-chain fatty acids, you say in the book, freely enter the mitochondria without the need for chaperone proteins or transporters. They simply waltz into the mitochondria and stimulate the processes necessary for energy production.

So, in that context, do you like tools like butyrate supplementation as a supportive nutrient for energy production? Or do you focus more on shifting the microbiome to better create short-chain fatty acids like butyrate?

[00:46:31] ARI: Great question. I think there's a context which I would recommend one or the other. I mean, I would always recommend the latter of the two to everyone. But there's also a context where I might recommend butyrate supplementation. I’ll say my friend Datis Kharazzian, who's a sort of world-renowned brain expert. I had him on my podcast maybe a year ago, and I asked him the question about his top supplements for brain health. And he put butyrate as his number one supplement for brain health, which I was actually surprised by. But he just raved about how much impressive research there is about butyrate supplementation improving brain health in so many different ways.

I think the context of somebody who is chronically ill and particularly the context of somebody who has microbiome issues of severity. And that can be assessed via different microbiome panels, GI effects. And there's a few that are very good. If somebody has chronic illness and they have chronic gut issues and they have microbiome disruption, there is a very strong case for supplementing directly with butyrate. And there's absolutely nothing wrong with that.

And I would even say there's nothing wrong with a healthy person with a good microbiome supplementing butyrate. They just might not notice any benefits from it. And it might just be sort of wasted money. But I don't I don't think there's going to be a risk of side effects of any significance by doing that. I could be wrong about that, but I don't think so.

On the other hand, if somebody has a relatively healthy microbiome intact, supplementing with something like partially hydrolyzed guar gum can massively boost populations of bacteria in the intestine that are butyrate-producing bacteria. And it can do it in a more robust way. And practically speaking, it's also quite a bit cheaper than supplementing with butyrate directly.

I would be more in favor of that – I mean, I’m in favor of that kind of approach with basically everyone, because it's a very targeted prebiotic fiber that specifically feeds beneficial microbes, Bifidobacteria species and a few others that are butyrate-producing bacteria without the risk of feeding negative bacteria that might be present there. So, I would pretty much recommend that sort of intervention across the board regardless of context. But I would be more inclined to recommend direct butyrate supplementation in the case of somebody chronically ill with dysbiosis.

[00:49:18] SCOTT: A number of people listening to this show who are dealing with SIBO, or small intestinal bacterial overgrowth, I know in some cases they may not always tolerate prebiotics and resistant starches and things of that nature early on. So, wondering what you see in terms of introducing these prebiotics and resistant starches in the people that you're working with? What are some of your favorites? And do you generally like to do that with food or with supplementation?

[00:49:45] ARI: It's a great question. This is something that I actually just took a gut course with one of the world's top gut experts named Dr. Jason Hawrelak. And it was a phenomenal course. I mean, he's legitimately – I mean, he's got to be in the top five people in the world in terms of gut health experts. And I learned a ton in this course.

And one of the things I learned a lot about was misconceptions around prebiotic fibers in general, and especially in the context of SIBO and IBS to some extent as well. But SIBO in particular. And there actually exists quite a lot of research showing that specific prebiotic fibers. While there are certain types of prebiotic fibers or colonic foods, which sometimes are conflated with prebiotics, there are certain prebiotics that are highly specific in nature like I just mentioned with partially hydrolyzed guar gum. Another one is fructooligosaccharides. Another one is galactooligosaccharides. And another one is lactulose.

And there is actually a large amount of research showing that use of these very specific prebiotic fibers as opposed to like food-based prebiotic fibers like resistant starches and things of that nature can actually be extraordinarily beneficial in the context of SIBO as a treatment. And they do selectively feed the beneficial bacteria without exacerbating the symptoms of SIBO and feeding the bad bacteria, the overgrowth of the negative species.

And the research is very clear on this. And there's a large gap between sort of the general thinking right now in the functional medicine community versus the actual research on this topic. There are a lot of functional medicine practitioners who are simply not aware of this research on these specific prebiotic fibers and who are sort of adopting very low fiber, low prebiotic approaches for fear of feeding the overgrowth. And there's a misconception around that.

The one thing that's a really important caveat to everything I just said is that you do have to go slow and low dosages of these prebiotic fibers initially so you don't get negative symptoms. And the truth is, even in a healthy person, if you use large doses of many of these different prebiotics that I just mentioned, you will initially experience things like gas and bloating.

There is a period where you have to sort of ease your body into it – Well, actually let me just add one more thing. When somebody experiences those symptoms who has SIBO, they will subjectively interpret that as, "Oh, this is bad for me. It's causing worsening of my symptoms." Okay? And it's important to understand the distinction there. Again, even a healthy person will have those symptoms. But they abate, as long as you go slow and dose low at first and just ease your body, ease your gut into that process. But again, the research is very clear that using many of those types of prebiotic fibers is actually highly beneficial for resolving SIBO.

[00:53:16] SCOTT: With the caveat that some people with mast cell activation syndrome and histamine issues may not always tolerate vinegar, I want to talk a little bit about vinegar. I know that you find it helpful for glucose and insulin health. Stephanie Seneff talks about acetobacter in apple cider vinegar being helpful for metabolizing glyphosate. So, how does vinegar play into the mitochondrial conversation?

[00:53:39] ARI: It's interesting about Stephanie Seneff saying that. I actually didn't know that. When we're looking at blood sugar levels, this is a really important contributor to fatigue that affects a huge number of people. Over 80% of the population in the United States has surges, daily surges, into the pre-diabetic or diabetic ranges of blood sugar. And that's distinct from the portion of the population with severe insulin resistance and type 2 diabetes that's basically in chronic hyperglycemia.

80% of the population and another one-third of the population has reactive hypoglycemia where they're dipping into low blood sugar levels two to five hours after eating a meal, which is largely due to insulin resistance. That's what's driving that for the most part. There are a few very simple hacks that you can use with your meal to really help this process.

Now, before I get there, I’ll mention the primary driver of insulin resistance is body fat, is excess body fat itself. And it is specifically the accumulation of excess body fat beyond your personal fat threshold. Every person has a specific fat threshold that is basically the amount of fat that their body can handle while remaining in good metabolic health before metabolic health deteriorates, before insulin sensitivity deteriorates.

And the reason why, it's sort of like a balloon. If you imagine, a balloon can only hold so much air before it pops. Our fat cells are kind of like that. We can store more fat in the individual fat cells. We can create more fat cells to some extent. But eventually, they all grow so big and so full of fat that they become leaky. And when they become leaky, that's when they don't soak up excess nutrients in the blood as well, and then we get insulin resistance. And at the same time, the excess body fat is also contributing to inflammation directly by producing what's called adipocytes. So, they're actually producing their own source of inflammation just by virtue of their presence of having too much body fat on your body.

So, the excess body fat is the cause of insulin resistance. The insulin resistance is driving up the blood sugar levels into too high of a range, either chronically or as spikes after meals, or both. And that high level of blood sugar is directly cytotoxic and mitotoxic. It is directly toxic to mitochondria to have very high levels of blood sugar. And actually, the cells create insulin resistance, this resistance to take in the blood sugar as an intelligent response to protect themselves from the damage that would be caused if they took in too much of that sugar that's floating around in the blood.

There are a few very simple strategies that I talk about in the book that you can use to mitigate high levels of blood sugar. The most important of which that is not a simple and easy strategy is losing excess body fat. That's the number one thing you can do. And it's so powerful that it's actually been shown in numerous studies that you can take full-blown obese type 2 diabetics who have been type 2 diabetics on medication on insulin for years and years and years, in some cases decades, and you can completely cure them of type 2 diabetes in a matter of weeks simply through weight loss, simply by losing the amount of body fat they're carrying on their body. It can cure type 2 diabetes completely in almost everybody. The exception being people who have been type 2 diabetic for decades oftentimes won't get completely cured. But many people get off medication within a few weeks.

Now, short of that more intensive effort and the more intensive dietary and lifestyle changes that are needed to produce that kind of effect, there are a few very simple tweaks that can produce fairly big results, one of which is consuming vinegar before your meals, like a teaspoon or a tablespoon of apple cider vinegar, or any type of vinegar before a meal or at the beginning of a meal. For example, if you have some greens or some salad on the plate, you can put the vinegar in the form of a dressing on those. And if you eat that at the beginning of your meal – So, the acetic acid itself is an insulin-sensitizing agent and also helps activate AMPK to help cells soak up and utilize the energy that's present more efficiently so that it doesn't hang out in the blood so much. And this actually works to create a pretty profound effect as far as lowering blood sugar.

Another very simple hack is related to what I was just saying about the greens, if you consume non-starchy fibrous vegetables at the beginning of your meal, this is another very simple thing that can help drive lower blood sugar levels. It doesn't even require changing what you're eating. Meaning, there are studies that all they've done is switch the order in which people eat what's on their plate. And they have people eat the non-starchy fibrous vegetables um at the beginning of their meal as opposed to mid meal or at the end of the meal. And that one strategy alone has been shown to take people's hemoglobin A1C, a marker of insulin resistance, from 8.3% down to 6.8% in a matter of weeks. And that's a pretty significant reduction. That's almost going from diabetic to pre-diabetic.

Again, I just want to emphasize what we're talking about. We're talking about not even changing what you're eating. You just ate the veggies first in the meal. Now, there's also similar research showing that if you do that with protein, for example, you eat that chicken breast or the fish that's on your plate first in the meal along with those veggies, well, in this case, the studies just eat the protein first, they show a similar effect of lowering blood glucose in response to that.

So, if you combine those three things that I just mentioned, protein and leafy greens, or non-starchy fibrous vegetables at the beginning of the meal combined with vinegar, you now have a three-pronged strategy that requires almost no effort where each of those things in isolation has been shown to have a very significant effect on lowering blood sugar. And so, you can create a very large effect just from almost zero effort strategies like that.

[01:00:50] SCOTT: Nice. Wow! That's excellent. In the super food section of the book, you talk about pomegranates, blueberries, acai, bilberry, maki berry, cranberry, camu camu, amla and others. So many good things there. But you talk about urolithin A, which comes from pomegranate, as another powerful mitochondrial tool. So, I’m wondering what your experience has been with urolithin A clinically? And do people commonly notice a difference?

[01:01:19] ARI: I haven't used urolithin A directly. I’ve attempted to for about a year and a half now. I’ve been at trying to get it in one of my supplement formulations. But for a long time, it wasn't available. It seemed like there was one company in particular was holding sort of the patent rights or something to that effect on this compound. And it looks like they were keeping it to themselves.

It's since then in the past couple months become available to other companies. But I just got a quote on it and they wanted something like $50 just for that one ingredient as my cost per bottle. I would have to charge a lot of money per bottle when my costs are $50 for just one ingredient.

As of right now, it's not conducive to dosing it at the proper range to get beneficial effects. It's very expensive. But having said that, there are a number of studies that have emerged on it already that show impressive effects.

The pomegranate extract is rich in a compound called ellagic acid or ellagitannins. And the ellagic acid gets converted by certain species of microbes in the gut into urolithin A. And that urolithin A is powerful. It's worth saying, it's a powerful promoter of mitophagy to help improve mitochondrial health.

So, what's unclear at this point in time right now is sort of the critical issue to distinguish between ellagic acid and urolithin A is to what extent there are – There is a subset of people who don't have the presence of the microbes necessary to convert ellagic acid into urolithin A. And I don't think there's a clear answer to that question yet.

It's also the case that – Well, I don't want to get too deep into a digression on this topic. I’ve looked for the specific species of bacteria that actually is involved in that conversion. There's one study in existence that I found that tracked that. And they found it's some very obscure type of bacteria that I’d never even heard of talked about anywhere else. I forget the name of it.

But I did talk with another gut expert about this question named Kiran Krishnan. You probably know. And he was very much of the opinion that you know sort of, "Nah. It's not just one species. There's got to be a bunch of species. There's always redundancy. It's not just one specific species that you either have or you don't."

It's really interesting how dynamic the microbiome is, in the sense that when we consume certain foods in certain compounds, it increases amounts of bacterial species that metabolize that specific compound.

For example, if you consume a lot of alcohol you'll get alcohol metabolizing microbes that grow in the gut. If you consume certain prebiotic fibers and partially hydrolyzed guar gum, you get butyrate-producing bacteria. And it's even to the extent I’ve seen research showing that if you consume a lot of sulfites, like, let's say you consume a lot of dried fruit, there are sulfite metabolizing bacteria that you'll end up starting to produce way more of that those bacteria and they'll produce a lot of hydrogen sulfide, gas, in your intestines. And there's many more examples of this.

But basically, certain microbes increase in our gut in response to whether we're consuming certain nutrients or not. So, this question of ellagic acid and urolithin A and the bacteria, do people have it or not, is further complicated by the fact that it is very probable in my mind. That if you took certain people that maybe weren't consuming any foods rich in ellagic acid and you took a measurement of their microbiome, they might not have the presence of any bacteria in significant numbers that metabolize ellagic acid. But if you start giving them ellagic acid and then measure them a month later, you might find that they have lots of bacteria that metabolize ellagic acid.

Now, I’m speculating. But that's a principle that is very clearly established in many other contexts in the gut in terms of gut research. So, we don't know the answers to those questions right now. And I’m very interested to see the research when it does come out.

[01:06:02] SCOTT: One of the other things that you talk about is spirulina and chlorella. My biggest mentor, Dr. Dietrich Klinghardt, has been an advocate for chlorella for many years. Not only helping detoxification. But also, being a really nutrient dense food as well. The source of the chlorella can be important, as many of them can be contaminated. So, wondering what types of chlorella do you think are helpful? And what your thoughts on chlorella in this realm?

[01:06:28] ARI: Yeah. I wouldn't say that I’m a world-class expert on that specific topic. And someone might disagree with something I’d say. But my understanding is clean sources of chlorella are generally Japan, Korea and Taiwan. And you have to be cautious with, for example, sourcing it from China. And meaning, I wouldn't source it from China. And it also needs to be processed in a certain way for us to get the benefits. And there's a few different methods that companies have come up with to crack the cell walls.

I think there's a method where they sort of tumble the chlorella in a chamber with glass beads and it sort of beats it up and cracks the cell wall. There's, I think, a Taiwanese chlorella that has very thin – Where they grow it in a way where it has a very thin cell wall that we can sort of digest. And there's also pressurizing it. Putting it in pressurized chambers that crack the cell wall. That's pretty much all I know about sourcing chlorella. And I don't know if you have anything to add to that. But those are the key points as far as I’m aware.

[01:07:36] SCOTT: Great. You also talk about broccoli sprouts, garlic, ginger and cacao. Sulforaphane from broccoli can be a really nice antiviral. It also supports Nrf2, which impacts inflammation, detoxification. So, do you like to incorporate sulforaphane using broccoli sprouts? Or is this one that you think supplementation can be helpful in?

[01:07:59] ARI: I am a huge fan of broccoli sprouts. And I’m very skeptical of supplements in this realm. The challenge with sulforaphane is it's an unstable molecule. And – Oh, I’m spacing on the exact compounds. But myrosinase and I think it's isothiocyanates I think need to combine. They're sort of stored separately in the cruciferous vegetable. And then when you chew it and/or cut it and blend it and that sort of thing, they get mixed together to form sulforaphane.

The problem is, again, that molecule's somewhat unstable. So, it's difficult to make into a supplement. There are, to my knowledge, two or three companies that claim to have gotten around this issue and claim to have stabilized sulforaphane in supplemental form. And I think they maybe even in some cases have third-party analysis verifying that. I know there was a company. The first one to do it was a company out of France.

And to be honest, I haven't looked in great depth as to whether those claims are really legitimate or not. And I have some skepticism around just the stability issues of sulforaphane. But the nice thing – And they're very expensive. So, for those reasons, the nice thing is broccoli sprouts are very rich in sulforaphane. It's very predictable. They're cheap. And they're even cheaper if you grow them at home which you can do in a few days very easily.

So, I’m a huge fan of broccoli sprouts. And I think the research is incredibly impressive for neuroprotective effects, anti-cancer effects, boosting detoxification and mitochondrial health. And I think that's just sort of scratching the surface.

[01:09:55] SCOTT: In the supplement realm, you talk about your top seven for energy and mitochondria. You have a comprehensive vitamin and mineral formula, methylated b vitamins, NT factor, which is phospholipids for supporting cell membranes, acetyl-L-carnitine, creatine, taurine and astaxanthin. So, wondering do you generally have people on one or two of these? Or is this something where someone might use all of these in a mitochondrial supplementation strategy?

[01:10:23] ARI: Yeah. Well, I have my own supplement formulations. So, the probably the easiest way to answer that is to say what do I do in my supplement formulations? And I have a mitochondrial formula. And it's called Energenesis. And I have everything that you just mentioned in it with the exception of the multivitamin mineral, which is its own supplement called energy essentials and superfoods. And I have a very comprehensive multivitamin and mineral combined with other superfoods like pomegranate, and chlorella, and spirulina, and several others.

And that's just because if I did them all together, I would have to charge $300 per bottle. And most people are just adverse. Psychologically, they're not ready to process the notion of paying that much for a single supplement. And there's also an issue of just how much powder is per scoop. People would have to do 30-gram scoops if I combine them together.

So, yeah, I think that all of those are absolutely wonderful to take together. And they work on different mechanisms at the mitochondrial level. A few examples of that, some of these ingredients are cofactors for mitochondrial energy production. B vitamins, for example, and CoQ10, and things like that are cofactors for the different complexes in the respiratory chain and the mitochondria to work properly to carry electrons properly to produce ATP properly.

Other compounds like, let's say, astaxanthin is a carotenoid pigment that originally comes from a couple types of algae that then get concentrated up the food chain. This is where salmon get their pink color. This is where flamingos get their pink color interestingly. It also concentrates in our tissues. And the chemical structure of it is very interesting and unique in the sense that it actually embeds itself across mitochondrial membranes, in the membrane itself of mitochondria, where it's been shown to stabilize the membrane and protect it from oxidative damage. That's a very distinct and different mechanism of supporting mitochondrial health compared to providing cofactors like B vitamins and CoQ10 and things of that nature. Both are important.

Similarly, the NT factors phospholipid has been shown in numerous studies. Well, mechanistically it works, by actually going in and replacing damaged phospholipids in the membranes of mitochondria with healthy phospholipids. When the membranes of mitochondria are not damaged when they're healthy, the mitochondria works better to produce energy. And that is another mechanism that is distinct from the others I mentioned. I would argue, synergistic with the astaxanthin. They work together to help stabilize and protect those mitochondrial membranes. You then provide cofactors. That's another mechanism.

Another mechanism is you are stimulating like sulforaphane and curcumin and resveratrol and pterostilbene and many, many other different phytochemicals. They're stimulating other pathways. They're stimulating the Nrf2 pathway, which is building up the ARE, the antioxidant response element, and building up the internal stores of glutathione, and catalase, and superoxide dismutase so the mitochondria can protect itself from oxidative damage via that mechanism. You're building up its internal resources to fight against oxidative stress. Again, another mechanism to support mitochondrial health distinct from the others.

You're also stimulating mitochondrial growth via that Nrf2 pathway and mitochondrial biogenesis via some of those phytochemicals and things like PQQ and EGCG from green tea. So, they are some of these nutrients which overlap in certain ways and kind of act on multiple different mechanisms at the mitochondrial level. But I’m a huge fan of providing nutrients that protect and regenerate and support mitochondrial health through a variety of different mechanisms.

[01:14:51] SCOTT: At the urging of my mentor, Dr. Neil Nathan, I’ve become excited about a form of B1 or thiamine called TTFD. Wondering if you've explored that form of B1 in the mitochondrial discussion. And when you're looking at these B vitamins like B1, B2, B3, B5, B6, all of these, do you find that the more active forms like P5P or R5P are better options?

[01:15:13] ARI: Definitely. I think that those methylated forms are better. The first thing that you mentioned, it's a TTF? What –

[01:15:20] SCOTT: TTFD.

[01:15:22] ARI: TTFD. I’ve actually never heard of that. I’m interested to go check it out now.

[01:15:25] SCOTT: Cool. Yeah, I did a podcast with Dr. Chandler Marrs on that topic recently. It's a book, Thiamine Deficiency Disease I believe was the name of the book from Dr. Derrick Lonsdale and Dr. Chandler Marrs. Really, really interesting.

[01:15:40] ARI: Nice. Yeah, I’ll check it out. Thanks for the tip.

[01:15:43] SCOTT: You talked about alpha lipoic acid. We talked about butyrate as well. There are many other nutrients you talk about in the book, CoQ10, curcumin, d-ribose, forskolin, EGCG, you just mentioned, NAC, some of the niacin derivatives. I mean, we're seeing lots of conversation about NAD and some of the precursors like NRM, NMN, those types of things. So, I’m wondering what are your thoughts on some of the niacin derivatives relative to mitochondrial function?

[01:16:11] ARI: Yeah, great question. This is an interesting topic because there's so much hype around these compounds right now. So much talk. So many people are getting on NR, nicotinamide riboside, or nicotinamide mononucleotide, NMN, and doing NAD therapy, NAD+ plus therapies. And many people online are talking about this like this is a really big key to energy to health, disease prevention, longevity.

What's interesting about it is how disconnected all of this hype is from the actual human evidence that we have thus far. It's actually kind of an interesting psychological phenomenon that we have managed to get so carried away with so much hype in almost the complete absence of research that warrants it.

The short answer is there are a number of animal studies that are very compelling and would lead one to think that these are critically important magic molecules that that have these sort of like almost fountain of youth effects. However, there are several human studies that have been done now. And almost universally, in those human studies, they have shown no discernible effect on virtually any marker of metabolic health. They've measured levels of mitochondrial health, and insulin resistance, and fat loss measurements, body composition metrics, measures of inflammation, and insulin resistance, and all kinds of oxidative stress. And almost without exception, in almost every one of these studies, they have failed to show significant benefit on virtually any of these markers.

So, I have nothing against these molecules. I’ve bought some and I’ve tried some myself for many months. I can't say I noticed anything. I know there's also on another level my friend Chris Masterjohn has also talked about the need to supplement with methyl donors if you're using high levels of them. And I think that's an overlooked topic that's probably going to turn out to be pretty important, like, TMG, trimethylglycine.

And, yeah. I guess, again, the short summary version is I think the hype is very disconnected from the research. If you have a body of research like what we have on that, it doesn't make sense to be running around talking about how amazing these molecules are.

[01:18:50] SCOTT: How about melatonin, which can protect the mitochondria by scavenging the reactive oxygen species that you mentioned earlier? Can help to optimize mitochondrial function as well? For many years, I personally call it my drug of choice. And I’m wondering if you found melatonin helpful in the mitochondrial discussion.

[01:19:09] ARI: Melatonin is an amazing compound that is extraordinarily underrated and underappreciated for what it does. It's starting to gain some recognition now. I’ve been talking about this for a few years, but people talk about melatonin like it's a it's a sleep hormone. And it certainly is involved in sleep. But it's also very much a mitochondrial hormone.

And one of its most important roles is in protecting mitochondria from damage. And our mitochondria are designed to be bathed in melatonin every night while we sleep. And that bathing in melatonin is actually vital for mitochondria to be healthy and to function well.

Not only does melatonin function as a direct antioxidant to help prevent damage, but it works to recharge the ARE. It works to recharge the internal antioxidant supply of other critically important antioxidants and detoxification compounds like glutathione, and catalase, and superoxide dismutase.

The circadian rhythm disruption that we have that I mentioned earlier, just being in standard room lighting suppresses melatonin levels in the blood by upwards of 70%, it's a huge issue. If you've got massive suppression every night for years, for decades, of melatonin, you are going to experience the consequences of that at the mitochondrial level. And it's also a very important – Very much related to its role in mitochondria, it's a very important anti-cancer hormone. So, if you're chronically suppressing it, you will have a much higher risk of cancer. Conversely, we also have lots of research showing that melatonin supplementation is useful in treatment of cancer of many types of cancer. So, we know there's a critical link there.

The story gets quite a bit more interesting, and in some recent discoveries, is that it turns out that melatonin is so important to mitochondria. That mitochondria actually evolved the ability many millions of years ago to produce their own supply of melatonin. Melatonin isn't only produced in the pineal gland in the brain like many people have thought for a long time. It's actually produced inside of the cells by the mitochondria for the mitochondria. It doesn't enter the bloodstream. That's separate source.

And interestingly, the primary stimulator of melatonin production at the mitochondrial level appears to be light, specifically red and near-infrared light, which is another avenue by which – Maybe we won't go too deep in this. But another avenue in which sunlight is critical for our health. And why taking a vitamin D pill as a replacement for adequate sun exposure is not adequate.

So, we need adequate exposure to sunlight. And if you're not getting it, supplementing with red in your infrared light is going to be critically important. I think it's going to turn out that this story of melatonin at the cellular level and at the mitochondrial level is actually a huge key to health and disease prevention.

[01:22:36] SCOTT: So, do you think that that topic is important enough that you would consider writing a book about it? Oh, wait you actually already did write a book about it.

[01:22:45] ARI: What's interesting about that, I did write a book on red and near infrared light therapy. What's interesting is that what I just talked about, that mechanism is so new that it didn't even make it into my book that I wrote a few years ago.

[01:22:58] SCOTT: I was going to come back to that as a later question. But when we talk about photobiomodulation red light therapy, how much of a role does exposure to red light therapy play in supporting the mitochondria? And do you think that exposure to red light itself could be enough to shift the energy conversation for those people that are dealing with chronic fatigue?

[01:23:19] ARI: I have a number of people who are members of my energy blueprint program that have said that red light therapy was actually the big thing that caused the transformation for them out of chronic fatigue. So, it can be, definitely. But it's not always. And not everybody gets that sort of magical massive transformative effect. But certainly, red light therapy is a very powerful therapy. There are over 6,000 studies showing all kinds of benefits, from skin anti-aging, to fat loss, to brain health, to improving your recovery from exercise, to decreasing autoimmune destruction of the thyroid gland and many other benefits.

So, I’m a huge advocate for it. And I think that this new mechanism that's been discovered of how it supports melatonin levels at the mitochondrial level is a really massive finding that lends further credibility to the importance of red and near infrared light therapy in health and longevity more broadly.

[01:24:24] SCOTT: Dr. John Lieurance and I did a podcast on melatonin. And then more recently we did one on methylene blue. I’m wondering, where do you think methylene blue sits in the mitochondrial and energy discussion?

[01:24:36] ARI: I don't know. I experiment with it. I use it for a variety of purposes. There's a lot of interesting aspects of methylene blue. Just interesting avenues to go down on how it interacts with viruses. How it interacts – Actually, it interacts with red light. There are many different studies on photodynamic therapies of how red light – Interestingly enough, it's specifically the wavelengths of red light that activate methylene blue and actually can create reactive oxygen species, that when methylene blue is in contact with viruses, it sort of selectively destroys viruses. It's also been used in cancer treatments to selectively destroy cancer cells without really destroying healthy cells.

Some really interesting magic there as to how it can accomplish those kinds of feats, there's also studies on methylene blue in the context of skin anti-aging and oral health, like, treating gum disease. And then of course, it's considered nootropic and considered a mitochondrial enhancer. So yeah, there's a lot of interesting stuff around methylene blue.

One of the things that's interesting about it is when I first started experimenting with it people were recommending doses of like a few milligrams a day. And then when I went and started exploring the research, the research was recommending doses that are 50, 100, 200 fold higher than that. As far as you look at some of the animal studies, they're using 15 milligrams per kilogram of body weight.

So, in a human who weighs let's say 80 kilograms, that's a lot of milligrams of methylene blue. And even if you did the calculation conservatively, you didn't use that exact calculation, but let's say you toned it back to one-fourth or one-fifth of that, it's still a massive dose.

So, there's a big discrepancy between a lot of the dosing that was going on in the biohacking community for many years and the doses that are talked about in the literature as having certain benefits. I don't know if anybody has made sense of that.

I know Dr. Mercola recently had a methylene blue researcher on his podcast. I actually haven't listened to the episode yet. But I’m interested to hear his thoughts on some of these questions. Hopefully they dug into that. But, yeah, I don't know. I don't have specific recommendations around methylene blue because of those kinds of uncertainties.

[01:27:10] SCOTT: So, as we start wrapping up, I maybe want to bring the conversation back to what you alluded to at the beginning. And that is when many people think of fatigue, I would say, historically in the functional medicine realm, we think of the adrenals, or maybe even the thyroid. But I think in the past few years, I’m seeing more health leaders suggest that the mitochondria is more of an issue than the adrenals. I want to get your thoughts on where the adrenals fit into the discussion relative to the importance of supporting the mitochondria.

[01:27:39] ARI: Oh, that's a big discussion. This is something I’ve put out multiple hours of content on. I spent a year of my life looking into the question of how adrenals relate to chronic fatigue. And this is something that deserves a proper treatment. So, forgive me for my very short answer.

But the very short answer is there is no scientific case for the existence of adrenal fatigue as a thing. There is no scientific case that chronic stress of any type for any duration of time reliably results in wearing out of the adrenal glands and low cortisol levels.

In addition to that – So, I’m going to say some big controversial things without necessarily building out the 20 minutes of other aspects of the research that we could talk about to support these things I’m saying. The other aspect of it is, if you look at the research, like I’d spent a year of my life doing, on the relationship of adrenal function cortisol levels and chronic fatigue, not just chronic fatigue syndrome, but also other fatigue syndromes, like burnout syndrome, and clinical burnout, and vital exhaustion, and stress-related exhaustion disorder, they go by various names in the literature. There are numerous studies. Actually 59 studies that have taken place over about 30 years by researchers all over the world most of which do a very simple thing, which is pretty much science 101, to test the adrenal fatigue hypothesis.

They take a group of people with those fatigue syndromes and they take a group of people who are the same age, and gender, and body composition, have the same exercise habits, and smoking, and drinking habits, and so on. So, control group of healthy people without fatigue. And they simply look at their cortisol levels.

And if abnormal adrenal function, or HPA axis function, or cortisol levels were a key factor in the symptomology of chronic fatigue syndromes or stress-related fatigue, and exhaustion syndromes, and burnout syndromes, that would clearly and obviously show up in those studies.

And what those studies show is that, if you want to get specific, 15 of those 59 studies showed evidence for a slightly lower cortisol levels being associated with the group with fatigue. Not even abnormal cortisol levels, but slightly lower on average that was statistically significant. Still within the normal range.

The 11 of those studies showed evidence for the opposite finding. Slightly higher cortisol levels in the group with fatigue. And 33 of the 59 studies could find no discernible difference in cortisol levels between the group with full-blown fatigue syndromes of various kinds and the healthy people.

Again, what this says is that it appears that the all of the talk for a few decades around adrenals and cortisol being so central to this topic of fatigue simply is not warranted by the scientific evidence. There is – Again, forgive my brief treatment of this complex deep topic. But this is not to say that HPA axis dysfunction doesn't exist, that it's not possible to have low cortisol levels. It is. But that is not common in people with chronic fatigue. It is a subset of people with fatigue. A relatively small subset. Not the majority of people with fatigue. And the most common cause of it is actually sleep deprivation and circadian rhythm disruption.

[01:31:29] SCOTT: My last two quick questions for you, and then I know you got to go, you recently released your Breathing for Energy Program. So, tell our listeners about your program and how that could contribute to improvements in energy.

[01:31:41] ARI: Breathing is absolutely a key factor in energy levels. Most people are chronically over-breathing. And there's a variety of factors of what drives that, chronic psychological stress, poor diet, a high potential renal acid load of the diet will drive this, and poor fitness levels. And ultimately, we have a situation of most people ending up in a chronic state of over-breathing, breathing too fast and too deeply. And this relates directly to energy production at the cellular level because it relates to oxygen delivery at the cellular level.

There's something called the Bohr effect, named after a physiologist named Christian Bohr, who discovered this phenomenon I think 100 years ago or more, where red blood cells that are carrying oxygen, their ability to deliver it to the cells depends on the presence of higher levels of carbon dioxide. Carbon dioxide isn't just this waste gas that we're supposed to get rid of. Actually, our body is intentionally retaining a certain level of carbon dioxide because it serves a physiological purpose. It's not just this waste product that we're designed to get rid of. And that physiological purpose that it serves is what's involved in regulating blood ph level, but it's also very importantly involved in facilitating oxygen delivery to the cells. The oxygen literally detaching from the red blood cell and getting into the cell in the mitochondria where it's needed to produce energy.

So, when you are chronically over-breathing, you are lowering your CO2 levels and actually hindering your ability to deliver oxygen to the cell paradoxically. So, in other words, breathing too much and too frequently, people would intuitively think, "Oh, this oxygenates my body." Actually, it does the opposite, because it lowers your CO2 level and hinders oxygen delivery at the cellular level.

So, learning how to breathe properly – And Patrick McKeown's and the Buteyko Breathing Method is the best I found for doing that along with combining intermittent hypoxic training breath hold practices is critical. So, I actually partnered with Patrick McKeown to build out this program called Breathing for Energy and developed a whole sequence of guided intermittent hypoxic training practices, breath hold practices to take people all the way from 15 second breath holds all the way up to three minutes and beyond. And there are many, many benefits of doing that particularly at the mitochondrial level. So that's the very short answer.

[01:34:22] SCOTT: Excellent. All right. So, my last question for you is the same for every guest, and that is what are some of the key things that you do on a daily basis in support of your own health?

[01:34:32] ARI: Starting my day with sunlight in the eyes while doing certain breathing practices. I combine it with intermittent hypoxic training actually, which is – So, I’ll say those as one and two. And number three, getting time outdoors in nature and ideally midday sun. So, I’ll combine another two as three and four. There are many, many, many benefits of sun exposure. So, I make sure to prioritize that. Melatonin at the mitochondrial level, vitamin D. There are actually other benefits of UV exposure like nitric oxide and the melanocortin system, which impacts body composition and appetite and all kinds of things. And time in nature. Forest bathing. Has a whole bunch of research on it as well to show profound benefits of that. So, I’ll leave that as my fourth for now.

[01:35:21] SCOTT: Excellent. You have gone so deep into this topic. I really love the conversation. I encourage people to get your book Eat for Energy: How to Beat Fatigue, Supercharge Your Mitochondria, and Unlock All-Day Energy.

Thanks so much for being here, Ari.

[01:35:36] ARI: Thanks so much, Scott. I really appreciate it. And wonderful questions.

[01:35:39] SCOTT: To learn more about today's guest, visit TheEnergyBlueprint.com. That's TheEnergyBlueprint.com. TheEnergyBlueprint.com.

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