The Tim Ferriss Show - #172: Dom D'Agostino -- The Power of the Ketogenic Diet

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Starting point is 00:03:15 habits, purchasing decisions, etc, that you can emulate test in your own life, whether they are from athletics, entertainment, business, military, or otherwise. This episode is a round two with Dom D'Agostino. Dom, that is Dr. Dominic D'Agostino, is an assistant professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine, and that is a mouthful, and a senior research scientist at the Institute for Human and Machine Cognition, IHMC. He has also deadlifted 500 pounds for 10 reps after a seven-day fast, and I consider him a friend. I call him, he's on speed dial for me, with many of my metabolic and nutritional questions. And many, many of you, after the last, I think it was two to two and a half hour conversation with Dom, and if you haven't heard that, you can go to fourhourworkweek.com forward slash Dom,

Starting point is 00:04:08 D-O-M, and it will take you to that URL. After that episode, he and I were just deluged with enthusiastic follow-up questions about ketosis, ketones, cancer, et cetera. The following is Dom answering your most popular questions with a particular focus on ketones, ketosis, ketogenic diet, etc. And for that reason, you could consider it the sort of ketosis masterclass, especially if you combine both episodes. But this one stands alone if you want to listen to it.

Starting point is 00:04:39 There are a couple of things that are not mentioned at length necessarily or in detail. For instance, the types of canned sardines and oysters that he eats, King Oscar and Wild Planet Foods. This is from the first episode in the show notes is where you can find the sardines. It's also why Whole Foods around the country sold out of Wild Planet Foods sardines is this episode. And then the canned oysters would be Crown Prince natural oysters. But you can find all of that in the show notes at 4hourworkweek.com forward slash Dom for the first episode. And we cover a lot. And what I would suggest is Dom did this on the road. It takes a few minutes for him to get warmed up. Be patient, listen to it. And if you want to skip around, I mean, there are a few things, for instance, around, I

Starting point is 00:05:25 believe, eight minutes, 55 seconds, let's just call it nine minutes after this intro ends. Can you gain muscle on the ketogenic diet? And related questions around 52 and 20 seconds after this intro, how does he handle travel? What does he pack? And if you're really considering exploring ketosis or just consuming exogenous ketones, like the Ketokana and Ketoforce that I've discussed with Dom and also with Patrick Arnold, very famous biochemist for performance enhancing compounds, shall we say,

Starting point is 00:05:57 then this is also relevant because there is data to suggest that you can slow, for instance, tumor growth by consuming these synthetic exogenous ketones, even if you're still consuming glucose or producing glucose, which is very, very exciting for all sorts of reasons. In any case, this is going to be dense. It's going to be worth it and just be patient. And I think that if you have an interest in these types of metabolic therapies, whether it is for performance enhancement and let's say endurance or for anti-cancer purposes or otherwise, you will find a gem within this conversation, which is more of a monologue, I suppose. So please enjoy this conversation with Dom D'Agostino. If you want to say hello to him, you can certainly do so on Twitter. It's imagine at Dominic, D-O-M-I-N-I-C, D'Agostino, D-A-G-O-S-T-I, and then the number two, I guess it was Dominic D'Agostino's taken. So at Dominic

Starting point is 00:06:54 D'Agosti two is his Twitter. And that will also be in the show notes. You can find all show notes at fourhourworkweek.com forward slash podcast. And what a fucking long intro. I'm sorry, folks. Enjoy. First question, this will be under the ketogenic diet category. Under that category is also some questions on fasting. I think Alex David writes, despite all the evidence, it seems that many dietitians and researchers, I'd add clinicians to that, still frown heavily on ketosis. Why is there so much resistance? So I think the main reason would be the lack of education in the medical community and even in the dietetics programs. So having gone through a nutrition science program in my undergrad 20 so years ago, there was a little bit of discussion on low carb diets,

Starting point is 00:07:58 very little, if any, discussion about a ketogenic diet there was a discussion kind of a negative discussion one day I remember on the Atkins diet so my particular professor at the time really sort of despise that diet so that's the problem like you know registered dietitians who are supposed to be at the cusp that the front of understanding sort of nutrition and how to manipulate nutrition for optimum health or weight loss. So most of the patients that they deal with are really trying to lose weight or manage type 2 diabetes. And we know the ketogenic diet is like a big hammer, you know, for type 2 diabetes.

Starting point is 00:08:42 As Jeff Folek would say, put a type two diabetic into remission within like two weeks or so. We could see that, you know, that that's known. I think the big stigma comes from the dietetic community is that it's just not feasible for people to follow. And, you know, if you lower the carbs, what type of macronutrient are you adding? You're adding fat, right? And saturated fat has been demonized. It certainly was demonized back when I was in college over 20 years ago. And that's going to be hard to change. I think our stance on that has softened up considerably, but it's going to take some time to change the minds

Starting point is 00:09:25 of the people who are the major influencers, which would be kind of the medical community and dietetic program. They need to accept that the low-carb ketogenic diet really has a place. And right now it's really doesn't have a place. It's getting more attention, which is good, but it doesn't have a place in the medical community too. So the lack of education there, I teach in the medical college and I'm on the, I was on the medical curriculum committee for medical school for a number of years, like three years. And the curriculum is already so compressed and it tries to fit in as much as possible. The information is sort of biased, if you want to say that, towards covering what's on the boards that the medical students have to take, the USMLE.

Starting point is 00:10:26 So there's just no room to fit in nutrition into the medical curriculum. So doctors are not going to have an appreciation of nutrition. They're certainly not going to have an appreciation for the ketogenic diet. So the medical school that I teach at, though, does have a functional medicine sort of group of kids that are very enthusiastic and really smart. And they really want this information. And they have a lunch sort of seminar series that they have people come in and talk. And I've given a talk. And my students or research associates have given a talk in this

Starting point is 00:11:05 and the feedback has been really good. I mean, they want the information, but it's just not taught in the general curriculum and it needs to be. So nutrition is really the foundation of our health. And if medicine wants to focus on prevention, there's no better tool than nutrition. Exercise helps, but probably not as good as nutrition. So nutrition research, too, there's just a lack of good research on low-carb diets and ketogenic diets or some out there if you look but the the rigorous sort of control multi university trials looking at the effects of a high carb diet versus Mediterranean versus low carb versus ketogenic diet these are really difficult studies to do and they're really expensive. And, you know, it comes, you have

Starting point is 00:12:07 the question of who's going to fund these studies, what kind of institutional support do you have to run these studies? Are the people at the institute knowledgeable? Do they have a team of dietitians that can control the parameters that are needed to ensure diet compliance. For example, are they measuring blood ketones for all the participants in the ketogenic diet group? So that rarely happens, and that's the kind of oversight that needs to happen to be able to to do this kind of research and you know the research is really going to be important because that's what the medical community are not thought nutrition that's what they're going to look at they're going to want evidence so if they say you know if you tell them that this is a powerful metabolic therapy and it's even the standard to care for drug-resistant or drug-refractory epilepsy,

Starting point is 00:13:07 it works remarkably well for that application, and I think it can work equally well for a number of other applications, they're going to want the research to support that. And I think that research is in progress. And I think the low-hanging fruit would be looking at type 2 diabetes and obesity. And I think that's going to be one of the most important applications for a ketogenic or maybe not even ketogenic low-carb diet. So a low-carb diet is relatively easy to do, but nutritional ketosis is really considered extreme and difficult to implement. So that's why the question is, why are researchers difficult job getting their patients to comply with this kind of diet. I could just tell you about it. People come to me, and many of them that attempt the ketogenic diet just can't follow it. It's really hard to follow.

Starting point is 00:14:21 And that's why I think something like a modified Atkins diet, you'll get four times the amount of compliance. If you can get maybe 10% of people that can follow a ketogenic diet, I would say if you screen them properly, you could get at least 40% of the people to adhere to a modified ketogenic diet defined as sort of following in a way that they consistently have an elevation of blood ketones day in and day out. So it's just a much easier diet to follow. I'll talk a little bit more about that later, I think, with questions. And there's also some resistance from the exercise community, too. The question is, what are you using the ketogenic diet for? And there's, at least on social media, there's a lot of talk and discussion and debate about the ketogenic diet for endurance athletes, long-distance runners.

Starting point is 00:15:25 And I think it definitely has an application there. Bigger question that I get a lot, is it the ideal diet or can you gain muscle size and strength, you know, doing resistance training, doing bodybuilding, powerlifting with a ketogenic diet? And I think you can, I know you can. The question is, you you know is it optimal probably not for everybody but I think it is for I think it can be for a Subpopulation of people and I think you know as we age our carbohydrate tolerance decreases with age so the the over 40 crowd, and I would fit into that,

Starting point is 00:16:09 responds remarkably well to a ketogenic diet, I think in the context of resistance training or a low-carb diet. But we really need more research on that. So hopefully we plan to do that. So the next question, probably spent too long on that question. So I'll try to hit these more rapid fire. The next question comes from Brad Gross. Could you please ask him about protein intake on, on ketosis? So it seems like there's thousands of different answers out there. So this is question and yes, everybody's got an answer to how much protein you should take on a ketogenic diet.

Starting point is 00:16:51 So in the case of me and in the context of treating kids with epilepsy, it's been found that keeping your protein between 1 and 1.5 grams per kilogram per day is really, you need to kind of stay within that range to consistently stay in nutritional ketosis. As protein can be insulinogenic, so you could, excess protein can feed into a gluconeogenic pathway and kick you out of ketosis or decrease your ketone levels. So I would say the higher protein, though, is probably needed in people that are more active and also heavy training. And I think when you get the person who's an ectomorph and is super fast metabolism and maybe on top of that, you know, a friend of mine, he's an ectomorph, and he has a very high output, you know, because he works outside all day.

Starting point is 00:17:52 So he needs, you know, two grams per kilogram per day. And that's typically far above what most people would take for a ketogenic diet, but his ketones stay remarkably high off that because his output is really high typical ketogenic diet quote-unquote the classical ketogenic diet four to one ratio four parts fat one part combination protein carbs has like 10% calories coming from protein. That's really low. So a modified ketogenic diet is 25% to 30% calories in protein, from protein, percentage protein.

Starting point is 00:18:38 And that's also called the modified Atkins diet. And it really evolved out of work done at Johns Hopkins. Eric Kossoff is probably the leader in sort of advancing the modified Atkins as a metabolic therapy for kids and adults with seizures. And that's really the diet that a lot of athletes are using. So myself included, not an athlete, but I think most of the people who say they're on a ketogenic diet are not doing the classical ketogenic diet, which is like 10% protein. So yeah, the protein intake, very general recommendation, 1 to 1.5 grams per kilogram. Matt Nelson asks, the impact of the ketogenic diet on type 1 diabetes? So it's an interesting situation that I have a type 1 diabetic student in my lab,

Starting point is 00:19:35 and he's a PhD student, remarkable student, big guy, 6'4", 250, Andrew Kutnick is his name, and joined the lab with an intense interest in this subject and took it upon himself to try the ketogenic diet as a type 1 diabetic, right? So he tracks everything, including his blood glucose, continuously because he has one of the sort of Dexcon units that continuously measures his blood glucose levels. And he's a remarkable subject for testing ketogenic food products because we could just turn his insulin off. So he has a glucose monitoring system and an insulin pump. If we want to examine the glycemic index or the glycemic response, I guess you would say of different foods, we can use Andrew and turn off his insulin pump and then

Starting point is 00:20:36 look at his glycemic response to the food. So it comes in very handy. So Andrew is a great sport, and he decided to try the ketogenic diet and has written up some notes here of things just sort of describing his response to the diet. And Andrew kind of is very kind of perceptive about many different things, including his insulin sensitivity. So he has a really good handle on how changes in his body composition, his exercise. exercise so when he does kind of brutal exercises training in the gym uh the frequency the consistency uh how that affects his his blood glucose the type of insulin that he uses and how that influences his caffeine use his fiber the composition of his meal the types of foods what he adds to his foods, things like cinnamon. So he's tracked all these different variables and how these variables influence his blood

Starting point is 00:21:53 glucose and the amount of insulin that he needs. When he got around to the ketogenic diet, he realized there was some really big perks to being a type 1 diabetic and being on a ketogenic diet. And the biggest would be the lack of blood glucose fluctuations. So tremendous difference between glucose fluctuations on a high-carb diet versus a ketogenic diet. The daily fluctuations were remarkably tighter. And he's been conversing with other type 2 diabetics who have switched from the diet that they have been prescribed

Starting point is 00:22:35 and the ketogenic diet. And, I mean, it's amazing the control of blood glucose that you have when you're on a ketogenic diet. And not only is his blood glucose remarkably kind of controlled when he switched to a ketogenic diet, but he was able to reduce his insulin levels to about one-third of the amount of insulin that he was using before. So whenever you can reduce the amount of insulin for a type 1 diabetic can do that, that's a good thing. So doctors need to acknowledge that. So he had a similar reduction in 24-hour insulin levels, or in his notes here, he noted that there was a similar reduction in 24-hour insulin levels reported in individuals who were underweight, who underwent a ketogenic diet but maintained body weight. So he lists a number of different publications to support sort of the same observation that he saw

Starting point is 00:23:48 when he switched from a high-carb diet to a ketogenic diet for managing his type 1 diabetes. His insulin sensitivity increased tremendously. And this has major implications potential protection against hypoglycemia right in my talks I always talk about the work of George Cahill from Harvard in 1967 mid 60s in 1967 he published an observation of fasted subjects who, when adapted to a state of starvation ketosis, were remarkably resilient against insulin-induced hypoglycemia. So they suppressed their blood glucose levels with IV-infused insulin down to something between 1 to 2 millimolar.

Starting point is 00:24:48 And that would be kind of universally, if not fatal, would put someone into a coma or a seizure. And we know that having blood ketones elevated make you remarkably protected against hypoglycemia. So that has real practical consequences from a safety standpoint. If you're driving, you know how many accidents are caused by or result from hypoglycemia in people who are diabetic. So much of that could probably be mitigated if they were on a ketogenic diet. So these benefits, and he described many benefits, you know, in our daily talks in the lab, and these benefits essentially eliminate the potential downside of type 1 diabetes in the short term and the long term, right? So short term, you're talking acute

Starting point is 00:25:49 hypoglycemia, mitigating that is really important, but also the long term. So if you're on a high carbohydrate diet and you have huge postprandial excursions in your blood glucose, that's going to, and you do that repeatedly, that's going to cause a lot of harm, you know, in the long term. And that can be completely eliminated or significantly attenuated in type 1 diabetics using a low-carb approach or a ketogenic diet approach so I know it's a controversial subject and I don't want to kind of base my comments or suggestions off you know the people that communicate to me and seeing firsthand what it did to Andrew who not only has much better control over his type 1 diabetes, but has an incredible amount of muscle and strength

Starting point is 00:26:51 and continues to surpass a lot of his lifts in the gym while following a ketogenic diet or a low-carb approach. So he more or less transitions from a ketogenic diet to low carb and kind of bounces back and forth. Doesn't stay ketogenic all the time now, but he's told me that he feels best while he's on a ketogenic diet and certainly uses much less insulin. So there's some resources out there to point people to, because I do get about at least one or two questions a week on this. I would point people to the Ketogenic Diet for Type 1 Diabetes e-book, and that's on ketogenicdietresource.com. And the authors of this book are Ellen Davis and Dr. Keith Runyon. And I know Dr. Runyon has been on several podcasts talking about his use.

Starting point is 00:27:45 He is a type 1 diabetic. He's a medical doctor with type 1 diabetes. Next question I want to address is by Bohenba Narqua and asks the question, ketogenic breath analyzer versus blood. So which one's best here? So the blood glucose slash ketone meter by Abbott labs, the precision extra. And one that I use personally is the freestyle Neo. I think it's called is really the gold standard. If you're getting into this and you want to, if you're not

Starting point is 00:28:22 on a tight budget, I would recommend measuring every day if you're really serious and to do it the same time of day every day. And I think that's really important. And the breath acetone meter, that would be the ketonics metereter is really useful and it just really needs more development and testing from my perspective. So we know from at least, you know, one, maybe two studies, breath acetone levels correlate with seizure control. So I think if you have kids that are managing a disorder and they don't want to be their fingers, you know, prefer not to be pricked, I think these breath acetone meters are great for kids. And I've talked to, you know, parents and kids that enjoy doing them. Because you blow in and you have, like, these pretty colors. You get the blue with low ketones or green,

Starting point is 00:29:27 and then orange and yellow, I think, and red. So they're very convenient for giving you a range of breath acetone that can correlate with seizure control. So I think more work needs to be sort of done with them. They're non-invasive. And I think there's what I'm interested in and is actually using these devices to look at other volatile organic compounds that may be important health biomarkers. For example, you know, it gives you information on oxidative stress. So you have things like isoprostanes, things that could detect from what I'm interested in is like oxygen toxicity.

Starting point is 00:30:14 Pulmonary oxygen toxicity will kind of be characterized by blowing off certain volatile organic compounds. And I think our gut microbiome too will influence, the gut microbiome will influence the volatile organic compounds that are coming out of our mouth. And I think these things can be picked up. And once we understand them, we can develop devices to measure these things in our breath. And I think no one has done it yet, but I don't know why it's not possible, but saliva ketone measurements, I think that might be something to look into. So if anyone out there is listening, maybe a saliva ketone measurement system could be useful. The next question is Jeff Henderson, and he writes, I'd be really curious about how ketosis affects performance at altitude. So I live in Big Sky, Montana, do a lot of backcountry ski touring, climbing, mountaineering. I've noticed a significant performance increase while in ketosis.

Starting point is 00:31:23 I'm currently trying to get enough friends willing to do a ketogenic diet so I can put together an actual experiment with a decent size data set. So I don't know what he'd measure if he did that. I would love to hear Tom's thoughts on this. Okay. So there's an increase in brain blood flow when you are in a state of nutritional ketosis. So that may reverse some of the things that we know happen as a response to altitude. There's, uh, some individuals can have hypocapnic cerebral vasoconstriction. So that could maybe be reversed or mitigated in part with nutritional ketosis. There's also things like at altitude, you can have an increased intracranial pressure. And the diet actually has a well-described diuretic effect. It's fairly mild, but it can maybe reduce some of that

Starting point is 00:32:25 intracranial pressure that people at really high altitudes can experience. So we know too that the energy production that our bodies in general probably can generate energy more efficiently with ketones than it can with other types of fuels, with glucose in particular. And then we can probably derive more energy per oxygen molecule. And I would probably direct you to some of the work that was done by Richard Veach's lab. And they did work with a working perfused heart preparation, and they looked at the delta G of ATP hydrolysis, and they look at the hydraulic efficiency of the

Starting point is 00:33:13 heart, which increased significantly when the preparation was perfused with ketones relative to glucose, right? So there's also a book written by Andrew Murray and Hugh Montgomery. And that book, the title of it, How Wasting is Saving, Weight Loss at Altitude Might Result from an Evolutionary Adaptation. So this book kind of describes how nutritional ketosis may mitigate some of the weight loss that's associated with being at altitude. Peter Attia also gave a talk, if I remember correctly, at IHMC. If you Google Peter Attia IHMC lecture, he gave a discussion on the performance enhancement effects that he had with the ketogenic diet and also described cycling at high altitude.

Starting point is 00:34:11 I think the balance of the data from a scientific perspective and from feedback that I get would suggest that being in a state of ketosis can enhance exercise performance at altitude. Another person I've been communicating with recently is Patrick Sweeney. He actually recently teamed up with professional mountain biker Rebecca Rush, I think is her name, and they did a climb and a descend on Mount Kilimanjaro on their mountain bikes, right? So this was a mountain bike climb. And the mission was totally self-supported, meaning that they didn't have any porters to carry their bags or anything.

Starting point is 00:34:59 And they abstained from using acetazolamide, which is Diamox, the medication that you take for altitude. And so they didn't get altitude sickness. So the goal of what they're trying to do, Patrick Sweeney and Rebecca Rush, the goal of the expedition was to raise $1 for every foot of climbing they did. So that amounted to a little over $19,000 for an organization called World Bicycle Relief. And Patrick had communicated with me prior to attempting this Mount Kilimanjaro bike ride. And I kind of coached him a little bit and just talked about the ketogenic diet and how you do it and sent a number of emails. Um, just Google Patrick Sweeney bike ride and should bring you probably to this event and give you more information on it. And the next

Starting point is 00:36:00 question is from Lindsay Watkins. Lindsay asks, I'd like to hear about any differences or considerations females need to have with the ketogenic diet. So what I've observed is that, and this may even apply to our rodent models, the transition into ketosis can be more difficult for females in general. It seems that they're more variable in their responses, reactive, I would say, to low blood glucose levels, especially initially. And I would recommend that females trying this sort of ease into it before just going all out ketogenic. So a slow transition into a ketogenic diet, maybe dropping your carbohydrates if you're at 200 down to 150, and just do it in 50 gram increments and titrating it down. Another option would be the use of exogenous ketones.

Starting point is 00:37:08 When you go on a ketogenic diet, your brain goes through what I'd call glucose withdrawal effects. You might be able to fill that gap initially until your body starts making ketones, upregulating the transport and utilization of ketones, you might be able to fill that gap by taking exogenous ketones or just simply using something like medium-chain triglyceride. The C8 would be the most ketogenic fat out there. Another issue that females run into is that when a lot of women start this, they tend to start a ketogenic diet in a calorie deficit. So they go right into a calorie-restricted ketogenic diet. So you have sort of the double whammy. getting to the brain and then calorie restriction on top of a radical shift in macronutrient,

Starting point is 00:38:08 you know, profile of their diet. So that they're going to get a reactive response from that hypoglycemia. And, uh, and some women can manifest itself in strange ways, from fainting to irritability to foggy-headedness. So the idea would be, and my suggestion would be, to keep your calories actually higher when you start ketogenic diet. So you want a calorie surplus, at least initially, to help with the transition that's high in fat. So do not, it's hard for some people, especially in the fitness industry, when they start a ketogenic diet, they have to be not afraid of eating fat. So, you know, 100 grams of fat per day is really not a lot of fat. So, you know, a hundred grams of fat per day is really not a lot of fat. So I'm getting upwards of about 200, 250, 300, even on some days. So for the average size female, you want to get,

Starting point is 00:39:17 you know, at least a hundred grams of fat upwards to, you know, depending on your size and your output, maybe even up to 200 grams of fat. That would be my suggestions there to help with females. Now, the hormonal changes that have been reported by some females following a ketogenic diet, suppression of thyroid. So I'm just looking through my emails here different females yeah that seems to be sort of that one of the major concerns when I probe a little deeper the people that are getting you know a suppression

Starting point is 00:40:00 of some of their hormones they're exercising a minimum of two, sometimes four, six hours a day training for an event. So the scenario that you have is you're transitioning your body to a new diet, high carb to low carb on top of calorie restriction. You do have an energy deficit that's caused by a restriction of calories, it appears, and also overtraining. And overtraining is the fastest way to really kick down your hormones. For males, it manifests as low testosterone. For females, it can manifest in many different ways. The thing that I see most is a reduction in T3. So the next question comes from Kami Orion, and she asks, can a female

Starting point is 00:40:57 obtain a sub 10% body fat with a ketogenic diet? if so is there a daily calorie threshold relative to my basal metabolic rate or other factors to reach that level of body fat also kind of another common question women wanting to do the ketogenic diet to get as lean as possible of course there's a lot of women in the fitness industry or fitness competitors that are using this approach. So the first question is, I don't know what she's doing, if this is for cosmetic reasons or if she is an athlete and wanting to just perform as optimally as possible and thinks she gets needs to get below 10 body fat so the first question i would have for her is why do you want to get below 10 body fat so essential fat from my understanding in women is between 8 and 12 so roughly 10 fat is needed for normal physiological, hormonal, and body functions in women. And I think it's important to keep above that, and it's highly dependent upon the person.

Starting point is 00:42:15 You know, some women are just naturally very lean, and other women have a higher set point. I would advise against trying to achieve 10% body fat for performance unless you're genetically exceptionally lean to begin with. When highly trained women at just 15% body fat, which is very lean for women, trains and diets to sub 10% body fat, they tend to get these hormonal issues. I would call it functional hypothalamic amenorrhea. So it even has a term, I believe. I just read an article on this. And this is extremely common in the fitness industry. And sometimes it's not easily readily reversible. So if a ketogenic diet approach is used, it will be a greater fat turnover. And I would advise sort of like the last question against consuming less than 100 grams of fat. So some of the macros that were sent to me by women that were doing a ketogenic diet were like 60 grams of fat, upwards of 70 and 80 grams of fat.

Starting point is 00:43:30 And they thought that was very high. So I would advise against consuming less than 100 grams of fat, especially for a female athlete. So consuming this high level of fat keeps your fat metabolism sort of optimized. And it also is the source of ketones, of making ketones. So probably the most experienced individuals on this topic achieving sub 10% body fat would be female fitness competitors who routinely get below 10%. And as mentioned, they do report a lot of menstruation irregularities. Women who have successfully implemented the ketogenic diet and are aware of how to do so, some of the women that come to mind would be Shannon Yorton Penna from Quest Nutrition, who is really a very experienced fitness competitor and just an overall great person around. And she has been in a state

Starting point is 00:44:39 of ketosis, I think, for at least two years now. And Quest Nutrition is sort of developing, testing, ultimately they'll be marketing ketogenic diet food products. They already have the Quest MCT oil powder, which is fantastic. So the next question comes from Renee Volcho. How does ketosis affect the microbiota, specifically the balance of formicides to bacterioides? So that's a great question. And it's highly dependent upon the diet that you're following, right? It's really, we're just at the cusp of understanding the gut microbiome. And there's, so relating this question to the ketogenic diet and to give an answer on it is kind of difficult because there's many variations

Starting point is 00:45:40 of the ketogenic diet, right? The modified atkins would be much more liberal in the amount of vegetables that you consume what I've garnered just from reading what I can as far as studies that have been done that and talking with the scientists who are this area of research is that you can train your gut microbiome to sort of be ketogenic. There's bacterial species in your gut. And I don't know, I have a list of them that actually thrive off fat. And these bacterial species tend to be the beneficial ones. They're very good for us. So that changes dramatically, you know, as when we change our diet, our gut microbiome also changes its diet and will adjust the ratios of various species in the gut and a shift towards more bacterial species that thrive off fat. My general recommendations to optimize the microbiome,

Starting point is 00:46:47 and my knowledge is nowhere near that of researchers out there like Alessio Fasano. I'm just a chair of pediatrics at Harvard Medical School. He actually gave a fantastic IHMC lecture. So IHMC is the Institute for Human and Machine Cognition lecture on this topic. So I would recommend that listeners go to that lecture and look up Alessio Fasano. He does not study the ketogenic diet, but he is the leading expert and most knowledgeable person out there on the gut microbiome. So for those following a ketogenic diet, things that I think could optimize the microbiome would be sort of the obvious things we always talk about or hear about would be probiotics. So green vegetables, preferably in raw form, salads, things like asparagus, artichoke, cinnamon

Starting point is 00:47:49 is kind of prebiotic, and probiotics. So lactobacillus, bifidus, there's a number of other bacteria out there that could be supplemented. I don't feel like the ketogenic diet would compromise the gut microbiome in any way, even in those individuals that limit their fiber. So I haven't heard that that's been a problem for them. But to prevent it from being a potential problem, the use of these prebiotics and probiotics, fermented foods, things like sour cream are part of my diet.

Starting point is 00:48:31 And it's important to pick a sour cream that has a good complement of live cultures in it. So another thing that people have emailed me about, and I think Rhonda Patrick actually mentioned this to me in passing, and a couple people emailed me about the benefits of a supplement. It's called VSL3 or VSL number three supplement. And I think that I haven't taken it myself, but just from the number of emails I got from people who have taken the supplement and they've taken it with a ketogenic diet. Not that they had problems before the ketogenic diet, but they felt that it was a good complement to the ketogenic diet. The VSL-3 supplement is a probiotic supplement.

Starting point is 00:49:20 It's used for people with Crohn's disease colitis IBS if you've used an antibiotic which I just did actually just finished a course of antibiotics I got a strange bug bite in Southeast Asia that sort of got infected and was like MRSA so I took a full course of antibiotics and used a probiotic supplement that was similar to VSL number three and had absolutely no issue with any kind of gut problems. And typically the last time I used an antibiotic was over 20 years ago and it completely destroyed my gut. And this time I took a probiotic supplement and had absolutely no problems. I don't know if I would have had problems if I didn't take the supplement, but it helped. And so a probiotic supplement may also be

Starting point is 00:50:13 good. I guess the lesson I learned is kind of when you travel too, when you move someone to a different location and they're for any sufficient amount of time, weeks, you're changing their gut microbiome. And I think that really needs to be studied. And I think in general, we need to understand if the ketogenic diet disrupts the microbiome. And we have to understand if things like travel can disrupt the microbiome. I imagine there's many things that are disruptors of the gut microbiome. And as we start to do research, I think these things will be more clear and things that can optimize the microbiome. And I think probably more importantly, even for our servicemen,

Starting point is 00:51:03 and I know the Department of Defense is interested in this, NASA is interested in this. Obviously, the space environment is probably not, or putting guys and, you know, moving them continuously across the globe is probably not the best way to optimize the gut microbiome. But there's also questions like things like artificial sweeteners, if we're drinking chlorinated water, antibiotics in our food. So many things to consider when we consider the gut microbiome. So relating back, I went off on a tangent, but when it comes to the ketogenic diet and the gut microbiome, we still have a lot to learn, but recommendations would be to have a diverse diet as much as possible. And from my understanding, the bacteria, there's going to be a bacterial shift from carbohydrate-thriving bacteria to bacterial species that thrive off fat. So from my understanding, that's not a negative thing. So the next question

Starting point is 00:52:07 comes from Mary Takala Adi, and she asks, she's currently on the ketogenic diet. However, she's confused. Should I count my calories? I'm definitely restricting my carbs and increasing my fat intake, but keeping track of calories along with meal planning seems overwhelming. If I don't worry about calories, will I gain weight on the ketogenic diet? So, yes, of course you will. So there's that simple thermodynamics. If you're putting in more calories into your body than you're burning off, those surplus calories are going to end up as stored body fat or manifest itself in metabolic derangement over time. A number of times when people transition to a ketogenic diet,

Starting point is 00:53:00 they will just kind of go crazy with some of the ketogenic diet foods that are sort of indulgent. And that would be things like butter or sour cream, or, you know, I can sit down with a bag of macadamia nuts or cashews and polish that off pretty quick. You know, that's a thousand plus calories. And this is really important to understand. The energy density of the ketogenic diet is about twice that of a normal diet. So the amount, the volume of food that you're eating is smaller. And it may seem like you're restricting. So the volume of food that's on your plate will be much less than when you are not on a ketogenic diet. If you're keeping it isocaloric. But chances are that over time that you'll inadvertently self-restrict on the ketogenic diet.

Starting point is 00:53:52 So your blood glucose will be, there's far less fluctuations. You won't have these big postprandial excursions in your glucose that kick off a surge of insulin that make you hypoglycemic a few hours later and make you kind of craving another bolus of food again. So that sort of whole cycle is eliminated. And that was really eliminated in me. Probably one of the most practical advantages that I've been able to realize from the ketogenic diet is the control of hunger. And I think that has a huge carryover effect when it comes to being able to have control of your food intake and not having your food intake sort of control you. So tracking is a very tedious process, but after you do it, after a certain point,

Starting point is 00:54:44 you really don't have to. I can look at a piece of meat or oil or some green vegetables on my plate and just calculate the macros in my head, really. And sometimes I'll just sort of weigh it out and do it and double check sometimes to make sure I'm right. But it's not a... Nowadays after you follow the QJ diet, it's not a laborious process. One trick I've learned is that before dinner, which is my main meal of the day, I'll have a bowl of soup.

Starting point is 00:55:14 And the kind of soup that I have is usually broccoli cream soup or cream of mushroom soup. And instead of using whole dairy cream, I used concentrated coconut milk in place of the dairy cream. And I thin it out so it's not super dense in calories. But after eating that, the amount of food that I want to consume, it's like cut in half. Obviously, that's a lot of calories too, but it's really super ketogenic. So the next question comes from Dominic Bushman is his name. And he asks, how do you feel about the usual crappy food served at scientific conferences? And in parentheses, the smartest people seem to have the worst lifestyle. And he asked, what are my nutritional tricks to survive attending these scientific conferences, which I'm about to jump on a plane now and go to a scientific conference in Europe.

Starting point is 00:56:16 And I know that the foods are going to be very tempting over there in Budapest, actually. They have very good food over there. Luckily, it's pretty keto friendly. So I'm not a purist when it comes to really following the ketogenic diet. So if someone was to follow me around when I'm traveling and looking what I'm getting off the menu, they probably wouldn't think I'm following any kind of weird dietary patterns. You can almost always get a salad and you can almost always ask for extra butter, extra olive oil to put on the chicken, beef, or fish that I put on the salad. But generally, I limit dairy, protein when I'm home, but will indulge a little bit when I'm traveling. Of course, cheese is ketogenic. So my recommendations for what I do,

Starting point is 00:57:15 as I've probably mentioned before, is that my bags are packed now and I have a case of sardines and a case of oysters, and they are packed in extra virgin olive oil. And I also go to a store near me, and I buy bulk macadamia nuts. And I think macadamia nuts agree with me more than almonds and other types of nuts. The conferences that I attend, they actually do have an appreciation for nutrition and they have a fantastic array of food there. Other conferences, not so much. But I think, you know, it's always people say, I can't follow the ketogenic diet because, you know, I'm a business person.

Starting point is 00:58:00 I'm traveling all the time. It's just not possible for me to follow this diet. So what should I do? I think it all the time. It's just not possible for me to follow this diet. So what should I do? I think it's actually easier. The ketogenic diet is far easier to follow if you are that kind of person who's on the move all the time. So the food that you're consuming is much more energy dense. It's less weight. It's less things that you have to carry in your bag. Sardines and oysters and macadamia nuts take up a very small amount of weight,

Starting point is 00:58:29 relatively speaking, and they have a really high energy density. So I tend not to like to take a check bag when I travel to scientific conferences. I can bring just my carry-on and get, and I've calculated this, I can get about 10,000 calories of food on my carry-on really easily and have all my clothes for a week. So I probably couldn't do that if I wasn't on a ketogenic diet. So the next question comes from Willie Chertman. Do stimulants aid in ketosis? And are there any particular stimulants that are good? Yeah, I think caffeine has a ton of research behind it.

Starting point is 00:59:17 The military is a big fan of caffeine, and the military has a really high bar in regards to their safety, in regards to their efficacy. And they're incorporated into different food products like the first-strike ration is something that they make up their innate combat feeding center there. And it's basically just sugar and caffeine. So I think they need to change that. But caffeine has long been a staple in my diet in the form of coffee. Right now, sipping on my coffee with MCT and caffeine is just starting to kick in. And I feel it. And I feel good on caffeine and I don't feel any negative effects from it. Over 200 milligrams of caffeine in me raises my blood sugar. 100 milligrams seems to be the sweet spot. 200 milligrams of caffeine will cause an overactivation of the sympathetic nervous system,

Starting point is 01:00:21 maybe produce some anxiety. And it tends to,ine mobilizes free fatty acids from adipose, but it also kind of breaks down glycogen from the liver. If my glucose is sitting at 70 and I take 200 milligrams of caffeine, I'll see a bump up to 75, maybe even 80 with that amount of caffeine. But 100 milligrams seems to be a good sweet spot for me. Caffeine is an appetite suppression. It has antioxidant effects in the form of coffee. And I have a couple papers on my desk.

Starting point is 01:00:57 I started reading about the effects of coffee on liver function, too, and improvement in liver function. So another stimulant that I like to talk about and that I used a lot when I was younger is ephedrine, ephedrine hydrochloride. I don't know if it's still available. We use it in the lab. We did experiments on pseudophedrine and CNS oxygen toxicity. Divers will pop lots of pseudophed before

Starting point is 01:01:27 they go diving because they want their sinuses to be clear so they can equalize, right? If you're not, if you can't equalize, if you reserve a whole day to go diving and you're stuffed up and you can't equalize, then you're out of luck. You can't dive. It's too painful and can be really dangerous. So ephedrine is actually pretty big in the diving community. I mean, I always took it before I went diving, but we did a study showing that ephedrine can actually decrease latency to seizure at a particular level of hyperbaric oxygen that would, you know, stimulate a Navy SEAL diet to say 132 feet of seawater. So you're, you're getting an overstimulation in the brain, uh, with, with ephedrine. Uh, so I think with, with a high dose, so that's the thing. It's all relating to

Starting point is 01:02:19 the dose. I think ephedrine is a great stimulant that could aid in ketosis and it can help the release of fat from adipose and enhance beta oxidation of fat in the liver. Personally, I've seen that ephedrine can kick me into ketosis pretty fast and ephedrine caffeine stack. It can kick on AFib in some people. So especially if the dose gets high, you know, 50 milligrams or more per day, but 25 milligram dose of ephedrine or less per day can elevate your mood, can cause pretty significant noticeable appetite suppression. And it's more of a psychological effect when it comes to getting a physiological response, 50 milligrams to 100 milligrams a day of ephedrine to get a really measurable increase in fat

Starting point is 01:03:14 oxidation rates. And that would give me side effects. So, and again, I don't, I don't even, I'm not sure if ephedrine is still legal. So don't, don't take this as a recommendation. But I think 25 milligrams of ephedrine can improve your adherence to a nutritional protocol just simply by suppressing your appetite and giving you more energy, which you're going to want to go work out. You're going to want to exercise longer. And I would strongly advise against the use of amphetamines. I don't see they're addictive. And generally people who take

Starting point is 01:03:53 these things just have a bad outcome. They get addictive to it, if not physiologically, psychologically. Modafinil is something I've kind of been interested in testing and i've but i've never taken it but i've talked to people who have taken it um i did get an email just yesterday actually from a woman who's been on modafinil for over 15 years continuously and she was able to get off of it well she had narcolepsy i think but she was able to get off of it uh when she got into a state of nutritional ketosis and um and wrote me a kind of a really nice email long email just saying that uh like this basically uh the ketogenic diet kind of saved her from this continuous abuse she thought She thought her use of modafinil was more or less like an abuse of it for many years. So it's approved for military use and before a mission.

Starting point is 01:04:57 So in a state where sleep deprivation is unavoidable and you need to maintain cognitive resilience, the use of modafinil can be a good idea. Tim actually asked me to address this question. Can a vegetarian or a vegan follow a ketogenic diet? You can look up. Beth Zupak-Kenia is the lead dietitian for the Charlie Foundation, and it may not be posted on the website, but I know she works directly with patients and customizes a vegetarian or even vegan ketogenic diet, many of her patients, and uses, to achieve ketosis, she uses higher amounts of MCT oil.

Starting point is 01:05:43 So there's a couple websites, too, that I noticed. I did a quick search online. Keto Motive, K-E-T-O-M-O-T-I-V-E, and Keto Diet App are two websites that I find were really helpful in regards to listing the foods and listing the type of different recipes that a vegetarian or vegan ketogenic diet could be sort of adjusted to. How do we help people that are vegan follow a ketogenic diet? And I think the solution, the main problem would be the protein. It's just hard to put together foods that have a complement of essential amino acids. So you could just supplement with essential amino acids, and that's one option.

Starting point is 01:06:31 And the other option would be plant-based protein isolates that are hemp. You have rice protein isolate. You have pea protein isolate. You have pea protein isolate. Ten years ago, there was plant protein, but it had a lot of carbs in it. And nowadays, you can get 30 grams of protein with like one or two or maybe three grams of carbs. And that completely fits in with a vegan ketogenic diet. So one of the products that kind of stood out, and just looking at the reviews and with the taste and the macronutrient profile, would be a product called MRM Veggie Elite Protein Powder. And the chocolate mocha is very good. So if you take this MRM veggie elite protein powder and mix it with coconut cream or what would be concentrated coconut milk, throw in a half

Starting point is 01:07:33 avocado, pour in some MCT oil, the CA oil and do it. So the little mixture that I made up was 80% of the calories were from fat and 25% of the calories were from protein. So I just titrated it. It's just like one scoop of protein powder, I think. And, uh, and 15% of the calories were from, uh, carbohydrates and it was really pretty much fiber, high-fiber carbohydrates. So this gives a ratio of 2 to 1. So 2 would be fat, and the 1 would be a combination of carbs and protein. So if we're kind of relating it back to the classical Johns Hopkins ketogenic ratio ratios that they use and it's 900 calories. And that was a really good kind of example of a pure vegan. And I posted that on my Facebook yesterday. So yeah, ketogenic diet is possible, pretty easy for vegetarian, a little more difficult for a vegan.

Starting point is 01:08:42 I'm going to work on this and maybe even work with a colleague of mine to write a book that covers this subject. And if someone hasn't kind of written a book already, I see some blogs online, but not a whole lot of resources out there for vegans that want to do a ketogenic diet. So many people, the next question, should I be concerned if the ketogenic diet increases my LDL or LDLP particle number? I'm a little bit concerned and I'm still learning about it. But if your LDL or LDLP skyrockets and stays elevated after several months, you might want to be concerned about it. Or just kind of pay more attention to tracking certain aspects of your health, particularly your inflammation and your blood lipid levels.

Starting point is 01:09:42 So the number of LDL particles may be increased because you're also carrying more triglycerides before you get a lipid profile test done and you start looking at these numbers. Make sure that you're rested. Make sure you're not stressed. Make sure you don't have any kind of infection, which will increase it. So what I've seen with the ketogenic diet is that the LDL will go up in about 50% of the people who follow a ketogenic diet, and especially if the calories are not restricted. So if you're restricting calories on a ketogenic diet, which many people do that use the diet to manage for the management of epilepsy or cancer. Even in that population where the ketogenic diet is sort of calorie restricted,

Starting point is 01:10:32 about 25% of them will sort of email back and say, well, my doctor's following me and this is going up, but a lot less if calories are restricted. See this phenomenon. So I think it's important not to stress out about it and to kind of look at the big picture. So the first book I had was the book from Johns Hopkins that was written by John Freeman and Eric Kosoff. And that described, you know, the classical kind of a dairy-based four-to-one ratio classical ketogenic diet. And that kind of shifted my numbers in interesting ways. My LDL went up, but so did my HDL doubled almost from like 50 to almost 100 after about four to six months, I think.

Starting point is 01:11:23 So right now my HDL is 98. Right now I've transitioned into what I call a supplemented modified Atkins or modified ketogenic diet and supplemented because I do take in C8 and I do take in some exogenous ketones in the form of some of the products that are on the market. I'll talk about that a little bit more. So I'm using a supplemented modified ketogenic diet similar to the macronutrient ratios that's described on the website. The Foundation website has a good description of the modified ketogenic diet. My ratio is looking pretty good. My total cholesterol to HDL ratio is like 2.4

Starting point is 01:12:10 right now for my last blood test. So my total cholesterol is 238 and my HDL is 98. Triglycerides range from 40 to 70. These numbers are really similar to other people that have emailed me that were concerned. And my inflammation, marker of inflammation, CRP, was really low. I'm going to do a whole cytokine assay. When I was on a high-carb diet, my CRP was 2, 2.4 a couple times. Now it's like 0.2. So literally in the last three blood work that I'm looking at now, it ranged from 0.1 to 0.3. So when I was on a high-carb diet, it's literally 10 times higher. Rarely have gotten sick when I'm on the

Starting point is 01:13:05 ketogenic diet. And I do think that it helps with immune function. That's another area I could talk about. We talk about the ketogenic diet being kind of a panacea for everything. It cures the common cold. I have not had a cold, probably maybe one cold in the last six years. And I used to routinely get a cold every year, at least once or twice a year. So in the last five years, I have one cold that I could remember. But infection, I did get, I traveled overseas, I believe it was to Honduras, and I picked up some kind of stomach bug or probably a virus, I think. And this really skyrocketed my LDL.

Starting point is 01:13:59 So I talked a little bit about stress and infection, sort of increasing that. And that was really surprising. I mean, it was like off the charts. So it may have been sort of something wrong with the test. But I think something to consider that when you do get these tests done, you want to make sure your body is truly at baseline when you're looking at the effects of the ketogenic diet. So in general, I would not be concerned with an elevated LDL unless it was in other biomarkers were also out of whack. So the things to look at would be your triglycerides, your CRP, and if your HDL goes down, that's not a good thing. I think the thing that I kind of focus on most is triglycerides.

Starting point is 01:14:47 If your triglycerides are elevated, that means your body is just not adapting to the ketogenic diet. Some people's triglycerides are elevated even when their calories are restricted, and that's a sign that the ketogenic diet is not for you. So you can't deny that. It's not a one- fits all diet. You do find about a quarter to a third of people just, you know, have these abnormalities in their blood work that would indicate they're not adapting to the diet. Maybe they could give it more time, but some people, you know, have given it three to four months and still have elevated triglycerides. Pretty rare. And most of the people

Starting point is 01:15:28 that I talk to kind of thrive on a ketogenic diet, but you do have many people who just should not follow it. The next kind of branch of questions I'm going to address would be exogenous ketones. This is a question that popped up recently and it comes from Carson Rowe. Dozens of people have asked me this question, so I want to address it right up front. So is it dangerous to use ketone salts, which are racemic? So there's the ketone salts that are on the market now, from my understanding, have a D and an L configuration. Dr. Richard Veach, who's a ketone expert on Bulletproof Podcasts, and Dr. Veach said that he would avoid ketone salts at all costs. Something about real versus mimicked molecules, etc.

Starting point is 01:16:22 As Dom and others, like Patrick Arnoldnold have said these are good and fine uh what gives what's going on so so dr beach's uh i admire before i even just like to say dr beach was kind of a mentor to me getting into this area um i think it was back in 2008 i didn't even know that 2008 and 9 i didn't know that exogenous ketones existed until I found some of his patents. And patents that even predated his were from Dr. Henri Bruningrabber at Case Western. I think the first was like a Canadian patent in the early 90s on a ketone ester. So Dr. Veach has been sort of a mentor to me in this process and helping me understand sort of the benefits of exogenous ketones. So his comments on Dave Asprey's podcast and more recently Ben Greenfield's podcast have created a lot of confusion because his comments

Starting point is 01:17:23 were not scientific fact. They were his opinion, and that's really important to keep in mind. Also keep in mind that Dr. Veach has a lot of intellectual property sort of tied up in the R enantiomer of the ketone ester. So more specifically, the R13-butanediol, R-beta-hydroxybutyrate, monoester would be like the main, sort of like the single ester that he's focused on. So the appearance of these ketone salts and the salt, the beta-hydroxybutyrate is not you know completely tied up with sodium so it's actually balanced across four different monovalent and divalent cations right you have sodium potassium calcium and magnesium that many of these products are using, like the Keygenics product, I think.

Starting point is 01:18:25 The Pruvit product, I'm not exactly sure what the blend is, but Dr. Veach is kind of critical about the sodium content and about what he called the non-natural isomer that was found in there. I know Dr. Veach is working very hard to commercialize, he's been working hard for a decade or more, to commercialize the monoester of the R-beta-hydroxybutyrate. So, Henri Bruningraber, who is Veach's colleague, they've actually published together, demonstrated the metabolism of racemic ketones. And a number of elegant studies he actually used, these were tracer-based studies, were

Starting point is 01:19:12 sort of labeled the carbons of the ketones and could see where they go. And it was clear from the science that the S enantiomer just simply gets broken down to acetyl-CoA and can even interconvert back to, by sort of further elevating levels of acetyl-CoA, that can actually kind of feed back into the biosynthesis of the R-beta-hydroxybutyrate. There's a couple of nice papers that kind of show that. The first one, the one that I'm thinking about, looked at the R and the S-1,3-butanediol metabolism in the liver of rats. There's no data to support Dr. Veach's claim that the ketone salts that are on the market are dangerous or ineffective. And that would include KetoSports Ketokena, Pruvit's product, KetoOS.

Starting point is 01:20:14 You have the Kegenix product is also using the racemic salt. Forever Green has product Ketonix or Ketopia. So many emails, dozens, if not hundreds of emails I've gotten from this of people that were concerned. And it's kind of easy. Dr. Veach is a very esteemed kind of researcher. And I think he firmly believes that the R enantiomer is sort of the way to go when it comes to exogenous ketones. And I did too. I think our lab, actually the first ketone ester that we tested for CNS oxygen toxicity

Starting point is 01:20:54 was the 1,3-butanediol beta-hydroxybutyrate monoester in the RN antemir, and it didn't prevent oxygen toxicity seizures. So it elevated pretty much exclusively beta-hydroxybutyrate, and I was going to give up on the project. And then I discovered an earlier patent by Henri Bruningrabber that had a 1,3-butanediol combined with acetoacetate. And that, to me, made perfect sense, right? Because when you consume it, it hydrolyzes in your gut, so you release the acetoacetate, and that's one of the ketones that the body uses. And then the 1,3-butanediol goes to the liver

Starting point is 01:21:39 and gets broken down completely to beta-hydroxybutyrate. And the pharmacokinetics were beautiful. You get kind of a one-to-one ratio of beta-hydroxybutyrate and acetoacetate in the liver. And that particular ketone ester gave remarkable neuroprotection against CNS oxygen toxicity. So that was like the second ketone ester that we tested. Patrick Arnold helped me synthesize it once we got the synthesis formula. And Henri Brunengraber was very kind to just give it to me and tell us how to do it. And that was racemic. So that was racemic 1,3-butanediol, which breaks down to the two enantiomers of beta-hydroxybutyrate.

Starting point is 01:22:23 So it was remarkably effective in our hands. So I knew there was more to the story than this. I've also served with Dr. Veach on various workshops and can say that he's very opinionated when it comes to the ketogenic diet. He thinks the diet is sort of a horrible diet and the high fat is very dangerous. And we know that's not the case. And there's not a whole lot of science to back up his claims.

Starting point is 01:22:59 I think there's one paper in Kids and Johns Hopkins that follow the four-to- one sort of classical ketogenic diet. And I think many of the kids were put on a product called keto cow, which is like hydrogenated vegetable oils and things like that. And they had an elevated triglycerides, not very surprising. Right. So I think when we talk about the ketogenic diet, it's really important to acknowledge, and most people don't acknowledge this in the medical community, that the diet, there's many, many versions of the diet. And we still, we have very little research. We still need to determine the optimal ketogenic diet in regards to the fatty acid profile. So we know we need a much greater omega-3 to omega-6

Starting point is 01:23:48 ratio is going to be really important. The level of monounsaturated fats for saturated. I'll say that no scientist, when it relates to the ketone salts, no scientist or toxicologist that I'm aware of would find Veach's comments to be true, that the racemic salts are dangerous in any way, unless of course they're consumed at really high amounts. As we know, water is toxic in high amounts. All things are dangerous. Caffeine, of course, I talked about. Tylenol will quickly kill you if you take too much of it. Many studies actually show, there's clinical studies that actually show these racemic salts are very safe in high doses, even in kids given pure sodium beta-hydroxybutyrate over periods of years. And that actually leads me to the next question that was asked by Emily Bent. And she asked, what's Dom's advice for fatty acid oxidation disorders like MAD or VLCADD, a medium chain or very long chain acetyl-CoA dehydrogenase deficiency.

Starting point is 01:25:06 So MAD is short for multiple acyl-CoA dehydrogenase deficiency. And since being added to newborn screenings, diagnosis have increased massively. So there's a lot of kids, more kids, being diagnosed. So the complications of this particular disorder can involve an acidosis, hypoglycemia, other symptoms such as general weakness, enlargement of the liver, enlargement of the heart is really a problem. So essentially what this disorder, multiple acyl-CoA dehydrogenase deficiency is, is a mitochondrial inefficiency. And it's interesting, if you just go to PubMed and type in MADD, M-A-D-D, and ketones, you get, this is one, just one of the disorders that can be effectively treated with racemic beta-hydroxybutyrate salts. And there's a number of studies.

Starting point is 01:26:19 I'm just going to PubMed now. First study pops up, highly efficient ketone body treatment in multiple acyl-CoA dehydrogenase deficiency-related leukodystrophy. And that was published in Pediatric Research. So that was using the ketone salts, essentially, that are on the market, at least the sodium, racemic sodium beta-hydroxybutyrate salts in these kids. It's a nice description, a summary of that. Another study by a different investigator, favorable outcome after physiological dose of sodium DL3 hydroxybutyrate in severe MAD. So sodium racemic beta-hydroxybutyrate was given, and this can be given in an oral dose or it can be given IV in very high doses. And no side effects from this. The dose that you need to get a measurable boost in blood ketones is not giving you a dangerous dose of sodium. So that needs to be acknowledged.

Starting point is 01:27:30 And I think that was touched upon in Dr. Veach's sort of talk, that there's no way, I think, quote-unquote, he said, there's no way that these ketone salts could even increase ketones, even 0.1 or 0.2 millimolar. But that's not the case. We know that we can get levels into the 1 to 2 millimolar range if you take enough. I think as the technology sort of evolves and we're creating various types of beta-hydroxybutyrate salts from monovalent and divalent cations in addition to alkaline amino acids will combine nicely with beta hydroxybutyrate and that's another

Starting point is 01:28:09 avenue so you can kind of envision a blend of beta hydroxybutyrate spread across you know monovalent divalent cations and alkaline amino acids like lysine arginine histidine cit, citrulline, these are all combined pretty nicely with beta-hydroxybutyrate. So another study actually comes from the Lancet, shows DL3-hydroxybutyrate, so racemic beta-hydroxybutyrate treatment, as a sodium salt treatment of multiple acyl-CoA dehydrogenase deficiency. So it's a really nice kind of study describing the use of this exogenous ketone in several patients that have this disorder. And it was really highly effective in treating that. So in short, ketone salts, the racemic beta-hydroxybutyrate

Starting point is 01:29:08 salts are not dangerous and they're definitely not ineffective. More research needs to be done on all forms of exogenous ketone salts and also exogenous ketone esters. So a lot of work has already been done. You know, one could be more confident in, you know, the medical applications of this and even potential performance applications because when they're consumed, the liver function and kidney function is normal, has been shown even with really high doses. So the next question is Jeff Urbane. Is he truly behind involved in ketogenics? The website is kind of sketchy and the product itself has a surprising number, carbs, but obviously, but still. So he's asking, am I behind ketogenics or involved in ketogenics?

Starting point is 01:30:20 The ketogenics formula or product on the market, it uses the exogenous ketone product is a great product. I use it myself. I used it yesterday. Sometimes I rotate, you know, different things if I'm testing. It uses a ketone formula, a beta-hydroxybutyrate medium chain triglyceride blend that we sort of developed and tested initially in the lab. And we found that if you just take ketone salts, and at the time these were sort of the liquid sodium potassium salts found in Ketoforce, we weren't really able to get an elevation of blood ketones that was really impressive before we started getting some GI discomfort and diarrhea.

Starting point is 01:30:59 So we started tweaking and playing around with different formulas and found that if we took medium-chain triglycerides and blended it together, we got a formula that the fat essentially was functioning like a controlled delivery system. So instead of the rapid peak was a little less rapid, but kept going up, peaked at around 60 to 90 minutes, and then extended out an additional hour or two beyond just taking the ketone salt. So when we blended it with MCT, it allowed the sustainment of blood ketones over time, which is kind of the big thing. And that's why, you know, with the kids that were administered a sodium beta-hydroxybutyrate, they were given IV formulas.

Starting point is 01:31:48 The GI sometimes doesn't tolerate it. And when you bolus it in, the blood levels shoot up and quickly come down. Fat and fiber and protein even, fat especially is a good sort of controlled delivery system. And there's ways to even package that and formulate it to optimize that. So the Keygenics product is not my product, but they incorporate a patented formula that we developed. And I don't own the patent. The university owns the patent.

Starting point is 01:32:20 So Keygenics has worked with our university to get the rights. So I use the product. I don't endorse the product. I need to use 1.5 packets blood into the one millimolar range. When you take it, you definitely feel it. You don't want to take it after like three or four in the afternoon, but you take it early in the afternoon. I'll probably take it, you definitely feel it. You don't want to take it after like three or four in the afternoon, but you take it early in the afternoon. I'll probably take it around lunchtime, one or two. The energy focus you feel is definitely real. My blood work, when I've taken it continuously to a fairly high dose, looked really good.

Starting point is 01:33:01 Markers of inflammation, like almost non-detectable. My blood lipid profile was probably the best it's ever been since I've been ketogenic. The carbs in there are very minimal. You know, what I look at is the glycemic response to a dose, and it's pretty much flatlined in me, so there's no glycemic response and a nice elevation in beta-hydroxybutyrate. Next question, Jimmy Holman, Ketogenics, Keto OS, Prove It, Keto Cream. Is he affiliated with these? Like they claim, if not, does he recommend them? So I've tried all the exogenous ketone products on the market and something I like to do, I like to figure out, you know, what formulas are going to be optimal from the standpoint of using these therapeutically too. So I feel like I'm kind of at the forefront

Starting point is 01:34:00 of understanding what blends of ketone esters of ketone salts whether it be mineral salts and amino acid salts and other things the fun comes in for me is when you start combining these things together and that's what we're doing now and we're doing mostly a lot of pharmacokinetics and toxicology work to understand like what would be the optimal formula of a blend. Is it five different types of salts with two esters in a different ratio? These are with some C8 oil to sort of increase and sustain blood ketones over time. These are the questions that we're asking and some of the questions that we're asking and some of the things that we're testing now. I think the Prove-It product tastes really good. It's

Starting point is 01:34:51 smooth and creamy, and it has a higher concentration of sodium, much higher. And maybe that's why it has kind of like this salty, creamy taste. I've ran out of it. I miss it. I was using it for a while and it ran out. So right now I'm using the Keygenics product, which is really sort of a pretty powerful product as far as the effects that I feel from it. So the Keygenics product, instead of kind of a creamy taste, it has more of a tangy, bitter taste. It's got some green tea extract. So the caffeine, it does give you a little bit of a caffeine boost, maybe about 80 to 100 milligrams of caffeine. And I think that's from the green tea extract. Might be some bitter orange in there. There's a couple thermogenic ingredients in there that you feel after you take the product because you feel a little bit warm.

Starting point is 01:35:46 Forever Green makes the ketonics product. It tastes really good. And I think it also gives, has caffeine in the form of green tea too. It's pretty similar to the ketonics product. It just has a different taste. So keep in mind that the early versions of these products were horrible. This is going back. And I used to blend them. Actually, I blended a mixture out and gave it to my friend Peter Atiyah. And Peter wrote a nice kind of a great summary of his experience with using jet fuel. He's tested a lot of these things, the ketone esters and the ketone salts, and did the study on the bike where he looked at oxygen consumption at a fixed power output, clamped it at 180 watts, and then looked at oxygen consumption before exogenous ketones and after. And at time peter was doing a uh sort of a modified

Starting point is 01:36:47 ketogenic approach so he was in a state of mild nutritional ketosis like 0.6.7 and he would take he took the ketone salts and it shot him up about one to two millimolar and uh kind of dosed him up with a blend that i knew would be approaching his GI tolerability. And I think he did okay. He didn't throw up or have diarrhea, from my understanding. And he really cranked it out on the bike and showed that he was able to maintain the same power output and consume less oxygen, like 5% to 8% less oxygen, which is tremendous. We need to go and reproduce that study.

Starting point is 01:37:27 The next question comes from Gavin Williams. What are his go-to products? His MCT powders, oils, ketone salts, anything else. I kind of cover this. So I test whatever the companies send me. I love to test things. That's why I don't take a whole lot of supplements because I like to keep, uh, unaltered, I guess you could say so I can, um, confidently test these things. And, and, and if I'm measuring various blood,

Starting point is 01:38:01 you know, whether it be comprehensive blood work or blood glucose ketones. I know it's coming from that product. I really enjoy testing the Pruvit product. And I told you I miss it now that I'm out of it. So if they're listening, they could send me some, please. The Ketogenics product is great. And I think they're on version two or three of that now. One of the first times I tried the last formula that they gave me,

Starting point is 01:38:26 I took the product at like 7 p.m. and it kind of kept me up a little bit later than I wanted to. Another product that's really a go-to product, and I keep it at my house, at work, and it's in my suitcase when I travel is the quest MCT oil powder and the quest coconut powder is a big staple of mine. Uh, I've talked about sort of the foods that I've consumed before the wild planet sardines. Sardines are, um, a much more sustainable than, say, like tuna or some of the larger fish out there. These predatory fish also, through bioaccumulation, can accumulate concern like mercury and other PCBs and other things that are out there. So that's important, especially if you're giving your fish to your young kids. Oysters are also one of my go-to food.

Starting point is 01:39:39 The Crown Prince oysters are a really good brand that I like. Lately, there was a bone broth that I use. It's a little pricey, but the company kindly sent me a sample of the test, and it's called Fire and Kettle Bone Broth. And I use it maybe like twice a week. I'll make soup out of it, and I think it's fantastic. I think it's super high quality. Another go-to product would be Cydation makes a product called Extend Perform, which is branched chain amino acids, leucine, isoleucine, valine in a two toto-one-to-one combination, leucine being the predominant branched-chain amino acid in the formula.

Starting point is 01:40:30 And we know that leucine's a powerful activator of mTOR, which is a good thing. Activating mTOR in skeletal muscle is really important. So intra-workout. So I use the product pre-workout and intra-workout. I've used the product a little bit during fasts and I think it could be an effective tool for mitigating some of the muscle loss that can accompany a longer short-term fast, if that makes sense. So like five days or seven days. So the Extend Perform product also has a mushroom blend in it. And I have to go and look to see,

Starting point is 01:41:13 I actually researched all the mushrooms, but they're kind of, it's leaving me exactly which blend it has in it. But the mushroom blend that's in there has been proven to have a pretty pretty impressive data behind it as far as enhancing performance and for lowering inflammation too. The other supplements I take sort of like staple things would be if if I'm not getting a lot of Sun d3 so 5,000 I use sort of if I'm not getting some on days and I'm outside all day I take 1000 I use so don't you know you don't want to get too much d3 so there's a bell-shaped curve and too much d3 will give you the same symptoms of too little vitamin D. So melatonin is something that I take.

Starting point is 01:42:13 It's part of a sleep cocktail I will take. I use it when I cross time zones, and I'll use up to 10 milligrams. But for daily use, I will use like anywhere between one to three or five milligrams, typically. Like three milligrams, I think, is what I have. So Idebanone is another product that I take. I take it when I fly, actually, or before hard exercise. I think of Idebenone as kind of the drug version of coenzyme Q10. It's more absorbable. It gets to the mitochondria easier. It's like a mitochondrial antioxidant. And it's also a drug. It's almost considered a drug for the management of something called Friedreich's ataxia. And I think in kids that take Idebanone, it actually helps them out a lot.

Starting point is 01:43:13 I'm not sure if Friedreich's ataxia is really a tough disorder, but I know from what I know, I'm just talking with the FARA Foundation. So I know a family and a child with Friedreich's ataxia. And the research indicates that idebanone prevents cardiomyopathy or hypertrophy. So it has a real effect. So just enhancing cardiac function has been shown with idebanone. So I think it's available. It used to be kind of hard to find because it was reclassified as a drug, but I think it's, I know it's available on smartpowders.com. You can find it, which has a lot of really interesting things there. Magnesium is a supplement I take daily. Magnesium citrate, magnesium chloride, and magnesium glycinate. I tried them all and they all impacted my blood magnesium levels in a good way.

Starting point is 01:44:12 So when I started the ketogenic diet, I started getting cramps. So one thing that popped out of my blood work is that my magnesium was at the low end of normal. And now that I'm supplementing, now I'm like mid to high normal and I don't get any cramps. If I exercise more, I definitely deplete my magnesium. So, you know, if you're exercising, just be sure that you're getting adequate magnesium. On a ketogenic diet, I think you're utilizing more, excreting more magnesium. And if I had one go-to magnesium, it would be this magnesium citrate powder that I have. So I've looked at things like GABA before sleep, sometimes phenibut, which is ventilated GABA. So GABA, has a, a fennel ring attached to it and makes it permeable to the blood brain barrier. It makes it more lipophilic. And when you take Fenibut, you feel

Starting point is 01:45:12 it. I feel it. You feel much more calm. You get, I get really deep, the most scary dreams when I take Fenibut. It has a pretty good calming effect. So I will use fenibut maybe two or three times a month, if that. I tend to use it when I'm traveling across time zones. I'll take a fenibut melatonin stack before I go to bed. Next question, Leo Falzon, are exogenous ketones, i.e. ketokina, only useful in a state of ketosis, or would they benefit someone who is not keto-adapted? Put differently, can ketones enter the TCA cycle, also known as the Krebs cycle, when glucose is still available to the cell? Or will the body preferentially use glucose, nullifying the effect of the ketones. So ketones can be readily transported into tissues

Starting point is 01:46:07 as fuel if glucose is low or high. And I think the body will sort of use what's available. So if the glucose is low, it'll use a greater proportion of ketones for energy. And it's also, there's some tissue specificity in regards to the monocarboxylic acid transporter. And there's transporters one, two, three, and four. And these have sort of different tissue distributions. Brain is pretty high in MCT2 and 3, I believe. The liver, you know, doesn't use, the liver is a ketone producer, but doesn't use ketones for fuel. And skeletal muscle is kind of like in between. So some data indicates that there may be enhanced glucose uptake and utilization in the presence of ketones. And I know Dr. Veach and others believe that ketones influence insulin sensitivity. And it does it through a number of mechanisms.

Starting point is 01:47:14 And I think through altering redox chemistry, it can do two things. It can enhance the sensitivity of the insulin receptor to the ligand insulin, and it can also cause a sort of a translocation of the receptor to the membrane. And so there's more sort of receptors that are available. And I think, you know, i was a little hesitant to believe some of that but our new data we recently published shows that as ketones go up and this is giving a bolus of exogenous ketones to an animal that's eating a high carbohydrate standard rat chow glucose goes down and you know we don't know why that's happening but that could be part of the effect could without exogenous ketones and how that's influencing liver metabolism. So an alternative explanation could be a decrease in hepatic gluconeogenesis. So I think it may be a number of things kind of working together. So Adam Rockhorst has a question.

Starting point is 01:48:48 Can exogenous ketones combined with a low-carb diet, in parentheses, but not a ketogenic diet, still give some or all the benefits of a strict ketogenic diet? The experiments that we run with exogenous ketones, most of them, excluding the one cancer experiment when we combined the ketogenic diet with ketone ester. So our experiments are typically run using exogenous ketones given to animals eating a standard high carb rodent chow. So I would say yes to this. And I would say yes because our first experiment, originally what I wanted to do was give ketone esters for one week and dive rats down to five atmospheres of oxygen, which is 132 feet of seawater. And we know that they have a seizure in about 10 minutes, and then look at

Starting point is 01:49:45 that latency of the seizure. After talking with a number of experts, and Dr. Veach, too, thought the ketones would work immediately, but a number of the experts were convincing me that you needed to be keto-adapted to get the benefits of exogenous ketones, to get the optimal benefits, I'll say. You know, and I thought they were right because we actually tried Dr. Veach's ester or version of the ester, the monoester of beta-hydroxybutyrate, and it didn't prevent oxygen toxicity seizures. So I was more inclined to believe, at least in acute dose, I was more inclined to believe that you needed continuous kind of long-term dosing to get the brain to switch over. But then we tried the 1,3-butanediol acetoacetate diester, which rapidly elevated beta-hydroxybutyrate and acetoacetate. And that a single dose 30 minutes prior to a five atmosphere dive gave like 600% neuroprotection

Starting point is 01:50:50 or delayed the latency to seizure from 10 minutes to like over an hour, which was pretty much more effective than any anticonvulsant drug like ever tested. So, and that was just simply feeding an animal that's eating a high carb diet, feeding and titrating in the dosage just enough to elevate blood ketones to a level of ketosis on par with a person fasting for one week. So you had fasting level, prolonged fasting level ketosis in 30 minutes. And unlike drugs where you get like a variety of effects, like it worked in this animal, not that animal, like every single animal we tested, we saw this remarkable neuroprotection with the ketone esters.

Starting point is 01:51:38 So that was, it was not my original hypothesis that it would work this way, but it did. I guess Dr. Veach was right, not right about the ester. I think we needed not only beta-hydroxybutyrate, we needed acetoacetate. And his particular ester did not elevate that. I think beta-hydroxybutyrate, elevating that would, for his, he's looking at exercise performance and cognitive benefits too. And I think it would work, you know, beta-hydroxybutyrate alone would probably work remarkably well for that. But when it comes to mitigating oxygen toxicity seizures and also other seizures, the animal models, it's very clear that you need to have an elevation of acetoacetate. And that spontaneously decarboxylates to acetone. And we know that can open potassium channels and hyperpolarize the

Starting point is 01:52:32 resting membrane potential and mitigate some of the glutamate excitotoxicity that's thought to be involved in seizure genesis. And you don't get that with just beta-hydroxybutyrate ester. So answer your question. Yeah, I think you can get exogenous ketones. I went off on a tangent. And you're really talking about combining exogenous ketones to a low-carb diet. Can you get the benefits? Absolutely. I think you can do that. Even on a moderate carb diet, it can probably get the benefits. But there's so many benefits to a low-carb diet in and of itself that we know about. I think it just makes sense to use it with some kind of carbohydrate restriction is really important. And if you look at our cancer study, we did the ketogenic diet and

Starting point is 01:53:25 hyperbaric oxygen, and that had a remarkable effect at prolonging survival in a model of advanced metastatic cancer. And when we combine the ketogenic diet with hyperbaric oxygen, and we combined ketone supplementation, we had a really significant increase in survival and suppression of tumor growth and also metastasis. Hey guys, this is Tim again. Just a few more things before you take off. Number one, this is Five Bullet Friday. Do you want to get a short email from me? Would you enjoy getting a short email from me every Friday that provides a little morsel of fun before the weekend? And Five Bullet Friday is a very short email where I share the coolest things I've found or that I've been pondering over the week. That could include favorite new albums that I've discovered. It could include gizmos and gadgets and all sorts of weird shit that I've somehow dug up in the world of the esoteric as I do. It could include favorite

Starting point is 01:54:35 articles that I've read and that I've shared with my close friends, for instance. And it's very short. It's just a little tiny bite of goodness before you head off for the weekend. So if you want to receive that, check it out. Just go to fourhourworkweek.com. That's fourhourworkweek.com all spelled out and just drop in your email and you will get the very next one. And if you sign up, I hope you enjoy it. This episode is brought to you by Four Sigmatic. I reached out to these Finnish entrepreneurs after a very talented acrobat introduced me to one of their products, which blew my mind in the best way possible. It is mushroom coffee. What on earth is this? Well, it includes chaga mushroom,

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Starting point is 01:56:04 not give you visuals. That's something else. And you can try it right now, this is the answer. So it is legal. It will not give you visuals. That's something else. And you can try it right now by going to foursigmatic.com forward slash Tim. That is foursigmatic, S-I-G-M-A-T-I-C, foursigmatic.com forward slash Tim and use the code Tim to get 20% off your first order. If you are in the experimental mindset, I do not think you'll be disappointed. Four Sigmatic.com forward slash Tim. This episode is brought to you by gymnasticbodies.com. This is the training system that I am most obsessed with at the moment. And I don't get paid any commissions or anything like that. You may have heard coach summer on the podcast to design the program, former national team coach for men's

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The Tim Ferriss Show - #172: Dom D'Agostino -- The Power of the Ketogenic Diet

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