Kyle Kingsbury Podcast - #48 Dr. Dom D'Agostino

Episode Date: August 27, 2018

Dr. Dom has appeared on The Joe Rogan Experience, The Tim Ferris Show, and many others. He is one of the leading researchers in the field of ketogenic diets, exogenous ketones, and elite performance. We discuss the latest in cutting edge research that he's undertaking, best do's/don'ts for Keto, what apps can help, and much more. Connect with Dom D'Agostino on Instagram Twitter Website Ketonutrition.org Connect with Kyle Kingsbury on Twitter and on Instagram Get 10% off at Onnit by going to Onnit.com/Podcast              Onnit Twitter        Onnit Instagram

Total human is our completely revamped, relooked at version of total primate care. It got the facelift because even though we're primates, well, we're not selling to all primates. We're just selling to humans in the primate category. What have we done with this thing? It is a common question that I get here on it is, which product should I take? Which supplement should I take? What's the most important thing I should put in my body if I was only to pick one? And the truth is, you'd take a little bit of everything.

That'd be the best possible thing if you're only going to choose one product. And that's what we've done with Total Human. There's day packs and night packs, and we take all the guesswork out. You get a little bit of everything we have to offer from our B vitamins that have come out to Shroom Tech Sport and Shroom Tech Immune. So you're going to get a boost in cardio as well as immune function, Virotech. Most of the best products that we offer, we've put into simple packets for you to take in the morning and in the evening.

They're incredibly convenient to travel with. And there's really no reason everybody shouldn't be doing this because it takes all the guesswork out of trying to figure out and fine tune which products are the best for you. Everybody loves Total Human. Get it now on it.com slash podcast for 10% off. We got Dr. Dominic D'Agostino on the show today. And this is, I mean, he's fucking bucket list guy that I've wanted to have on since I got into podcasting. I heard him first on the Tim Ferriss Show in 2014, right when I retired from fighting.

And he was one of the major reasons I tried the ketogenic diet. And that was because of the promise it showed for cognitive function and healing when it comes to dramatic brain injury. That's shaped the way that I look at food. It's really just an incredible shift that you can make that changes your body in a number of ways, from fat loss to cognitive function to sleep, betterment of sleep to mitochondrial function. And we even dive into some of the other things

like cancer prevention and curing and just a ton of stuff that can go into this diet. It is probably the most scienced back podcast I've ever recorded. And I would have been happy with him just diving into the basics that he did on the Ferris show and the Rogan show. I recommend people listen to those. But the cool surprise was that he dove into quite a bit of new shit on this podcast that really blew me away. I was taking notes.

We linked his stuff in the show notes so you can take a deeper dive into his company, what he's doing, the Charlie Foundation, which he mentions, and a lot of cool apps that support people that are trying to get into a ketogenic diet just to smooth out the edges and make things a little bit easier, a little bit more manageable, because it is tough. I mean, I had done this for two years, went off the wagon for a while, came back on, and it probably took me two weeks to actually feel good. I had the keto flu and a lot of typical symptoms, but we cover a lot of ground in this podcast. I know it's easily one of the favorites that I've ever done. So check it give it a listen thanks for tuning in dr dominic diagostino has joined us

yeah thanks for having me yeah this is an absolute treat you know i i first heard you i think in 2014 on tim ferris and uh not long after that or before that i heard dr peter attia and right then i was like all right now i'm looking into this yeah and uh not long after that or before that i heard dr peter attia and right then i was like all right now i'm looking into this yeah and uh started diving through any of the old books that were out i think uh finney and volick had a couple yeah that i dove through first and then started taking a deeper dive into the ketogenic diet there's staple references for my lab like mandatory reading you come in you gotta read Finney and Bullock. Yeah.

Yeah. And, you know, one of the things that I've loved in following you over the years is that you're just, you're on the cutting edge. You're constantly searching and looking for stuff and it's really based around performance. So talk a bit about your background. And again, I apologize for people that have listened to you and followed you over the years. There'll be a little bit of cover, some layover here, but that's okay. Yeah, there's always new stuff we're doing too.

So my background would be, I mean, going way back, I was always interested in nutrition and training. You know, my brother was probably the biggest influence, Erdemy. So he was sort of a beast in the gym, but never actually went to the gym. We had weights in our basement, but he was well under 200 and benching 405 for reps, which always inspired me. And it was just this natural strength. So I aspired to that. That was the thing that got me into training and football. And of course, you know major influence there watching things like commando over and over and that really got me into yeah that was like I had the little VHS tape and probably watched that about 50 times and these were the things you know you look back at your

early childhood and then that really sets the trajectory of your life, you know. So I was really inspired to be as big as strong as possible. And that got me interested in just understanding the body. So I studied. I wasn't very good in school until maybe my senior year. And I challenged myself with sort of honors level biology. And then I really started studying, you know, when I got to college only. I had very mediocre grades. And then in college, I got really interested in just understanding my body.

And that is sort of a selfish motivation that really drove my academic performance. And then I majored in nutrition. And throughout nutrition program, I realized that there really wasn't any good jobs in nutrition. And it was kind of like a foo-foo science right so after my undergrad I majored in neuroscience because the 90s was a decade of the brain so that was I was really fascinated with the brain how I could change my brain understanding fundamental you know brain activity so I did what was called patch clamp electrophysiology where you record from neurons in the brain and we look at the effects of low oxygen the effects of different metabolites the effects of the neural control of autonomic regulation so how our brain stem

mechanisms control our respiration and our physiology so So that was sort of what I did my PhD on and under extreme environments of hypoxia, so low oxygen. And so after I finished my PhD, what was most interesting to me was diving physiology and what we didn't understand in diving medicine, which was hyperbaric oxygen toxicity or CNS oxygen toxicity, which is a limitation for Navy SEAL divers using a closed circuit rebreather. And it's also a limitation for hyperbaric oxygen therapy, which I was really sort of into at the time. So I decided to do a postdoc in a lab that was funded by the Department of Defense, and they created various technologies that were environmental hyperbaric chambers where I could do things like electrophysiology, fluorescence microscopy.

And as I did my PhD, my PhD or my postdoctoral fellowship was developing hyperbaric atomic force microscopy and laser scanning confocal microscopy inside a hyperbaric atomic force microscopy and laser scanning confocal microscopy inside a hyperbaric chamber so we could look at mitochondria, so we could look at the membrane, so we could look at neuronal activity in the context of environments that would be experienced by the Navy SEAL warfighter or the deep sea diver, or if we pull a vacuum on the chamber, the high altitude, the top of Mount Everest. So this gave me a fundamental understanding of what cells, in particular neurons, do in the context of these extreme environments. So that actually led to me studying different metabolic fuels. And one of those fuels would be ketones, ketone bodies.

And the observations that I made from a very fundamental perspective of measuring, you know, reactive oxygen species, measuring cellular activity, measuring membrane lipid peroxidation with very fundamental, you know, mechanistic tools gave me the insight to sort of look into the ketogenic diet. Because basically, the military was funding me to understand oxygen toxicity seizures, which manifests as grand mal seizures. And there's no way to prevent or predict them. But to basically understand what they are, you have to understand them at the level of the mitochondria and the cell. So the insights that I got from the technologies that we developed, we were looking really for drugs to do that. for drug-resistant epilepsy, my research got steered in the direction of understanding fundamentally what is nutritional ketosis, how does it alter our metabolic physiology,

and how does it alter our brain neuropharmacology to make the brain more resilient in the context of environmental extremes, which is high pressure oxygen, and preserve that activity. So there was some evidence that fasting could do it. And I think it was in 2008 that I got onto this idea. And in 2010, I kind of pitched the idea to the Office of Navy Research. And they like the idea of a ketogenic diet in a drug and or sort of ketogenic diet in a pill uh at the time now i think they've warmed up to the idea of a ketogenic diet in and of itself you know being used by the warfighter to maybe perhaps preserve nutritional status and energy status in the field. They didn't really legitimately look at a carbohydrate deficient diet in that. So

carbohydrates was mostly the fuel that they were sort of vested in. So they really wanted me to develop, to circumvent the dietary restriction that would typically be associated with getting into that therapeutic ketosis state. And to do that, we're looking at probably 50 different compounds. And some of them are ketone esters and some of them are ketone salts or formulations of these things or like ketogenic fats, like medium chain triglycerides so that research started over 10 years ago and and led to the development of various technologies that are patents and that use patents and and the original application was cns oxygen toxicity seizures but now we look at things like angelman syndrome we have a clinical trial on that. Kabuki syndrome is like a rare genetic disorder that looks to be responsive to this.

Glucose transporter type one deficiency syndrome. Cancer is a big area of research. We have a couple PhD students and research associates just studying cancer. But I mean, it's taken a little bit farther step back. The thing that actually got me interested on this track was the Charlie Foundation. So I connected with them early on, and I saw that Jim Abrams, the Hollywood producer, had a foundation. That was the first thing that came up on a Google search. I don't think it's first thing now because now the whole internet is flooded with keto diet articles and websites and products and things like that.

But at the time, 10 years ago, the Charlie Foundation was the resource and should remain the resource for people looking up the legitimate applications of nutritional ketosis of the ketogenic diet. And on that website was Charlie Abrams' story and his epilepsy was cured with the ketogenic diet. And on that website was Charlie Abrams' story, and his epilepsy was cured with the ketogenic diet. So as of now, we do not have any therapy that can cure epilepsy. So he used the ketogenic diet, weaned off of it, and never got a seizure again. And that's coming from the context of using multiple high-dose anti-seizure drugs at the time.

So his father, Charlie's father, Jim Abrams, was really fed up with the medical system and realized there was other things out there like we know now, like CBD is something we're looking into. There's many other things. And the ketogenic diet was legitimately the standard of care back in late 20s and 30s and 40s when drugs didn't exist. And then drugs came on the market and it was much easier just to prescribe a drug for the parents of kids, you know. And these drugs have tremendous developmental consequences. So when a kid's put on anti-seizure drugs, you know, it will decrease his IQ,

you know, in time, it'll have tremendous developmental consequences. And the ketogenic diet was a grossly underutilized approach, you know, for, for seizures. And I locked onto that because I was always interested in, you know, the ketogenic diet was using things like, you know, to cut up for bodybuilding and things like that. But I didn't actually know what the ketogenic diet was used to cut up for bodybuilding, but I didn't actually know what the ketogenic diet was until I understood it from a medical perspective that your brain has the metabolic flexibility to adapt from using glucose as its primary energy source to using ketones. We always need a little bit of glucose there. And we make glucose through gluconeogenesis and the glycerol backbone of fatty acids. But the ketogenic diet converts the metabolic physiology of your body from burning primarily carbohydrates to burning primarily fat and ketones, which are water-soluble fat molecules that can largely replace glucose in the context of a strict ketogenic diet or prolonged fasting. And that changes tremendously your brain energy

metabolism, the neuropharmacology of your brain, and really just your mental state. So we talk about fasting for autophagy, fasting for mitophagy, for clearing out. I think of fasting as a way, for me, it was a way to, I think of like mental autophagy. It's kind of clearing out all the clutter in my brain and makes my thinking much more lucid and clear. And at the time, I was very inspired, and this is 2008 or 9 before I was technically funded to do ketogenic diet research. I need to test the system on myself. So actually, I reached out to Johns Hopkins and got the book by Eric Kossoff and John Freeman, the ketogenic diet for, at the time, it was a ketogenic diet for pediatric epilepsy.

And now the book is called The Ketogenic Diet for Pediatric Epilepsy. And now the book is called The Ketogenic Diet for Pediatric Epilepsy and Other Neurological Diseases because there are so many expanding applications of it. But I got a scale. I weighed out everything. And the diet that I ate was 87% fat, I think. And maybe it was scary for me to do it at the time because I was eating, you know, three, 400 grams of protein, but I backed off to like something like, uh, you know, uh, less than one gram per kilogram of protein. So it was like 70 grams protein or something, which I actually needed to do to without MCTs. I needed to do that to get into a state of nutritional ketosis. So, uh, and at first I felt horrible. I felt terrible. You know, my, uh, I felt sluggish. I had a little bit of, I had to get about 225 grams of fat a day. Now I probably get about 250 grams of fat a day. And it took about

three to four months for me to actually just feel normal again. Wow, that long. It did because the diet that I was following was a pretty strict ketogenic diet and at the time 10 12 years ago you know it was mostly dairy so basically i'm just eating you know butter a couple sticks of butter you know i went to egg yolks and things like and i went from relatively like moderate to low fat high protein uh to very, very high fat. And, but once I started doing it more, the more I did it, there was a learning curve, the easier it got and the more benefits I started deriving from it. And the fear that I had was like losing muscle,

tremendous amount of muscle, losing my energy in in the lab like i'm transitioning to a uh tenure track faculty position which requires it's like five years of super intense you know uh academic performance from you know you got to publish manuscripts bring in like millions of dollars of funding pretty much uh teach uh you know and a lot of responsibility there. And it actually made it easier once I eased into the ketogenic diet. I was much more even keel and I had my flow of energy was such that I could just work on grants and manuscripts, it seemed like, and there was no stopping me. So I didn't have those peaks and valleys in blood glucose that would set off my hunger and I would have to stop to eat. So the more I started delving into nutritional

ketosis and learning about some of the experiments that were done early on in 1967 at Harvard Medical School by George Cahill, where they fasted subjects for 40 days, administered a dose of insulin that typically would be fatal for someone, and pushed their blood glucose down into like the 20 milligram per deciliter. That's almost about one millimolar range. And the subjects that were fasted were asymptomatic for hypoglycemia. And to me as a neuroscientist that's fascinating because you know the brain uses glucose to some extent lactate so ketones were another energy source that i could potentially uh develop and leverage and so i started doing some uh experiments on myself i was working with patrick arnold at the time you know uh and he was because because I reached out to many people in academia

who were interested, but you know, academia, you're, you're busy. So the people at the top who are able to synthesize and develop these things in academia, it typically takes some time. There's paperwork, there's material transfer agreements and things like that. So, so I reached out to a chemist that was a little bit more nimble and was motivated from the perspective of performance. And I sent him enough literature where he realized that this could be something pretty big. And so him and I started working on some projects and he started sending me things. And I was motivated to do... I, uh, I, I believe that

getting out of your comfort zone is the only way to grow. And for me going from eating six to eight meals a day to not eating for a week was like a big part of getting out of my comfort zone. And, uh, and I realized that I wouldn't die. Uh, and I just wanted to experience what it felt like for your brain to run on ketones. So I got all the equipment to measure it. I did lots of blood work before, during, and after. I had some other compounds that allowed me to push my blood glucose down while I was in a state of ketosis and where the meter wouldn't read it. So I was definitely at probably somewhere between 10 to 15 to maybe 15 milligrams per deciliter.

That was my glucose, which is ubiquitously fatal if someone to achieve that. It was just the meter wouldn't read it. So the meter would read down to about 20 milligrams per deciliter. And after fasting, I was, and taking exogenous ketones, I had the realization that your brain can run on ketones. And this is an interesting finding that has not been studied before in the context of,

it has been studied in the context of fasting. You can fast and your brain can adapt to using ketones. But what I was doing sort of was artificially pushing my glucose levels down to severe hypoglycemia because I didn't want to fast 40 days. And I realized that taking ketones could be a way to preserve and maintain brain energy, metabolism, and consciousness in a lucid state in a metabolic physiology situation that is pretty much perceived as ubiquitously like fatal. And that was sort of what did it for me to send the trajectory of my career to study this. And that was about almost 10 years ago, eight years ago. And then I started writing grants and I got funded by the Office of Navy Research to develop strategies, therapeutic ketosis as a strategy for preventing CNS oxygen toxicity. So that study was done in rats and we published it in rats. And now we have studies like at Duke University. We have a number of studies that are kind of being done now in humans. And we continue to do mice and rat studies probably in about 12 different

applications from decreasing blood glucose to enhancing exercise performance for a number of rare diseases like Angelman's, Kabuki is another one that we study, cancer cachexia, which is muscle wasting with cancer, anxiety. So that's another thing that we study, behavioral effects of being on nutritional ketosis. So my wife heads that up. She's a behavioral neuroscientist. So her lab is looking at the behavioral effects of ketones so it's been kind of like a pretty cool ride yeah it's been it's been absolutely amazing to watch you covered a lot here um and yeah thank you i talked a little too much but um yeah yeah you know rebreathers yeah obviously big issue right so we have we have high high operating navy seals that are having seizures and you dive into this research potential for having seizures yeah seizures and we have we're supposed to dive within the limits right but if you're diving

with an oxygen rebreather you generally stay pretty shallow you know you're just trying to avoid the enemy right and swim across the lake or something. And then there's a stealth component to the rebreathers because there's no bubbles that come up. That's the advantage. The disadvantage is that if you go down to 50 feet of seawater within 10 minutes, you're at the potential for oxygen toxicity seizure. So, so if you're down there and you get to your destination and the enemy's there and you can't surface and you have to plant a mine at the bottom of a ship or at the bottom of a bridge and you're taking fire and the water's clear, you got to go down deeper. There are scenarios where you can't always adhere to the dive tables, right? So we want to give something that will provide safety and performance.

An anti-seizure drug may provide that safety, but what we've discovered in the lab is that you get about, with an anti-seizure drug, you get about 200 to maybe 250% increase in latency to seizure. But with a ketone ester, we find about, you get 575, almost 600% delay in that latency to seizure. So that's tremendous. And if you can do that and also provide the warfighter with an energy dense source of nutrition that, and we're studying the performance aspects of it now, but my role as a neuroscientist is to study the neuroprotective

aspects so that's my sort of focus uh that's the idea okay so yeah and so you dive into the sorry you dive into the rebreathers yeah yeah yeah and obviously you you stumble upon all this research that's been previously done nearly 100 years ago with yeah you know with fasting and seizures fasting millennia if you want to go back to like hippocrates and even scripture where fasting was a cure for seizures probably through uh altering brain energy metabolism with fasting ketosis yeah and from that you figure out this the og diet for keto right like the this original ketosis where you're going to be in a very high state of fats you know when you're comparing you're looking at a macronutrient standpoint 80 to 90

percent of your diet coming from fat yeah pretty hard to accomplish for a lot of people definitely hard for children and um you know you talk you spoke a bit about diving into that and and then of course practicing your own fasted state where you push this down. How has your diet changed over time to what it is now? Because there's a lot of talk in the ketogenic diet of what is original ketosis versus this modified keto and how that looks. Yeah. So the ketogenic diet is one of the few diets, the only diet, I guess, that would be, you can measure it with an objective biomarker, right? So that's urine or blood ketone levels or something. And if someone

says they're on a keto diet or ketogenic diet and they have not measured ketones, so you question that, right? The only definition of a ketogenic diet is that your body is producing ketones. So that should be clearly stated up front. And the original diet used for pediatric epilepsy, which was the four to one or the three to one, essentially that means it's four parts fat and one part protein with very minimal carbohydrates, right? And then that translates in percentage of macronutrients to about 85 to 90% fat, you know, with the classical ketogenic diet.

When I got into this in 2008, Eric Kossoff at Johns Hopkins had created sort of the modified ketogenic diet that was actually used for adult epilepsy, where the protein was much more liberal in protein. So it was 20 to 25 and even upwards of 30% protein could be used to metabolically manage seizure disorders in adults. And that's sort of the diet that I follow. So the diet that I originally tried, I think it even predates the development

of the modified ketogenic diet or modified Atkins was the classical ketogenic diet. And that's like, that's like almost impossible. That's really not sustainable, uh, for an adult, you know, for a kid, it may be sustainable because the parents, the mother is, you know, typically is making this and they can also, uh, you know, if it's a really young child they could drink a liquid formula that is has the ketogenic you know like keto cow was the formula back then and you know it was hydrogenated fast it was like a horrible mix of things but nutrition has evolved to where they changed the formula on that um so you know i went from a standard sort of classical ketogenic diet, and that was difficult to do,

but I think I adapted faster to being fat and keto adapted simply because I went deep into it. I went from high protein, moderate carbs, relatively low fat to very high fat, very low protein actually, to almost zero carbs. And then I ultimately, over the next year, I realized if I'm supposed to keep muscle, I really needed more protein. So I needed at least about 100 to 150 grams protein a day. So that's one to 1.0 gram per kilogram of protein to maintain sort of my weight even. It was amazing.

I was eating 250 grams fat a day, but I kept losing weight. I started maybe 247 or 240, and now I stay about 222, something like that. So I've lost weight over the years, but I feel better. All my metabolic biomarkers are going in the right direction. I felt that in a state of nutritional ketosis, it really helped my career. I was told that it would be academic suicide,

like switching your whole academic program or research program from a drug-based pharmacological physiology to this weird high-fat diet sort of thing. Like, what are you studying? And exogenous ketones, which were thought to be metabolic poison at the time. But different iconic scientists like Richard Veach at the NIH and Dr. George Cahill, who I communicated with, he was at Harvard, Theodore Van Italy. These were like icons to me because they understood that the state of nutritional ketosis could be sort of, there were novel ways to achieve it and that it had legitimate applications outside of the world of pediatric epilepsy. But it hadn't been explored. Like no one was studying this stuff. So it looked like,

you know, the world was kind of like my oyster and there was like so many applications if you're developing a strategy that that elevates an alternative fuel in your blood that and that fuel is superior in its ability to produce atp and to maintain brain energy metabolism and even change the neuropharmacology of your brain to enhance brain homeostasis. Essentially that's what it's doing in epilepsy. The etiology of epilepsy is largely unknown, but in many cases, the etiology is varied,

but it brings the brain back into balance in a way that prevents the seizures from happening, even in the presence of a persistent molecular pathology, for example, in something like Angelman syndrome, where you have a rare genetic disease. It can symptomatically sort of silence the pathological symptoms that that disease produces. So that really blew my mind. And then I realized that food is really medicine, at least in the context of a ketogenic diet. So as I started experimenting on myself and doing lots of little mini experiments on myself, I transitioned to a modified ketogenic diet. And I started using

not only the nasty tasting ketone esters, but we started developing these ketone salts. And Patrick Arnold was, a decade ago almost, he was like, there's a sodium salt, but if you develop, if you can spread beta hydroxybutyrate across monovalent and divalent cations and balance the electrolytes, you could create a very powerful ketone electrolyte salt. And I don't even like calling it salt because salt has a negative connotation in the scientific world. So I call it ketone electrolyte or whatever. But you can also combine ketones with amino acids and other things. So I knew there was the potential there to do that, that that could be a way to rapidly induce nutritional therapeutic ketosis, which needs to be done in an ABC or Warfighter. He's not going

to sit around for 72 hours to try to get into ketosis before the dive, right? So you want rapid neuroprotection and you want you want a rapid elevation in ketones that's sustained over the course of hours that's the idea right so the ketone esters are still the most powerful compounds and that's what we work with mostly in the lab but like I said we have dozens of different compounds that we work with and the the focus now is to vet out and understand from a top-down approach what actually works. So we do experiments where we test a bunch of different things and put mice in chambers and we go to seizures. We run them on little treadmill

devices. My wife does anxiety studies. So we do a battery of stuff and just, we throw away what doesn't work and then we keep what does work. And then we sort of fundamentally understand how can we take this formula, whether it be a particular ketone, exogenous ketone in isolation, or a formula of various ketones. And how do we make that palatable? How do we make that palatable how do we make that tolerable how do we uh transition that to a human to determine uh the safety the pharmacokinetics and things like that so that's kind of where we're at now a lot of it you know the whole exogenous ketone thing sort of evolved out of a single ketone monoester that was developed at nih and at oxford and was funded primarily by a project through DARPA. So defense organization that, and a lot of it was kind of kept secret, but I kept, when I got into this,

I kept digging and digging. I was like, well, DARPA is funding this stuff, you know, for war fighter performance, you know, before I even got into this, you know, there was, you know, there was like $15 million funding a warfighter performance program but on a single uh ketogenic agent which is technically a 1-3 butanediol you know beta hydroxybutyrate monoester and what we study is uh 1-3 butanediol acetoacetate diester so it's a a little bit potent so you have these are like the typical jet fuels that that peter would talk about exactly very hard to palette yeah like on paper they're very simple molecules uh These are like the typical jet fuels that Peter T would talk about. Exactly. Very hard to palate. Yeah. Like on paper, they're very simple molecules.

But in practice, they become almost impossible to consume. Well, the agent that we work with can be put in the capsules and things like that. But that was the initial agent. But it stimulated thinking to where we go back to our organic chemistry books and we realize, wow, there are so many different molecules that you can make. And it's not possible. It's absolutely sure that some agents may decrease performance. Some agents may work remarkably well at enhancing brain energy metabolism,

but others may produce ketone levels that are so high, energize your brain, you might have like anxiety. So we are, it's very clear, actually my wife has done most of the research and looking at all these different things and all these different ketogenic compounds and formulas and their particular effects on one, you know, one variable, whether it be a behavioral variable or glucose variable or something like that. So we're at that stage now where we're, you know, doing the tedious

work to identify the most promising agents. And at the same time, you know, we're studying the ketogenic diet. So I follow the ketogenic diet. I don't think it's a replacement for the ketogenic diet. That's the original, the military sort of wants that. But now they're even more, over the last 10 years, their view of the ketogenic diet has changed, where I communicate with a lot of special ops guys, guys at the top and now they've adopted a low carb and even ketogenic diet approach and they're doing things like intermittent fasting and this didn't nobody nobody did this 10 years ago and now they're doing it yeah you know so that's been kind of cool to see that evolution and thought in nutrition you know so 100 well you're definitely moving the bar on this uh i want you there's many people too so i'm

people were doing this way before me i'm not i think peter attia called me the keto king but really i mean the guys who are the keto kings were the icons in the field like uh richard veach who is uh the p the graduate student of hans krebs of the krebs cycle, George Cahill, who I got to talk to, he passed away in 2012. But he did this study at Harvard where they fasted subjects for 40 days, which would be totally unethical today. So we can't do those kinds of studies today because they would ethically not be approved. We couldn't even do them in mice, actually. So inject them with a fatal dose of insulin. But these were the guys.

These were the real pioneers. So when people come to me and they want to learn this stuff, I tell them, you got to go back to the early literature and get an appreciation for the science, the metabolic physiology. This kind of studies, these experiments are not being done today. It's more biochemical. Metabolism is in sort of the realm of biochemistry and not so much metabolic physiology.

I'm a physio, I'm a neuroscientist and a physiologist. So I like to understand metabolism in the context of physiology, not like, biochemistry is very important and it's important to understand that, but you have to understand how it's affecting all the systems, how your sleep is impacted by this, how, you know, heart rate variability, how, you know, your liver function, you have to view the body from a systems perspective.

And unpack some of that because there's so much that goes into this diet. And I mean, certainly when I got into it, I had a reason having fought for a long time and with for sure, traumatic brain injury, things of that nature um also not training as hard as i used to so like how can i manage you know weight loss and optimum performance and cognitive function um talk a little bit about what your wife's doing with anxiety because you know new research is coming out i think dr ronda patrick just recently retweeted a thing on how the microbiome shifts and we produce more gaba in the gut and the GABA pathways. It's wonderful.

There's supplements for that, but obviously we can change this through diet. That has a huge impact on how we feel, our anxiety levels, how we sleep at night. Talk a bit about that. That's a huge focus. Well, I'll just say real quickly that the GABA to glutamate ratio changes pretty profoundly

with the ketogenic diet. So it activates an enzyme called glutamic acid decarboxylase and that shifts more excitatory amino acid if you have traumatic brain injury epilepsy uh the i would even say pathologically speaking the excess glutamate excitotoxicity is at the root cause pathophysiologically to all neurological degenerative diseases and neurological disease, excess glutamate neurotransmission.

So it shifts that, it takes the excess and converts it to more GABA, which is brain stabilizing. It hyperpolarizes the membrane potential of your cells where it stabilizes synaptic activity. So just getting back to the anxiety stuff, which I think is going to be huge for PTSD. And my wife, when you study rats, what we do, we don't, sometimes we feed it, we integrate the exogenous ketones into the food and then have them eat it. And then you could see behavioral effects,

but more acutely, what we do is called an intragastric gavage, where we basically just stick a little tube down their throat and then feed them, tube feed them. And shortly after you tube feed them, 30 minutes after, if you look at the blood of a rat or a mouse, it looked like you or me fasted for 10 days, for something. So the ketones can be up

to four or five millimolar. When that happens, my wife made the observation that they are much more calm. They're much more easier to handle. If you do it with mice, they're not trying to bite you. The rats, they like to be pets. they it sort of attenuates that fear response that they have that uh that anxiety response so she said in her lab she set up uh what's it's called an elevated plus maze so it's a it's a experimental paradigm that's used by pharmaceutical companies to vet out and understand the anti-anxiety effects of different drugs. So we use sort of the same methodology. And what she determined, and this was a project, we didn't really have any funding for it,

so we had to scrape up some funding to study this. But she knew that it was a very important study because she could see the effects. She was much more sort of in tune with animals. She's a behavioral neuroscientist, but she studies manta rays. So she does a lot of field research and just has a very good sense of animal behavior. So I trusted her on this. And she did a study where the rats were fed a number of different ketogenic compounds and the elevated plus maze is like a catwalk, right? So you can walk out on the catwalk and be,

you could fall off the edge and you're in an open environment. And, or you could go back into an enclosed environment where you're in a little cave, right? So the more time you spend in the open arm is indicative of exploratory behavior, is indicative of less anxiety. The more time you run back into the cave and hide in the cave and don't come out into the catwalk, that's indicative of anxiety,

antisocial behavior, fear response. So what we observed is roughly a 25, maybe 30% increase in the animals going out into the open arm relative to the closed arm. And it was a very significant effect along the order, probably more robust than most anti-seizure or anti-anxiety drugs like Xanax or Valium and things like that when you compare it. And the ketone ester sort of worked well, but one of the formulas that kind of really stood out was beta-hydroxybutyrate salt combined with a ketogenic fat, medium-chain triglycerides. So that combination tend to work really well for that application. And now we're delving into it more and doing more learning and memory tests. And we're looking at gait.

We're looking at doing open- field test or a wide variety of behavioral things but we uh so she discovered that and now we're mechanistically looking to determine well how is brain how is neuropharmacology changing from an acute administration of an exogenous ketone to produce that effect like what neurotransmitter system is it working through? So we're looking at GABA to glutamate ratio, we're looking at serotonergic effects, we're looking at adenosinergic effects, the adenosine A1 receptors, one of the areas,

dopaminergic, we're looking at all the different neurotransmitter systems and we can use antagonists or agonists to block the effect. And so we're into that now, sort of vetting out what works and then mechanistically going after to determine sort of how it works, which from my roots, I did a lot of mechanistic stuff, discovery stuff that doesn't always translate. So a lot of uh funding through the national

institutes of health is uh it's basically mechanistic you identify a mechanism and you try to work to a therapy but that doesn't always work like with the ketogenic diet it's like a top down approach so it like works so let's figure out the best way the key to the problem with the diet is implementation right so uh it it works remarkably well for a wide variety of things. For some things, it doesn't work. And for some things, it might be contradictory to. There's some things, definitely people who do not adapt well to the ketogenic diet. But we have to understand what it works for

and mechanistically how and why it's working. And also from a nutrition genomics perspective to identify, I think it's going to be important in the future, the next five years, to really nail down genetically who may be the best candidates for this based upon their metabolic profiling and their genetic profile too, so nutrigenomics areas. Yeah, I've noticed when taking a little bit of a deeper dive into my genetics that my fasting glucose will go up

if I have animal-based saturated fats, but medium-chain triglycerides, butter, don't quite affect that the same. And MCT, a pure MCT may decrease it too i mean we see that in rodent models that um so i actually had kind of the same experience like if i'm pounding a lot of dairy which i did early on uh with the ketogenic diet it was mostly a dairy-based diet and still is i mean from a pediatric perspective uh i started seeing things changes in my like my triglycerides did not go it started to go down a little bit uh but a number of things which would

be alarming to a medical doctor like my ldl cholesterol skyrocketed but when i replaced a lot of the dairy fat with uh monounsaturated fats and um uh olive oil yeah yeah and i started seeing more positive and that could have been just an adaptation and enhancement of just being fat adapted but some big changes yeah by shifting you know not the macronutrient percentages but where the uh yeah the macronutrient sources and there's not an appreciation for that actually in the medical realm it's more about macros and it's not about source i think it i mean we're we're learning more as we move along but there's there's a lot of a lot of education being done on that yeah we've seen that quite a bit over the last decade you

know that shift in between all right maybe saturated fats aren't the devil maybe cholesterol truly isn't an issue one thing i've noticed that even as my ldl has come up my vldl has tanked which is great yeah obviously that's one of the more important markers when we're looking at cholesterol yeah um i've seen that go in single digits single digits so, wow. So very low. And your triglycerides? Triglycerides look great. Okay. Everything has improved.

I think our blood glucose is probably the most important health biomarker that we have. And not just fasting, but our postprandial excursions in blood glucose will really predict our metabolism so i think wearing uh and that you can get a 20 glucose monitor at any drugstore and a cgm uh or just not a continue it my i have a student who just did a ted talk actually on using nutritional ketosis low carb for type 1 diabetes and the power lifter big kid super strong and maintains you know size and strength and performance on a ketogenic diet as a type 1 diabetic which is when i would give talks on the ketogenic diet i would be this is a great approach for a number of things type 2 diabetes but no if type 1 diabetics you don't want to do it and i

you know my phd student was doing it and living the lifestyle and probably maybe even saving his life because when if he'd go hypoglycemic he would be protected the ketones would be protecting him from that and i saw him do some pretty dangerous dips in the lab uh so his his the group that he's involved in was called type one grit and it's on facebook and he's part of that group. And the data from that group was just published in a Harvard study that validated the use of nutritional ketosis or low carb for metabolic management of type 1 diabetes, which totally flies into the face of convention. So you get a high impact peer-reviewed publication from a prestigious university like Harvard who sort of publishes this. I mean, this is, we've come a long way in the last 10 years. So for it to be accepted as a therapy for type one diabetes is a huge step. And my student was doing this and he wears a

continuous glucose monitor. And when I get foods like the keto brownie or the keto cookie or various products that are coming out on the market uh you know we can test them in animal models too but uh i get my student andrew kutnick and i you know we turn off his insulin and then i give him the product and when we can look at his glycemic response with a continuous glucose monitor in response to the food to determine if it's truly ketogenic and uh if i was to like pay for this service it would probably be like thousands of dollars but i just walked down the hall to his office and say hey i have another product i needed to test and i gave you a guinea pig i gained more insight from that

that's like i mean that's like uh invaluable having you know a student who's super disciplined with his diet because he's you know bodybuildbuilder and he measures out all the macros and everything, but to have him there to vet out and test some products that are quote unquote keto, that gives me insight. And also different foods too, and combinations of foods, and ketone supplements too. So I think that's, if you can do it, a continuous glucose monitor is a way to do it,

but you could just get it, a continuous glucose monitor is a way to do it, but you could just get a simple finger prick glucose monitor and just do it 15, 30 minutes, 60, 120 after eating a particular food. And if your glucose excursions are going up to like 220, that is really setting off a lot of pro-inflammatory cascades in your body right that that's really from a neuroprotective point of view that's dangerous if you could follow a diet and always keep under 100 milligrams per deciliter even postprandial that's going to add five to ten years to your life uh if you could eat a diet like that, in my opinion, in contrast to a diet

that's sugar, processed carbohydrates, where you're spiking up, depending on the individual, if you're spiking up. And I've seen excursions in the 300, 400 range where people didn't know it. I've done a lot of health screenings where I'm at the table and there's a line of people and you're doing, you know, you're 383 milligrams 380, you know, three milligrams per deciliter. And they didn't know that. And that's a walking time bomb. You know, the glucose is basically at a level where your, your blood is like sludge and it's impeding blood flow to your eye.

You know, you could damage your, your, your eye and your brain cells. There's so many, you're creating a scenario that's causing tremendous oxidative stress in your body and not knowing it i had read uh wired to eat and i did his yeah rob will's carbohydrate test just to see which carbohydrates were good for me and bad for me and like rob there was quite a few carbohydrates that i didn't tolerate well at all yeah you know white rice being one of the biggest culprits uh I was surprised to see. You didn't tolerate white rice. At all. Really? Like I looked pre-diabetic every single time, even at small amounts. What did you go up to? It was like 160 to 180.

Yeah. That's pretty high. Pretty high. Yeah. And even with, you know, like if I'd have Thai food with, you know, higher fat, higher fiber, higher protein, didn't matter. Yeah. Yeah.

Still high. But I could have a plate of yams with honey and butter and drop on you know right around 120 and under so not ideal but still like tolerable in comparison you know something that i try to mention to people is like we have this idea that we'll eat clean for a while and then we'll reward ourselves with shitty food and that we just look at that as a measure how that measures on the scale you know like well i've lost 20 pounds and i might gain a couple from this bad meal but we don't think of how that affects inflammation how that affects joint pain

cognitive performance sleep emotional state absolutely like it's all connected yeah yeah it is i mean your blood glucose is impacted by your stress levels. You could wear a continuous glucose monitor, get in your car, and if you're type A personality where you're just pissed off and stuff, you see spikes going all over the place. If you have an infection, if you're battling a viral infection, if you're stressed in your life from any source, various foods can set off your immune system and make you transient. Or you could have protracted insulin resistance just from setting off your immune system from a food that you ate,

where you have not necessarily an allergy that you would detect. Maybe you get a little bit of congestion in your nose or like sinuses or something. If you eat a little bit of dairy, but you're running, your glucose levels are high and it's important to be perceptive to that. And I think blood glucose is a very sensitive measure that is so easy to measure. Hemoglobin H1C, you know, is one of, you know, you want to do that. You want to measure. Hemoglobin H1C is one of, you wanna do that, you wanna measure that too, but, cause that'll give you a snapshot of really what's going on and your- The area under the curve.

Yeah, yeah, it's sort of the area under the curve. But I think the average, when it comes to the average person who just wants to get a handle on enhancing their metabolic health. And whether it be for performance or longevity or just feeling better, a glucose monitor is the way to do it. And of course, if you're doing a ketogenic diet, you want to probably easy to start out with urine ketone steps, which should tell you if you're in ketosis or not and then from there you can get something like the abbott's lab precision extra and and measure you know your ketones thankfully the cost of those

strips has come down considerably yeah it used to be like six to eight dollars a strip when i was first getting oh yeah yeah and i think now you can order in bulk on amazon and different places yeah we do that because we've probably I've probably tested myself more than anybody else on the planet. I mean, literally like probably hundreds of thousands of strips over the last decade. I did buy a box of strips from Israel and all I had to do was pay customs. I paid 10, no, one cent per strip, but I just had to pay the customs. Yeah. They were giving them away essentially. the expiration date was uh four to five months and this goes 10 years ago i bought it was a refrigerator box

size box and it was full of the ketone strips and uh and we did a ton of research with those strips uh but yeah that's hard to find that deal but now you have devices like the keto mojo that are out there i don't know if you've seen that. I got a link on my website, Keto Mojo. So we've tested that against the Precision Extra and that's always $1 per strip. And that's a pretty legitimate alternative to, if you don't, Abbott kind of corners the market on that.

And maybe there's a few others coming, but the Keto Mojo is a legitimate, it took us a while to sort of compare it, but it's a very legitimate alternative. I think I saw they're at Keto-Con. Yeah, they're probably at Keto-Con. They're a blood strip, right? Yeah, yeah.

It's a good device. We've tested it and we'll probably publish with it and actually published the comparison of the two. I think someone really needs to do a very comprehensive, they did it with blood glucose measurements. So there's a couple publications out there where all the different devices are tested and there's big variabilities. And when you're messing with blood glucose, it's not good to have variabilities in that, but someone needs to do a comprehensive study to validate and test these new technologies that are, you know, measuring blood ketones. So we hope to do that pretty soon. Yeah. Talk a little bit about, I mean, the last time you were on Rogan's,

you mentioned some apps that were coming out because one thing people pay attention, you know, when I first started in that, I was like, I only paid attention to carbohydrates, you know, get my fats up, eat more fat than I think I need, drop my protein and just count carbohydrates. And that seemed to work for me because I was testing blood glucose and i'd see you know consistently over uh 0.6 but you know that would kind of fall in between one to two millimolar um but for a lot of people that that really struggle to get into that because maybe they're not as active you know obviously i had a cheat code in working out as often as i did yeah to really help dump glycogen. For a lot of people, it's harder, especially if they're sedentary or they're just getting into working out.

What are some of the apps that you've found that have really helped people to count macros and factor in everything they're putting in their body? So I've used a variety and now I can just kind of look at food and just kind of calculate it and maybe just run a few numbers on paper. Yeah, I can do that now. But I think it's absolutely important for most people to use an app in the beginning. From a medical perspective, if you're doing this from any kind of medical perspective, the Keto Calculator is probably the most legit. It's been out there the longest, I think, and that's Beth Zupatkania,

and she's with the Charlie Foundation. So you might need to get a subscription to that to actually use it, but it has a variety of foods. Like if there's some kind of keto bread on the market or this or that, it's usually, it's probably part of the keto calculator. So you just, you know, punch it and it pops the macros magically into that. So medically speaking, if you have a child or using the ketogenic diet for metabolic management of any kind of disorder, Keto Calculator would be that go-to site. And then you have simple apps like MyFitnessPal,

Chronometer is a really good one, I think the name. And then Avatar. So I talked about Avatar, that app. So at the time, uh, and then avatar. So I talked about avatar, uh, and you shouldn't that app. So at the time those guys, uh, my friend Lane Norton was kind of involved in that company and the idea. So that platform is really used for changing body composition, you know, uh, adjusting macronutrient profile to, uh, to hit your, your body composition goals. So the, the technology in that platform is very, very good. It's very innovative. So I thought that would be a good platform for, for incorporating a ketogenic diet option within the avatar platform. So if, but the the the way the algorithm was set up and the way you know there

was some sort of uh rearrangement of the company and things you know outside of my knowledge uh that was going on i i think i think it is by far probably the best platform if you're a bodybuilder or fitness athlete or something like that the ketogenic component of that never really manifested because the the program's really not set up for ketogenic macros i think you can you can slide the macros you know the protein to add more fat and things like that so you could probably do a modified ketogenic diet um but the idea my sort of vision was for the ketogenic diet community whether they're using it for a clinical application or uh weight loss or you know type 2 diabetes or whatever that that would be an option within the the avatar system and that really never manifested i worked with some of the dietitians and people involved in that uh so it's not i I don't think it really offers the true, you know, option for ketogenic option.

So keto calculator would be the way to go then. For clinical, yeah, for sure. And then, you know, like MyFitnessPal, I think Chronometer is the other one. Yeah, they're all good. I mean, they're all sort of basic ones. Some of them are subscription services and some of them you might be able to do kind of for free. But I think the more you do it, the easier it gets. So once you set up some, your meal plans and you basically select the foods that you personalized diet to yourself and you have everything worked out, it takes about three

months to really understand how the macronutrient ratios and the sources of your macronutrients are impacting your glucose and ketone levels. And once you do that over the course of a couple months, then you're automated over time. But the reality is that most people just don't have the discipline to do that. So most people getting into this you know uh i was speaking in an entrepreneurial sort of event and it was about entrepreneurial health a lot of entrepreneurs they get into business so much that their health starts to gradually decay as they get into it and uh and you know you're way more educated on this than you know i mean you're at like phd level

if you were to go to doctors and speak on this your knowledge about this stuff you don't realize it is above and beyond just from all the the reading that you've done i just know you know that you're doing it you have the personal experience uh most people don't have that and it would be take quite a while for them to learn it. So they just want food. They want a meal service where they could go and a la carte sort of have beef stroganoff or a brownie for dessert and some cauliflower, mashed potatoes, or whatever. And then it's like they get their Monday meals, Tuesday meals, Wednesday, and every day and have that service.

So I think a lot of entrepreneurs are scrambling to the market now to create food, ketogenic, low-carb, and ketogenic food options that would make the implementation of the ketogenic diet much more easier. And for me, I think that's awesome for people who are using it for legitimate medical purposes, but also super awesome for the athletes out there who want to, you know, do it from time to time. Uh, the person wanting to lose weight, uh, Virta health is, uh, an organization that is basically, you know, curing or managing type two diabetes with nutritional ketosis, you know, and eliminating virtually eliminating, uh, or severely, uh, uh, restricting, uh, the use or the need for diabetic drugs by using a nutritional ketosis. So that's tremendous. I mean, they're using food as medicine and they've created the platform, which is an app based system that if you're following the Virta program, you have essentially access 24-7 to a dietician. So if there's a particular food or particular question that they have, that patient would have, is educated before sort of implementing all this,

but is coached along the way as they get their health and they essentially wean themselves off of most insulin and anti-diabetic drugs. So there's a number of different platforms. And I think an app is only as good as, you know, something that someone will use. And I think apps are great, but they involve a certain personality like i i still can't see my my parents sort of you know if i think about them like would they use an app do this i mean they just want it like what can i eat so i don't want to put in my numbers like what can i eat if they can look at a menu and actually see the foods and then it hits the macronutrient ratios and they eat this and it puts them into ketosis like that's what they want. So for all the entrepreneurs out there,

so it would help me out. Of course, you know, I'm sort of, we started a company and we are working to become entrepreneurs in this space. And a big motivation for us is making nutritional ketosis accessible to mainstream, mostly focusing on military and some of the stuff that we do at NASA and stuff too. I mean, that's sort of what our expertise is, but at the same time,

we want to have a bigger impact on the society and the world and make nutritional ketosis or a modified low-carb nutritional ketosis approach accessible to people because we know experimentally when we're looking at doing experiments in the lab ketones are not only alternative energy sources for the brain but they have profound effects on inflammation on reducing inflammation they function as a class one and class two class two histone deacetylase inhibitors. So they actually have epigenetic effects. You elevate your ketone levels up to a level that can be achieved with fasting or the ketogenic diet.

And that ketone, beta-hydroxybutyrate, can function to turn on gene transcription. In the mouse model of kabuki syndrome for example it can silence that gene and prevent uh the degenerate degeneration of neurons in the uh in the hippocampus and in and that's that's remarkable that it can actually salvage neurons you know through an epigenetic through a non-metabolic likely a non-metabolic effect in the area called the dentate gyrus you know so this has been established in mouse models and it is a proof of concept uh and i think you know that's for diseases that have no therapy right now i mean that's very important for parents parents and children who are stricken with this disorder.

My question on that is, were you finding this through the ketogenic diet or through the administration of exogenous ketones? Good question. That particular paper was done at a research group at Johns Hopkins, Dr. Bjornsson, and he did in the mouse model of Kabuki syndrome, which was a remarkable study because it's showing that ketones turn on gene transcription that was done using a ketogenic diet and also uh they used an exogenous ketone which was sodium beta hydroxybutyrate and they sort of pumped it in and and it had it essentially silenced the uh the pathological effects of this rare genetic disorder.

And Kabuki syndrome is an imbalance between gene expression, you know, turning on and off. And functioning as a gene activator through its histone deacetylase activity, it was shown to essentially open up the chromatin and reactivate a gene pathway that could restore the neurons in the dentate gyrus. And it was a remarkable study. And we are following up on that because we want to create various ketone supplements that could be rapidly transitioned into a human clinical trial for kabuki syndrome. So, you know, something I never thought I would be studying when I got into this, looking at, you know, Navy SEALs, oxygen toxicity, that we're studying the therapeutic effects of nutritional ketosis on epigenetic regulation on gene expression. So we're working with an organization called

All Things Kabuki. And it's an amazing organization. And I learned so much from the parents who want to do everything possible to help their kids with this disorder. So we are at the fundraising stage of that right now. And I've done the paperwork to get the mouse model and to start this and start vetting out and we do a trial where we do the ketogenic diet and we compare it to an exogenous ketone and a standard diet and maybe we want to do exogenous ketone with a modified ketogenic diet because the reality is that some people are unwilling or unable to do the ketogenic diet. But most people, adults, many of them, or at least kind of like me, they're highly motivated. If they have PTSD, if they have traumatic brain injury. And I do, I'm pretty networked with the special ops community

and the military community who really don't have any options for that. And there's nothing, if you have a penetrating traumatic brain injury, about 80% to 85% of those guys will have seizures. So it just makes sense to use nutritional ketosis to metabolically manage the potential for them for having seizures. But the profound reduction in neuroinflammation that accompanies nutritional ketosis. I think just simply by lowering blood glucose and elevating ketones, which in suppress the NLRP3 inflammasome, which that is kind of a protein complex that when it's activated, a whole host of inflammatory cytokines are flooding the system and in the brain. If you were to get a TBI, if you were to get radiation,

if you were even a rare neurological disease or a viral illness, right, like HIV, for example, will activate the NLRP3 inflammasome and that neuroinflammation will cause headaches, it'll cause changes in behavior, it'll cause reactive oxygen species, the formation of amyloid and tau plaques, all these things. That whole, that's set off by the activation of an inflammatory complex that could be suppressed by an endogenous metabolite, beta-hydroxybutyrate, which could be made, you know, increased through fasting, through the ketogenic diet, or through administration of exogenous ketone compounds. so perhaps the combination maybe

ketogenic intermittent fasting with supplementation of you know that's kind of the approach that i do and even if i'm sort of not eating i can go a couple days without eating because your body is adapted to you know fat and ketones much easier to fast when you're starting in ketosis and it's amazing i mean you know uh i never thought i'd really be that kind of into fasting but uh it is a way to sort of hack the system and it's it's really remarkable that once your body is adapted you know keto and fat adapted that you can fast and you don't get hungry and you can preserve your ability to work on a manuscript to, you know, if you're a warfighter and you're faced with limited food availability and an austere environment where you're at the top of a mountain or you're diving,

your performance resilience will be maintained. So we always talk about, you know, performance, but in the context of what I study in special operations forces and things like that, it's about performance resilience. It's about preserving and maintaining that capability, you know, not enhancing that capability, but maintaining that capability in an extreme environment. You know, that's what's really important and i mean you could say the same thing for a ceo you know they they can hammer out a ton of work in the first 12 hours but if they have some kind of deadline you know three days from now can they go without lack of sleep you know in an extreme environment of pressure and maintain that work performance to achieve that outcome you know but they need to sleep

too and i know you know a lot of the guys that uh in meeting with uh dr kurt parsley ex-navy seal you know uh doc parsley is really big on sleep right so i'm kind of testing his ketone his uh his sleep supplement right now which is fantastic so giving a plug to doc parsley yeah yeah i slept you know i didn't i didn't sleep much last night i slept six hours but i have uh i typically i wear the aura ring and my sleep was uh oh you got the new one yeah i got two brother yeah so we used the gen one for our nasa nemo uh extreme environment mission operations and now we're going into another nemo mission and i think we're going to get the gen twos so sleep is probably the most under

appreciated performance enhancing like no amount of nootropic no amount of ketones could probably compensate for lack of sleep you can preserve you know your performance with uh in a sleep deprived state to some degree but nothing i mean sleep i don't know if you guys talk to talk about sleep a lot but you should have a sleep expert on here it would be so michael walker on joe rogan's podcast phd who wrote why we sleep excellent book that was one of my favorite podcasts amazing yeah i think sleep the book sleep by nick little hills is a better how-to guide i think that's probably my favorite how-to guide on how to hack sleep yeah and uh but certainly the importance of sleep can't be understated and michael walker does a tremendous job on that podcast and in his book why we sleep

yeah recovery man you're putting your body through body through things. I'm talking to guys, NFL guys, that they need up to 12 hours sleep a day to recover from time he was benching uh 535 for five squatting 800 for reps and and just a beast out on the field but for him to maintain that size and performance and strength you know he had to be sleeping 12 hours a day i was like 12 hours down you know if i could sleep that much like i mean i wake up at six hours and I think that's one of the advantages of being in a ketogenic state is I think it decreases my sleep requirement probably about 30 to 60 minutes per day just based on my numbers and tracking sleep. And I think the restorative phase of sleep is about restoring your neurotransmitters and about there's a system in your brain called the glymphatic system and it's sort of the lymphatic system of the brain and similar to that and it clears out all the gunk when you sleep and a lot of the buildup exactly and i think the uh the the glymphatic flow my opinion is is that it's enhanced in uh when you when you adhere to a nutritional ketosis or when you

do intermittent fasting, simply by virtue of maintaining your blood glucose is low and the ketones, they relax some of the blood vessels that are associated with that glymphatic flow and brain flow too. And also being in nutritional ketosis is sort of anaplerotic, we say, and it leads to the accumulation of Krebs cycle intermediates or TCA cycle intermediates like alpha-ketoglutarate, which are precursors to neurotransmitters like glutamate and GABA. So you're generating many of the intermediates that are needed as raw precursors for your body to make neurotransmitters.

And when we sleep, sleep is a very restorative process. And we are synthesizing glycogen and the astrocytes. We're making neurotransmitters. And our glymphatic system is kind of working overtime to clear out a lot of the gunk in the brain, like the amyloid plaques and other accumulated proteins. And I think that's facilitated when you do nutritional ketosis. So I think that's why I can sleep less. Yeah. I certainly feel better in travel and changing time zones and a number of those things when I'm on a ketogenic diet. One thing we haven't

touched on that I'd like you to touch on, I know we're definitely going over an hour here, which is completely fine, but I want to be mindful of your time. Cancer. I think cancer as a metabolic theory was a big one that kind of changed the minds of a lot of people, especially in the medical field. But what has come out lately? Which types of cancer can benefit from this?

And what are you guys researching? Good question. So taking a little step back. So when we developed the technology to image cells under hyperbaric environment, one of the cells that we looked at was a U87 glioblastoma cell that was derived from a brain tumor patient, a 44-year-old. And we observed that high-pressure oxygen caused elevated rates of reactive oxygen species. In this case, it was superoxide anion at a much higher level than, for example, primary cortical neurons or fibroblasts or something. So I thought that was a really interesting phenomenon back in 2007, 8. And I think we published it in neuroscience in 2009.

The observation was that hyperbaric oxygen causes membrane lipid peroxidation. And we did atomic force microscopy and malondialdehyde, something called a T-BARS test, to show that oxygen was toxic to cancer cells uh relative to normal healthy cells and we were in in some ways we were the first to image it and quantify it in that way because we had an atomic force microscope inside a hyperbaric chamber and could do that like these technology but i was using it for a military application, but it was a side project that I really got interested in. So I started growing these different brain tumor cell lines in the absence and presence of ketones too. And my lab tech was doing it at the time. And then the cells were not expanding. They weren't growing like they should. And I asked her,

you know, what was going on? Could they be infected or something like that? Well, when we remove the ketones, they would start growing. We add ketones, it would sort of have a stasis effect on their proliferation. So I got more and more interested in this, like what was happening. And I really wanted to understand why increasing the partial pressure of oxygen caused an exponential increase in oxygen-free radicals. So I could, with the technology that we had using laser scanning confocal microscopy, we could look at the mitochondrial production of the superoxide and the cancer cells were chock full of mitochondria. It was clear that they're using mitochondria. It was clear that, you know, they're, they're using mitochondria. But what was also very evident, it was that they were overproducing Ross. They were lighting up like little fireballs inside and they're moving all around. They're very dynamic structures.

And I didn't know why that was happening. And I didn't know why it was happening relative to normal healthy cells. So I reached out to a number of people, Moffitt Cancer Center, a number of experts, and some of the work by Thomas Seyfried, which his work was kind of hinging upon the work of Otto Warburg, which he got the Nobel Prize for his work on metabolism and cancer. And the Warburg theory is that damaged mitochondria causes insufficient production of ATP through insufficient mitochondrial oxidative phosphorylation. And then a consequence of damaged mitochondria is compensatory fermentation of the glucose, which is a reason why cancer cells pump out lactate even with a normal amount of oxygen there.

So you have damaged mitochondria. And then the nucleus essentially is detecting this energetic crisis that the mitochondria is not producing enough ATP. And that's called sort of this retrograde response. So the nucleus is kind of like the brain of the cell, but the mitochondria, we also know are a bunch of little satellites that are reporting back to the nucleus about many different things, inflammation, many different things, but the generally the bioenergetic state of the cell, it reports back to the nucleus. And when the nucleus senses that mitochondria are damaged, it kicks on a number of genes and some of them are oncogenes. And when the nucleus senses that the mitochondria are damaged, it kicks on a number of genes, and some of them are oncogenes. And it's a sort of a self-survival response where these oncogenes that when they're activated, many cells will die. But if the

complement of oncogenes are activated that could ensure cell survival, the normal healthy cell, well, that's damaged, can transfer to a cancer cell that has the hallmarks of cancer. So you have unlimited growth proliferation, you have inflammation, it evades the immune system. Now we know that there's additional hallmarks. One is aberrant metabolism. So only in 2011 did they accept altered metabolism as a hallmark of cancer. So you have all these hallmarks of cancer. But the metabolic theory of cancer posits that the initial damage to the mitochondria and a reduction in oxidative phosphorylation triggers genomic instability that triggers that cell from transitioning from a normal cell to a cancer cell. It's the sensing of that energetic crisis

through a number of provocative mechanisms. So you have radiation, inflammation, hypoxia, viruses. The viruses that cause cancer are the viruses that are more likely to damage the mitochondria. So the mitochondria have DNA too, and the DNA repair mechanisms of the mitochondria are far less robust than the DNA repair mechanisms of the nucleus, right? And the DNA repair mechanisms in the nucleus need to rely on ATP. It's a very energy-dependent process. So if the ATP levels fall in the cell and, you know, the mitochondria are making the ATP, if the ATP levels fall in the cell, then the fidelity of the nuclear genome is compromised because it's

not accelerating those DNA repair mechanisms. So it's more likely to trans, you have a scenario, and if your immune system is compromised, if you're getting radiation, if you're under stress, if you're, have inflammation, if you're, have hypoxia, just through poor circulation and things like that. All those factors are sort of exacerbated and you are facilitating sort of whether it be in the liver, if you're drinking and you're bombarding your liver with, you know, a toxic compound, for example, that could be the site where your healthy cells will transform into, but it really depends on the health of the mitochondria. So, healthy mitochondria are the ultimate tumor suppressor. So if your mitochondria are robustly healthy,

the bioenergetic state of your cell will be very robust and that will facilitate very rapid DNA repair mechanisms and ensure the stability of the nuclear DNA. It's much more complicated than that, but, and I broke it down. That's like super simple, actually. But so you can, there are many different pathways and, and, you know, and it may be different for some cancers and other, but the metabolic theory in general is basically the most simple is that if you maintain mitochondrial health, and you could do that through, you know, mitophagy, fasting,

ketones actually enhance mitochondrial energy production, lower mitochondrial ROS production, and help preserve the vitality and the energetic flow, the electron transport chain, the energetic flow of the mitochondria to preserve that genome stability. And it also knocks down inflammation and many other drivers. So that's kind of the, so the whole field of the cancer researchers are not really embracing this. They accept that the Warburg phenomenon happens and that there's aberrant metabolism in cancer cells and that cancer cells use primarily glucose and to a lesser extent, glutamine, as their fermentation fuels for growth and proliferation.

And they use something like a fluorodeoxyglucose PET scan to image the location and the aggressiveness of the tumor. But they don't, now they don't really use that information to target the tumor, tumor metabolism. There are cancer biologists out there that are spearheading a movement of targeting energy metabolism, like Luke Cantley, who will be a speaker at our Metabolic Health Symposium, which is going to be outside of LA. And he will be talking about PI3 kinase and targeting tumor metabolism. And his observation is that when patients are on a ketogenic diet, the drug doesn't work as well, maybe as it was originally thought, but it works remarkably well when the patients are in a state

of nutritional ketosis. So nutritional ketosis sort of cripples the cancer cells ability to defend itself by impeding sort of something called the pentose phosphate pathway, which generates glutathione so the cells can protect. So the ketogenic diet impedes sort of some of the antioxidant defenses that the cancer cells use. So we are at the point now where we're sort of developing a very comprehensive metabolic-based protocol to target cancer as a metabolic disease. And it's not like going in there with a flamethrower to kill a cockroach in your house. It's about, you know, giving it small amounts of poison so you gradually kill it over time. So it's a more gentle approach where that's why we call it metabolic management of cancer. So if you

have a tumor and you go in there and try to eradicate it, even with like surgery, chemo radiation, the patients coming out are much less healthy than they were going in, right? So a metabolic-based approach for cancer management, the patient will come out of the therapy with more robust health than they had going into it. So that's the idea behind doing it. And that could be a personalized ketogenic diet protocol, perhaps using exogenous ketones, perhaps using like metformin or glucose lowering agents, or things like 3-bromopyruvate or lonitamine or 2-deoxyglucose, which inhibits hexokinase, which is like a glycolytic pathway. So these things need to be used a little bit with more precision. But we're calling it the PRESS pulse protocol.

So a PRESS, you have a PRESS where you do continuous things like low-dose metformin. You can do ketogenic diet where you have a glucose ketone index of one to two, which essentially means you get your ketones, you get your glucose to three millimolar, and you bring your ketones up to three millimolar. And in that state, that would be a glucose ketone index of one. In that state, you are limiting glucose availability to the tumor cells, eliminating the spikes in glucose, dramatically suppressing insulin and insulin signaling. So IGF-1 signaling, which drives cancer growth. And you're elevating ketones, which is generally a form of energy that the cancer cells, most cancer cells cannot use effectively to produce ATP. So they may use the ketones for

biosynthetic process, but nothing like glucose and glutamine. And there's a little bit of a protein restriction there too. So you do this and you incorporate things like exercise and sleep and other things that are kind of like no brainers. And that creates a scenario where you're taking the foot off the gas pedal of cancer growth. And then you come in, that's the PRESS protocol. And then we have a PULSE protocol, which could be hyperbaric oxygen, high dose, three times a week, depending on the cancer. You don't want to use it for like lung cancer. If you have a glioblastoma patient, it's a little tricky because they could have seizures.

But when you hyperoxygenate the body, you reverse tumor hypoxia, which shuts down things like VEGF and HIF-1-alpha and other things. But you stimulate, when you hyperoxygenate tumors, they overproduce oxygen-free radicals, and you sensitize that tumor to other modalities. For example, radiation therapy is proportional, or I should say the PO2 of the tumor is dependent, is proportional to radiation therapy. So the response to that. So the higher the level of oxygen that you get in the tumor prior to radiation or immediately after, the more you're going to sensitize that tumor tissue to radiation. So you can prime it for typical procedures that we've been using.

Yep. Efficacy of radiation is proportional to the PO2 of the tumor, but also the reactive oxygen. So you could give someone hyperbaric oxygen therapy. They get out of the chamber. The oxygen goes down in the tumor tissue, but the reactive oxygen species kind of hang around for another one or two hours. And we know cancer cells overproduce oxygen-free radicals, so it will sensitize

that tumor tissue to the radiation. There's also various chemotherapeutic drugs that work through an oxidative stress mechanism, so it may work with that. But generally, the pulse protocols could be hyperbaric oxygen. That needs a little more experimentation. It's already used for radiation necrosis. So some people could actually even get their insurance to cover it. But there's also things like metabolic drugs, like 2-deoxyglucose, which is in phase 2 and phase 3 trials now for different disorders. Dichloroacetate,

lonidamine is one, 3-bromopyruvate, some of these things. So these drugs generally are very powerful anti-cancer compounds that are much probably less toxic than chemotherapy. And they could be used for two weeks on, two weeks off. So your body can recover from it. And these modalities can be combined so you get a synergistic effect. And in and of itself, 2-D oxyglucose may not eradicate cancer, but if you've done the PRESS protocol and you've sensitized a tumor and crippled its antioxidant defenses,

then many of these other modalities are going to work better. And the PRESS protocol, better. And the pulse protocol, you can also incorporate chemotherapy, radiation, and immune-based therapies, but the chemo and radiation should be like the last resort, right? You get the patient healthy, get them into nutritional ketosis. I think exercise is something we could talk about too for muscle mass preserving. Your muscle is your sort of metabolic engine. And the more healthy and robust we keep our skeletal muscles, the press and then the pulse you pick and even customize various modalities to target that particular patient's tumor. And it could be,

you know, different depending whether it's a liver cancer, lung cancer, brain cancer, you know, leukemia, lymphoma, testicular cancer, these cancers, you'd be crazy not to do standard care chemotherapy, but there's no reason you can't incorporate, you know, a press pulse protocol as a way to synergize with your existing. I mean, if you, if you go to your oncologist, you may have no idea what you're talking about, but, but, you know, we've, we've, we have publications on this and the scientific rationale is there. Some of the clinical rationale is there with pilot studies and and some clinical trials have been published but a lot more research needs to be done and that's the point and uh we're working just before i came out here uh working at the university of south florida we work with moffitt cancer center

to submit a fairly large grant that would hopefully fund nutritional ketosis as an adjuvant to the standard of care for low-grade glioma and maybe in the future glioblastoma. So that's a big mission that our lab has. And my team at USF is really responsible for kind of spearheading that. They reached out and opened up those channels because 10 years ago, the major cancer institutes had no interest in the ketogenic diet. And now the National Cancer Institute is actually looking for funding. They're actually reaching and saying, Institute, we need to study this. This is a legitimate thing and we have funding to study this in a well-designed study.

But at this point in time, it's about enhancing standard of care, not a therapy in and of itself, but as a means to further enhance what's already being implemented. But the big vision is to develop something that's very strategic, very tactical, and very personalized for an individual based on the metabolic theory of cancer so that's the that's sort of like the another side project which has become sort of a life mission of ours a lab mission yeah well kudos to the guys who came before you but yeah yeah definitely carrying the torch now yeah well, Thomas Seyfried has been a big inspiration and mentor to me. And when I read his first publication in 2010, Cancer as a Metabolic Disease, I read it.

And I was like, if this is true, this has major implications. And the data that I had collected a few years prior was, I was just trying to explain my data. I was a neuroscientist trying to explain why these cancer cells were overproducing oxygen-free radicals and why their mitochondria was damaged, sort of, or aberrant. And there's a debate whether they're damaged or aberrant. But his theory nicely explained my data. So I had to sort of I had to vet out his theory in my lab and the first experiment we did was the ketogenic diet and hyperbaric oxygen in a mouse model of metastatic cancer and after like three weeks nearly all the animals were dead that had the tumor cells implanted in them that were

on the standard diet. And most of the animals, nearly all of them were alive at the three week mark that were on ketogenic diet and hyperbaric oxygen. So I started thinking this might be something that my career could go into. And that was like 2010, I think. And kind of the rest is history.

So now we're continuing to expand it into other model systems. So breast cancer, I want to study lung cancer, pancreatic cancer, and different types of brain tumors. So you could have a glioblastoma, right? And a lot of people are targeting sort of the genetic effects of tumor. One person with a glioblastoma's genetic profile could be totally different. And you could take out a person's glioblastoma brain tumor, and the genetic abnormalities that are in the cells over here can be totally different than the cells over here. So these cells are rapidly dividing and mutating. And there's so many mutations in the DNA of these cells, it's nearly impossible to come in

with a genetic, a gene-based therapy that's going to have any form of efficacy. But one ubiquitous feature of cancer cells is that they have what's called the Warburg phenotype, that they over consume glucose and they over consume glutamine. And there are sort of this ubiquitous sort of metabolic phenotype that can be targeted with relatively easy strategies, like getting a glucose ketone index of one, right? And then using some low cost, you know, fairly safe metabolic drugs to at the very least just suppress the tumor growth. And then you can come in here

with a toolbox of other modalities to target. And I'm making it super simplistic, but it is relatively simple compared to some of the things that are being tested right now and working on being validated right now and working on being validated right now. So that's what I like, the simplicity of it. Well, thank you so much, brother. We've covered a lot here. I definitely want to have you back

on because you are on the cutting edge of all this. And where can people find you? I know you have a website with a lot of references. Yeah. The best place to find me is ketonutrition.org and uh and i'd also like to some of the references that i i want people to go to are uh with the ketogenic diet the charlie foundation is an amazing resource a lot of people contact me for uh about the ketogenic diet because they're interested from a clinical perspective. So the Charlie Foundation is a great resource. And I'd also like to mention that our lab and we're working together with a team of people at Epigenetics, which is the Epigenetics Foundation, is working to host the Metabolic Health Summit. And that's going to be in LA. There's a banner on my website for the

Metabolic Health Summit. Every two weeks or so, we do a Facebook Live on their Facebook page. And we talk about the different aspects of the conference that are very unique. It's going to be a very unique conference. It's going to talk about the basic science, the clinical science, and also a big part of the conference would be implementation of the ketogenic diet and the benefits of the ketogenic diet for the everyday person. And it's not just going to be the ketogenic diet. We're going to do just metabolic based research we'll be talking about. We're also going to be hosting a lot of influencers and companies and entrepreneurs that are scrambling to get to this space to showcase their new product or new technology. So as new entrepreneurs, we wanted

a place personally where entrepreneurs can meet to people who are interested in investing into the space and just wanting to get from a business perspective, wanting to get into the space. This will be the place for that, the Metabolic Health Summit. And that's going to be January 30th to February 3rd, I think it's going to be like a four-day event. And we'd love to have you guys there. And we're looking for sponsors and we have some super high-end speakers that'll be coming, guys that you know, like Jeff Volek, for example, Thomas Seyfried, Lou Cantley, who's sort of a leading edge of the metabolic approach to cancer.

So I just want to plug that. And thank you for giving me this platform to speak about my research. I feel very blessed that I'm in a position that I could be so passionate about doing what I'm doing. I majored in nutrition as an undergrad and was able to kind of pull that in full circle and incorporate nutrition into a department that's classically pharmacology and physiology. But nutrition is medicine. And I think really that's the message of our of our conference that uh it's a very powerful form of medicine not only for disease management but also disease prevention and even performance so nutrition is a way to change your overall

metabolism to enhance performance and performance resilience so thank you for yeah thank you for all the stuff you guys are doing too i mean you guys are really at the leading edge of bringing supplements and technology and people through your uh platform here your podcast to have a huge reach so uh i thank you for allowing me to be part of that reach oh the pleasure is all mine brother thank you and uh you're on is it is it what's the twitter handle oh it's uh yeah i i did the twitter before actually like looking into what would be the best twitter it's dominic diagosti2 yeah that goes to two so uh and then dominic diagostino1 yeah i'll give you all the links to that. And, uh, keto nutrition.org would be, uh,

and our company is ketone technologies, LLC. And, uh, we're working on, uh, we're, we're working on meeting with different people to develop our first product,

you know, and partnering with people to develop our first product. So, uh, so stay tuned for that too. Very cool. Thanks for coming on brother. Thank you.

Yeah. Thank you guys for listening to the on it podcast with my man, Dr. Dominic D'Agostino. Maybe I'll start calling him Dom like Tim Ferriss does since we're, since we're boys now, but, uh, just chock full of information. Um, I know, uh, there were some words that flew over my head. I'm sure that was the case with some of the listeners, but he does a great job of dumbing it down, at least to make it somewhat palatable. Hopefully you get the gist of what he's talking about. And really we're at the tip of the iceberg when it comes to what we can do with food for disease management and prevention. And I think he's carrying the torch forward. There's no doubt that the people that came before him really set the bar high and allowed

him to take their work. I think the quote from Einstein is, if I can see further, it's because I'm standing on the shoulders of giants. Something similar to that. I'm sure I just butchered that quote. But bottom line is, Dom is carrying the torch now. He's the guy that's on the cutting edge of the science, not only for disease prevention and management, but for performance, you know, working with the military, working with special forces and how we can tackle this from all angles, not just from diet and nutrition, but from supplements as well and really fine tuning what works best. So thank you guys for tuning in.

Thank you for listening. Leave us a five-star review if you thought this podcast was dope and tell your friends and family to tune in. Thanks for listening.