What is the latest keto research telling us? Here to break it down and disseminate it for us is Dominic D’Agostino. You might remember him from episode 35: Dominic is actually Dr. Dominic, a professor in the Dept. of Molecular Pharmacology and Physiology at University of South Florida.
He’s also a research scientist at the Institute for Human and Machine Cognition. His lab works to develop and test metabolic-based approaches for neurological disorders, cancers, etc.
Today on Awesome Health Podcast, we dig into how biohacking is trickling into the worlds of academia and clinical science, and how much experimentation Dominic does on his own. For example, if he is doing his own testing he wears a glucose monitor continuously with sensors strapped to the backs of his arms. For devices he likes the Freestyle Libra with the Levels Up app.
That combination garners a lot of insights into how fasting, how stress, and different types of foods, even with the same macronutrient ratio or meals, can affect glucose levels. He also wears a Fitbit or an aura ring to determine how metabolism and meals and meal timing affect sleep. As we all know, sleep is a huge variable in health. Optimizing sleep is probably one of the most potent aids out there for enhancing performance.
Dominic also tells us who might benefit most from a ketogenic diet and who might not. Keto is very helpful for people with seizure problems, but aside from that specific population he believes most people should focus on metabolic flexibility first and foremost. Keto can help with that as can intermittent fasting, but he doesn’t recommend being on a keto diet all the time.
For some simply lowering their carbs can be beneficial, they don’t have to become strict Keto followers. There should be room for individual variability, again with the focus on metabolic flexibility.
How does he define metabolic flexibility? There are several ways to define it, but one primary definition is how quickly and easily a person can go into a fasting state. Dominic explains the science behind this and also tells us some ways we can train our metabolism to go back into ketosis faster even when we resume eating more carbs.
We’ll dig into those topics plus neurofeedback/brain enhancement. There’s so much more to discover so join us for today’s fascinating episode of Awesome Health Podcast.
- Dr. Dominic D’Agostino’s Website: https://www.ketonutrition.org/
- Dr. Dominic D’Agostino on Twitter: https://twitter.com/DominicDAgosti2
- Dr. Dominic D’Agostino on Facebook: https://www.facebook.com/dominic.dagostino.1
- Dr. Dominic D’Agostino on LinkedIn
- Dr. Dominic D’Agostino on Instagram: https://www.instagram.com/dominic.dagostino.kt/
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- Awesome Health Course: https://bioptimizers.com/awesome-health-course/
Read The Episode Transcript:
Wade Lightheart: Good morning, good afternoon and good evening. It's Wade T Lightheart from the Awesome Health Podcasts for BiOptimizers and we are pumped and excited today, because we have got one of the world's best ketogenic experts. You might have heard of him on episode number 35. His name is Dr. Dominic D'Agostino, who is a professor in the department of Molecular Pharmacology and Physiology at the University of South Florida and research scientist at the Institute for Human and Machine cognition. His laboratory develops and tests metabolic based strategies for neurological disorders, cancer and enhancing safety and resilience of military personnel in extreme environments. And for his info, of course, he was a research investigator and crew member on NASA extreme environmen, mission operation, doesn't get more extreme than space. The main focus of his lab over the last 12 years has been understanding the anticonvulsant and neuroprotective mechanism of the ketogenic diet and ketone metabolism supplementation. This is a very interesting topic for people are suffering from convulsions and epilepsy, things like that. His current project is to identify cellular mechanisms of seizures from CNS oxygen toxicity and to develop mitigation strategies against it. And of course his research is supported by the Office of Naval Research, Department of Defense, private organizations, and foundations. Dom, welcome back to the show. Dominic D’Agostino: Thank you for having me Wade. It's great to be here. Wade Lightheart: It's really fascinating, because one of the things that I think is really interesting about the world that we live in today is that there's kind of deep double-blind research, doctorate type analysis and research, which happens in labs and institutions and, obviously, in your case with military and space exploration and things like that, and these require an excruciating level of detail. And we're putting people's lives on the line. And then we have quote unquote, the biohackers of the world, who are looking at improving their aesthetics or their performance, or their health, which is more of a clinical kind of environment. You're kind of doing both. You're running experiments at home on your side, but you're also doing this side. You're obviously a fitness enthusiast and stuff. I would like to ask you. And we'll kind of dive into some of the new things that you're doing, but when it comes to setting up experiments for oneself versus setting up in a lab environment, what do you think is the biggest benefits and liabilities of maybe both sides of those equations? Dominic D’Agostino: That's a really good question. No one has ever asked me that, but that's a really good question. Well, I have to say before I answer that question, that federal agencies like the national institutes of health, Department of Defense and other military agencies actually draw off a lot of ideas from the biohack itself. So I think the world of podcasting and people self experimentation is recognized and that is actually feeding back to academia and clinical science to direct some of the research, because there are experimenters out there and devices out there sensors out there, like I'm surrounded by a number of things that I'm testing, continuous glucose monitoring system,breath, ketone analyzer, the Biosense device and these devices tend to be used by people self experimenting, then they get recognized. But I'll say that having done a lot of research in academia and also research with NASA on extreme environment mission operations project,the IRB, the Institutional Review Board, it's a committee of people who have to approve the experimentation and methodology, safety, ethics. Dominic D’Agostino: That's a pretty high bar to pass, especially, when we're talking about federal agencies, NASA, Department of Defense, Office of Navy research. So, sometimes it's best to vet out and understand various procedures, dietary supplements, technologies, and vet that out before actually going for a federal grant. And there are things, many things that you just cannot do in an IRB approved study. And I have done quite a few things with self experimentation that would never be approved and I gleaned a lot of data from that and an insight into what will work and what won't work. So my own self experimentation guides experimentation in a basic science research lab and also in clinical experiments, and also in an operational environment where, we are, so I say we, because my wife was also a crew member on Nemo 23 and I was on Nemo in 22. I mean, the things that we sort of self experiment on really directs our research programs. I use the Oura ring, the polar a hundred devices and incorporated that into the research. My wife likes the motive ring, so she was able to get that into it. So some of the things that we actually test and experiment on ourselves, it can make it into a research program's. Pretty cool. Wade Lightheart: Well, it's such an interesting, cause' you're intersecting with, I would say kind of three interesting environments just from a research perspective. It's kind of like what qualifies as kind of doctorate level work in a very controlled environment, then you have kind of these military and space explorations, where I would say that the risk parameters are significantly higher than what you might go into the lab and, you know, obviously I remember you were talking about, you had too much oxygen. Benefits of being on a ketogenic diet would extend how people could perform without having seizure in underwater operations for like Navy seals and things like that, like with their oxygen content, which obviously… Navy seals aren't hanging out at the lab in a research facility, they're dealing with kind of covert, very high risk issues. And then you have the ordinary guy or gal, here, that's listening to the podcast and saying: you know, I want to try a continuous blood sugar monitor to see how rice affects me versus donuts or whatever. How do you determine, like going through that process and your own self experimentation, are there some parameters that you set just when you're doing your own experiments that maybe our listeners can kind of incorporate if they're doing their own experiments? Dominic D’Agostino: Yeah. Well, if I'm testing for example, I'm wearing a continuous glucose monitor sensors on the back of my arm… Wade Lightheart: What one do you like by the way, which ones do you feel are the best? Dominic D’Agostino: Well, right now I'm using the Freestyle Libre that shows up but Level's health app, which is really the premier sort of technology for evaluating CGM data. The Levels app currently works with the Libre and will soon work, I believe just next month with the Dexcom device. So, and then on the horizon, I'm sure many other devices. When I first started using the CGM, I just wanted to figure out what my everyday diet was doing, right? So I didn't change anything and I wasn't experimenting with anything per se. I just wanted to keep everything exactly how I have been eating and the macronutrient ratios and even the types of foods. And then once I established like baseline, then I started evaluating different supplements to determine how my bite baseline changes. Dominic D’Agostino: For me, it was a low carb diet on Sundays and a ketogenic diet, which has really lowered carts on other days and occasionally I would do intermittent fasting. So, it gives me an opportunity to evaluate supplements and, for example, I'm evaluating the BiOptimizers secret formula. It's not out yet, but I'm on secret formula number two and using a continuous glucose monitor and months of tracking my data, I was able to determine even with higher amounts of calories, I ate slightly higher amount of calories over the last couple of weeks when I was evaluating the glucose lowering formula and I had my best glucose numbers yet. So it's a combination of understanding the types of foods that will affect postprandial glucose excursions but my foods pretty much stayed the same. I try to keep everything the same. Dominic D’Agostino: So it gives me a lot of insight into how fasting, how stress, how different types of foods, even with the same macronutrient ratio or meals can affect your glucose levels and your glucose level will really dictate kind of your energy flow throughout the day. And for me, if I can stay in a state of mild ketosis and typically in the one building molar range, and sometimes later in the day, like right now as a day that I'm intermittent fasting and around two on the breath ketone meter, I'm about 20 CES, which keeps me about, which correlates very nicely with blood ketones, which is about two millimolar. And that's when I kind of feel a good state of flow. I like to evaluate different things under different scenarios, and the CGM is also extremely useful to evaluate the different types of low carb ketogenic foods that are entering market. Dominic D’Agostino: So that's maybe where it has been extremely valuable because I tend to test a lot of foods and I can refer the foods to various organizations like the Charlie foundation or Matthew's friends. We work closely with Max love project which is, you know, they're all focused on dietary therapies for managing seizures or brain cancer. It gives me an opportunity to figure out what foods are truly ketogenic or truly low carb. And then we can highlight them on our website and actually do a review of the food. So these technologies that have emerged over and they didn't exist 5 to 10 years ago when I started doing this research. So the technologies didn't exist, like the Breath, Ketone meters, there's different blood monitoring devices, like the Keto mojo. I like to take a blood measurement and put it on all the different devices to determine how each one performs relative to the other one and how the blood correlates with breath. Dominic D’Agostino: And I have that data combined with my continuous glucose monitor, and I can determine, also I wear a Fitbit or an Oura ring, and I could determine how my metabolism and meals, and meal timing affect my sleep. So sleep is a huge variable, probably, if you can optimize your sleep, that's probably one of the most potent ergogenic aids out there for enhancing your performance. Right? Over the last couple of years, it just has not been recognized as much. Matthew Walker has brought a lot of attention to it. So these technologies have really helped me advance my understanding, and then I can take this information and have some really important questions and testable hypotheses for larger scale clinical trials, Wade Lightheart: So much to unpack and what you just said there, that was really thorough. So going back to your own integrations and dietary stuff, and one of the things I remember years ago, there was kind of the Atkins diet, remember? It was a big trend, and then it was in the seventies and then it came back maybe 15 years ago, it kind of had a thing and then all of a sudden saw these like high sugar bars basically, or alcohol sugar bars that were coming in, quote, unquote as Atkins. One of the things I think is really interesting is that you're monitoring your diet and kind of found the foods you want. How much variance is there on individuality between how you metabolize foods and then how much is impacted by environmental stressors, like maybe sleep or adrenaline response? I mean, I think of as someone that's running a space mission or someone that's a Navy seal is under, probably, stress that the average person can't even comprehend, let alone apply in their lives. What have you noticed in those variables? Dominic D’Agostino: Another really good question. The individual variability to different types of foods and different meals, and even things like exercise or stress is tremendous. And I think that's where the CGM technology, but more so the application that's actually reading the output. So like the software. So the Levels health software is really good in that regard and it trains you to optimize your diet and to optimize your metabolism, and your metabolic response to the meals. So the CGM combined with the software gives you insight and information that you can use that no coach would be able to give you, because it's objective data. You can, especially if you're tracking your meals, your macronutrients just taking, just writing down what you're eating. So there's really no coach that could give you that kind of insight. Dominic D’Agostino: So if you're working with a coach that understands CGM and understands sort of the data output, then they can evaluate it and tweak things as you go. But I think the individual has at their disposal now tools that can allow them to optimize their nutrition. If you're really motivated, you'll take the time to learn enough about nutrition and enough about meal timing and things like that to optimize your own dietary schedule. There are people that want others to do it for them, but I think the benefits of CGM with the right software is that it empowers the individual to do that. And this is just the everyday individual and I think it's most important for people with type two diabetes or, you know… I have, one of my students of mine that graduated as type one diabetic, and it was extremely important for him or his life, really to understand how nutrition impacts his insulin. Dominic D’Agostino: So how much insulin he needs to administer and how to optimize his glycemic variability to prevent a whole host of problems that could come up. You're at a higher risk of dying for everything, if you're a type one diabetic, you know, in an accident there's atherogenic effects of dysregulated, glycemia, cancer, heart disease, all these things are at a higher risk if you're not regulating your blood glucose. So now, the everyday person really has this technology and I think it'll evolve to the point where there'll be multiratio sensors that will not only show glucose, but will show glucose, lactate, ketones, and even hormones, insulin, probably be like a really important one. So essentially you'll have real time metabolomics that you can look at your phone and then adjust your activity, your dietary needs, you can supplement or even adjust your medication, like if you're a diabetic. It's going to be pretty interesting. Wade Lightheart: Yeah. One of the things that I know both Matt and myself do is we like to correlate kind of our qualitative feedback, how we feel, how we perform these types of things with the data, so concurrently so that we're kind of saying, what is my brain state, what's my food, am I tired, am I energizing, am I pumped. And then how does that correlate with the data that you can kind of almost tell what the results are going to be before you can kind of feel it, but what are some of the common variations or deviance when it comes to diet that you've noticed whether it's genetics or epigenetics as far as metabolizing carbohydrates or other foods? What are some of the kind of anomalies that people should look for, but when they start that? Dominic D’Agostino: Yeah, it's really interesting you brought that up, because I would encourage people to do that, so just going back to what you said, to evaluate subjectively how you feel what your performance is like in the gym and then take a measurement. So before, you know, strips used to be something like $8 a strip, I think maybe even $15 a strip, like back in 2009 or 10, it was very expensive for me and I didn't really have the funding. A lot of I was paying out of pocket. When I first started doing it, I would tweak my diet and adjust my diet, and determine when I felt optimized. And then I would take a reading. I actually take like a cardio-metabolic kit, which measures insulin and glucose, and other things, and subjectively make the decision of when I felt optimized and try to take a metabolic snapshot and go back and look at the data to say: okay, I feel great when my glucose is at, you know, 72 and my ketones are at 1.5, but when my ketones are at like 4.3, I start to feel a little bit off or woozy. Dominic D’Agostino: And then if I'm hypoglycemic or my glucose is like 60 and my ketones are like, 0.2 then I feel, you know, lethargic. Over the course of doing exactly what you just said noticing subjectively how you feel, and then taking a measurement or metabolic snapshot if you will at that point in time, that's actually how I started to learn my metabolism. After teaching physiology and metabolism, and nutrition, I always thought if my glucose dropped below 70 I would have a sharp decrease in performance, but when it comes to sort of brain optimization and just flow of energy, I actually feel great when my glucose drops below 70 and my ketones start climbing and you're using that alternative fuel, you get into a flow state, at least for me, and it might not happen with everyone when they first started, but you train your body to function in that state. Wade Lightheart: What do you think some of the benefits and liabilities of the ketogenic diet are and who might it be for, and who might it not be for? I think that might be a good distinction for people who might be considering it and then we'll get into maybe some of the integration of that type of diet. Dominic D’Agostino: Yeah. Another good question, because a lot of people think they should be on the ketogenic diet and follow it all the time and some of them will reference me. What they have should know is that the main focus of our research is actually seizures, like developing strategies to prevent seizures, whether that be for epilepsy, genetic disorders, like Kabuki syndrome or Angelman syndrome, which we have a clinical trial evolve out of our research and also what we call environmental physiology resilience. So being able to prevent a seizure, so you have resilience in an environment that would otherwise pose a danger to you. For example, in the studies that we did in our rat model seizures, they'll pressurize to find out in the spheres of oxygen and that will typically trigger a seizure in about 5 to 10 minutes. Dominic D’Agostino: But in studies dating back almost 10 years now, we observed that a rat could stay in this hyperbaric oxygen environment, 600% longer. So we observed that being in a state of therapeutic ketosis made the brain much more resilient and it was doing it by optimizing brain energy metabolism, but also changing the neuropharmacology of the brain and hitting another, a number of other signaling pathways that we're studying now. There's still a lot of unknowns, but some things we do notice and some things we don't. That's kind of the advantage. I mean, when I started studying the ketogenic diet or ketone supplementation for seizures, I realized pretty early on before I was even aware of Jeff Bullock's work or Steven Finney's work, or other people who were using it outside of the realm of epilepsy that there were some people who were actually using the ketogenic diet for performance and I was vaguely familiar with it from a bodybuilding perspective in regards to ketogenic diets being used for body composition alterations, you know, rapid fat loss from the early days of Dan Dushane and… Wade Lightheart: Vince Gironda way back in the day was really using it. In the 'Wild Physique' his high fat cream and eggs diet and then he put people 21 days on that, and then he would do 10 days of cycling on only vegetables. They would go green so they could bring their pH back and align. So he's very sophisticated, on a lot of glandulars. It was really, really, really ahead of his time. Dominic D’Agostino: Yeah. Mauro Di Pasquale too. Wade Lightheart: Yes, and the anabolic diet which got Matt turned on to the ketogenic diet 25 years ago. I think it was so. Dominic D’Agostino: So I had a pretty negative view of all that, because I went through a nutrition program at Rutgers university as an undergrad and just had like a negative view of all. And then I got into neuroscience and then I came back around to the ketogenic diet, because it worked for seizures. And I didn't even know that, I'm kind of embarrassed to say, I didn't know that the ketogenic diets, that it was the standard care for epilepsy when drugs fail. So the more I started investigating the ketogenic diet, and then we started using ketone esters and various forms of ketone supplementation, which we could talk about that too. I started seeing the real world benefits in our animal models and the more, I became increasingly interested in using this approach myself. So I was experimenting with the ketogenic diet and then it kind of set off a whole cascade of self experimentation to following a ketogenic diet and then later on intermittent fasting and then prolonged fasting. Dominic D’Agostino: I realized I didn't have to eat six times a day. I realized that once my body sort of transitioned away from being carbohydrate dependent I could go quite a long time without intense hunger. I might get a little bit hungry, but it was so much easier to power through it and then once I kind of get through the hunger, then it was like mental clarity. I was doing all this at a time when I was in a tenure track position and really had to have a very high level of output in regards to publications, research, teaching, committee work and just had to like really grind it out. I feel that that actually gave me a significant advantage, because didn't have to stop cook food, eat food, you know, clean up. Dominic D’Agostino: I mean, sometimes just fast all day, pound out a lot of work or eat a meal in the morning and then work all day and just eat dinner. And this was unheard of in the past, because I was always carrying my food around with me, and you and Matt could probably relate too, especially in the world of bodybuilding. I would sort of panic if I went like two or three hours without eating. It was very liberating. Logistically, it was very favorable and I think this appeals to federal organizations like the military, NASA too, if you could free up more time for the operator, whether that be a special ops guy or out in the field, or an astronaut, which are under extremely high time demands for output like stopping and eating this throws a monkey wrench in a lot of things that they need to do. If they're doing an EDA an Extra Vehicular Activity, if they're going outside of the space station or shuttle, they might be tethered out there working in space for, you know, five, six, eight to 10 hours. And if they get hungry, you can't really have a meal out there. So adapting your body to be resilient against limited food availability is a significant logistical advantage and I think the military is starting to recognize that and recognize the benefits of being keto slash fat adapted. Wade Lightheart: Who do you think, or if there is, there might not be, do you think that the ketogenic diet is something that's beneficial for just about everybody? Is it something that you stay on continuously or is there times that you should cycle off at? What's your kind of overarching based on all your, both clinical and trial research? Dominic D’Agostino: Yeah, I prefer to stay on it most of the time, but I would have to say, I don't think it's a diet that it would be wise to stay on it all the time. Just because I believe that most people should try to promote metabolic flexibility in their metabolism, but it comes back down to individual variability. So I think people need toif they're not wearing a continuous glucose monitor to simply buy a $20 glucose monitor at CVS, and if they're used to having a high carbohydrate meal and they just haven't had the energy, they feel sluggish during the day, I'd encourage them to measure their glucose response to the food that they're eating. And if they do have a postprandial excursion elevation in glucose, they're going to have a postprandial dip in glucose about in app two hours later and that's going to result in intense hunger, sluggishness. Dominic D’Agostino: So the idea is that if you could attenuate that glycaemic variability, you're going to have a much better energy flow. The ketogenic diet does that remarkably well, and it doesn't have to be ketogenic diet. It could just be a carbohydrate restricted diet. And it could be, for example, there's a lot of people in the Level's program that are eating quite a bit of carbohydrates and staying within 70 to 110 milligrams per deciliter off, a relatively moderate carbohydrate diet and even a vegetarian diet. So as you learn to put your meals together, select the foods and the ratios of foods over time, you could eat a fairly high carbohydrate diet and maintain pretty remarkable glycaemic variability. So it really depends on the food preference, your individual metabolism, but for me, a ketogenic diet seems to work very good. I have a really high fat metabolism. I also tolerate very high amounts of protein, where I could just cook a pounds of steak and eat it and my glucose doesn't even climb over a hundred. Most people probably wouldn't be able to tolerate that much protein. Wade Lightheart: Very important illustrates, you know, when I was doing my homo IR test to blood glucose testing and things like that with my MD, I've been on a plant based diet for a long time and I always laugh I'm a carbivore. With Matt, particularly, my business partners is the keto guy, he's very sensitive to carbohydrates compared to myself, there seems to be a significant variance. And, you know, I'm where most ketogenic people would like to be ultimately eating a fairly high carbohydrate, but I have no meat proteins, which is interesting. So it's a pretty big variance, even though I have Northern genetics and stuff, which leads me to the next question and I think you're talking about maybe this in the research as well. Metabolism, epigenetics, and genetics, and its ratio about, maybe how quickly you become fat adapted, how well, or maybe the range that how many carbohydrates you can allow into the diet while still re retaining ketos? What are you learning now from the latest research and where is that going? And what do you maybe foresee in the future for being able to help people determine what their optimal zone is? Dominic D’Agostino: Well, I do think I'll come back to this idea of different technologies that are inexpensive or wearable technologies that give you insight into your individual metabolism. We are studying over the last couple of years, the epigenetic effects of ketone metabolites beta hydroxybutyrate in particular. So there was a study that was done I believe 2016 at Johns Hopkins in the lab of dr. Bjornsson who has moved to Iceland actually but he developed a mouse model of a genetic disease called Kabuki syndrome and we actually had those minuses… Wade Lightheart: What is Kabuki syndrome? Dominic D’Agostino: Well, people out there who are familiar with Japanese culture may have heard of the Kabuki dance and with the eyes that are kind of slanted down and the Kabuki mask that you wear. In Kabuki syndrome, the kids are adorable and they kind of have like a features of the Kabuki mask like it, but in a very interesting way. So I'm kind of friends with a number of people who have children with Kabuki syndrome and they have a number of developmental difficulties and many of them have epilepsy too. And they are looking for ways, there's really no drug therapy. They're looking at histone deacetylase inhibitors, which are epigenetic regulators and the research from dr. Bjornsson lab which also focused on an epigenetic regulatory drug histone deacetylase inhibitor, but also discovered that indogenous metabolite, beta hydroxybutyrate functions as it pretty remarkable epigenetic regulator that can help to suppress some of epigenetic pathways that are genetic pathways that are impaired in Kabuki syndrome. Dominic D’Agostino: And he demonstrated this pretty remarkably in a mouse model of Kabuki syndrome and in vitro culture system and from a behavioral standpoint to had some nice data from the perspective of brain signaling. So this was with the ketogenic diet. The idea then, is that kids that are following or kids that have Kabuki syndrome and trying to follow a ketogenic diet often find it difficult or impossible. So the question is, if all you need to do is elevate beta hydroxybutyrate, which was discovered to be an epigenetic regulator, can you circumvent the dietary restriction associated with the ketogenic diet, elevate the ketone body beta hydroxybutyrate to produce these therapeutic epigenetic effects? So we've asked that question and we are now in the process of doing the experiments to determine an answer to that question. If ketone supplementation and we're using beta hydroxybutyrate in the form of a mineral salt combined with medium chain triglyceride oil and a particular ratio and when this is incorporated into the food or given as an intragastric kibosh, then we can get ketone levels higher, much higher than the ketogenic diet, if it's done the right way. Dominic D’Agostino: Another way, another thing that you can do, is incorporate supplementation with the ketogenic diet to further augment that therapeutic efficacy at the ketogenic diet. So we're in the process of doing this now, breeding up the micegenotyping them and it's the PhD project, a dissertation project of one of my PhD students right now. I never really thought I would have went down that path years ago but just an example where you never know, you know, where science is going to take you. And we think that other metabolites like lactateprobably all the Krebs cycle intermediates, alpha ketoglutarate, succinate, malate, fumarate… Like all these endogenously produced metabolites are intermediate. Dominic D’Agostino: Probably also have effects independent of metabolism on regulating genes and probably regulating various epigenetic pathways. So we don't necessarily think it's unique to beta hydroxybutyrate, although the science is pretty strong that it is having a positive effect on epigenetic regulation in the context of this diet. So you could be affecting genes in a positive way or a negative way and we're hoping that we're influencing gene expression we'll be able to find a dose and a therapeutic regiment that will influence gene expression in a positive way. Wade Lightheart: That's super cool information. I want to, for people who are maybe new to your work or considering a ketogenic diet and as part of for whatever performance or aesthetics, or for health perspectives, what do you see happening? Like what would be the challenges that takes to kind of get into, you know, kind of ketosis and what have you noticed as far as maybe with getting people into it, kind of the levels or stages that they become fat adapted? What are some of the practical components? Dominic D’Agostino: Yeah, well, for a lot of people that I've talked to, that gave up the ketogenic diet, they could not tolerate the high fat. A lot of people don't understand that a ketogenic diet is really high in fat. Wade Lightheart: That was my challenge. That was my challenge when I attempted it. I would get fat in my stools. It was like I couldn't metabolize and then Matt developed CapEx, which had the four lipids and all of a sudden I could up my fat and I didn't get the fat in my stool. So it was interesting. Dominic D’Agostino: I do. So that's a supplement that I do take, especially on days where I'm doing intermittent fasting or I don't get a lot of meals in, but just get one or two meals in. Obviously I have to take in a huge amount of fat and that supplement extremely helpful in that context. I mean if you're on a ketogenic diet, I think that should even be promoted throughout the clinical realm where the fat malabsorption and fat intolerance is a big problem. So I think there's a lot of potential for that. The fat intolerance is a big thing typically in the beginning and some people can adapt to the high fat intake and some people can't. Some people get nauseous, they have continued GI problems, you know, in the early study is probably the main side effect that concern most people, even like federal agencies, was the kidney stones. Dominic D’Agostino: So kids that follow the ketogenic diet were about a five times higher risk for kidney stones, but then follow up studies were done and paying attention to hydration, and they also use potassium citrate as a supplement to offset the mild metabolic acidosis, which could have resulted indicating stones and then there was really no correlation. Pretty much, there was no higher incidents of kidney stones when you hydrate and take a potassium supplement. Then you have things like certain nutrient deficiencies like carnitine. So when you're on a ketogenic diet, you're transporting, your fat metabolism goes off the charts, right? And there are various things in our diet that can assist the transport of fatty acids into the mitochondria to be burned as energy. And one of them is carnitine. And if you're burning a lot of fat many kids on a ketogenic diet become deficient in carnitine. This was observed early on. Wade Lightheart: The first paper nutrition, by the way, was on the carnitine shuttle, going to transporting fats into the cell and docetaxel enzyme. So it was very interesting, you know. Dominic D’Agostino: So carnitines is a very useful supplement, magnesium. Some people get cramps Sodium, it's actually important to get, to like kind of load up on sodium, especially when you start the diet initially, because insulin will go way down and with low insulin, you tend to dump a lot of sodium into your urine. So a high level of insulin will facilitate sodium retention, right? If they're on a ketogenic diet and they eat some carbs, they go off their diet and they have their face bloats up, they get very bloated. It's a consequence of the carb induced elevation of glucose, which elevates insulin, which facilitates sodium retention and then therefore water retention. You have to really understand some physiology to understand what's happening in your body. Wade Lightheart: That's big. That's the whole thing in bodybuilding, of the difference between dry and hard or be spillover in public, something that we noticed in those really extreme conditions. And now you're saying clinical research is actually confirming what bodybuilders knew 40-50 years ago. Dominic D’Agostino: Absolutely. I mean, if you restrict water, you know, and you do it wrong and you misfire, boom, you're going to retain water really quick. So like a lot of natural bodybuilders that I know, that refuse to use things like diuretics, like laxatives, what they'll do with their contestants is they'll feed them. They'll ramp up their sodium two weeks out up to where they're getting, 10 to 20 grams of sodium for really big guys towards the end and then without having to use a diuretic they just taper the sodium off 72 hours gradually before, and then the water comes off real quick, because you've trained your body. So then again, you have the renin angiotensin system is incredibly adaptable, your metabolism is also incredibly adaptable in regards to macronutrient, the ability to break down, assimilate, digest, and utilize macronutrients for energy. Dominic D’Agostino: So you can train your metabolism to be fat adapted. And there's also like, what I would call, a metabolic memory. If you go back to like lifting or bodybuilding, and it takes you 5 years to work up to a 400 pound bench press, right? And then you take three months off It's not going to take you 5 years to get back up there again, if you drop back down to 200 pounds, you'll get back up there probably in like two months, a month or in a month and a half. The same thing happens with the metabolism. As you train your metabolism through fasting, through carbohydrate restriction, you are opening up pathways associated with beta oxidation of fatty acids, so the metabolism of fats. You're activating a genetic program, if you will, that actually confers enhanced fat metabolism in your body. Dominic D’Agostino: So if you go back to eating carbohydrates and you've trained your metabolism after months, and you go back to eating fat again, that you will quickly adapt to producing ketones. You upregulate various fatty acid oxidation enzymes. If you adhere to the diet over a protracted period of time, and you also upregulate things like catalytic enzymes ketogenic enzymes to the enzymes in the liver that are responsible for producing ketone bodiesinteresting lead deliver lacks succinylcholine transfer rates, which prevents deliver from metabolizing ketones for energy. So they spill into the bloodstream and then tissues, skeletal muscle, heart, and brain have high levels of catalytic enzymes that allow these tissues to use ketone bodies as an energy source. And if they're elevated over time, especially in the context of insulin suppression and mild hypoglycemia, it basically enhances the upregulation of these catalytic enzymes across the tissues. Dominic D’Agostino: And there seems to be a memory that's retained in that. So if you go back to eating carbohydrates and for a couple of months, and then go back to a ketogenic diet, you can be in a state of fat oxidation and ketosis, like 50% faster. I think there's a metabolic memory that's probably analogous to a muscle memory, you know, after you've trained your muscles to adapt to a certain scenario, a certain stimulus, the same thing is true for metabolism. It needs to be studied more. We have some preliminary data some things need to be published still, but I think anecdotally, this was reported, but now I think there's experimental data. Wade Lightheart: Beautiful stuff. I love this. This is so fun. One of the things that I know for myself that I like to do is I've been a fan of fasting and I've been fasting for now over, well over 20 years. I started off, I remember with the one day fast, and then a two day, three day going as long as five and then 10. And now, right now, for example, I'm doing an alternate day fasting program, which is a 36 hours of fasting, 12 hour eating window, 36 hours of fasting. And I do that three times a week, and then I kind of refeed for two days as experiment now. That was an impossibility when I first started fasting. I was going through the hunger and the brain fog, like all those kinds of things. But now it's very easy for me to go from eating tons of carbohydrates and then dropping right into a fast, for an extended period of time. Wade Lightheart: And there seems to be no drop off in performance or functionality and stuff. It does seem that I've had that adaptability. You talked about metabolic flexibility. And one of the things that we advocated BiOptimizers is that, we believe that the healthier a person becomes, it actually increases the amount of choices you have, as opposed to decreasing the amount of choices. In other words, you can adapt to various environments that you might find yourself in for whatever reason. What would you say, from your research base side of things, you would define as metabolic flexibility? Like how would you define that and how would someone achieve it? Dominic D’Agostino: I would define it, well there's different ways to define it, but I think being able to fast is a pretty good example. If you're on a plant based diet and primarily carbohydrate rich diet from plants and can go into a fasted state and it's rather painless, your brain doesn't go through glucose withdrawal and it knows it can rapidly adapt to liberating fatty acids from adipose tissue, which then traveled to the liver and your liver is an energy sensor and detects in mild caloric restriction, which up-regulates a whole host of inthematic systems, which amp up beta oxidation of fatty acids that contributes to accelerated acetylcholine, that condense it to acetal acetate and beta hydroxybutyrate starts spilling into your bloodstream. And your brain is readily adapted to using beta hydroxybutyrate as an energy source. So it's less likely to go through a glucose withdrawal or you're more resilient to hypoglycemic events that a lot of people would probably experience. Your glucose levels would probably be the same. Dominic D’Agostino: They may even be lower. But you're essentially asymptomatic for hypoglycemia, because your brain has done two things. It's adapted to being a functional in a state of mild hypoglycemia if you're fasted. There's very powerful homeostatic mechanisms that maintain blood glucose and people need to realize if you stop eating, you're not going to go hypoglycemic, like your body knows what to do, but your body knows what to do better, because it has been there before. You've adapted it for functioning in that state and you've opened up other metabolic pathways and alternative energy systems, ketone bodies that can supplement as to restore and preserve and enhance brain energy metabolism. So you might actually feel more lucid and more energetic in that fasted state than you do otherwise, you may actually look forward. A lot of people described looking forward to fasting again, cause' they can get more work done. Dominic D’Agostino: They're more productive. They have better energy flow. And I think the supplements BiOptimizers has really enhanced that process, so if people are struggling with the amount of fat they're eating or fasting I really do think it could be a nutrient deficiency, and supplements I found really help. And even if you measure blood levels of supplements magnesium, for example. I was low in magnesium, when I was fasting and on the ketogenic diet and magnesium has been a very valuable asset to me, and during fascinating, the ketogenic diet and the magnesium formula you guys have is particularly impressive. I think it's a very remarkable bioavailable form of magnesium. Wade Lightheart: Oh, thanks so much. You know, it's shocking since we released that, of course I also ran into a magnesium deficiency back in the day and we started experimenting with all these, and of course Charles Poliquin talked about the variants of different types of magnesiums and his Olympic athletes and I thought that was fast, and that kind of led the research. Thanks to Charles on that. But what's interesting over the last six or seven months since we released that product is the sheer amount of testimonials for. Sleep and blood sugar metabolism, and weight loss, and irritability going down, the list just keeps going on and on and on. You wouldn't think that magnesium is really that important it turns out to be.Switching gears though, one of the things that I like to do when I do neurofeedback training… Wade Lightheart: So I go to neurofeedback, which is a type of brain enhancement. We're working various, outside of beta, which we're in now, but alpha or theta training and we've been adding ketone, exogenous ketones. And I get a significant energetic boost when I add just the right amount of exogenous ketones. In your opinion though, I'm not an expert in this, when do you think is a benefit to adding ketones into a diet for someone who maybe not be on a ketogenic diet or for someone who is on a ketogenic diet? So when, who's it for, what does it do and then maybe some types of exogenous ketones that would be beneficial for people and then maybe the last thing would be some things that you need to be wary of? That's a lot of questions in one, but I want to kind of just go through them whole. Dominic D’Agostino: Sure. I guess make it as simple as thing, if you're doing a ketogenic diet and you're transitioning your body to make ketones and to metabolize fat, incorporating something as simple as medium chain triglycerides, MCT oil. So MCT oil goes directly to the liver by a hepatic portal circulation and helps to generate. It's a ketogenic fat. So that's like kind of like the poor man's ketone ester, I guess you could say. And then you have, I guess on the other end of the spectrum, you have ketone esters and we've used, we've done quite a bit of research with ketone esters. They're potent, they don't taste great, they're a bit expensive,but they do have pretty remarkable effect at elevating and sustaining blood levels of ketones. And then you have in the middle ground, I would say ketone mineral salts. So sodium potassium, calcium, magnesium bound beta hydroxybutyrate. Dominic D’Agostino: These are pretty useful too. They can elevate ketones into like the one to maybe two millimolar range and they tend to work better experimentally. We've demonstrated that you get positive effects on lowering blood glucose, anxiolytic effects, which is anxiety reducing effects, anti-seizure effects therapeutic effects kind of across the board as a supplement if the beta hydroxybutyrate is combined with MCT. And there seems to be a benefit if you're delivering an exogenous ketone, it seems to be beneficial to deliver a ketogenic fat at the same time, because it slows the entry of the ketone into circulation, so you get a protracted sustainment of that ketosis over time. And if you just throw in exogenous ketones, it may actually trigger like an insulin release and your ketones can go up and then it can actually decrease your own ketone production slightly, not a whole lot, but if you deliver the exogenous ketones with a medium chain triglycerides, it's stimulating endogenous production of ketones as you're exogenously elevating it. So the pharmacokinetic profile seems to be favorable, and that explains some of the observations, at least in animal model systems, where we have a better therapeutic effect of the combination of a ketone salt with a medium change breakfast right together. So I think for listeners out there, I think there are formulas out there, where the MCT and beta hydroxybutyrate are combined, or you could just buy the two supplements and mix them together. Wade Lightheart: Are there any things that enhance this, like caffeine or other supplements that can also prolong the benefits of those stacks? Dominic D’Agostino: Yeah. That's another good point. If you deliver MCT with caffeine, caffeine is a pretty remarkable drug, actually, if you don't abuse it and get the right doses. Caffeine stimulates lipolysis, it stimulates elevation of ketones from medium chain triglyceride. And we're not exactly sure why, but it has been demonstrated in human studies. I think Steven Koonin demonstrated this and he was looking at Alzheimer's disease. He discovered that when you deliver medium chain triglyceride with caffeine, you have a further elevation of ketone bodies, probably because you're further augmenting a beta oxidation of fatty acids, which really are a driving force for elevating ketones. So caffeine seems to work sort of synergistically with the ketogenic diet. I think with fasting too, it can help people. I know my body's much more sensitive to caffeine if I'm in a fasted state. So instead of three or four cups of coffee a day, I'll back down to one, maybe two, the second one in the afternoon, but I tend to back off because your body just becomes more sensitive, when you're in that fasted state. Wade Lightheart: Very interesting. Is there any other supplements or something that can enhance that process other than caffeine? And you mentioned carnitine as well. Dominic D’Agostino: Yeah, well carnitine can assist. There's some study, I think in animal models and in myself, I've kind of observed that taurine. I think one study showed about a 20 or 30% increase in ketone production with taurine. So I've always sort of incorporated taurine. I have a sort of a mix of powders that I formulate sort of my own supplement and taurine is in that formula. I don't use a whole lot of supplements. I continued to use the ones that you guys make, the magnesium. Capex is very good for large meals. I think these supplements are… There are supplements out there that really can enhance the body's adaptation to the ketogenic diet and maybe tolerance of the ketogenic diet, especially with, one of the side effects that I had, that a lot of people experience with fasting too it's cramps at nighttime. It was always in a certain time of night, probably when my body went into rem, I would get cramps in my calves and my feet. This early on, this was like a daily occurrence and I rarely get cramps anymore, even if I do extended fast and things like that, magnesium really helps with that. Wade Lightheart: It's fascinating and have seen a lot of reports on cramping and magnesium, of course, which is related to the relaxation of muscle tissue. Let's talk about I know you've been so generous with your time and information, I just want a couple of things. Where do you see kind of the relation between metabolism and epigenetics, ketogenic diets and kind of where your research is going? Like where do you see the ship going over the next 5 to 10 years? Both maybe in the high performance world, military and space exploration, obviously these are extreme environment, but also how does that translate into the everyday person in the world? Because obviously we see this massive rise in type two diabetes. We see all this high sugar, and then there's also a lot of alcohol based sugar diets and stuff like that. So there's a lot of hidden components. Where do you see all this going? And what do you see happening over the next 5 to 10 years with all this? You talked a little bit about tech feel free to unload. I love to see where things are going. It's always fascinating to me. Dominic D’Agostino: Well, I'm a little biased in that, I think metabolic control and metabolic parameters really drive our health in general, but also our gene expression. It doesn't have to be so complex. We tend to focus in our lab in the context of cancer, at least on the glucose ketone index. So the average person has a glucose level that's like at least 25 times higher in millimolar concentrations than ketone levels, right? So if you go into fasting 24 hour fast, we'll probably get you pretty close to a ketone glucose index of maybe two or three, and a really strict ketogenic diet followed for a protracted period of time could get you a glucose ketone index of one or two. So we're talking then the average glucose being about, you know, four or five millimolar in US we use milligrams per deciliter, but, you know so 80 milligrams per deciliter is like four millimolar, something like that. Dominic D’Agostino: And ketones are essentially zero, right? I mean, with the standard American diet. But if you can adjust your diet or do fasting periodically and get your ketone levels into that range where your glucose ketone index is like one or two. So a glucose ketone index of two would be a glucose level four and beta hydroxybutyrate level of 2 million millimolar, which is pretty easily achievable, is probably where I'm at right now. And if you can just do that, if people can do that intermittently, that is going to have a pretty profound effect on gene expression, and it's going to have a profound effect on things like that we measure like high sensitivity, C reactive protein, hemoglobin A1C is going to come down. Your insulin is going to come down and that insulin suppression and all the downstream pathways impact so many different functions in the body and your immune system. Dominic D’Agostino: So you are also stimulating the mitochondria to work a bit harder and through, you might want to call it a hormetic regulation. It's a mild stress initially, but you're forcing mitochondrial biogenesis, you're forcing an upregulation of enzyme associated with the electron transport chain. You're making the mitochondria more resilient, and you're also giving your tissues a greater metabolic mitochondrial capacity, because it's stimulating mitochondrial biogenesis, and also stimulating autophagy. You're clearing out dead and damaged cells and you're also stimulating autophagy, which is you're clearing out the mitochondria, which are not working so well and regenerating new, more robust mitochondria. So the health of the mitochondria is intimately associated with the DNA repair. I guess state another way, fidelity of the nuclear genome it's tightly regulated to mitochondrial function. If we have robust, healthy mitochondria making lots of ATP, that's our energy currency, that ATP will assist in DNA repair and also epigenetic regulation in a positive way. Dominic D’Agostino: If we enhance the bioenergetic state of the cell, we're going to have more robust DNA repair, more robust transcription protein synthesis, you know, yada yada. So therefore, you know, gene, epigenetic programs or gene regulation will be contingent upon the health and vitality of metabolic control, which comes down to mitochondrial function. And we know from lots of research that caloric restriction fasting and quite a bit of data is showing ketogenic diet. Some data would indicate that the ketogenic diet needs to be calorie restricted. Producing a calorie deficit can produce remarkable effects, but if you have a protracted calorie deficit, then you can cause pathological consequences. So it becomes the dose is very important. Intermittent periods of ketogenic diet, intermittent periods of fasting, I think are important, because you need to reintroduce calories and nutrients for sufficient repair of tissues, anabolic processes. The immune system can be compromised with too much restriction. So this where kind of falls back to monitoring systems, right? I mean, bodybuilders or physique athletes or athletes know this too, just your performance. Your performance, we can't forget that there's a lot of tech out there that can help us, but how we perform on a daily level, our daily basis, our energy levels, our strength levels, our body composition changes, all need to be factored in and correlated with various biological measurements too. Wade Lightheart: So to summarize, I would say, based on what you've said, it seems that periodic calorie restriction getting fat adapted through a ketogenic diet so that you can build those metabolic causes and you can easily transit into periods of fasting, seem to have profound effects on energy metabolism through the mitochondria, as well as potential repair dynamics when it comes to DNA, as opposed to say eating six times a day, like the average bodybuilder or average American person, who stopping at every couple of hours on the highway to get another hit of sugar and stuff. Would that be accurate? Dominic D’Agostino: Yeah. I think it comes down to the point where you want to, if your glucose levels are low and stable, and that is in my opinion optimal, because very large fluctuations in glucose levels that relative change in glucose levels and insulin levels can kick off a lot of signaling cascades that can be pathological or have negative health consequences. Some of the things can be benefit in regards to tissue repair, right? So insulin, an anabolic hormone can aid. It can be anticatabolic and anabolic. But if you're doing that every day, sitting at your desk, eating carbohydrates, then that will contribute to progressive insulin resistance and metabolic derangement, and chronic systemic inflammation, which kind of characterizes a large percentage of the population. But carbohydrate restriction, intermittent fasting are ways also to moderate just total calories, right? Dominic D’Agostino: We inadvertently reduced our calorie load if we eat less carbohydrates, because I think there's a hedonic effect to eating carbs, especially carbs and fat together, and that can contribute to serve less amount of calories and it's really that calorie load. But some people are just truly carbohydrate intolerant and that can dysregulate their metabolism. I was sort of the opinion that the calories were almost all that mattered. Like I'm kind of in between this argument of like calories in calories out, but have observed in myself that I could eat a tremendous amount of protein and fat more than it actually makes sense and my glycemic control is still remarkable and, insulin still stays low. And other if I do a cardio-metabolic test and measure inflammation, markers, and hemoglobin A1C, it looks remarkably well on a high calorie ketogenic diet. Dominic D’Agostino: I think that just goes to show I'm sort of genetically hardwired to work really well with this diet. I have not, you know, I know you're on a plant based diet. I've been wanting to do a plant based diet experiment, and it'd be nice with CGM to do that, to construct a vegetarian diet and maybe even a vegan diet and follow that for a period of time where a large percentage of the macronutrients are carbohydrates. But I think I'm pretty metabolically flexible where I adapt pretty well to that. Wade Lightheart: Yeah. That's one of the things that I think I can do well on any diet now that I've kind of optimized and learned about my body and supplement it out of it, maybe the deviations. I have another question for you that kind of I think is interesting, because one of the common elements andcalorie restricted feedings continued, or without having metabolic slowdown for extensive dietary or weight loss is to include a spike day, a cheat day or refeed day or whatever. What do you see the impacts? So, I'll give you a specific example. Let's say that someone's following a 2000 calorie diet and maybe they were getting a 500 calories restriction from metabolism and 500 restriction from exercise. They're in a thousand calorie deficit over the period of a week, and they've been doing this consistently for a period of time. So they've kind of adapted to that level. We also know that if they continue that piece, the body starts to down regulate a lot of mechanisms. How do you suggest doing, is there any things that you've learned about how to do a refeed or a spiking day, or maybe an extended period of time where you'll kind of boost the metabolism up before you make an end? Have you been done any research on that or learnt anythings? Dominic D’Agostino: It became apparent to me that if you're on a reduced calorie diet, for example, for 12 weeks, you know, I was of the opinion years ago that you could just refeed for a couple of days and then have your metabolism ramp back up again and after like 12 weeks of dieting, that is completely not the case. So it may take an equal amount of time to gradually introduce calories back in if you have restricted it for 12 weeks. It does take quite a bit of time. I mean, people call this reverse dieting. I think Layne Norton does a pretty good job at coaching people into this and he's kinda got it down to a science. Another approach what I think can be helpful is that you can, if you're on a reduced calorie diet to prevent metabolic shut down, slow down. Dominic D’Agostino: Possible if you're trying to achieve a certain body composition or strength, or weight at a certain strength level to do it gradual. The more gradual you do it, the more strength you're going to retain, the better body composition alterations you're going to have and the less metabolic shutdown. One approach could be to reduce calories for three or four days and introduce 25% surplus calories every three or four days. Some studies shown that you could prevent a reverse T3 from elevating. So essentially keeping more active thyroid and T3 relative to T4. And it would only take a surplus amount of calories in the form of like an increase 25% of the calories or carbohydrates, cause that pathway is in part regulated by insulin. If you take an extra protein too, you'll probably get enough of an insulin spike to prevent or at least slow down that pathway. But it really does come into like calories, total calories come into play. And I think if you just basically not necessarily shift the macronutrient ratios, but keep eating the same foods you're eating, just eat 25% more calories, every third or fourth day of the calorie deficit diet that you're using to get into shape, or get into certain weight class. So I've talked to a number of athletes that are trying to make to certain weight category, whether it be wrestling, power lifting or other types of sports. And this seems to work pretty well. Wade Lightheart: So every third day. If you're on say a 2,500 or 2000 calorie diet, you would increase it, it'd be 2,500 on that third day, and then back down to 2000 the next day, and then the next third day you would do it again and that sort of thing over an extended period of time and that would keep you from your metabolism from crashing essentially. Dominic D’Agostino: Yeah, it doesn't sound too exciting, but it's a simple approach, no radical changes kind of steady course, but it's really that protracted calorie restriction. These low calorie diets that are followed for a long period of time results in slowing down your metabolism and there could be some benefits to that, you knowthe more restriction and the longer you can sustain a fasting state, you are really tapping into autophagy and other things, but I'm not completely convinced that the science that that's really beneficial. I think you could probably achieve the same with just simple calorie restricted diet over time. But I find fasting a lot easier way to do it. If you put someone on a calorie restricted diet to do it through intermittent fasting is a lot easier than trying to give them five or six small meals a day and having them hungry all the time. Wade Lightheart: Yeah. I find the variance pretty interesting. Also, what's your opinion on people who are doing the… So one of the performance mechanisms that I learned years ago from Scott Abel, was my former bodybuilding coach is, he would take people and you'd get down, maybe have 12 weeks of dieting. You would get to kind of single digit body fat zones where you are in a hyper adaptive state. And then he would introduce refeeds. And these refeeds would be extraordinary levels of calories in one day. I remember way back in the late eighties, I think Chris, who was a well known bodybuilder, was following Scott around all day long to see how many calories he would eat on that one day. And then he would go back to a significant calorie deficit for six days, and then he would hit another spike. Wade Lightheart: What is the research saying? Because one of the things that I think that Scott really kind of overlooked was what is the potential consequences from a health perspective. So there was no doubt the performance parameters were there, the aesthetics was there, but what is the health consequences of doing those hyper calorie spike days of, you know, if you're at 2000, maybe 5,000, 6,000, even 7,000 or 8,000? Scott used to crack over 10,000 calories a day, which is an exorbitant, of course in that kind of diet you're eating boxes of donuts and everything else and then the thermic temperature rises, you're sweating. It's pretty interesting. And then it takes maybe two or three days. I can remember when I was doing it way back in 1998. I went from a body weight of 198 pounds to a body weight of 217 in one day and by the end of the week I was at 196 and even leaner. That was the kind of variance I was experiencing and that would be common. You'd spike up 10, 12, 15 pounds and then at the end of the week, you'd be two pounds lower than you were prior toHave you experienced in any of that, or do you notice that, are you seeing any of the results of that far as potential damage? I don't know if that's healthy, but you know. Dominic D’Agostino: There's a lot of things going on there. That 20 pound weight gain in one day is, part of its glycogen, a lot of it's exercise, water, some of it is excess food and water in your GI track. So it's not all muscle audits but the extra water in your muscles creates a cellular leverage, if you will, probably makes you stronger in the gym, especially on things like pressing exercises. What you just described, I think it's far from optimal, but I think it can work in the context of guys with a lot of muscle and they can get away with crazy amounts of calories, especially if their muscle has depleted levels of glycogen due to hard and prolonged training. Then that becomes essentially a sink for glucose, for nutrients, for water and things like that. Dominic D’Agostino: You have some pretty remarkable aesthetic changes that can occur and the more people do it, it's like bodybuilders, you know, if the average person did it, it just would not work for them, but they've trained their body to basically to capitalize on glycogen, super compensation and they've trained their body to tolerate this huge amount of calories to the extent where it almost looks like it's beneficial. But I think these extremes are just the reality of the bodybuilding world and they're going to do it and it appears that it's working, but I don't think it's optimal. I don't feel like it's scientific, but as a scientist we can observe this and realize that something is going on here that we need to understand and there are individuals who can do this, get away with it and get some pretty remarkable effects. So I think it's something that from a bodybuilding, from a physiology perspective, I would be interested in studying individuals like this, through, and it could be a consequence of various ergogenic supplements that they're taking. Could be further augmenting and allowing them to… Wade Lightheart: Testosterone. And these type of things obviously change the dynamic significantly. One of the potential consequences I always thought of that is like, what is the correlative damage of eating these quote unquote damaging type foods to the body as it, you know, that's not accounting for the health parameters. There's a certain cosmetic effect or there's a certain performance based effect, but over the course of doing that for 20 years or 30 years, or 40 years, do you have any theories of what might transpire as far as potential damages of doing that kind of thing to the body? Dominic D’Agostino: Yeah. I think it's really important to track what's happening in the liver when you're doing this. The liver is a very, very good barometer of overall health. So liver enzymes are probably off the charts, especially if there's other pharmaceuticals being used and, your triglyceride levels, your insulin levels, your glucose levels, your hemoglobin A1C. And another thing to look at would be, which I found on a high calorie diet and heavy training, my systemic inflammation was higher. So if I looked at HS CRP hyper caloric diets with heavy training shoted up two, three, five right now always like 0.1 or not even detectable and that's even with training. I think that's another biomarker that I look at to say this diet is working with my body. There are people that who follow a ketogenic diet and their inflammation goes up. Dominic D’Agostino: It could be a consequence of things like polyunsaturated fatty acids, like too much of mega six fatty acids, and what exactly are they eating? They could have pro-inflammatory fats. For my diet, which is eucaloric diet, like gaining or losing weight, my HS CRP is like nondetectable or 0.2. But if I go hypo caloric and even do a bar less extreme version of the scenario that you were talking about, in the context of training too, my inflammation, markers go up quite high and if that's done over and over again over years of time, I think you're probably knocking potentially years off your life. If this is what you do, if this is part of the lifestyle that you're following. And it may have resulted in an early demise of some of the bodybuilders or the health consequences that they had with kidney function, liver function, things like that. Wade Lightheart: Yeah, it's interesting. I know Scott always would be monitoring his athlete's blood panels and stuff, and looking at some of these things, because of course this is an extreme sport and probably not recommended. Just as a final piece, when you do upregulated calories in your own world, how much do you bring them up and for how long do you sustain that for before you drop them back down? What's a normal range for you? Dominic D’Agostino: Well, today my calories have been zero so far, but I will have a larger than average meal tonight, but I won't try to sort of meet all my requirements today, but I'll probably get about 2000 calories from when we get off this podcast till when I go to bed. I think we have good access to grass fed grass finished beef. So that's an easy way for me to get calories. We get beef through butcher box, but we also have a local guy. We have cows ourselves here on the farm but my wife would never sacrifice cows for meat. We more or less have a animal rescue at our place. We have cows, but there's no way that my wife would actually sacrifice one. But we do have close friends who have cows and I have about 320 pounds of beef coming in a day or two. Dominic D’Agostino: So beef is a pretty easy way to meet my calorie needs. I could just eat a lot of itSour cream, I tend to mix like ketomeal product with like chocolate keto meal. I have a selection of ketogenic ice cream from Killer Creamery rebel, rebel chocolate ice cream, my wife like Ben and Jerry's, she has hers, I have my keto version. Ketogenic diets and ketogenic foods are very calorically dense, so it's relatively easy for me to make up my calories if I'm doing intermittent fasting and not run into calorie deficit, whereas like compromising my strength and performance in the gym. Wade Lightheart: That's great. And just so we wind things up, cause' I know you should probably go eat, been fasting all day. Anything that you see coming down the ramp, as far as your research goes and where that's going? Dominic D’Agostino: Yeah, I'm excited about incorporating CGM technology and software like the Level's app into our research, where we can use this technology to sort of optimize, to enhance metabolic optimization. In the context from a clinical scenario, but also to catch a prediabetes before it turns into diabetes or to get folks that are in their fifties and sixties, the baby boomer population, to get them healthy, to prevent early onset of chronic age related diseases. So I think, I'm working with a couple groups now that are, that are already doing thisbut not really using CGM or using a software that could help optimize the approach. I'm excited about that. And also moving into larger scale clinical trials with ketone esters and looking at administering ketone esters to not only look at oxygen toxicity in humans, but also in the same study, focused on cognitive function and also physical performance. Dominic D’Agostino: So the setup that they have at Duke university, they have an amazing hyperbaric facility. They're run by dr. Richard Moon and dr. Bruce Derrick. You get inside a hyperbaric chamber and you're also doing a simulator, and riding a bike at same time, and there's an IV in your arm that goes to a mass spec and it's pulling out, you know, analyzing metabolites, and this is all being done like inside hyperbaric chamber. So it provides an amazing opportunity to evaluate some of the metabolic strategies like ketone esters that we developed and that's kind of, you know, we're doing the diet studies now, but I'm really excited to see if we can replicate that and improve upon these results with exogenous ketone formulations. Wade Lightheart: Wow. I could see what the benefits would that be translating into like mission kind of contingent things with people doing extensive endurance components and what these military people or space people are subjected to, so fascinating research. Dr. Dom D'Agostino, you are a wealth of knowledge and I just love how you flow from practical application to clinical research, the latest stuff. I really appreciate that you're taking the time to test some of our products and give us your feedback, and your insight from them, and of course, it's always a pleasure to have you on the show. Thanks so much for joining us today. And where can people reach you to kind of follow what you're doing out there? Cause' you're certainly one of, I think the most well known researchers in the world, particularly in its application of ketogenic diets as well, correlated to performance, as well as the medical side of the health benefits, particularly for people with epilepsy or seizure, anything that results in seizures. So where can they find you and where they can follow you? Give us all the data, please. Dominic D’Agostino: Yeah, thanks for asking. Well I'm on Twitter, I'm on Instagram and Facebook. So just kind of search and you'll find me there, but ketonutrition all one word .org. So ketonutrition.org is my personal site and we have a blog there. We have recommended products. We have, there's links to consultants. People ask me about resources for different things. So check that out. I have podcasts list there, you know, consultants, products and we have a blog and look for a future blog, I don't know when this is going up, but I will be evaluating the glucose lowering formulas and also posting more of my continuous glucose monitor personal studies I'm doing with the Levels health software too. I'm having a lot of fun doing this. I will be putting it all into probably a multi series blog articles on that website. Wade Lightheart: Well, thank you so much for joining us. This is great stuff, and it's always a fascinating. Thank you for taking the time for joining us today. And for all our listeners at the Awesome Health Podcast, be sure to check out Dom D'Agostino work and information. He's a wealth of resources and you can count on what he says is the gospel. So thank you so much. And see again, next episode.