Dominic D'Agostino and Dr. Mike T Nelson: The Ketone Episode [OPP 75]

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Table of Contents:

Dominic D'Agostino is THE authority when it comes to ketone knowledge and research.

Metabolic Flexibility champion Dr. Mike T Nelson literally wrote the nutrition textbook.

Put them together on the Optimal Performance Podcast, and you're in for one of the best keto discussions you'll ever hear.

Meet The Experts: Dominic D'Agostino & Dr. Mike T Nelson

For an introduction to ketones, check out this blog post.

Today, we're diving deep in to the world of ketosis, optimal fuel utilization, applications for ketosis, and new research frontiers with two nutrition and performance leaders.

Dominic D'Agostino Ph. D, is an associate professor in the department of molecular pharmacology and physiology at the University of South Florida. He is also a senior research scientist at the Center for Human and Machine Cognition where he studies nutrition interventions for a wide range of pathology and performance applications - including Department of Defense and US Navy funded ketosis research.

Dr. Mike T. Nelson has spent 18 years of his life learning how the human body works, specifically focusing on how to properly condition it to burn fat and become stronger, more flexible, and healthier.

He has a PhD in Exercise Physiology, a BA in Natural Science, and an MS in Biomechanics and he's an adjunct professor and a member of the American College of Sports Medicine.

Like D'Agostino, Mike also been called in to share his techniques with top government agencies and his clients have been featured in international magazines, in scientific publications, and on websites across the globe.

What you'll hear from Dominic D'Agostino & Dr. Mike T. Nelson on the OPP:

  • Ketones improve brain energy metabolism, signaling and inflammation 
  • Ketones for cancer, Alzheimer's, and peak performance 
  • Who shouldn't use ketosis? (Speed and power athletes. People with extreme fatigue)
  • Does ketosis affect high intensity output? (Not if we focus on adaptation)
  • Why you need carbs to prevent down regulation of the PDH pathway and how to mix carbs and ketosis for optimal performance and health
  • How fasting, ketosis, creatine and calorie restricted diets affect strength
  • How well can you transition between fuel sources - why this is crucial for survival and optimal health
  • Tricks or hacks to flip fuel sources faster and more efficiently 
  • How individual enzyme expression can impact your ketogenic experience 
  • How fasting improves fat oxidation efficiency (it's about reducing insulin)
  • 20-93%...massive range of variability in individual fat use as fuel for BMR
  • How much protein should you be eating
  • How well can your body handle both ends of the spectrum - good indicator of overall resilience and ability to switch between fuel sources
  • Are exogenous ketones safe? Salts or esters?
  • How ketosis makes your CNS more efficient and can increase strength
  • Ketones accelerate muscular regeneration - independent of M-Tor and Amp kinase
  • Ketones completely abolish the insulin response from glucose bolus...Type 2 diabetes implications
  • Behind the scenes of Dom's new research
  • The future of exogenous ketone supplements
  • The neuroprotective powers of beta-hydroxybutyrate and how it can help combat or prevent diseases of inflammation
  • Where you can find more of Dominic D'Agostino and Dr. Mike T Nelson 
  • Mike and Dominic's Top 3 Tips To Live Optimal 

Watch the Video Version:

Links & Resources

Dominic's site: ketonutrition.org

Dominic's published papers

Mike's website  

Mike on Twitter

Exogenous Ketones

Papers, Studies and Journals mentioned on this show

HMG lyase & Ketogenesis Enzymes

PDH Enzyme Regulation

Nutritional Ketosis for Performance Athletes Paper in CELL Journal

D'Agostino's Fueling Performance: Ketones Cell Metabolism (free download from Dominic)

Dominic's Paper on BHB (beta-hydroxybutyrate) published in Nature & Medicine (free download from Dominic)

Dr. Veech on Ketones & Insulin Response

Dr. Veech on Metabolic Flexibility 

Dominic D'Agostino: Starving Cancer at TEDx Tampa:

Natural Stacks Performance Optimizers

MagTech - Increases synapse density for enhanced mental performance and promotes relaxation for improved sleep 

Prebiotic+ - Our resistant starch complex designed to help you optimize gut health and sleep

Smart Caffeine - 2:1 Ratio of L-Theanine: Caffeine, the exact ratio shown in studies to boost mental alertness and increase cognition

CILTEP - get "tunnel vision" focus so you can avoid distractions, focus on what matters most and increase your productivity

Transcript Version

 

Ryan Munsey: What's up, Optimizers? I'm your host, Ryan Munsey. Welcome to another episode of the Optimal Performance podcast.

We're going to get right into it this week. We've got an amazing episode for you. This is one that I have been looking forward to and wanting to record for almost six months, now. Busy schedules and a little bit of experimentation were required before this one, but we've got two great guests today, Dr. Mike T. Nelson, and Dominic D'Agostino, who is the expert when it comes to ketones.

We are talking all things ketones. Ketogenic diet, ketosis, who should use this, who shouldn't use this, more importantly. We'll be talking about exogenous ketones. Lots of really cool information here for you. Both of these guys are incredibly well-versed and intelligent, so we're going to cut this intro as short as possible. We're going to get to these guys.

A couple housekeeping notes, as always. You will be able to go to NaturalStacks.com to see the blog post for this episode of the OPP. We did not record this with video, but there will still be a video on there. More importantly, you'll be able to get the links to all the studies, and any other resources and show notes that you want to be able to get at that blog post.

Please go to iTunes, leave a five-star review, let us know how much you like the OPP. And if the Optimal Performance podcast is helping you, if you enjoy it, if you're a regular listener, please share it with the people in your life who are into the same stuff that you're into, and people who you know would get a kick from the things that we're talking about. We appreciate your time. We appreciate your support, and I'm going to turn it over to these guys. Enjoy.

Dominic D.: I'm an associate professor at the University of South Florida, Morsani College of Medicine, and in the department of molecular pharmacology and physiology; and I'm also a senior research scientist at the Institute for Human and Machine Cognition. And I study nutrition interventions for a wide range of pathologies and performance applications.

Mike T. Nelson: Cool. I'm Dr. Mike T. Nelson. I teach for Columbia University. I run my own business through Extreme Human Performance. I did some certifications through Eat Perform. I did a PhD in exercise physiology, primarily more on the metabolism area, and before that I did a masters of science on mechanical engineering, biomechanics.

Ryan Munsey: So, the translation here is two really smart people with a lot of experience helping other people optimize both physical and mental performance. So, for you guys listening, sit back and enjoy this one. This is an episode that has been several months in the making. I wanted to do some experiments with ketosis myself. Mike and I talked a little bit about some of this experimentation back in Paleo Effects in May, and the three of us just have crazy schedules, so it took a while to get our schedules the same. But we're going to do this for you guys today.

When it comes to ketones, ketosis, ketogenic diets, all that kind of stuff, if you're not familiar with it, if you want that introductory course, the 101, we're going to have a blog post for you guys on the Natural Stacks website. Just go to the Natural Stacks site, and in the search bar, you can type in keto, or ketones, and that blog post will come up, and you can read about the basics and the foundation of this stuff.

There's a ton of research that has come out lately and over the years supporting the ketogenic diet, and talking about who should and why they should use it. I want to start with that, and Dom, if you will, just kind of highlight some of the benefits, from a cognitive and a physical standpoint, of being in ketosis or following a ketogenic diet.

Dominic D.: Yeah. I like to start ... My primary focus has always been seizures, and in the process of studying the effects of nutritional ketosis, which includes the diet and also ketone supplementation on mitigating seizures from a broad range of ideologies. I became interested in, kind of fascinated with the effects that ketones have on brain energy metabolism, and more recently, on signaling, and on inflammation, things like that.

I guess I could talk about, go many different directions, here, but I think just from the perspective of the normal person, ketones provide an alternative form of energy that can provide the brain with a metabolic advantage in certain ways, and can influence the narrow pharmacology of the brain and the balance of neurotransmitters that can promote the restoration of brain homeostasis in people who have a pathology, but also a preservation of brain energy metabolism under conditions of environmental extremes, which we study in our lab, in different environmental chambers.

Also maybe of relevance would be a preservation of brain energy metabolism, even when glucose availability is limited, which could be during intense exercise, or during a fast, or whenever your blood glucose levels drop and you're hypoglycemic, your cognitive performance will take a sharp dip. But if you have the ketones living in your blood, that's kind of insurance to prevent against any kind of performance decrements that would be associated with hypoglycemia.

So, that's kind of my 30,000-foot perspective, and then we study all the signaling stuff is used, and things associated with that, through electrophysiological recordings, to metabolomic studies, to signaling properties, and things like that. So, we're kind of building into how, mechanistically, how it's so effective at ... nutritional ketosis, how it's so effective for so many different applications. And there's a pretty long list of applications, from weight loss, we're all familiar with that; but a wide range of seizure disorders, about 10 of them; Alzheimer's disease; Parkinson's; perhaps brain injury. A big focus of my life is cancer management, and probably at the top of the list is really human performance and resilience.

Ryan Munsey: So, you set this next question up on a tee so perfectly, and I'm so glad you did, because I asked the first question because I really want to set up the next question. This is really the question that I want both of you guys to chime in on and answer for us on this podcast, and that is, with all of these seemingly beautiful applications for the ketogenic diet, being in ketosis, whether it's, like you said, performance, resiliency, longevity. It has applications for neurological, or any number of, as you said, states. What I really want to know from you guys is, is there a population or demographic who should not follow a ketogenic diet?

Dominic D.: I think so. Mike, do you want to talk a little about that?

Mike T. Nelson: Yeah, I'll take a stab at that. There's a couple populations I think of. One of the ones I work with is moderate-ish level crossfit athletes, or people doing heavy amounts of glycolysis, or carbohydrate use during exercise. In my experience.

Ryan Munsey: Let me just interrupt for just a second, so if somebody is not a masters or a PhD in energy systems, explain what type of exercise that is.

Mike T. Nelson: Yeah. In the simplest terms for exercise, we can primarily use fat, we can primarily use carbohydrates. Then I'd say we've got accessory few sources, such as ketones, lactates, and a few other things you can throw in here.

But I've seen that people who are primarily doing exercise in that higher-intensity, 30-90-second bouts of pretty all-out exercise, that's primarily fueled by carbohydrates. We do know that if you measure the amount of basically power, or for lack of a simple term, energy that you can produce, carbohydrates are actually higher than fat. So I've found the people that work in that zone a lot of the times that a ketogenic diet would be extremely difficult for them, probably because they can't quite achieve the same amount of speed and power.

Now, if you get away from that, that's a little bit different thing, because you can make arguments about, do you need that much speed and power? That type of thing. So, speed, power type athletes, I'm not, at this point, convinced that a ketogenic diet would be best.

The other one, which there's actually even less data on, that I've seen, is people who have a super-high amount of residual fatigue. Their comments were maybe adrenal fatigue, as I do my little air quotes, and that kind of stuff. Just in my experience, those people tend to do better on lower amounts of carbohydrates, but more frequent. Basically trying to mitigate everything to less stressful situations in their body.

But again, I think part of that may be the additional stress of maybe trying to get into ketosis. We'll leave out exogenous ketone salts for now. It appears to be a little bit too much of a stressor for them to handle. Now, if we could maybe magically wave our wand and induce them into ketosis, maybe they would be okay, but that sort of transition, I find it to be much more difficult.

Ryan Munsey: Okay. Very cool. Dominic, anything to add?

Dominic D.: Yeah. I think what we lack, as far as the intensity, and if you achieve nutritional ketosis and maintain it, will it blunt your performance at high intensity? That's kind of a repeat question that I get. And I think we need to focus on adaptation, which is probably harder than what people realize.

For someone who gets into nutritional ketosis, and maintains it, and is of the mindset that they're going to maintain it, they need to train their body, high-intensity exercise in a state of ketosis, or else you're not going to be able to adapt. I think the body, and your metabolism, and your skeletal muscle, and your metabolism overall, is incredibly plastic in its ability to adapt to exercise intensity, if you're training within that state.

So, if you are, for example, limiting glycolytic flux to the muscles, your body will cope and upregulate adaptive mechanisms. That's what I think, but I don't think ... We just don't have the data. That's my speculation. We don't have the data to show that. And my kind of preference would be to train that way, to train in a state of nutritional ketosis with high-intensity exercise, and maybe during the actual event, when it matters, you may take a small amount of carbohydrates, or even a ketone supplement, because I think both of those things, a large enough dose of ketones, will actually cause in insulin a small insulin release, and enough to activate PDH complex.

And that has been kind of the argument in the exercise community, that you're really going around and blocking [inaudible 00:15:27] complex, and that is limiting your glycolytic capacity in the muscle. But I think, through metabolic adaptations, your body can upregulate various energetic pathways to compensate for that, and I think you can do that during your training, and then get the benefits of PDH activation with small amounts of carbohydrate supplementation during the actual event, when it may matter. Or during particularly intense training sessions, maybe once, perhaps twice a week, to make sure that pathway is kind of open, if that makes sense.

Ryan Munsey: No, it makes perfect sense to me, and hopefully makes sense to the listeners. I think a couple of questions for you, Dominic, on that. You said, making sure that you keep that pathway open by stimulating it maybe once a week. How many ... Or, how long would we have to go without stimulating it to see a downregulation, or that pathway no longer being available?

Dominic D.: Yeah, I think it's going to depend on, athlete to athlete, on the person in particular. The athletes are pretty adaptable, and in their metabolic flexibility, I would say, just based on feedback. So, I think it's going to depend, and I think this is where it becomes personalized approaches, here. People will have to experiment, and start out, basically transition their body into nutritional ketosis if they want to try this.

I just think of it, too, as a tool in a toolbox. There's emerging data to suggest that it could be beneficial for some athletes, but of all the different athletic applications, I think high-intensity training, we have the most limited amount of data for that, and I think we're talking to people to set up experiments now that will answer some of these questions.

But I think, from my perspective, what I would do and tell some athletes to do, and they're professional athletes and Olympic athletes that are trying this, and the feedback that I get is that they basically train in ketosis, and then once or twice a week, like I said, they will add carbohydrates in these amounts, depending on the duration, and depending on the intensity, ranging from just 20 grams, to 40, maybe 50 grams of carbohydrates. And that's a pretty small amount.

But their body, they go into the event into ketosis. Some of them go into it fasting for a pretty long time. And then, their intra-workout fuel source would be a fat-based, maybe an MCT-based drink with some carbohydrates, slow-burning carbohydrates.

Ryan Munsey: Do you have a ...

Dominic D.: It really depends on the athlete, though.

Ryan Munsey: Okay. Do you have a preference for the source of those carbohydrates?

Dominic D.: Yes, kind of. It varies across the board. But the UCAN starch that Jeff Volek was ...

Ryan Munsey: Yeah.

Dominic D.: That's used by some of the athletes. And then other ones have just used things like dextrose, or high molecular weight carbohydrates, [inaudible 00:19:08] starch, or something like that. So, it really depends across the board. I'm kind of more focused on the total macronutrient, and not ... And it could be dark chocolate, or something. A couple people use that. It kind of depends, but I think the amount is what's most important.

Ryan Munsey: Okay. Mike, I see you nodding. I'm going to give you a shot at this in just a second, but before we go away from lifting all together, Dominic, you mentioned that we don't have a big sample size, big data on this, but we do have data on you, and I don't remember the loads and the numbers, so you may have to fill in that gap for us. But you recently lifted a very, very large amount of weight on a deadlift, and then you reduced the load and did something like 18 reps, what was it, with like, 500 pounds. So, can you give us the exact numbers on that, and then maybe a little bit of insight into how you built that base up, I'm assuming in ketosis?

Dominic D.: Yeah. And that exercise, really just a maximal intensity for a very short amount of time, so it may not translate to things like mixed martial arts, or sprinting, or soccer, or something. But, yeah, I kind of have a powerlifting base. When I did transition from higher-carb diet to low-carb and then keto, I guess about seven years ago, I realized that my strength didn't suffer much at all. My workouts were never very long in duration, so I didn't really get to test if it would kind of decrease my stamina in workouts more than 30 minutes.

But as far as overall strength on things like the deadlift, I found that if I was not calorie-restricted, and I continued to supplement with things like creatine, my performance on the major lifts did not suffer at all. I did fast, I guess it was a couple years ago. It might have been three years ago, now, that I fasted for a week. Three or four years ago, I fasted for a week, and then I deadlifted 500 for 10, and then went up in weight, actually, 585 for a couple.

But that's not my ... I'm a little bit conservative, and my approach is probably not the smartest thing to do when you're fasted, but I felt relatively confident that I could handle the weight. My best deadlift is higher than that, but it just goes to show you that your maximal strength is pretty much not affected too much in a fasted state, where people may actually question whether you could even walk.

And I've found that to be the case. A number of people kind of heard what I did, and then went and did it themselves. A couple people said they were stronger. I kind of question that. But a number of people have kind of replicated what I did, with the amount of weight they're comfortable handling, and so I know it's not some kind of phenomenon that happened for only me. A number of people have been able to fast a week or more ... I think did three weeks ... and did some strength feats that were pretty remarkable.

But when it comes to things like exercise intensity over time, whenever your body is de-energized, really in a state of fasting, exercise that is anything more than five or 10 minutes is probably going to suffer. But things like maximal strength demonstrations, it's not going to suffer too much. Your body, in a week's time, your liver actually stores quite a lot of nutrients. So, even at the end of the week, you're not deficient in things like vitamins at that point in time. Your liver does a pretty good job of storing things.

But at the end of the week, I was starting to feel the effects of fasting, so I slowly transitioned back to eating normal. And I lost about nine pounds during that time.

Ryan Munsey: Okay. So, we'll shift gears. Mike, your thoughts on this? I know, Dom, you mentioned the words metabolic flexibility.

Mike T. Nelson: Yeah, my favorite words.

Ryan Munsey: That's your favorite phrase. You wrote that chapter in the nutrition textbook, right?

Mike T. Nelson: Yeah! And if anyone's seen Dom lift before, he's a freak, so it's ... I've had the luxury of lifting with him before. I don't know if I'm going to do a week fasting and test my deadlift, but it's very interesting to hear about.

To me, for metabolic flexibility, for people who aren't too familiar with it, in essence, it's how well can you transition different fuel sources? All the way on maybe the right end of the spectrum, we've got ATP, PC, very, very short duration, simply put, carbohydrates, fats. Then, maybe throw some lactates in the middle. Then you've got ketones on the other end. Now, ketones are interesting, because the energetic output of them, there's a little bit of a debate about where they land in that spectrum. But in general, without supplements, to access ketones, you usually have to restrict carbohydrates from the left end of the spectrum for that.

In terms of training, Dom mentioned PDH. That seems to be kind of the main regulatory one. Because in my head, I've always thought, okay, if I think metabolic flexibility is good, which is my bias, if you go back to your body, it's very much wired for survival. So, metabolic flexibility is very good for survival. If you run into a whole bunch of honey, hey, eat a whole bunch of honey, you'll be okay. If you can't find the damn wooly mammoth, and you're hunting for two days, or maybe in Dom's case, seven days, and you find one, you're still going to be okay, right? You still have fasting, now you've got a high amount of food.

But the thing that I've had the hardest time getting to work is if you're in, let's say, ketosis for a long period of time, a lot of times, just putting back carbohydrates just doesn't seem to work quite as well. I mean, you may be able to store them in glycogen, but you may then, for a short period of time, or a longer period of time, have a harder time accessing them, right? I think Peter [inaudible 00:26:13] made this comment once that you see these big oil tanker trucks that are full of gasoline driving down the road, and you see one that got stopped along the road because it ran out of gas, right? You have all this gas in the back, but you didn't have it in the tank that you actually need to get it to run.

So, I like Dom's point that maybe if we do something with supplements, other things, to not entirely basically close off that ability to use carbohydrates, and maybe we can still stay in ketosis, so then we can feed back some small amount of carbohydrates to maintain high-intensity exercise. I haven't quite figured out exactly how to do that, to be honest, but I think with some of the supplements and stuff we'll talk about coming up, I think now it may be possible.

And there was also one study that took athletes who were in a ketogenic state, and they did add the carbohydrates back to them, and they did see an increase in performance. Granted, it was a small, single-digit percentage, but these are pretty high-level athletes, so it was pretty significant. And we will talk about the health implications of that, too.

Ryan Munsey: Yeah, I definitely have that question lined up and want to talk about that. But it's interesting that you look at ... I've heard that analogy of the tanker running out of fuel, even though it has this enormous fuel reserve right there. But actually, I've heard that more often with not being able to tap into fat stores.

So, if you look at a marathon runner, we know the bonk is world-famous. It's so famous that it has a name. We say "bonk," people know what we're talking about. And there's this whole industry built on carbohydrates goos, gels, whatever, and I think that's a prime example of the body not being able to shift in fuel sources to go ... If you're a carbohydrates burner, or burning, and you run out, then you can't tap into that stored body fat. And what would you say to that? I mean, is that just an example of somebody having the same issue that you're talking about, just on a different pathway, not being able to tap into fat instead of glucose?

Mike T. Nelson: Yeah. A couple things on that. A lot of the studies that have been done show that it's probably not how well your body can liberate fat, or glycolysis. It's probably a limit in fatty acid oxidation, so how much you can burn if we're just talking about fat itself. And I have seen data on some endurance athletes who use carbohydrates all the time with really high frequency, and if you put them on metabolic cart, and you look at their crossover plane, when they're doing a moderate-level intensity exercise, some of them don't even cross over, meaning that the point where you're 50/50 carbs to fat, they're pretty much burning carbohydrates all the time.

Now, if you're winning Olympic performance marathons, yeah, you're probably going to be mostly carbohydrates. And if you're more of an average athlete that's doing it for body composition results, then I think, moving down the spectrum to using fats better is going to be a benefit. The downside, too, is that at some point, fat cannot compete with carbohydrates for the sheer bioenergetic energy you can get from it.

And the second part of your question is, it appears that in some of the ketogenic studies, if you go super far down that pathway, and you keep carbohydrates super low in order to stay in ketosis, at some point, those athletes have a harder time using carbohydrates. Now, that means using them to the fullest extent. It doesn't mean that their body just stops using carbohydrates, and that it can never be changed.

And what Dom was saying, how long that takes to come back, how far is it depressed, if we completely crush PDH, does that make it harder? All that, I think, is still trying to be sorted out. And in my experience, I've said, in some athletes it seems like it's a couple days, to sometimes several weeks before they kind of get that back. The hard part, then, too, is if you want to stay in the level of ketosis, which again, is a relative scale, if you give someone just a crap-ton of carbohydrates right away, you will probably boot them out of ketosis, also.

So, it's kind of this balancing act, where if you wave your magic wand in the perfect world, you go, all right, high-intensity exercise, boom, you're using a ton of carbohydrates, your backup fuel is maybe ketones and fat, depending on the intensity. And then, once you're done with that, maybe you want to go all the way back to being in ketosis again, too, and that gets into the whole cyclogenic, ketogenic diets, which there's always use for those, too. But I think it comes down to how fast can you make those transitions? And I think, unless someone has really been in ketosis for white a while, I think those transitions tend to be a little bit slower. You probably want them to be faster, in more of a perfect world.

Dominic D.: So -

Mike T. Nelson: I want know what Dom thinks on that.

Dominic D.: Yeah, I was going to say that that's all really good points, and I think the individual variability -

Mike T. Nelson: Yeah, it's huge.

Dominic D.: In someone to adapt into ketosis really blows my mind, for some people. This one guy, within 24 hours, his ketones were 6.

Mike T. Nelson: Whoa!

Dominic D.: He went from a carb-burner to ketosis, and he was a soccer player, and he has found that ever since, he's had great energy. But he was the kind of person who was really busy, so would go into a soccer session somewhat fasted, always eating carbohydrates, though. So, he may have been bouncing in and out of post-exercise ketosis.

But one of the things that Mike pointed out that I think can't be overemphasized more is individual variability and various fat oxidation enzymes. And there are many different enzymes associated with fat oxidation, and we know that humans have all sorts of mutations in these enzymes that may not be manifested or diagnosed, and there's a spectrum of kind of their expression levels of these different enzymes, and even in the enzymes that are associated with ketogenesis. And that's thiolase, HMG-CoA synthase.

HMG-CoA lyase is an interesting one. I've got a couple papers on this. There's 30 potential mutations in that particular enzyme that have been found in humans, and the clinical manifestation is that you have vomiting, seizures, metabolic acidosis, and hypokinetic hypoglycemia, which means if they got hypoglycemic, their energy level just plummets, and they can't even move. And that's basically, HMG-CoA lyase is one of the most important enzymes for your body to make ketones. And there's 30 potential mutations just in that particular enzyme, and there's about a half-dozen enzymes that are responsible for our bodies making ketones.

And I'm convinced that we all have different levels and activities of these enzymes, and I think people who say that they just cannot adapt to a ketogenic diet, I think you're probably finding out some of these people who have different mutations in the expression levels of these different enzymes.

Ryan Munsey: So, we are biohackers. We want to take these systems and optimize them for the results that we want. So, based on some of the things you guys have just said, let me ask you both for tips to optimize fat oxidation. Are there ways that we can make that more efficient, faster, better? Or are we just kind of stuck with the hand that genetics have dealt us?

Mike T. Nelson: I'll go first, and I'd love Dom's opinion on that.

Dominic D.: Do you want to go, Mike?

Mike T. Nelson: Yeah. So, I'm a big fan of actually increasing fatty acid oxidation as high as you can, without it costing you the ability to use carbohydrates. Simple level, you toss ketones and stuff in there, too. I'm a big fan of fasting. I've used intermittent fasting off and on for, oh man, probably 10 years, now, somewhere around there, 8-10 years. And back then, when I first heard of it, I thought, that's the stupidest idea I've ever heard of. All the muscle is going to fall off your body, all this horrible stuff you've been told from all the bodybuilding magazines, which turns out not to be true. So, I feel fasting, by definition, you're not consuming any calories during a period of time, is to muscle, pretty neutral. You're not going to gain a ton of muscle, but you're not going to definitely lose a ton of it, either.

The cool part with fasting is, you drive insulin levels down. And as you drive insulin levels down, you push the body to use fats, and if it goes long enough eventually ketones, too. But then I also have people match their primary intensity at that time. So, if I have an aerobics session with the goal of moderate intensity, you can use the Phil Maffetone equation, 180 minus your age for your heart rate, then I'll have most of my people I work with just do that fasted, right? Because I want the ability to use fat, it's a moderate intensity, and things of that nature. If it's weight training, I'll primarily have them use carbs.

Ryan Munsey: If they're doing that aerobic session, and let's say I'm 30, and I do 220 minus my age, 190 is my max. What range ... We want to be in that middle zone, that cardio zone?

Mike T. Nelson: Yeah. I use the 180 minus your age, which is the Phil Maffetone's equation, and that's a rough equation to get you in that exact middle zone you were talking about.

Ryan Munsey: Okay.

Mike T. Nelson: I hate using the word fat-burning zone, because that has been so ugly bastardized to possible end. And it is true, without a metabolic cart, you don't know exactly where people are in that type of thing. But you're trying to get insulin levels low, there's not calories coming in, and you're just trying to get a moderate aerobic effect, and you're trying to train the body to use fat better as a fuel source. Because like I said before, glycolysis, or the fat that is released, doesn't appear to be the limiting step as the body's ability to do fatty acid oxidation to basically burn fat.

The other part that people forget too is that their resting metabolic rate accounts for easily about half of the calories that's burned all the time. And I keep trying to get more and more data on this too, but there's limited data to show that that resting metabolic rate, the fuel mix of that may actually be very different from one person to the next.

It's like Dom was saying, we do know that in training studies ... I do one with the University of Minnesota, [inaudible 00:37:27]. There's one other one. That the amount of ability to use fat at a low intensity varied from 20 to 93 percent. So, pretty massive variation in people just walking around. The downside is, you need a little bit more expensive equipment to do resting metabolic rate, and to look at what fuel is being used. So, my advice is, I think fasting is probably one of the easiest ways to do that.

Last part, too, is that there's a couple studies showing that fasting doesn't appear to screw with PDH enzymes, meaning that if you took someone and had them fast, because liver glycogen will actually go down, muscle glycogen actually won't, unless you're doing some high-intensity work. Maybe that allows PDH to work a little bit better. So, if you then re-feed them with carbohydrates, again, assuming this is not an extremely long fast, their body can still tap into the use of carbohydrates a the same time.

Ryan Munsey: Awesome. Dominic, what do you think?

Dominic D.: Yeah, so, the question is, how do we get our bodies fat-adapted as fast as possible? Yeah, I think, in my head, thinking of the fastest way to do that, could be fasting, but I think above all, a glucometer could be helpful for this. The suppression of the hormone insulin, which is driven by glucose, is a pretty good indication. And fasting, that doesn't have to be prolonged fasting. I just think if you do, from a practical standpoint, it would probably be good to do some form of calorie restriction that's pretty moderate, and also a calorie-restricted ketogenic diet with intermittent fasting. And I think intermittent fasting is a lot easier when you've adapted your body to the ketogenic diet, right, because you can withstand the hypoglycemia that occurs in that fasting state.

And once you do a mild, calorie-restricted, ketogenic diet with intermittent fasting, you could do something like a high-intensity interval training, HIIT training, and you do a short HIIT session, and then do, following that, you can do prolonged low-intensity exercise. Go for a walk. Go for a 2-3 hour walk, and that will, the combination of these things, the calorie restricted ketogenic diet with intermittent fasting, over just the course of a couple of days, with a HIIT session and then a walk, will really get your body into fat-burning mode faster than anything else. There's going to be acute evidence of this, which would be an elevation of ketones, or blood or urine ketones that you can measure, and that's a direct byproduct of fat oxidation.

So, you could really amp up this process, and I had someone send me their blood profile, doing this with and without the caffeine-ephedrine stack. I don't know if ephedrine is still legal now, but they did a caffeine-ephedrine stack three times a day, and did that, and it really shot up their ketone levels, and it was a pretty good indication that they were spiking up their metabolism. Just from the literature, if you're not already adapted to that stack, it's increasing your metabolism about 10 or 15 percent.

That's another way. I'm just throwing out, not giving advice to anyone, but if they want to get their body into that fat-burning mode as fast as possible, that would be the way to do it. And really, with a calorie-restricted ketogenic diet, I think it's also important to keep your protein not at the levels like a clinical ketogenic diet level, which is one gram per kilogram, but more like 1.5 grams per kilogram. And that's still pretty low, relatively speaking, but that would be enough to prevent some of the muscle loss that could occur. So, that would be my strategy to transition into fat-burning as fast as possible.

Ryan Munsey: Okay. So then, let's flip that and say, what are some of the best tips that you guys can provide our listeners to make our bodies be better at ... Because you guys had mentioned earlier that I think the goal is just to be able to have the resilient, flexible body that can adapt and flip the switch between fuel sources. Do the same tricks apply to being better at flipping that switch, or are there different tricks that we can use to optimize that?

Mike T. Nelson: I'll go first.

Ryan Munsey: Thank you. Yeah.

Mike T. Nelson: My thought is, I agree with that. If you look at a rough marker for performance is how fast can you do a transition? So, a transition may be how fast can you go from not running to running really fast, right? Usain Bolt would score really well on that. How fast can you do a deadlift, or some performance metrics, vertical jump? How fast can you switch fuel sources, right? How fast could you go from, say, fast to carbohydrates, carbohydrates back to fast, like the one guy Dom was mentioning? To me, I think that's a pretty good marker for, again, metabolism, metabolic flexibility, which is probably a good marker for increasing resilience, increasing your body's ability to survive.

So, the first thing I do with that is, I just measure people's response. How well do they do to each extreme on the end of the spectrum? Fasting is a pretty simple intervention. Again, you could use a ketogenic diet. You could use other things like that. And then, how do they report that they feel?

If you're really aggressive and do, say, a 24-hour fast on day one, not saying I'd recommend that, but if they report that, "Hey, I felt great. Everything was good. I got lots of stuff done. Hell, I even went to the gym. It was perfect." Okay, they probably handled that pretty good. If they report, "After 8 hours, I felt like I wanted to gnaw my arm off, and I passed out on the living room floor," probably didn't handle that quite so well, right?

And then, I will also have people do a high amount of carbohydrates, maybe even at breakfast, just as a testing thing. So, a lot of people report, "I had a bowl of oatmeal, and I got halfway through, and I'm facedown in it, right, because I fell asleep." So, do what is the effect of carbohydrates, different types. I've even used the [inaudible 00:44:14], something that has a really high insulin release on purpose, just to see how they handle that. And over time, I'd like to see them handle both of those extremes quite well, and that kind of gives me, in the practical world, without lab equipment or anything else, something to work with and to play around.

So, if they crash at 10 hours into a fast, hey, let's try nine hours once a week, and see how that goes. Cool, that was good. Okay, the following week, let's go to 11. Just a oldschool, progressive overload on it.

Dominic D.: Yeah. To pick up from there, I would agree with everything Mike said, and I would emphasize that for me, it's like that ketogenic transition. The speed ... That goes to what Mike said, the speed of you transitioning into going from a glucose-based metabolism to a fat and ketone metabolism, and that can be, you can monitor that different ways, from performance, subjective feelings. Some people feel absolutely great, and then others, several people ... happen to be women. I think women may have a hypoglycemic reaction in response to fasting, where a couple of them have even fainted, even taking in sufficient fluids and minerals. And that's an indication that in a fasted state, their body is not making ketones, because we know that ketones can provide resilience against hypoglycemia, which would occur with a short-term fasting.

So, I think the response to fasting short-term, 12 hours, even 24 hours, or 36 hours, that response is a really good indication of metabolic flexibility, and the important thing to realize is, the more you do that ... If you've never done it before, it will be a stress, and it will be uncomfortable, but the more you do it, the easier it gets, and the better your body can rapidly transition into adapting to that stress response.

And there's the acute response, but there's also, it really, now we know it's activating a genetic program, if you will. It's activating a whole host of genes and metabolic enzymes that makes your body react with much more resilience to the next stress of fasting. So, you're more capable of greater fat oxidation, and even ketone production, when you go into it again.

And you'll talk to athletes that need to cut weight, or bodybuilders or fitness athletes that need to diet for a show, and they'll tell you, the first time that they diet is the hardest, and then every time after that, it gets progressively easier. Usually, unless they're doing some wacky thing. And that's a pretty good indication that their body has adapted to that stress of caloric restriction, and shifting their metabolism into fat-burning mode, because it becomes easier with subsequent events.

Even as they age, even as they ... they kind of describe it as getting to know their body, but I really think it's their body, it's activating a familiar sequence of metabolic events that they have experienced before, and they have a greater activation of accessing their fat metabolism, of triggering that.

Ryan Munsey: That's really interesting. I would love to maybe go down some of those rabbit holes, but I think that's for another day, because we're running long on time, and we haven't even talked about exogenous ketones yet. So, a couple of questions on what is quickly becoming a million- or billion-dollar industry, with exogenous ketones. I guess, first of all, for both of you guys, do you see exogenous ketones as one tool to help flip that switch faster, and get into a ketogenic state, or burning ketones? Or is that just kind of like a marketing ploy?

Dominic D.: I think the studies still need to be done, but some of the recent studies that come out are kind of suggestive. At least, if you're putting in that fuel source, you are ... And I wrote an article on this with Brendan Egan in Cell Metabolism, and the title is "Fueling Performance: Ketones Enter the Mix." And it was a commentary on the article that was published in Cell Metabolism entitled, "Nutritional Ketosis Alters Fuel Preference, and Thereby Endurance Performance in Athletes."

And the main takeaways from that publication, which I did the commentary on, is that nutritional ketosis during exercise reduces glycolysis, and these were athletes that were not carbohydrate-restricted, and shifts metabolic physiology to increase fat oxidation, specifically muscle fat oxidation, but also adipose oxidation. It improved performance. It was cycling time trials to exhaustion, and interestingly, it preserved muscle glycogen, so glycogen's bearing effect.

And I think the biggest thing from that study, if I remember, it was a 50 percent reduction in lactate. So, by using proportionally less glucose for fuel, you're reducing lactate, and I think that's significant when it comes to performance. Your brain is also kind of sensing the level of lactate, and the pH of your blood, too. And I think that the ketones will be energizing and preserving your central nervous system, and that's your CNS that's activating your muscles. So, you get greater motor unit improvement when you're in a state of ketosis, and that can translate to more efficient contractions, heavier lifts in the gym, just by kind of energizing and ensuring that your CNS is functioning optimally.

And those studies that I'm talking about, the one study that was done in athletes that were not on a ketogenic diet, they took a ketone ester, and it was a 1:3 butanediol acetoacetate ... or, 1:3 butanediol beta hydroxy butyrate monoester that elevated ketones pretty significantly, like in the [inaudible 00:51:22] million molar range.

Ryan Munsey: Okay. So, you said that was an ester. We'll come back and we'll talk about the difference between salts and esters as it applies to exogenous ketones. But before we do that, anything to add, Mike?

Mike T. Nelson: Yeah, really quickly, I think the use of exogenous ketones is fascinating, and years ago, I said that's kind of a game changer for supplements, and I still get hate mail about that. But in terms of ... And that term is so incredibly overused, but I think in terms of the potential that we're just trying to figure out now, I think it has a massive potential, because it gets rid of the main issues of the long transition to get into ketosis, which most people have to do.

And so now, you can do a whole bunch of crazy stuff, right? You can take, like Dom was saying, athletes that are completely, 100 percent glycogen, carb replete, and then give them maybe a crap-ton of some type of ketone before the race to get an acute effect, to kind of shift the fuel. You could combine that with a carbohydrate solution even during, which there's one study on that. But I think we're still just trying to figure out exactly how much of that can be used for a higher intensity, or a higher power. I think it's still debatable. But I think, especially as the races go longer and lower-intensity, it's definitely a huge benefit.

And I really like what Dom said, too, about I don't think we know enough about the CNS effect, right? So, maybe you're doing a high-intensity thing. Maybe you can be replete with carbohydrates. Maybe you can still access them. And maybe the ketones are just helping keep the lights on in your brain better. You go back to the Noakes's central governor theory. Maybe that then allows you much higher-level performance, as Dom was saying. So, I think it's very fascinating, and lots of work to sort out what's what.

Dominic D.: Yeah, and I'd like to add to that that ketones are much more than just an energy source, too.

Mike T. Nelson: They have signaling effects, too.

Dominic D.: So, now we know that they have really potent signaling properties, like they function as a histone deacetylase inhibitor. We published in Nature Medicine that they suppress the inflammasome, the NLRP3 inflammasome, which is associated with age-related chronic inflammatory autoimmune disorders, and even certain forms of cancer. And there was a recent publication in the Journal of Biological Science that showed that acetoacetate, which is part of ... it related significantly with a ketone ester that we studied, accelerates muscle regeneration and ameliorates muscular dystrophy in a mouse model. It's kind of the gold standard for that. And what was really interesting about that is, it was doing it in a metabolic-independent way. So, it was doing it independent of AMP kinase, and even independent of MTOR. It was doing it by sensitizing the muscle cells, IGF1. There was greater satellite cell activation. They also showed that it antagonized the effects of myostatin. And that was completely new data that just came out in the last month or so.

Mike T. Nelson: Yeah, I got that from you.

Ryan Munsey: I was going to say that. Like, I want to read that, but I'm out of space to take notes on all these articles, so Dominic, if you can ... I'll send you an email after we complete this, but I want you to send me either links or PDF copies of all of these articles that you're mentioning, and just as a note for you guys listening, go to the blog post version of this. We'll have all of the links to articles and stuff that both guys have introduced throughout this episode.

So, then, let's talk about the safety. Do we know yet the safety of long-term use of supplementing with exogenous ketones? Does it matter if they're salts or esters?

Dominic D.: Do you want to go?

Mike T. Nelson: I'll let Dom go first. I have one other ... Dom is more the one ...

Dominic D.: Okay. Yeah, that's a good question, I think. One of the most potent exogenous ketones that's entering the space now is the beta hydroxy butyrine ester, and it's essentially 1:3 butanediol with the beta hydroxy butyrate connected to it with an ester bond. And it causes a really high elevation of beta hydroxy butyrate, and it's been studied extensively in animal models, and it was studied also in humans, and published by the group NIH in Oxford, that work together on that ketone ester. And it's GRAS approved, at least for five days. I know it's GRAS approved in Europe, and I think it's recently GRAS approved in the United States.

Ryan Munsey: I believe you're right.

Dominic D.: And the ketone ester, the kind we work with, is a diester. It has a 1:3 butanediol, which breaks down to beta hydroxy butyrate, but attached to it are two molecules of acetoacetate. And it causes a rapid elevation both in beta hydroxy butyrate and acetoacetate over a pretty long time frame. And it's been studied in mice, and rats, and pigs, and dogs, and even some human studies, and we did a long-term very high dose, 25 grams per kilogram, chronic feeding study of 15 weeks, which in humans is like many years, in rats.

And we looked at liver function, kidney function. We looked at the inflammatory markers and stuff, too, and saw some really interesting positive health benefits to even that high dose. Enough that it's kind of motivating us to do a longevity study, where we take rodents in the middle-aged group, rodents of about one year, which would be like 50 years old in humans, and then give them the supplement and see if we can extend their lifespan, because there's no indication that even a high dose was impacting any markers of toxicity.

So, we're doing ... And that's with the ketone ester. That would be even more potent than the ketone salts. The ketone salts kind of bring up a little bit of a different issue, because the ketone is bound ionically to monovalent and divalent cations, which is sodium, potassium, calcium, magnesium. And these things, you don't want a large load of sodium, so the mineral has to be, you have to formulate it in a way to balance the electrolytes, to ensure you're not getting a mineral overload in the gut, because that can cause some GI issues, but even systemically. Of course, you know you don't want a huge bowl of potassium, right, because that could be fatal.

So, you have to formulate these things with some strategy to ensure not only that you balance the electrolytes, but you also have to make it palatable, GI-tolerable, and then ensure that these things are safe in the long term. And we've done enough studies that I'm confident that they're pretty safe, and from a regulatory hurdle, they're kind of easier than the ketone esters, because they're more or less bound to nature. We have the minerals in our body, and we have ketones. If you're eating meat from an animal that was ... any animal is going to have some level of ketones, and if it's in the fasting state, you're going to have beta hydroxy butyrate in the free acid form in the muscles.

And the precursors to make these synthetically are derived from nature, or they can be derived from nature. So, you're taking sort of nature-based plant compounds, and then doing some fairly simple chemistry to combine the precursor to the ketone, to make the ketone, and ionically bonding it to the mineral. So, it's a little bit different than the ketone ester, where you could take a petroleum-based compound or a plant-based compound, depending on how you synthesize it. But there's a number of steps. The chemistry is a little more advanced. And there's an ester bond that was not found in nature, so it's a bigger regulatory hurdle, so it involves more testing.

But I think the testing on those compounds would kind of reinforce and ensure that other compounds that cause bioidentical elevation of ketones, which you can measure in your blood, which are identical to what your body produces, into safe levels, would be safe, relatively speaking. But we still don't have the long-term, high-dose chronic feeding studies in humans. But we don't have that for anything. You go to GNC and grab 99 percent of the stuff on the market, which we don't have that data for.

Ryan Munsey: Right. I'm really glad you mentioned the salt content, because I think that's ... I've done experiments for the last few months using Keto OS, as well as KetoCaNa, and both are salts, and with both, you're looking at 1.4-1.5 grams of sodium on the label per serving. So, it's definitely a consideration that a lot of people don't even realize when they start playing with exogenous ketones, so I'm glad that you pointed that out. Mike, what are your thoughts on safety, and anything you want to add?

Mike T. Nelson: Yeah, really quickly. I mean, I agree with everything Dom said. I think that generally the data that we have now shows that they're probably safe, as best as we know. The only concern I have, which is really a theoretical one at this point, is now you can create a state in the body where, for a period of time, ketones are really high, and insulin may also be very high, right? So, what happens if I mix ketones with a high insulogenic beverage? That makes me a little worried, because, and Dom can correct me on this, but I don't think there's any other point, sort of naturally ... there's no natural argument that that ever really happens. Because insulin is usually available of ketones, and that type of thing. So, I don't know if Dom has any quick words on that.

Dominic D.: Yeah. It's interesting. Well, Dr. [inaudible 01:02:10] has published some studies showing that ketones do not increase insulin, a bowl of ketones, and mixed in with the animal chow. And the recent study, I believe by [inaudible 01:02:25], that was the athletes, just showed an attenuation of the insulin response when it's given with carbohydrates, the same load of carbohydrates.

And we did some studies, I can't talk about it too much right now, but essentially what we've demonstrated is not published yet. If we give five grams per kilogram of glucose, we get a big spike in blood glucose. And if we give five grams per kilogram of glucose with five grams per kilogram of ketone ester, it completely abolishes that elevation of glucose when it's given together.

Mike T. Nelson: Really?

Dominic D.: And that, yeah, that's a random study, and we collected the serum for insulin. So, we're running the insulin aphase right now, but we did it ... that was with a ketone ester. I don't know if it occurs with all the different ketogenic agents, so we're screening over a dozen of these compounds, and formulations of these compounds. But it's fascinating as to what's happening, what's going on there.

Mike T. Nelson: Yeah.

Dominic D.: But it's really remarkable, huge. And the application, obviously, is bringing ... for type 2 diabetes, where you get a massive elevation of the glucose and insulin. Regardless, we do see, there will be significant evidence that there's going to be less insulin, just because of the glycemic response was less. But we have to ... we're collecting all the data now, and then looking at the dose relation. But we use really high doses of glucose, typically what you use to do a glucose tolerance test.

So, that to me is probably one of the more important, fascinating discoveries that we made. I mean, it's not published yet, but that's one of the more significant sort of results that we've seen with our ketones, in addition to the antiseizure effects. And it needs to be studied a lot more.

Ryan Munsey: That's amazing. Dominic, is there any other new research that you can leak, or give hints about?

Mike T. Nelson: My head is still spinning. I'm like, we want more!

Dominic D.: Yeah. We've published some things in abstract form, but without saying too much, we're looking at the behavioral effects of ketones, of acute ketosis, and also chronically being in ketosis, on things like anxiety. Of course, learning and memory has always been important to us. We're doing motor function and performance, as you know. But we're also probably directing our effort on the effects of ketones on behavior, and also inflammation, as it relates to different pathologies, even cancer.

And next thing on the horizon is to do a longevity study, right? So, we were talking about give the ketogenic diet, or ketone supplementation, or metformin, or rapamycin to middle-aged rats or mice, and let them live their healthy, happy lives in the cage, and then take blood measurements periodically, run them, do exercise studies periodically, so we can assess that, and see if there's any survival, and extension of life benefits that we see with these interventions. And then correlate that, if we see it, with various biomarkers, and that could be something like global metabalomics, to cytokine profiles, to something as simple as glucose or CRP and ketones. So, that's kind of what we're doing now, and that's a project that will probably be handed off to the next PhD student in our lab, but we're doing some of the preliminary work right now.

Ryan Munsey: Nice. So, I want to know another question. Where can we get some of these esters that you're having success with?

Dominic D.: Yeah, they're made in pretty limited supply. We work with a chemist, you guys probably know Patrick Arnold. But we're making them ... We get them from a variety of different locations. I know Patrick was the first one to synthesize it for us, and then we've kind of developed the methodology to synthesize it in-house. And I think you could probably source these things out in China, but I would be very hesitant to give them to a human, and probably even test them and do some third-party testing before putting them in an animal.

So, right now, they're really, in our hands, being developed and tested and tracked towards a clinical trial for a rare disorder called Angelman syndrome, and then also a clinical trial for cancer. So, they're not really tracked for the general public. And special operations community, too.

But the ketone salts, I'll say the ketone salts are just at the infancy stage of development and testing, and they think ... completely confident that they can be formulated in a way to be every bit as potent as a ketone ester. It's going to take some strategy and formulation, and the formulation may not be the cheapest. I know it's going to be a lot more expensive than the ones that are on the market right now.

But I know that the salts can be formulated, and it doesn't have to be a mineral salt. It could be an amino acid salt. So, simply combining an amino acid, like lysine or arginine or histine, to the hydroxy butyrate with an ester bond, that's a salt. From a chemist's perspective, that's a salt. And these things can be made, too, and you can even ... I think you can make a creatine beta hydroxy butyrate, but we've not gotten our hands on that, yet.

So, I think in time, and it may take a few years for this to evolve, you'll start seeing ketone salt products that are increasingly more complex and advanced, to the point where you can get ketone levels up near or about where you could put them with an ester.

Ryan Munsey: Wow. Okay. Quick question on that, Dom. Is that only for beta hydroxy butyrate, or could you do that with the other ketones?

Dominic D.: Yeah, that's a good question. Acetoacetate, we're working with that now. The only stable salt is lithium acetoacetate, and you don't want to load up on lithium. But the bond is very strong, ionic bond is strong with lithium, and it degrades slower. But it's really easy to synthesize chemically, to make it, but the stability of something like sodium acetoacetate, especially in a solution, and this is the problem that we have even working in cell culture, is that it kind of breaks down, spontaneously decarboxylates to acetone.

So, we are working on different ways to get aceto ... As of now, the way that we deliver acetoacetate is with an ester, and the ester that I mentioned, it's a 1:3 butanediol acetoacetate diester. It gives a really high elevation of acetoacetate, and a monoester with less. But those things right now are our kind of go-to ketogenic molecules to elevate acetoacetate. And I'm becoming increasingly interested in acetoacetate because all the animal work from the last two decades suggests that acetoacetate is really providing that antiseizure, anticonvulsive effect. And then, the new study, the one that I just mentioned, shows that it has direct effects on muscle protein synthesis, and muscle regeneration, acetoacetate does. So, I've become increasingly interested in that.

But we haven't been able to develop a ketone salt that could, for example, sit on a shelf of a nutrition store and be stable. We can make it, and use it in-house, but there's not something that's developed yet into a commercial product, unless you want to take lithium acetoacetate. So, we're still working on that.

Ryan Munsey: And then, quick question. Last I heard on that, for seizure and also possibly head trauma. Is that correct? Like, you would need that one, maybe not beta hydroxy butyrate?

Dominic D.: Yeah. That's a good question. But head trauma, if it's penetrating traumatic brain injury, about 80 percent of people who have that will have seizures. So, I think it's really important to implement a ketogenic strategy for traumatic brain injury that also prevents seizures, because most people who have severe TBI will have seizures.

But I think beta hydroxy butyrate, there's good evidence that that can be neuroprotective, just simply because CTE that you get from concussions ... Lately, I've been talking to quite a few NFL guys that have this, that have a concern. They've even started on a ketogenic diet. For example, just not only the energy component, but also the neuroinflammation that's associated with CTE could be mitigated just though the antiinflammatory effects of beta hydroxy butyrate, because we know that NLRP3 inflammasome is really tightly linked to that neurinflammation, and there's good evidence that beta hydroxy butyrate can suppress that.

So, I think the big things that we're focusing on are not only restoring normal brain homeostatic energy mechanisms, but suppressing that neuroinflammation. That's really key for that long-term management, for suppression of the effects that you get secondary to the traumatic brain injury.

Mike T. Nelson: Very cool.

Ryan Munsey: So, if we wanted to take that and run with it, Dominic, I guess, as people who are interested in cognitive performance, brainpower, or even just looking at it from a longevity standpoint, beta hydroxy butyrate reducing neuroinflammation, is that something that has maybe not as profound an impact as fixing or recovering from TBI, but it's something that people can apply to everyday life for greater focus. Is that maybe what you're looking at in some of these cognitive performance studies?

Dominic D.: Yeah, I think so. I think, with TBI, you're compromising a blood-brain barrier, so there's a lot of things going on there, but neuroinflammation is a big factor in the overall outcome of that. But there's a lot of things that can actually cause neuroinflammation, from common viruses, like ... I just got off the phone with a guy studying herpes simplex virus, and he's convinced that that's contributing to Alzheimer's disease. We know HIV-induced dementia is tightly linked to the activation of these inflammatory pathways that are suppressed by beta hydroxy butyrate. So, many of the investigators studying HIV-induced dementia are considering these nutritional interventions, and specifically things that elevate beta hydroxy butyrate.

And common viruses can contribute to neuroinflammation. That's why we get a headache. We get people that have shingles, for example. I was recently talking to some docs. I guess, when you get shingles, the first thing you start to feel, I think with herpes simplex, too, is a headache. You start getting a headache, and that's the neuroinflammation. And a number of people have contacted me that they have shingles, and they've been fasting, or they did a ketogenic diet, and above all, it's helped them more than anything else. Because I think the antiviral therapies for that are not very effective, or maybe they have side effects, too.

So, it's interesting. I never thought what I'm studying would have implications for things like that, but the feedback that I get is pretty compelling, and I realized that this is something I should be studying, or at least looking into, because there's some pretty compelling data to suggest that. There's a wide variety of things out there that can cause neurinflammation, and neuroinflammation can impact our cognitive function, and sense of wellbeing, and many other things, and I think nutritional ketosis can help with that.

And even Tim Ferris, talking with him, he had Lyme disease. The effects of Lyme disease are really the result of chronic inflammation, and in talking with Tim, the only thing that helped him ... And he tried everything. I mean, he's pretty well-connected to try everything. The only thing that helped him was really fasting and the ketogenic diet and ketones. So, that's another thing. Lyme disease is kind of a hot area, kind of a controversial area. But I'm getting a lot of feedback, now, from people using nutritional ketosis for that, because there's not a whole lot of things that can help.

Ryan Munsey: Well, this is why I wanted the very first question to be something along the lines of who should not be using ketosis? There's so many potential applications and beneficial things. I mean, from a research standpoint, there's obviously so many ways to go with it. There's no way that you alone could cover it all, but we are grateful for everything that you're doing, and for all the jumpstarts, like you mentioned the PhD student that's going to take that next project and run with it. So, it's awesome that you're doing that, and propelling this conversation, and advancing so many areas of science. So, we're grateful for that.

I guess we'll start to wrap this up. I'll give both you guys an opportunity to tell our listeners where they can find more of you.

Mike T. Nelson: You can just find me at -

Dominic D.: Do you want to go, Mike?

Mike T. Nelson: Yeah. MikeTNelson.com. I think I'm on Twitter by the same thing, MikeTNelson. If you have any direct questions, they can just email me. DrNelson@MikeTNelson.com, and just put in there, subject line, "Adaption podcast."

Dominic D.: Yeah. So, you can find me ... I guess the best place to go would be KetoNutrition, all one word, .org. And on that website, kind of just a skeleton website, but I have a link on there to my academia site, I think, and that will take you to pretty much all of my publications, even books that I've uploaded there for free, so you can kind of circumvent having to pay to download them. So, they're all uploaded on there for a free download. If you go to KetoNutrition.org, I have links to all my podcasts. Or, not all. I've done, like, 100 podcasts, and I've put maybe 50 of the ones up there. There's ketogenic diet consultants. There's doctors. There's clinical trials. Resources, books, things like that, on KetoNutrition.org.

Ryan Munsey: Beautiful. I wish I'd known about that a few weeks ago. Somebody was asking for a ketogenic doctor in LA. So, I will point them in that direction.

Dominic D.: Okay, cool.

Ryan Munsey: So, before we let you guys go, any final thoughts on ketosis, or anything that we've talked about, that you want to make sure people leave here with?

Mike T. Nelson: My general thoughts are just, do your own experiment. Find out what works for you. I mean, obviously we know some principles from research and science, and like Dom was saying, too, that there's a huge amount of interindividual variability. So, I'm a big fan of, what is it you're trying to measure, and then also what is the cost of doing that? So, maybe you're just looking at body composition, but you feel like dog piss all the time. That's a high cost you don't want to pay. Maybe it's okay. So, just set up the experiment, I say, do things we think that are safe. I think research can be a good guide to push you in that direction, and then the sort of me-search, or the n=1, will give you more answers that you're most interested in, which are you.

Ryan Munsey: Beautiful.

Dominic D.: Yeah, I think that's all great points, and I think the ketogenic ... people ask me, should I be on a ketogenic diet? Definitely not for everyone. I do know, from my own research, and from feedback from others, that it does have an enormous amount of therapeutic and even performance benefits, and in an emerging amount of applications. So, I encourage people to try it, and to do their research, and to ... It's probably best, if you're really fresh at this, to work with a nutritionist. I actually have some on KetoNutrition.org, some exercise people that work with performance folks. And to just give it a try.

And some people actually find the diet kind of hard to do, but they can do intermittent fasting, and I think the combination of a low-carb diet and an intermittent fasting can work really well, and put your body into ketosis during the midpart of the day, where you're feeling the effects. So, yeah, just do your research, experiments, and see what works for you.

Ryan Munsey: All right. Final question. Mike, you've answered this before, as a previous podcast guest, so we're going to let Dom go first, and then if you have any bonus ones, we'll let you get a couple bonus ones. I'm going to preface this: You guys are not allowed to say sleep. We know sleep is one of these. So, Dominic, your top three tips to live optimal?

Dominic D.: To live optimal. Let me see. I think, I'd have to say, take downtime. Like Mike and I, all your listeners are probably go, go, go all the time. But it's good, and you have to do this, have some diligence behind it, but you have to set aside, create a downtime every single day. And I think that's super important to do.

Other than that, focus on relationships. Instead of just getting work done, prioritize relationships with people, with your colleagues, and you'll realize you'll get more work done.

And take a full vacation sometimes. I think we really need that. My wife forced me to take a four-week vacation through southeast Asia, which was really stressful for me, to make that kind of time commitment, but we do that. We realize we work really hard, but we try to play hard, too. So, I encourage people to do that.

Ryan Munsey: Awesome. Those are really good. Mike, what do you got?

Mike T. Nelson: Yeah, I love those. I don't remember what I said last time, so maybe this is good. Maybe it will be the same or different. But very similar, I had relax. That's something I've been working on a lot more, especially the last couple months. Always keep learning. I think that's just one of the keys. And then also, some of what Dom said, too, just have fun. Because I think I'm very similar, easy for me just to focus on one thing, and then at the end of the day, you don't really remember all the days you spent working. You remember the days, and people you spent them with, and people had fun, and did things that you never thought you were able to do. So, yeah.

Ryan Munsey: Awesome. Well, gentlemen, thank you so much for your time. This has definitely been worth the wait. For you guys listening, go to NaturalStacks.com to see the blog post for this with all the links and resources that we've talked about. Make sure you share this podcast with anybody you know who is remotely interested in ketones or ketosis, anyone you know who would benefit from the things we're talking about on the OPP. And thank you guys for listening. We will catch you guys next Thursday. Dominic, Mike, thank you so much.

Mike T. Nelson: Thank you very much.

Dominic D.: Thank you, Ryan. Appreciate it.

  

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