Dr. Dominic D’Agostino, PhD: Mastering Metabolism - The Intersection of Ketosis, Brain Health, and Elite Performance

In this enlightening episode, I had the distinct honor of speaking with Dominic D’Agostino, Ph.D., an esteemed Associate Professor at the University of South Florida. He is also a Research Scientist at the Institute for Human and Machine Cognition (IHMC), dedicating his vast expertise towards optimizing the health and resilience of both warfighters and astronauts. His remarkable background, which spans from neuropharmacology to physiology and from neuroscience to medical biochemistry, offers a unique perspective that makes him a thought leader in his fields.

Our in-depth discussion delved into the intricate details of metabolic health, with particular emphasis on the ketogenic diet and its impact on various conditions including epilepsy, cancer, and even Alzheimer's. Dr. D’Agostino shared invaluable insights into how the body's metabolism is intimately connected to overall health and well-being, including how ketone supplementation can play a pivotal role in brain health. The conversation didn’t stop there. We further ventured into the intriguing realm of CNS oxygen toxicity, discussing its profound implications on the brain, and the potential therapeutic avenues that might mitigate its effects.

I am confident that our listeners, whether familiar with these topics or just diving into the world of metabolic health, will find immense value in Dr. D’Agostino's insights. So, grab your headphones, find a cozy spot, and tune into this episode.

Dr. Dominic P. D'Agostino, affiliated with Audacious Nutrition, co-founded KETOSTART® to address the market's long-standing need for a trusted exogenous ketone supplement, delivering all the benefits of beta-hydroxybutyrate without the pitfalls of rushed and poorly researched product development. Their singular goal was to do it right, making KETOSTART stand out among the myriad of exogenous ketone supplements available.

Key Points From This Episode:

• Understanding ketosis' impact on the central nervous system [00:05:30]
• Exploring CNS oxygen toxicity  [00:11:20]
• Diving into dietary protocols  [00:15:45]
• Importance of self-monitoring and physiological baselines [00:20:40]
• Dominic's emphasis on journaling for health and training [00:24:50]
• Ketone esters require caution [00:34:40]
• Ketones have neuroprotective effects [00:38:48]
•  Exogenous ketones can cause harm [00:45:20]
• Ketones may enhance mental performance [00:55:04]
• Discussing the metabolic health summit  [01:23:42]

Links Mentioned in Today’s Episode:

Click HERE to save on BiOptimizers Magnesium

Audacious Nutrition

Peter Attia

Dr Richard Veech

Keto Nutrition

The Metabolic Link

Metabolic Health Summit

Dr Dominic on Twitter

Dr Dominic  on Instagram

Dr Dominic  on Linkedin

Transcript

00:00 Dominic D’Agostino

As your metabolic health improves, your body's ability to convert macronutrients, proteins, carbohydrates, and fats into energy currency ATP will improve, right? So our ability to make energy at the level of the mitochondria improves.

00:13 Andres Preschel  
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Well, Dominic, here we are on the know your physio podcast. I've had the chance to digest your work online and some of your, you know, some of your research over the past few years, actually, I've been following you and what I'm most impressed by because you have without a doubt, objectively, an extremely impressive resume and you're so accomplished in this field. But what I'm most impressed by is your ability to distill this information and your ability. Well, your passion for enabling this in your personal health and wellbeing. And I can tell that the research is really a part of your lifestyle. And I think that's one of the most valuable things that I try to accomplish in this format on this podcast for my listeners is helping them enable a lot of the science. Because I think a lot of people will take old science that is now finally established. And by the time that they implement these habits, it's like, there's new stuff and you're always on top of it. You're always doing more research and you're fighting for the citizen scientist. So I want to welcome you on the show and I hope we can explore a conversation that gives these folks more incentive and more data, more evidence to improve their quality of life.

04:50 Dominic D’Agostino
Thank you. I appreciate being on and appreciate what you're doing with education outreach too. It's a big part of kind of what I've been doing, just being on podcasts. I host the Metabolic Link Podcast and also a conference, the Metabolic Health Summit, which is really early on. I didn't know it was going to go in that direction because I kind of hated public speaking, but we realized this information is important to get out. And it's fun to share, especially if you could do both at the same time, you know, it's like, and give other people the platform to talk about it. So I  appreciate you giving me this platform to speak about it.

05:19 Andres Preschel
Absolutely. It's my pleasure. And if we can start with metabolic health, how would you define metabolic health and specifically, what does everyone need to know about metabolic health? I think most people might be maybe, I don't know, intimidated by the verbage there, the wording. What does it actually mean and how can people appreciate that definition? 

05:42 Dominic D’Agostino
I like to kind of, from a really broad term, just do it cardio metabolic health and anything that's going to be healthy and optimal for your cardiovascular system is also going to be ideal for your brain. So my training is physiology and neuroscience and what's good for your heart, it's good for your brain. So I think it's really important to longitudinally know, like, you know, over time, if you don't have baseline blood work, like a comprehensive metabolic panel, a CMP or CBC, you know, your listeners definitely need to go out and do that. Like, you know, if you have healthcare, if you have health insurance, that's covered at least once a year, sometimes twice a year. So go and get that done. And in addition to a comprehensive metabolic panel and CBC, you should also do add a number of different things that is not really going to cost that much like your fasting insulin, your hemoglobin A1c, your, you know, your cholesterol, ApoB is probably important too, it might be like 50 bucks to add ApoB. And probably I like to tell people to add to high-sensitivity C-reactive protein, HS, you know, HSCRP, and know your blood pressure, of course, and also get a DEXA scan. So to look at your body composition, that's going to be really important and also your bone mineral density over time. And I've seen in particular in women that have contacted me how it goes down, I think that's due to some, you know, different diets that they're on, or caloric restriction, or just losing body mass can impact your bone mineral density. So, but taking a step back, yeah, metabolic health is something that you don't want to make it too complicated, right? So it's probably at its most simple level is just like your body composition and then your fitness level. And that could be your VO2 max, or can you do, you know, if you're a guy, can you do 40 push-ups? If you're a girl, can you do like 10 push-ups, pull-ups, things like that? So these are very baseline, what I consider kind of functional biomarkers. So there's functional biomarkers, then there's blood biomarkers, and then there's things like, you know, your VO2 max and body composition, you know, biomarkers, DEXA. So these are all things that you should know, and you should have a baseline because as you age, you know, when I was in, when I was your age in my 20s and 30s, you know, I didn't care about these things. But now, as I'm approaching 50, you know, I realized, man, it would be great to have a DEXA when I was 20. I did have actually blood work in my teens, I was on a drug for acne, so I had to get like routine blood work. So I kept all that. I always asked my doctor for like, you know, blood work so I could just keep it and I have a record of all that so I can look back to see what my liver enzymes were and things like that. So I would encourage people listening to this just to get baseline measurements, and that's going to be value. If you really value your health, especially metabolic health, which is the foundation of your personal health, that data is going to be important.

08:54 Andres Preschel
 And once we take this data and we start to make certain lifestyle changes, what can we feel as far as, let's say, improving metabolic health? Besides seeing the markers on paper change, how does it feel to improve your metabolic health? 

09:12 Dominic D’Agostino
Yeah, that's probably the most important thing, right? It's like when you go to the doctor, you know, your, maybe your hormones could be low or things could be out of whack. But the most important thing that he's focused on, at least in modern medicine, is like, how do you feel? Right? So you are going to feel as your metabolic health improves, your body's ability to convert macronutrients, proteins, carbohydrates, and fats into energy currency ATP, this is like the most simple description, will improve, right? So our ability to make energy at the level of the mitochondria improves. And our metabolic health is tightly coupled to what we study in the lab, which is mitochondrial health, right? So we have different tools, we can measure mitochondria, the seahorse, biosciences, we can look at mitochondrial ATP production, RAS production, under different conditions where we feed cells, animals and humans, different macronutrients, and then we look at outcome measures. So we know that we could, even at the level of the cell, if we improve the energy flow of the cell by optimizing what the cell is eating, meaning giving it different nutrients, and then we hit that cell, even in an in vitro preparation, with stress. It could be hypoxia, it could be hyperoxia, it could be an oxidative stress challenge, it could be high levels of glutamate or potassium or something like that. When the bio-energetic state of the cell is optimized and the cell can make ATP and also produce, you can stabilize the bio-energetic state of the cell in the context of an oxidative stress environment. And what we do is we challenge it with hypercapnia, hyperoxia, things like that. That will have a translational effect. In my career, I've moved from cell-based systems to animal systems, and now we do human studies, right? So it is very obvious to me that if you can alter metabolic health, but also the various metabolites that the body is using for energy, then you can confer protection and produce what we call in military medicine, we call it performance resilience. So being able to achieve and maintain the same outcome and task, whether that be cognitive function tasks or using the NASA TLX, we have the NIH toolbox, we have different functional things that we do in various operational studies. If we can preserve the function of that task under extreme environments, knowing what causes your performance to decrease and then understanding that from a fundamental level, then we can work back and create a countermeasure, what we call a mitigation strategy to target those things that are being impacted by that extreme environment, that stress, that lack of sleep, that low level of oxygen, high level of oxygen. It's very kind of a niche research, but it has major implications for people, for athletes, for people. Everybody's under stress, right? In some way or another, they're lacking sleep or whatever. So a lot of the stuff that we do in our lab, which is mostly DOD, ONR funded, has implications for the everyday person, for the athlete and for many people that you work with too.

12:53 Andres Preschel
And so if you're looking at this from a cellular level, if you're isolating the cells, if you're giving them these stressors and understanding how they work and how you can optimize from that perspective, how effectively does this translate on the systemic or the human level? What's the correlation there? How strong is the relationship between our cellular function and our total body wellness? 

13:14 Dominic D’Agostino
Yeah, that's a great question and not as well as you would think in regards to, say for example, I guess I'll give you two examples because I study a lot of the research that we do is in seizures and we also do, we have quite an active research program in cancer. So we've been able to like basically arrest and stop cancer growth and proliferation in various cell lines, glial blastoma cell lines, even things that grow rapidly. And we've moved that to animal models and we can get a pretty robust effect, but we've cured cancer in cells, we've cured cancer in animal models, and we develop metabolic based approaches. And many of these things we realize in cell-based systems and in animal models as a standalone therapy, they're quite effective. But I think once we move to humans, I think they have a very negligible effect unless they're actually kind of combined together, right? So a dietary intervention that targets insulin, IGF-1, lowers glucose, elevates ketones, is not going to cure cancer. And some people are talking about fasting or the Q-genic diet curing cancer and that's very unfortunate and kind of have to do a lot of damage control. Actually, some of our research gets misinterpreted and gets promoted that way. But at the very best, dietary interventions from the cells and animal-based systems can function as maybe an adjuvant or a way to further augment the therapeutic efficacy of standard of care. That could be radiation, chemo, or an immune-based therapy like checkpoint inhibitors, PD-1 inhibitors, for example. I think there's tremendous potential there. So on the other hand, that's in cancer. So very, not super good translatability. But animal-based studies are informative but not predictive. However, studies that are done on various seizure models, so the anti-epileptic drugs, for example, and actually have very good translatability from animal models of seizures to humans. So that would be almost the other end of the spectrum. Essentially, things that work in humans, work in animals, and anti-epileptic therapies that work in animals tend to work quite well in humans. So Alzheimer's disease, that would be kind of like the same situation as cancer. I mean, we can arrest amyloid plaque and tau and do a lot of therapeutic things with these transgenic animal models of Alzheimer's disease but not very efficacious. So maybe from your audience would be interested in performance. So we're at the level now where we're testing different things in rodent models and we see that, for example, if we put animals on a ketogenic diet or give them ketone supplementation, they could run 20, 25 percent longer on a Rotarod device, which is like a treadmill. I do not think that's going to translate to humans. I think the things that there's a lot of, if you look at ketone supplements and ketogenic diets, there is, we study seizures and therapeutic applications, but it seems like the mainstream biohacking community is really about cognitive performance too, but they're also about physical performance. We develop various ketogenic agents and we work with ketogenic agents that do have the potential to augment performance, but we study this performance outcome in the context of an extreme environment. So we produce a deficit and then we do the ketogenic intervention to preserve performance in the context of the deficit. However, so a lot of marketing people and a lot of people are selling ketone supplements and other things to optimize. When a person has a normal, healthy, function physiologically and they don't have a pre-existing condition that significantly impairs their cognitive or physical performance, not too many things are really going to enhance. I mean, caffeine will, creatine. So I am actually of the opinion that exogenous ketones will enhance exercise performance and cognitive performance, but I think it's going to be kind of small. The data, I mean, there's just enough data, but I think the exogenous ketones, which is something that I study, is probably like the next creatine. When I was in 1992, I bought my first bottle of creatine from TwinLab. I remember because I was playing football at the time and it was like this new supplement and it offered a very small benefit. Maybe my bench press went up like two or three reps with like 225 or something like that after about a month or so of using it. So it was an observable thing and I think once we understand and optimize the formulation of various energy metabolites, I'm also interested in lactate, alpha-alp-ol-lactate, which is something that I think could be combined with creatine and ketones formulated in different ways. So you have like a dual fuel system. That's something that I'm working on. So I think there's a lot of potential there for these metabolic-based therapies, but also metabolic-based formulations that can augment exercise performance specifically under different, in the context of different stressors.

18:42 Andres Preschel
 And as far as the null benefit of exogenous ketones, the research support is not on an individual basis. I mean, you are in the camp that is for exogenous ketones. Are you comparing that to endogenous production? Like if I'm fasted, is there no net benefit if I take additional exogenous ketones? Is that what you mean? Or you mean just in general, there's no benefit to exogenous ketones?

19:04 Dominic D’Agostino
 Like adding in a ketone supplement? Yeah. Well, I would actually say like in the context of things that I study, there's significant benefits to ketones in the context of like, if you're not having a seizure, but if you're using a rebreather and diving down the 50 feet and your partial pressure of your brain is going up, that's going to cause some stress. So we know that ketones essentially have anti-convulsant effects, and that's the accepted application of the ketogenic diet is for drug refractory epilepsy. So it works through a GABAergic mechanism, through glutamic acid decarboxylase. So you make a lot more GABA relative to glutamate. It suppresses oxidative stress. It does these things. So it tends to, that effect is very observable and robust in the context of extreme environments. If someone was to consume exogenous ketones and they're like keto adapted, if I was the everyday person and I wanted to use exogenous ketones in a race, I would at least three to six months out start experimenting with them in small amounts during my training. And then you can see how your body can adapt to it, like during your training. Right? You don't want to, if you read about athletes that are running ultra marathons on a ketogenic diet, you don't want to start that a month out. Your performance is going to tank pretty fast. But there is, I know it gets criticized a lot, but there is something to keto adaptation. So it's just like, if you have a factory making a certain thing, if your body is a factory and it's used to running off a glucose-based metabolism, carbohydrate metabolism, and you dramatically limit carbohydrate availability, suppress the hormone insulin, it's not like you're going to be burning fat at an accelerated rate and making ketones. It's going to take a long time to adapt to, even to adapt to having a palatable diet where you can get enough energy and be able to digest the lipase enzyme, the pancreatic enzyme, the bile, things like that. There's so many things that need to adjust to be even able to tolerate a carbohydrate restricted diet, a high fat diet over time. Then you have energy systems where you have the production of ketones, ketolytic enzymes, ketone transporters like monocarboxylic acid transporters are upregulated pretty significantly, like 50% at the level of the blood brain barrier and things like that. So there's going to be required adaptation over time to get benefits over a ketogenic diet. So that brings up the idea of doing whatever diet you're following. I think there are side effects to a ketogenic diet, whereas a standard Mediterranean low carb diet, not so much, where you could just follow your own diet and then consume exogenous ketones. I prefer ketone electrolytes with sodium, potassium, calcium, magnesium, actually similar to the supplement element. So I use a supplement, but instead of the electrolytes are bound to beta hydroxybutyrate. So you deliver the electrolytes and that's a good thing. And then it's ionically bound to beta hydroxybutyrate, which is a ketone molecule. And then it liberates the energy and it liberates the electrolyte and there's no sugar or whatever. So these things can be very helpful to restore, preserve electrolytes and also give your body to elevate an energy metabolite in your blood in the millimolar concentrations, which actually represents a significant amount of usable energy because whatever blood level you have of beta hydroxybutyrate that will go across the blood brain barrier and your brain will have free access to it. Once you get up to like six or seven or eight millimolar, then it becomes kind of rate limiting. But if you can elevate your beta, if your beta hydroxybutyrate is one millimolar, your brain is deriving about 10% of its energy from ketones. So you could put it in that context. If you look at the dual PET scan, where you look at ketone and glucose PET imaging studies, which suggest that. So what I'm saying is like that people that are trying to experiment with ketogenic diets and ketone supplements, I think they should start out very slow and start titrating these things in. Maybe just use medium chain triglycerides. Some people can't tolerate them or to add like a ketone electrolyte and small concentrations and then ramp up. And then just, you know, if you're using device to measure your activity, looking at your heart rate, you know, some studies that I did going back over 10 years ago, one of the things when I was formulating these things, I'm sure you know, Peter Atiyah, I went to Peter Atiyah's and stayed at his house and then we woke up, he got on a metabolic car and he maintained 180 watts on a bike. And then, you know, I gave him a ketone formulation and then he maintained that 180 watts. But he did it consuming less oxygen. So like oxygen consumption went down, I think like 10% or whatever. Yeah, yeah. So yeah, shifted his RQ in a way, but he was his oxygen content went down significantly. So while maintaining 180 watts, so his metabolic efficiency, increased and he was already on a ketogenic diet though. So I mean, you could say that, but we did, you know, as he's riding the bike, I'm stabbing his finger, making blood measurements. And that was, I think his ketones went up just like maybe 1.5 or 2 millimolar offsoles. So we've never, we always wanted to follow up and do like a trial, like a more comprehensive trial, but I was just, my focus has always been therapeutic applications of these things. But that's an example, right? So it's like he was following his diet and then he just simply added exogenous ketones. And he's very methodical about doing it in this way. He was like, no, we're going to design it. I'm going to maintain 180 watts and we're just going to look at option consumption. So I do think that there's something to be said and maybe not everybody will experience this, but, you know, the late Dr. Richard Veach, who was a student of Hans Krebs did his whole career. Yeah, ketone aid is part of that. Yeah. There's a little bit of, yeah. So ketone aid, I think is the brainchild. So that's one, that's R13-butanediol, beta hydroxybutyrate, monoester. I love ketone aid. Yeah. So ketone aid, so we've, the very first, the very first ketone that we studied in the lab was R13-butanediol, beta hydroxybutyrate, monoester. And that did not prevent seizures. So I didn't give up though, but what we found is that when you elevate ketones, it needs to be in a ratio of beta hydroxybutyrate to acetoacetate to keep the redox ratio. So we got another formulation from Case Western from Henri Bruningraber and that was R13-butanediol acetoacetate diester, which produces the, that. And so most of the research that we do is actually on ketone esters. And I do think there are tremendous therapeutic applications. My only issue with exogenous ketones in the form of esters, and I have to be careful because a lot of my funded research is with esters. I don't want to, you know, talk negatively about them too much. I do think there's a lot of applications, but you have the R13-butanediol. So R13-butanediol, as you know, is a di alcohol. It's a glycol molecule. And then when you metabolize R13-butanediol, it goes through the alcohol dehydrogenase pathway. So you do produce a toxic aldehyde and also your liver enzymes. So if you consume it, at a, you know, if you consume multiple doses and you're doing blood work, you've probably seen that your liver enzymes will go up, right? So like mine, my liver enzymes, AST, ALT are usually about in the low twenties. But if I consume R13-butanediol 30 to 50 grams per day for two weeks, those liver enzymes will double. So, I mean, you could double it drinking two or three beers per day. So, you know, it's a mild stress, but I worry about people who are older who may not have like, you know, hepatic detoxification potential. So it is putting a stress on the liver. It's also, so I think, I like exogenous ketones in the form of ketone esters to be used acutely for things like CNS oxygen toxicity and for like, you know, therapeutic applications. But if someone's going to use ketones on a daily basis, I would suggest using a beta hydroxybutyrate electrolyte salt. And that way, you know, you're not, you don't have to force the liver to metabolize the R13-butanediol than to make the ketones. So you just have the ionic bond. But yeah, I think so you have ketone salts, you have ketone esters, you could also have a glycerol triester of acetoacetate or beta hydroxybutyrate. And then you have the free acid form of beta hydroxybutyrate, which is usually sold in like a liquid medium. And then R13-butanediol, which is kind of being sold as a ketone ester, but it's really not. It's a ketogenic di alcohol. And then you have something called medium chain triglycerides, which is caprylic or capric triglyceride, which is a C8 or C10 ketogenic fat. So all these things are out there. We I'm kind of agnostic to all them, but they're all tools in the toolbox. And what we do is we take and then we have, you know, whole library of like dozens of different ketone molecules. But these are like the basics ones that I'm mentioning that I think all are commercially available that I just mentioned. But we like to formulate them and titrate them and use them in different animal models of disease and also different scenarios for performance, right? Or different operational activities. And I think this is a very nascent area of research that I got into, God, like 15 years ago. And I was like the kind of people thought that like I started this research, but Dr. Avich was doing it for a long time and many people were doing it. They just weren't very public about it. But I did maybe kick it off in different directions, right? So like we're studying probably a dozen or more different applications of therapeutic ketosis. And I do think there's tremendous potential therapeutically, but also for health optimization and then prevention of certain disease states, including insulin resistance, type two diabetes, things like that.

30:08 Andres Preschel 
And do you believe that in order to improve metabolic flexibility sustainably for the long term that people should in fact try to change their lifestyle and their diet rather than just kind of adding in ketones and helping for the best? Like for the average person, are you more for a lifestyle change rather than adding those in? What's the difference there? What are you potentially taking away from if you just take the ketones and cross your fingers versus actually challenging your body to do this endogenously, naturally?

30:42 Dominic D’Agostino
Yeah, well, I don't, you know, obviously I'm not one or the other. I'm a huge fan of the diet. Actually, my original proposals to the Department of Defense was the ketogenic diet. And there was a lot of pushback about you can't give a warfighter a high fat diet. They're not going to adapt. It's going to be, you know, cardiovascular risk, all those things. So they basically tasked me and said, well, go back to the drawing board and come up with some kind of ketogenic strategy, which is a ketogenic diet in a pill, right? So I looked into that and one of the first things that came across, you know, through PubMed and searching this was 2D oxyglucose. So 2D oxyglucose is a hexakinase inhibitor. So by inhibiting glycolysis, then you're forcing the mitochondria to, you know, inhibit glycolysis and then burn fatty acids for fuel. It is actually it's being used in seizure studies. Joseph Larris So it accelerates the body's adaptation response to ketones in a way. Matt Stauffer Yes, it'll produce a mild, yeah, almost like an SGLT2 inhibitor, right? So by eliminating glucose, you limit glucose availability and simply by doing limiting glucose availability and lowering the hormone insulin, whenever you lower glucose availability or its excretion, then your insulin is going to be lower and the production of ketones are just tightly correlated with suppression of the hormone insulin. And then there's some definitely some therapeutic benefits, especially in people with hyper insulinemia or type 2 diabetes. So, you know, I don't want to get too much on a tangent, but it was like, you know, we had to search for ways to produce therapeutic ketosis. And what we have shown is that you can put animals on a standard diet, high carbohydrate diet, do an intergaster gavage of ketones, and then you do get remarkable effects on glycemic control, on seizure, actually some cancer models show show benefits. So I was skeptical that this was going to be the case. I talked to Dr. Richard Veitch at the time, and he'd always call me stupid. He's like, no, stupid, your body can use ketones. We're like, genetically designed through periods of fasting that the metabolic machinery is there to use ketones anytime, because I was under the impression that you follow a ketogenic diet and over a period of time, you adapt to it. But he was very adamant, of course, you know, he had many patents and the ketone ester too, even before I was tinkering with this stuff. But he was very adamant that you could just drink ketones and then get the metabolic benefits of ketones. And I was very skeptical. So and some of the initial studies in our lab showed no, if actually some animals are seizing faster. And I was like, I don't think this is going to work. And then then I talked to a person that was running the NIH metabolomics core. And he was kind of convincing me that, you know, you need to have a redox balance in the brain and you have to deliver the ketones under certain ratios. So I had a very difficult time finding someone to make this particular ketone ester. So I reached out to a chemist who had like a very interesting background in designing molecules for performance enhancement, right. So a very well known chemist. So in that field, not in academia, so but he was able to make long story short, he was able to synthesize this particular ketone molecule that would elevate beta hydroxybutyrate and acetyl acetate. And then our very first experiment, the animals had amazing resilience to hyperoxic stress. And then we ended up using this in a variety of different studies. So the message here is that not all ketones are created equal, certain ketones will have favorable effects in disease models, and some disease models, and some disease models may have no effect, actually may be do more harm than good. So we really do. And I actually believe ketone esters should kind of be a drug. We've killed a lot of animals, unfortunately, and I don't want to make light of the situation. But you could quickly kill an animal by not even injecting an IP, but actually doing an intragaster gavage of like beta hydroxybutyrate, well, mono ester, 1,3-butanediol, or the diester, especially. These things are very potent, and you have runaway ketosis. And you can't have respiratory or renal compensation with the levels of ketones that you produce. The autoregulatory mechanisms are just completely overwhelmed, and the animal will die of ketoacidosis. So this occurs, especially in mice, because their metabolism is so fast, about seven times faster, but also in rats, too. So we observe it. So it actually made me very cautious in regard to, and I've probably consumed more exogenous ketones than anyone on the planet. And I have the utmost confidence saying that. I've had many gallons of ketone esters go through me and buried a wide array of different experimental molecules in testing. But I test in very small dosages, and I do blood work and things like that. So I do it in a very methodical, controlled fashion. But it's given me an appreciation for things that they can do and things that they can't do, and also some of the harm that they could cause, too. So we're very cautious when I talk about the research and the extrapolated implications for humans using this stuff. I do think there needs to be some regulation, not so much with the ketone electrolyte salts or MCT oils and things like that, or even the free acid, because a ketone electrolyte salt will be self-limiting just based upon the mineral load. Your GI can only absorb so much. Not so much the ketone esters. The ketone esters will dose-dependently put you into ketoacidosis. So the volume has to be pretty high to do that. I know people are experimenting with them out there, and typically what will happen is you'll just start throwing up if you take too much of a ketone ester or even 1,3-butane-dial. But I caution people because I get so many questions from people using it for applications that don't necessarily study. But I do think it's a very nascent area of research, and I do think you're keeping an eye on this because 10 years ago, you go on clinicaltrials.gov and you type in ketone supplement, and you might have three studies. You go to clinicaltrials.gov right now and type in ketone supplement, you're going to have 100 studies. If you go to PubMed and type it in, you're going to see an exponential rise in studies on this. Just for example, cancer. 10 years ago, if you type in cancer, ketone, even ketogenic diet in clinicaltrials.gov, you might have two studies. Now there's something like 48 studies, and that's cancer. That's something that's kind of marginalized. I think the ketogenic diet can be a great adjuvant. It could help things like PI3 kinase inhibitors work better because you have a counter-regulatory elevation to insulin when you use these drugs. I think they could augment certain metabolic-based pharmaceutical therapies. I think that's a fascinating area of research. Also, coupling ketosis with checkpoint inhibitors. I think it's a very fruitful area of research. I think a lot needs to be done in that area. Also, things like Parkinson's disease, Alzheimer's disease. Oxidative stress in the brain is driving it, and ketones, for example, like with Parkinson's disease, monoamine oxidase can drive, especially if you have high levels of iron. Some people have higher levels of iron. For example, in this substantia nigra, that could drive the Fenton reaction. Those neurons are selectively vulnerable to oxidative stress. A lot of work has been done in cell-based systems and animal models to show that ketones are neuroprotective, and especially for oxidative stress conditions. 

38:53 Andres Preschel
I actually have an anecdote that I want to share with you about this, but before I get there, you keep mentioning seizures. My question for you is, what is the underlying mechanism there as to how ketones can support that? What I want people to understand here is that it's not like you're not going to see a benefit if you don't suffer with seizures. It's just like that's the proof in the pudding that something's working properly. What can we say about the underlying mechanism that anyone can appreciate from that perspective, whether they have seizures or not?

39:29 Dominic D’Agostino
Yeah, good question. The etiology of epilepsy is largely unknown, and it's multifactorial. Kind of the same could be said for Alzheimer's, although some people may debate that. Let's talk about seizures. Seizures could be caused by… I mean, we study seizures from glucose transporter type 1 deficiency syndrome. They're lacking the glut 1 transporter at the blood-brain barrier, so their brain is starved of energy, and that triggers seizures. Then when the child is put into ketosis with a ketogenic diet, the ketones then restore brain energy metabolism, and that suppresses the seizures. However, some people have… I mean, there's so many different reasons that you could have a channelopathy, like a potassium channel that doesn't… When potassium channels close, then that actually causes the membrane potential depolarization. Interestingly, I think the important thing is that independent of the etiology, ketogenic diet therapy controls seizures like temporal lobe seizures, absence seizures, Lennox-Gastaut-Dravais syndrome, a wide variety. We study Kabuki syndrome, we study Pomp syndrome, we study Angelman syndrome. We study all these different things, and the ketogenic diet has very remarkable anti-epileptic neuroprotective effects independent of the etiology of the seizure. That's really incredibly remarkable to me. That's what brought me to it. Also what brought me to it was the Hollywood producer, Jim Abrams of the Charlie Foundation, and the movie he did with Meryl Streep. Meryl Streep did a movie about the ketogenic diet. It's called First Do No Harm. I watched this, and I was like, wow. I started digging in, and then I discovered the center of Johns Hopkins, John Freeman, the late John Freeman. At the time, he passed away in 2012, but his protege is Dr. Eric Kossoff, who runs the neurology epilepsy clinic at Johns Hopkins. Eric Kossoff wrote a book called The Ketogenic Diet for Pediatric Epilepsy. Now it's called The Ketogenic Diet for Pediatric Epilepsy and Other Disorders. It's proven to be efficacious for adults with epilepsy. It's a long-winded answer to your answer. What's causing epilepsy? We don't know, but then again, the ketogenic diet doesn't work through a single mechanism. It works through many different mechanisms in synergy. It lowers reactive oxygen species. It changes the bio-energetic energy production in the brain. It stimulates glutamic acid decarboxylase, which converts more glutamate to GABA. A big part of what we do research on is adenosine receptor signaling. It inhibits the NLRP3 inflammasome. When that gets activated, things like IL-1-beta go up. A big part of what we're doing now is actually looking at beta hydroxybutyrylation. So ketones, the metabolic control of epigenetics is pretty robust. Lactate can actually influence epigenetics. Beta hydroxybutyrate can influence different enzymes called histone deacetylases. Through HDAC inhibition, they could alter genetic programs and have epigenetic effects. And then through beta hydroxybutyrylation, the beta hydroxybutyrate can directly interact with the histones and alter gene expression in ways that are neuroprotective and even anticonvulsant. We're studying that in the context of Kabuki syndrome right now. It's a PhD dissertation project to one of my students. 

43:13 Andres Preschel
If you look at ketosis as being involved in all these different mechanisms and those mechanisms having all these benefits, can you make the argument that lifestyle change therefore gives you more benefits than exogenous supplementation? Does the exogenous supplementation work through these mechanisms the same way that lifestyle change does?

43:33 Dominic D’Agostino
It's a good question. I get this a lot. It's the obvious question too. And it deserves a very, very thorough answer. Your question is a very good one and it deserves an incredibly nuanced, articulate answer. But the reality is that we do not have the human outcome data for me to even speculate on that. So I was just blown away that you could actually gavage, you could give animals straight up ketones and have all these effects. I was like, no, let's do this over again. Let's do this over again. Well, because too, I guess it was more convincing to me because the first experiments didn't work. The ketone, the beta hydroxybutyrate monowester did not work with seizures. But I think it has other applications that are very remarkable. So I became like a true, I was like, okay, I knew it. I'm not going to get funding for this project. And then we went in another direction. So I have an immense appreciation for the potential to acutely alter energy metabolism and the potential therapeutic effects and also performance effects that you could. But from an evolutionary perspective, the only way that we could get into that level of ketosis is like fasting seven to 10 days. So I could administer a ketone ester. I could pull blood on you and it looks like you fasted for a week, which is pretty remarkable. And so the obvious question is that if you're eating a normal diet and then you ingest these ketones, where does the glucose go? And that's, I think this is a really important conversation, what I'm about to say right now. So I think high doses of exogenous ketones can cause energy toxicity and this can do more harm than good. And I think that's an important message for people who are consuming exogenous ketones, trying to get to like chasing ketone levels, trying to get to three, four or five millimolar. Your body is not going to be able to use that unless you're like doing an all out sprint or something like that. If you're just sitting at your desk and elevating your ketones, even two to three millimolar, your body is working to get rid of those things. It's creating a metabolic acidosis and through renal compensation, you have to eliminate these things through ketone urea. But I think actually more importantly, we eliminate these things by counter regulatory mechanisms. So there's ketone urea, but also as ketones elevate, the ketones cause the pancreas to release some insulin and then the insulin shuts off lipolysis and also shuts off the ketogenesis. And that's a negative effect of using ketone esters. So I just presented some data on ketone salts and ketone esters. And if you take a ketone ester and shoot your ketone levels up a delta of two millimolar, it causes an increase in insulin. If you get the same level of elevation of beta hydroxybutyrate with a ketone electrolyte salt that's balanced electrolytes, you get the benefits of the ketones in circulation, but it doesn't trigger the counter regulatory ketone induced insulin release from the pancreas. And even glucagon, we measure glucagon, doesn't really change that much. But if you go higher than that, then you do. And I've had to change my tune on this a lot. But I do think for certain therapeutic applications, you may need to go to three to four, even five millimolar for glut 1D, for example. So my recommendation would be to use a ketone electrolyte, get no more than one millimolar somewhere like 1.5 to 1 is kind of the sweet spot for me. Stay between one and two and that way you're not triggering an increase in insulin. So I have a whole stack here of insulin tests. And a lot of people don't measure insulin, but it's something I've measured like hundreds, if not thousands of times and coupling that with my CGM, my continuous glucose monitor. And that gives me a lot of insight into how macronutrients impact. My insulin is always pretty low, like three to four. But if I take a dose of ketone esters, it can shoot up to six to eight, which is still not bad. I mean, we do studies where we have people with insulin that's like 30, one guy's 100. So, and he's, you know, he observably has no overt really, you know, negative effects that we can see. But, but you don't, if you want to be in a fat burning mode, if you want to be, have maximal metabolic flexibility, you want to be able to use metabolic substrates without triggering a counter regulatory physiological response. And my background trained in as physiologists. So I was trained by an APS, you know, physiologist who was like the Dean of Research at Rutgers University. And she really instilled in me like neuroscience could be important, but you need to understand physiology. So she would drill in, you know, systems physiology, mammalian physiology. So I always view metabolism, a lot of people who train in nutrition just basically get, they're like nutrition biochemists. But I believe that if we really fundamentally want to understand nutrition, we have to understand nutrition physiology. That is the most important thing. And then, so I first learned physiology through medical school and then PhD training. And then, and then did my PhD dissertation work in neuroscience doing patch clamp electrophysiology, actually wholesale perforated patch clamp electrophysiology, where you record from neurons in a special way using nystatin. And then you actually can feed the neurons different types of energy sources. And then you basically look to see how they respond under different levels of oxygen. And doing that work with hypoxia gave me an appreciation for, I never really thought about what my brain is using for fuel, right? Or that it could use anything other than glucose. In grad school, my postdoc, I was really mostly dialed in on lactate, you know, developing ways to increase lactate production, but then I got steered into ketones. So I do think there's tremendous applications for creating formulations that are alternative energy sources that people can use, you know, and there's things that are commercially available, creatine, monohydrate, you know, different amino acids, alpha-alp-polylactate, different ketone formulations that I talked about. So these are like the low hanging fruit that people can purchase. They're relatively inexpensive, I think, if you're just going to tinker with them, and then add them to your regi- there's not going to be any randomized clinical trials soon, right? So you have to be your N of one data. So it goes back to this idea of getting as much baseline data as possible if you're one of these people who really want to optimize their performance and health longevity too.

50:46 Andres Preschel
 And so what you're describing here is that essentially there's a trade-off if you take something like, you know, straight ketone, just straight, I say, you know, beta hydroxybutyrate, etc. And so do you believe that high performers can get away with the occasional supplementation of something that brings their ketones way up just for like a one-off event? And then let's say otherwise just taking a ketone salt or going by endogenous means to establish ketosis? 

51:12 Dominic D’Agostino
I think they could get away with it. I just don't think, you know, they have to do the measurements to show if it's going to be optimal or not. Is it increasing their performance? I think it has an equally high potential chance for decreasing performance, right? You know, we've dosed animals in ways that decrease their performance if you hit the sweet spot, you know, so I encourage people to experiment with them. Like I said, we always study therapeutic ketosis in the context of a disease process or a significant decrement. So that could be an extreme environment, you know, an impairment of a metabolic process. We're doing glycogen storage disease type two right now and, you know, seeing some interesting data from that. So I'd think there are other things out there too that if you were dialed in on performance that could be worth it. But I just think- I do think potentially that throwing in a large dose of the ketone ester, that's going to put a metabolic strain on your body, you know, because your body has to- if your energy output is coupled with your intake that could- but if you have an energy toxicity- so it does take some time for your liver to metabolize. And when you're exercising really hard, a lot of the blood flow is kind of limited to the organs and goes to your muscles. So that's in some ways like limiting hepatic metabolism. You know, I'll say this, I don't think we published this, but you know, we gavage rats, sprague dolly and fisher rats for periods of time and then we take out all the livers and then we do, you know, histology on the liver. We see signs of liver toxicity when we feed these things over long periods of time. So there's like more red blood cells in the liver and then the precursors of, you know, just some mild, maybe necrotic- pre-necrotic events. And that always concerned me and that's why, you know, I have in my refrigerator and in my- like I have tons of ketone esters but I don't use them. So I only- I default to ketone electrolytes even when I have all the options, right? I mean part of it's kind of like taste too, right? Oh yeah, the beta-HRT butyrate is nasty. Yeah, yeah, it's kind of nasty. So there's 1,3-butane dial. They're never- I'll tell you, I mean, I've been in this world for, you know, almost two decades now. I don't think they're ever going to flavor. You can put it, like I have capsules made that we're using in a clinical trial and that's- you need to do that if you have- you need to have a control, right? So we have like just a vegetable oil as a control. We had not seed oil. We used- not that I'm like a big fan of like, you know, dissing seed oils but I think we use like light olive oil instead of like, you know, a seed oil. But yeah, so we have to- when we do studies, we have to put these things in capsules or otherwise, you know, our participants are not going to consume it. 

54:12 Andres Preschel
And back to this anecdote that I wanted to share with you. You mentioned how this can be promising for things like, you know, Parkinson's and Alzheimer's. I actually did a genetic test and I do blood regularly and I found that I actually have a genetic predisposition for Parkinson's and I have a genetic predisposition for hemochromatosis. So I store too much iron. On top of that, I have an early diagnosis of ADD and I took medication for it for years. And this is actually how I fell in love with all the science because I wanted to, you know, support my body and be authentic in my ability. And I found that fasting has helped me tremendously. I found that, you know, fasting mimicking diet, so generally low carb, sometimes often ketogenic, especially on like rest days, low carb diet. And I've also found that if I take, you know, ketones either right before bed or before a podcast like this, that my mental acuity and my mental endurance in a way is enhanced. Now, I don't know how much of this is placebo. I don't know how much of this is actually warranted mechanistically and it gets to be supported by research. But do you think that generally someone like me is headed in the right direction with these predispositions by using both the lifestyle and the ketones together?

55:25 Dominic D’Agostino
Absolutely. I think it needs to be a combination of two. I also think the two are kind of synergistic. So like one in one equals three, right? So you're doing like an exercise, you know, just lifestyle, diet, and then also supplements. And I don't know, what am I taking here? Oh, so yeah, I use this product called a keto start, which is a ketone electrolyte. And I got an email the other day, remind because you just mentioned ADHD. Someone said this is I got off Adderall and this the keto start is my new Adderall. So the keto start plus has caffeine, but it's only like 60 milligrams. So it's probably not the caffeine, but I have people that reach out to me and said, I have many people reach out to me and said, I got off these ADHD medications. And like Adderall basically like, I don't know if you've taken is basically amphetamine. Right? I know I took it for 10 years. Oh, for 10 years. Wow. Until I was 18. I'm 26 now been offered for eight years. And through lifestyle change, I've accomplished more than I ever would on Adderall. Oh, that's amazing. You know, when I first met and you probably know him, Lane Norton. He's a good friend of mine. He's actually coming over this weekend. We're going to hang out. But when we met, I think he was just like getting off Adderall or I'd just gotten off of it.

56:44 Andres Preschel
 And yeah, I know he suffered with ADHD. I actually have a podcast coming up with him in a few months. Okay. I wanted to talk about, you know, this stuff with him.

56:55 Dominic D’Agostino
 I don't know if that's public knowledge, but now it is, I guess. But I think he's pretty, yeah, I think he's been talking about it online. Yeah, he's talked about it. Yeah. He might not have talked about Adderall, but he at the time and I didn't know what Adderall was. And I looked it up because I was asking about ephedrine. Right. And I was like, yeah, I'm cutting out. I was thinking about using like ephedrine, caffeine stack. And I was like, have you ever tried ephedrine? And yeah, I was using like small doses. This is when you could get a ephedrine. This is like, this was a long time ago when we met. He was like a grad student at the time. Maybe you're posting. Yeah, he was a grad student. And now he's like, Dom, I'm on it. I was on Adderall. I got off Adderall and I was like, I didn't know exactly what it was. And I looked it up and I'm like, damn, it is amphetamine. Oh my gosh. Yeah. And I just mentioned that because I've gotten many emails, especially over the last five years about people, some of them on the diet, but actually it's been more so that they're taking the ketone supplements and it's helped their focus. And they've been able to, whether they have a preconceived idea that this is going to help me and then they do it and then they believe it. But I do think- I didn't expect it. Oh yeah. Yeah. I guess maybe they didn't. And I do feel when my ketones get up a little bit too high, I almost feel a little bit too stimulated. So that's why too, I just dial it back. Like right now I'm sitting at like 1.5 millimolar and that's kind of like my sweet spot. If I get a little bit higher, especially this time of day, I start to get a little bit too hyper. But I've learned to sort of adjust it. But I've also supplement ketones because if I follow a very strict ketogenic diet, my APOB and my LDL become elevated. And I know this is a pretty big topic on like in Twitter and online about the lean mass hyper responders. But I'm of the opinion that if I could just add a little bit of carbohydrates in the form of some fruit, maybe some vegetables and things like that, and it makes me- and my protein level is too, it's kind of high and it kind of keeps me out of ketosis. But then I just add some MCT or just some ketone supplements throughout the day. So I stay in a state of mild ketosis and get all the benefits from the phytonutrients, from the fiber. For me, that's optimal. Some people on a carnivore or on a strict ketogenic diet, and they are of the opinion that they don't want to supplement even something like MCT. But I do believe in studying this and communicating with hundreds, if not thousands, of people. I think the ideal diet, if I just have to like one diet, it's kind of a low carb Mediterranean diet that's low in carbs enough, especially that if you do some intermittent fasting that your ketones start to get elevated a little bit. And then you just kind of top off the tank a little bit and do some finishing touches with a little bit of exogenous ketones periodically. And I have experimented with so many different approaches and that's really what works for me and my lifestyle and many people that I consult with. 

59:52 Andres Preschel
Yeah. And I know this is anecdotal and I want to make sure that we stick to the research, but I want to show from our experience how helpful it will be for folks tuning into tests, not guess, and to see what works for them. And in my case, I'll add these things in strategically. I try to match my carbon intake to my activity levels, and I actually experimented for a while. I was fasting every single day, like 16, 18 hours, and I followed a very low carbohydrate diet. I did some testing and what I found was that my free testosterone went down. My sex hormone binding globulin went up, so I had less free testosterone and my CRP was a little elevated. So I was overdoing, there was a point where I was overdoing the ketosis. 

01:00:41 Dominic D’Agostino 
And interestingly enough, I wanted to ask you about-
 Was your weight stable? Did you lose weight during that? Because any kind of caloric deficit will lower testosterone and also maybe elevate SP. But the other thing, the HSCRP, yeah, that's kind of surprising, especially mine's always like 0.1 or something like that.

01:00:57 Andres Preschel
It wasn't HSCRP, it was CRP. Yeah, it was just CRP. It was just CRP, okay. Yeah. And I did lose a little bit of weight, so- Do you know what your bubble was? Yeah. I can't remember, but my sex hormone binding globulin was like 60 something. It was pretty high.

01:01:12 Dominic D’Agostino
 Yeah, that sounds kind of high. Yeah. My testosterone is always like, I don't know, people say you should supplement here and there. I take DHEA and that brings my testosterone from like 400. My testosterone has never really been too high to like 500 if I do the test an hour after. But I feel like my androgen receptor density must be high or something because I can keep like 225. I'm like six foot. It's just, it's always like keep my protein levels up high and things like that. But I've been down to like, my testosterone is 290 if I do a strict keto and I'm losing weight. But then if I go back to a eukalluric diet or titrate in more protein and calories, then it starts to get back up into the mid, even mid to upper range a little bit. If I'm like super well rested and getting in like surplus calories, things like that, then- Right.

01:02:01 Andres Preschel
So it's not so much the amount, it's also the androgen receptor density of what you have in the body. You can actually use it. Interesting. And then I did lose some weight, but I think strategically adding in carbs, especially surrounding activity was very helpful. And I want to ask you about ketones before bed because I noticed I do track my biometrics with a clinical grade wearable device. I use either the Ora or the BioStrap or Whoop or sometimes all of them if I want to get fancy with it. And what I've noticed is on nights where I anticipate less sleep, this is something I discovered by accident. For whatever reason, I took ketones late at night and I got like six hours. Typically I got seven and a half, eight. My HRV skyrocketed and I woke up feeling super refreshed and actually repeated this. And now anytime I can, I can only afford a few hours, actually take the ketones. And so I started thinking about this. I'm like, what's happening? I actually noticed my respiratory rate went down. So my hypothesis is, well, maybe because I was in metabolic ketosis and I shifted the respiratory quotient, all of a sudden I am breathing less, there's less sympathetic activity. And as you've described, and maybe this is, I might be going over the top here, but maybe there's an adaptogenic effect, like the GABAergic effect, the ketones can facilitate sleep and can further the parasympathetic activity.

01:03:32 Dominic D’Agostino
These are all very interesting and well thought out hypotheses that could be tested. There's something called obesity hypoventilation syndrome that people have. There's a guy at Johns Hopkins, Jonathan June, I think that studies it. And it is interesting. There's data from the GPR109A receptor, which is actually the receptor for ketones. And when you hit that, it actually can suppress sympathetic activation or actually reduce sympathetic tone. So yeah, ketones are almost like a hormone. Your liver makes it and it gets into circulation, and then we have ketone receptors. That receptor, when it's activated, it decreases sympathetic activity. And I actually think that when people, during starvation or during extended fasting, when your ketones are elevated, there's a pretty sharp reduction after about a week or so in your metabolism. And that's partly due to your sympathetic nervous system being suppressed, and then your body temperature starts to go down. When you do this, and I fasted for a week, no more than that, but your anxiety levels are like, you have no anxiety. Things that would typically trigger an anxious response in me, it's almost like I took a big beta blocker or something like that. In many ways, I feel emotionally kind of flat until I jumpstart my metabolism back again. But there is a remarkable suppression in sympathetic activity and actually an increase in parasympathetic tone with ketosis. This has been observed, it's been talked about. But some people, typically when publications are written about this, it's in the context of an energy deficit. So is it the ketones or is it just the state of being calorically restricted when AMP kinase is activated, mTOR goes down, all these different pathways, the insulin IGF-1, a lot of things are altered in ways that could decrease sympathetic tone. But then you have sympathetic tone goes down, but also parasympathetic tone and that's independent from exercise. So that's the only thing I know other than exercise that will sharply, within a week, you have to fast. But I guess no one's really done that with exogenous ketones. That would be a very interesting study. Actually, we could do that because we measure… Hey, if you guys do that, I'd love to join you and maybe be a test subject. Yeah, actually, that's actually a really good thought for a study. It's something that I've thought about a lot, but I tend to think that it's probably mostly attributed to just creating a calorie deficit. I think that's a big driver for suppressing sympathetic tone and it's almost part of the starvation response. I remember anyone, actually, if you talk to Lane even about when he was dieting for a competition, I remember him telling me he was always cold. And I remember he was pretty much at the end of his dieting phase when we were somewhere and I was stabbing his finger to get his blood measurements and measure his ketones. And he was in, this is back in like a long time ago, and I just remember him saying that he was kind of always cold and it's like his speech was even slurred a little bit. Which is odd for Lane, right? But he was like shredded beyond… I mean, his skin was like tissue paper thin at the time. So he was at like, he was at that point where most people would have stopped a month ago dieting. He was just doing that. And yeah, it does. You get a pretty profound suppression of your sympathetic nervous system when you diet for… And that's not in ketosis. So his ketones were not very high. That was just from a calorie deficit. We'll do that. But I do think that we do know that ketones stimulate that receptor that suppresses sympathetic tone. So there could be a ketone dependent effect there. And that combined with the GABAergic effect that you described earlier. Yeah. Yep. Yep. And that's a real effect. Actually, there was literature in humans on a ketogenic diet. And then we did a study in an Angelman syndrome mouse model doing the ketone ester and saw… We looked at GAD65 and GAD67. Yeah. And those… We just did like PCR and those proteins are those… Go up. We did westerns for them and their proteins go up. And that's like in two to four weeks, you get a pretty big increase in the mechanism or the enzymes that convert the glutamate to GABA. And then if you did our metabolomic studies too showed… What we shared with that glutamate levels don't change. You just get more of a conversion to GABA. And I think that could be therapeutic, especially in the context of most neurodegenerative diseases. Actually, I would say all neurodegenerative diseases are pathophysiologically linked to glutamate hyper-excitability or excess glutamate, even Alzheimer's disease, which you would think is there'd be less neurotransmitters, but there's actually excess glutamate hyper-excitability with Alzheimer's disease, but traumatic brain injury, Parkinson's disease, ALS, all these different disorders. So yeah, being able to convert more of that glutamate to GABA can be therapeutic in a lot of different ways and may contribute to the anxiolytic effect of ketosis, which has been observed even in our studies. My wife is a behavioral neuroscientist. She trained in Hungary at Semmelweis University, but when she started doing research for us, for me in our lab, she was gavaging the animals before the seizures and was saying they're much more easier to hold. They're much more calm. And she was like, well, we need to do a study on behavior. I wasn't interested in anxiety at the time, but we were able to get the equipment, the elevated plus maze and some other things. And it had a very robust, acutely administering ketones. And then you put the rats on an elevated plus maze. It's almost like giving them Xanax. They actually spend considerably more time in the open arm. They're much more social. They have less of an exaggerated fear response. Their fear response is not triggered as much. So yeah, that was, we published a series of studies, 2016. And then we actually looked at the mechanism. There was suggestion that there was an adenosinergic mechanism came into play there, but also GAVA too.

01:10:22 Andres Preschel
Wow. That's fascinating. I'd love to dig into some of those studies and just check them out and see what I can take away. I'm not a rat, but I would love to see how I can maybe occasionally modify anxiety or even share that with my community. And I wanted to ask you here about something like fasting or therapeutic ketosis, the influence it has on BDNF and CREB in the brain for memory to mental performance and neurodegenerative disease prevention. I've looked at some studies that show that fasting for at least 14 hours or so, you get this intermittent metabolic shift and that's really what upregulates CREB and BDNF in the brain. And I just wanted to get some of your thoughts there. What can be said about fasting and ketosis for memory and mental performance? 

01:11:26 Dominic D’Agostino
Yeah. Two things that elevate BDNF that I'm aware of are aerobic exercise. Hard aerobic exercise will elevate circulating brain-derived neurotrophic factor. And then actually circulating BDNF in blood is fairly correlated with brain BDNF. So if you do a blood draw, measure BDNF. So you can do it that way. And then the authority on this, the person who has published that was put on my radar in 2007 or 2006 was Dr. Mark Madsen. And Mark Madsen, he was at the National Institutes of Health. I believe he's still there. I actually interviewed Mark Madsen for STEM Talk Podcast when I used to be the host of the podcast for Institute for Human and Machine Cognition, IHMC. But we delved into this topic of ketosis, fasting, and BDNF because he published a paper that got me very interested that showing fasting dramatically increases BDNF and other factors that could enhance learning memory, what we call long-term potentiation. But he had another study that came out that indicated that the elevation in BDNF from fasting was due to beta-hydroxybutyrate. And the mechanisms from my understanding have not been worked out specifically how beta-hydroxybutyrate is circulating BDNF to go up. But the work is, and it could be multifactorial, maybe not a single mechanism. But the general consensus is that fasting, at least from the Madsen body of literature, which is quite robust, he's got a lot of publications on this, is that fasting induced elevation of ketones, the ketones are contributing to the elevation of BDNF. But I do not think that that has been replicated, for example, with ketogenic diets or exogenous ketones. And I've looked into this and I just haven't seen that connection there. But I do think that he believes and that there's research to indicate that fast BDNF elevated by fasting and exercise is associated, correlated with beta-hydroxybutyrate. So maybe beta-hydroxybutyrate is just a good indication. It's almost like a biomarker that you fasted for a period of time. And of course, high performance elite level athletes are always getting into ketosis. So especially like cyclists that go for four to six to eight hours on a cycle, they deplete all their liver glycogen and then they're mobilizing fatty acids for fuels and they have post exercise ketosis all the time. So that could be contributing to that. But exercise is the best tool that we have for brain health. And then fasting, maybe exercise coupled with fasting. I know Mark Madsen likes to go for running on trails, which activates your sensory and you have stability and there's a little bit of sensory overload running through the woods, which I'm kind of getting into now. Doing that in a fasted state. So exercise in a fasted state in an enriched environment is what he does. And I tend to be inclined to follow what he does. It would probably be the best thing to stimulate brain health and BDNF.

01:15:11 Andres Preschel
And this is something that then drives neurogenesis, neuroplasticity, synaptogenesis. So I like to believe that a lot of the fasting that I did over the years has helped me get my brain to where it is today because I depended on exogenous medication to get by in school. And curiously, I'm interested to get your take on what this means for women because I know fasting is just, women are heavily underrepresented in the research. So do women need to take, are you versed in how women can approach this based on, let's say, where they are in their female by rhythm or in their cycle? What can they do to get the benefits without neglecting their unique physiology? 

01:15:58 Dominic D’Agostino
Yeah, there's no reason women can't get benefits from a low carb diet. They need to be more cautious when approaching what I call a prescription ketogenic diet. So a ketogenic diet that's quote unquote prescription strength, meaning that it mimics what's used clinically, can cause amenorrhea. So there's, if you look at the literature for epilepsy in adolescent girls, there's about a five-fold increase in amenorrhea on girls. And that could be, there could be a factor of some of the anti-epileptic drugs. It's a little bit debated, but from my perspective as a physiologist, I think the problems that women can have with low carb diets or ketogenic diets is that the restriction in protein can alter insulin and insulin signaling and other metabolic signaling and hormones in ways that could cause amenorrhea. But typically, and this comes from probably a decade and a half of getting hundreds of emails from women who are sending me their blood work. And then when I, when I probe and ask questions, it's like, you know, they're following a diet and then they start a low carb ketogenic diet and then they couple that and then they ramp up their exercise when they're starting their cutting phase or their preparation for an event, for a marathon or something like that. So it's like, you get a double whammy of caloric restriction, carbohydrate restriction, and coupled with over-exercising. So that's a, that'll put them on a fast track for amenorrhea. And not always the case. I mean, some women are weight stable. They're using it for polycystic ovary syndrome or something like that. And maybe having good success with that. But in some women, like in PCOS, sometimes it restores their cycle and actually balances their hormones. But women's physiology are more reactive, I would say, to perturbations in metabolic control or energy status. So it's going to perceive an energy deficit and have a reactionary effect. And that could be amenorrhea. It could be in women that have been in our lab that tried fasting, they actually like, they faint or they borderline faint. I remember they just have a much more difficult time. And I don't know if it's males, it's kind of like an ego thing or whatever that they can push through it. But I do think males are kind of set up metabolically to basically push through fasting easier. And women have, maybe it's just their blood volume collapses and just through the diuretic, natriuretic effect, they become hypovolemic and they faint. And, you know, but I really push that you need to get hydration, you need to get electrolytes, you need to get sodium in things like that. My wife does not follow a ketogenic diet. She can fast for a day, but then, you know, she doesn't like to do that. So she does quite well with carbs. And she probably eats less than since we've been together. But she does communicate with people, you know, women that are following ketogenic diets. And I just think women need to be more cautious with the implementation of a ketogenic diet. And it's better to transition if they're not, you know, treating epilepsy or something like that. And I've talked to Dr. Allison Hall, who's one of our clinicians for one of our clinical trial, that she's had a lot of success treating like 10,000, you know, treating thousands of women by gradually introducing it over six weeks, that you have to do this for long term sustainment. A lot of times it just you fail miserably if you don't have a transitional period. So her experience in treating thousands of patients is really so super important, especially for women to have that six week transitional phase.

01:20:10 Andres Preschel
Wow. And I know we can have the whole podcast set aside for just this topic. But I just want to have I have one more question for you. I know we're super short on time, we're pretty much out of time. My last question for you here is, you know, what are some of the things that you've learned just generally from working with these elite populations that you think everyone should either dive into learn a little more about or incorporate in their own, you know, lifestyles or approach to health and well being? You know, what are some things that you've learned that you think everyone should know about their physiology?

01:20:40 Dominic D’Agostino
 Yeah, good question. You know, if I had to say that, everybody is a very unique metabolic entity. And, and that's there's a lot of different hierarchies of, you know, of research. And so I think the end of one is probably one of the best, right? There's like cohort studies, there's case studies. But I think the end of one where you're your own control is super important. So that's why I would really emphasize that people get baseline to understand where they're at from metabolic health perspective, from body composition perspective, and from a what I call functional biomarker perspective, you know, like, how many pushups can you do? What's your VO2 max? What health asks? Can you run a mile? And then from there, start implementing, you know, dietary or supplement protocols that are backed by science. And I mean, there's some emerging science that we don't have our CTs yet, right? So you want to like ketones, for example. So you want to delve into that cautiously, in a way that you're not going to do any harm. But I think from a physiology, from speaking as a physiologist, we have to know our physiology. And that actually comes back to measuring. And I think the more documentation you have now, especially for guys and girls out there in their 20s and 30s, trust me, when you're approaching 50, that data is like gold, because that becomes the motivating factor for when you see your body composition change, once you, you know, when your 20s and 30s is pretty easy to put on muscle and keep it. But once you're approaching 50, I mean, you got to really work hard. And then that data will become the motivating factor for a healthy longevity. So, so yeah, so keep your blood work, you know, optimize. And also, if you're approaching your training, I always did like a linear periodization powerlifting template. And I thought that was super important for me, probably one of the biggest factors in my success and like PhD, and just in academia, and in just my fitness goals has been keeping a journal. So keeping a journal, writing all these biomarkers down, writing all my weights down, you know, and you don't have to get too technical about it, you could just write down, you know, how many grams of protein or how many total calories are, but you know, I'm going to work out today. And I already wrote down the sets that I'm going to do. So I already know in advance what I got to do. And it's like, you know, I'll do that in the morning. And then all day in my mind, it's like, okay, yeah, 500 for six, 500, like it'll, I'll have the set in my head, the weight, I'll know what the weight feels like. And I'll just run it through my head all day, you know, during different periods. So I just pre-program myself to do what I need to do that day. And I think that becomes a really important tool. And I know Tim Ferris was really big on that too. I remember him mentioning, and I have a stack of training journals, stack of nutrition journals, but I have my blood work and my physiology in there too. So that's an important aspect of it.

01:23:42 Andres Preschel
 Wonderfully said. That's absolutely wonderful. And I think one of the biggest things that I admire about you is not only do you have the knowledge, but you're out here busting 500 pounds for multiple reps in the deadlift. So you are, you're living proof of, you know, the, how amazing it is to know your physio, to apply this, to challenge yourself, to track every single step of the process. You continue on this journey of optimization throughout your life. And I too am a fan of Tim Ferris. Anyway, Dominic, this has been absolutely amazing. I can't thank you enough for joining us and for standing for the research, for standing for all the nuance in the research and helping us, you know, find our truth. And hopefully I can be involved in some future studies at some point. That'd be absolutely amazing. So thank you so much for your time.

01:24:40 Dominic D’Agostino
Yeah. Well, I'll keep you up to date on that. And also just, you know, want to direct people to, if they have like questions about what I do, keto nutrition.org is my website, but I'm also a co-host for the metabolic link podcast and also the metabolic health summit, which is going to be in Clearwater, Florida, January 25th to 28th. I'll be there if you're interested in this topic. Yeah, that'd be awesome to meet you in person. And yeah, just, you know, for your listeners out there, it's going to be basic science, clinical science, but also human optimization. And we're going to have, you know, a lot of networking opportunities too for people and they like that.

01:25:13 Andres Preschel
 Amazing. Thank you so much for sharing. I'll link to this in the show notes. Great. Thank you. Awesome. Appreciate it. So that's all for today's show. Thank you so much for tuning in today for all of the show notes, including clickable links to anything and everything that we discussed today, everything from discount codes to videos, to research articles, books, tips, tricks, techniques, and of course, to learn more about the guest on today's episode, all you have to do is head to my website on dresspreshell.com. That's A-N-D-R-E-S-P-R-E-S-C-H-E-L.com and go to podcasts. You can also leave your feedback, questions, and suggestions for future episodes, future guests, so on and so forth. Thanks again for tuning in and I'll see you on the next one. Have a lovely rest of your day.