Dr. Mark Holthouse returns to The Thorne Podcast to discuss mitochondrial uncoupling to generate heat and burn fat. Listen in to learn how this process can promote healthy aging and how the powerhouse of the cell reacts to oxidative stresses in the body.
Robert Rountree:
This is the Thorne Podcast, the show that navigates the complex world of wellness and explores the latest science behind diet, supplements, and lifestyle approaches to good health. I'm Dr. Robert Rountree, chief medical advisor at Thorne and functional medicine doctor. As a reminder, the recommendations made in this podcast are the recommendations of the individuals who express them and not the recommendations of Thorne. Statements in this podcast have not been evaluated by the Food and Drug Administration. Any products mentioned are not intended to diagnose, treat, cure, or prevent any disease.
Hi, everyone, and welcome to The Thorne Podcast. Thanks for joining me this week for another episode. And this week we have Dr. Mark Holthouse, who's joining us again. He's a physician that has taught hormone health for the Institute of Functional Medicine since 2014, many years. His specialty is men's health, prevention of cardiovascular disease, dealing with cognitive illnesses, and intestinal disorders. How are you today, Mark? It's great to have you back again.
Mark Holthouse:
I am doing well. Always great to have fun with you and talk about these really great topics.
Robert Rountree:
We keep the fun in functional medicine.
Mark Holthouse:
Functional medicine has to be fun because it's too hard not to be.
Robert Rountree:
Yeah. Let me ask you this. How many years have you been in practice?
Mark Holthouse:
Oh my goodness, since 19-
Robert Rountree:
More than you want to know.
Mark Holthouse:
A long time. Let's see. Well, medical school ended in '90, so family practice residency in '93-4. 30 something, early 30s.
Robert Rountree:
Right. And did you always do integrative medicine or was that something you evolved into?
Mark Holthouse:
I got to the point where I was ready to “vamos” medicine, because I was tired of being, as my partner and I would put it, a glorified drug rep. I just felt like my scope of care had dwindled from residency training so severely and I went into it for the preventive piece and I felt duped when I realized that all that meant was taking account of the last mammogram. It's like, wow, no, that's a cancer that's already there. I'm looking at prevention.
Robert Rountree:
Prevention.
Mark Holthouse:
About 15 years into that 30 year stint, we had a course correction. I refer to myself as a recovering MD now.
Robert Rountree:
Well, I'm glad to hear that you're on the road now. And from previous discussions with you, I can tell that you've really gone in deep into that road less traveled. You really like the science and the physiology, getting into some depth about what's going on.
Mark Holthouse:
I didn't realize how much of a nerd I was in family practice. You learn this stuff in residency and you just say, "OK, I'll study for the test every 10 years," but functional medicine is a jealous mistress. It's just the task master where you find yourself in these rabbit holes. But I guess we must have some desire to go there to be attracted to this style of medicine.
Robert Rountree:
Well, let's get into the main discussion for this week, which is mitochondrial uncoupling. Wow, what exactly is that? And what's the effect of this mitochondrial uncoupling and longevity? How does that impact longevity and what we call biogenesis? This is the perfect topic for a geek that has gotten into the science, but your job is going to be to explain what the heck this means and why would your average person care about this? Can we break some of this down for our listeners that maybe don't have a background in the physiology or the science, but are interested in optimal health, feeling better, etc. Why should they care about mitochondria? What are mitochondria?
Mark Holthouse:
Oh my goodness. No, it's a wonderful discussion. And you follow the bouncing ball with me, if you will. I'm a hormone guy, and hormones are largely made in the mitochondria. That's the justification that I gave some of my mentors and really the mitochondria is this ancient thing. We think it might have been a bacteria probably at one time, a long time ago, before I was ever a gleam in my dad's eye. And probably you as well, Dr. Rountree
Robert Rountree:
Maybe a couple of billion years ago.
Mark Holthouse:
It's a while. And so the cells decided they would be better off engulfing these bacteria and they help each other out. Plants have a similar kind of organelle in them called a chloroplasts that does this. And the chloroplasts and the mitochondria are like these little motors inside the plant and animal kingdom's cells that generate our energy. An important, but thankless task. In that process, like a combustion engine, there's waste. We have fumes and exhaust from our automobiles. Well, we have oxidative stress and reactive oxygen species, and other alien types of names that these poor mitochondria have to generate and endure during their lifetimes.
And so this whole idea of uncoupling really is nothing more than the idea of, hey, let's give those mitochondria a trip to Tahiti with an umbrella glass for a couple weeks, a vacation, if you will, so that they can take the time to do some housekeeping, get rid of those oxygen species that they've produced, and work on longevity and anti-aging. And oh, by the way, when they're not coupled – and uncoupled – we find that they make heat from the calories we ingest, as opposed to storing ATP energy and making more fat around our midlines.
Robert Rountree:
So the uncoupling part… What is being uncoupled, if you can explain that. What is coupled in mitochondria?
Mark Holthouse:
Great question.
Robert Rountree:
What does that mean exactly?
Mark Holthouse:
Great question. Has nothing to do with marriage counseling and what happens is these mitochondria have within them, these things that we call the Krebs cycle, and that brings the hair on the back of any medical student's neck up.
Robert Rountree:
Well, you got to learn that for the exam and then –
Mark Holthouse:
Horrible.
Robert Rountree:
– forget it as quickly as possible.
Mark Holthouse:
You memorize it to forget it. And this is the geek part of functional medicine. You got to go back into that realm. Well, this Krebs cycle thing come to find out is where it's all happening within the mitochondria to take the calories and the carbs, the fats, the amino acids, the proteins that we eat and convert it into a usable form of currency, which the cell calls ATP that pretty much does everything we do from thinking to detoxing, to whatever you can come up with.
Robert Rountree:
We couldn't function without ATP.
Mark Holthouse:
Couldn't function. We'd be dead without it. And that's what causes a lot of us to go into rigor mortis when things aren't doing that well, when we buy it.
Robert Rountree:
Why can't you just take ATP in a pill? If it's that great, why can't you just say, I'm going to have X amount of ATP every day.
Mark Holthouse:
I've heard certain companies claim they have that, but –
Robert Rountree:
Yeah, I have. I know. How would that work?
Mark Holthouse:
How would that work? That would be a best seller tomorrow. You've got this Krebs cycle that's turning out all of this conversion of food to ATP and in the Krebs cycle in the very bottom has basically using vitamins to transport electrons from this process of eating food to something that's very obscure sounding, but it's called an electron transport chain, ETC. And this is where life is happening because you're literally taking electrons from food, transferring them via vitamins, cotransport molecules, and literally making this gradient of protons, which is an energy, a biochemical gradient, that allows you to make energy in the form of high phosphate energy bonds. We call those ATPs.
And the uncoupling comes when the mitochondrial membrane, instead of tossing those electrons in such a way that we make ATP, we actually just make a bunch of heat. It's called thermogenesis. And it's how our brown fat generates heat. And this is why actually our brown fat is brown. It's chuck full of mitochondria that are uncoupled and doing this. We've got brown fat, lots as we're a little kids, and we lose it over time, but converting white fat to beige brown is a good thing because you've got all this mitochondrial uncoupling and heat generation as opposed to energy storage going on. This is what the uncoupling is. It's at a mitochondrial cellular level.
Robert Rountree:[AR1]
What we're really talking about is having your mitochondria make heat and be efficient at burning fat –
Mark Holthouse:
Exactly.
Robert Rountree:
– to make that. That heat is coming from burning fat. And I know hardly anyone, I don't know anyone, two double negatives. I don't know anyone who doesn't want to burn fat.
Mark Holthouse:
Exactly. It's an interesting question whether the mitochondria are becoming less efficient, like a Ferrari engine, or more efficient, like a Toyota Prius. If you really look at it and see that they're wasting caloric energy and making heat instead of storing, it's really a more of a form of inefficiency that's allowing you to go after this oxidative stress, promote these longevity genes and antiaging effects, all while the mitochondria are making more of themselves. We call that mitochondrial biogenesis.
Robert Rountree:
Biogenesis.
Mark Holthouse:
Yes. And so a lot of people will say, "Well, why would I want to uncouple and be less efficient with my calories? I'll get fatigued. And I'm going to be hungry and cold and tired, like a low metabolism." And in fact, just the opposite turns out happens. As we're uncoupling, we're actually making more of them. There's the net neutral energy issue going on as far as more work being distributed amongst more workers, more soldiers, if you will, as it makes more of itself. Some of these cells have got thousands of these mitochondria.
Robert Rountree:
Thousands of them. This begs the question, what about this guy, Wim Hof? You ever heard of Wim Hof? Tell us a little bit about what Wim Hof's theory is and why I go for a swim at my local gym, and I see people taking a plunge in, they have this cold water pool at the end of the swimming lane. And I see people even the middle of winter going and jumping in this cold water. Why are they doing that? And what's that supposed to accomplish?
Mark Holthouse:
I think they're absolutely certifiable is what I think, but finishing your shower with a cold one minute exposure to water, jumping in these polar clubs that are in Scandinavia and whatnot, there's data now that says that these so-called crazy people might not be as crazy as we thought. They're uncoupling mitochondria when they get exposed to cold water and other crazy things like staring at a red light, red light therapy, sitting in an infrared spa or sauna that's got this certain wavelength of energy have now all been shown to help with uncoupling. Even the FDA has approved some of these red light therapies for things such as wound healing and whatnot. There's all of these things outside of just what you eat or how you eat that can cause this uncoupling cold water exposure is one of them. Red light's the other one. And there's others with food that are specific too.
Robert Rountree:
I've just been reading this book about bird migration, which you might say, what? Why the heck would you read about something like that? Well, it's written by a biologist who talks about what happens in bird's metabolism before they get ready to go fly 8,000 miles, 10,000 miles nonstop. You think, well, they've got to have pretty darn good mitochondria to do that, which is exactly why there are physiology labs that are studying this. And one thing they found is when they're preparing to do these long flights, they eat like crazy. And they basically become diabetic. They get fat. They put on all this body fat. They get so fat, they can hardly move around.
My point is that the enzymes that control how our mitochondria turn on and off are a lot more flexible than people realize. There's things that we can do that will change how our mitochondria function. Birds can do it. Humans can do it. All animals can do it. There's obviously dietary things, environmental things that can influence our genetic expression, which then changes whether our mitochondria are coupled or uncoupled. Our mitochondria are not just little furnaces that are off doing their thing, and there's no influence. They're highly influenceable. Can you speak to that a little bit?
Mark Holthouse:
Absolutely. It's a signaling issue, and we know that ketones are intracellular signaling agents that turn up when we basically bring fat from our periphery into the liver, and some of this fat is converted to these ketones. And we used to think that the ketones in and of themselves were somehow this magical, somehow preferred energy source over glucose. When in fact, most of the data now is saying it might supply at best 30% of the total body energy needs in a day. And so that's not really making a lot of sense, but now we're seeing that maybe they're signaling uncoupling and we know that this is going on. We see that other things besides ketones, which you generate from certain types of macronutrients in the way that you're eating, but also in intermittent fasting, you're generating ketones.
We think that this is really where ketones are working for weight loss is promoting thermogenesis and mitochondrial uncoupling, as opposed to somehow making us a more efficient fat burner. One of the other things that's fascinating to me is the plants, the plants. Everyone's talking about in functional medicine, the plant predominant diet. And you look at it, the plant kingdom, their mitochondrial equivalent is this chloroplast thing, which has to put up with all the UV oxidative stress that they're sitting out there in the July heat right now, and they can't run away. They can't pop up on easy up. And so they've got all these things that they use, these tricks up their sleeve to deal with oxidative stress. And those are these plant sterols, these phytonutrients, these phyto-sterol pigments that are giving all these plants their beautiful color that are not only anti-cancer, but we're finding that when we, as mammals, eat these chemical pigments that plants have made to service the oxidative stress of their mitochondrial equivalent, their chloroplasts, if you will, we get the same benefit of uncoupling our own mitochondria in ourselves.
This is the twofold, one-two punch of eating plants. You get the fiber. Come to find out the fiber causes our gut buddies to make these things called short chain fatty acids, which are uncouplers. And then they've got the pigments, which are also uncouplers. Plants, you get this one-two punch of making all these wonderful post biotic products after you've eaten them, our microflora munches on them and makes things, strange names like butyrate and acetate, which are in their own right precursors to ketones, butyrate and acetate. You've got these feed forward positive cycles towards regenerating and giving your mitochondria a break to promote housekeeping whenever we're doing these things. You'll see a lot of people doing intermittent fasting, doing red light, doing cold baths at the end of their shower or at the end of their routine.
Robert Rountree:
You're pulling out that Wim Hof app on their phone
Mark Holthouse:
Pulling out the Wim Hof app, which I haven't got on my phone. I'll come clean. In addition to eating a plant-predominant diet and getting good, lean, clean sources of protein and fats, as a method of not just weight loss, but longevity and dealing with all this oxidative stress in our internal combustion engine, we call the mitochondria of ourselves.
Robert Rountree:
Just to clarify for readers that may not understand what oxidative stress is. We're talking about free radicals, and you may not know what free radicals are. Maybe you could give us just a basic definition of what we're talking about. And then as part of that, respond to the question about whether a little bit of free radicals are a good thing or a bad thing. Are all free radicals bad? What are free radicals? What is oxidative stress? And is it all bad?
Mark Holthouse:
Yeah. The good thing is, like most things in life, the truth is somewhere in the middle. And we need a little bit of these stressors to keep our immune system in top shape and to keep actually our mitochondria sensing that everything is still okay. We used to think that the reason that we had such good health with certain folks was because of their oxidation capacity to soak up antioxidants. It could soak up these guys.
Robert Rountree:
All antioxidants are good and that's the cure for everything.
Mark Holthouse:
Right. And then we started seeing data that, wow, some of these things are promoting cancers, and don’t use them with radiation for head and neck cancers and things like that, because it’s going to be a problem or prostate and colon cancers. We started to realize, wow, well, maybe some of these antioxidants just flooding the body like we were isn't the best approach. And maybe they're acting as these signaling molecules to do other things that we weren't aware of. On the other side of the coin is their reactive oxygen species or free radicals. These are when things like oxygen have electrons added or taken away that make them, from a chemical point of view, unstable. And when they're like that, they're unhappy until they can complete where they were initially, where they like to exist in nature.
Robert Rountree:
They're very reactive.
Mark Holthouse:
They're very reactive. And you might say that they're acting out within the body and –
Robert Rountree:
They're promiscuous.
Mark Holthouse:
They are promiscuous. They do things like oxidized fats and DNA, and –
Robert Rountree:
Tear up your cell membranes.
Mark Holthouse:
– tear up membranes and membranes are where all our receptors are, which tell our cells what to do when, when and how. So having a lot of these characters around it can be problematic because of their DNA damage can cause cancer, or they can cause cellular malfunction at multiple levels. Having a lot of them around is a problem and the place where they like to hang out where it's the steamy barroom club where they all go is in the mitochondria is where it's happening.
Robert Rountree:
That's where most of these molecules are made actually in the mitochondria.
Mark Holthouse:
Right. Absolutely. By far and away the majority was at 90% of them at a cellular level, that's where you're going to find these guys. We want a little bit around just like with most concepts, with functional medicine to stimulate, let the body know it's still alive, but at the same time we don't want excesses of these things. And sometime we'll have to talk about cell danger response with mitochondria that ties into this whole discussion.
Robert Rountree:
It's a little bit like the Hans Selye's idea that all stress isn't a bad thing. That a little bit of stress, actually, it's like you're poking the butt to get up out of the chair and go do something. That's what mitochondria need is that little bit of a poke with these unstable molecules tells the mitochondria, “OK, I got to stay alert and active and keep going.” It's just when there's a lot of them around and that would be what happens when somebody smokes cigarettes –
Mark Holthouse:
Exactly.
Robert Rountree:
– or lives or goes out, and always… I joke about this, but when I see people jogging by the side of a superhighway, I think this is not good. I'm glad that you're exercising, but you don't want to be exercising, increasing your need for oxygen while you're breathing in all this automotive exhaust. It's not a good thing.
Mark Holthouse:
Right. Right. Right. And bones are a great example of this concept. When they get stressed, they grow. When you put an older person in bed in the hospital for four or five days, they lose their bone and it happens very quickly. The body has this need for a little bit of stress. We like to give it a fancy name called hormesis, but it is an overlying concept in biology.
Robert Rountree:
Yep. Cool. Well, I think we're going to need to take a break right now. And when we'll come back, we'll answer some questions from our listeners, maybe get into some specifics about things people can do for their mitochondria, lifestyle changes, etc.
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Robert Rountree:
And we're back. Now it's time to answer some questions that have been submitted from our community. Thank you all for sending these in, by the way. Our first question this week comes from a listener who asked, why does mitochondrial biogenesis slow down over time? And what does this have to do with longevity? If we're eating the right thing, shouldn't we just keep on making new mitochondria our whole life? I'm going to add my own question here. Does something change where we suddenly stop making new mitochondria? What goes on there?
Mark Holthouse:
Yeah. And this is an area beyond my area of expertise, but from what I understand thus far, you've got these little powerhouses in our cells that have their own DNA.
Robert Rountree:
They're separate from the nucleus?
Mark Holthouse:
Right. Separate from nuclear DNA. And so they have the ability to reproduce themselves independently of the rest of the cell. Thank goodness. And this is why we're able to do biogenesis in the first place. With those DNA that exist within the mitochondria, there are all kinds of clocks and programs that we're just now understanding. And there seems to be an intelligence that the mitochondria has that runs the whole show for the cell at large. There's a term that we use called apoptosis, which is programmed cell death, where we're learning that the mitochondria and what's happening in the mitochondria and what it's sensing is going on within the cell has this unique ability, a kill switch, a death switch, if you will, to take out the cells.
And when these things are dysfunctional, sometimes it leads to things like cancers and uncontrolled cell growth or zombie cells and cells that really should be killed but are secreting now things that are contributing to aging, not just in the immune system, whose cells are particularly active, but can affect other organs, such as the heart, the kidney, and the pulmonary aging. And so there's this switch and this programming going on within the cells, we think largely within the mitochondria and the wisdom that's held there possibly in its DNA. And there's a finite number of replications and potentials for errors to develop in this mitochondrial DNA, just as we see with nuclear DNA, when cells divide and replicate themselves.
As time goes on, as oxidative stress takes its toll, as errors occur in this DNA, as these programs realize, “Hey, I'm not really pulling my own weight here anymore as a cell in a different tissue, making up an organ.” This is particularly a problem in neurological diseases where we see things in the neurons that avoid us having Parkinson's symptoms, checking out. If that's happening because of things that are prematurely signaling the mitochondria that you, as a cell, don't observe to draw breath any longer, we need to hit the death switch, are occurring. These are the kinds of things that we're seeing, but this is something that occurs over time. And Bob, you can speak to possibly some of the things you're hearing about with specific timing on that occurring.
Robert Rountree:
Yeah. Well, along those same lines, I think there are two things. I think there is some kind of built in program in ourselves that says, time to go shut down, time to take the long nap. There is some program that we don't really understand, some signal to do with aging in general. And then B, there is daily wear and tear. The DNA in our mitochondria don't have the same protection that the DNA in our nucleus does. The nucleus has got all these proteins, histones, that are wrapped around the DNA in the nucleus to protect the DNA from being bombarded by these free radicals, the unstable molecules. Mitochondrial DNA doesn't have that protection. It's an ominous image, but our mitochondria are basically getting bombarded every day with these free radicals, every day that we're alive. At some point we just can't keep up with the repair. And that's why the anti-aging specialists are saying, well, the secret to longevity is to improve the repair mechanisms. If we know how to do that better, then maybe we can unlock the door to longevity.
Mark Holthouse:
Correct. And these enzymes that are involved with protecting that sacred code, if you will, the DNA, these telomeres and these telomerase enzymes being one that's been isolated, but now there are multiple mechanisms that they think have to do with aging at the mitochondrial level, beyond just telomere length, which was the first big “eureka” about cellular aging that was stumbled upon.
Robert Rountree:
Absolutely. That ties into the next question, which is, well, at what age do we start losing mitochondria? When do things start going downhill?
Mark Holthouse:
And we always talk about health age versus how long you've chronologic age, your lifespan versus your “health span,” if you will. Your lifespan being what your birth certificate says and your health span being what your mitochondria know about you. And so we have folks that are prematurely aging because of oxidative habits, because of their diet, because –
Robert Rountree:
They smoke.
Mark Holthouse:
– they're smoking, because of pollution. Because of heavy metals that promote reactive oxygen species like gangbusters in the mitochondria and can be problematic at disrupting the Krebs cycle and the ability to make energy in general. And these are the people that are coming in saying, “I can't think anymore. I have brain fog. I have COVID brain. I have chemo brain. And, by the way, I'm also fatigued.” Who's responsible for clarity of thought in the neurons, and who's responsible for making ATP so that can happen there so our skeletal muscles can perform and exercise in the gym? Well, it's the mitochondria. This is the source of life in ATP. We refer to it earlier as the cellular currency. Cellular aging and more specific mitochondrial aging is a fluid situation.
You can see folks that are prematurely aging because of lifestyle changes. And certainly we know that most of the physiologic functions, whether you're looking at gastric acid secretion, whether we're looking at how efficient we are at getting oxygen out of the air we inhale, whether we can filter our blood and make urine, how much renal reserve we have. These are all age related things that are really hard to do a whole lot about, but start really kicking into gear midlife, 50, 60 years of age, when you look at the data. And my experience has been that as a whole, this is where you really start seeing things occurring with mitochondria as well. This is where there's a log rhythmic point to the curve, if you will, of aging in general.
Robert Rountree:
In other words, we can't really pinpoint a specific age for the general population, but that's what testing biological age versus chronological age is about. Because one person may be chronologically 60, but biologically their mitochondria are 50, or even 45. Could be 10, 15 years younger than the chronological age. And a lot of that has to do with how effective they are at repairing their mitochondria, how efficient this biogenesis process is. And I mention this, because I'm thinking of this French guy's name, escapes me right now, but he took up bicycle racing at the age of 103, and he raced under supervision for about two years and actually won some races and they measured his oxygen uptake and it improved over two years. If his oxygen uptake, what's called his VO2 max, maybe you can talk about that, what VO2 max is, but he improved his ability to utilize oxygen over two years. The only way that could have happened is if he made more mitochondria.
Mark Holthouse:
That's right. And there's a certain element to VO2 max, which we know is genetic. However, we do also know that at varying degrees there's been demonstrations like that. That's an amazing one. I've never heard that before where you can actually acquire an improvement. And the way that VO2 max works, it's a measurement of your cellular respiration, your ability, your mitochondria's ability to use oxygen and spin this Krebs cycle efficiently to generate muscular and energy for the body. That's phenomenal. That's amazing.
Robert Rountree:
Don't do this at home.
Mark Holthouse:
Don't do this.
Robert Rountree:
Don't try this at home if you're 103.
Mark Holthouse:
Oh my goodness. Yeah.
Robert Rountree:
Yeah, yeah.
Mark Holthouse:
That's fascinating. But no, the mitochondrial story is becoming one of how do we help support it? How do we help it do its job of repair and replacement? How do we support changing the old worn out batteries in our flashlights, in our cells, which we call autophagy, in general? There's a whole movement of being very muscular and very lean and focusing on maximizing physical physique and appearance and growth of the body, growth hormone and testosterone and things like this. And then you have to balance that with the mitochondria's need to really promote anti-growth, more longevity, more antioxidative purposes and autophagy. And like anything, like we talked earlier, there's a balance at a dance. It reminds me of hormones, estrogen and progesterone, estrogen and testosterone. The recurring theme of there needing to be a delicate balance between the two. when I get a lot of my patients come in that are really, really focused on their physique and how lean they can get and their 75-percent saturated fat diet to make killer ketones. And then we look at their labs and their inflamed as all get out.
Robert Rountree:
Yeah. The CRP's elevated. The lipids are off the chart.
Mark Holthouse:
Right. And I'll say to them, if I know them well enough, I'll say to them, "Enjoy how you look now, because it ain't going to last. Your DNA is suffering. Your body is aging, whether you see it or not, very rapidly."
Robert Rountree:
Yeah. Well that actually is the part answer to this next question, which is how can I improve my mitochondrial health in general? And then there's a corollary to that. Can you talk about what the Mito diet is? You're talking about the ketogenic diet. What's the Mito diet? How's that compare to the ketogenic diet? And is the Mito diet, is that a good thing for people to follow in general? And before we dive into that, I did want to define one term, you've mentioned a term, autophagy. Maybe you can explain people what that is, because I think when you start talking about what's good for your mitochondria, you're going to have to come back to this autophagy concept. What is that?
Mark Holthouse:
Exactly. Autophagy is really the discussion of supporting recycling of old cell parts that are literally worn out that are inefficient. And the mitochondria has this huge role in dictating and being the conductor of how this is all going.
Robert Rountree:
It's garbage disposal.
Mark Holthouse:
It's the garbage disposal and it's the programmed, "What is your trash day? Is it every Tuesday?” And we'd better make sure that's continuing to happen because there are things in the cell that they wear out and they're not doing anybody any good. In fact, they start creating intracellular inside the cell havoc if they hang around too long by producing –
Robert Rountree:
Which is like amyloid in the brain with Alzheimer's right?
Mark Holthouse:
Exactly. A souvenir of a battle that's gone on before. And so these excess proteins, even these other organelles, we call the mitochondria an intracellular organelle, but there's other organelles that they start to outlive their shelf life and they really need to be recycled. And this is RNA, it's DNA, it's proteins, it's all kinds of other things that we won't bore you with, but autophagy –
Robert Rountree:
Improving autophagy is part of this mitochondrial health.
Mark Holthouse:
It's all part of it.
Robert Rountree:
A big part of it.
Mark Holthouse:
It's all part of it because of their relationship. We have a Mito keto diet now that the functional medicine folks promote. And it's really because they've, I think, recognized that these are potentially one and the same things. Things that support the mitochondria are things that promote membrane health, because the mitochondria are made up of a bunch of membranes, an outer and an inner, and the inner is what in fourth grade you drew that looks little squiggly lines. And so we know that things that support healthy fats, omega-3s –
Robert Rountree:
Fish oil.
Mark Holthouse:
– fish oils are going to be incredibly helpful there. It's helpful for all these fancy molecules that can reside within these membranes and follow up signaling that's supposed to get across that membrane and tell the mitochondria what's going on. We want a certain amount of both omega-6 and omega-3s in there. Healthy fats are always a big deal. We talked about all the things that support mitochondria a little bit already in that the uncoupling. Things that are uncoupling, the plants, the fibers. Sometimes we get into some of the elements of the plants specifically like butyrate, we call is a short chain, fatty acid – like acetyl-L-carnitine, like CoQ10 – that have areas that are specifically needed, not just within the Krebs cycle, but also within this electron transport chain, which will get us into that NAD discussion that's there.
Robert Rountree:
Yep. Yep. Since you brought that up, people were have been asking me a lot about NAD because they're hearing about it. What does NAD have to do with all this? A corollary to these other questions.
Mark Holthouse:
Right. Right. You remember talking earlier, we talked about how the Krebs cycle takes calories and food and rips off these electrons within this Krebs cycle. And it does so via a couple of vitamins. And the ones that we really are talking about are vitamin B3 and vitamin B2, and NAD being a vitamin B3 – B as in boy – derivative, is one of these chauffeurs that transports this energy to this electron transport chain. And it docks there right at the beginning of it. And so NAD has become a point of interest with many functional and integrated providers for energy or what we call mitochondriopathies, where the mitochondria are failing in whatever organ you might be talking about.
If it's the pancreas where you make insulin, and now you're not able to make insulin anymore, and your sugars are starting to rise, it's not always because of being overweight and being inflamed. Sometimes there are toxins. Sometimes there are things, infections, that we know that can affect things and drive oxidative stress and damage the mitochondria. We know that NAD is now being touted as something that you can give as an IV. And what we're currently in the process of our clinic doing is looking at some of the literature on some of the real experts in this science of NAD, which is just a vitamin B3 derivative that –
Robert Rountree:
Right. It's niacin.
Mark Holthouse:
Niacin. It's part of this electron transport chain to make ATP. It's a bigger discussion in that I think sometimes just giving the IV form of NAD, which has a relatively short half-life, may be missing the mark if we're not looking at it in the bigger context. There are people in this field that are looking at different pathways, something called scavenger pathways, and some other things which really keep the NAD that we have around there. And if you do end up getting an IV, having it hang around a little bit longer, getting a little bit more bang for the buck, so to speak. The NAD and the IVs that are being done, people are making a lot of money doing this. I think there's going to be more to this story.
We're currently developing an energy module where it's going to involve mitochondria support in general. We're going to address some of these scavenger pathways to preserve NAD and some of these CD pathways that are involved with NAD that will make this a little bit more pragmatic, a little bit more practical, and it's expensive though. It's a fad right now. They've capitalized on niacin and its involvement with the ATP production pathway. We've got B2, riboflavin, that's involved a little further down the chain. Next year, we may have a FAD trend that starts hooking up.
Robert Rountree:
Yeah, well, I have to say, I've gotten very interested in this whole pathway of the nicotinamide riboside, which is a precursor to NAD. I know some people are not as enthusiastic about it as others, but what I've seen is that as the studies have evolved, they've learned how to exactly characterize what's going on. The animal studies have all been great. The initial human studies, some showed absorption, some didn't show an effect, but then they found it really depended on how you did the study. And if you do the study correctly, it does seem to show that nicotinamide riboside, which if given with the right other nutrients, like resveratrol, etc., and the methylating agent, like trimethylglycine, when you give all that stuff together, it really does seem to optimize NAD. That's one to stay tuned with, I think.
Mark Holthouse:
Right. The big question now is do we give precursors? Do we give the real deal? I think you nailed it, Bob. It's going to be the whole context. And if we're paying attention to the physiology, the biochemistry of how this exists, how it's recycled, like the glutathione story. There was so much more to that when we figured out selenium was needed to regenerate and glutathione peroxidase and all these other antioxidative mechanisms with catalase and whatnot, you start to see a bigger picture evolved. And I think that we've seen one small piece of a picture. And so I guess I'm not the first one that jumps on these things, because I always want to build that better mouse trap. I want to understand it in the context of everything else before moving ahead with treating it with a modality. We're getting close to launching our energy module for patients as a protocol. This will be one small piece of it.
Robert Rountree:
Wow. I'm really looking forward to that. OK. I think we've got time for maybe one more question, and this is an extension of something you talked about earlier, but the question is, how long do I need the fast to really stimulate my mitochondria? Is there too long of a fast? Can I overdo it and cause a problem? Maybe we can give just a short answer to that. If you fast for nine hours, is that long enough? Do you have to fast for three days? Is three days too long? What's the balance in there?
Mark Holthouse:
Yeah. As with everything, it's individualized. I have some premenopausal females who we don't have doing 16- to 18-hour fasting periods during the third week of their cycle because of what that can do to cortisol and stress and some other things, so putting it in the context of the individual. What I'm quick to say is that you'll start getting benefit as soon as you go to sleep and it's been four hours since your last meal, your body starts looking for places to keep serum glucose stable outside of what you're eating immediately through glucose neogenesis, whether it be glycerol from the fats, whether it be amino acids. We know that at 10 and 12 hours, we're already starting to see significant amount of ketones being generated. For those that can push that first meal out four hours from where they usually do, they're going to have some significant signaling and uncoupling going on from ketones.
Mark Holthouse:
We also know that you've got this sweet spot around 16 hours of fasting and an eight-hour window where you are going to see probably some of your best payoff for some of these ketones and weight loss anti-inflammatory purposes. Looking at autophagy and things like that, you're supporting stem cells and autophagy. Most of the data that I've seen has been out closer to 18 hours and longer, 24 hours in that realm. We know that the hormone ghrelin that stimulates our hunger peaks at about 48 hours. I always tell patients it's as hard to fast for two days as it is to do three or four days as your ghrelin starts to peak and then actually come back down after that 48 hours. But most of the time I'm telling people you're going to get the biggest bang for mitochondrial support autophagy somewhere between 18 to 24 hours, even out to as long as a three-day water fast.
But I don't recommend folks doing that all the time. Periodically. Your body likes to see things as a changeup. We don't want to do the same probiotics forever and ever. We don't want to have you doing the same fasting period without interruption. Many of my patients will do a three day water fast once a month. And they'll do a 16/8 fasting and eating window five days a week, the rest of the time. But from what I've seen from Dr. Davis Phinney and from Jason Fung's stuff, as well as some of even Valter Longo's stuff, somewhere in there seems to be pretty consistent. And there's some great work that's been done at Harvard with some foundational work on this as well.
Robert Rountree:
Great. I have to say that when I first went into practice in functional medicine, that whatever a person came in with, they were fatigued. They weren't feeling well. I would say, "Oh, well, my initial approach is to have you do a three- to five-day fast." And what's changed for me over the years is that I've moved towards reserving these longer fasts for people that are mostly healthy that want to clean out. Because I found that when I run people through a three-day fast and they weren't healthy, it can actually make them feel pretty darn sick. I think you'd just have to be careful when somebody has got a lot of imbalances going on. That would be my only caveat.
Mark Holthouse:
Exactly. They're going to have a lot of fat loss, which is where we store our toxins. They're going to mobilize this stuff and feel really flu-like and awful. I think it's important to individualize the therapy. We have an intermittent fasting class that we do, a group class. One is basically intro. The second is what to do when it's not working. Part three is based on specific special groups. We talk about premenopausal women versus 30-year-old men who are doing CrossFit every day. We talk about prediabetic patients who are incredibly metabolically inflexible. They don't know how to use anything but glucose. And so they get hypoglycemia very, very easily and it takes them a lot longer. And we go out these things at a much slower pace to get them.
Robert Rountree:
Those people wouldn't do well if they had to migrate 8,000 to 10,000 miles across multiple oceans during a typical cycle.
Mark Holthouse:
No. They would need a Red Bull somewhere about mile 5.
Robert Rountree:
You're going to need a little help from caffeine or something else. Well, folks, that's all the time we have for this week. Dr. Holthouse, I have to say something. You have said a lot of things today and our previous podcast that I did not hear talked about in my family medicine residency. And so it's really gratifying to be able to talk to a family practitioner that has taken such a deep dive into the science and has so many insights. Thank you so much for sharing all that information on our podcast. And again, I want to ask you, if people want to follow your work, how do they get in touch with you? What's your best contact source?
Mark Holthouse:
Thanks Bob. The website Functional Medicine of Idaho is available. We use info@funmedidaho.com is the most direct way. And that'll find its way through the patient navigators and things like that. And if you're looking to get information and you're in one of these states that I currently have a license, I can do at telehealth with you as well. California, Nevada, Idaho, Oregon, you're in luck. Everybody else, I'm still working on them
Robert Rountree:
All right. Well, thank you so much again for being on the show and I would love to have you back in the near future and thank you everyone else for listening. Until next time, bye-bye.
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