Keto diets have been extremely popular lately, but how does being in ketosis impact our training and performance? The expert on these topics is Dr. Dominic D’Agostino. Dr. Dominic 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 (IHMC). He is well-respected in the science world as well as the performance industry having been featured on Tim Ferriss’ podcast as well as having his research supported by the Department of Defense, the Navy SEALs, etc.
In today’s episode, we dig into Dr. D’Agostino’s research plus his own personal experience and experimentation with keto diets and bodybuilding, including how he achieved his personal best deadlift while fasting! We also discuss what it means to be “fat adapted” and why our bodies can run on both ketones and glucose at the same time. Dr. D’Agostino says the idea is to adapt our bodies over time by training while we’re fasting periodically; if we are training in a state of nutritional ketosis and occasionally consuming carbohydrates then our body recognizes carbs and as ketones both as fuel sources.
One strategy to do this could be to eat a carbohydrate-based diet that is low enough to maintain optimal insulin sensitivity while including ketogenic nutrition, such as MCT oils or ketone supplements. But it’s important to also do this without necessarily restricting carbohydrates to the point of entering ketosis.
And we finish up with a chat about when it’s beneficial to be on a keto diet as well as how often to follow a ketogenic protocol to get the full benefit. Dr. D’Agostino suggests we can achieve many of the metabolic benefits and anti-cancer benefits by going keto for just three to five days per month either through fasting or by going down to 500 calories per day.
You’ll hear him explain the science behind these approaches plus much more on this fascinating and enriching conversation on today’s edition of the Awesome Health Podcast!
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Read the Episode Transcript :
Wade Lightheart: Good afternoon, good morning and good evening. It's Wade T Lightheart here today with co-founder Matt Gallant. And a super special guest, Dr Dominic D'Agostino. I have been, you know, hoping for this interview for a long time. For those who don't know who Dominic D'Agostino is, he is one of the preeminent experts on ketogenic diets and ketosis. He works with the Navy seals and in a variety of projects that he's done, they're heavily research oriented and the benefits that this potential dietary practice can have both in performance applications as well as physical health issues, you know, related to cancer, things like that. Cognitive function, a bunch of different things. Dom is a professor at the department of molecular pharmacology and physiology at the university of South Florida and a research scientist at the Institute for human and machine cognition. His laboratory develops and tests metabolically based strategies for neurological disorders, cancer and for enhancing the safety and resilience of military personnel in extreme environments. His research is supported by the office of Naval research, department of defense, private organizations and foundations. He just recently came back from a trip from Australia where he was speaking literally in what, five cities in 11 days. And he was gracious enough to take the time to join us on the Awesome Health Podcast. So delighted to have you here. Dom, welcome to the show. Dominic D'Agostino: Great to be here. Thanks for having me Matt and Wade. Matt Gallant: As much as Wade is excited, I'm, I'm even more excited. You know, I've been a fan of your work since. I think I first heard you probably I think on the Tim Ferriss podcast which, which was very enlightening and I've been a longtime keto user and dieter for over 26 years on and off nonstop now for four and a half. And a BiOptimizers, you know, we have these, this three sided triangle of, you know, aesthetics, how we look, the performance and the health side. And I think you're one of the top guys in the world to talk about the performance side and the health side of keto. Cause most people talk more about the aesthetics, the fat loss and that, that component. But today I really like to dive into maybe we could start with some of your background and what you've been doing research wise and then we can get really into all of their current stuff you're doing in a run performance and help. So maybe give us a little bit of background as far as what you've been up to the last five, 10 years. First Quito and kettle research. Dominic D'Agostino: Yeah. for 10 years, well, this quickly, going back to 25 years ago, I was always interested in nutrition and I majored actually in as an undergrad in nutrition scientists and dietetics. And as I navigated my, you know, college career, I realized that there wasn't a whole lot of jobs in nutrition. So I kind of moved to majoring in biology too. And then I did my PhD actually in neuroscience and, and when I finished my pHD I was funded by the office of Navy research for my fellowship, a postdoctoral fellowship. And that was really to understand oxygen toxicity seizures as it pertains to the Navy seal dieter that's using a closed circuit rebreather that they use or operational conditions. There's a stealth component to this equipment. There's no bubbles when you dive underwater. A disadvantage would be that you're breathing high oxygen 100%, actually with a certain type of breather and it just did the be the seawater. Dominic D'Agostino: You can have a seizure and within 10 minutes some people you know can have that and there's really no way to predict or prevent them. So the first area of my research was developing different technologies that would allow us to understand sort of how the brain is working under these conditions. And if you understand the problem, then you can come up with a solution. But we didn't fundamentally understand the problem. So we developed things like microscopes and electrophysiology equipment and telemetry equipment and we adapted that for use inside a hyperbaric chamber. And then over, you know, five or six years, I started to realize that targeting brain energy metabolism and the neuropharmacology of the brain are two strategies to protect the brain under these extreme conditions. And I was sort of interested in antioxidants, loading up animals with antioxidants really did not seem to work much, although in theory it should have. Dominic D’Agostino: But then I started moving towards like coaxing our own bodies to be more resilient. And there was some studies that we've done with fasting rats for 24 to 36 hours and that actually had a remarkable effect at preventing the seizures and it was actually greater neuroprotection than the antiseizure drugs. So I began sort of became interested in how fast and could mitigate and be a mitigation strategy or counter measure against these types of seizures. And then discovered the ketogenic diet, which I thought of, sort of thought I knew, but I really didn't know the whole history of the ketogenic diet, you know, growing up you hear about low carb diets, Atkins diets and you know, I had interested in the ozone diet at one point and a little carb a little bit and I did it kind of on and off for different years. Dominic D’Agostino: But when I delved into the history of the ketogenic diet and met with the practitioners at major universities, like especially Johns Hopkins group I realized that this could potentially be, I could incorporate nutrition back into my research program and do sort of like a nutritional neuroscience project. I would just have to convince my program officer at the department of defense or Navy that, you know, this was a good strategy and the science was actually there like on PubMed, you know, I mean it was good peer reviewed studies sharing that independent of the etiology independent of the cause of the seizures. The ketogenic diet seemed to help across the board. So, and oxygen toxicity seizures are powerful. Tonic clonic seizures we think are being generated in the hippocampus, which was an area that I was studying and published on. And also maybe influencing the neuro control of autonomic regulation and actually did my PhD on respiratory neurobiology brain set. Dominic D’Agostino: So I had a sort of an understanding of, of sort of what was happening and, and a new understanding and appreciation for nutrition as a metabolic therapy. And and I was never taught anything about the ketogenic diet through my four years of training and two, two semesters actually, the advanced nutrition and graduate nutrition. I never even heard about the ketogenic diet being used, and it was like the standard of care for drug refractory epilepsy. So long story short the dietary approach wasn't, it didn't really grab the attention of the program officers. They wanted to see a ketogenic diet sort of in a drug. So I went down the path personally from a research perspective of just studying ketones and different formulations or ketones. But I also started doing the ketogenic diet myself to understand it from the implementation perspective. And, and, and not people weren't doing the ketogenic diet, the clinical ketogenic diet back when I started and maybe 2008, seven or eight. Dominic D’Agostino: But as I followed it, I realized after I got through the initial adaptation, I felt really good. And I I, prior to this, my, my meal frequency was five or six meals a day and I transitioned actually to eating less often and to the point where I adapted to doing intermittent fasting occasionally, once in awhile. And, and then as we developed ketone various ketone technologies, including ketone esters and ketone electrolyte preparations mixed with a MCT and started studying it, we realized that these are very powerful neuroprotective compounds that have a wide range of applications, not just oxygen toxicity seizures, but different metabolic disorders are highly responsive to nutritional ketosis. Some are the standard of care are the ketogenic diet, I should say, is the standard of care for things like metabolic disorders, like glucose transporter deficiency, other deficiency complex. We studied Kabuki syndrome, which is a genetic disease. Dominic D’Agostino: And we look at the role of ketone bodies as an epigenetic regulator activating some genes and silencing others that can impart their therapeutic effects. So, and then cancer too is another area. I've had three PhD students graduate under me training under me that actually focused on looking at the ketogenic diet to impact the growth and proliferation of cancer, metastatic cancer. We we're looking at cancer parts, which is muscle wasting associated with cancer. We're also looking at drugs like Metformin and other metabolic drugs that sort of target different pathways that overlap with the ketogenic diet. So, so I started studying it for something that was relatively esoteric to most people. Oxygen toxicity seizures are now, we now are studying, I would say probably close to a dozen different things including glucose regulation, you know, everything from ALS to angelman syndrome to Alzheimer's disease, Kabuki syndrome, glucose transporter syndrome a number of other kind of even more rare things that you may not have heard of. Dominic D’Agostino: And, and we're also, you know, developing forms of ketogenic compounds, diets, and also supplements that would allow the war fighter and potentially even the astronaut to implement some form of ketogenic nutrition to enhance performance and resilience in extreme environments. You know, so going back to the, the Navy project, I've continued to be funded by them, you know, for like almost 12 to 13 years now. And I continue to have projects and we've developed the animal work and now we're actually doing studies in humans. And, and now we've actually moved on to working with NASA where we, eh, we do experiments where we live in an undersea environment for an extended period of time in what's called saturation. And when you're in saturation, it takes a long time to decompress and to come up. So your body is an extreme environment, not just pressure, but higher ATA of oxygen, higher partial pressure of carbon dioxide too, which has an effect. Dominic D’Agostino: So we have projects where I look at the gut microbiome, psychological testing, body composition. We look at a number of other factors, you know that are influenced, you know, in these extreme environments, a lot of like psychological, what we call team-building or cognitive team cognition. So how the group works together and that can be impacted by our energy state, our metabolism, and our pharmacology. So we're looking at a whole suite of parameters of people in these environments. So we figure out where the detriment is. And then once we understand that, then we develop a sort of a lifestyle, which is micro focuses, nutrition and supplementation to basically enhance, you know, resilience in that environment. And that would be physiological resilience and psychological resilience. So that's, we're putting a lot of time and effort into that project now. Wade Lightheart: That's pretty exciting stuff. Yeah, no I just wanted to comment on that. And one of the things I think from a practical standpoint that I think people can relate to. And I'm curious about this one because I think as listening to you on Tim Ferris, you had gone an extended period time of fasting and were able to like do a ridiculous deadlifts set. Do you want to talk about that just, just briefly, cause I'm just, this is a curiosity component of I heard about it. I want to be confirmed that I heard it correctly. So I'll let you speak from the hearts because what it seems that you've been able to do is something that almost no one would believe possible. Dominic D’Agostino: Well, I, I don't, I don't think fasting or being in it, and I don't think the ketogenic diet has, some people didn't accuse diet will dramatically impair your strength and performance and once you're adapted, and I don't see that as being necessarily a problem if you have protein a equate for protein and total calories. So fasting is sort of like another thing, but also kind of similar in a fasting state. It after about the second or third day it gets hard around that time, but once your body adapts you actually feel better. Your energy level starts to get a little bit low. Towards day five or day seven in me. I haven't went beyond a seven day fast. And I realized that, you know, I wouldn't want to do a high volume workout during that time, but I realized that my, my overall strength just by how I felt really was not impaired much in a, I just wanted to, you know, kind of feel how the weight spell on my body and actually my inflammation was gone. Dominic D’Agostino: Like, I mean, I felt good in so many ways that I just kept adding weight. One 35 to 25, three 15 four or five, four or five easier than I expected. So I was like, okay, let me try five plates. And I did five and I was thinking maybe I should stop there and my body's sort of in a low energy state and I just kept going. I normally can do more, but I, I felt that the 10, I don't even think I got sore the next day. But yesterday actually I just, I got back from traveling in Australia and I picked up a stomach bug on the last day as I really didn't eat for about two or three days. And yesterday I just posted it on Instagram, Facebook, I deadlifted five plates for 15. And my body weight was really low to one 98. Dominic D'Agostino That's extremely low for me. I'd be, haven't been that low since I was a teenager and I was kind of in a backseat state again. And again, I don't for exercises, like if for things pressing movements, if I lose weight, my, my strength goes way down. But for things like deadlift, I always kind of feel strong in a semi fasted state. And I think I've mentioned this to Tim's brand and Tim friend told Tim and then he unexpectedly added it to that podcast and it's like, I don't, I don't, don't, it's like, no, no, I think it's, you've got to start off. That's how you engage people. So I requested it not, you know, I mentioned that, but he mentioned it and it's like, then I had to live up to it, then I had to actually go and do it. Wade Lightheart: That's a fascinating, it's the next fascinating segue cause it's a pattern interrupt for most people who think three or four hours without eating, they're going to die. Especially bodybuilding six times a day probably. Yeah, exactly. So it's a point of interest. I think that kind of, you know, creates another level of curiosity for people to find out, well, well how is that possible? What is this guy doing? You know? And, and it, I think it just adds a a level of verification about the efficacy of what you're doing and what you're promoting and, and, and how you're going about doing it. It also opens a door, I think, which Matt's going to dive into here about asking some very specific questions because as is, he'll reveal he's, he's been deep down the ketogenic adventure for as long as anybody I know. Matt Gallant: So, so I want to get into I guess some nerdy stuff and you know, one of the things I believe in, I'm curious what your thoughts on this phone is that if we look at health as a spectrum on one side you got, you know, sickness and then your death and that in the middle what people call normal. Wade Lightheart: And then at the very end of the other side you have peak performance, peak health. So what I've seemed to notice is that all the things that might fix health issues, you know, for that get us from no sickness to normal will typically also get us from normal to a peak state. And you know, I want to get into the neuro cognitive enhancements that happened with the ketogenic side and you really want to understand what's happening exactly, again on a brain level and on a nervous system level that is producing enhancements. Like why, why is ketones enhancing the cognitive side? Dominic D'Agostino: Yeah, that's a subject of intense research and numerous labs right now. We have garnered sort of a lot of information over the years. Well personally doing it myself and actually measuring my neurotransmitters and, and other blood markers of metabolic health and inflammatory health and neuroinflammation. Matt Gallant: So can I ask you, like what have you seen on a neurotransmitter level? Wade Lightheart: Yeah. And what tests are you running. Dominic D'Agostino I Oh, have different kits here in my drawers. I was going to say that for neurotransmitters, it's not a great test, but one of them that I did, and I did a couple ZRT labs has a urine neurotransmitter test. And I think when I did it down inside the habitat for the NASA emo mission, a couple of them for some reason didn't come out. But the things that came out and made a lot of sense you know, I've, I've done repeated measurements and my GABA to glutamate ratio is very high. It's on the order of two to three times outside the range of normal. So I tend to, at least in a ketogenic state, you make the neurotransmitter gamma-Aminobutyric acid GABA you make, it's a brain stabilizing your transmitter. You actually make that from an excited Tori neurotransmitter called glutamate through the an enzyme called glutamic acid decarboxylase and being in a state of nutritional ketosis with the diet and now we know with supplementation activates the GAD enzyme to convert more glutamate to GABA. Dominic D’Agostino: So you go from a a state of the brain that's hyperactive in the context of what we study. There's excitotoxicity, glutamate, excitotoxicity and it, I think it's in part therapeutic because you are reducing in neurotransmitter that's causing a neuronal hyperexcitability and making GABA, which I don't want to get too down in the weeds, but it mediates, it does chloride mediated post-synaptic inhibition, which it opens up an ion channel that hyperpolarizes the membrane potential of the cell. And when a membrane potential is hyperpolarized, it doesn't fire action potentials as fast. It's more, it's very stabilized. And if there's lots of glutamate excitatory, that will deep polarize the membrane potential and it comes closer to its threshold for firing. So it starts firing action potentials very fast. And if all your neurons are doing that, then you're like dumping glutamate, you're dumping potassium, you're dumping calcium potentially. And this can create a scenario where you have excited toxicity. So in a nutshell, what being in nutritional ketosis does is it changes the neuropharmacology of your brain to prevent you from entering that hyperexcitable state. And so that's one of about a dozen things. And I could go down that sort of list of that on a dozen different things. Another thing that we can, Matt Gallant: No, but that's, that's, that's fascinating. Cause I've done some tests and I'm on the slightly deficient side of, of GABA. So it's probably one of the reasons why I love keto in general and, and why I respond well in that I did not know it what you just reveal. That's fascinating. Dominic D’Agostino: Yeah, we've published that too actually in well it's been published in Humans. But we, we did it in a model of Angelman syndrome and we actually have an Angelman syndrome clinical trial at Vanderbilt right now because of, you know, some of this, the work that we did in preclinical models. Matt Gallant: So a question. I mean when obviously common belief is that the brain runs on glucose, what's your answer to people that go with that? Dominic D’Agostino: Well, you know, that's what I was taught, that that was part of my training in nutrition. You know, you never go below a 60 grams of glucose because that's what the brain's obligate requirement. But then because I got interested in fasting, I was thinking, well, like what does happen when you fast? And I was thinking you know, well, how can people, how can people fast and not go hypoglycemic? And then I started reading a work of Dr. George F Cahill from Harvard medical school where he facet subjects for 40 days. You know, towards the end of that, he injected them with insulin to push their glucose down farther. And it revealed that they were asymptomatic for hypoglycemia because they're the fact that their bodies are adipose was releasing for energy to be used by skeletal muscle and the heart, the brain really doesn't use these large fat molecules for fuel because of the blood brain barrier. Dominic D’Agostino: So the liver converts them to small water-soluble fat molecules. We call ketone bodies or fat derived molecules. And then the ketone bodies can largely replace glucose as an energy source. Although we still our blood glucose levels, they're very powerful homeostatic mechanisms that maintain our blood glucose levels. So glucose really doesn't change all that much. It'll go down to like maybe three millimole or something like that at the glycerol backbone of triglycerides. We'll make continue to make glucose. And then you have gluconeogenic amino acids, especially Alanine that gets released from muscle tissues and that becomes can become glucose. But the primary fuel for brain energy metabolism can switch to from glucose to ketone bodies. And I say that I say primary fuel because more than 50% of brain energy metabolism, it's kind of universally agreed that after prolonged fasting that we are using primarily ketones. And the same thing can happen with a, a strict clinical ketogenic diet. You're primarily running the brain off a ketone bodies. Matt Gallant: So, just to recap, your body has a lot of different ways to internally produce glucose, which is kind of a fascinating cause I've noticed that too, that even when you know, zero carbs, carb or fasting, that, you know, my blood glucose might drop as, you know, high seventies, but it's, it's, it's hard for me to go lower than that even if I'm zero carb and fasting and what not. So, yeah. Have you noticed too that the longer, and I've seen some interesting research recently on this that if you're, it'd been on keto for a long time. That seems to be another level of adoptation where even while you're exercising, the glucose is staying in the muscle. Like the body's actually not even touching some of the glucose, cause I've noticed that even in the last like year or so that I, I just seem to be holding onto more glycogen in the muscle than I used to, even when I'm doing all the same things. Dominic D’Agostino: Yeah. That'll be dependent to some extent on calories. So if calories are if you're, you caloric and you're not at a calorie deficit actually, well I'll come to that later. But if you are, if you do become at a calorie deficit and you're carb dependent, you lose glycogen really fast. If you do become calorie deficit and you're adapted to a ketogenic diet, you, you, you lose glycogen much slower because you are using fat for energy or more fat. The ratio is higher than the ratio of glucose you're using. So, but yes, I think Jeff Bullock has published on these two and athletes is that skeletal muscle glycogen, not liver glycogen, but skeletal muscle glycogen does not change that much. And athletes that are extremely carbohydrate restrictive with their diets, which is difficult for some people to believe. But once you understand metabolic physiology and that we've had adapted the skeletal muscle, the primary engine, you know, that's, that's burning and a substrate to using fatty acids for fuel that actually has a glucose sparing effect and the glucose sparing effect because you're using more fats as opposed to glucose will preserve muscle glycogen. Dominic D'Agostino: Over time there becomes a tipping point. And I think everybody's a little bit different. But I think the point is that, you know, athletes that are, that are adapted to nutritional ketosis really do have a remarkable ability to retain also glycogen. Matt Gallant: So one of the big concerns that some people have and Wade has this concern as well is the loss in kind of, let's just call it the, the last 10% like that peak, especially if you're more of a power athlete. What's your opinion on that? Is that something that if you're fat adapted for long enough that you can regain? What have you seen as far as peak performance, again from a sprinting, weight lifting, those types of athletic endeavors? Dominic D’Agostino: Yeah, these are really good questions. You know, I do believe I've seen enough data to suggest that if you are on a very carbohydrate restricted ketogenic diet and you push an athlete to two dates, extreme short bursts of, of output, total power output may be compromised would likely be compromised to some degree. If someone's on a very restrictive ketogenic diet if you don't add carbohydrates in. So I think, you know, there, there's a lot of nuances here but, but I think that if you take the average athlete who's carbohydrate adapted and adapt them to a low carbohydrate diet forcing their body to sort of burn preferentially more fat for fuel, they can get 80 to 90% of the benefits of low carb without compromising their glycolytic capacity. And you can do this simply by titrating in the carbohydrates back into the diet. Dominic D’Agostino: A tip, you know, low glycemic index carbohydrates, small amounts of carbohydrates will keep glycolytic pathway sort of open various enzyme systems like every big dehydrogenase complex. So that enzyme, the people who favor high carb diets will say, well, your pre-rebate dehydrogenate complex will be suppressed. You won't make as much protein and that the enzyme itself won't be as active. I think one way to keep that, that energetic path open is to periodically add some carbohydrates in, maybe in around your training. And that could be beneficial too. And also if you are, if you are a low carb athlete, when you fuel up intro workout, the type of workouts I do, I don't, I don't really have a fuel up if I, I work my workouts are like 15, 20 minutes or something. But for athletes that work out for like hours at a time to then introduce a sort of a, you know, a carb and a bat sort of supplement at the same time like MCT oil or maybe even mixed with some long chain fats but also a slower burning carbohydrate source after a certain point because you do get carbohydrate, you know it does become a limiting substrate under some conditions and I think each person is a unique metabolic entity. Dominic D’Agostino: I need to experiment, but like the take home messages that if you go on a super strict diet, your low end maybe knocked down a little bit. But if you learn how to use carbohydrates as a performance enhancing substance and you use it sparingly, then I think you can get the best of both worlds. From, from my perspective. Matt Gallant: Yeah, I've seen, I know some guys that have tested their, their, their ketones by doing some cyclical carb re feeds, intro workout, and you know, they've gone as high as like 80 grams on a leg day and had no changes. So they've been able to just maintain ketosis. And because obviously in a squat day, you know, the big deadlift day, you're just going to be burning that glucose in real time. Dominic D’Agostino: The keto community may like cringe at this, but I, I really believe that carbohydrates are a powerful performance enhancing sort of substrate. If you strip strategically and if you deliver a certain types of carbs. I mean, it could be any kind of carb. I mean, when I experiment, I'll use chocolate. I mean, I'll, she's like stuff like that. So it doesn't really have to be a particular kind of carbohydrates, but if you add also lots of water and sodium too, while you're delivering the carbohydrates your blood volume will go up. I mean, you'll notice things in the gym, you know the energy that you feel may just be due to the hyperhydration you get and it doesn't take much. So that's the key. You don't have to throw in like three, 400 grams of carbs and it can be as little as 30 or 40 grams of carbs. If you're a really big guy doing a long workout. Yeah, you might want to titrate, you know, 80 grams of carbs over that duration and maybe a little bit with a refeed. But it certainly doesn't take a lot of carbs to when you're talking about someone who's fat adapted and the, I think 30 grams of carbs for the typical, you know, one, one and a half hour workout, however long people work out these days. Matt Gallant: So you really open up a topic that I had in mindful on time, which is the idea of dual fuel, right? So the idea that you can both run on glucose and ketones simultaneously. I mean, I've done it personally many times. Can you, first of all, can we start with the physiology? Like, how, how is that happening? How is the body burning both glucose and ketones at the same time? Dominic D’Agostino: Yeah, there doesn't seem to be like, it's a strange question for me, like someone who studies physiology because I mean it's just, that's what the body does. But I know there's two camps out there who just kind of believed that, you know, we fuel off carbohydrates or refuel off ketones and fat. But your body has in your brain. We now know, has amazing metabolic flexibility. So if we adapt our bodies over time, and the best way to adapt is to train under specific metabolic conditions. So training while you're fasting periodically, I mean, some people cringe at that, but I think doing it occasionally is a good idea. Training in a state of nutritional ketosis occasionally throwing carbohydrates in so your body recognizes that fuel and to do that periodically. So I mean, I'm coming at a, at a neuroscience perspective because I, I believe a lot of our digital output and our brains are wired to our muscles. Dominic D’Agostino: So if our central nervous system is energized and we have good fuel flow to it, it's going to buy our muscles and can attract more muscle fibers so we can actually get stronger contractions and maintain that over longer periods of time. If we give, our brain has metabolic flexibility and we'll use whatever fuel is available. So glucose and, and ketone bodies we know it can use lactate to a little bit amino acids, but usually, you know, glucose or ketones. So it will use whatever's available and whatever's in the blood. So one strategy could be to do a carbohydrate-based diet that you know, low enough that you maintain optimal insulin sensitivity and then throw in ketogenic nutrition, which could be MCT oils or on supplements without necessarily restricting carbohydrates to the point where you are in ketosis. A MCQ oils can achieve that. Dominic D’Agostino: And also ketone supplements on the market can also achieve that. This is a new idea. But we do know that independent of a carbohydrate restriction, if you administer a ketogenic agent, whether it's a ketone salts, even MCTs or ketone esters, the body will use what's available. So if you elevate that substrate, interestingly, if your ketones are elevated, it seems to facilitate a glucose disposal into the tissue to although it, it kind of appears that because your blood glucose goes down when you administer acutely a ketogenic agent, some individuals, some labs believe that that's an increase in insulin sensitivity that's facilitating glucose disposal that could be happening. But I think when you orally administer a ketogenic compound through counter-regulatory mechanisms, we don't quite understand. There's a decrease in hepatic gluconeogenesis and thereby a paddock glucose output is reduced. We have not done a liver metabolics to figure out what's going on, but it kind of makes sense that it delivers, you know, seeing a high concentration of ketone bodies, it's going to want to spare glucose. Dominic D’Agostino: The glucose you have in your blood now is not like it's the glucose that your liver regulates. So your liver is the master regulator of the glucose that your peripheral tissues seats. So the glucose that's in your blood now, it might be from a couple of days ago, the glycogen that's stored in the liver a couple of days ago. So your liver is like the master regulator. It's why it's important to keep the liver healthy. And when the literacy is ketones, I think that it's a decreasing glucose output. This is important therapeutically for like type two diabetes and also, but it's also kind of important too from a fuel, a dual fuel perspective, which was the question I think people will ask, well what will happen if you throw ketones on top of glucose? You know, then you're just, you're creating this artificial scenario, which could be dangerous. But I believe that, well, we now have experimental data to show that the liver does a pretty good job at recognizing it. Dominic D’Agostino: You know, the, the level of ketones that you have and, and utilizing those fuels and people maybe look at exogenous ketones as an artificial fuel, but it's really just another energy source. I mean you could say that it's creatine, right? I mean, we take or we make creatine, we store it a little bit and when we drink it, we're getting super physiological levels. And from the literature all we can tell it's doing positive things. And I think ketones are kind of like it's good to make them through our own physiology because that forces adaptations and adaptations are necessary for the ketogenic process, that ketone transporter process going across biological membranes. And also with cell C ketones, you're also up regulating keto lit enzymes which allow cells to derive energy and ATP from the ketone molecules. And I think that happens faster when you do it naturally with the ketogenic diet or fasting. And then if you throw ketone supplements on, you know, sparingly. I don't, I don't use em today. I don't use them every day, but I think you can kind of gain, you can kind of gain the system a little bit and gain an advantage. I mean, what our research shows. Wade Lightheart: I can, I would echo that from just a clinical conspiracy, my own stuff. Matt, of course, has been on the ketogenic diet. I'm a, I'm a plant based guy and, but I have an extraordinary blood insulin response, you know, whether it's genetics or whatever. I, you know, when I measure myself, I'm often in a ketogenic state almost when we do our typical fasting on a HomeAway or that sort of stuff. But when I've added ketones, exogenous ketones that Matt's provided for me I, I noticed an instant cognitive performance benefit. Like it's like, okay, I'm a little sharper, everything's a little, little, little crisper and the endurance factor seems amplified for sure. So I, I would echo that just, and that's not very scientific, but it's certainly experimental. And I, and I'm curious, do you kind of do these experiments on your own and then start doing the data and kind of like hitting your bio feedback and then go, I didn't, let's dive into this and see if this is true. I'm just projecting. Or is it you come up with a theory you do in the lab and then you go the other way? I'm kind of curious which way you like to go. Dominic D'Agostino: Well that's a good question. It goes both ways sometimes. And when I got interested in fasting and I read the Cahill studies, then I was like, okay, I gotta do this myself. You know, I gotta, you know, I'm not going to do 40 days, but I'll do a week and see what happens and do the blood work and things like that. And basically all my health markers improved, kind of as you guys would expect. And you know, and as we develop things in the lab, like synthetic ketogenic agents, you know, we'll use them experimentally and sometimes I, you know, take a little myself through the years and, and so some of the things that we use are not, you know, they are experimental compounds right now, but they are tracked towards a clinical use. And once you tinker with these things, then you start to realize some of their potential, right? Their therapeutic potential because some of them like you can actually feel you know, quite remarkably with a acute administration and it's not acting like stimulant. It's not, you know, you're not mixing with caffeine, you're just, you're just elevating the level of available fuel that your brain sees and that has, that has an effect. Matt Gallant: I have a question on that. Cause I usually a twice a year we, we go and do some really extensive hardcore difficult brain training. It's about six hours a day of pushing your brain to its absolute limit, be the equivalent of probably running a couple of marathons a day. And I D I did the first couple of times without ketones and then we started adding like, you know, 30 to 60 grams of esters a day and that allowed us to just continue training cause usually your brain crashing by day three, day four, you know, Wade and I've gone through that. But with the, with the, with the testers, there was no crash. Like day four, day five, day six. I mean you're, you're kind of getting tired, but that's more of a nervous system, you know, but at the same time we were able to continue the training, but the thing that really blew my mind, and I don't understand the, what's going on was the recovery. Like yeah, it gave me a little more energy, but what I really noticed was one, it seemed like I needed almost less sleep taking that many ketones and that I just felt relatively fresh the next day. Again, even despite pushing myself. So from a recovery standpoint, like why, what's going on there? Dominic D’Agostino: Yeah, that's a good, interesting observation too. If you collected data on that, it'd be good to put that together. I, I guess going back to the experience that I can draw off of where I've quantified things to as much as possible would be the NASA extreme environment, mission operations NEMO 22 where a lot of people think I use ketone supplements like every day because we kind of, we're kind of like the people who brought them to market. It mean like Patrick Arnold actually had and you know, years ago and, and different companies or some now. But you know, I don't use ketone supplements every day, but I did during that mission, especially doing the EDAs, the extra vehicular activities and things like that. And for morning multidose and Europe day and and I experimented with in the past. And what I do consistently notice getting back to recovery is that if I'm in a state of deep ketosis I do tend to sleep a little bit less. Dominic D’Agostino: Like lately I've been sleeping like eight hours, sometimes not, but I could sleep about six and a half. And then my amount of deep and REM are the same. So the restorative sleep that I'm getting when my body is in a state of nutritional ketosis seems to be better. So if you have ketones, if your brain has ketones available we now know that the carbon backbone of those ketones are part of the biosynthetic process of making neurotransmitters. Like alpha-ketoglutarate for example, is the precursor to glutamate is the precursor to GABA. And this is called an anaplerotic pathway. So the try-carboxylic acid cycle or the Krebs cycle and the cycle of the NSX make you make the Murray Mallee etc. All these, the, we have demonstrated through metabolomics that these become elevated and you are sort of driving the biosynthesis of neurotransmitters by virtue of increasing TCA cycle intermediates. Dominic D’Agostino: So I believe that this is accelerated a bit because you have the substrate available, you have more precursors can make neuro-transmitters when you sleep. Also, if you're in a state of ketosis, our astrocytes, so we have neurons and we have astrocytes and there's other cells like, like oligodendrocytes and other. But if we just talk about, you know, the two main cells, neurons and astrocytes, the astrocytes tend to store energy in the form of glycogen. When you're on, when you're in a state of ketosis, the ketones will spare just as it does sparing muscle glycogen. The ketones will spare that glycogen in the astrocytes. And part of the restorative process of sleep is to restore the glycogen levels in the astrocytes. So because you're using ketones, you don't have to kind of restore a glycogen levels. So I think that's something. And also there's something called the glymphatic system. Dominic D’Agostino: So your brain has a system that is activated. It's activated all the time, but more so when you sleep and there are things ketones can enhance brain blood flow by 30% with an acute when you acutely elevate ketones with like different ketogenic competence. So I believe that that increase in blood flow and other other factors that are associated with ketosis will increase the glymphatic system performance, if you will. And we'll get a, and this needs to be tested. It's just my, my speculation is that you're enhancing astrocyte glycogen neurotransmitters synthesis and also the glymphatic activity while we sleep. Makes sense. That's a multi-day thing that you're doing. So you're looking at it. So sleep is what would be really important. Matt Gallant: It's critical and we're running dual fuel during that time. So like I'll, I'll, I'll eat a little more carbs. So actually running dual-fuel seems to help. Your thing it seems to help too is like I'll, I'm not a big branch chain amino or amino guy, but adding aminos. So I'm taking 60 grams of ketones, taking like 20 grams of aminos. Plus I'm eating carbs and a lot of good fats as well. And it just seems to help on a lot on all levels. One question that I've had in a, and I haven't seen too much research on this, but experientially I've certainly noticed that. What have you seen in terms of the types of fats and their ketogenic response? Cause for an example, like if I eat animal saturated fats and I measure my ketones, especially like things like pig fat or that it definitely seems to produce more ketones then, you know, monounsaturated, you know, like just different fats seem to produce a different ketone response. What have you seen around that? And, and do you think that's important? Dominic D’Agostino: Yeah, so that's an ongoing question in a ketogenic diet. Well, it should have been ongoing for like 20 years, but only recently are they kind of recognizing that, you know, different fats have different effects. It's not just like macronutrient profiles. And I think it people will have, people have different food sensitivities. So some people who have a dairy a mild dairy allergy, if they take a dairy-based spat it the, the activation of the sympathetic nervous system or various immune factors may actually prevent ketone production. You know, so that's, I found that mildly in myself. But I kind of going back to your observation, I think a fat in the form of butter, you know, a meat fat like pork fat be fat and to some extent maybe chicken fat, these all contribute to very stable, predictable ketone production and meat. And when I tried to sort of mimic that with more of a plant based, I could get my ketones elevated, but it's a little bit less predictable. Dominic D’Agostino: But I think that's primarily because of sort of the plants that I'm getting the fat from. Like nuts, like macadamia nuts and almonds and avocados. You're delivering fiber with it too. So sometimes I can get my ketones elevated to the same extent. And sometimes I think because the natural fibers that are in plants are maybe preventing the release of the fat. And it's going through me. I know if I like a lot of raw homage or something like that, I'm definitely not absorbing all those fats, you know. So if I eat an equivalent amount of fat from raw almond as opposed to pig fat and I acutely do it, I eat the meal and then measure fat. There you're keeping on production will be like proportional to the amount of fat that the liver is seen, dietary fat. So it's kinda hard to quantify that. I guess you could use plant oils and things like that, but Matt Gallant: It seemed that though of course there's the neutrogenomic aspect, there are certain certain genes that obviously seem to indicate better saturated fat breakdown and so on and so forth. So there's probably a pretty strong genetic component to that question. Dominic D'Agostino: Absolutely. And you know, I sh I would like to know more about that and I try to keep up on that as much as possible. I have my own 23andme data and just looking at, you know, putting it on different platforms. I kind of know what works me just through experientially and I know some people have, you know, they have different snips that prevent them from, from metabolizing fatty acids as efficiently as possible. And it may not be an honor off kind of thing, but on a spectrum, right. And some people are just poor oxidizers or metabolizers of fat, so they will if they eat a high fat diet of animal fat, they feel sick, they don't feel good and their triglycerides go up and then does it come down over time. And I would tell that person don't do an animal based. Dominic D'Agostino: You know, and some people feel really good on a, on a plant based diet and all their health markers improve. And you know, I don't know if they give the ketogenic diet enough time, but cause your body does need to adapt to that over time. But I'm not one or the other. But actually I probably eat an enormous amount of plants and I have lots of and I do believe that they should sort of be in the raw form as much as possible. A lot of broccoli, asparagus, cauliflower, things like that and a big salad pretty much every day. And then I add a fatty beef, chicken or a lot of fish and eat a lot of fish in our house to that salad typically. And then maybe add oil on top of that in the form of avocado oil, macadamia nut oil, olive oil. And then I mix MCT oil with the salad dressings too. So I find that the optimal way to get my ketones as high as possible. Matt Gallant: I mean, Wade is the king of the big ass salad. He is, you know, we had introduced me to that know 20 years ago when we were both living in Vancouver and a half to say. And usually I'll try to do at least one big, a solid a week that just like another energy component that I feel from, I don't know if it's a phytonutrients or what's going on exactly. But you know, it, it kicks her, it just kicks something in. So wait, I mean maybe talk about your big ass salad strategy. Dominic D’Agostino: Yeah, I'd like to hear that. I mean, from a, I'll add this real quick if you, cause there's a lot of people are carnivore now and they do one or the other, but if you put your meat, if you eat it with a salad, the fiber from the salad will delay gastric absorption. And also it's aiding your gut microbiome, especially if you have a diverse array of things in the salad. And that's actually enhancing. It's decreasing your glucose and insulin response to the protein. But but I also think it's promoting, you know, healthy digestion, optimal gut microbiome. So I'm just kinda throwing it out there because I dunno, I just posted something recently and someone said, I'm killing myself by eating plants or something because plants are trying to kill you. So it's like, Wade Lightheart: Yeah, that's a pretty extreme position that something Wade Lightheart: We have adapted convenience land. Like wow, I didn't know my salad was so dangerous. Yeah. I've, I've been a big proponent of, you know, there's this certain, you know, when I go, I go to obviously whole foods and things like that to the salad bar, especially when I'm on the road. That's my first stop. And there's something I, there's two things that I think are anecdotally interesting. One is I noticed they're at different times I'll be attracted to different colors. Like I like and, and, and I always indicate to me that there's some sort of mechanism that's letting me know that I need to get more beets today or I need to get more cabbage or whatever it happens to be that. And so I always find it interesting about the colors. The second thing that I've noticed, it was without a doubt, and I'll be going to whole foods right after this call in variably I make these giant sounds like I get the big green bowls at the whole foods that they have them and it's piled up and it's 30 bucks or whatever for my salad. Wade Lightheart: And every single time somebody in the lineup or the cashier will comment that and say, that looks amazing. And I find that's a very interesting response that it's so across the board that there's seems to be some sort of internal recognition that that's good or that's healthy or that's something that I'd like to try. You know, cause it's obviously a ridiculous salad, but I think there was a good point you brought up was the fiber relation to insulin response or the use of fats. And it's, I believe it's one of the reasons why I have such a great insulin response to spite the fact I'm on a plant based diet. I eat a ton of carbs. Yet when you do my testing, it's like, it looks like I'm on a ketogenic diet from a, from an insulin response. Any other comments on your work? Dominic D’Agostino: It doesn't surprise me. I mean, you know, all those vegetables are carbohydrates, right? So as you would expect an increase in glucose, but if you have a steak and then you have that same steak with a big salad you will have a less of a glycaemic response and less of a rise in insulin too because it's the fiber is delaying gastric absorption to some extent and just delaying the breakdown and release of amino acids into the blood. And and I think it's even more pronounced if you add back to that salad. I actually think of in ketogenic diet formulation, the vegetables are a way are a fat delivery vehicle. So you could lightly steam vegetables, saute them, and then add a lot of fat to that or a salad. You can add a significant amount that to that you can add up condos and nuts and olive oil or a mixed oil dressing and then deliver in a relatively small salad, you can deliver 50 or 60 grams of fat. Dominic D’Agostino: So that, that's, that's important clinically. And this, these approaches are now being used and to keep the genic diets that are having better outcomes as far as seizure controls or metabolic management of particular disorders. And it kinda goes against what was traditionally that the carbohydrates need to be below a certain level. You're adding a lot more carbohydrates in the form of these essentially non glycemic fats, but the fiber and the phytonutrients and other factors are greatly helping to actually induce and sustain ketosis. And you're actually probably significantly enhancing the nutritional status of that patient too by not, you know, eliminating plants, which some ketogenic diets do, but actually being very liberal with your plants consumption, which I think as our nutrition evolves, we need to start incorporating more plants into ketogenic diets. Wade Lightheart: Sounds like there might be an actual unification between ketogenic and plant based diet. Yeah, I'm on that. I'm on that train because you know, we're just into optimal. What is the optimal diet for any given person in there, any, any given lifestyle and something they can sustain. So yeah, great, great to hear that you're on the bleeding edge of that. Matt Gallant: Speaking of optimal diets, I mean when one thing I'll share is I optimize my big ass salad using VIUM data. So the VIUM data is, it got tests and you can send them a school sample and it tells you which foods you should eat, a lot of which food you should eat less of. So I decided, you know what, I'm going to build like a super salad kind of just with the foods that it's saying or should eat a lot of. Matt Gallant: So for example, watercress, rucola those came up because I, I guess I have the gut biome that breaks those foods down. So what was really fascinating was despite eating like two pounds of, it almost sounds about two pounds. I would just incinerate it, like almost nothing would come out and like even my weight would go down. It almost like it almost defied science in the sense that it's like, okay, I'm meeting two pounds, almost nothing's coming out and my weight would drop. And, but if we look at it from a gut biome perspective where they're eating all, like I'm feeding all the bacteria that I have and they're just devouring that food, then it does make sense. So I just wanted to share that anecdotal story cause it kind of surprised me so significantly. You know, it is to shift gears here. You know, to talk about a subject that I think is, is near and dear to all of our hearts, which has cancer. I lost one of my best friends and recently an Matt Gallant::Aunt and an uncle and I like Wade to share his story about his experience with this. And then I love to get into what you've seen as far as ketosis, ketones and cancer. But Wade, why don't you share your story? Wade Lightheart: Yeah. So for those who don't know my sister died at the age of 22. She got sick with Hodgkin's disease of formula lymphatic cancer and progressed over four years. When I was young, it had a big impact, got me into kind of physiology and exercise and performance. And I've been graced now to actually serve as an advisor for the American Anti-Cancer Institute. And we help people who are either going through cancer or recovering from cancer to, to, to make better nutritional solo selections and to prevent it in the future or to optimize their diet. So it's something I'm really, really passionate about. And I'm curious what you have kind of revealed, cause I think one of the, one of the things you talk about was the death at cancer. The, the powerful effects of both the ketogenic diet and its relation to the pre cancer prevention or even as an augmentation. What, what, of, what's kind of fueled that and what have you learned and how can people who may be in one of those situations, where would they go and how would they start researching and for the self to kind of create the best survival situation for them? Dominic D’Agostino: Yeah, that's a, well, it's kind of a long story, but I'll make it as short as possible. Some of the, some of the technologies that we developed for the office of Navy research allowed us to look at a variety of cell lines. And one of them was a equal glioblastoma, a cancer cell line. And I made two observations. One was that high pressure oxygen killed the cancer cells faster than normal healthy cells. And that was because cancer cells had a dysregulation in their mitochondrial function. And if you hyper oxygenate them, they divert more molecular oxygen to super oxide anion, which is the precursor free radical that can go on to other radicals that can basically trigger apoptosis and cells. So we observed this acutely and I thought it was interesting and nobody had observed it before because they didn't have a confocal microscope inside a hyperbaric chamber. Dominic D’Agostino: So so this was like, I was curiously interested in that. And also when I grew cancer cells under different substrates, including low glucose or high glucose in particular high ketones, the ketones suppressed the growth and proliferation of the cancer cell lines I was looking at. So I made, I made two observations studying a military project, which is oxygen and how high oxygen high ketones are bad for cancer. So, so a, a PhD student came along and actually this became a PhD. She's now Dr Angela Pop. And throughout her PhD studies in the lab, we observed that a ketogenic diet with hyperbaric oxygen therapy given three times per week suppressed the growth of a cancer in a particularly aggressive form of metastatic cancer, a model of metastatic cancer that we had in the lab. And you know, so it, it kind of begs the question then, how does a high fat ketogenic diet, how does that contribute to suppressing cancer growth? Dominic D’Agostino: And proliferation and it does it through a number of different pathways. One is that we understand now we actually did back, you know, in the 1920s and thirties, that cancer growth is primarily fueled by glucose and cancer cells preferentially use a higher consumption glucose than normal. Healthy cells do. And we can, we can use a fluorodeoxyglucose pet scan oncologists use a pet scan to image the location and aggressiveness of cancer, but they don't really use that information to target the cancer. But we can, we can share through our best imaging techniques that, that there are consumption of glucose a hundred times higher in certain cancers relative to the healthy tissue that's surrounding it. So it's out competing the healthy tissue to get the glucose. So it keeps a genic diet restricts glucose availability to some extent, right? We know baseline glucose doesn't change all that much unless calories are restricted. Dominic D’Agostino: But when you eat a ketogenic diet, there is a very minimal increase in blood glucose and insulin. When you eat at carbohydrate-based diet, there's a relatively high spike in glucose and insulin. Those spikes in glucose and insulin are abolished if not significantly attenuated on a ketogenic diet. So I think that's important. And, and really what's important, it's a suppression of the hormone insulin. That's how actually we make ketones. The ketogenetic diet works by suppressing the hormone insulin, maybe slightly increase in glucagon and that accelerates fatty acid oxidation in the liver. And that continual suppression of the hormone insulin is absolutely necessary for us to stay in a state of ketosis. Cancer cells are there, growth is driven by insulin. IGF1, PI3-kinase, AKT/mTOR pathway and a few other, you know, things related to that. So what the key to dining diet does is suppress insulin and insulin signaling. Dominic D’Agostino: IGF1, PI3-kinase, AKT/mTOR pathway is acutely and continually suppressed if you follow a ketogenic diet. So what that does is it takes the foot off the gas pedal of cancer growth. Most cancers are driven in growth and proliferation by this particular pathway. And that's why pharmaceutical companies are scrambling to develop drugs that target enter PI three kinase IGF one, things like that. So that the ketogenic diet does that naturally as this fasting, but that that can't be sustained. So what you do is create a scenario where you slow down cancer growth. The ketogenic diet is not going to cure cancer. So that's really important. But what you do is you see in some people it has actually, so I should kind of stop and there's anecdotal or it's an even case board, but most importantly it will slow cancer growth and make cancer a more vulnerable target for other modalities. Dominic D’Agostino: And those modalities could be chemotherapy, it could be radiation. We know from clinical data that chemo and radiation can be a lifesaving for many people there are things like advanced brain cancer and metastatic cancer where these things do not offer much of an advantage. But in the context that I keep a general diet, you may sensitize the tumor in a way or make it more vulnerable to make the cancer or the tumor solid tumor more sensitive to these modalities. And also immune based therapies to may work better in the context of the ketogenic diet where you are limiting glucose availability. So essentially what's that's doing? It's suppressing the glycolytic pathway. That's how cancer cells are primarily making energy, glutamine and glucose. When cancer cells do that, it activates a particular pathway called the pentose phosphate pathway. And that pathway develops, it generates reduced glutathione, and that reduced glutathione makes that cell like a super cell. Dominic D’Agostino: It can protect it against a chemo and radiation because it's, it's an endogenous antioxidant. If you inhibit the glycolytic pathway, you could do it with a Cuban drank diet. There are now drugs that inhibit glycolytic pathways. You crippled the cancer cells ability to defend itself by virtue of suppressing reduced glutathione. And so now that cancer cell becomes more vulnerable target, especially to modalities that kill cancer cells through an oxidative stress mechanism. And that could be various chemo drugs and also radiation. So I'm trying to keep it as simple as possible, but I think that the thing is that the, the, the ketogenic diet works through many different ways. I just described a metabolic way, but it also functioned that suppressing inflammation, which is a major driver of cancer. And then the ketone bodies themselves are epigenetic regulators by acting as class one and class two histone deacetylase inhibitors. So that's an intense area of focus now in our lab and other labs as ketones functioning as signaling molecules, even hormones, if you like, in ways that have anticancer effects by activating tumor suppressors and actually turning off or turning down a oncogenic drivers. So that's an area of intense interest right now that ketones functioning independent of metabolism as influencing various anti-inflammatory pathways. NF-Κb, NALP3 inflammasome, but also through epigenetic regulation. Matt Gallant: I'm gonna steal a question from Tim Ferris and see if your answers is different today, which is if you or a loved one had cancer, what would you do? Dominic D’Agostino: Find out what all the options are given the type of cancer if it's an option where, or if it's a type of cancer where the options are very limited in regards to the standard of care not being very efficacious, and if it's minimally efficacious, you have to evaluate the patient, you know, with their doctor, whether it's worth doing that. Right. So I guess the simplest thing to do is to use a what's called a glucose ketone index. So we know if we can normal glucose being five millimolar, say if we could bring our glucose down to say three millimolar and elevate our ketones to three millimolar, that would give us a glucose ketone index of one. So if our glucose stays at four millimolar and we get our ketones only at two millimolar, that would give us a glucose ketone index of two. Dominic D’Agostino: If you could maintain a glucose ketone index of one to two, even one to four, normal American is like 25, right? So if we can bring that down from 25, which is a glucose dominant metabolism to a glucose ketone index between one and four, again, which is glucose over ketones in millimolar concentrations. And in America we use milligrams per deciliter for some reason, but in millimolar concentrations, so get a GKI of one to four and that will slow cancer growth. Right? I think that's incredibly important. Evaluate the potential for drugs like Metformin. Metformin is available. You could jump online and probably get it. Metformin is when we started studying Metformin, there was maybe two or three clinical trials. Now there's about 200 clinical trials looking at the drug, Metformin as a means to enhance other cancer therapies. If you have, you know, type two diabetes, we know that it knocks down your chances of getting pancreatic cancer and type two diabetes population at least by like 50%. Matt Gallant: So what's the pathway? Cause I've been using Metformin now for a few months. What's the pathway that Metformin works on cancer? Dominic D’Augstino: Yeah, so that's another area of intense investigation. My PhD student studied it and we know that it it actually impairs the complex one of the mitochondria, which actually triggers more oxidative stress in the cell. And it may be partial to stimulating more oxidative stress in cancer cells, which could trigger apoptosis potentially. But without a doubt like it works by probably suppressing the hormone insulin to some extent and knocking down AMP kinase, maybe suppressing, enter. I think it works not just through one mechanism, but it's, it is an interesting drug that it probably works through several mechanisms. In synergy. It probably also has at higher doses a mild calorie restriction effect because people who take it tend to reduce their appetite a little bit. Dominic D’Agostino: They lose a little bit of weight. Some people there's speculation that influences the gut microbiome but it does seem to mimic many of the metabolic aspects of the ketogenic diet. So so net form in, I think a patient could add that in, titrate it to a dose that tolerable to them, which is somewhere usually between 1000 milligrams to 2,500 milligrams, and then maintain that glucose ketone index that could be done with a combination of intermittent fasting, well formulated ketogenic diet, and potentially ketone supplementation. So that's three different ways to achieve that glucose ketone index. And you know, exercise is critically important, right? So maintaining your metabolic machinery, but your skeletal muscle. So resistance training combined with, you know, moderate, low to moderate intensity cardiovascular training to that can help sort of optimize your metabolism. It's not one or the other. Dominic D’Agostino: I think both forms of exercise are really important. Getting outside natural light I think is really key. Getting light in the morning, reset your circadian rhythm, getting activity throughout the day, sleep, optimizing your sleep is probably incredibly important. You know, biofeedback, meditation your faith, people, relationships, sort of that. So all these things I would categorize as press and now we can talk about therapies that would be pulse. So all the press therapies create an environment to slow down or stop the cancer growth. And the pulse therapies are things that can help sort of eradicate or slowly attack the tumor. And that could be chemotherapy, radiation, immune based therapies, standard of care. We tend to focus on things that are more non-toxic. So hyperbaric oxygen therapy by itself does not have an impressive anticancer effect, if at all. But in the context of the things that I just talked about, then that can make the tumor vulnerable to hyper oxygenation. Dominic D’Agostino: So hyperbaric auctions, their therapy reverses tumor hypoxia at least when you're giving it. And that can kick on tumor suppressors and actually deactivate oncogenes. And if given three days per week, Monday, Wednesday, Friday, one hour at 2.5 at atmospheres of oxygen, you know, we have found experimentally that works in animal models, the translation to humans, that's my best guess. That would work. I don't think it needs to be done five days a week as a use it for wound healing. I think Monday, Wednesday, Friday, I think that day off in between for the adaptation is necessary. Another thing is intravenous vitamin C, I don't want to come off as a quack said that IB, vitamin C works. But there are peer reviewed scientific publications and registered clinical trials right now showing that vitamin C can enhance different cancer therapies, particularly chemo radiation I think maybe and maybe some immune based therapies too. Vitamin C if given in high concentrations as an IB increases vitamin C, becomes a pro oxidant at a very high level. Dominic D'Agostino: It's an antioxidant at lower levels. At a high level, it becomes a pro oxidant and can drive things like the Fenton's reaction, which can actually increase oxidative stress in cancer cells. Especially in cells that have like a high turnover where you're releasing a lot of heme and in the presence of heme iron and oxygen vitamin C becomes a pro oxidant that can have a very powerful anticancer effect, but only in combination with these other things. Wade Lightheart: What would constitute a high concentration? And, and is it like whole vitamin C or just ascorbic acid? Dominic D’Agostino: Ascorbic acid with the not oral vitamin C. Wade Lightheart: How much, what kind of dosages are we talking about here on the vitamin C though? Dominic D’Agostino: So typically you have to get your blood levels like towards a millimolar concentration and at that concentration, so that would be anywhere between 25 grams. Dominic D’Agostino: And I just met with a doctor that was using like 150 grams, but I think usually about 50 grams is going to be a lot. And when you get vitamin C up to that, you know, millimolar concentration, it's functioning as a glucose antagonist. Right? So the vitamin C uses the same transporter as glucose and it's sort of blocking the transporter. Not only is it blocking the transporter and kind of restricting glucose availability to the cell, but as vitamin C gets into the cell, it's, it's having that imparting that pro-oxidant effect. But anywhere between 25 to maybe 75 grams I think would be safe. Anything higher than that, I'm not sure it's safe. But I personally had 50 grams I think. And is there some interesting effects from that. I was just using that, you know, just to test it, to see what it felt like when you get vitamin C, one of the issues is when you do get it, you have [inaudible] shortly after you do these IVs. Dominic D’Agostino: So a lot of people asked you to be do it right before a hyperbaric chamber. And it's hard to do that cause you don't want to get in a chamber for yourself. Matt Gallant: What else would you add as far as pulse? Dominic D’Agostino: Well, there's a lot of experimental drugs that are coming online now that are targeting cancer metabolism. So, they have been around for a while. One is 2-Deoxy-D-glucose, and that's actually used, it's a glucose analog that blocks glycolysis and it's being used experimentally as a ketogenic diet in a pill for epilepsy, and I think, and some cancer trials now it might be like a phase three cancer trials. So that's 2-Deoxy-D-glucose. There's 3-Bromopyruvic, which is a bit controversial. The drug tripping over the truth talks about this molecule and the history behind it at, at Johns Hopkins. Dominic D’Agostino: So now I believe, you know, it's in clinical trials, it's also a glycolytic inhibitor. Low-Nitrosamine is one. And then Lew Cantley Cornell has sort of developed a company that's developing these PI 3-kinase inhibitors and he's published some work on it. And interestingly the PI 3-kinase inhibitors and this little complex, it influences counter-regulatory mechanisms that actually elevate insulin. And that can be that can negate the effects of the drug the anticancer effects. But what he found is that when the pediatric kinase inhibitors are combined with a ketogenic diet, that sort of unmet the ketogenic diet that thereby suppressing the hormone insulin under conditions of insulin suppression with a who ketogenic diet PI 3-kinase inhibitors are remarkably effective. And they may be the most important class of chemo or I wouldn't call them chemo drugs cancer targeting drugs that we have on the market. And I think it's interesting that they work really only in the context of a low carb ketogenic diet. So I think, you know, you have to look at the the ClinicalTrials.gov lists, what novel trials are ongoing. And I don't know now if that's going to be available to patients, but it's being tracked in that direction. Wade Lightheart: I think one of the exciting things that you're actually eliciting here is the role of solving and addressing dietary components as a, as a methodology to, you know, accelerate or advance maybe drug treatments that someone would be doing in that case. And that's, that's an area that I'm very passionate about. Because I think what happens is with the typical cancer patient, it's like they focus all on the drug stuff, but almost nothing on the lifestyle. You know, people in the holistic thing that's focusing almost completely on the lifestyle stuff but not on the drugs. And I think really both people would benefit from sharing their information, data and patterns to create a a more holistic and unified approach from, you know, when you're in a cancer challenge, I mean it's a life and death situation. You want to bring every resource you can to the table. Wade Lightheart: And I think it's, it's great a salute. The fact that you're bringing attention to that, especially in the circles that for a lot of cases, avoid those conversations around diet with the kind of, the negligent of nutritional training that medical doctors have, which blows me away. You know, these very accomplished, very intelligent people and they're there. There's no attention to diet in regards to people's cancer treatment, which to me seems completely insane. Matt Gallant: The diet or even all the, you know, things like Hyperbaric Chambers, biohacking and all the things that we do. So yeah, I mean, as guys come in from the bodybuilding universe, we all know the power of stacking. So yeah, bringing that mindset and that strategy to, to me aid to any health problem, I think you're going to achieve far more success than trying to just have one single minded approach. Just like they do in Las Vegas, you want to stack the odds in your favor and just do every possible advantage. Dominic D'Agostino: Yeah, it makes sense. If you take a multifaceted approach, then you don't have to use an astronomically high dose for a particular agent, right. Because you can use many things synergize together so that can, and many things can counter regulate some of the side effects like keto, if you employ the ketogenic diet, that greatly reduce it. The side effects of some chemotherapeutic agents and we know by Valter Longo is work and at least that half dozen publications now, fasting prior to chemo can dramatically decrease the nausea to side effects. Even the pro inflammatory, you know, storm that the body has you know, that attacks your healthy tissue. So when you fast, and I don't, I don't advocate fasting loosely, it needs to be done under really tight take conditions. But you can mitigate with a ketogenic diet. When you do that, that's really setting the stage for these other therapies to work better. I mean you're really, you're making the tumor more sensitive to that modality by crippling its antioxidant capacity. But you also may be sort of up-regulating some of the transporters to may take up more of the drug. So investigators are looking at that too. So maybe you might be like sort of saturating the tumor if you deliver a drug in a site specific way when in a fasting state. Matt Gallant: You're a wealth of knowledge and we could probably keep going for at least another 12 hours before we run out of questions. I would love to probably have you back as a guest in the relatively near future. Wade, any final comments before we wrap up? Wade Lightheart: Yeah, I guess the big thing is where do you see the future of this going? Dominic with your research and then I know you're kind of dealing with kind of extreme conditions with, you know, health challenges and also, you know, a security force type of stuff, people in extreme conditions. Where do you see this going and how do you see this kind of spiraling down to the general population or people who are certainly on the cutting edge or of of bio bio hacking or biological optimization, which is what we're entails. How do we optimize the biology for the performance that we want to get? What do you see happening in the next say 5, 10, 20 years? Dominic D’Agostino: I think it will and I hope it will continue to explode. I mean, in 2008, it was a little blip on Google and a little blip on PubMed. And then there was an explosion of the research and I think the actual peer reviewed research was driving interest in these ketogenic diets. And I think it helps to have, you know, podcast celebrities like, like you guys, you know, Tim Ferriss and other people have sort of helped sort of cross promote it in different ways. But I think the science as it's emerging now and there's a lot of studies and progress will drive interest and sort of legitimize the diet, not just for epilepsy but all these emerging applications. And you have athletes in the field, you have people like Jeff Volek and Steve Finney studying it for athletics. Even strength training, two studies are being done. Dominic D’Agostino: I think it's going to, I think people will see it as an important tool that can be used continuously, if not intermittently. Maybe. I think intermittent use of the ketogenic diet and normal healthy person has so many benefits. And and even I think our military personnel, we had a, a weight problem in the military even, you know, type two diabetes problem. And I think that can be addressed with low carbohydrate nutrition. I think our nutrition was really favor and processed carbohydrates and sugars and that's contributing to the problem. So I think first and foremost is appreciation. That our bodies can be fueled off fat and ketones in a healthy way, and that we need to minimize and start to decrease sugar and processed carbohydrates. And, and also this idea that Akita genic diet is not necessarily just bacon and eggs and lard or dairy high dairy fat, that it's, it can be rich in fibers, vegetables enrich and, and phytonutrients and things like that. So the advancement and the evolution of ketogenic diets changing from highly restrictive diets to diets that can be formulated and engineered in ways that optimize our nutritional status or phytonutrients. And you know, and, and the, the sort of knowledge we get on the different types of fats and different protein sources will all be incorporated into the knowledge of ketogenic diets and they can be formulated and even customized and personalized to the patient, perhaps even based on their new genetic profile. Wade Lightheart: Real quick on that one, one segment of that, I'd like to kind of just as a, as a someone who say, Hey, I'd like to do the ketogenic diet. I'm on our follow intermittently or periodically. What do you think could be the beneficial time? Like how many, how long does a say it? Say it says I'm on like a cell phone, I'm falling my typical diet up, I moved to a ketogenic diet, say on a per annual basis. How long do you think that duration should be in order to elicit the benefits and then how frequently would I kind of draw back to that? Dominic D'Agostino: That's a good question. I think some of that, you know, Valter Longo has this fasting modified diet and the idea is to do it for five days out of the month where you, it's it's a calorie restricted diet that sort of puts you in a, in a state of ketosis, but it's more of a, a plant derive it's powders and stuff all mixed together. But I think one can achieve many of the metabolic benefits, the anticancer benefits and sort of the autophagy benefits by employing nutritional ketosis for just three to five days per month. And it doesn't have to be fasting. I think they could just knock their calories down to maybe 500 calories a day and just do a calorie restricted, well formulated ketogenic diet, which could be a salad with some fish in it by the nutrients, olive oils, things like that. And just have that as a single meal, you know, one day per week for five weeks and and just moderate the calories to like 500 calories. And in towards the end of that week, you'll accumulate a significant calorie deficit that will trigger many of the, the signaling and metabolic pathways that we know are associated with many of these benefits, including, you know, activating autophagy, activating anti-cancer pathways that could potentially help purge our body's a precancerous cells and also stimulate and maybe revive our immune system to. Wade Lightheart: That's great. Matt, you got any other words you'd like to throw in here? No, but where can people kind of keep up to date? What's your social media? Dominic D’Agostino: Yeah. I think, I never know them off hand, but I think I said that too. But the one stop shop, like for all our information would be ketonutrition.org. We have a blog and we post like once every two weeks or so. And we have, I, we don't have, we don't sell any products but we have products on there that we'd like and we support and that we've tested and we have I have my podcasts on there, I have a scientific publication, stuff like that. So, and you can also email us through that if you have any questions too. And I try to try to handle as many as I can. Wade Lightheart: Dom, you are a wealth of information and you know, we were excited to do this interview. We're excited to bring you back because I just, every time you answer a question it just, it just triggers off another array in my own mind. And I could see Matt kind of lit up the same way. So hopefully we'll get you back really soon. I also want to, I also want to thank you for doing the work that you're doing. I think you're providing an extraordinary service to mankind and thankfully through podcasts and this kind of dispersion of information you're providing options and, and, and opportunities for people who may not have access to this ingredient, but could actually save their life or certainly let them live at a higher quality of living. So thank you for that. We can't wait to publish out. I know you'll probably get a lot of questions and stuff. We will put everything in the show notes, all of the points that you brought forth, and if anything else comes up, let us know. We'll be happy to do that. I guess in closing, I want to thank everybody for joining us today on this podcast, a checkout Dom stuff. It's fascinating. Go to his website, ketonutrition.org. It's been a great podcast. Thank you Matt. Thank you, Dom for joining us today. It's another day and Awesome Health world and so happy to have you here and keep the message flowing.