FoundMyFitness - #074 Dr. Dominic D'Agostino on Developing a Well-Designed Ketogenic Diet and Harnessing Its Benefits

Episode Date: April 28, 2022

Dr. Dominic ("Dom") D'Agostino is an expert on a wide range of topics related to metabolic health, ketosis, and ketogenic diets. As one of the world's foremost experts on the ketogenic diet, Dom has personally practiced some variation of ketogenic diet for over a decade, bringing a substantial amount of practical experience along with his anecdotes from human and animal research. In this episode, we discuss: (00:00) Introduction to Dr. Dominic D'Agostino (04:59) What is "keto" (and what it is not) (08:42) Types of ketogenic diets (15:27) Lifestyle Ketogenic Diet (26:36) Biomarkers and hyperlipidemia (29:41) Micronutrients and Supplementation (33:40) Exogenous Ketones (55:48) Optimal blood concentration of ketones (Dom's pick) (01:13:31) Exercise performance and anti-catabolic effects (01:34:37) Brain and Memory (01:42:39) Intermittent Fasting (01:51:43) Neurodegenerative Diseases (01:58:05) Migraines (02:04:17) Autoimmune diseases (02:06:15) Cancer (02:22:03) Carnivore diet (02:28:22) Dom's lifestyle habits (02:31:46) Measuring ketones Watch this episode on YouTube If you're interested in learning more, you can read the full show notes Join over 300,000 people and get the latest distilled information straight to your inbox weekly: https://www.foundmyfitness.com/newsletter Become a FoundMyFitness premium member to get access to exclusive episodes, emails, live Q+A's with Rhonda and more: https://www.foundmyfitness.com/crowdsponsor

Hello, ladies and gentlemen and lovers of beta-hydroxybutyrate. This episode features Dr. Dominic Dagestino. Not only is Dr. Dagestino a world-class researcher on nutritional ketosis and specifically ketogenic diets, but he has the practical long-term use of ketogenic diets, which sets him up in my mind as the authority on ketogenic diets and ketogenesis. This episode covers a lot of ground, everything from what ketogenic is to practical tips on eating a ketogenic diet to differences between exogenous ketone supplements and their role in the ketosis world.

I had Dom on the podcast a few years back and I just want to add that he is really one of the nicest people I have ever met. This podcast goes really deep and I think that anyone interested in metabolic ketosis and ketogenic diets will absolutely love this episode. In this two and a half hour episode, you will learn some practical tools and tips with respect to how to optimize a ketogenic diet. diet, how to go into ketosis more easily, and how to not get kicked out so easily. How going into cycles of a ketogenic diet may have similar benefits as the fasting-mimicking

diet. What biomarkers Dr. D'Agostino thinks are the most important to monitor when starting a ketogenic diet for the first time or in order to determine whether a person is responding favorably or unfavorably. The differences between ketone esters and ketone salts in terms of what they are, efficacy, side effects, and safety. What we know and don't know about the effects of a ketogenic diet on gut health. How preclinical data suggests that a cyclic ketogenic diet improves brain aging and health span

and whether Dom thinks this will translate to humans. Some preliminary clinical evidence that ketogenic diets and supplemental ketones may improve some types of migraines. How ketogenic diets and or supplemental ketones may affect various types of exercise performance and muscle mass. What Dr. D'Agostino typical meals look like, his meal timing, supplements, and workouts, and so much more. Before we get our beta-hydroxybutyrate levels up to at least 1.5 millimolar, I have a couple

of quick announcements. First, I wanted to mention that Dr. Dagistino, along with his colleagues, organize a metabolic health summit that happens pretty much every spring. They bring together phenomenal speakers from all over the country that present data on everything from gut health to mental health. This year's event takes place on May 5th in Santa Barbara, and I'm going to give a keynote lecture at this event. There are also virtual attendance options.

You can learn more about this at metabolic health summit.com. Second, if you have been listening to this podcast for a while, you may already have noticed that this podcast does not have advertisements. That is because this podcast is 100% fan supported by listeners like you. We give our supporters some perks to show our thanks. It's called the Found My Fitness Premium membership. It includes a private podcast called the Alawquot, where we post a short episode usually weekly.

In our most recent episodes, we've discussed dietary and environmental factors that may impact autoimmune diseases and dietary strategies to improve symptoms of autoimmune disorders, such as multiple sclerosis. We've had 55 episodes so far, including a three-part series on the brain and longevity benefits of a ketogenic diet and tips and tricks for experimenting with a ketogenic diet. We also have monthly Q&A episodes that are. posted to the aliquot and involve live participation, which many members really enjoy. Members often post questions related to ketogenic diets.

For example, in Q&A number 27, I gave an update on my personal experience with the ketogenic diet. In Q&A number 19, we covered what I think any possible shortcomings of the ketogenic diet may be. In Q&A episode number 33, we covered whether there are sex differences in response to a ketogenic diet. In Q&A, episode number 29, we covered differences in fat types on a ketogenic diet. learn how to support the podcast, learn answers to questions like that, and get the benefits by going

to foundmyfitness.com forward slash premium. That's P-R-E-M-I-U-M, premium. You can also try out our premium membership trial for one month for free and join our next live Q&A at foundmyfitness.com forward slash trial. That's T-R-I-A-L, trial. And now let's jump deep into ketosis with Dr. Dom Degistino. Hey, everyone. I'm sitting here with Dr. D'Am Degistino, who is an associate professor at the University of South Florida. He's also a research scientist at the Institute for Human and Machine Cognition.

His research lab focuses on metabolic therapies, including ketogenic diets, ketone supplements, among others. I'm super excited to have you back on the podcast, Dom. It's been six and a half years or so. It's been quite some time since we had a conversation. conversation. And since then, keto, as it's called for sure, in the popular world, has really, it's exploded in popularity. And I feel like with that explosion in popularity, it's lost a little bit of, it's become a little bit more of a brand in the popular mind and less

of a distinct metabolic state. And so I'm excited to have you here to talk about, the science, to give us a refresher about the science of ketogenesis, ketosis, ketogenic diets, ketone supplements, and all those things. And as someone that has been researching it over the years, who's been practicing ketogenic diets personally for also many years, maybe we can kind of just start with a refresher, what ketogenesis is? Yeah, I think that gets lost in all the noise. all the noise because it has been commoditized, so to speak, and commercialized in ways that are not always very good.

So a ketogenic diet is unique from a dietary therapy point of view in that it's the only diet that we know of that is defined by an objective biomarker. So that's ketones and you measure that in your blood, in your urine, and also in your breath, right? So there's different ways to do that. If you are not in a state of hyper ketoneemia, elevated ketones, you're technically not on a ketogenic diet. What most people don't really appreciate is that to really get higher levels of ketones that are therapeutically linked to what it's used to treat, which is like neurological

disorders, seizures, and things like that, you really have to increase the fat, drop the carbohydrates especially, but moderate the protein and really consume a really high fat. diet, and that's not always sort of appreciated in the mainstream. And a clinical diet is probably not the best choice for a lot of people, a clinical ketogenic diet. But there are variations of the diet from a 4-1, which is a classical ketogenic diet, which is 90% fat and one part protein and carbohydrates. And then all the way on the other end of the spectrum, there's the modified ketogenic

diet or modified Atkins or low-glycemic index therapy or LGIT. And that's more of a one-to-one ketogenic diet is personally kind of what I follow. And I think you can construct the diet in a way that produces a mild state of ketosis. I think that could be a good lifestyle diet. But it's far different than the classical ketogenic diet, which was used for pediatric epilepsy. But they both have, you know, therapeutic effects that we can delve into. Can you give us an example of that type of diet and also what is defined as being, in either mild ketosis to actually, you know, basically identify you as being in a state

of ketosis from a ketogenic diet or even from other, we can talk about other ways. Obviously, we've had a lot of people in the podcast talking about fasting. Yeah. So a ketogenic diet produces ketosis by suppressing insulin, right? And I think of it as like, almost like insulin suppression therapy. So when you fast, you suppress the hormone insulin, you deplete liver, glycogen, and then that accelerates beta oxidation of fatty acids, and it's the oxidation of fatty acids in the liver or the over-oxidation of fatty acids that accelerates

production of aceto-CoA, and then that condenses to acetoacetate and beta-hydroxybutyrate. So that's accelerated at a maximal state with fasting, and you can mimic that state of fasting with a classical ketogenic diet, which is like 90 to 80 percent fat. with a level of carbohydrate that almost has no effect on insulin, really. So you maintain, so in many ways it mimics fasting in that you have a low insulin, low IGF1, a little bit suppression of mTOR because protein is moderated to. And then that diet is used classically for epilepsy. And then there's, that's the four to one ketogenic diet.

In extreme cases, they use a five to one ketogenic diet. But, and then if you move down the spectrum, it's three to one, two to one, and then modified Atkins, which is like a 1.5 to one ketogenic diet to a low glycemic index diet. So what that would mean as far as, to give an example for me, so yesterday I counted my macros and I had 200 grams of protein, 150 grams of fat, and 50 grams of carbohydrates. So 200 grams of protein compared to a combination of 150 grams of fat and 50 grams, or 150 grams of protein, sorry, and 50 grams of carbohydrates. So that would be a one-to-one. So I have 200 grams of fat, 150 grams of protein, and 50 grams of carbs, right?

So it's 200 grams and 200 grams. So that's how, you know, that's how it's constructed in the world of epilepsy or dietary therapies by grams. not percentages. So that's a one-to-one ketogenic diet, and that sounds extremely high in fat, right? 200 grams of fat and 150 grams of protein. But that's actually the very liberal, more loose version of the ketogenic diet that produces a very mild state of elevated ketones. Whereas a 4-to-1 ketogenic diet would be like 400 grams of fat to like 90 grams of protein and 10 grams of carbohydrates, right? So that would be very high in fat. So they both, interestingly, the research over the years have shown that they both have anti-seizure effects. And we're getting a better appreciation

for a more liberal version of the ketogenic diet that is not so protein restricted and not so extremely carbohydrate restricted, then something like a low glycemic index diet, which can produce little or no ketones, it can still have an anti-seizure effect and still have benefits, even independent of high ketones. So that's kind of interesting to me because it was always thought of that you needed to get really high ketones to achieve a therapeutic effect. But it looks like you could probably get many benefits from low ketones, but you're also suppressing insulin. And and suppressing a lot of other pathways that are, you know, therapeutic in some ways. They're altering, I should say, different pathways.

What? I don't know if I answer your question, but it's, yeah. I'm just trying to, there's variations of the ketogenic diet. And I think that over the last 10 years, I guess it's longer than that. I think in 2008, Dr. Eric Kossoff from Johns Hopkins, he worked with Dr. John Freeman, the late John Freeman, and developed, a modified Atkins diet or modified ketogenic diet for adult epilepsy. And then it was published that the diet can work for adults too back in 2007 or eight. Think around that time. So we have many variations of the ketogenic diet even used clinically. And then when people talk about the

ketogenic diet in the mainstream, that could be anything. I mean, typically it means carbohydrate, you know, restriction and it could be a carnivore diet. It could be, and we can talk, obviously, about that. And there are many different variations, but clinically what you have is a five to one, which is very extreme high fat, four to one, three to one, two to one, and then a modified ketogenic diet or low glycemic index diet. And all of them are therapeutic in one way or another, and they're used for a variety of different neurological disorders, seizure disorders, metabolic disorders. But some are more efficacious for others. It depends on the individual. It depends on compliance, on the family. There's a lot to be considered when it comes to implementing these approaches.

For a person who is, who is not done a ketogenic diet before, what would be a good starting point? Like, you know, would you want to start with something that's one of the more like four or five to one, you know, because from my own personal experience, and I, you know, I'm going to be doing another ketogenic diet very soon. I just haven't gotten my biomarkers measured. But it was very challenging for me, even someone that does a lot of intermittent fasting, to really, to get into ketosis and to really stay in. And also what levels, like if someone's measuring, and we can talk about biomarkers and measuring things, but like, you know, what would be considered a mild state of ketosis if you're wanting to go by ketone levels, for example?

So very good question. It's very good question. It's very context-dependent. So if you are using the ketogenic diet to manage a metabolic- or a metabolically linked disorder or a brain disorder like epilepsy, right? You probably want to start with a clinical ketogenic diet and be under the supervision of a registered dietitian and a neurological team. So this is what they'd use in epilepsy. And there used to be an induction phase where they would fast you, and that actually helps facilitate metabolic switching, which is the transition into ketosis from being primarily a glucose oxidizer to a fat and ketone utilizer. So you can speed that with fasting. But then you have, most people are doing it, you know, for as a lifestyle approach.

So in our clinical trial that we're doing, using in non-diabetic people, they, they, they, We tend to be a little bit on the heavier side, maybe, but they don't have type 2 diabetes. They're using it to optimize their metabolic parameters and glycemic variability. We transition them into a ketogenic diet over four to six weeks. So we titrate the carbohydrates down. And what we have found, or my colleague has found Dr. Allison Hall, who's, we're working, she's at the Florida Medical Clinic and has a wellness program that compliance and adherence to the diet and ultimately the results are better if you take someone who's eating two 300 grams

of carbohydrates a day, that's standard, you know, American diet, and you drop them down to, you know, 100 and then the 75 and then 50 at about the 4 to 6 week point. And you get a very nice improvement in many different subjective and objective, you know, biomarkers. They feel better, signs of mood are increased, anxiety, using the GAD 7 test, the PHQ 9, SSQ, sleep actually improves. If you were to abruptly start the ketogenic diet, you're more likely to get side effects, and you're more likely to get things like sleep disruption, lipid abnormalities, elevated triglycerides. You get a quick spike in LDL. This can occur if you rapidly start the ketogenic diet, especially in the context.

of not calorie-restricting. When you calorie-restricted ketogenic diet, it sort of mitigates some of the, many of the things that are negatively associated with high-fat diets. So the transition is a lot easier if you calorie-restrict with a ketogenic diet. So that needs to be appreciated. But for a lifestyle, I would recommend if you're not used to, if you're not on a carbohydrate-restricted diet, to ease into it and titrate it in over time, if you're not in a rush, right? So for me personally, I follow what would be considered a very modified supplemented ketogenic diet that would be more along the lines of a low glycemic index diet. So I have about, you know, 10 to some days, 20% of my diet is actually carbohydrates, but in the form

of fibrous vegetables, right? So essentially non-glycemic carbohydrates. So a lot of of leafy greens, a lot of the carbohydrates that make up my ketogenic diet are on the, like typically have about one-third to almost half of it is fiber and has very little impact or actually can improve glycemic variability or reduce it in that it moderates the digestion of protein and helps delay gastric absorption so the nutrients and things that I'm eating actually get into circulation in a protracted way. So the fiber helps to slow digestion. And so fat and fiber together are really important for the ketogenic diet.

And that's not something classically that's accepted or considered, but as we learn more about ketogenic diets, we have an appreciation for the types of fats that are in the diet and actually incorporating fiber not only to improve digestion and protein assimilation, to enhance and preserve the gut microbiome, which is to be appreciated. So there was a lack of that understanding 20 or 30 years ago, and it came into the conversation about 10 years ago. And now it's actually become a major focus of a lot of these dietary interventions, low-carb and ketogenic diets.

We need to appreciate fiber as a part of improving the diversity and maintaining the gut microbiome. You've just answered one of the main questions I had about being on a modified ketogenic diet and somehow intelligently designing a diet that include more fiber and, you know, your thoughts on how fiber would be important. And it's really interesting to hear you say that because, you know, the other thing is that, you know, fiber, you are making butyrate in the gut when your, or your bacteria is, you know, making it microbiome inside your gut, and that is fueling the colonocytes, right, giving them energy.

Is it, you know, like for me, I, when I was doing the kidney-jerk diet, I did find that that I ended up just naturally fasting more because it's so difficult, like, things I could eat. It was like, well, I can't eat, I can't, like, you know, I would snack on some macadamias, and after a certain point, it was like, well, this is like too much, the ratios of the protein in the, you know, so I'd have to like not eat. And then, and then I found that I was basically just dietary, doing a lot of dietary restriction alongside the ketogenic diet.

But I also found that when I would add like dark leafy greens, the portions really made a difference for me. Like for example, cooked spinach, like you don't think about it, but like because you're cooking it, it's like a lot more spinach than you would think it is. And so like a little serving of it looks small, but it's actually quite a bit. And so I noticed that cooked, if I had like a portion of cooked spinach, you know, I wouldn't totally take me out of ketosis, but it wasn't getting me into that higher level. So, you know, I would go from like three millimolar down to, you know, one.

So you were cooking your spinach. Yeah. If you take raw leafy greens, so the cell wall's intact. But when you cook vegetables, green vegetables, they heat ruptures the cell wall. So you make the carbohydrates a little more accessible. if it's green, leafy vegetables. So that's going to impact, believe it or not, you know, within the context of a ketogenic diet, it makes a difference. If you have greens that are raw, the glycemic impact is essentially nothing. But if you cook your greens and, you know,

it does make it proportionally much smaller, so you're more likely to eat more, but it also makes the carbohydrates accessible because the heat is rupturing the cell wall. So you, similar to like juicing or a smoothie or something like that, right? So, although with a smoothie, you got the fiber and stuff in with it too. So that's a big consideration that people need to consider. Yeah. So, yeah, but volume. But with a salad, like a salad that would, an example of a salad on a modified ketogenic diet or modified Atkins diet would be, you know, fatty fish like salmon, leafy greens like arugula, maybe some spinach and robes. main lettuce and stuff. And extra virgin olive oil, lots of that. And I tend to mix it with MCT

oil. So a combination of extra virgin MCT, MCT, we can get into that as a ketogenic fat. And some, like, nuts are great, but I don't go too crazy with nuts, but a little bit of walnuts. So you have fatty fish, a little bit of leafy greens, and a very fatty ketogenic dressing. that's made with MCT and olive oil and herbs and things like that would fit in well with a ketogenic diet. So you get monounsaturated fats, right, and you're getting polyunsaturated fats and MCTs, which are saturated, but go to a different, they do not disrupt the gut microbiome in ways that other types of fatty acids do.

And that's the kind of nutrition that would be no effect on a continuous glucose monitor. And it would, so your glycemic response would be like nothing. And your ketones would likely go up because of the macronutrient ratio, but also because of the MCTs that are in it too. So that's a very normal kind of typical diet that I eat. So most of your greens or most of your carbohydrates are eaten raw? If I do, like, we do broccoli a lot and asparagus, so I lightly steam it or cook it.

but I don't make it to the point where it's like mushy. So I lightly steam vegetables like cauliflower, broccoli, asparagus. I always have a salad with my meal. And not with the ketogenic diet, when you wear a continuous glucose monitor, you can observe that the order in which you eat your food will impact the glycemic response. And if you're attenuating the glycemic response by eating food, foods in a certain order or a certain combination that's also reducing the insulin. So you need to continually have a suppression of insulin and insulin signaling to maintain a state of ketosis.

So if you're in a state of fasting ketosis or on a ketogenic diet and you inject a little bit of insulin, you'll see your ketones go down. There'll be a delayed response. That's because that reduction in insulin plays a big role. When you increase insulin, it dramatically, automatically increases glycolysis, you know, translocation of the glut transporters to the membrane and things like that. So you could do that. Exogenous ketones can actually increase insulin if it's too much. And we can talk about the different variations of that and why that could be problematic in some conditions. But, you know, taking a big hit of protein, like drinking way protein will kick you out of ketosis because you're going to get the insulin response from the essential

amino acids and branched amino acids too can increase that. So you could, so it's really important to incorporate fat and fiber with the meal, especially up front. Yeah, to attenuate any kind of insulin response. Right. Yeah. Yeah. And you learn these things as you go. And there's a learning curve to the ketogenic diet. And I found, I went right into the classical ketogenic diet. I bought the book, you know, the ketogenic diet for pediatric epilepsy. And now it's the ketogenic diet. And now it's the ketogenic diet for epilepsy and other neurological disorders, same author. Dr. Eric Kossoff, Dr. McKenzie Cervanka from Johns Hopkins and the team there, and they advocate for a variety of different types of ketogenic diets and then adjusting it to the patient and their circumstances,

too. It's going to be important in the world of epilepsy. So we're talking. So it remains the only widely accepted application of the ketogenic diet at this time is really, epilepsy, and metabolic disorders, like glucose transporter type 1 deficiency syndrome, P.D.H deficiency, and things like that. And interestingly, there are inborn errors of metabolism that are contraindicated with a ketogenic diet, like, you know, carnitine transferase activity, CPT1, you know, whether it be primary or secondary, too. So it could be deadly. A ketogenic diet could potentially kill you if you have carnitine, you know, transferase deficiency. So that's a whole other topic we could. You bring up an interesting point with the

contraindications because I'm interested in a few of those aspects. So for one, perhaps other genetic variants that maybe aren't as rare. So for example, you know, APOE4 allele, which, you know, a quarter of the population has one of those alleles. Like how is it known how people with that polymorphism respond to ketogenic diets? And also, you mentioned, you mentioned, And briefly about people that sort of race into the ketogenic diet without any sort of carbohydrate, slowly carbohydrate restriction and how it can elevate some biomarkers like triglystorides, for example. I'd love to talk about, like, what biomarkers do you think are good to monitor and to

see if someone is favorably or unfavorably responding to a ketogenic diet? And at what point would you, like how many times did you, would you do it before you sort of give up and sort of modify the diet or change that maybe types of fat. You mentioned the types of fat or, you know, things like that. Yeah, I think it's important. A lot of people jump into the ketogenic diet and, you know, just from a standard diet, it's important to test the water. If you're not using it for epilepsy or another disorder, you want to titrate the carbohydrates

down and track and monitor along the way. Maybe do, like, cut your carbs in half or by two-thirds. or whatever, and then at the four or six week mark, get blood work again. And look at your glucose response, check for hypoglycemia, things like that. So APOE4, that's about one quarter of the population. I get this question a lot, and I don't think it's ideal. Even the books on ketogenic diet say that it's an unnatural diet and it's not healthy and it's not sustainable.

So these are from the people who research the ketogenic diet, who published the most on the ketogenic diet, who are in the trenches using this diet as a medical therapy for, like, known conditions that are responsive to the ketogenic diet. So with that said, you know, dietary teams that manage patients for up to 10 years, 20, and even I had some correspondence with a team that are measuring people and cardiovascular parameters. to their heart health for 30 years. So in patients, for example, with inborn errors of metabolism, that need to be on a like a classical type ketogenic diet for like three decades. And they're still doing all their blood work looks great. So I think that's a good example that the diet's not

going to kill you. It would have done that a long time ago in these patients that are on like a four to one or three to one ketogenic diet. But I think it's important to when in the context of APOE4, a high fat, extremely high fat is probably not ideal. And so you want to take probably a more moderate approach and just restrict carbohydrates. I think it's really important to get lots of fiber, lots of phytonutrients. We know the data on fiber is just really, really good. So there's just, there's no arguing, people argue it against fiber,

But I think the data for fiber is really good for, not just for the microbiome, for the phytonutrients, the micronutrients, as you know. There's been a lack of appreciation for micronutrients and ketogenic diets, and that has caused problems like selenium deficiency, which led to cardiomyopathy. And there's case reports where people have literally, I think one or two, where people have literally died from cardiomyopathy because of selenium deficiency. associated with the ketogenic diet. So you want to make sure you supplement appropriately,

but you don't have to supplement if you formulate the ketogenic diet appropriately with the right type of foods. But it's not always possible. But for APOE and getting back to your APOE, so a diet that's moderate in fat, moderate in protein, and I think of carbohydrates is fiber. So plant-based fiber, moderate protein. And then fats, the types of fats are important.

So mono-unsaturated fatty acids as opposed to long-chain, like saturated fats, medium-chain triglycerides are probably helpful. There is a study that was done using a product that is caprylic triglyceride, which is MCT. At the time, it was called AC-122 by XERA. It was a product that was designed for Alzheimer's disease as an alternative energy. substrate that would be given. And the results of the study showed that improvements in mild cognitive impairment were associated with ketones. So there was a correlation with that. But they did not see the correlation in people with APOE4, which is kind of interesting. Although I think a larger study probably would have shown like a difference, but I think the take-home message is that

a diet that's like super restrictive and high in fat is probably not ideal for APOE4. patients and adding ketones in the form of exogenous ketones could probably be ideal. There was a case report on a patient that I am familiar with that I'm familiar with the wife of the patient that had passed away, but he was maintained on a ketogenic diet and then later on ketone esters and exogenous ketones and was, did quite well on this diet for a long time. wasn't a restrictive ketogenic diet, but he did much better with ketone supplementation as it means to improve his cognition and different behavioral parameters too. So I think that would probably be the better way to go.

I'm very cautious and speculating and giving medical device. I'm not a medical doctor. I am a professor and I'm professing that I think that a more moderate-style Mediterranean-like low-carb slash ketogenic diet with supplementation. in the form of things like omega-3 fatty acids, MCT oils. The fatty acids comprising the diet should be more along the lines of monounsaturated fats and not so much heavy saturated fats, which in the context of APOE4 is probably not a good thing to chronically maintain a state of ketosis with super high saturated fat.

Yeah, so maybe more avocados, more of the nuts and olive oil, salmon, which is a good type of polyunsaturide fatty acid. I mean, that's the kind of diet that I was doing and we'll try it again. And we'll talk a little bit more about why I'm so interested in ketogenic diets. I don't have epilepsy and I'm certainly not someone that eats a standard American diet either. But there are so many interesting effects that being in the state of ketosis and having the ketone bodies elevated and that to me are very, very interesting effects.

interesting and, you know, I think possibly beneficial for health span, for cognition. And so, but with the supplemented ketones that you keep mentioning, like with respect to, you know, having a diet you follow, which is more of the low glycemic index one-to-one ratio with supplemented ketones, it's another really big area that's exploded over the year, past few years. And can you talk a little bit about for people that aren't familiar Like, supplemental ketones, there's different types of supplemental ketones. You mentioned ketone esters, salts, and then even MCT, oils or powders. So maybe we can kind of jump into that a little bit.

Yeah, I think the question is, like, why would you even want to short-circuit the state, you know, why would you want to circumvent the dietary intervention that produces ketosis, i.e. the ketogenic diet. But why would you want to circumvent that? I mean, the reasons are kind of obvious and just throw ketones into the mix. Like what's going to happen physiologically? I mean, there are people who are unwilling or unable to do the ketogenic diet. So that was the motivation behind developing and testing and ultimately publishing a number of articles and studies on exogenous ketones.

and there are different formulations and not all types of exogenous ketones or formulations of combinations are applicable to different disorders, right? I think some conditions are more responsive to ketone esters, whereas some are more responsive to ketone salts or formulations of MCT and ketone salts. So when I first got into this research in 2008, eight or nine, I believe, I contacted a number of people who remained to be icons in this field. So Dr. Richard Veach, I like to always acknowledge him as being a pioneer in developing the rationale and developing ketonesters, you know, and the rationale for using them and writing

a number of reviews that actually motivated me to pursue this path. Dr. Henri Bruningerber, George Cahill, Dr. Theodore Van Italy. I mean, they're all sort of friends and collaborators, and they published on this. So I was really focused on the ketogenic diet, but when you're writing a grant, a federal grant, and you're trying to sell this approach as a means to, you know, reduce seizures or enhance warfighter performance, resilience and things like that, the high-fat diet is still looked upon as something that is very negative. So the question was, can you develop a ketogenic diet in a pill? And essentially that was sort of the path we took with ketone esters.

And so the ketogenic diet, it was my understanding that the body at the time, that you need to have adaptations over time that would change your physiology, that would change your brain neuropharmacology, that would then have an anti-seizure effect. And that happens. There are physiological, by changing your system. your system's physiology, you're changing your brain neuropharmacology and your brain metabolism. So your brain is switching from using glucose and pretty much only glucose to using glucose and ketones. It never switches completely off of glucose and ketones. So the homeostatic mechanisms that maintain your blood glucose are very powerful. So your glucose pretty much stays normal, but insulin goes down. So that's a thing that we see. But the ketogenic diet,

The effects of the ketogenic diet are, and sorry it's a long-winded version, but I want to kind of provide a framework. So it was, you know, I was educated on the role of ketones as a metabolite and also later as a signaling molecule as a drug-like mediator of the ketogenic diet. So we produced these endodges metabolites, and they not only serve as alternative energy for the brain and the heart and other tissues, but then they have signaling effects that mediate many of the beneficial effects associated with being in a state of therapeutic ketosis. So that's things like elevating adenisin, activating various ketone receptors, GPR 109A receptor,

for example, anti-inflammatory pathways. I was really interested in the oxidative stress associated with high-pressure oxygen. So we measured like super-o-exemptive. dioxide-anion production using a thidium molecule like the fluorescence and showed that mitochondrial Ross production goes down with beta-hydroxybutyrate and ketone molecules. So there was all these things that were happening as a consequence of the hyper ketoneemia. So undoubtedly, there's things that happen with the ketogenic diet that are therapeutic and very beneficial that don't happen with exogenous ketones, but there's a lot of overlap. And then later, as we developed ketone esters and ketone salts and used MCTs, we saw that if we

administer these things to animals that are not on a ketogenic diet, we saw remarkable anti-seizure effects, anti-cancer effects. We saw changing the brain neuropharmacology, meaning that the GABA-urgic tone went up. So GABA is made from glutamate via an enzyme called glutamic acid decarboxylase. So we have glutamate is the most ubiquitous neurotransmitter in the system in our body. And we make, and that's an excitatory neurotransmitter that activates the AMPA receptors and NMDA receptors. And then glutamate via the conversion to GABA through glutamic acid decarmoxylase is a brain stabilizing calming neurotransmitter. And I've even measured my own neurotransmitters and showed that GABA is like twice as higher.

than what would be expected. My GABA to glutamate ratio, right? In animal models, we see this too. We did an animal model of Angelman syndrome, which is responsive to, we knew from case reports that the seizures could be silence with the ketogenic diet. So we had an animal model of Angelman syndrome, and we administered ketone ester with a standard diet and saw an increase in GAD 65 and 67, and essentially an increase in GABA. And then that resulted in what we saw, saw increase in learning and memory, we saw, you know, anti-anxiety effects, and the increase in GABA-urgic tone likely contributes to the anti-seizure effect of that. And many anti-seizure drugs, like Viagbatron and other drugs, work through GABA. So the ketogenic diet works through

many different mechanisms in synergy, and one of them is GABA. So we're sort of interested in it from that perspective. So you can replicate and mimic many of the effects that I'm interested in from a neurological perspective, neuroprotective, with simply administering exogenous ketones to animals, at least, on a standard diet. So this has actually spawned many, the preclinical animal model data was so compelling that it has inspired, not from our lab, from other investigators, you know, looking at this too, a dozens of clinical trials that are ongoing right now, if you just go to clinical trials.gov and Google and just type in ketone supplement, I think you get like 30 or 40 clinical trials that are looking at ketone supplements.

And just a few years ago, there was none, right? So there's a lot of other people instead of us looking at this idea of, I guess you could call it a ketogenic diet in a drug. But I think of exogenous ketones are calorie-containing molecules that are essentially in some ways found in nature. Some of them are, some of them aren't. But they do elevate a bioidentical ketone bodies in the blood and in tissues. So in many ways, they're not so much like a drug, but they are, it's like creatine monohydrate, right? So you can take, creatin is found in meat and it's found in other things, and we can create, we can take exogenous creatin, and it has

not only an effect on skeletal muscle, but on the brain. And I think we're getting an appreciation for creatine as like a neutropic even. So I think I look at ketones as being kind of the next creatine, but it's going to take a while for the research. I think there's like 700 or more trials or studies on creatin, you know, showing the efficacy and the positive fact, whereas as maybe there's maybe like 50 to 100 with ketones, but it's expanding very rapidly. So it's very nascent literature, but the nascent literature has spawned many other labs, you know, outside of our lab and labs that were doing it well before our lab. But I became so interested in this idea that I just changed my whole research direction

away from drugs to look at diet and supplements. If, I know, sorry that was long-winded. No, it's fantastic, so much information. You mentioned that, you know, in different contexts, these different types of ketone supplements can have, you know, varying effects or be used for different things. If you're just looking at ketone, you know, beta-hydroxybutrate levels as a endpoint, what would be the difference in taking a ketone ester versus a ketone salt? How long would you see an increase in the, you know, beta-hydroxyveterate levels?

Is how transient? Is it side effects-wise, you know, with these different formulations as well? Like, you know, there's all kinds of formulations that you see. Yeah. So you can get an elevation of ketones for one hour or six to eight hours, depending on the formulation. And depending upon if you took the ketone supplement with, on an empty-stitone, you know, or taking it with food, or combined, for example, a ketone ester with a ketone electrolyte salt, right?

If you take ketone salts and you combine it with medium chain triglycerides, the fat delays gastric absorption and pushes the pharmacokinetic curve, if you will, to the right. So you get – and this is important, you get a slower, a little bit slower elevation of blood ketones, And then you have a significant sustainment of hyper ketoneemia over time. And the decrease in the spike, so a very rapid spike in ketones, contributes to a release in insulin. So if you consume a ketone ester at a large dose on an empty stomach, you have a very large increase in beta-hydroxybutyrate and acetoacetate, too,

depending on the formulation. and it's that rate of change, the relative rate of change of metabolite, similar to like, if you have a very rapid, you know, relative spike in leucine, it's going to kick on skeletal muscle protein synthesis. But if it's a gradual spike, maybe it won't kick on the metabolic machinery associated with skeletal muscle protein synthesis. The rapid elevation of ketones can produce a counter-regulatory effect, which is a release and insulin. And then that can shut down your own natural ketone production. So the way to go about

doing it is to formulate something that causes a predictable but gradual rise in ketones and sustains that for a period of time and has a predictable decrease over time. So the way to do that simply is to take the way that I do it on a daily basis is beta-hydroxybutyrate that's bound to electrolytes, sodium, that has sodium, potassium, calcium, calcium, magnesium in that formulation. So balance electrolytes, more or less like the electrolyte supplements that are on the market. So element is one, I think maybe liquid IV or Gatorator, even these things. So the higher sodium, you know, but you want to match it with some potassium, calcium, and then the electrolytes in the themselves will actually delay gastric absorption a little bit.

So salt does that. And if you combine that with MCT, too, that could delay it. But ketone salts, the salts can actually delay gastric absorption, so it's not so much of a rapid rise. If you take a beta-hydroxybutary ester, you have 1-3butyne dial typically is bound to beta-hydroxybutyrate. When you consume that, the beta-hydroxybutary is quickly liberated, so it spikes your glucose, or your ketones up very high, but in regards to glucose, actually, that comes down pretty low. And you had asked me that question, why does glucose drop so down into hypoglycemic ranges with a single large dose, like 30 to 50 milliliters of like a pure ketone ester, something like that, right?

Yeah. So in the beginning, I thought it was insulin, and it is insulin. So the threshold for me, at least, and I measure insulin quite often in response to this. And what I find is that if you take a ketone supplement and it boosts you 1 to 2 millimolar, like a delta, a change, an increase, then the elevation of insulin is almost imperceptible, according to, like the assays that we're using. But if you were to consume a ketone ester and get up into the 3, 4, and 5 range, then that produces an elevation of insulin,

equivalent to eating, you know, drinking like two to four ounces of OJ or like 10 grapes or like a small orange, right? So for me, it goes from like three to six or six or eight or ten, right? Or insulin, my blood insulin levels. And it's equivalent to maybe eating about 30 or 40 grams of protein. So you would get that amount. Whereas if you consume, you know, keto. start or another exogenous ketone supplement and you consume it like 10 grams of BHB, pure BHB. And you get that elevation of about 1.5 millimolar. Is that a full packet of keto start? Keto start's about, it's kind of like double, like almost like double dose in a way. So I usually do half a packet. And then. Which is I'm drinking right now. Yeah. Yep. So consuming a full packet,

typically I get about 1.5 millimolar. So I feel the effect. But, But I've actually consumed two packets and I start to get a bump in insulin, but one packet, you know, and the bump in insulin is relatively small, probably because the mineral load is delaying, you know, the absorption into the system a little bit. So I think that's really important because we know, like, insulin suppression is also important for the anti-seizure effects. So we think that a reduction in glycolysis is therapeutically, part of the scenario of the antiseachia effect of the Qigine diet because 2-deoxy glucose has a pretty

strong anti-seizure effect, and that is being advocated and used clinically in some studies as the ketogenic diet and a drug, so a glycolycolytic inhibitor, two deoxy glucose. So you consume this drug and it's like 25 milligrams per kilogram, and if you go higher than that, then it becomes cardiotoxic. So it's not an ideal approach, but it inhibits. It inhibits, the glycolytic pathway in a way that sort of mimics effects of the ketogenic diet. And so when we increase insulin, insulin stimulates glycolysis. And I think that that could be a negative thing in the context of maybe cancer or seizures or other things that we're interested in therapeutically managing. So I view there's the ketogenic diet and exogenous ketones,

and they're not mutually exclusive, but I actually think they're synergistically when they're you know, when they're combined together. So if you follow a more liberal version of the ketogenic diet, like a modified Atkins diet or modified ketogenic diet or low glycemic index therapy, which is like a one-to-one ketogenic diet and then supplement ketones on top of that, then I think what you have, in my opinion, is an optimized ketogenic diet for a lifestyle, but also, and this needs to be studied and validated in clinical trials, but I think it would also be optimal for epilepsy, for cancer, for managing type 2 diabetes, and also for weight loss.

So the ketones have a satiating effect on the brain. So the ketones are alternative energy substrate, and when your brain is metabolizing ketones and it actually experiences low glucose, it doesn't go into an energetic crisis. So it's not signaling that you need to eat. And I think that's really interesting. There have been cases where you could produce a hypoglycemic shock that would be fatal, otherwise fatal. But if your ketones are elevated, you're asymptomatic for hypoglycemia. So that's a remarkable example of the effects of ketones on preserving, maintaining brain energy metabolism.

And that has real world effects in the context of everyday living. And if you go on a diet, you inadvertently need to. to go into a calorie deficit. So calories do matter, for one thing, and you have to achieve and maintain a protracted calorie deficit to lose weight and to some extent sustain that weight for a period of time. Then you can go back to a more eukolaric keto diet or eukolaric diet. But it will necessitate like low glucose, low insulin, and you're going to get hungry. But if your ketones are elevated, that's where ketones shine. They really show. shine in the context of calorie restriction or an energy deficit because you have a better

fuel flow to the brain in that context, right? So if you're on a low calorie diet that's producing a state of hypoglycemia, but your ketones are not elevated, that's going to be a painful diet to adhere to and sustain. Right. Yeah. What's the... Not fun. No. And it's funny. Like, I'd absolutely... I noticed that when I was doing my Kogenic diet, I was, like I said, I was doing a lot more

intermittent fasting, and it was a lot easier to do. I mean, you do feel satiated. But, and this kind of gets into another topic, and I did want to kind of ask you about the difference between, you mentioned the diester for ketone esters, but there's also monoester, right? Is there a difference in terms of efficacy? If you're just looking, I mean, if you're just kind of wanting to elevate your ketone levels. And again, it seems as though I prefer, like, I've done, I've tried all these different types

of ketone supplements. And I personally am not a huge fan of the really quick spike. And then, like, crack. Like, to me, it's kind of crashing because my glucose levels get so low. Yep. And then when the ketones wear off, it's like, where's my energy? So you have. Yeah, hypoglycemia and hypoketonemia, and you might also be kicking yourself out of ketosis.

So it could be a dose thing. The 1-3-butane dial, beta-hydroxybutyrate monoester that was developed by, in part, by Dr. Richard Veach, and that was one of the first ketonesters that we actually, you know, I became interested in, and it did not have anti-seizure effects. So I kind of, I didn't lose enthusiasm because I knew there was so many other molecules that could be developed. So what we worked on a couple of different molecules and the next one was the diester. Actually, first we had the monoester, 1-3 butane dial acetyate monoester had very strong antiseure effects. And then we could do more of a transesterification reaction is just more or less a stoichiometric reaction where you just add more ketones, in this case acetoacetate, to a 1-3-butan dial. So it's 1-3-butan dial, which gets metabolized in the liver completely pretty much to beta-hydroxybutyate.

That molecule with a reaction we can add to acetylacetate molecules, and both of these things, the mono-esterine diet, they taste nasty. They taste like gas. But they have very distinctly different effects, at least in the context of the antiseachia effects. So when we developed the ketone diester, and we used that in our animal model of tonic chronic seizures, which was in this case high-pressure oxygen, but we then tested it in various other seizure models too. It had a very strong anti-seizure neuroprotective effect.

And then if we use 1-3 butane dial or any other ketone, it didn't really have that profound anti-seizure effect. So, what? Gava? Is there like a difference in the GABA? That's an interesting, you know, theory. But one of the things that kind of stood out was the elevating acetoacetate seemed to be really important.

And some of the animal model work, it was brought to my attention by people who had been studying this for longer than me. One of them was Dr. Jong-Roe. He was looking at beta-hydroxybutyrate and acetoacetate and saying, you know, there's really good literature with acetoacetate and acetone too having an anticeasure effect. So the 1-3-butan dial acetoacetate diester elevates beta-hydroxybutyrate and acetoacetate more or less in a one-to-one ratio. So we did blood work and we, you know, we took, we measured blood and we sent it out

to mass spec. And there's like kind of like a nice, there's a quick spike up in acetoacetate and beta hydroxybutyrate from the 1-3 butane dial. And that happens over hours. And we had a 600% increase in the latency to seizure, which means that animals could go 600% longer. And we published that. And then later, we actually combined the ketone ester with MCT and saw a little bit of a boost. You know, The MCT seemed to further elevate ketones and extend the sustainment of ketosis. So that has been the ester that we've focused mostly in our studies, but at least initially, but then we started tinkering with the ketone salts and putting ketone salts and mixing that with MCT.

So ketones salts alone or mixed with MCT seem to have a lot of favorable effects on glycemic regulation, anti-anxiety effects. You know, they also have an anti-seizure effect, maybe not as strong as the ketone esters, which are just more powerful on a per gram basis. But I personally would not, I have access to these things, and I would not want to, even if ketone esters tasted great, I would not be consuming them day in and day out.

I don't, just for the same reasons, I don't think it's good to spike glucose throughout the day. I don't think it's really favorable, to throw a lot of energy in the system in a way, especially if ketones get high, you do get a metabolic acidosis that you can, we see pH drop in our animals. So we measure like, you know, our pH levels and blood gases and things like that. And we see that the pH level will drop typically when the ketones get above about three millimolar. So that's probably not a good thing. So I'm of the opinion personally and experimentally by, you know, in the idea of keeping

exogenous ketones within like an elevation of one to three millimolar. I think is pretty optimal unless you're managing like a very serious form of epilepsy or you have glucose transporter type 1 deficiency syndrome or some other inborn error metabolism where having higher ketones can be favorable because you have a decrease in other metabolic pathways or transporters like in the case of glucose transporters deficiency. It sounds like though, you know, so for my own personal anecdote, when I was trying the ketone esters, you know, at first it was like, oh, maybe more is better. I want to get, you know, at least above three-millimeter. I was, you know, I got to like 3.5 with consuming about

30 mils of, I believe, the 103 by that. Yeah, mono-ester. Yeah, that formulation. And like I said, you know, 30 mils, that's a lot. So, you know, there's people that might be doing that, like, every couple of hours even. And it sounds like that could potentially be a dangerous thing to do, especially if they're getting in that range where there could be a pH change. And if they're not measuring it, you know, no one's going to know. So it's something... I don't think we'd know. And I think it's like...

If you have like type 2 diabetes, if you have Alzheimer's disease, you have cancer, I think it's better to spread out the dose too. So I think from my perspective, I'd rather take something that's also delivering electrolytes that my body can use and also it tastes good. And the 1-3 butane dial is also a consideration, right? Because the liver has to work harder. So it uses the alcohol, the hydrogenase pathway. And I noticed, you know, playing around with these things over time, just one three butane

dial, which the ketone esters, if I consume that at a certain dose for two weeks and then get blood work, my liver enzymes are elevated. They're still within normal range, but they creep up into that upper range of normal, consuming, for example, like one gram per kilogram per day. But that's the amount that's needed to sustain hyper ketonemia equivalent to a QJank diet. it. You know, so I notice, I feel intuitively that it's probably better to take a more natural form of ketones where it's just ionically bound to a monovalent or divvalent cation, like electrolytes, which our body tend to deplete anyway when you're on a state of ketosis. So

I use the product element, LMNT, but once we got the ketone formulation kind of figured out, you can deliver the same electrolytes that are bound to ketones. So I think it's a good adjuvant or a good supplement to add to a low-carb diet to Qigna. How often do you, is this a daily electrolyte's sort of supplemental thing that's? Yeah. And I just use maybe like a small dose in the morning and I combine it with like creatine, acetyl-carotene and a couple other like Torin. There's some supplements that I think are really beneficial with the ketogenic diet.

they can help boost ketosis. And then when you're on a ketogenic diet, you're oxidizing so much fat, you tend to be deficient in carnitine. And we see this like in kids that are on. So I think carnitine is like really important. The selenium, some studies may show up that that's really important. But I think that's more of the type of foods that you're consuming. I mean, a standard multivitamin too also would be.

Yeah, multivitamin. But I think you can get a lot of nutrition from, you know, a lot of eggs and sardines and fish and oysters and things like that that are very rich in some things that may be depleted in other people, at least clinically. So I take a little bit of ketone salts in the morning and then later in the day, like midday, as it pick me up, like I'll do the other two-thirds of a packet, you know, and I feel it. Any other supplements that you take or that, you know, think, or... Yeah, well, I take, you know, from listening to you a lot, the omega-3s to DHA, EPA, carnitine because that's really important kind of aspect. If I wasn't taking ketone salts, I would

be taking more electrolytes, but I take magnesium. Magnesium 3 and 8 and also bio-optimizers make some magnesium breakthrough product, which is magnesium in like five different forms or six different forms. So I've measured my blood levels of magnesium and it goes up pretty high. with that, and I take vitamin D, which was actually low, even though I get tons of sun and I was supplementing four to eight thousand IUs a day, and I got a blood test done, and I was on the lower end of normal, which was really confusing. So I got another blood test that confirmed the other blood test that I was on the low end of normal. So I got prescription vitamin D, which is vitamin D2. And, but then I ran out of that and I was using another vitamin D supplement from another maker.

I think it was mind-body green. I was supplementing with that and then got another vitamin D test after, and I stayed elevated in the upper range of normal. So maybe I was using a well-known vitamin D formulation, but it was like from Walgreens or CVS. And I was taking 8,000 I use a day and I was still on the low end of normal, even though I'm getting a lot of sun exposure. So this was really probably one of the most weirdest things. Could have been a polymorphism or, you know, because there are polymorphisms that some people require, you know, in some cases two to three times the normal dose to actually just bring you up to like a normal level, like 30 to 40 nanograms per mill.

But the other would be that there's been a variety of studies now over the year showing if you take, if you just randomly take different vitamin D supplements off the shelves like Walgreens, you know, grocery stores, that the actual concentration of vitamin D3 in each supplement varies so widely that you'll often get a supplement that says it's, you know, 4,000 IU, but it's more like 400. And it's really a big problem, honestly. So it is good to like kind of find some go-to-reliable brands. Maybe third-party sites have tested the concentration of the vitamin D3.

I know Labdor does one and then Consumer Lab, they actually go around and test the actual concentration of whatever active ingredient, in this case, vitamin D3 in a variety of pretty readily available supplements. So that could be, that could have been in as well, right? It really shocked me because, I mean, I'm out, we're in Florida. I'm outside, you know, working on the farm, short off a lot. And I double dose on, I'm pushing like the upper limit, I thought, of vitamin D supplement. And you're getting, you have enough magnesium, obviously, because magnesium's important. Yeah, get a ton.

Yeah. Have you done a genetic test? Yeah, I did 23 and me, like back in 2010. So I have all the raw data. And I haven't put it into, for me. Because we do a lot of the vitamin D3 snips. There's quite a few. And, you know, there's several that affect your ability to convert.

So there's several steps in vitamin D3 metabolism. But to convert vitamin D3... I've just become fascinated with vitamin D3. Yeah, vitamin D3 converting it into 25 hydroxy vitamin D, which is what is the major circulating form, which is what you're getting measured, when you're getting your blood test. There's snips that affect that. So, and I've had several friends, and I've seen, you know, looked at the data, but I've

had several friends that have had to take, like, up to 30,000 a day because they have the snip. And... Well, D2. And explain to me why prescription is D2? I don't know why it is. And to be honest, I ask my daughter. I'm not terribly thrilled.

Maybe it's a cost thing because they're getting it from like plant, like mushrooms or something. But I know there's been a couple of studies over the years. I don't quite understand like the mechanism and I don't know if it's known or how much has been studied. But there was some preliminary data and I haven't checked back. I don't know how much of this has been confirmed. But vitamin D2, supplementation with vitamin D2, supplementation with vitamin D2, seem to like inhibit some of the effects of vitamin D in muscle. You know, so I was kind of like, ooh, that's kind of concerning.

And I know a lot of vegetarians like to take vitamin D2 because, you know, they want something that's plant-based, but you can actually get vitamin D3 from lichen. Oh, really? Yeah, they produce vitamin D3. Yeah, like the stuff that grows on rocks and trees. Yeah. You can eat it. You can boil it.

Yeah. So there are companies that like, I know Thorne makes one a vitamin D3. for vegetarians and stuff from lichen. In skin-wise, if you have more olive skin or, so I formed chiloids, like this was a big, if I get a cut, I form chiloids like African-Americans do with dark skin. So I was thinking that there's something, you know, biochemically in my skin, although I don't have like an overproduction of melanin, but I have aspects of that, of having darker skin, especially like informing chiloids.

So I'm thinking there's something in my skin and I'm not synthesizing it. That's interesting. I mean, I tan if I'm outside. I mean it's winter now, but usually, yeah, I'm usually pretty dark. Yeah. But yeah, to have like to supplement and double the amount of dose that's recommended and to be outside all the time and to have low levels. Like I got the call and said, yeah, we need to get you on a vitamin D cell.

I was like, no, that's not right, order another. And I got it and it was like low, like super, like right at the cutoff. But I did take 50,000 I use of vitamin D2 as a prescription. And three or four weeks of that, you just take one per week. I was on the upper range of normal slightly above. Then I stopped and it went back down the normal, but I was supplementing. I changed to a different brand. And you've been able to maintain levels?

Yeah. Yeah. What does you take? I think it's like back to 5,000. Yeah, 5,000 I use. Maybe it was. Maybe it was the, yeah. Yeah, look at your snips. That would be like my first snip. But then I absolutely could be the

actual supplement brand. And is there anything acutely or chronically that you could have that would use, would deplete vitamin D? So that was another thing. I researched it, but really couldn't find too much. I figure you would know this. I mean, there's, there's some evidence that like, you know, being in a state of like inflammation and, you know, like illness, like which you're not. My HSCRP is like usually non-detectable or 0.1 and everything else, you know, micro-nutrient status is really good. Yeah, it's, it's, it's, it's, it's mostly comes down to the metabolism of it, like forming vitamin, the 25 hydroxybuty vitamin D3, and then also the brand of supplement.

And then there's another thing about doing like a weekly dose versus daily. Again, if you are getting, if you're doing a weekly dose, that's really, really high. So if you're doing like 20,000, 50,000 IU a week, you're much less likely to have that huge variation in the concentration of the vitamin D supplement, like for some reason. And it seems to be absorbed a little bit better too. So, but I don't know how much, you know, how negligible that is in terms of what you're experiencing. I would say the SNPs is probably the big elephant in the room.

So super interesting. But I'm going to get back to. So we're talking about acetoacetate and beta-hydroxybutyrate. I was interested in you kind of already sort of answered some of that question. If there's varying effects of these two, I'm calling them ketones, I think, acetoacetate is a ketone technically. Beta-hydroxiburates, ketone body, you don't really hear that as much. But antiseure, so that's one.

Acetoacetate seems to really be important for that. Are there any other known difference? Distinct effects. Yeah. Yeah. There are, yeah. Well, we know, like, beta-hydroxybutyrate has epigenetic effects as far as activating, you know, histone diacetylase inhibition. And also there's something called beta-hydroxybutylation, similar to lack. So beta-hydroxybutyrate can directly interact with the histone to cause epigenetic modifications. And it has become the theme of my PhD student's dissertation to look at Kabuki syndrome, which is a rare genetic disease where, the ketogenic diet in the lab of Hans Bejornson at Johns Hopkins demonstrated that the ketogenic diet silenced these neurological abnormalities associated with this Kabuki syndrome, which is a rare genetic disorder and cause seizures too.

So we want to see if we can recapitulate this with ketone therapy using ketones as metabolite to alter epigenetic effects. And so we have those studies going on right now. So there's ketone-induced epigenetic effects specific to beta-hydroxybutyrate, maybe acetylacetate, but we don't know. Acetoacetate, on the other hand, has effects, at least in muscular dystrophy, in regards to increasing skeletal muscle regeneration. And it does it through an ERC-MEC-Cyclin-D, I think, mechanism.

So it's a very unique mechanism that was kind of new to me. But a pretty good publication came out using, showing that acetoacetate stimulates. So beta-hydroxybutary, I was going to go down the path. And acetoacetate, too, maybe have anti-cadabolic effects. Let's talk about that. Yeah. So the research that we've done uses an ester. that elevates both of them and shown that it works in a model of cakexia.

And we know that acetoacetate has an enhancement, as I said, proliferation or muscle regeneration and beta-hydroxybutyrate as a fuel undoubtedly has antichatabolic effects. And we know that when we administer, even in human studies, if we IV administer beta-hydroxiboutrate, there's a decrease, a sharp decrease in alineine and also a preservation of branched-chain amino acids like lucine is elevated and it prevents a drop. So alanine is like your main gluconeogenic amino acid that is liberated under conditions of stress, high cortisol, high gluconeogenesis, glucagon, things like that. We are going to liberate alenine as a

gluconeogenic amino acid. It goes to the liver. We make glucose. And elevating ketones seems to reduce that. And that could be, that could play into the anti-cadabolic effects. What are your thoughts on, I'm interested in your thoughts on the anti-cadabolic effects of ketones in a various context of, I mean, I guess in human development or even, you know, with respect to humans that have different lifestyles. So, for example, people that are physically active, more young, athletic, versus people that are older and are battling sarcopenia, you know, versus people that are just sedentary. I mean, everyone has, they have different protein requirements, you know, between these groups. But, you know, how can ketogenic diets or perhaps supplementing with ketone supplements, sort of can they have an effect on muscle mass in some way? I think so. And I think skeletal muscle, and maybe I'm a little bit biased because I've always been

super interested in strength training and weight lifting and things like that. But muscle mass is probably the most important factor for healthy aging and focusing on building as much muscle as possible, I think is super important and preserving that muscle with time. So ketogenic diets are probably not optimal for adding as much size and strength as possible, right? But I do think they are important for preserving muscle while improving metabolic parameters like glycemia, hyperinsulinia, things like that. So I do think they're the ideal strategy in the context of a calorie deficit to preserve muscle

under that sort of condition. And it does it by a number of different pathways. So I think the elevation of ketones, one of the functions, to prevent muscle loss. during periods of fasting. So with limited glucose availability or limited food availability, we start liberating fatty acids for fuel and then the body makes ketones and then the ketones provide energy flow to the brain which has very high demands for glucose. So if we didn't produce ketones we would liberate a lot of alanine and other gluconeogenic amino acids from skeletal muscle and we would

quickly waste away and die. The fact that we're able to make ketones from fatty acids as a water-soluble fat molecule that could cross the blood- brain barrier, that actually becomes our safeguard to catabolic processes that would allow us, cause us to waste away, right? So in the context of, and we are sort of wasting away in the context of a weight loss diet or in the context of intermittent fasting. So then the ketones come into play when we're in a calorie deficit, like I said, but also when we're doing time-restricted feeding, I think the ketones provide an anti-cadabolic effect.

But from our perspective, we're super interested in ketones preventing age-related sarcopenia, skeletal muscle wasting associated with cancer catexia. I think that's important. And they're doing it, I think, not only providing, in the context of a disease phenotype or a chronic aging phenotype, the alternative energy. function is there, but the anti-inflammatory effects, I think. So with kakexia, for example, you have high elevation of I-L-1 beta, TNF alpha, which used to be called kiketsin, I think, as inflammatory media. So the ketones then work

through anti-inflammatory pathways that can mitigate the inflammation-induced muscle wasting. So we did study with lipopolysaccharide. LPS. So LPS causes massive muscle wasting and sarcoquemia with time. And in that model, too, the ketones are protective in some ways by inhibiting some of the anti-inflammatory, inhibiting the inflammatory effects of LPS. Do you think that people that aren't, for example, in a constant state of ketosis because they're on a ketogenic diet, but perhaps they would like to take, you know, a supplement, ketone salt. You think that's something that, like, is it like the chronic elevation or the constant constituent

elevation of these ketones that's important or, you know, are little bumps throughout the day? Yeah, it's a good question. So I get that a lot. And I think chronic ketosis is probably not natural or not ideal for most people, unless you're managing a chronic disorder that's responsive to chronic ketosis, like epilepsy and other metabolic disorders. But I'm a big believer in relative changes. So even with intermittent fasting, like, I think I'm fasting today. Maybe I just had some ketone supplements, but like yesterday I did. So I only do intermittent fasting probably two, maybe three times a week at the most because if I did it every

day, I feel that I lose some of the benefits of it. Also lose too much weight. Like I can't get enough calories. I end up eating too many calories at the end of the day. So the body works good, you know, Relative changes are really good to the body. So you get a lot more benefit. I personally get a lot more benefits doing intermittent fasting if I use it more intermittently. You know, right? I feel the benefits a little bit more. So I think the same is true with ketosis.

And I think Dr. Volta Longo has a great idea, this idea that I actually gave it a lot of thought. So it was good to see that he came out, you know, with this idea of the fasting-mimicking diet being implemented for just a one week or five-day period, right, per month. And that can have long-lasting metabolic benefits even throughout, you know, weeks, even a month or more after you do that as far as resetting insulin sensitivity and improving different metabolic biomarkers. So I think chronic ketosis is probably not ideal for most situations unless you're doing, you're trying to get your insulin managed, trying to lose weight and maintain that weight loss

over time, and you've had difficulty doing it with other types of diets. But I think there's so many different factors that need to come into play when you're choosing to do a ketogenic diet, including monitoring. People really need to track nutrients, track calories. Some people put, you know, they eat a ketogenic diet, but they put the same amount of food on the plate, and the caloric density of the ketogenic diet is like 50% higher. So you can't eat. So typically, you know, we have auto-feedback mechanisms that will tell us when we're

stationed in full, but for some people, they don't work well. So they do need to count calories and macronutrients and track, at least initially, so they have some idea of how many calories we're eating. I know until I started tracking calories, I had no idea how many calories I was eating. So I thought I was eating more like 3,000, but it was more like 4,000, 4,200, pretty much every day. I want to talk about these cyclical kineogenic diets, but before we go, there, since we're talking about muscle and the anti-catabolic effects of ketones on muscle, I'm also sort of interested in exercise performance

as well, like anaerobic exercise versus aerobic exercise. If you are either on a ketogenic diet or doing some sort of modified or cyclical form of it, whatever it is, versus supplementation as well, you know, like how being in ketosis affects, you know, some aerobic versus an end. anaerobic exercise? I get asked that question more than any other question, I think. So in animal models, when you put them on a ketogenic diet, I think one of the first studies we did published at the Alzheimer's Institute at USF, the bird Alzheimer's.

We didn't see a big, robust effect on amyloid beta in tau, but we started the intervention after the pathology kicks in in these mouse models, double and triple knockouts. So, although I think Dr. Veach and Dr. Mattson, Mark Mattson, maybe they did ketone ester or started earlier in the ketogenic intervention. So, but in our study, we didn't see any, like, major changes in tau or amyloid, but the mice, like, ran faster. They ran, like, 30% longer and faster on the treadmill, and it was, like, remarkable. And I remember one of the PIs on the project, a very experienced Alzheimer's researcher was

like, yeah, we've never seen anything. like this. So that was an MCT supplemented ketogenic diet, but we also we've done some research with ketone esters too. So performance, you know, in animal models, we see it. In humans, the data is messy and it's hard to make sense of it. So my general opinion, my speculation is that ketones probably have a small effect on exercise performance in the context of aerobic performance. and in regards to strength performance, my ideas about that have been changing over the last couple of weeks because we're giving ketone supplements to some CrossFit athletes and they're breaking PRs.

But I think it could be potentially a placebo effect. But since everyone excluding one person out of dozens of people, I think there's maybe something more. But I think ketones with caffeine, especially ketones salts with caffeine. caffeine are a pretty powerful ergodgenic aid. So I would loosely say that that's probably a performance-enhancing supplement, the combination of ketones, caffeine, and electrolytes. But I think where ketones shine is using exogenous ketones as a means to preserve performance, resilience in extreme environments. So that's in the context of hyperoxia.

So that's what I study. So, of course, when you're not having a seizure and your neurological function is maintained and preserved in the context of extreme hyperoxia, like three or four or five atmospheres of oxygen, high pressure oxygen, that's going to be advantageous. But on the other end of the spectrum is hypoxia, right? So a lot of people who are mountain climbing, running, cycling at hypoxia, we know if we put athletes on a treadmill or bike in a hypoxic environment and give them glucose, that the performance-enhancing effects of glucose are not observed in hypoxia, which is kind of, you know, interesting. Whereas it's also shown that there may be an inhibition under hypoxic environments of pyruvate dehydrogenase. there might be some PDH deficiency or some snag or bottleneck in the metabolic pathway associated with glycolytic energy production under hypoxia. And you would think that hypoxia, you know, chronically it activates like HIF 1 alpha

and you have increasing glycolysis and transporters and things like that. But in the context of, you know, exercise performance under hypoxia, carbohydrate supplements don't seem to help. Whereas there seems to be, and it was brought to my attention in a couple of reviews and also serving on grant committees and stuff like that, there seems to be a good rationale for the use of ketones for fueling performance in a hypoxic environment. And that could be very strategic and beneficial in like a military setting or like a space, you know, setting or altitude, you know, setting. So my general feeling is that ketones have a small effect at increasing athletic performance.

And so there's only a few things that actually are powerful ergogenic aids. So we have caffeine. We have creatine, monohydrate, typically. There's other forms of creatine because, you know, beta alanine kind of works pretty good. And a few other odds and ends, but, you know, there's just a pretty short list of ergodetic, you know, supplements out there. I do think that with time, as we understand dosing and the application of specific types of, types of ketones in certain settings, that ketones will be added to that list. But I'm not sure it'll be in the top tier list. But I do think it would be in the top tier list under

extreme environments. What about swimmers or surfers? Yeah, I think being anesthetic ketosis could be beneficial from the context of like brain injury, inflammation, and maybe just, you know, the stress of being out, you know, in certain extreme environments or when we're at, you know, exercising, too, we're overproducing oxygen-free radicals, and these, in part, an adaptive response to the muscle, too, so there could be a benefit to increase oxidative stress. But I think the ketones, I think the real benefit of ketones are not, I'm talking about this in their response, and I think your question is in the response to an acute setting. Like, consume ketones, go exercise to what happens, right?

Or be on an acute diet, yeah. Yeah. Yeah. So where I think exogenous ketones help, will help and when I was talking that they would be added to the short list of ergodogenic AIDS is used chronically in as an adaptive response. So when we exercise, a lot of bad things happen. If we pull blood, you know, there's inflammation or active oxygen speech, things like that. If we use exogenous ketones chronically over time, I think it will help to facilitate the adaptive response to exercise over time. So suppressing inflammation or chronic inflammation, which would sort of enhance the

enhance or augment adaptive responses to exercise over time, I think there's a good rationale for that, but the science is not there yet. But the science is being done now. So, like, rodent studies are being done. I'm aware of a couple human clinical trials that are studying this. And what about, like, maximum, like, doing a maximum effort, like, you're doing some kind of sprint, you know, because you do need, if you're going into a state where your mitochondria can't work hard enough to produce energy, you need glucose, right? And if you're doing, taking, if you take one of those big boluses of ketone ester, drop your glucose, what's that going to do for your, for your sprinting?

That's, that's a good point. So one of the criticisms of the Keogynic diet was that it inhibits the pyrupe dehydrogenase complex. So whenever we're doing carbohydrate restriction, we're limiting glucose availability, but also lowering insulin. And by lowering insulin, especially, that inhibits glycolytic enzymes like hexachines. It also, like the glucose, the transporter for glucose gets internalized into the cell if glycolate, so you don't, you know, the glycolytic flux is essentially decreased. But I think if you follow a ketogenic diet where you intermittently add small amounts of carbohydrates in, you can keep that PDH from being reduced.

So there's, you know, I think I've seen data to indicate that severe carbohydrate restriction could decrease the production and the activity of PDH. This is actually what happens with Alzheimer's disease too. So with Alzheimer's disease, it's pathophysiologically linked to impaired glucose metabolism. So if you do an FDG PET scan, the PET scan shows glucose hypometabolism in the brain scan. So alternative ketones as an alternative energy substrate makes sense. And in the context of, you know, athletes, you're kind of doing that with chronic ketosis. It decreases the glycolytic pathway, but your muscles and your heart and other tissues actually use fatty acids for a source of energy.

The brain, not so much, right? So, and also when you're on a ketogenic diet, then you're feeding ketones to the brain. So the brain's kind of like a different story. But I do think that it gets overblown. I think, you know, very severe carbohydrate restriction will decrease PDH and then that will impair exercise performance with maximum exertion and aerobic. But I think that it's really important that if you do a low carbohydrate, that you have to train under those conditions.

You know what I mean? So you have to, you can't implement a ketogenic diet or low carb and then train and expect to maintain the same performance. You have to put your body into. that state of ketosis and then train very hard to induce those adaptations to make it possible for your body to perform and maintain your performance in the context of insulin suppression and low glucose availability. So those adaptive processes will then come to benefit you come game time or performance time where you can then titrate the carbohydrates back in

in small amounts. So this is just called metabolic flexibility, right? So train low when your glucose is low and your insulin's low in a semi-facid state. And that will induce metabolic adaptations, i.e. metabolic flexibility that will then benefit you in the context of the actual event where you can add in titrate carbohydrates back in or mixed fuels. Really, you want to be able to optimally use glucose, fatty acids, beta hydroxybutyrate, ketone bodies, lactate too, which is an important to fuel. One of the things that I used to take when I was mountain biking was cytamax, which is alpha-l polylactate, which is like lactate as an energy zone. And my original interest in academia as a post-doctoral fellow was actually using lactate

for brain injury, like stroke and hypoxia. And I was tinkering around with that in a hippocampal brain slice preparation doing different measurements on that. And somehow I just got steered towards ketones, but I always wanted to revisit the lactate thing because, yeah, I think there's a lot that can be done in formulating more of a comprehensive, multi-fuel delivery system for the brain. And lactate's been a bit underappreciated and kind of stigmatized and criticized, but I think it's got a lot of potential.

Yeah. Really good info, Dom. I've been reading some meta-analyses over the years about training in a fasted state versus fed state and how, you know, if you eat before, you know, you go for a run or something that, you know, a lot of the mitochondrial adaptations can be blunted somewhat. And of course, a lot of those studies are using high refined carbohydrate, like some toast with jam, you know, where, and I've always wondered, like, you know, what, and there is like sort of a cutoff where if you're training in a fasted state for longer than an hour, you're going to have performance drop off, right? But I've often wondered, like, if these studies were done using a more modified Atkins diet or some form of a ketogenic diet, those adaptation, mitochondrial adaptations

that are being blunted somewhat with a high refined carbohydrate fuel intake prior to exercise. I'd wonder maybe that wouldn't happen. Yeah, I think it comes down to like nutrient sensing, right? I mean, it's the whole thing going back to autophagy and like, you know, and just entering a state of ketosis, that if we're in a state where like amp kinase is high, like mTOR is low, you know, insulin is low. That whole pathway is low. When you exercise in that state, it may not optimize performance, but it will optimize the

adaptations that could serve you later on for performance. And then when it comes time to, you might want to train sort of in a fasted state to induce adaptations and then tinker around with different fuel sources periodically to see if you could further augment your performance. But I think we need to, that's why we need to. really periodize our training under certain content. There's, you know, training to force adaptations, and then there's sort of game day nutrition, which is going to be a little bit different than training nutrition if we want to force adaptate, you know, if we want to maximize our performance.

So, but one thing you don't want to do is actually radically switch your dietary approach or supplement approach just prior to, you know, you don't want to train for an event and be like, oh, I want to start slamming, you know, MCTs and ketone esters and stuff on game day. No, you want to experiment with it very methodically, you know, before you do that. But I do believe that the health benefits are really important when it comes to exercise, you know, and then not only the health benefits, but I think you're going to get more adaptation in regard to maybe not so much for powerlifting and strength training and things like that. But I think for aerobic performance and just cardiovascular benefits and just actually benefiting at the level of the skeletal muscle and the nervous system,

too, benefits. So speaking of the nervous system, this is one area where, in my opinion, ketogenic ketosis, ketogenic diets really shine. And I'm really, what has thoroughly convinced me is, you know, just the overwhelming evidence that you've talked about with. the effects on the brain and epilepsy and other types of brain disorders, but also some of the preclinical studies that have come out of our mutual friend, Dr. Eric Verdon, and I know John Ramsey also did some publications where they fed mice. In the case of Dr. Verden's study mid-life, they started them on a cyclical ketogenic diet. And I'd love to get your idea, thoughts on why he said the reason they did it was because the mice.

were overeating, which I found to be interesting because I've always been satiated on a keyogenic diet. But anyways. A lot of nuance here I can discuss. Yeah, yeah. Let's get into that. But also, the thing that was so striking, and you know much more about the details of these studies than I do, but the effects, I mean, their health span was improved. Their median, so their median lifespan was improved.

So they were dying less earlier, but maximum lifespan, I guess, wasn't affected. But the effects on the brain and cognition, like he said, you know, that these, the older mice had better cognition than younger mice. And when he said that, I mean, I was like, you know, like, that's really. So things are magnified in rodents. So I'll say that as far. Yes. So my question is, do you think this is going to translate to humans? Rodent model studies are in very, very informative, especially mechanistically, not always predictive. There are some of the nuances is that there's different strains of rodents that will overeat ketogenic diets.

In some, like early studies before some colleagues were feeding it and said, this is not going to work. They're hoarding the food. They're eating. They're getting blown up. There's like, this is obisogenic. You know, so the high fat, you know, there's a question, there's a lot of high fat diet research that detractors of ketogenic diet will point to and say this diet is. you know, cause all these bad things. But that's a westernized, obesogenic high fat diet. So what Dr. Verdon used in Ramsey, Dr. So they did actually the study that I really wanted to do, and they

probably did it better than I could ever do. They have really great molecular tools and everything, and they did it in a very clever way. And I kind of, from my understanding, they did, and the results were to be expected. You know, I think the results are what I would expect. So my understanding, understanding is that they did the cyclic ketogenic diet because, yeah, they didn't want them to gain weight, which could negate. So I have to look to see what animal model they use, but the C-57 black six mice will eat a ton of the ketogenic diet food and they don't gain weight. Whereas other, depending upon the strain, and then we have the VMDK mice that we use for our cancer research. And they tend to, it corrects their eating behavior, meaning that if you

give them the standard diet, ad libidum, they just gain weight like a couch potato, but a ketogenic diet, they will lose weight and everything improves. So they're like the other end. The C.5s7 and Black Six are kind of like athlete mice, I think, where the other models are more like sedentary mice. They're not as active. But what we found, I have to look exactly at the feeding protocol, but when we did a little bit of calorie restriction, our calorie restriction is just putting you know, five or six grams of food into it every day, and then they eat it within an hour, and then they essentially fast for 23 hours, and then eat it again. So it's kind of more like, but you have to individually house the animals, and then, you know, sometimes if you house

them together, they get, they'll start, like, fighting and eating each other because they're kind of hungry. But one thing that we saw very consistently early on is that a mild amount of calorie restriction makes these mice like super mice. Like they become, you know, they're thinking faster. They are really thriving in the context of a calorie deficit. And I think that goes back to human evolution too. So we survive today because we undoubtedly experience food scarcity and limited food availability and in the context of being hungry that enhanced our cognition,

even exercise performance to be able to acquire resources, right? So the same thing I think is happening in their mice, and it could be, I have to look at the weights of the mice, but a lot of it's kind of like weight dependent and producing that energy deficit. But you just get a whole plethora of things happen in regards to suppressing age-related chronic diseases with just a little bit of dietary restriction. Seems to unmask this. Probably because with a standard rodent chow fed ad libidum, they, they're a little bit of, they

they overeat and it just basically fuels metabolic derangement that contributes to early onset age-related chronic diseases and also the formation of spontaneous tumors. And I think in their studies, maybe with both, or at least one, maybe both studies showed a suppression of spontaneous tumors too. So this has major implications, I think. We're very interested in actually taking animal models that have inducible tumors. For example, various genes that will kick on at 200 days and then form spontaneous tumors or a melanoma model where you're subject to UV radiation.

And if they're fed a ketogenic diet, can you suppress that? People don't do these studies because the NIH doesn't really fund like cancer prevention research, but I feel like these are the most important studies that need to be done. You put a wide, you put a variety of different rodent strains under different conditions. that are known to, like, induce tumors and you feed them, you know, a low-carb diet or ketogenic diet that you could actually feasibly maintain and do. And you see if you could suppress these spontaneous tumors. But that's what they did in this experiment. And they showed, like you said, enhancement of cognitive and learning ability, relative the older mice

learned better than the younger mice. Yeah. I know in John Ramsey's publication, Dr. Verdin mentioned also in the podcast when we had them on a few years ago that they had a time-restricted feeding aspect to it because they were feeding the animals proportions, so very specific proportions. And they were only, you know, they were only given their food when the people, the scientists were going there into the house and giving the food. So they had this sort of dietary restriction component to it. Whereas Virden's, they were ad libidim, but they were going to be.

on, they were cyclic, they were going on this cyclic ketogenic diet. And Ramsey's data was more pronounced, like you mentioned, the combination of the dietary restriction plus ketogenic diet seems to be like secret sauce in a way. But, you know, to me it was, and again, like you said, it's, you know, the animal, rodent research isn't necessarily predictive of what's going to be, you know, occurring in humans. But it certainly is promising, in my opinion. And it's, It got me very interested in it. And, you know, I've got neurodegener of diseases on both sides of my family, Parkinson's, and Alzheimer's. So I'm very interested in, you know, any types of lifestyle.

And I also have genetic factors there at play as well. So I'm certainly very interested in any sort of lifestyle factors that can mitigate that genetic risk, which, as we know, there are many things that you can do in a life cell that can help. But doing some sort of modified ketogenic diet, cyclical maybe, you know, because it is for me hard to sustainably do it all the time, you know. That's where intermittent fasting kind of comes in too because people don't have to tinker around with their... I mean, the foods that we eat are super important, just like eliminating processed sugar, carbs, things like that.

That's going to move the needle, like quite a bit. But there are some people that I know, like family members and things. there are just some people who are not going to count carbs even to do that. You know, there's just not going to happen. But so, but eating within a predetermined time window is pretty easy for, that's like a good introduction. And I think if, once you start doing that, then you start realizing how good you feel in this mild state of ketosis. And then you start maybe that becomes the entry point to where you start manipulating your food and your macros and things like that. So happen with me. Totally. Yeah. Yeah. In that very

order. I mean, I practiced a lot of time restricted eating and started to notice in the mornings and stuff. It was like, I'm just so much sharper and my anxiety was a little bit lower, you know, believe it or not, while I was not eating. And so I decided to experiment with ketogenic diet. And while I did do it, as you mentioned earlier in this podcast, one of the most pronounced thing I noticed, and this is totally subjective, was my anxiety level was so much lower. And, I mean, very noticeably, I'm somewhat of an, I mean, I've got some anxiety, you know, that can kind of kick in. And high performers are like that, though. So that's like pretty much a staple personality. Yeah, sure. And then you leverage that into productivity. Yeah. Yeah. But I did,

I felt like it was, it was very noticeable for me. And with the anxiety, and then, you know, it's like that feeds into if it's affecting anxiety, what else in the brain is it a affecting, you know, cognition-wise, you know, if you're anxious, it does sort of limit cognition in a way. It can kind of, like, you know, distract you. And you did this back, like, in grad school, you started doing this? I started doing it, like, before big talks, I would chew on a propranolol and hold it under me to get, like, a beta blocker. I, like, needed this when I was, like, in grad school, I think in my early, and then I realized as I think I got into my postdoc, and I started tinkering with intermittent fasting at first and just carb. I was like, wow, this is how

I feel, you know, especially when I kind of dieted and brought my weight down a little bit. It's like, wow, I just feel like super calm. It's like I can't even get anxious under certain conditions, you know. So, well, I didn't do a ketogenic diet. Like a metropic almost too. Yeah. Well, I didn't do the ketogenic diet until I was recent. Like this was like last summer. But caloric restriction, I used to do a lot of that combined with exercise as well. So I was kind of like, I was getting it. And ketosis without, you know, without having to do. Yeah, I mean, I was running, you know, this was, this was like, like, even before grad school,

but, like, early in grad school, too, I was running, like, 10 miles a day. And I was doing that, like, four or five times a week. I was running 50 miles. I mean, I was really, you know, I had gone almost to an extreme, too, where it was, like, I had changed my menstrual cycle where I wasn't getting it, you know, because I was very active. And then I was doing a lot of caloric, which I felt great. I mean, I really did. But that was, you know, that was actually a long time ago.

And it wasn't until, like, sort of, my time restricted eating when I had Sotchan on the podcast back in 2015. I mean, that's when I really got hardcore about trying to, like, time, my timing went, my food intake. And following that really, you know, obsessively for the last, you know, has it been like six or seven years, you know, that's really helped. But the ketogenic diet was also unique. And I do want to sort of incorporate that into my, I want to do some kind of cyclical version of it. it, like, I really want to, and I want to, you know, measure my biomarkers and all that, which I have- And do them together. So you're still going to do intermittent fasting. Yeah, and do them together, you know, as well.

That's the key. Like, people think it's one or the other or whatever, but low-carb intermittent fasting, so just a modified, you know, that probably has, low-carb intermittent fasting probably has more benefits than chronic ketosis eating, like throughout the day, I think, for a normal healthy and maybe even therapeutically from managing, because I'm communicating with adults that have epilepsy and they're following ketogenic diet, they had breakthrough seizures, but then they take the same diet, same calories, and then do an intermittent, and this is not promoted in the world of epilepsy, but when they take their ketogenic diet where they're having breakthrough seizures and they implement time-restricted feeding, then they get seizure control again.

And I think the people in the trenches know this, like the neurological teams and dietitians, they realize, hey, well, if you can do this, they don't, it's not part of the medical literature, but they know this intuitively just because of the information people are putting out all the information on intermittent fasting. You know, Mark Madsen has been studying this stuff since the 90s, and I first stumbled upon his stuff in grad school, and it always kept his papers with me. I was like showing people. It's like, look at this.

Why don't people looking at this research? It's like so important. I haven't read his book yet, but he has a new book out too. Yeah, he does. He inspired me. I think that's how I got inspired into the ketogenic diet. It was looking at the calorie restriction and then fasting, and then that led me to ketones. But it was Manson, actually, that actually sparked my fire.

And then that led me to some of the ketone researchers. I asked Mark this question when he was on the podcast, and I'll kind of ask it to you in reverse. And that is, and you've mentioned a little, you've already sort of touched on it, but like, what do you think the overlap between being on a ketogenic diet, a modified ketogenic diet, is with intermittent fasting, whether we're talking about these epigenetic changes, with beta-hydroxybutyrate being an epigenetic modulator, a signaling molecule, autophagy is one that I'm very interested in as well. Yeah, two things in my mind. Insulin and insulin signaling, like IGF1, you know, activation of amp kinase, IGF1, mTOR that,

but also the ketones as a drug-like mediator on not only alternative energy substrate, but also as a drug-like mediator for all these different things, like suppression of inflammation, activating epigenetic effects, and things like BDNF, which I think, I think, you know, Madsen's work actually showed that many of the benefits of intermittent fasting were associated with beta-hydroxybutary-induced growth factor effects on like BDNF and things like that. So I see there's the hormonal effects of intermittent fasting are replicated with the ketogenic diet and then the hyper ketonemia that's associated with intermittent fasting in the ketogenic diet then have their own effects through beta-hydroxygenic diet.

Puteyrate and acetylacetate. So that's two main things, but there's a whole, it's playotropic, right? So the ketogenic diet, given talks to pharmaceutical companies where I go there and they say, well, let key in on the mechanisms that we can sort of drugify, right? But the end summary slide is like a dozen or more mechanisms, and there's probably many more, that are all sort of working in synergy. And I think that becomes the reason why the ketogenic diet works when drugs fail, because you have drugs work through a gabaergic mechanism,

drugs work through suppressing glutamate. You have a variety of anti-eleptic drugs that work through different pathways, but combinations of them used in high dose often work initially than they fail, and then patients are put on a ketogenic diet, and it works. So the ketogenic diet is working through a mechanism independent of what we know these pharmaceutical drugs are working.

And that becomes, you know, the complexity of metabolism is very, is like daunting, right? And to key in on something that's really having, and it could be depending, the ideology of epilepsy is largely unknown. And the ketogenic diet works, seems to work through all these different types of epilepsy, whether it's like tonic, clonic, there's Dravet syndrome, there's different metabolic disease, there's absence seizures, and the ketogenic diet seems to work across all these different seizure types, probably because working through all these different mechanisms. What do you think about a ketogenic diet for the treatment of neurodegenerative disorders

like Parkinson's and Alzheimer's disease? I think there are different subtypes of Alzheimer's disease. Again, I think the etiology of Alzheimer's is complex and there is probably a metabolic phenotype that Dr. Bredesen talks about like in his book. And I think that phenotype would be very responsive to the ketogenic diet where I don't know, you would screen, potentially screen for these patients by doing an FDG PET scan, and if you see, you know, there's like brain atrophy, but if you see a dim PET scan, then a metabolic intervention may be a good, you know, approach for that. But I can tell you just by communicating with hundreds of patients over the years, the ketogenic diet works remarkably well for some patients and has no effect on others. And I don't think it's ever hurt or decreased

anyone's cognitive capacity or anything that I'm aware of. Typically, I get biased feedback, and people are telling me that it's working, but I've seen it not work too. Dr. Mary Newport was one of the people that really inspired me in the beginning. Actually brought her to University of South Florida, and she actually gave a lecture. She used to lecture for some of my classes, and at the time, the early time, she would bring her husband, Steve.

So I don't know if you know that there was a case report written on the use of beta hydroxybuty butyre as a therapy. And this case report was her husband. And I witnessed that her husband, she had many more years. Well, you know, years, maybe like five or six years, just from an outsider looking in, it seemed like she had that amount of time extra with her husband to spend because of the ketogenic intervention. And the early part, it was just coconut oil. And then she realized that coconut oil had medium chain triglycerides and then found the patent by Xera AC 1202. And the active

ingredient was caprylic triglycerides. So she went out and bought MCTs and then had an effect. But then learned about the ketone ester and the ketogenic diet and was administering that, and that was helping him. So when 2009, she was a guest speaker in my class and then we went out to eat and her husband was shaking with Parkinson's disease like symptoms. She had Alzheimer's disease. And then he had a vial of MCT and coconut oil. And when he consumed that, when about 15 to 20 minutes, the tremors stopped and he became animated and was commenting on our conversation. So when I saw this in 2009, I realized that he was not really changed. It wasn't the food he was eating, he consumed that supplement. It elevated MCTs in his blood, which can also cross the

brain barrier, but produce a state of hyper ketonemia. And that acutely stopped the tremors he was having, and he became more animated. And that was being in contact with her and seeing this and witnessing it and also seeing his clock tests and the mini mental status exam or state exam, convinced me to go in that direction for my research. So there's no. There's no. No doubt he was a metabolic phenotype, but he was also APOE4 positive, which is very interesting, right? Because we talked about, you know, different dietary intervention. So there was no doubt in the study of Axera in AC 1202, the APOE4 phenotypes were the ones

that were not responsive to hyper ketonemia, but he's APOE4 and he was responsive and I saw it with my own eyes. And then that motivated me. Actually, the first study that we did was an alpha. Alzheimer's mouse study at the Alzheimer's Center. And then I developed the ketone ester because the funding agency didn't want to look at the diet per se, so we focused on the ester later in seizure studies. It seems like, you know, with, in particular with some of these neurodegener disorders like Parkinson's disease, I mean, you mentioned the tremor, that, you know, the standard care

of treatment, you know, like carbola daupa, there's a lot of terrible side effects with time. And if there was another possible either adjunct treatment or alternative in some way or something, that it should really be explored more. And, you know, like with, for example, if you could, I mean, ketogenic diets are so widely accepted now for epilepsy. Like what about some of these other brain disorders? Is there any movement in research to kind of push to, our understanding of whether or not ketosis is going to be beneficial for other types of brain disorders?

Yeah, it's so much easier to do a ketone supplement as opposed to a ketogenic diet for a randomized controlled clinical trial is very hard with a ketogenic diet, right? But with a supplement, you can have a control, you can do things. So I think those studies are happening. And we know that, you know, just by virtue of the ketogenic diet altering brain metabolism, brain pharmacology, We know, I mean, I observed early on that this is going to be important for many different neurological disorders and then cancer too. So that's why we got steered towards, you know, so I didn't want to initially, you know, study cancer, but the data was so compelling that we should at least test this and it became

a whole other track in my research, you know, that we're doing in the lab. So I think we are, but it's just, it's slower to go in that direction, and we really do need clinical trials before we can start prescribing these things to people, the ketogenic diets or the supplements. And, I mean, that's happening now. But there's groups of people getting together, you know, there's a group that I'm involved in that's associated with metabolic psychiatry, and they are looking at dietary interventions for a broad range of psychiatric disorders.

It could be depression, they could be bipolar, that could be, even eating disorders like anorexia is under the umbrella of a psychiatric disorder. So there's a lot of potential interventions there. And there's clinical trials, but the data is not there yet to, you know, be able to prescribe this to that. People are, I mean, people are out there experimenting with ketogenic diets. They're taking, there's ketone supplements that you can buy on Amazon. I mean, so, you know, there's a certain element of, you know, their, their family.

out there that are wanting to try different lifestyle changes, dietary changes. Talking to their physician about them is, you know, obviously recommended. But I mean, they're doing it. They're trying them. And I can tell you, like, so my mother has, she has different types of tremors, essential tremor. She's got orthostag tremors. She also gets migraines. And she did do the ketogenic diet with me somewhat. She, like, cheated a lot more than I did. But I also have given her ketone supplements and it's noticeable and it's the reason why she even tried the key, what's wanting to try the ketogenic diet because she's very much addicted to refined carbohydrates. But it, I mean, noticeably stops her essential tremor and somewhat her orthostatic, which

is her legs when she stands still, but noticeably the essential tremor and the migraines. She will, and this is totally anecdotal, so I'd love to hear your sauce on it, but she She will take a ketone supplement and Esther has worked for her and ketone salts, so she's done the keto start. And it totally takes away her migraine, which is phenomenal because I'm not a big fan of the migraine medicine that she wants to take, you know. But she gets migraines that are debilitating. Like she can't.

Oh, yeah. Good rationale for migraines. Yeah. So, yeah, I get, I mean, a lot of emails about that. I try, because I'm a researcher, I go in the. other direction and try not to oversell it as much as I can. Totally. Because, yeah, I mean, that's just not very academic.

So I get so much feedback and I'm so excited. I want to cut and paste things and put it on social media about responses because people will even send blood work or test results or their doctor. But I'm very cautious to do that because I know the power of placebo. I know the power. But I know what I saw years ago, the stopping of tremors and becoming animated was not placebo because the patient at the time didn't really know that he was taking, really. I mean, he was pretty far advanced.

But in regards to migraines, the PhD student by the name of, or now Dr. Elena Gross, so we wrote a review together, which kind of highlighted many of the benefits associated with migraines. So she was a person who had crushing migraines and discovered that the ketogenic diet and then later ketone supplements could recapitulate that. actually help to manage her chronic migraines that she had. And it was likely, just like the ketogenic diet for epilepsy, is working through multimodal mechanisms. So by probably increased gabaergic tone, increase brain blood flow. Some people get migraines because of like an increase

in blood flow and some people because of basoconstriction. And we know that the ketogenic diet and exogenous ketones increase adenicin. And from our metabolomic data, adenicin, I was not really interested in it at the time, was like manyfold higher relative, it was a thing that was really hot on our metabolomics data. I was like, oh, this is very interesting. So I recognize adenicin is a very powerful basidilator for cardiovascular, you know, physiology. So when you fast, or even when you go on a ketogenic diet, when you fast, blood flow to the brain can increase by 30%. So it's acute, you can acutely elevate it, and probably through this adenisinergic mechanism. So there's adenisin, there's probably dramatic effects on brain blood flow, on, you know,

neurotransmitter systems, energy systems, and also neuroinflammation can trigger a seizure. I don't like to go to anecdotal evidence, but I have a lot of people will contact me that have like herpy simplex or shingles or different things where the virus like attacks their body. and the first sign that they get is like a crushing headache, and then they get like full body inflammation, and then they get like sores, if it's like shingles or something like that, and they'll start fasting or they'll acutely use ketone esters or ketone salts. Actually, they've been using, I've been recommending it, and it's like, okay, please give me, you know, give me feedback.

And I've been giving them recommendations or not recommendations. I've been suggesting this as a potential way to mitigate the inflammatory cascade and the feedback has been pretty remarkable, that they can basically stop, you know, an episode from, you know, like shingles or herpes simplex. And the same thing happens. They get the crushing headaches, and then usually that's a sign that the virus is starting to shed, and it produces, you know, changes in the brain. Systemic inflammation contributes to neuroinflammation, which contributes to the headache, and then usually you get the cascade kind of after that. So it has worked through a variety of different people and people get headaches for different reasons. So I think it's kind of like Alzheimer's

where you're going to get, you know, certain phenotype will be more responsive to end. I probably should mention that there's products on Amazon that people are using ketone salts where they take it and it gives them a headache. So, and I think I've taken some of these because, you know, I try to test as many things as possible and there are supplements out there, quite popular ones where I consume it. And then I just get like a headache, almost like the caffeine headache or something like that after that. I think that's a good, that's a very reliable sign that there's something wrong with that supplement. So if you're getting headaches from supplements, and I've gotten quite a few emails about this, so I know there's listeners out there listening to this, I would say change

the ketone supplement that you're taking. And it could be the electrolytes. It could be contaminants, purity, potency, tolerability, gut issues. If it disrupts your gut, that could contribute. to a headache. But I am firmly of the opinion that ketogenic diet and fasting, fasting was also used for headaches. So ketogenic diets, fasting, and exogenous ketones can be used to manage migrants. The other area that kind of is interesting and leads into the carnivores and we mentioned it earlier and it is an interest in mine as well is autoimmune disease. And I know there's been some preliminary evidence. Well, last I checked, maybe there's been more since then I haven't done. I've done a ton of reading on that.

But with ketogenic diets actually helping with autoimmune disease, I know there's been also a lot of work with intermittent fasting, fasting-mimicking diets, helping with autoimmune disease. And so there again may be some overlap with ketosis from either ketogenic diet or fasting, helping with a variety of types of autoimmune disorders. And I know you're not, you know, you can't, you're not going to say ketogenic diets are going to help with autoimmune disease. But it is, it seems like a promising area.

to continue to research as well. Yeah. There's a couple. I was just teaching one of my classes yet. So there was a couple studies on MS and other, of course, GI-associated autoimmune disorders. And I'm not an immunologist. And, I mean, we do some work, you know, in measuring, you know, immune factors like cytokines and chemokines and things like that. I can say that we know that dietary interventions, nutritional interventions,

can be powerful modulators of the immune system. And in some cases, a hypersensitive immune system will contribute to increased intestinal permeability. So intestinal hyperreactivity is an immune response, and that intestinal hyperreactivity will always lead to intestinal permeability, which can lead to impairing, you know, exacerbating an autoimmune condition. So I think dietary interventions are working through that way too and maybe suppressing some of the inflammatory mediators, IL-6, I-1-Beta, TNF alpha, things like that. So the ketogenic diet, interesting, can also augment the immune system in ways that makes it hypervigilant in being able to detect things like cancer cells, right?

So the ketogenic diet enhances the anti-cancer immunity of people that are following it. Yeah. So a colleague, my Dr. Adrian Sheck, did research with a glioblastoma cell line showing enhanced cancer-specific immune regulation, you know, with a dietary intervention. She was also using radiation. And also, I think it needs to be appreciated that there's a lot of people are against the standard of care. but I think the standard of care in the context of the ketogenic diet is a much more synergistic approach. So when you give radiation, when you give chemotherapy, it's stimulating autophagy and it's stimulating tumor lysis syndrome. So you're actually like breaking down, you have bits of

tumor that are entering circulation. And I actually, and it's not really talked about, I always think about it in this way. When you give someone chemo, it's killing cancer cells and then you're stimulating autophagy and tumor lysis syndrome, and then that's stimulating the immune system. So, you know, I think chemotherapy in general is carcinogenic. It's bad, but it's also stimulating the immune system to then attack the cancer cell. In the context of a ketogenic diet, that a ketogenic diet, especially if it's calorie restricting, is stimulating cancer, is putting metabolic stress on cancer cells and actually stimulating autophagy sort of in cancer cells is stimulating cancer cell death, and it makes the tumor more sensitive to a chemotherapy

and radiation. So you have more tumor die-off, and you're also protecting the normal healthy cells. And it's augmenting the immune system in a way that's actually stimulating it more to attack the cancer. So I think... So what I'm saying here is probably you can't go to any publication, but we just know that from tumor biology that, you know, when you stimulate, when you kill cancer cells, you know, through any means, you can have this process called tumor lysis syndrome, which could kill

the patient if you do it too abruptly, right? But that's why we're very, you know, adamant in advocating a more gradual approach, which would be like ketogenic diets, maybe metabolic drugs and also hyperbaric oxygen therapy or something that we studied. But it needs to be acknowledge and recognize that chemotherapy and radiation also work by stimulating the immune system, and it works better in the context of the ketogenic diet, which makes the immune system more hypervigilant to be able to recognize and attack the cancer cells. So there's a lot of research being done on that now, and I know the Moffick Cancer Center, which is by USF, is very interested in immune-based therapies and using ketogenic diets to enhance, like, P.D.E.

P.D.L.1 inhibitors, like checkpoint inhibitors. There's a big, a paper just came out in a pretty high-impact journal. I forget the name of the journal, but it showed that PDL-1 inhibitors were greatly augmented in the context of a ketogenic diet. And even drugs like metabolic drugs, like the PI3-Kinase inhibitors, are remarkably effective and promising, but they have a counter-regulatory effect at increasing insulin. So when we take these things, they can target tumor metabolites. But there's also an increase in insulin. And in the context of insulin suppression with a ketogenic diet, that can unmask and augment and enhance, greatly enhanced, PI3 kinase inhibitors. So Dr. Lou Cantley is really spearheading some of that work. And I think it's, and I've been

in contact with a few of the patients in that that are doing really well. And they're using a ketogenic diet to enhance the, you know, the efficacy of that. And I know, of course. Gliomas are one type of cancer to seem to be responsive. At least preliminary evidence suggests, right? Yeah, that was my first interest in, because I started doing hyperbaric oxygen, and I saw some, I saw like cancer cells exploding under hyperbaric oxygen. So this got me very interested in cancer. It was that.

And I didn't know why they were exploding. And we had a dye that was looking at superoxide production in the cytosol and also in the mitochondria. So what I would see is that the mitochondria would light up really quick. We were doing optical sections with a laser scanning con focal microscope. And I can see that superoxide production was ramping up, like super high and super fast when we hit it with oxygen. And then I would see the mitochondria disappear and then the cells would rupture. So they're exploding.

So we're giving high pressure oxygen and the tumor cells were taking that oxygen. And because the cancer cells have defective mitochondria, they put out proportionally more superoxygen. antioxid anion, which then can be converted to hydrogen peroxide and more reactive intermediates, like hydroxyl radical. And then that damages membrane lipids, and then you get rupturing of the cells. So I was like seeing this, and I was like, this is very interesting. And what it was telling me is that I didn't know why it was happening, but later found out of the Warburg effect, where you have an altered metabolism.

Like some people say the Warburg effect is the cancer cell sort of changing metabolism for its own benefit to redirect nutrients and biomolecules to the biosynthetic anabolic production of, you know, for the expanding biomass of the tumor. So that's why. And other people, like Warburg, said it was damage respiration leads to compensatory fermentation so the sugar cell consumes more glucose. But it was sort of looking at this effect, which got me very interested in cancer and ways to target sort of cancer cells and then manipulate the substrates. So that actually was the precursor to our cancer work with ketones because I was using hyperbaric oxygen.

And then under different conditions, I started growing cancer cells and feeding them glucose and ketones. and then I would take away the glucose and keep the ketones and the cancer cells would die. And then I would have glucose and when I added ketones, it would decrease proliferation. So this is before I ever published anything. But it got the wheels turning and was like, there's something that needs to be studied here. So I had a few different med students replicate each other so they could replicate it. So that gave me some confidence. And then a PhD student came along, Dr. Angela Poff, who's hosting Metabolic Health Summit.

So she's now a research associate and does research and among other things. And then she actually moved this to the animal model, which was ketogenic diet and hyperbaric oxygen, and then later ketone supplementation. And that was a synergistic combination. So the modified ketogenic diet we used was we took out the lard and we put like a large percentage of the fat, maybe 40% was MCTs. and then we also used omega-3 fats with flaxseed oil. So at the time, I was very interested in muffas and puffas.

So we looked at what ketogenic diet researchers were using, and was like, well, let's make our own. So we did like 20%, instead of like 10%, you know, protein, we did like 20% or more protein, 25. And then we replaced the fats with essentially MCT, flaxseed oil. and then we put some fiber in there too. And then that became the diet we actually used for the Alzheimer's research. And then we used this diet for our cancer research. And our effects were pretty robust. And I often think, you know, was it because we were using, you know, a diet high in like, you know, omega-3 oils.

And we just, we also had higher protein, which I think was a little bit beneficial. But we had high ketones. So we did different diets. And this diet, especially with the MCTs. gave us higher ketones and seemed to work really well. Wow. Super interesting. What about the, you know, the different, there's different types of cancer, and I know we were discussing this a little bit earlier, you know, the potential for some types of cancer, at least in rodent studies, to, you know, maybe metabolize some ketones and

use them in a positive way to benefit the cancer cell? Is that something? There's no doubt they do. So there's a little bit of, I think cancer cell is, cancers are more heterogeneous than we'd sort of like to believe. I think the field at whole, at large, believes that. And that's why we have all these different cancer therapies. There are some cancers that are very responsive to the ketogenic diet. But when I think of the ketogenic diet as a cancer therapy, I don't think of it as, I don't think of the hyper ketonemia. treating the cancer cells, I think of the therapeutic efficacy of the ketogenic diet is through

insulin suppression and suppressing the insulin pathway, limiting glucose availability, and also to some extent elevating ketones. We know this because if we put exogenous ketones into a standard diet, we can extend the life of animals that have metastatic cancer. So we've published that in the International Journal of Cancer. But what was happening was when you put the ketones in the THANDAOns in the Thames, standard diet food, they probably eat a little bit less and it's also lowering blood glucose and changing metabolic physiology.

But so it may not be. And then the reviewers rightly asked, they said, well, go do a calorie restriction group. So we took a standard diet and calorie restricted like 25%. And we saw an increase in survival, but it was nowhere near the increase in survival from adding the ketones to the standard diet. So we did that control. So to get back to your question, yeah, I think, you know, brain tumors, aggressive, you know, solid tumors, endometrial cancers, maybe certain GI cancers, maybe lung cancer, you know,

are responsive. The cancers that are associated with metabolic derangement are probably responsive. Also cancers that are more aggressive or more glycolytic, so they're more likely to respond. And brain cancers are a good cancer to study because you get seizures with brain cancers and because the tools, the treatments are so limited. Like glioblastoma, we just know the standard of care does not work. So you want to use something. A dietary approach can then potentially make the existing drugs work or augment the many

different factors that could make the brain cancer more responsive. to the tumor. But there are different mutations. There's one for melanoma, B-Raf B-600-E mutation, I believe, which changes the tumor metabolism in a way that can actually maybe cause CO-acetate to be used as fuel. Some cancers may respond to ketones in ways that are different than other cancer cells, like the brain tumor cells that we've studied in the lab. So in particular, there's a melanoma cell line at least that has a B-Raf 600, B-Raf V-600 E mutation, I believe. And those cancer cells have been shown to use acetyte as potentially an energy source, but also for biosynthetic reactions.

And I suspect there's a variety of during cancer cells that can use ketones not only as a biosynthetic molecule, but maybe even for energy too. but I think largely cancer cells that are more aggressive have reverted back to a glycolytic phenotype where they're primarily relying on fermentable fuels, and that includes glucose and glutamine are the two fuels. And cancer cells that are more glycolytic and very sort of damaged in their respiration due to the hypoxia of expanding tumor mass. So as a tumor grows, it outstrips its ability to supply blood flow and oxygen to the tumor. So it becomes hypoxic. And that further damages the mitochondria. So it causes the tumor to be more glycolytic and less of the oxidative

phosphorylation pathway. So literally this would mean that tumor cells, especially the core of expanding tumor biomass, would not be able to use ketones as an energy source because it's a mitochondrial energy event. So in that way, we think that ketones are not an ideal fuel for tumors. In our model systems, it's very clear that they cannot run in the absence of glucose, tumor cells die. Whereas even in the presence of consistent glucose, when we add ketones, there seems to be a decrease in proliferation.

And we think that could be due to a ketone-induced decrease in hexokinines, which is a glycolytic enzyme. So there's a lot of potential, I think, for using ketogenic diets as, you know, an adjuvant therapy, and then maybe some potential as using exogenous ketones, as it means to influence the tumor microenvironment and also to influence essentially the metabolism of the tumor as a whole. And also, as you mentioned earlier, with Dr. Eric Brunin and John Ramsey's co-published studies, there was a reduction, and there's a possible preventative mechanism as well with, at least according to animal research, there being a reduction in spontaneous tumors in these rodents seems promising to study as well.

If there's any way we can reduce cancer incidents, it's always easier to not get cancer than to try to treat it. Exactly. So, you know, that's also really a sort of interesting and promising field that... And I think, I mean, those results were impressive. So suppressing tumor growth through probably IGF1 and MTOR and just suppressing, keeping inflammation low and many other, you know, biomarkers, I think it's optimizing to do that. But if we take these ketogenic diets and optimize it with specific phytonutrients and we add

some fiber in. And we add, I mean, then I think, then it becomes difficult to figure out what's doing what, but I do feel that there's some synergy in optimizing a ketogenic diet with plant, you know, fiber, and phytonutrients that we know have antaclycogenic effects like curcumin and turmeric and EGCG. And, you know, there's groups at the Cancer Institute that spend their whole life studying just a handful of these phytonutrients and they show that it has remarkable chemo prevention effects. So we should be incorporating these into the ketogenic diet. Which brings us to the all meat, no carbohydrate diet real briefly.

I mean the carnivore diet. There's a lot of people that sort of feel like they've done a ketogenic diet and they need to graduate somehow to another level of zero carb. And what are your thoughts on, I mean... Well, I'm not sure if it's like... I think it's going back towards kindergarten. So I do think there's no doubt that a carnivore diet is beneficial for some people. And I think it's therapeutic in some ways.

It is a form of a ketogenic diet. I followed it. Actually felt pretty good on it subjectively. But objectively, my biomarkers were, my LDL, I think, was doubled on it. And then my triglycerides started to creep up. So this was a little bit of a concern for me. Like, if you have the fat pathways, we're a little bit backed up. For example, if you have an inborn error metabolism, like carnitine deficiency, either primary

or secondary, a telltale sign is like an elevation of triglycerides, hypoketonemia, and then you have, like, you know, a lot of a cascade of different things. Like, you're just not metabolizing fat as well as you should be. Whereas we know that certain omega-3 fatty acids can actually increase. the carnetil transferase and actually augment fat oxidation, certain fatty acids can. For me personally, I felt good. I felt fine, but my blood work was a little bit concerning. And when I went back to just adding more fish and omega-3 fats and more plants back into my

diet, maybe it was a fiber, maybe it was vitamin nutrients, I felt just as good, but I brought my biomarkers, especially my triglycerides, came back down again. But I think it depends on the type of meat that you're eating, the amount of food that you're eating. If you're eating the carnivore diet and creating a calorie deficit while you're doing it, I think it could be beneficial. But I don't think it's something that would be sustainable or optimal long term. So it could be sustainable. It is for a number of people that I know. But I guess the question is, is optimal? And I have no science, I'm not aware of any science that supports a carnivore diet is optimal for treating

anything, although I've been in communication with people who have benefited greatly from it, so I'm not going to criticize it too harshly. It is a form of a ketogenic diet. Yeah. I mean, it's, again, as you mentioned, it's like, well, are these people severely calvertricting themselves? Yeah. Are they just getting off of a terrible diet that's, you know, I mean, there's so many factors. And again, it's like, well, you know, it's me. And the lack of fiber. Lack of fiber and, you know, the phytonutrients, which.

Which kind of brings it back to the fiber issue too, right? Because it's obvious that we could do, we could do well off no fiber at all. So the question is like, you know, is fiber necessary? I don't think it's necessary, but I think it's optimal. So I think excluding it altogether is not. doing our bodies any favor. And I think when we add it back in, there's just so much good data on fiber that it's hard to ignore. So that's why, you know... What do you think the colonocytes and like getting the butyrate from fiber, like what

do you think is happening in the gut, in someone with a no fiber diet? Like what, like the, like the butyrate is so incredibly important for gut health. It is, yeah. And it's a primary fuel for colonocytes. So, um, I don't know, but I do know that if it caused like a massive disruption of the gut microbiome and intestinal permeability, it would show up on blood work as like HSCRP elevation. Mine trended. It actually went up like from point one to like point two or point three. But that's like, so I think humans are omnivores and they're incredibly adaptable to any kind of diet. And I think that dietary diversity might be a good thing.

But you have populations of people like in Africa or other areas where they just eat like one food all the time. And it could be like some cornmeal or it could be whale blubber in another. And they do perfectly well. They survive. They live a healthy life. So it's just staggeringly remarkable that we have the metabolic flexibility and adaptation to eat almost anything. You know, the question is what is optimal? Should we even be eating such a huge diversity of things?

And I think that could be beneficial, at least, you know, it gives us an array of different things that we can eat and we're grabbing nutrients from different areas. But yeah, I am kind of a little bit neutral on the carnivore diet. I think it's beneficial for some, but I think it's suboptimal as a ketogenic diet. And as you mentioned, there's just a lack of empirical evidence. Like, there's anecdotal evidence, which again is confounded all the time by many things. But there's really not a lot of research that have been done on, I mean, published and peer reviewed and, you know, actually. Yeah. But there are people doing it and they're thriving on it.

That's true. They've corrected, you know, various, everything from autoimmune disorders, you know, there's super high achievers. You have Sean Baker, who's just like a physical specimen. and he's just eating nothing but meat and doing very well. And I don't know, I haven't seen his blood work, but I think it's okay. I mean, he's smart enough. But I do think that if you're eating a carnivore diet and you're getting surplus amount of calories, which I kind of did because I added just a few pounds,

and I think that negatively affected a lot of my blood work. But if you eat a carnivore diet and a calorie deficit, then I think it could be therapeutic and potentially helpful. So it all comes down to calories. People ask me if calories matter, I think they most certainly do, and I think you need to appreciate that. Because a lot of the ketogenic diet community, they say don't count calories, just count carbs. Or, you know, calories don't matter if you eat this way.

But calories absolutely matter. You mentioned having a – you do intermittent fasting sort of cyclically. And is it like how many times a week or how many meals a day? Like, you know, is it something that you alternate each week? My normal pattern is to have like a small ketogenic breakfast and then more or less fast through midday I'll have like a ketone supplement or maybe a small coffee but not past two o'clock. And then I eat wheat dinner typically between like five and six. Probably try not to do a little bit later if I'm working late sometimes is later.

But I consume the most of like 80% of my calories between six and nine p.m. I know nine sounds kind of late, but we go to be. bed around, you know, 11 o'clock. But I get the bulk of my calories probably with dinner, which is around like six-ish, five, five or six-ish. So, and a lot of my protein, too. But in the morning, I eat a ketogenic breakfast. Lately, I've been eating waffles and making waffles. There's different ketogenic waffle recipes that are really, really good. So I've been experimenting in the kitchen a bit with my wife. What about your exercise routine? Yeah, I try to do some form of exercise every day. I mean, we have some pretty, we live on a farm, so farm work occupies

probably about 10 to 20 hours a week of my time doing, and that's good outdoor activity, getting sun, exercise around the cows. We walk our dogs, you know, usually like twice a day, and then I do resistance training, no less than twice a week, but sometimes I try to get four times a week if I can. And I like to do a lot of body weight exercises. And I think when you're traveling and you're pretty busy, like chin-ups, push-ups, dips, a lot of chin-ups are probably like one of my favorite exercises, pull-ups, chin-ups. And then you're doing some hot tub therapy? Hot tub therapy, yeah. So the benefits, so your article on sauna and just hypothermia in general. So I did some experiments measuring my core temperature and showed that I can, getting the hot tub to about 105 to

110, I can get my body temperature up to about 102 within about 15 minutes. And I really believe in looking at the literature. And also, after I do this, I then measure, well, I've measured my glucose and my blood pressure comes down and it seems to be, I'm like, my blood pressure is like the lowest it's ever been. It's like 97 over 60 or something or 58 or something. It's really low. And I always trended on the higher end of systolic especially, like 130, 140, I think, during grad school was like 145 consistently systolic pressure.

Always ran a little bit higher systolic, although I carried more mass at the time. But the one thing that has really moved the needle and my blood pressure has been not changing anything and just doing what I'll call heat therapy with a hot tub. That's awesome. Brought it down five to 10 percent. And I was like measuring like five times a day blood pressure throughout the day because I would love to have a continuous blood pressure monitor. That would be really cool.

My continuous glucose monitor with the Levels Health app is very insightful and gives information and I can do like a comparison of this meal versus that meal and sauna versus, you know, cold. I can actually, I can market and time market and do a CGM comparison. What's the best way to measure your actual ketones? Is it blood, breath? Good question. Yeah. Best versus also most like easy for people as well.

I mean, they're both kind of important. Again, like people don't like this, but it depends. So that's my answer to a lot of things. So it's context-dependent. The clinicians that are managing epilepsy patients say that urine is great, and they're not going to change from urine. And they're doing – because they don't want to prick the kid's finger, too, right? So I did blood.

I like using the glucose ketone index. What is that? It's your glucose over ketones in a millimolar concentration. So if you're fasting, it takes me about 72 days – 72 hours to get, although the guy fasted for 360 or 80 days, fasting for 72 hours gets my glucose ketone index to one, where my glucose comes down to about 3 millimolar and my ketones come up to 3 millimolar. So that would be a glucose ketone index of 1. And it's my belief, although I haven't measured LC3 and other components of the autophagosome, it's my belief that

achieving and sustaining a glucose ketone index, of one for 24 hours will induce and perhaps maximize autophagy. No doubt that you can get more benefits five, seven days. But then at five days and seven days, I see a suppression in testosterone and other things I don't like. So for me, three days is like the sweet spot. I can achieve a glucose ketone index of one. And then my breath acetone is off the charts. And I think breath acetone is probably your best ketone to measure if you want to lose fat. So all the carbons of the acetone you're blowing off essentially are from fat. So when you look at the device and it's reading like 40, it's like, you're just like basically

exhaling fat carbons. So from that. So I think it's breath acetone is great because with beta hydroxybuterate, I could be at two or three millimolar and just walk around the house or do some activity and then I'm back down to like below one. That's because your body's using the beta-hydroxybutyrate as fuel. And if you have a calorie deficit, you have a high tissue uptake of beta-hydroxiboutrate, right? Whereas my breath acetone seems to be more stable and a better correlate of fat oxidation.

And it's also easier. So if you're blowing into a breath acetone meter five times a day, that's a lot of money in strips and a lot of poking your finger. So I use the readout health biosense device. And I don't know, I've bloated into mine like a thousand times. And that would be cost prohibitive from a ketone monitoring perspective. And a lot of fingerpricks associated with that. And it has a pretty cool app. And also a fasting sort of meter in with it.

I think they collaborate with zero fasting. So I think there's some collaboration there, but it can show you if you're doing a fasting and using that. Although it's more of a clinical device, but it's now it's broken into more mainstream. So it's an FDA-approved class one or whatever physical device, medical device for measuring ketones. And I became interested in acetone because it correlates with seizure control. So acetone does.

So I recommend it to parents who have kids that are managing and they don't want their fingers pricked and the urine ketone strips are not very accurate. So to answer your question, I think both blood ketone measurements, if you're just starting the ketogenic diet, it may be good to just use urine to say yes, you're in ketosis, you're not. It's like semi-quantitative and then spend the money to get a ketone meter, like the ketombojo device is probably one of the best. And then a breath acetone meter is good for people who are doing fasting and for people that are really interested in, like, weight loss.

What about using blood glucose levels, like, as a proxy? Like, is there... That's, like, super interesting. Yeah, we had an NIH workshop sort of on this, and I brought this up as a continuous ketone monitoring, or continuous glucose monitoring system. And now you have the ketone monitoring system. With Abbott has a lingo device now,

which does, like, glucose, ketones, lactate, and also alcohol. But a CGM device is like the ultimate device to look at dietary adherence to a ketogenic diet because it should be, the trace should be completely flat. And if there's big excursions, then that person's not on a ketogenic diet. I guess if they're under stress or they're exercising really hard, you might get a blip. But generally speaking, like a CGM trace is a very, very good way to tell if someone is adhering to a ketogenic diet. So these things should be used. I think generally speaking, the community also feels that this needs to be used. But it's an off-label use.

Is there like a level that's like a range or if you were to give an estimate, guesstimate of what the-blood glucose level, like to like... For a ketogenic diet. Yeah, to say like I'm probably in ketosis because my blood glucose levels are X. Yeah. Well, I could show you on my... So what was very interesting when I woke up this, morning, I spiked 40 milligrams per decilator. I've never seen that before, like, ever. And so my CGM trace typically looks like, oh, probably now it's going to be, maybe I'm excited. Maybe it's all over the place, but it's going to look like.

So I didn't, what I said it to, I added like an extra 30, so it wouldn't go off negative during anything. But right now, if you subtract 30 from that number, that's, that's what your CGM trace should like on a ketogenic diet. And you've wearing, you've worn a CBM before. So I'm 74. Yeah. So, but when I woke up this morning, it's not, I had a big, I only had maybe like four and a half hours sleep or something. So it could be that. It could be the different time zone or something like that. Oh yeah. Totally. That's it. I mean, that was the first thing I learned from my CGM was because I started wearing it when my son was like four or five months old. So I was really like I was waking up multiple times to breastfeed.

And, you know, I mean, so my sleep was insanely disrupted and fragmented. And my blood glucose was just out. It was just going out of control. And it was always on the nights when I was like waking up multiple times and not getting enough sleep. And that was like one of the biggest things I learned from my CGM. That was surprising to me. Where were your highs? Like how high were your highs?

So mine spiked to almost like 130. or 140, and that's unheard of. Like, I've never seen that, but that just could be due to the time change and getting about half of the normal seat that I get. I can't recall. I mean, I feel fine now. It's been too many years, but they were... It was just highly variable, yeah.

It was, yeah, it was something like that. It was above 120, you know, like, where it was like, this is post-perandial level. Like, you know, like, this is pretty, like, you know, intense, you know, like a robust effect. High intensity training, I was doing a lot of spin class and stuff. hour-long, like a pretty intense spin, that was really, that would help. Like, so if I do the spin and then have the disruption that night after the spin, it was way better. Like, my glucose was way better. So, like, the exercise totally helped negate some of the glucose dysregulation that I was at. I don't know what exactly was happening, but my glucose

spiking so high. So that was also a learning. I learned so much from the, from the CGM. I haven't worn it for a couple of months because I have to re, I think I'm going to do levels, because my prescriptions like... Levels is great. Yeah. I'm like, okay, I think I'm going to move to levels. So I did, I'm not going to mention the other, but I did a couple different companies and I just wore it.

But levels, well, they're in beta now, but the difference about levels is that it's kind of coaching you, and you also have the option to, I mean, you could just push and get to a nutritionist. So I guess that's good for people, maybe not like us, but for the average. But it has so many features built in. where I exercise, it'll say, you know, what did you do here? We saw that you exercised. So it learns my body, even if I have a cup of coffee in the morning. It learns my sort of dawn effect. And I just take a picture of my food. It event marks it. And then it sends me an email the next day of the picture of my food.

My average glucose effect, my metabolic score and things like that. So it's so easy. Otherwise, I mean, you could just buy a CGM. I guess if you had some and prescribe it to you and just look at the CGM trace and then make your own inference. But I kind of like having, as long as I engage with the app and I take a picture of my food and everything, I get the email the next day. And that tells me what happened to my glycemic response the whole day. And it also gives me a weekly thing. So all I have to do is just engage with the app once a day and it sends me like a daily report and also a weekly report where I could see like every day.

And there's so many features. I don't even use like 90% of the features, but I use like 10% of the features, and it's very useful to me. And I think so we're doing a clinical trial right now with CGM. And people have app fatigue. Not everybody wants to be on an app all day, but you can engage with it as much as you want or just, you know, engage with it two or three minutes per day is enough to really be getting a lot of insight into your metabolism. I found just wearing the CGM without even having to do all the app stuff really help me figure out what foods that I should be eating and portion sizes and all that stuff because it was like

What were your biggest surprises? The spinach, the cooked spinach was the one because I was like, oh, the sugar and it was a low glycemic, you know. Yeah. But what you said makes a lot of sense. I think that was a big surprise. And then another really big surprise was like. A lot of these, like, cauliflower rice, you know, like, I was traveling in part, on part of this,

you know, where I was on the Kogenic diet. And so I would, like, order food that was like, this is keto and you get something this is keto. And I'm like, this is not keto at all. I'm like, it's, like, spiking me so high. And then you, like, track down the ingredients and it's, like, sugar. And I'm like, really? You're calling this keto, but you actually have added sugar in it.

Other surprises where I was taking some, like, collagen gummy chewables that didn't have any sugar allegedly. And my blood glucose just went through the roof and I'm like, what's in this? This something. Same thing. I tried some kind of sugar-free gummy. It shot me off the chart. Yeah. And all the bars that I get sent. So 90% of the, yeah. The only bar that's has completely ketogenic is keto brick. So it's like the brick is 90 grams of fat. Like, and I think 20, like maybe 30 grams of protein and like hardly any carbohydrates. and it's a thousand calorie brick. And that's like truly the only ketogenic, you know, bar.

There's a bunch of bars out there, keto brick. Oh, there's, I mean, if you go to Costco now, it's like, oh, I know, everywhere. Like keto everything. And it's, I haven't yet to find actually something when you turn around the back and you look at the sugars and the ingredients that, like, one of these things that was like, it was like this coconut keto crunch and my mom loves coconut. And she was doing keto and, like, ordered it on Instacart. And then I came and I'm like, there's a lot of sugar in this.

This is not keto. Like, how dare they call it keto? It's so misleading. Again, it takes us back to the beginning where it's like this keto has become, it's very much become trendy and it's almost like this marketable thing. And, you know, I think the essence of ketosis has been lost somewhat. So it's really been nice having to talk about all this. I want to talk even longer, but we probably should wrap this up.

Thank you so much, Dom. I want to, we're going to have dinner tonight and talk more, so that'll be great. But, and I want to talk to you about all sorts of things. But like for people, people that want to learn more about your research, they want to follow you, they want to learn about metabolic health summit or you blogs, your, you know, all those things. Where's the best places to find you on social and all those? Yeah, thanks for asking. Yeah.

Ketonutrition.org. So ketonutrition.org. And we have a blog there. Subscribe to the newsletter. When this podcast comes out, we'll put it in the newsletter, of course. And a lot of other information that I don't post anywhere else is in the newsletter, as you do too. So subscribe to your newsletter, which I did. And it's like an awesome source of information.

Metabolic Health Summit, which will be happening May 5th through the 8th. Amazing event. We have clinicians, you know, basic scientists. and entrepreneurs scrambling to this area and influencers. It's an amazing event in Santa Barbara, California. I'm excited to be a co-host for that. And yeah, I guess, yeah, most of the information that we promote will be on our blog and on our website.

I personally do not have any products. People always ask me, Dom, what's your ketone product? I don't have a ketone product, but I do support a number of different companies, and it's on the website, the exogenous ketone product that I use is keto start. Keto brick is my go-to keto bar. I get that question asked all the time. And Keto Brains is a coffee creamer that I use. It's got alpha-GPC, Thienine.

It's got Lyons mane in it. I've also got C-8. So these are three supplements that I use pretty much on a daily basis. Not a huge supplement guy, but these are supplements we love and promote on that website. And you're also on Twitter. On Twitter, yeah, if you search my name, always forget my Twitter handle, but on Instagram, Twitter, Facebook, I like to share new literature that's out, our publications, and others in the space. So I try to be a resource, not as much as you, but we should put out amazing

information and truly appreciate you giving me this platform to give my information to your followers. Oh, my pleasure. Thank you. Thank you for all your research, Dom. I'm looking forward to more and to a future conversation. Thank you. Thank you so much to Dr. Dom Degasino for such an engaging conversation and thank you all for listening. For those of you listening today that want to dive even deeper into some of the material we cover today, please check out our topic article on beta-hydroxybutyrate, which is the major

circulating ketone when in ketosis, either from fasting or a ketogenic diet. This molecule is very interesting and seems to be changing the way genes are activated in a way that is beneficial for health span. You can find that article on my website at foundmyfitness.com. You should also know that this episode has nearly 200 accompanying slides with extra definitions, supporting information, figures, and references. All our premium members get access to these slides, as well as a private podcast called the Aliquot, where I released new episodes almost weekly, a live monthly Q&A, and a science digest I send out twice a month. This premium membership is how I support the podcast, videos, and articles we make freely available.

You can try it out for free for 30 days and submit a question for my next Q&A at foundmyfitness.com forward slash trial. That's foundmyfitness.com forward slash T-R-I-A-L trial. Thanks again. I'll talk to you guys soon.