Dr. Dominic D'Agostino on Fasting, Ketosis, and The End of Cancer

1. 0:00 – 5:28

   Start

   1. TFTim Ferriss0:00

      Quick soundcheck. What did you have for breakfast this morning?

   2. DDDr. Dominic D'Agostino0:04

      Eggs and sardines and oysters.

   3. TFTim Ferriss0:07

      Eggs and sardines and oysters. Did you just throw that in the-

   4. DDDr. Dominic D'Agostino0:10

      And broccoli

   5. TFTim Ferriss0:10

      Just-

   6. DDDr. Dominic D'Agostino0:10

      A little bit of broccoli

   7. TFTim Ferriss0:11

      ... you just throw it in a Vitamix? [laughs]

   8. DDDr. Dominic D'Agostino0:14

      [laughs]

   9. SPSpeaker0:15

      Optimal Living. At this altitude, I can run flat-out for a half mile before my hands start shaking. Can I ask you a personal question? Now we're just sitting here talking. What if I did the opposite? I'm a cybernetic organism, living tissue over metal endoskeleton. Tim Ferriss Show.

   10. TFTim Ferriss0:38

       This episode is brought to you by Audible, which I have used for years. I love audiobooks, and I have two to recommend right off the bat. Number one is perhaps my favorite audiobook of all time, and that is The Graveyard Book by Neil Gaiman, the only audiobook I've wanted to immediately listen to a second time as soon as I finished. It's amazing. You will thank me. The Graveyard Book. The second is Vagabonding by Rolf Potts, which had a huge impact on my life and formed the basis for a lot of what became The 4-Hour Workweek. So all you need to do to get your free audiobook and a free 30-day trial is go to audible.com/tim, and you can choose one of those two books, The Graveyard Book, Vagabonding, or more than 180,000 audio programs. So that could be a book, that could be a magazine, that could be a newspaper, could be a class. It's that easy. Go to audible.com/tim. That's audible.com/tim, and grab a book. Enjoy. This episode is brought to you by 99designs, your one-stop shop for all things graphic design related. I have used 99designs for everything from banner ads to book covers, including sketches and mockups that led to The 4-Hour Body, which later became number one New York Times, number one Wall Street Journal. And the brainstorming, a lot of it took place with designers from around the world, and here's how it works. Whether you need a T-shirt, a business card, a website, an app thumbnail, whatever it might be, you submit that project, and designers from around the world will send you sketches and mockups and designs. You choose your favorite, and you have an original that you love, or you get your money back. It's that straightforward. And many of you who are listening have already used it and created some amazing things that I'll be sharing in the future. But in the meantime, if you want to see some of my competitions, some of the book covers, as well as get a free $99 upgrade, go to 99designs.com/tim. That's 99designs.com/tim. Hello, boys and girls. This is Tim Ferriss, and welcome to another episode of The Tim Ferriss Show, where it is my job to deconstruct world-class performers. That means that I interview people ranging from chess prodigies like Josh Waitzkin to celebrities and governators like Arnold Schwarzenegger to everything in between, whether those are athletes, scientists, military strategists, or otherwise. And this episode is a very fun one. It gets into the weeds. If you've loved the episodes with Dr. Peter Attia, for instance, or Pavel Tsatsouline or others, you will most likely love this one. My guest is Dr. Dominic D'Agostino, better known as Dom. Most people refer to him as Dom. He is an Assistant Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine and a Senior Research Scientist at the Institute for Human and Machine Cognition. And when I have questions about ketosis, about fasting, or about the deadlift, I call Dom. Why? Well, among other things, for instance, he has fasted for seven days and then deadlifted 500 pounds for 10 reps. [laughs] He is a beast, both physically and intellectually. He has published or co-authored many different, uh, fascinating papers, research papers. And no big surprise, he's a good buddy of Dr. Peter Attia, uh, whom I mentioned shortly ago. Now, Pete, of course, drinks so-called jet fuel in search of optimal athletic performance, sometimes ends up dry heaving in the kitchen trying not to wake his family, and I enjoy these types of human guinea pigs, of course. The focus of Dom's laboratory primarily is developing and testing metabolic therapies, including ketogenic diets, ketone esters, and ketone supplements to induce nutritional and therapeutic ketosis. There is a lot more to it. Some of his research has been funded by the Office of Naval Research, Department of Defense, et cetera. He's a fascinating guy. If you are remotely interested in, say, cancer prevention or longevity or maximal performance, then this episode will touch on many, many cutting-edge, uh, aspects, theories, and practical implementations of research that is at the forefront right now. So please enjoy my conversation with Dom D'Agostino. Dom, welcome to the show.

   11. DDDr. Dominic D'Agostino5:04

       Thanks for having me, Tim. Appreciate it.

   12. TFTim Ferriss5:06

       Of course. I have my notebook out always when I'm on the phone with you, walking around. I'm, I'm sort of struggling to find paper in my pockets or record notes, so I have all, all of my materials ready. I've spoken with our dear friend, Pete Attia, to sort of plot the, the, the arc of questions that I would ask you, mostly out of pure self-interest.

   13. DDDr. Dominic D'Agostino5:26

       [laughs]

   14. TFTim Ferriss5:26

       But for those people who

2. 5:28 – 9:53

   What Dom does

   1. TFTim Ferriss5:28

      are unfamiliar with you, when someone asks you, "What do you do?" how do you answer that question?

   2. DDDr. Dominic D'Agostino5:33

      Um, well, it depends on who it is, but I tell them... I try to be brief as possible. I just say I'm a scientist and I study, uh, nutritional neuroscience, I think is kind of how I like to phrase it as concisely as possible.

   3. TFTim Ferriss5:50

      And if you're talking to a fellow scientist, how would that answer change, if at all?

   4. DDDr. Dominic D'Agostino5:57

      Uh, I would... I kind of go into kind of, uh- Describing how I study, uh, integrative, uh, metabolic regulation and how what we eat or certain supplements can change our metabolic physiology to, you know, treat, prevent disease, or enhance performance.

   5. TFTim Ferriss6:22

      Very cool.

   6. DDDr. Dominic D'Agostino6:22

      That just kind of sums up, yeah.

   7. TFTim Ferriss6:24

      And speaking of, speaking of performance, and this is a, a question I ask all of my guests, but what is the most you've ever deadlifted after fasting for seven days?

   8. DDDr. Dominic D'Agostino6:33

      [laughs]

   9. TFTim Ferriss6:37

      [laughs]

   10. DDDr. Dominic D'Agostino6:37

       Wow, I'd... Imagine you get a range of responses from that-

   11. TFTim Ferriss6:41

       [laughs]

   12. DDDr. Dominic D'Agostino6:42

       ... question. Uh, oh, okay, so you've talked to Peter Attia. He's filled you in on that. Yeah, so I guess going back, when I really got interested in fasting, I did a seven-day fast, and, uh, it just happened to conclude, uh, right before I had to give a lecture kind of on the topic. And, uh, I went into it, you know, with my glucose, uh, in the mid, maybe 30s, low 40s, and my ketones up there at about five millimolar or so. Uh, and then I, I did go to the gym. Yeah, I, I deadlifted 500 pounds for 10, and I, uh, and I finished off with a one rep of 585, six plates. So that's... I haven't done that since. I haven't done anything that extreme since, but I just felt like, uh, I was inspired by George Cahill. Uh, he was a researcher at Harvard, uh, Medical School, and, um, he did a fascinating study that, uh, that really-- where he fasted people for 40 days, actually, and I've, I've delved into the literature studying that. Well, I thought, "Well, I can do, I can do seven days, you know, if these study subjects were IRB-approved [laughs] in his exten-

   13. TFTim Ferriss7:51

       [laughs]

   14. DDDr. Dominic D'Agostino7:52

       So, uh, yeah, I did that, and I, I found, you know, the first three days were a little tough, but, and then I started cruising along. But at day five and seven, you know, I was feeling my energy level was taking a dip, for sure, but it was-- I was amazingly resilient. Uh, you know, and I felt that had a lot to do with being in a state of fasting ketosis. And I was firmly convinced that, uh... And this is when I just started kind of studying this field, so I was doing a lot of blood work on myself, too, to figure out what was happening. Um-

   15. TFTim Ferriss8:26

       And what, what was the time, uh, what was the year? Roughly, when was this?

   16. DDDr. Dominic D'Agostino8:31

       Uh, this was 2010-

   17. TFTim Ferriss8:34

       Got it

   18. DDDr. Dominic D'Agostino8:35

       ... I think. Going into, yeah, 2009 into 2010. So I'd been into this area of research for about, you know, a year or so. In 2009, I really started, you know, getting research funding to do what I'm doing now. Um-

   19. TFTim Ferriss8:49

       It's, it's funny to me that, uh, these subjects were able to be fasted for 40 days, and everything got approved. But if you, if you wanted to fast animals in certain circumstances, it seems like you can't [laughs] go beyond, you know, one to three days.

   20. DDDr. Dominic D'Agostino9:07

       Oh, yeah.

   21. TFTim Ferriss9:08

       [laughs]

   22. DDDr. Dominic D'Agostino9:08

       Yeah. That's, that's good. You know, I, I serve on, uh, the, the university, uh, Institute for Animal Care and Use Committee. It's called the IACUC. It's just, it's like the animal IRB. And, uh, yeah, they, they, the committee usu- has, like, a reactionary response to anything under 25% calorie restriction, you know? [laughs]

   23. TFTim Ferriss9:29

       [laughs]

   24. DDDr. Dominic D'Agostino9:29

       And if they lose more than, you know, 20, 25% of their weight for a fat rodent, really that's not much, you know. You have to... You can't, you can't do that anymore. You gotta re-feed them.

   25. TFTim Ferriss9:39

       [laughs]

   26. DDDr. Dominic D'Agostino9:40

       So yeah, I am, I am amazed at some of the stuff, you know, got, got approved. I think the IRB was probably on vacation or something [laughs] back then. But-

   27. TFTim Ferriss9:51

       Can you-

   28. DDDr. Dominic D'Agostino9:51

       ... yeah, IRBs are a little different now. [clears throat]

3. 9:53 – 12:13

   The Institutional Review Board (IRB)

   1. TFTim Ferriss9:53

      Can you, uh, explain what IRB is, or define that for people who aren't familiar with that?

   2. DDDr. Dominic D'Agostino9:59

      Yeah. It's the Institutional Review Board that, uh, will review kind of the ethics and the safety of a study before signing off on it, essentially, and, and allowing. It's a committee of people that have kind of, uh, uh, a broad range of expertise and, and they review the, uh, the reason why the study's gonna be done, the methodology, you know, the ethics, the, the purpose and all that stuff, and approve, you know, whether or not the study can be conducted. And it, it really depends on what institute you're at. It, you know, you can use an outside IRB that's outside of the institution, and, uh, you know, companies do that. Industry does that. Uh, but they, they can be a big hurdle. And, and I've found vastly different IRBs. Uh, you know, there's a small college about 10, 15, uh, minutes from here that ran a, a ketogenic diet study in advanced lifters for us, and the IRB was approved in like two weeks [laughs] uh, at University of South Florida.

   3. TFTim Ferriss11:07

      Which is, which is fast.

   4. DDDr. Dominic D'Agostino11:09

      Very fast, yeah, like two or three weeks. So in other IRBs, I think I did one, a pharmacokinetic study for ketone esters, which I'll probably talk more about later. But that one, I think it's been rejected somewhere about seven or eight times. And, uh, and it, I mean, it's just giving it as a single dose, kind of more or less a bioidentical molecule that our body makes, and the committee is just, because it's, quote unquote, first in human, you know, it's, it's very difficult. And, and this is an outside R- IRB, which is less, you know, less, uh, restrictive in many cases. So they can be a big hurdle to an investigator.

   5. TFTim Ferriss11:48

      Yeah, the, uh, uh, especially if, if the 25% or more loss is deemed cruel and unusual punishment. [laughs] And-

   6. DDDr. Dominic D'Agostino11:57

      Oh, okay, for the animal study, yeah.

   7. TFTim Ferriss11:59

      Yeah, yeah.

   8. DDDr. Dominic D'Agostino11:59

      So in, uh, in, yeah, in these, yeah, human studies, it's, you know, there's, there's pretty, uh, pretty stringent criteria on, on the humans and stuff, so.

   9. TFTim Ferriss12:08

      What was the, what was the-

   10. DDDr. Dominic D'Agostino12:10

       But yeah, the, i- the animal studies are pretty bad. [laughs]

   11. TFTim Ferriss12:12

       What was the s- the,

4. 12:13 – 15:53

   Research on advanced lifters in ketosis

   1. TFTim Ferriss12:13

      uh, what was the study that you did on advanced lifters as it related to ketosis, and what's, what's kind of the abstract on that?

   2. DDDr. Dominic D'Agostino12:20

      Mm-hmm. Uh, yeah, that's under review right now.

   3. TFTim Ferriss12:22

      Ah, got it.

   4. DDDr. Dominic D'Agostino12:23

      Uh, and yeah, I'll, I'll give you kind of like the synopsis of it. So we had, uh, 12 subjects, and these were advanced, uh, resistance-trained individuals, meaning that they could squat, and deadlift, uh, and bench a certain percentage, you know, of their body weight, which is, kind of puts them in the range of, you know, the top 10%, uh, of, of lifters out there.

   5. TFTim Ferriss12:44

      What was that percentage, just out of curiosity?

   6. DDDr. Dominic D'Agostino12:46

      Um, I gotta go back. It was, it was some funky number, not like, it was like, you know, 185% or 75%-

   7. TFTim Ferriss12:56

      Got it

   8. DDDr. Dominic D'Agostino12:56

      ... of their body weight squatting for, you know, seven reps or eight reps or something like that.

   9. TFTim Ferriss13:00

      Got it.

   10. DDDr. Dominic D'Agostino13:00

       So it was pretty... It would be, uh, it would be like me, let me see, squatting, you know, 425 or something-

   11. TFTim Ferriss13:09

       Okay

   12. DDDr. Dominic D'Agostino13:10

       ... for a set of six or something like that.

   13. TFTim Ferriss13:11

       Yeah, these are very-

   14. DDDr. Dominic D'Agostino13:12

       It's pretty significant

   15. TFTim Ferriss13:13

       ... yeah, significantly advanced trainees.

   16. DDDr. Dominic D'Agostino13:15

       Yeah. So, uh, yeah, the gist of that is that we did a, a parallel. The control group was on a Western diet, and which is pretty similar to kind of, you know, moderate protein, higher in carbohydrates and, and moderate fat. And the ketogenic diet had roughly 75 to 80% fat, restricted carbohydrates to about 20 to 25 grams per day. And, um, and the fat was also supplemented to some extent with MCT oil and coconut oil. And all the subjects, it was two weeks they had to be on the diet and had to confirm ketone levels by blood and urine. And once they did, we only did a two-week adaptation, which is kind of another subject we could talk about, but they adapted for two weeks and then kind of trained the heck out of them, and every workout was done in the lab, in a human, uh, performance laboratory. Um, and every- everything was recorded. The volume was controlled. All the parameters were controlled. Uh, blood work was done. And, uh, the, the take-home on it was that strength, you know, body composite or I would say strength and performance were maintained and increased, and there was muscle hypertrophy was seen with a ketogenic diet. And, uh, there was similar increases, yeah, in power, in hypertrophy. And the big, the big difference was kind of the overall body composition was more favorable in the ketogenic diet group, meaning they had similar increases in lean body mass, but they lost proportionally more fat. And, uh, that's the study that we completed. It's under review right now. Uh, the first journal kicked it back, so we went in for another journal-

   17. TFTim Ferriss15:02

       What-

   18. DDDr. Dominic D'Agostino15:02

       ... and did some follow-up work with it.

   19. TFTim Ferriss15:03

       Now, what is your, uh, what is your hypothesis, or maybe you already know, but w- how would you explain the maintenance or even development of hypertrophy and power in the ketogenic group when a lot of people associate, say, insulin, uh, with different growth factors and whatnot? And I, I had a conversation, I wanna say it was with, uh, Steven Phinney, very short conversation, and I asked him this because I'd been in a ketotic state for two or three weeks and had experienced, uh, a, a non-trivial amount of muscle growth, and I was really surprised by it. And, uh, he explained in terms that I, I can't recall, but how the ketogenic might- diet might have a, I guess a, like a branched-chain amino acid sparing effect of some type. But

5. 15:53 – 20:48

   Can you get big and strong when in ketosis?

   1. TFTim Ferriss15:53

      is it possible to get very big and, uh-

   2. DDDr. Dominic D'Agostino15:58

      Mm-hmm

   3. TFTim Ferriss15:58

      ... powerful on a ketogenic diet? And if so, h- what's the mechanism in the sort of absence of higher spiking insulin levels?

   4. DDDr. Dominic D'Agostino16:07

      Mm-hmm.

   5. TFTim Ferriss16:07

      If that is the parent anabolic hormone-

   6. DDDr. Dominic D'Agostino16:09

      Yeah

   7. TFTim Ferriss16:09

      ... and I'm not saying it is, but a lot of people view it that way.

   8. DDDr. Dominic D'Agostino16:12

      Yeah. So, you know, there's insulin and insulin signaling, right? Uh, certain diet, like when you calorie restrict a rodent or even, you know, humans or any mammal, they, you will enhance insulin sensitivity, right?

   9. TFTim Ferriss16:26

      Right.

   10. DDDr. Dominic D'Agostino16:26

       So you will be more, more sensitive to a given amount of insulin. Uh, and I think we're seeing some of that in, in the athletes. I mean, exercise itself is, you know, enhances insulin sensitivity. So i- in guys that are, uh, advanced lifters who've been at it for like 10 years may have a different response to a ketogenic diet than, say, a 15-year-old kid, you know, who's trying to bulk up for football.

   11. TFTim Ferriss16:52

       Right.

   12. DDDr. Dominic D'Agostino16:52

       You know, he would [chuckles] probably not be a good candidate for, uh, for the ketogenic diet. You know, your sensitivity to things like IGF-1 and insulin are much higher when you're younger, in your teenage years especially. So you could compromise a lot of your potential development and strength if you're younger and doing that. But if, you know, say guys, the older we get, the less carbohydrate tolerant we get. So we lose, you know, our ability to kind of process carbs as we get older, and our insulin sensitivity declines. Uh, you know, just going back to your question, as it relates to being on a ketogenic diet, we know that ketones are anti-catabolic. You know, that's why-

   13. TFTim Ferriss17:30

       Right

   14. DDDr. Dominic D'Agostino17:30

       ... we can fast for 40 days, and the ketones have an anti-catabolic protein-sparing effect. And if our, our blood is flooded with ketones, we're less likely to liberate gluconeogenic amino acids from our skeletal muscle for fuel because the ketones can more or less replace glucose as the primary energy, energy substrate to maintain your central nervous system, which is, you know, like 3% of our body by weight, but sucks up like 20 or 25% of the energy. It's a big metabolic engine. So the ketones kind of drive a lot of that substrate, you know, energy need. Uh, so in a, in a k- situation where you're at a, at a caloric deficit, I think that's where ketones can shine. You know, if you're trying to make weight If you're trying to preserve or even increase your performance and strength, you know, and, and alter your body composition. So if-- I don't think the ketogenic diet is ideal if your goal is maximum, uh, a purely ketogenic diet. I think, you know, there's different... We have to kind of figure out w-what ketogenic diet we're talking about. [chuckles] But I don't think a purely ketogenic diet as it's kind of, uh, described in the literature, right? A 90 or 85% fat diet is an ideal diet for growth and repair. Uh, the diet that we use in our study is actually a little higher in protein, like 25% protein, which is like really almost double that used by the, you know, by the Johns Hopkins group that developed the classical ketogenic diet, and it's really that, that protein level is important. So growing on a s- classic ketogenic diet would p-pretty-- be pretty hard. I mean, kids do it. Their growth rates are a little bit less, you know, uh, with these kids that have, uh, drug-resistant seizures when they're put on the diet. But if you simply just do what's called a modified Atkins, and there's a lot of literature coming out now on the modified Atkins. Eric Kossoff at Johns Hopkins, he's a colleague of mine and more in the clinical realm, and he's done a lot of work showing that a modified Atkins, which is about 70% fat and like 20 or 30% protein, is, uh, has the same sort of ability f-to metabolically manage seizures, and I think that sort of diet can be used pretty successfully in the performance world and, and specifically for bodybuilders. I think with that amount of protein, you would be able to grow muscle for sure. And it's calories too, right? I mean, calories are the driver. Your caloric intake. If you have a surplus amount of calories, you're more likely to push insulin up-

   15. TFTim Ferriss20:15

       Mm-hmm

   16. DDDr. Dominic D'Agostino20:15

       ... and, and drive anabolic processes. Uh, but a lot of times people when they follow a ketogenic diet, because ketones have a really good appetite suppressing effect that they will inadvertently restrict calories and, and may not even know it after a while and, uh, and may be losing weight without even trying. And that's, I mean, that's one of the benefits, [chuckles] I guess you could say of the ketogenic diet. You can lose weight, and you can alter your body composition without necessarily even trying, just through the appetite suppressing effect.

6. 20:48 – 28:23

   Defining ketones and ketosis

   1. TFTim Ferriss20:48

      And the-- l-let's, uh, let's define a few terms for folks who may be outsiders to this world. Uh, I mean, you're talking about ketosis. Uh, let's define ketosis. What, what is ketosis? Let's, uh, I guess we could talk about nutritional, uh, and sort of fasting ketosis, but what, what is ketosis exactly, and what are ketones?

   2. DDDr. Dominic D'Agostino21:13

      Okay. Um, I kinda like to start out with fasting, right?

   3. TFTim Ferriss21:16

      Sure. Perfect.

   4. DDDr. Dominic D'Agostino21:17

      So if we're, [chuckles] if we're on a normal diet and we stop eating all of a sudden, um, we will mobilize and use up our stored glycogen, mostly in the liver, right? And, uh, our central nervous system more or less demands that we have a steady fuel supply to our brain, and in the absence of glucose availability, uh, we'll be depleting our, our liver glycogen. The insulin levels will be suppressed, and we'll start mobilizing fatty acids for fuel. The fatty acids, long-chain fatty acids, don't cross the blood-brain barrier very efficiently, so the liver, um, in, in-- while you're suppressing the hormone insulin, you'll upregulate beta oxidation of fatty acids in the liver and an accumulation of, of products from fatty acid oxidation will start forming ketone bodies, and these ketone bodies are-- they're more or less like water-soluble fat molecules that... and they're small molecules that can readily cross, uh, the blood-brain barrier and get inside cells into the mitochondria. And, uh, as we fast to within about 24 to 48 hours, we'll start registering ketones to the level that clinically is defined as being in ketosis, which is-

   5. TFTim Ferriss22:34

      I was gonna ask you about that

   6. DDDr. Dominic D'Agostino22:35

      ... you know, above point five millimolar.

   7. TFTim Ferriss22:37

      Above point five.

   8. DDDr. Dominic D'Agostino22:37

      Typically. Yeah, so a person on a, a high-carb diet would probably take about 24 to 48 hours to start even getting into mild ketosis. And but fasting is the fastest way to get into ketosis, and that's why if you have a child with drug-resistant seizures and they're administered or they're, uh, they're admitted into, uh, uh, a place like Johns Hopkins, the, the old protocol was to fast them. Uh, they, they're not exactly sure if that's absolutely necessary with things like, uh, more with ketogenic diets have MCTs and stuff. But you can, um, fasting has classically been the fastest way to get into ketosis. So the ketogenic diet has a macronutrient ratio, uh, that's high in fat, typically 90 to-

   9. TFTim Ferriss23:25

      And, and by macronutrients, we're referring to protein, fat, carbohydrates.

   10. DDDr. Dominic D'Agostino23:29

       Yeah.

   11. TFTim Ferriss23:29

       Mm-hmm.

   12. DDDr. Dominic D'Agostino23:29

       Yeah. And, uh, maybe ketones could be the fourth macronutrient maybe [chuckles] if you talk about exogenous ketones.

   13. TFTim Ferriss23:36

       Right. Right.

   14. DDDr. Dominic D'Agostino23:36

       But, uh, so a ketogenic diet has a macronutrient ratio that, that mimics the metabolic physiology that you have when you're fasting. So if you were to take the blood out of someone, you know, do a blood sample of someone on a strict ketogenic diet, it would look like they're fasting, like they've, they've been fasting a few days. And it's that, that allows you to get some-- that changes your physiology incredibly, like your metabolic physiology changes acutely, and then there's, there's long-term changes that occur with that, uh, epigenetic changes. You know, we know that, that beta-hydroxybutyrate, which is a ketone body, can have, uh, in, you know, interesting effects on gene expression.

   15. TFTim Ferriss24:20

       What types of effects?

   16. DDDr. Dominic D'Agostino24:22

       Uh, well, there was a science paper showing that, uh, beta-hydroxybutyrate is an HDAC, class one and class two inhibitor, and can activate genes that play a role in enhancing, uh, endogenous antioxidant mechanisms, specifically superoxide dismutase and catalase. So these, these mechanisms, when they're upregulated, it confers protection against the environment. It, it sort of enhances our cellular defense mechanisms. It, uh, enhances the robust kind of protective mechanisms that the cell has that can preserve the genome stability. So maybe being in a state of ketosis and maintaining that can protect your DNA from damage, so that's the implications. Um, also anti-inflammatory. So we, we published a, a paper, uh, our colleagues actually did it at Yale. Uh, I developed the diet for them and sent it up to them. It was exogenous ketone. But the paper demonstrated that it, it, uh, activated or prevented the activation of a particular inflammasome that's, that's linked to age-related chronic diseases. So it inhibited, inhibited a specific inflammatory pathway that is really associated with all chronic age-related diseases, and it was independent of the ketones' effect on metabolism.

   17. TFTim Ferriss25:52

       Oh.

   18. DDDr. Dominic D'Agostino25:52

       So they teased out [laughs] ... They, uh, did a lot of studies to tease out the mechanism and, and demonstrated that, that the effect of it, you know, suppressing in- this inflammatory pathway, um, was, uh, completely independent of its metabolic effect. So we understand that, you know, when I got into this, I just knew that ketones were an energy metabolite, so now we know it's much more than a metabolite. You know, it's an, it's an HDAC inhibitor, and the-

   19. TFTim Ferriss26:22

       How do you spell that?

   20. DDDr. Dominic D'Agostino26:22

       The pharmaceutical-

   21. TFTim Ferriss26:23

       I apologize. The H stack?

   22. DDDr. Dominic D'Agostino26:25

       Oh, yeah, a histone deacetylase inhibitor. So HDAC would be-

   23. TFTim Ferriss26:30

       Oh

   24. DDDr. Dominic D'Agostino26:30

       ... H-D-A-C.

   25. TFTim Ferriss26:32

       Got it.

   26. DDDr. Dominic D'Agostino26:32

       And then there's class one, two, three, I think four. So class one and two, uh, HDAC inhibitors are a big, big, uh, of, are of big interest to the pharmaceutical industry, so there are many. For example, we do a lot of cancer research. There's a lot of pharmaceutical, uh, companies focusing on, uh, histone deacetylase inhi- inhibitors for, as targeting specific pathways-

   27. TFTim Ferriss26:58

       Right

   28. DDDr. Dominic D'Agostino26:58

       ... to, for cancer therapy. So, so you have an endogenous HDAC inhibitor-

   29. TFTim Ferriss27:03

       Mm-hmm

   30. DDDr. Dominic D'Agostino27:04

       ... you know, uh, with beta-hydroxybutyrate.
7. 28:23 – 30:48

   Preventing neurodegenerative diseases

   1. TFTim Ferriss28:23

      I don't know if those fall into the age-related, uh, issues that you were talking about, but are there implications for fasting or, um, nutritional ketosis or exogenous ketones for helping to prevent or mitigate the onset of those type of neurodegenerative diseases?

   2. DDDr. Dominic D'Agostino28:42

      [inhales] Yeah, and, you know, fasting has to be done, [clears throat] you know, under... You have to know your body, right? [laughs] And fasting should probably be done, uh, under pretty strict medical supervision-

   3. TFTim Ferriss28:56

      Sure. Agreed

   4. DDDr. Dominic D'Agostino28:56

      ... to some extent. Yeah.

   5. TFTim Ferriss28:58

      Yeah. Agreed.

   6. DDDr. Dominic D'Agostino28:58

      So someone would have to do a little research on it. Uh, and, [clears throat] and it would depend on, you know, the particular person. If, so i- if you have a cancer patient that it's a, a woman with breast cancer, say, and she has a BMI of 28, you know, and, and is going in for chemo, I think it's a good idea for them to fast before they go in.

   7. TFTim Ferriss29:18

      So BMI, body ma-

   8. DDDr. Dominic D'Agostino29:19

      But if you have someone-

   9. TFTim Ferriss29:20

      Body mass index.

   10. DDDr. Dominic D'Agostino29:20

       Oh, body mass index. Yeah.

   11. TFTim Ferriss29:21

       So that would-- And that would make her obese? I actually don't know kind of the scale of BMI.

   12. DDDr. Dominic D'Agostino29:26

       Uh, yeah, that would make her kind of a little pudgy, I guess, [laughs] and-

   13. TFTim Ferriss29:29

       Yeah

   14. DDDr. Dominic D'Agostino29:29

       ... and have some, some extra weight to lose. So, so, uh, we w- we know that getting chemo in a, in a fasted state, there's a couple reports out there showing that it could, uh, it sensitizes. Uh, it can sensitize the, the tumor to the, um, therapeutic effects of the agents. And also, uh, there's some evidence showing that, um, that it could prevent some of the side effects associated with chemotherapeutic agents, uh, specifically things that, you know, cause cell damage. So, so being in a state of fasting ketosis can sensitize the tumor to the damaging effects of the chemo and, and enhance your healthy cells' resistance against the toxic effects of, of the, of the, um, chemotherapeutic agent. So that's... Yeah, and you'd wanna do it-- I think, you know, the majority of patients could probably do it, but if you have someone with severe cancer cachexia, muscle wasting, uh, you'd want to do it in a very cautious way. But I- I definitely think, you know, this, this is something that should be implemented, you know, in our, in our oncology wards.

   15. TFTim Ferriss30:43

       Yeah.

   16. DDDr. Dominic D'Agostino30:43

       That, um, fasting before chemo, uh, definitely has some real benefits-

   17. TFTim Ferriss30:47

       Well-

   18. DDDr. Dominic D'Agostino30:47

       ... that we

8. 30:48 – 34:48

   Cachexia, sarcopenia, anabolism, and catabolism

   1. DDDr. Dominic D'Agostino30:48

      should be utilizing.

   2. TFTim Ferriss30:49

      No, it's, it's so fascinating. And is... So cachexia, man, you are a treasure trove of vocabulary. So is that the, is that the, uh... Is that acute muscle loss as opposed to, like, sarcopenia, which would be the... I'm not up to speed on my Latin, which would be sort of the muscle loss attributed to aging? Or, uh, what is cachexia?

   3. DDDr. Dominic D'Agostino31:09

      Yeah. So cachexia would be defined as, um, uh... Yeah, actually [laughs] investigators are trying to get a clear definition of it and, and understanding of it, which our lab, I have... One of my students is, just studies cancer cachexia. Uh, cachexia is defined as, i- in cancer, as, uh, you, you're in a, a physiological state where your body is releasing factors like, uh, tumor necrosis factor alpha and inflammatory cytokines that, inflammatory mediators that are catabolizing your muscle tissue, your lean body mass.

   4. TFTim Ferriss31:47

      And just, and I apologize, I just want to, for people who are, are, uh, unfamiliar with the voc- vocab, so, so anabolism would be building tissue in general and catabolism would be breaking down tissue. Is that fair or is it, uh-

   5. DDDr. Dominic D'Agostino32:00

      Exactly.

   6. TFTim Ferriss32:00

      Okay.

   7. DDDr. Dominic D'Agostino32:00

      Like anabolic steroids are building, and catabolic processes are the breaking down-

   8. TFTim Ferriss32:06

      Okay

   9. DDDr. Dominic D'Agostino32:06

      ... of things. So you're-

   10. TFTim Ferriss32:07

       Great. Sorry to interrupt.

   11. DDDr. Dominic D'Agostino32:08

       Oh, no. It's great. So you're, yeah, you're in a state where you're, you're basically wasting lean body mass. You're wasting, um, you know, uh, tissue. And a lot of cancer patients succumb to cancer cachexia, and its mortality is, is closely, intimately re- related to that. So as you lose lean body mass from being in a state, say for example, if someone's ha- has advanced metastatic cancer, that they will, their survival will be tightly correlated with, with that, the ability to preserve their lean body mass and maintain their function. And in a lot of situations, you get, [laughs] you get this situation where you have an older patient that gets cancer, like 70-year-old, and you have age-related sarcopenia, right? They're already losing muscle-

   12. TFTim Ferriss32:59

       Right

   13. DDDr. Dominic D'Agostino32:59

       ... uh, compounded with [laughs] cancer cachexia, which increases lean body mass loss due to the, the pathology on top of chemo-induced cachexia.

   14. TFTim Ferriss33:12

       Oh, wow.

   15. DDDr. Dominic D'Agostino33:13

       So chemotherapy is a pretty powerful destructive agent to lean body mass on top of [laughs] uh, inactivity, so being immobilized. So you have age-related sarcopenia, cancer cachexia, chemo-induced cachexia, and this typically, you know, you have a patient that's bedridden, so they're not stimulating their muscle with activity. So you have four factors coming together that cause, uh, a ma- like a perfect storm for you to just kind of waste away, and patients can go down so fast when, um, when they're put in that situation. So I think, uh, so we're developing protocols to nutritional, you know, nutritional ketosis. We're looking at branched-chain amino acid formulas. Uh, and we're, we wanna do some work with, uh, to define specifically what types of exercise can mitigate all these factors, and maybe some drugs and stuff too, uh, we're interested in testing. So yeah, I think that's, that's not really being studied much.

   16. TFTim Ferriss34:15

       Yeah.

   17. DDDr. Dominic D'Agostino34:15

       There's not a whole lot [laughs] of investigators out there studying this, and I've been in touch with a lot of patients, and I realize that this is key. Like, I think a lot of patients would be alive today if we had, uh, effective ways to mitigate. 'Cause once they lose their mobility, once they get weak enough where they just can't move around, I mean, their whole psychology just deteriorates.

   18. TFTim Ferriss34:37

       I would imagine.

   19. DDDr. Dominic D'Agostino34:38

       You know? Yeah. So there's, there's a lot of reasons that we should be looking into keeping patients as strong, uh, and preserving their

9. 34:48 – 38:53

   Anabolic agents and cancer patients

   1. DDDr. Dominic D'Agostino34:48

      muscle as much as possible, you know?

   2. TFTim Ferriss34:50

      Is, is, is... Are there any, uh, knowledgeable folks out there, I was gonna say scientists or researchers, but we both know a lot of folks who don't operate in the more formal worlds, [laughs]

   3. DDDr. Dominic D'Agostino35:01

      Yeah.

   4. TFTim Ferriss35:01

      The, uh... Are, are there people out there who have, who believe that there's a role of anabolic agents, whether steroids or otherwise, in th- those types of circumstances with, say, cancer patients? Um, and I don't the... And I'd be really interested to hear your thoughts just because we, uh, there are also a lot of people who are trying to, say, minimize IGF-1, uh-

   5. DDDr. Dominic D'Agostino35:23

      Mm-hmm

   6. TFTim Ferriss35:23

      ... among other things for longevity purposes, uh-

   7. DDDr. Dominic D'Agostino35:26

      Yeah

   8. TFTim Ferriss35:26

      ... or even for anti-cancer purposes. But w- how do you, how do you think about that, or how do other people think about that?

   9. DDDr. Dominic D'Agostino35:35

      Well, I, I think it's a little outside of mainstream, uh, cancer kind of, uh, world-

   10. TFTim Ferriss35:42

       Sure

   11. DDDr. Dominic D'Agostino35:42

       ... that I'm linked in with, but I think it should be. And I think, you know, we wanna develop a pretty solid, uh, program here in our lab to, to look into this. Uh, when it comes to anabolic agents, I think, you know, you go to the literature and it shows that anabolic steroids do not promote, within, within certain dosing levels, they do not promote the growth and the spread of cancer. Uh, pretty sure the literature says that there are, uh, specific androgen receptor modulators out there. They're called SARMS.

   12. TFTim Ferriss36:18

       SARMS.

   13. DDDr. Dominic D'Agostino36:18

       And there's a few SARMS, yeah, SARMS that are out there. They basically have... They're designed to have the anabolic Tissue building potency of, of testosterone and other anabolic steroids without the androgenic or the hormone effects.

   14. TFTim Ferriss36:37

       Right.

   15. DDDr. Dominic D'Agostino36:38

       And, uh, they are actually developed specifically for cancer cachexia.

   16. TFTim Ferriss36:44

       Oh, really?

   17. DDDr. Dominic D'Agostino36:44

       So there's a few out there. Yeah, there's, there's actually a few out there, and I think, you know, we're kind of interested in studying them. Uh, we're looking at branched-chain amino acids right now, which we think are, are pretty, uh, important, too. Uh, uh, but if you give, so testosterone for example, and a lot of males take testosterone to build muscle in the gym for, you know, hormone replacement therapy. If you administer testosterone, and the studies have been done, up to a certain point, once you get to about 300 milligrams, uh, per week, uh, say, you start to increase systemic IGF-1 levels. And if you go up to about 600 milligrams a week, which would put you at a supraphysiological level about twice or three times that of a normal male at least.

   18. TFTim Ferriss37:32

       Right.

   19. DDDr. Dominic D'Agostino37:32

       Uh, that causes the liver to increase IGF-1, um, release.

   20. TFTim Ferriss37:39

       Got it.

   21. DDDr. Dominic D'Agostino37:39

       So your, your systemic IGF-1 will go up. But a dosage of, say, 100 to 200 milligrams a week, uh, does not increase, to my knowledge, uh, uh, factors, uh, hormones, uh, growth factors that would, uh, cause cancer to grow and spread. And I think at that dosage, ch- especially with a lot of male, uh, uh, cancer patients, that, that would have a p- pretty remarkable protein-sparing effect. And we know that, you know, anabolic agents can be life-saving drugs for HIV patients-

   22. TFTim Ferriss38:15

       Absolutely. Yeah, for muscle wasting

   23. DDDr. Dominic D'Agostino38:16

       ... for patients with wasting diseases. Yeah, I mean, they can... You know, just look at the literature and you talk, you know, if you talk to, um, to the, uh, physicians and the doctors that treat their patients, that are familiar with these agents and know how to, uh, intelligently prescribe them and administer them, they will tell you that, you know, they, they, they save lives.

   24. TFTim Ferriss38:39

       Yeah.

   25. DDDr. Dominic D'Agostino38:39

       So, and I, and I think that application may be, um, may be useful in cancer. So, but I think the SARMS are, are kind of an interesting, uh, compound that's coming out, and I think there's, there's some, definitely some potential for some

10. 38:53 – 43:23

    The advantage of SARMS

    1. DDDr. Dominic D'Agostino38:53

       drugs out there.

    2. TFTim Ferriss38:53

       Now, is the advantage of SARM, a, a SARM over, say, a high anabolic, low androgenic, uh, steroid, uh, like, uh, like a nandrolone or a oxandrolone, for instance, which is very popular with, uh, HIV patients who are trying to increase their T cell count and avoid muscle wasting. Is the primary advantage of the SARM that it doesn't have the stigma associated with it of anabolic steroids? Is, is it primarily kind of a political advantage that it doesn't carry that baggage, or are there other metabolic reasons to use it as opposed to just standard kind of-

    3. DDDr. Dominic D'Agostino39:32

       Yeah

    4. TFTim Ferriss39:32

       ... uh, you know, a- anabolic agents that are, that are low androgenic? Uh, and just so, so, so people understand-

    5. DDDr. Dominic D'Agostino39:38

       Mm-hmm

    6. TFTim Ferriss39:39

       ... and please feel, correct me if I'm screwing this up, but just for, for people to understand the context. When people talk about anabolic steroids, they're, they're usually talking about anabolic androgenic steroids, right? And that, and i- insomuch as they have anabolic, i.e. tissue building, muscle building effects, and then they have androgenic effects which can, uh, uh, can acc- accelerate the development of secondary sex characteristics, whether that's like a, a s- a square jaw, male characteristics, or a, uh, you know, deeper voice in the development of the vocal cords, more hair, acne, et cetera, that kind of stuff. So in the case of someone with, say, a wasting disease, particularly if they are, uh, females than a male, they will want to minimize the androgenic effects because they don't want to become men or become cavemen and maximize the muscle building effects in this particular case. Um, is that a fair-

    7. DDDr. Dominic D'Agostino40:31

       Mm-hmm

    8. TFTim Ferriss40:31

       ... is that a fair description? Feel free to add or, or edit anything that I just said, but I'd be curious to hear sort of the advantage of SARM, SARMS over preexisting low androgenic anabolic therapies.

    9. DDDr. Dominic D'Agostino40:46

       Yeah. Okay. So SARMS are designed, uh, with the intention in mind to minimize the androgenic component down to nothing. You know? That-

    10. TFTim Ferriss40:56

        Right

    11. DDDr. Dominic D'Agostino40:56

        ... that's really the goal. Uh, and I think they're pretty close to doing that. [laughs] The pro- the problem is I don't... I- in the real world, when you read about guys taking this for muscle building, they have very kind of minimal anabolic properties compared to their, uh, anabolic steroid counterparts or cousins. Uh, but the, the advantage is, you know, is that, uh, if you have a guy with prostate cancer, or all males, you know, probably get prostate cancer, uh, i- in time. So, uh, you can, high testosterone could drive the g- the growth of your prostate and prostate cancer. Uh, and, and anabolic steroids, uh, could obviously have major side effects for women. I mean, we see this in women's bodybuilding, right? Uh, we see the side effects are pretty real and, and pretty n- non-reversible. So a, a selective androgen receptor modulator can have the advantage of, you know, potentially, um, giving the protein-sparing anabolic properties o- of, of the agents, you know, without, uh, without the side effects. So there's not... There's research going on, but it's, it's, I don't think it's moving as fast as what we had initially anticipated as far as them being super potent, uh, anabolic agents that would make anabolic steroids ob- obsolete. [laughs]

    12. TFTim Ferriss42:27

        Got it.

    13. DDDr. Dominic D'Agostino42:27

        So, um- They're not at that level yet, but there's quite a few pharmaceutical companies working on it, and agents are-- there's studies going on right now, and I think that data will probably come out in the next couple years.

    14. TFTim Ferriss42:40

        Yeah, I wanna chat with you separately about how to marshal resources to do a lot more studies, 'cause I just-- it's so frustrating to see these attractive targets or hypotheses that just for lack of funding, particularly with technology and sort of the ability to do distri- uh, distributed studies potentially. Anyway, you and I-

    15. DDDr. Dominic D'Agostino43:01

        Mm-hmm

    16. TFTim Ferriss43:01

        ... I would love to chat more about that. But in, in the case-

    17. DDDr. Dominic D'Agostino43:03

        Yeah

    18. TFTim Ferriss43:03

        ... coming back to the chemotherapy, 'cause I, I love looking at cancer in sort of extreme states because I think then you can, you can form hypotheses and test in those circumstances, and then adapt findings to test in normal populations, which would, if, uh, you know, I suppose I would include myself in that,

11. 43:23 – 49:18

    Mimicking benefits of fasting with exogenous ketones

    1. TFTim Ferriss43:23

       although [chuckles] normal is kinda pushing it. Uh, the-- is it possible or to what extent is it possible to mimic the benefits of fasting pre-chemotherapy with exogenous ketones?

    2. DDDr. Dominic D'Agostino43:39

       Yeah. So I think we can view exogenous ketones are an energy-containing substance, right? So you could potentially take them as a source of energy.

    3. TFTim Ferriss43:50

       Right.

    4. DDDr. Dominic D'Agostino43:50

       Um, they're energy that your liver only produces under certain circumstances of what's considered, uh, kind of strange metabolic physiology, [chuckles] like a fasted state where it's just-

    5. TFTim Ferriss44:04

       Right. Durous of some type.

    6. DDDr. Dominic D'Agostino44:05

       Yeah.

    7. TFTim Ferriss44:06

       Yeah.

    8. DDDr. Dominic D'Agostino44:06

       Uh, so, so the ability and, you know, we're interested in, in doing this, the ability to, um, to adm- to elevate, to produce an artificial state of ketosis, uh, is possible with exogenous ketones, and it mimics many, many effects of therapeutic fasting, which would be, uh, an, an acute and sustained reduction in blood glucose. And we don't really know why there's, uh, a remarkable decrease in blood glucose. That's a dose-dependent decrease, but it, it seems to do-- seems to be related to the liver's, um, output of glucose. So your liver is the master regulator of your blood glucose really.

    9. TFTim Ferriss44:56

       Mm-hmm.

    10. DDDr. Dominic D'Agostino44:56

        And, uh, it's, uh-- so the, the drug metformin, uh, in Type 2 diabetics will decrease hepatic gluconeogenesis.

    11. TFTim Ferriss45:05

        Right.

    12. DDDr. Dominic D'Agostino45:05

        So the liver's ability to, to make glucose and, and put it into the bloodstream. We, we think that, that ketones are doing this also. Uh, and I think-

    13. TFTim Ferriss45:13

        Interesting

    14. DDDr. Dominic D'Agostino45:14

        ... maybe it's kind of telling the body, "Hey, you're in a fasted state, so why don't you conserve the glucose that you have?" And, and also a big dose of ketones could potentially cause a small release of insulin, and, uh, that's kinda how we regulate our, our, our endogenous ketone production is that if our ketone levels get too high, that, that ketone will cause a very s- tiny release of insulin from the pancreas, and that will signal the liver to kind of turn down or turn off, uh, hepatic ketogenesis. And it's, uh, you know, we have-- when we're in a state of ketosis, we lose ketones through our urine, we burn them up through peripheral tissues, and if they get really high, we stimulate a small amount of insulin release. Um, so-

    15. TFTim Ferriss46:02

        What is really high on a millimolar basis as measured by, like, a Precision Xtra device from Abbott, which is what I have six feet from me, which I've been using? What would, what would, uh-- how high do your ketone levels need to get before that insulin gets kicked out? Of course, it depends on the person-

    16. DDDr. Dominic D'Agostino46:18

        Mm-hmm

    17. TFTim Ferriss46:18

        ... but roughly speaking.

    18. DDDr. Dominic D'Agostino46:20

        Yeah, I think it's, it's pretty rare to see over five millimolar. In kids, you know, uh, with kids that have a disorder called glucose transporter type one deficiency syndrome, uh, I'm in touch with their parents, and they routinely stay in the three to five millimolar range. But typically, that's rare. They have to be on a really strict ketogenic diet. Um, but typically, yeah, getting above five is kind of abnormal, and sometimes, you know, if I'm measuring, sometimes I'll just hit a peak. You know, it's kind of like your hormones. They're gonna, gonna fluctuate throughout the day. So if you measure and you hit seven, I wouldn't panic or anything. I mean-

    19. TFTim Ferriss46:56

        Yeah

    20. DDDr. Dominic D'Agostino46:56

        ... 'cause it's probably a little peak that you're getting. Uh, but yeah, typically-

    21. TFTim Ferriss46:59

        You know, or your, or your PETA tea and doing a cycling workout. [laughs]

    22. DDDr. Dominic D'Agostino47:02

        ... you know, most peop- yeah. [chuckles] Yeah, there's that, you know, you have post-exercise ketosis where guys that are on a high-carb diet, after four or five, six hours of intense exercise, they're going to deplete their liver glycogen and ramp up fatty acid oxidation so high that they're, they're naturally just gonna be in ketosis. So their, their body is used to seeing ketones, you know, because of the exercise that they do. Uh, but generally, yeah, I mean, like, like moderate to mild ketosis is kind of what I like to promote for health and longevity, and that's between one and three millimolar. If you're within that range, that's a range that you'll, like, pretty much never get into if you're not on a ketogenic diet or not fasting. And I think staying in that range has some real world benefits as far as, uh, you know, health benefits, longevity benefits, performance, resilience. I think there's some real world benefits to staying in that, that range. And I-- you'd be hard-pressed to find any potential adverse effects that could be, you know, uh, uh, like linked to having ketones in that range. But once you get into five, six millimolar range, that, that produces a metabolic, a mild metabolic acidosis that needs to be compensated for through your kidneys.

    23. TFTim Ferriss48:26

        Right.

    24. DDDr. Dominic D'Agostino48:26

        And, you know, so it is putting a stress. It's, it's a substrate load to your, your system, and your body's gotta deal with that. So I think, you know, that, that needs to be taken into account.

    25. TFTim Ferriss48:38

        How, how do you currently... Well, actually, let me, let me ask a couple of questions just because I'm in the middle of doing some ket- ketosis experiments myself. With exogenous ketones, so I have two jugs of [laughs] exogenous ketones in my fridge.

    26. DDDr. Dominic D'Agostino48:55

        Okay.

    27. TFTim Ferriss48:55

        Then I have, uh, some powdered beta-hydroxy, beta-hydroxybutyrate, which is, I guess, the... Well, most people read it as Keto CaNa, the C-A-N-A, which I guess is what-

    28. DDDr. Dominic D'Agostino49:07

        Mm

    29. TFTim Ferriss49:07

        ... calcium potassium. Am I getting that right? Screen that.

    30. DDDr. Dominic D'Agostino49:10

        Uh, calcium s- sodium, yeah. [laughs]
12. 49:18 – 56:13

    Accelerating the induction of ketone projection

    1. TFTim Ferriss49:18

       the... So I have the powdered, uh, the, the powdered b- uh, beta-hydroxybutyrate. If I use that when I'm trying to induce ketosis, right? So let's, for instance, this past week, I ate a low carb but still glucose dependent, uh, diet f- up until Friday night and then I fasted from Friday after dinner until Sunday evening, and now I'm squarely into ketosis. I'm probably at 1.1, 1.2 millimolars, I would say, uh, upon waking. How could I u- d- can I accelerate the induct- the induction of my own ketone production by, through use of exogenous ketones or am I just temporarily spiking my readings when I'm ingesting these things, and really my body is going to get to its sort of steady state 1.1, 1.2 in the same amount of time regardless? Does that question make sense?

    2. DDDr. Dominic D'Agostino50:18

       Mm-hmm. Yeah. Um, I think there are significant advantages to, uh, speeding up the process, uh, as far as how you feel, and I think that there's... If, if you transition from a state of using glucose as your primary energy source to using ketones, that usually involves a gap in, uh, fuel flow to your brain.

    3. TFTim Ferriss50:46

       Yeah.

    4. DDDr. Dominic D'Agostino50:47

       So your brain will-

    5. TFTim Ferriss50:48

       You feel grumpy and shitty. [laughs]

    6. DDDr. Dominic D'Agostino50:49

       Yeah, you go, you have glucose withdrawal. I mean, your brain go- goes through glucose withdrawal, and it uses glucose to, not only for energy, but to make, you know, uh, neurotransmitters to your brain homeostasis is, you know, your glucose levels are, are basically telling your brain that it's, you know, at a, in, in, it's happy. It's in a homeostatic state. So if you feed your, your body, your brain ketones, it is preserving more or less that, uh, neurophysiological homeostasis, I think, and you're not going to have a, um, maybe a stress reaction.

    7. TFTim Ferriss51:27

       Ah.

    8. DDDr. Dominic D'Agostino51:27

       So if, if you, um, fast, and this is in subjects that just kinda go cold turkey and fast, within the first 24 hours, they, you know, it's a stress response. Their cortisol level spikes. They, your sympathetic nervous system is activated. Uh, their immune system could be suppressed. Uh, and I think that if you were to do the same thing but use exogenous ketones, you would cruise into a state of nutritional ketosis or sustained nutritional ketosis without some of the, the, the bumps along the way.

    9. TFTim Ferriss52:02

       Got it.

    10. DDDr. Dominic D'Agostino52:02

        And I think that you could probably reap some of the, the performance benefits, and I think it'd maybe be... And then, but then you could, you know, you may make the argument that that stress, that physiological stress that you're giving yourself is, you know, you're familiar with the hormetic effect. [laughs]

    11. TFTim Ferriss52:20

        Yeah.

    12. DDDr. Dominic D'Agostino52:20

        That that stress could be kicking on mechanisms that when activated can kind of, you know, be protective in and of itself.

    13. TFTim Ferriss52:31

        Yeah.

    14. DDDr. Dominic D'Agostino52:32

        You know, but I-

    15. TFTim Ferriss52:32

        Or beneficial in some way, right? That's, like, when, when people are taking ibuprofen after workouts or other, like, anti-inflammatories and reducing subsequent hypertrophy, right?

    16. DDDr. Dominic D'Agostino52:43

        Yeah. Yeah.

    17. TFTim Ferriss52:43

        From inhibiting the sort of pain that was, uh, unpleasant in the short term, but beneficial in the longer term.

    18. DDDr. Dominic D'Agostino52:51

        Yeah, where, you know, in the, the case of NSAIDs, if you're, you dose them right after your workout, maybe those inflammatory mediators are linked to activating the signaling cascades that are responsible for the hypertrophy effect.

    19. TFTim Ferriss53:05

        Right. Right.

    20. DDDr. Dominic D'Agostino53:05

        You know? So you could be, could be negati- negating that effect, but we have not shown that to be the case. Actually, I think, I think you could get a lot of benefit... You could, uh, I, I see it as not one or the other. Like, I think the ketogenic diet actually goes pretty well with exogenous ketones, and one would not have to be on such a strict ketogenic diet, 'cause it is very restrictive.

    21. TFTim Ferriss53:29

        It is.

    22. DDDr. Dominic D'Agostino53:30

        And you could do, like, a modified Atkins, which is kinda the, the way I think we should eat anyway. [laughs] I mean, just eliminating all processed carbohydrates and just, you know, protein, fat, veggies is kinda how I eat, and I pretty much always stay in a state of ketosis just by using MCTs, like a little bit of exogenous ketones here and there. Uh, and I think it would allow us to optimize the therapeutic effects of the ketogenic diet and, and probably further augment the therapeutic efficacy if we're talking about the clinical realm, and maybe, maybe further augment the performance enhancing effects of-

    23. TFTim Ferriss54:06

        Mm-hmm

    24. DDDr. Dominic D'Agostino54:06

        ... the ketogenic diet too, and I think that's, that's possible. Um, but a lot of people just want something in a pill, and we-

    25. TFTim Ferriss54:15

        Yeah

    26. DDDr. Dominic D'Agostino54:15

        ... kinda, we did that study. Well, we're, we're doing those studies now, and we are... Uh, I'm a big fan of the ketogenic diet, and I'm actually pretty impressed and, and even, not shocked as in a world, but I, I, we're getting, we're getting results better than I expected just by giving pure ketones than I, I thought the, that you would need a level of adaptation To being in a state of nutritional ketosis to get the benefits from exogenous ketones, and that's, that's not the case.

    27. TFTim Ferriss54:47

        Yeah.

    28. DDDr. Dominic D'Agostino54:47

        We showed that really in our first study.

    29. TFTim Ferriss54:49

        Now, is that true even in the presence of higher carbohydrate intake or higher protein intake?

    30. DDDr. Dominic D'Agostino54:57

        Yeah, it is in our animal models, and we think it is in humans right now. So we have some studies, uh, approved where we're gonna be looking at that in, in humans, uh, looking at the metabolic effects. But, uh, kind of the first study that we did in, is a rat study where we, we did, uh, uh, an acute feeding. Well, it's kind of a gavage, so we kind of give them a bolus dose, and these are rats that are maintained on a high carbohydrate standard rodent chow, and they've never been in a state of ketosis before, you know, unless they were deprived of food or something, which, which is, they probably weren't. So they've never really seen, uh, ketones before. And in this, uh, study that we did, uh, we acutely, you know, gave them, uh, a, a ketone ester, and within about 15 minutes to 30 minutes, they achieved a level of ketosis that would take about seven days of fasting for a human. They were in the four to five millimolar range. Uh-
13. 56:13 – 1:16:08

    Ketone esters

    1. DDDr. Dominic D'Agostino56:13

       name? [laughs] It was, uh-

    2. TFTim Ferriss56:13

       Or, well, uh, maybe I should, maybe I should take a different approach. What is a, for, for people listening, what is-

    3. DDDr. Dominic D'Agostino56:18

       Oh

    4. TFTim Ferriss56:18

       ... a ketone ester?

    5. DDDr. Dominic D'Agostino56:20

       Okay. Uh, so your body makes, you know, primarily two ketones that it uses for fuel. One is acetylacetate, and another is beta-hydroxybutyrate. And, um, they're both kind of interchangeable, and they're converted to one another, uh, in the body. Uh, beta-hydroxybutyrate actually has to break down to acetylacetate, you know, to be used for energy. Uh, but the beta-hydroxybutyrate tends to be the primary, uh, the highest level, you know, primary ketone in our body just because it's more stable, so, but it does need to break down to acetylacetate. So a ketone ester is taking one of these, acetylacetate or beta-hydroxybutyrate or both, and taking those molecules and attaching it to something [laughs] and with an ester bond that functions as, like, more or less a carrier to it. So you can esterify a ketone with a wide range of things. Uh, you could use glycerol. You can use, we use what, something called 1,3-butanediol, and you can attach ketone molecules to this with a transesterification reaction. A- and when it's ingested in the body, there's various enzymes we have, hydrolytic enzymes that will, uh, esterases that will break off the ketone, and you'll get, uh, when you ingest it orally, you'll start to liberate the ketones from the molecule that it's esterified with, and these will build up in your blood. And the idea, right, is to have a molecule that, you know, slowly releases the ketones in a very predictable fashion, where you get a nice pharmacokinetic profile, you know, where you have, you know, you can take it orally, and then within 10 to 15 minutes you're in starvation ketosis, and then you stay in ketosis for, you know, six, eight, 12 hours is ideal.

    6. TFTim Ferriss58:14

       Right, right.

    7. DDDr. Dominic D'Agostino58:14

       And it depends on, you know, the molecule you're talking about. So that, that's kind of what we're doing now. We're kind of screening various compounds to figure out which ones have a favorable pharmacokinetic profile in isolation, and then we start combining them together so we can get, you know, formulas where we hit the ideal, you know, formula for a particular application. So a ketone ester, yeah, is a ketone that is orally active, so you can take it and it can increase blood ketone levels. In, in the rat study that I was describing, they are quickly put into ketosis, and then in that particular study, we would dive them [laughs] in a hyperbaric chamber and increase the pressure and the level of oxygen within the chamber, so it would be, it would simulate a Navy SEAL diving [laughs] down to 132 feet of seawater breathing 100% oxygen on, uh, in a, a rebreather that they use called a Draeger rebreather, uh, closed oxygen.

    8. TFTim Ferriss59:15

       Yeah. And the pur- and the purpose of that, of course, is so that they don't give away location by having bubbles come out of their system. Is that, is that right?

    9. DDDr. Dominic D'Agostino59:22

       Yeah. So there's, uh, definitely a stealth component to a closed circuit rebreather. Um, if you're using it and you're in the middle of a pond in the middle of the jungle [laughs] and it's perfectly quiet, like, you would not know the person's under there, whereas if you're using standard scuba, you would see a bubble trail c- coming across the pond at you, you know? And you could just, you could just sit there patiently and wait till they come out and shoot them. [laughs]

    10. TFTim Ferriss59:47

        Right.

    11. DDDr. Dominic D'Agostino59:47

        So with a, with a rebreather, there is a, a, a big advantage, a stealth component. Uh, the disadvantage is obviously, you know, if you go down to just 50 feet of seawater, uh, you're at the risk of getting what's called oxygen toxicity seizures within, like, 15, 10 to 15 minutes-

    12. TFTim Ferriss1:00:06

        Wow

    13. DDDr. Dominic D'Agostino1:00:06

        ... just at 50 feet. So you have to stay very shallow, and which is not always hard to do during a mission. If you have, you know, helicopters over you and they can see you in the water, or you're taking fire, or you gotta, you gotta dive down to plant a mine on a bridge or a ship, uh, it's not always easy to do. So we developed these things for, you know, providing resilience and safety and, and performance. Uh-

    14. TFTim Ferriss1:00:30

        Now, when you say developed these things, you're talking about the exogenous ketones?

    15. DDDr. Dominic D'Agostino1:00:34

        Yeah, that's, they're developed, you know, originally with that application in mind, with, um, with-

    16. TFTim Ferriss1:00:39

        Yeah

    17. DDDr. Dominic D'Agostino1:00:40

        A defense application in mind, a military application, and that's, that's how my project originally got started. Uh, so-

    18. TFTim Ferriss1:00:48

        Like def- and because you've done, uh, you've, you've had studies funded by the Department of Defense and so on. Is that right?

    19. DDDr. Dominic D'Agostino1:00:54

        Yeah, yeah. That was the original idea for this [laughs] was, uh, I got turned on to the ketogenic diet 'cause it was used for drug-resistant seizures, and my program officer, uh, I ran the idea by him, and he didn't really like the idea of a diet per se. I mean, his attitude of the diet for performance has changed, you know, over the years. But he was like, "Well, let's, you know, why don't you kind of look into developing a ketogenic diet in a pill and see if that's even possible?" So I spent, and that was like 2008, and then that kind of started my journey into seeing if this was possible. And when we tested it in our, in our rat model, uh, you know, I remember [laughs] the first time we did it, we, you know, fed the rat and put him in there, and we typically see a seizure in about 10 to 15 minutes. And we're standing around the chamber, and we have a video camera system and a little window port. And we were, we were standing there, and it's like 30 minutes has gone by, 40 minutes, and we're up to an hour, and everybody's just kind of like looking at one another.

    20. TFTim Ferriss1:01:54

        Whoa.

    21. DDDr. Dominic D'Agostino1:01:54

        And it was like, "This is unbelievable." [laughs]

    22. TFTim Ferriss1:01:57

        [laughs]

    23. DDDr. Dominic D'Agostino1:01:57

        And I wasn't getting excited. I was like, "Okay, calm down. Calm down. This could be like a, a major outlier or something."

    24. TFTim Ferriss1:02:02

        Right. [laughs]

    25. DDDr. Dominic D'Agostino1:02:03

        And then every single rat we've ever done, and we've done many rats, you know, every single rat has gone way beyond the control to where the average is that it can resist oxygen toxicity, uh, 575%, and that sort of blows away any anticonvulsant drug out there. [laughs]

    26. TFTim Ferriss1:02:23

        Yeah.

    27. DDDr. Dominic D'Agostino1:02:23

        So similar to the ketogenic diet, right? If you go to the Charlie Foundation website, you know, the Charlie Foundation was set up, you know, working with Johns Hopkins-

    28. TFTim Ferriss1:02:32

        Yeah

    29. DDDr. Dominic D'Agostino1:02:32

        ... University, is for kids with drug-resistant seizures. And in the studies published, the original studies by John Freeman, uh, s- published showed that in ch- kids that have failed all standard of care, all, even combinations of like six anti-seizure drugs, when they're put on the ketogenic diet, two-thirds of those kids have, you know, seizure control, like remarkable seizure control. And a percentage of them, like a third of them, have absolutely no seizures. Like, or like 95% reduction in seizures. So it made sense. So I, I was actually thinking that, well, the original [laughs] study design was to feed ketone esters for a week and then dive them, but, uh, my source was only making like a little bit at a time [laughs] and, uh-

    30. TFTim Ferriss1:03:18

        [laughs]
14. 1:16:08 – 1:20:43

    Benefits of eating exogenous ketones (especially in Italy)

    1. DDDr. Dominic D'Agostino1:16:08

       I-

    2. TFTim Ferriss1:16:08

       [laughs]

    3. DDDr. Dominic D'Agostino1:16:08

       ... kind of cheat along the way. Um-

    4. TFTim Ferriss1:16:09

       So if, if, so if you go to like-

    5. DDDr. Dominic D'Agostino1:16:11

       Yeah

    6. TFTim Ferriss1:16:11

       ... Italy and you're eating bread and pasta, what are the main benefits... I, I'm making that assumption, but I, that's what I would do, 'cause I'm a glutton. But, um, and-

    7. DDDr. Dominic D'Agostino1:16:21

       Yeah

    8. TFTim Ferriss1:16:21

       ... and love carbs when it comes down to it. But if, if you went to Italy and were consuming all of that, what is the benefit of ingesting the exogenous ketones, and how would you ingest them?

    9. DDDr. Dominic D'Agostino1:16:35

       Okay. Uh, depends on, you know, kind of the person, what you want it to, uh, if you were working out or, or whatever.

    10. TFTim Ferriss1:16:43

        Yeah. What's, uh, yeah, just for-

    11. DDDr. Dominic D'Agostino1:16:43

        Uh, just, but just for general health and energy.

    12. TFTim Ferriss1:16:45

        Uh, I would, I would say for your personal, your personal use. So y- like, if you could describe sort of how much you're working out, just i- in a scenario like that, right? You're traveling with these, um, these exogenous ketones.

    13. DDDr. Dominic D'Agostino1:16:57

        Yeah.

    14. TFTim Ferriss1:16:57

        How do you, how do you use them and why?

    15. DDDr. Dominic D'Agostino1:17:00

        Okay. Um, I will... Well, there's two that I kind of bring with me. One would be, um, a, uh, MCT powder, and it's basically caprylic triglyceride, like a Brain Octane, but a powdered form of it.

    16. TFTim Ferriss1:17:14

        Mm-hmm.

    17. DDDr. Dominic D'Agostino1:17:15

        And I'm kind of, it's not on the market yet, but I just kind of have it. [laughs]

    18. TFTim Ferriss1:17:18

        Yeah.

    19. DDDr. Dominic D'Agostino1:17:18

        And, uh, and I use the Keto Caana product-

    20. TFTim Ferriss1:17:21

        Uh-huh

    21. DDDr. Dominic D'Agostino1:17:21

        ... that's put out by Keto Sports. Uh, I will, it's kind of the first thing I take when I get up. I drink a glass of water, and then I, I take some, a small amount of ketones to bump me up to about one millimolar.

    22. TFTim Ferriss1:17:35

        And that's a combination-

    23. DDDr. Dominic D'Agostino1:17:36

        And then I eat a ketogenic diet breakfast

    24. TFTim Ferriss1:17:37

        ... and that's the combination of the MCT powder and the Keto Cana, or Keto Caana. God, I need to... It's like Gymkhana, like that, that horrible but awesome movie I saw ages ago.

    25. DDDr. Dominic D'Agostino1:17:46

        Yeah. [laughs]

    26. TFTim Ferriss1:17:47

        All right. Keto C- Keto Caana, is that how you guys say it? Okay.

    27. DDDr. Dominic D'Agostino1:17:50

        Keto, Keto Caana. Yeah.

    28. TFTim Ferriss1:17:51

        So do you combine-

    29. DDDr. Dominic D'Agostino1:17:51

        Yeah

    30. TFTim Ferriss1:17:51

        ... those two when you first get up and take it with water?
15. 1:20:43 – 1:25:08

    The traveling ketogenic breakfast

    1. TFTim Ferriss1:20:43

       And you'll, so you'll take the, you'll, you'll take your MCT powder in the morning with water, then you'll have a keto breakfast. What does the breakfast look like?

    2. DDDr. Dominic D'Agostino1:20:51

       Mm-hmm. Uh, this morning, um, I had, uh, eggs. Uh, I usually have four eggs and some kind of fish. I'm a big believer of kind of, um, I eat beef, but I've been phasing out beef and chicken and probably getting about two-thirds of my protein from fish. Uh, so I had eggs and fish in the form of sardines, and, uh, a half of a can of oysters. I've been on this oyster kick for a while. [laughs]

    3. TFTim Ferriss1:21:20

       Why is that?

    4. DDDr. Dominic D'Agostino1:21:20

       And, uh, oysters, well, I mean, they're, they're like a nutrition powerhouse, right? So are sardines. So I get the sardines, uh, packed in olive oil. But, um, they're really high in micronut- nutrients like selenium and, uh, which are, you know, things that are m- may be hard to get from other sources out there, but, um, but I think, I just like the taste of them, too, so.

    5. TFTim Ferriss1:21:44

       Right.

    6. DDDr. Dominic D'Agostino1:21:45

       Um, so sardines are really good to travel with. They're, they're my travel food, too. So whenever my bag is packed, I usually have about a dozen cans of sardines packed in extra virgin olive oil. So I tend to just, I like them so much, I eat them when I'm home, too. So I have, yeah, fish and eggs and some kind of green, usually asparagus, broccoli, or spinach, or kale. And if I make kale, I like to cook bacon, and I cook the kale in the bacon grease. But I didn't do that this morning, but I'll probably do that tomorrow.

    7. TFTim Ferriss1:22:15

       Mm-hmm.

    8. DDDr. Dominic D'Agostino1:22:15

       Uh, so that's what I had for breakfast. But before I eat breakfast, I always kind of drink water first, and I, I take, uh, branched-chain amino acids, uh, with the ketone products that I just told you about, and that kind of gets energy to my brain, like immediately, and I'm kind of, like, really good to go after that. And usually, but, well, before that, I let my dog out, and he just kind of goes crazy. So I kind of run around and watch him chase animals off our property. So [laughs]

    9. TFTim Ferriss1:22:42

       [laughs]

    10. DDDr. Dominic D'Agostino1:22:42

        It's always an entertaining thing while, uh, while coffees or, I got water brewing for my coffee, and I got my, my, uh, breakfast cooking, and, uh, so that usually goes on in the morning. And, uh, but yeah, I always, my, my breakfast is always pretty much ketogenic, and if I have coffee, I do put butter in it, and I put, uh, MCT powder in it on top of the butter. So it's very ketogenic. And, uh, the macronutrient ratio of my breakfast is always about, about 70 to 80% fat and, uh, with the balance being, you know, protein and a little bit of carbs from whatever green vegetables I have.

    11. TFTim Ferriss1:23:25

        And, um, the, uh, BCAAs, what brand are you using?

    12. DDDr. Dominic D'Agostino1:23:31

        Yeah. I use, uh, SciVation.

    13. TFTim Ferriss1:23:33

        How do you spell that?

    14. DDDr. Dominic D'Agostino1:23:34

        Yeah. It's short for s- uh, science and innovation. So, uh, S-I, oh, S-C-I-V-A-T-I-O-N, right?

    15. TFTim Ferriss1:23:46

        Yeah.

    16. DDDr. Dominic D'Agostino1:23:46

        Yeah, SciVation. So SciVation has been an incredible supporter of our, um, our cancer research program. So [laughs] as you know, getting, getting funding to do metabolic therapy research or research on diets and nutrition and just basically cancer metabolism in general, just people don't study it.

    17. TFTim Ferriss1:24:11

        Right.

    18. DDDr. Dominic D'Agostino1:24:12

        Uh, the CEO of SciVation's a, is a close friend of mine, and, um, he has been for personal reasons and just kind of, you know, scientific reasons, he has supported our cancer research program. And his branched-chain amino acid product is called Xtend, uh, and it's, you know, it's probably the most popular one out there, and it's, you know, on, probably the most popular on bodybuilding.com. And, uh, it's actually the product that we're using in our cancer studies.

    19. TFTim Ferriss1:24:41

        Mm-hmm.

    20. DDDr. Dominic D'Agostino1:24:42

        So I, he asked me, he contacted me and wanted me to, to study this, and I looked at the formula, and it had a, a high amount of glutamine in it. So, um, I said, "You know, I wanna study this, but let's remove the glutamine and just do pure branched-chain amino acids and- Uh, I think he replaced the glutamine and put some taurine in it or whatever, and we, we started with that. And, uh, we added

16. 1:25:08 – 1:32:18

    Reasons for using glutamine

    1. DDDr. Dominic D'Agostino1:25:08

       branched-

    2. TFTim Ferriss1:25:08

       Yeah. Now, is that because the glutamine is, uh, glucogenic, or what was the reason for-

    3. DDDr. Dominic D'Agostino1:25:13

       Yeah

    4. TFTim Ferriss1:25:13

       ... removing the L-glutamine?

    5. DDDr. Dominic D'Agostino1:25:14

       Yeah, I should describe. So, uh, cancer cells in, um, kind of default to a metabolic phenotype called the Warburg effect, right? So they, they basically derive most of their energy from glucose metabolism and their biosynthetic processes. As a, as a tumor grows, it's using glucose for energy, but it's also using glucose to expand the biomass of the tumor, so it becomes the primary, uh, source of energy. And, and we, we knew this for some time, and that's sort of underlies the basis of using what's called a PET scan for imaging the location and the aggressiveness of a tumor in imaging, an FDG PET scan. So it basically shows sugar metabolism or glucose metabolism. So now investigators understand that the amino acid glutamine is also used at a fairly high concentration relative to other amino acids, I guess I would say, uh, by cancer cells. So, and we call that glutaminolysis. So cancer cells can use glucose, primarily glucose, but they can also use glutamine. And there's, this is understood now and, and kind of well-defined in the literature. So y- but we know that glutamine, I mean, some formulas actually promote, or hospitals will promote giving, uh, IV glutamine or oral glutamine to cancer patients. Uh, that's not necessarily proven to be a bad thing, but I think I was erring on the side of caution by removing the glutamine, uh, from the XTEND product, at least for our studies.

    6. TFTim Ferriss1:26:57

       Right.

    7. DDDr. Dominic D'Agostino1:26:58

       And we wanna go back and do a parallel study with the glutamine actually to see. But, um-

    8. TFTim Ferriss1:27:01

       And the, and the IV glutamine in the hospitals is for, um, waste, to pr- to, to, for an anti-cata- catabolic purpose, or is it for some type of recovery purpose? Why are they doing that in the first place?

    9. DDDr. Dominic D'Agostino1:27:14

       Yeah, glutamine is-

    10. TFTim Ferriss1:27:14

        'Cause I know a lot of people take glutamine post-workout, for instance.

    11. DDDr. Dominic D'Agostino1:27:18

        Yeah. If you're ingesting it, the gut pretty much, the gut and the liver, I think, probably are pretty greedy and take their share. Uh, I'm not sure how much glutamine you're actually getting to the muscles-

    12. TFTim Ferriss1:27:28

        Right

    13. DDDr. Dominic D'Agostino1:27:28

        ... when you do that.

    14. TFTim Ferriss1:27:28

        Right.

    15. DDDr. Dominic D'Agostino1:27:29

        But glutamine, I would say, is a conditionally essential amino acid, so under periods of high stress or catabolic physiological state, your body will use more glutamine. Uh, glutamine is also a, uh, an important amino acid for maintaining your immune system, so it plays a, a pr- uh, I would say if you're deficient in glutamine, it can compromise your immune system. So you wanna make sure that if your immune system is challenged, which it would be, you know, if you have, if you have cancer, if you're getting chemotherapy, if you, if you're a burn patient, um, you know, you're gonna want, you, you might want, uh, glutamine. Although we don't, we wanna, we're, we're testing a hypothesis [laughs] that, uh, we wanna metabolically starve cancer cells in our experiment and preserve muscle at the same time. So the XTEND product that, that's out there by CytoVision is a remarkable product. I think people like it because it tastes so good. So the people who formulate the product really know what they're doing with taste. So it tastes, like, really, really good. So, and that's, that's, if you want a successful product, it doesn't matter if it, you know, cures cancer, enhances your performance, you know, 10 times over. If it doesn't taste good, people are not gonna take it. So the CytoVision and the branched chain amino acids, they taste really good, but they're also, you know, very tolerable and very, you know, palatable. Uh, but they, you know, this particular product had glutamine, so we removed it from, uh, the formula for our studies, and we ran a study with a ketogenic diet, and we added the branched chain amino acid to the ketogenic diet, and we, uh, looked at survival of mice with, with advanced metastatic cancer. And, um, adding the branched chain amino acid to the ketogenic diet, we had, like, a 50% increase in survival with the ketogenic diet alone. And when we added branched chain amino acids to the ketogenic diet, there was trends for an increase in survival, but I think the big thing is that we saw, uh, the animals were maintaining their, their weight better, uh, with the branched chain amino acids added to it. So with branched chain amino acids, one of them is leucine, and we know leucine can activate mTOR. And [laughs] mTOR has been associated with, uh, driving, a major driver for cancer growth and proliferation. But, you know, and, and there's cancer biologists out there that would say, "Well, if you give leucine, you're just gonna drive cancer because you're stimulating a, an anabolic process that can drive cancer growth and proliferation." But I would kind of argue that, uh, that's not the case here. We definitely don't see it in this model, and some of the other studies out there, uh, do not show that branched chain amino acids cause cancer to grow faster, and some of it shows the opposite actually. Uh, but I, I, I think branched chain amino acids have, their effect on anabolic processes are relatively specific to skeletal muscle, and I think that's, that's really important to understand, is that stimulating anabolic processes is not a global effect, is that, um... It's kind of similar to anabolic steroids, right? So there's specific receptors on the muscles. [clears throat] And we think that- That the, um-

    16. TFTim Ferriss1:31:02

        [laughs] Right, and that's also why if you take a sort of less selective growth agonist, you end up looking like you're seven months pregnant as a bodybuilder [laughs] 'cause your-

    17. DDDr. Dominic D'Agostino1:31:11

        Yeah, yeah, yeah

    18. TFTim Ferriss1:31:12

        ... your, your intestines are the size of, uh, your forearms, yeah. [laughs]

    19. DDDr. Dominic D'Agostino1:31:16

        Yeah, IGF-1 is great for, like, growing your skin and your organs, yeah.

    20. TFTim Ferriss1:31:21

        [laughs]

    21. DDDr. Dominic D'Agostino1:31:22

        So it has a pretty global systemic anabolic effect, whereas, uh... And we didn't, we haven't proven this yet, but I think just based on literature and, you know, really, we're really delving into it, we think that the branched-chain amino acids will be relatively specific for skeletal muscle. And, uh, and to look at this, you know, we're gonna, you know, feed animals the, the branched-chain amino acids, and then we take the actual tumor tissue out, and then, you know, we do a series of, you know, metabolic analysis and, and assays and everything to look at the, uh, the signaling and, um, the, you know, insulin signaling, the metabolomics, the growth factors, and whatnot, so, and compare it to the groups without the branched-chain amino acids. So we're really delving mechanistically into this.

    22. TFTim Ferriss1:32:09

        Which is, which is something I, I love and enjoy about your research and our conversations, is that,

17. 1:32:18 – 1:41:38

    On being considered a “nutritionist”

    1. TFTim Ferriss1:32:18

       I mean, you're... You have a lot of expertise in neurochemistry, neurobiology, cancer chemistry, but you're not... Y- would you consider yourself a nutritionist?

    2. DDDr. Dominic D'Agostino1:32:30

       Uh, you know, I, as an undergrad, I, I enthusiastically went into a nutrition science program at Rutgers University.

    3. TFTim Ferriss1:32:39

       Right.

    4. DDDr. Dominic D'Agostino1:32:40

       And, uh, and my, uh, who would you call it? I guess my guidance counselor at the time, you know, just wasn't a very interesting person, and it was like, well, I kept going to her and I said, "Well, y- direct me to labs that are doing interesting nutrition science research." And there wasn't a whole lot going on at Ru- I mean, I like Rutgers and everything, but there just wasn't-

    5. TFTim Ferriss1:33:02

       [laughs]

    6. DDDr. Dominic D'Agostino1:33:02

       ... a whole lot of stuff [laughs] going on there that really interested me. And the more people I talked to, I, I was kinda going the pre-mout- pre-med route, and, um, and people were like, "Well, yeah, you should probably, you should probably major in biology, too." So I double majored in, in nutrition biological sciences, and, uh, but I really had a passion for nutrition. And then when I went into a PhD program, it was neuroscience, 'cause I was really fascinated with the brain, but also did physiology. And, uh, I studied the neural control of autonomic regulation, so how the brain controls our body, our physiology. And then, uh, you know, I started, uh, did my postdoc in, um, you know, looking at, uh, physiological resilience and the oxygen toxicity thing, and it brought me back full circle.

    7. TFTim Ferriss1:33:49

       Yeah.

    8. DDDr. Dominic D'Agostino1:33:49

       Because when I started, you know, as, basically, a pharmacologist, as a neuroscientist, trying to find a drug that would mitigate oxygen toxicity seizures, and I'm looking at all these drugs and I realize that they're not, they're not very good. You have-- they would be good if you give them at a dose that would sedate a war fighter, [laughs] you know-

    9. TFTim Ferriss1:34:08

       Yeah

    10. DDDr. Dominic D'Agostino1:34:08

        ... and basically put them into a coma, and it's not very, uh, ideal-

    11. TFTim Ferriss1:34:12

        Not the ideal way to prevent seizures. [laughs]

    12. DDDr. Dominic D'Agostino1:34:14

        ... ideal situation. Yeah. But then when I discovered, you know, the ketogenic diet, and I wasn't, you know, really excited when I first discovered it. And I was like, "Eh, let me see the research on this. There's a lot of things out there." But the research on it was so, like, cut and dry. I mean, there was an overwhelming amount of scientific research showing the efficacy of the ketogenic diet for drug-resistant pediatric seizures, and now, now in adults, too. And I realized, wow, this is like the most powerful metabolic therapy out there for seizures, like bar none. And I be- I was like, you know, I realized this was grossly underutilized, and if I could harness the power of this and apply it to something as esoteric as, you know, CNS oxygen toxicity, that would be really cool. So I could kind of bring back my passion for nutrition, uh, which was always there. I always, even, you know, throughout grad school and postdoc, I was totally into working out and nutrition and understanding, you know, different diets and trying lots of stuff on myself. Uh, it, it, it allowed me to, you know, kinda come full circle and, uh, and incorporate, you know, nutrition research into my research now. So our entire research program is really based on the ketogenic diet. So we do ketogenic diet studies, exogenous ketones, but we also do metabolic drugs. So we do, you know, metformin and a few other drugs. Um-

    13. TFTim Ferriss1:35:41

        Well, and a lot of, I mean, you mentioned metformin as sort of a regulator of, uh, you know, uh, liver glycogen, hepatic glycogen. Um-

    14. DDDr. Dominic D'Agostino1:35:50

        Yeah

    15. TFTim Ferriss1:35:50

        ... and there are plenty of folks who take metformin, uh, is it still called Glucophage? The, um, or Glucophage, I'm not sure the, uh, the brand name. But the metformin prophylactically. I mean, these are otherwise what-

    16. DDDr. Dominic D'Agostino1:36:01

        Yeah

    17. TFTim Ferriss1:36:01

        ... you'd consider healthy people who are taking it primarily to prevent, uh, cancer growth, if I'm not mistaken. I mean, is that fair to say, or are they using it for other purposes?

    18. DDDr. Dominic D'Agostino1:36:13

        Yeah, you can use it for a variety of reasons. Uh, you could use it as kind of a metabolic prophylactic to prevent you from getting type 2 diabetes [laughs] down the road.

    19. TFTim Ferriss1:36:24

        Right.

    20. DDDr. Dominic D'Agostino1:36:24

        But when it comes to cancer, yeah, it definitely, uh, activates, uh, or dampens or activates signaling pathways associated with cancer growth and proliferation. And if you're activating AMP kinase, which it's well known to do that, and, um, and activate various downstream signaling processes, uh, it, it, it mimics in many ways calorie restriction and fasting, uh, the, the same processes that would be activated. Uh, it doesn't, you know, it comes with some side effects, and some people have intolerance to it, you know, GI issues with it. But overall, it's a really safe drug. I mean, so many prescriptions Have been written for it, like we know what it does and what it doesn't do. Uh, we don't really... The cancer, the cancer, uh, there's a lot of research in cancer right now, and when you go to a cancer conference, you hear there's a lot of discussion, a lot of buzz about metformin, but there's also a lot of debate as to how it's working. So some people think it's, it's, it's toxic to the mitochondria, and it's inhibiting complex one of the mitochondria. And other people are saying it works purely by activating AMP kinase, and other people by its ability to regulate hepatic glucose output or a combination, and, and some people through other mechanisms. So we don't know how it works, but I think, you know... I, I did a, I did a run where I took one gram of metformin for, I think it was 12 weeks, and, uh, and I got blood work. And the only thing I saw was that my testosterone was lower.

    21. TFTim Ferriss1:38:05

        Oh.

    22. DDDr. Dominic D'Agostino1:38:05

        [laughs] So that was, I think that's a side effect. I have since got off of it.

    23. TFTim Ferriss1:38:09

        Okay.

    24. DDDr. Dominic D'Agostino1:38:09

        And I, I rechecked, and my testosterone levels, like, are back into the normal range that they were.

    25. TFTim Ferriss1:38:15

        Did, did you feel anything-

    26. DDDr. Dominic D'Agostino1:38:16

        And that's the only thing I... No, I didn't. And [clears throat] well, I felt, I don't know how to describe it, a little, maybe a little less anxious, a little bit kind of like you're, you kind of set the governor. Like, my highs weren't as, as high, and s- uh, like, and I would kind of dose it, I'd dose it twice a day, and my bigger dose would be at nighttime before I went to bed 'cause that would be my bigger meal. So I would kind of dose the metformin according to my food intake, which I think is important. Um, [clears throat] but I, yeah, I didn't really notice any side effects. I, I went up to two grams a day initially and found out, okay, that- that's about my tolerance to, to it.

    27. TFTim Ferriss1:39:00

        [laughs]

    28. DDDr. Dominic D'Agostino1:39:00

        So I, I backed down to one.

    29. TFTim Ferriss1:39:02

        S- [laughs] Now, now, so-

    30. DDDr. Dominic D'Agostino1:39:03

        Yeah
18. 1:41:38 – 1:46:18

    Metformin and cancer survival rates

    1. DDDr. Dominic D'Agostino1:41:38

       give a pretty big dose

    2. TFTim Ferriss1:41:39

       ... i- is that with some, uh, you're talking about metformin.

    3. DDDr. Dominic D'Agostino1:41:44

       Yeah, yeah.

    4. TFTim Ferriss1:41:44

       It's, it's-

    5. DDDr. Dominic D'Agostino1:41:44

       Just metformin to a standard diet increases the survival times of animals that have, um, metastatic cancer. We've presented this at several meetings, and we're finishing up the data now to, to publish it, which would be published pretty soon.

    6. TFTim Ferriss1:41:59

       And that, does that include in the animal models, I'm not sure if this is in the animal, but like, um, glioblastoma multiforme, like the, the GBM, sort of the uniformly, what's, what are considered kind of the, the, the uniformly fatal cancers?

    7. DDDr. Dominic D'Agostino1:42:12

       Yeah.

    8. TFTim Ferriss1:42:13

       Is that also, uh, do you still see the 40 to 50%?

    9. DDDr. Dominic D'Agostino1:42:16

       Yeah, so [laughs] it's interesting. So the, um, the metastatic cancer model that we have, the primary tumor is derived from a tumor that pathologists confirmed was a glioblastoma. What's interesting about these cancer cells are so aggressive that we have them in culture, right? We have, uh, isolated cell cultures of these cells that are metastatic and very aggressive, and they're transfected with a gene that makes that, that, uh, makes the protein, uh, luciferase. So, uh, it basically makes the cells glow in the presence of luciferin. So, uh, not to get too complicated, but if we take these cells in culture, right, we harvest them, and we implant them inside, uh, the flank of the animal or underneath the skin, it, uh, the cells uh, metastasize to all the organs and even the brain. So typically, a glioblastoma is thought not to metastasize to other organs of the body, and it stays in the brain. Uh, but I think our-- I think we don't typically see people with glioblastoma with liver cancer because they die of the glioblastoma before it metastasizes.

    10. TFTim Ferriss1:43:33

        Right.

    11. DDDr. Dominic D'Agostino1:43:33

        So, uh, we've basically, um... And this is a model that was generated by Thomas Seyfried from, um, from Boston College. He wrote the book Cancer as a Metabolic Disease. It's a really, really good book. Uh, it's like required reading for all my students. But, uh, he developed this model and it made, like, the cover of International Journal of Cancer, and it's, it's probably the best model out there. So it's, it's why we chose the model. But it's a, it's a model of advanced metastatic cancer, and the primary tumor was, um, had a glioblastoma kind of cell type to it, and these cells were, uh, kind of described as tumor-associated macrophages. So they can travel along blood vessels. They can metastasize to organs very aggressively. And it makes it a, it makes it a, uh, a convenient model to use 'cause when you implant the cells, the experiment goes real fast, right? Because, [laughs] because the animal succumbs to the tumor burden within about 21 days. So we can test, and we can basically test a lot of things really fast. Because the tumors grow so fast, within 21 days, we have to put the animal down, uh, because they, you know, it'll succumb to the tumor burden. So it allows us to test various drugs and diets and, and ketogenic agents. And when we tested metformin with a standard high-carbohydrate rat chow, and we formulated it into, uh, into the food so it would be equivalent to a person taking about 2.5 grams a day. So metformin comes in, like, 500 milligram tablets. I think even sometimes one gram tablets. So with the 500 milligram tablets, it would be taking, like, five tablets a day, uh, would be the human equivalent to that. The animals lived about, about 50% longer, anywhere about 45 to 50% longer survival time. So instead of living, you know, 21 days, they lived, like, uh, almost 40 days.

    12. TFTim Ferriss1:45:37

        That's amazing.

    13. DDDr. Dominic D'Agostino1:45:38

        And so, so what we're doing now and, um, so we have to, like, tediously test all these things in isolation, and then we have to do different dose ranges too, right?

    14. TFTim Ferriss1:45:47

        Right.

    15. DDDr. Dominic D'Agostino1:45:48

        So we gotta do a variety of dose ranges and make all these dose curves and everything. But I'm-- I just wanna jump right into it, you know? I wanna do a calorie restricted ketogenic diet with ketone supplementation and metformin and hyperbaric oxygen. [laughs] Yeah, I wanna jump right to it. But, uh, and we're, we're kind of doing some of these things as pilots, but, uh, but we're testing. I think it's really important to get a handle on what each of these things do-

    16. TFTim Ferriss1:46:15

        Now, here's-

    17. DDDr. Dominic D'Agostino1:46:15

        ... at different dosages.

    18. TFTim Ferriss1:46:16

        No, definitely. I-- let me,

19. 1:46:18 – 2:03:03

    What Dom would do if he had cancer

    1. TFTim Ferriss1:46:18

       let me-- I, I apologize for interrupting, but if you-- and you would find this-- you would've figured this out earlier, of course, but if you found out you had relatively advanced cancer of some aggressive type, what, what are the tools that you would throw at it that you have a decent degree of confidence would have a beneficial effect? Like, so you mentioned a few things, right? You mentioned, uh, calorie restricted ketogenic diet, so I'd love to hear-

    2. DDDr. Dominic D'Agostino1:46:44

       Yeah

    3. TFTim Ferriss1:46:44

       ... um, what calorie restricted means, right? Um-

    4. DDDr. Dominic D'Agostino1:46:47

       Okay

    5. TFTim Ferriss1:46:47

       ... you mentioned metformin, you mentioned, uh, hyperbaric oxygen treatment, um, you mentioned exogenous ketones. We talked earlier about fasting. But let's just say you found out, "Oh, shit, uh, I'm in, I'm in a bad situation here, and, uh, this is a very, very aggressive cancer." Putting aside the chemotherapy and some of the other, um, therapies that, that you might have administered-

    6. DDDr. Dominic D'Agostino1:47:11

       Mm-hmm

    7. TFTim Ferriss1:47:11

       ... of the toolkits that we've been discussing, like, what would you, what would you do?

    8. DDDr. Dominic D'Agostino1:47:17

       Okay. Um, well, you know, so I, I'm not the kind of person [laughs] some, some of my colleagues are kind of very anti standard of care, some of them, for some ways, but I think you have to-- I know you told me not to talk about chemo, but if you have something like testicular cancer or, or leukemia or lymphoma, uh, there's a variety of cancer, you'd be crazy not to do the standard of care.

    9. TFTim Ferriss1:47:42

       Sure.

    10. DDDr. Dominic D'Agostino1:47:42

        So, uh, so, so, so when I, when I talk about this, uh, it could-- one could potentially use it as a standalone therapy, or one could use it as a way to further augment the efficacy of standard of care-

    11. TFTim Ferriss1:47:55

        For sure

    12. DDDr. Dominic D'Agostino1:47:55

        ... which we, we plan to do both. Uh, [clears throat] so say, you know, worst case scenario, like glioblastoma, right? Um, a glioblastoma is, in, in some ways, it's, it's a really a good, a good model to look at because your survival time is, like, one year, give or take a few months. So it, it's almost, you know, uh, [laughs] you know, if we do a study with glioblastoma patients, it's almost like you have historical controls that you can refer to.

    13. TFTim Ferriss1:48:23

        Right.

    14. DDDr. Dominic D'Agostino1:48:23

        Uh, so, uh, so the ketogenic diet, I think, would be, would be absolutely, like, your base therapy, right? And it, and it would be not just a macronutrient ratio, it would be the sources of the, the macronutrients itself. Like, you would have to-- you would do a macronutrient ratio that would put you into ketosis, but take extra care to get, you know, fish that was from a natural source or grass-fed beef. And, and I think these things would probably be important because we know the fatty acid composition changes dramatically from, you know, a corn-fed cow then to a grass-fed or, or a salmon that's farm raised or, or wild. So the ketogenic diet would be kind of the base. And instead of the normal, you know, three day or three times a day eating pattern, I would go to an intermittent fasting, um- personally, and I think that would be, that would-- you could further harness the power of ketosis by fasting throughout the day and then having a ketogenic meal once a day.

    15. TFTim Ferriss1:49:29

        So you'd have-- So your single meal would be, like, a dinner?

    16. DDDr. Dominic D'Agostino1:49:33

        Uh, it would be dinner, yeah. You would eat probably within a window of, you know, four hours, like so.

    17. TFTim Ferriss1:49:38

        Right.

    18. DDDr. Dominic D'Agostino1:49:38

        And I think-- And I've experimented with that, and that's possible. I just like eating, though, so I like, I like sitting down and having, like, a social breakfast. And I don't eat during the day, and then I have a nice sit-down social kind of dinner at night. So I like that. So either way, I think ideally I would probably do one meal a day. And, uh, ketone supplementation, I think, I mean, we've shown independent of even the ketogenic diet that ketones have an anti-cancer effect. They not only do... Our ketones cannot be utilized as an energy source by aggressive cancer cells that have defective mitochondria. So cancer cells cannot use ketones effectively as an energy source because they have defective mitochondria. Structurally, they're defective. If you look at the mitochondria of, uh, cells of a glioblastoma patient, they're-- the inner cristae, the little folds inside the mitochondria where ATP is actually produced, is completely screwed up. And they're also deficient in various ketogenic enzymes that would allow the cancer cells to make energy from ketones. So ketones, uh, ketones as a source of energy is a very poor energy source for, for cancer. So putting our state into-- putting our body into a state of nutritional ketosis would be a way to marginalize, you know, the fuel source to ketones and enhance the energy capacity of our healthy cells.

    19. TFTim Ferriss1:51:06

        And for-

    20. DDDr. Dominic D'Agostino1:51:06

        So exogenous ketones-

    21. TFTim Ferriss1:51:07

        Yeah. What type-- Like h- for you personally, what would-- h- how, how much would you take? When would you take them?

    22. DDDr. Dominic D'Agostino1:51:13

        Yeah. I would take a level of exogenous ketones that would put me above whatever baseline I was at, between one to two millimolar. So if I'm cruising along at, like, one point five, you know, staying on a modified Atkins-like diet, I would further boost that to, like, three or three and a half, uh, with, with exogenous ketogenic agents. I think the easiest could be medium-chain triglycerides, you know, uh, MCT powder, which will be available soon, um, the Keto CaNa product. Uh, there's some-- There'll be some products coming out pretty soon, uh, ketone salt products that'll taste really good and will be-- will allow you to easily achieve this. And-

    23. TFTim Ferriss1:51:59

        How much would you have to take, you personally, to jack your ketone millimolar up one to two millimolars like you described? Is it a three times a day-

    24. DDDr. Dominic D'Agostino1:52:08

        Yeah

    25. TFTim Ferriss1:52:08

        ... twice a day? Like, what, what type of dosing and frequency are we looking at?

    26. DDDr. Dominic D'Agostino1:52:13

        I would do twice a day. It's probably twice a day or maybe three times a day, depending. See, the MCTs kind of allow you to maintain the levels up a little bit higher. Uh, but I think it's okay to not continuously, you know, provide an exogenous source of ketones, but maybe just use them, uh, when you need them, if you need a boost in energy. So you might-

    27. TFTim Ferriss1:52:36

        But if you, but if you had the glioblastoma, you would do-

    28. DDDr. Dominic D'Agostino1:52:39

        Yeah

    29. TFTim Ferriss1:52:39

        ... two to three times a day.

    30. DDDr. Dominic D'Agostino1:52:39

        I would do, I would do two to four times a day probably, 'cause the way kind of our experiments are panning out, it just looks like, you know, the, the, the stronger you stay in ketosis, the higher levels you get, the, the better, uh, tumor suppressor effects that you get. So, um, yeah, I would, I would use them to the extent where I was pretty much constantly, uh, from the time I wake up, keeping my ketones more or less artificially elevated. Well, I guess it wouldn't be artificial if you're adding MCTs, but, um, which are a good carrier for the other forms of, of exogenous ketones, uh, to keep it further boosted an additional one to two millimolar-
20. 2:03:03 – 2:08:23

    Thoughts on therapeutic fasting

    1. TFTim Ferriss2:03:03

       dose, um, in your colleague's mind, or your... I'm not sure if it was a colleague or student, but-

    2. DDDr. Dominic D'Agostino2:03:09

       Uh, yeah. Um, if you wanna do it kind of hardcore [laughs] -

    3. TFTim Ferriss2:03:13

       Yeah

    4. DDDr. Dominic D'Agostino2:03:13

       ... and, uh-

    5. TFTim Ferriss2:03:14

       It's k- kind of my MO. [laughs]

    6. DDDr. Dominic D'Agostino2:03:15

       You're resilient. Yeah, yeah. Uh, okay. So, so and, and this would apply to someone on a high carbohydrate diet too, but what I've seen, I mean, you just described it very nicely [laughs] there. You know, the back pain, some, you know, your body goes into kind of more or less a stress-

    7. TFTim Ferriss2:03:32

       Shitty, shitty sleep, like horrible.

    8. DDDr. Dominic D'Agostino2:03:34

       Yeah.

    9. TFTim Ferriss2:03:34

       Like, I guess that's a co- is that a cholinergic response? I don't know, but like every... I was in a location where there were 40 people fasting, 50 people fasting, some of whom-

    10. DDDr. Dominic D'Agostino2:03:42

        Yeah

    11. TFTim Ferriss2:03:42

        ... had been doing it for two weeks, three weeks, four weeks or, or, uh, or so.

    12. DDDr. Dominic D'Agostino2:03:46

        Wow.

    13. TFTim Ferriss2:03:46

        And ev- but everyone reported horrible insomnia and, like, tachycardia, you know, like rapid heartbeat-

    14. DDDr. Dominic D'Agostino2:03:53

        Yeah, yeah

    15. TFTim Ferriss2:03:53

        ... when they were trying to sleep.

    16. DDDr. Dominic D'Agostino2:03:55

        So yeah, that, that's an activation of your sympathetic nervous system. It's your body saying, "Hey, this is a stress response." So that's lack of fuel flow to your brain [laughs] will trigger brain fog. It'll trigger a headache. It'll trigger activation of sympathetic immune system. Uh, it will, your insulin levels will go down very rapidly, right? And when insulin goes down, it has a natriuretic effect, which means that you lose sodium, so you're peeing out all your sodium. So your blood volume drops. You become hypovolemic, and your blood, uh, pressure will drop, and that'll contribute to your headache and, you know, just feeling crappy and-

    17. TFTim Ferriss2:04:33

        Dizziness when you stand up and all that

    18. DDDr. Dominic D'Agostino2:04:34

        ... you know, some people faint.

    19. TFTim Ferriss2:04:35

        Yeah.

    20. DDDr. Dominic D'Agostino2:04:35

        Yeah, I've seen several women, it seems to be more pronounced in women that try this, that, that, that they faint and they, they, um, you know, I had a couple of them, like, call me up and just, it just made them go crazy. Like, it, they thought they were gonna die. [laughs]

    21. TFTim Ferriss2:04:48

        Yeah.

    22. DDDr. Dominic D'Agostino2:04:49

        Uh, so if you can get past that, and I, I, I think- [laughs]

    23. TFTim Ferriss2:04:53

        [laughs]

    24. DDDr. Dominic D'Agostino2:04:53

        If you can get past the feeling of, uh, you know, and that's usually the second and third day.

    25. TFTim Ferriss2:04:58

        Yeah.

    26. DDDr. Dominic D'Agostino2:04:59

        Uh, I've got reports as early as the end of the first day, but I think they were kind of wimps. But usually the second and third day-

    27. TFTim Ferriss2:05:04

        [laughs]

    28. DDDr. Dominic D'Agostino2:05:04

        ... you're kind of hurting. If you can cruise through that, and I think cruising through it would, would be a lot easier with exogenous ketones.

    29. TFTim Ferriss2:05:12

        Absolutely. 100% agree.

    30. DDDr. Dominic D'Agostino2:05:12

        So if you're giving your body, you can kind of cheat through that. [laughs] So this is, this is something that I'm kind of working on, like developing, like thoughtfully, uh, developing protocols that would make this whole process easier and even enjoyable potentially. Uh, so but so, okay, like in a perfect world, if you can tolerate fasting, I would do it, uh, ideally, yeah, like maybe once every quarter for five days. Uh, I think five days is the, is sort of the point where you start to level off everything. Five to seven days. Some of the, that work by George Cahill at Harvard showed them kind of leveling off at about 10 days, but they were, like, severely obese people starting from absolute baseline. Uh, so I would say a five to seven-day fast two to three times a day, or maybe two to four times, uh, not per day, per year-
21. 2:08:23 – 2:14:33

    Observations of people who experiment with fasting

    1. DDDr. Dominic D'Agostino2:08:23

       do it.

    2. TFTim Ferriss2:08:23

       Y- yeah.

    3. DDDr. Dominic D'Agostino2:08:24

       So it's just, it's-

    4. TFTim Ferriss2:08:24

       It is very liberating to realize that you-

    5. DDDr. Dominic D'Agostino2:08:26

       Yes

    6. TFTim Ferriss2:08:26

       ... don't have to eat on the clock three times a day, and that in fact you'll be fine, and in some cases even better. Um, I was-

    7. DDDr. Dominic D'Agostino2:08:32

       Yeah

    8. TFTim Ferriss2:08:32

       ... astonished, I mean, when I went through my very unpleasant, like, plane crash simulation of starvation. Um, I was miserable from, uh... Well, miserable is exaggerated. I was f- fatigued in day two, and then I had the, the low back pain and so on, uh, day three and part of day four, and then I was fine. But the latter part of day four, five, six, and then, uh, before breaking the fast were f- I felt fantastic. I mean, I went for long walks. I felt, uh, extraordinarily, um, cognitively sharp. Um-

    9. DDDr. Dominic D'Agostino2:09:06

       Yeah

    10. TFTim Ferriss2:09:06

        ... have you found that you, uh, you or other people, subjects in ketosis require less sleep? Because I, when I get past a certain millimolar point, for whatever reason, and I love sleep and I tend to sleep quite a bit, you know, eight to 10 hours a night, but I found that I would wake up at s- after six hours, six and a half hours and not have any morning fog and be able to go about my day without fatigue. H- has that, have you observed that in other people or is that just a, a, a Tim thing?

    11. DDDr. Dominic D'Agostino2:09:39

        Yeah. I, I have. I've gotten emails about that. I found a, a couple, you know, kind of articles on discussing that, and I've found that in myself that, uh, like last night I got to bed at 2:00 AM. I try to get to bed at about like midnight and I woke up at 6:37, so I'm running on four and a half, maybe five hours, and I feel totally fine. I've been pretty productive today. Um, did, did a lot of work in the morning. Uh, and I typically run better, best on about six hours as opposed to maybe seven or eight that I felt I required. Um, and that depends on, you know, my activity level and kind of what's going on. But generally I feel like I, I need about one or two hours less sleep, that my requirement for that is less now. And, uh, and I think there's different reasons for that, and I think when we're in a state of nutritional ketosis, we have, uh, better fuel flow to our brain without the fluctuations in glucose throughout the day. And I think that we're, our, our astrocytes actually kind of spare... Our astrocytes have-

    12. TFTim Ferriss2:10:48

        What is an astrocyte? I apologize.

    13. DDDr. Dominic D'Agostino2:10:50

        Oh, I'm sorry. [laughs] There's different brain cells, uh, neurons and, and glia cells.

    14. TFTim Ferriss2:10:56

        Right.

    15. DDDr. Dominic D'Agostino2:10:56

        And, and among the glia would be astrocytes. And it's thought that astrocytes are, uh, they actually store glycogen, uh, a form of carbohydrates, a form of glucose for the neurons, and it's thought that, that, that may be their function. And that when we go to sleep, the astrocytes, uh, can actually build up their glycogen levels. So there's a couple studies, uh, that indicate this and, and I think sleep is a restorative process obviously, but I think we, we, we restore neurotransmitters and we restore the bioenergetics of the brain when we sleep. And I think that process is more, uh, is enhanced or, or is, uh, augmented, you know, when you're in a state of ketosis or if you've adapted to living in a state of ketosis. I think our brains are better, uh, able to restore homeostasis of our, our brain chemistry. Uh, and I think that, that metabolic, so enhancing global brain metabolic activity or preserving brain homeostasis, uh, or metabolic homeostasis in the brain is a reason why the ketogenic diet is so effective for all these different seizure disorders independent of the etiology. So whether it's a glucose transporter deficiency or temporal lobe epilepsy-

    16. TFTim Ferriss2:12:16

        What does etiology mean?

    17. DDDr. Dominic D'Agostino2:12:17

        Oh, etiology is like the independent of the cause of the disease.

    18. TFTim Ferriss2:12:21

        Ah.

    19. DDDr. Dominic D'Agostino2:12:21

        So, um, so for example, uh, glucose transporter deficiency syndrome is actually, there's a defect in the transporter that gets the glucose across the blood brain barrier for the brain to use glucose as an energy source. So if, if a child has glucose transporter deficiency, the only therapy that, uh, that's offered is a ketogenic diet, and it restores fuel flow to the brain so the child can live a normal life, right? So even in the, in the presence of a persistent molecular pathology, uh, like the, the glucose transporter deficiency, and we know the cause, we've identified the gene and the protein product. So even in the presence of that persistent molecular pathology, the ketogenic diet can completely, like, silence the symptoms of that disease. And it's doing that by restoring homeostasis in the brain. Like the neuro, not only the energy to the brain, but the neurotransmitter levels are restored. There's a balance of, uh, glucose or, um, of, of, uh, glutamate to GABA, so the GABA levels are restored. And I think that's what's happening too when it, when it comes to sleep. So we know if we do, um, a cerebral, you know, uh, CSF, uh, the, the cerebral, um, fluid of the, of the brain in people that are on a ketogenic diet, it shows that there's a higher GABA to glutamate ratio. So glutamate is excitatory, whereas GABA is kind of like inhibitory. It's kind of like the chilling out, um, neurotransmitter. So there's various things out there that you can take, like Phenibut or, um, or GABA, you know, that can, that you can take before bed, helps you sleep. So the ketogenic diet elevates these things naturally, so that may be offering some sleep promoting potential. But I, I do think that being in a state of ketosis and getting, having ketones elevated and having them available for your brain, uh, can enhance your restorative

22. 2:14:33 – 2:22:45

    Risks of consuming a cocktail of exogenous ketones

    1. DDDr. Dominic D'Agostino2:14:33

       processes that, that occur when you're sleeping in the brain.

    2. TFTim Ferriss2:14:38

       So I am looking, uh, to shift gears a little bit. I'm looking at some goodies that I'm, I'm making a cocktail with in front of me, and I've been, I've been fasting since I got up, and it's about 1:30 my time, and I can feel my brain starting to get a little grumpy even though I'm in ketosis. And, uh, so I, inspired by our conversation, I have Keto Sports KetoCaNa, calcium and sodium-

    3. DDDr. Dominic D'Agostino2:15:02

       Yep

    4. TFTim Ferriss2:15:02

       ... beta-hydroxybutyrate, and the label says, "Dietary ketone supplement for enhanced physical and mental performance." Um, this one is not for resale, for R&D use only, so this is must be an early one. Um, and then I have the branched-chain amino acids, uh, and then I have a Purrillo MCT oil CapTri-

    5. DDDr. Dominic D'Agostino2:15:24

       Mm-hmm

    6. TFTim Ferriss2:15:24

       ... which is, uh-

    7. DDDr. Dominic D'Agostino2:15:25

       Yeah

    8. TFTim Ferriss2:15:25

       ... the caprylic acid. Um, now on the side of the calcium and sodum, sodium beta-hydroxybutyrate, the KetoCaNa, um, they have the directions. You know, consume 15 minutes prior to cardio intensive exercise, may be used with carbohydrate supplements if desired, blah, blah, blah, do not exceed three servings per day. So I want, I wanna ask you about the, the risks or toxicity of consuming, uh, e-exogenous ketones. And s- and part of the reason I'm wondering is because I think of consuming these while on a standard American diet or a high carbohydrate diet, and it just seems like a very unnatural combination to me, but I could be totally off. Uh, so I'd love for you just to talk about the-

    9. DDDr. Dominic D'Agostino2:16:10

       Mm-hmm

    10. TFTim Ferriss2:16:10

        ... the toxicity risks or other risks associated with exogenous ketones.

    11. DDDr. Dominic D'Agostino2:16:15

        Okay. Uh, so it says, "Do not exceed three servings per day." So you will, you will-- The, the GI intolerance will far exceed sort of the, [chuckles] the biological intolerance that you'll get from the-

    12. TFTim Ferriss2:16:34

        So your body will stop you through diarrhea before you get close to anything that'll hurt you? Is that [laughs]

    13. DDDr. Dominic D'Agostino2:16:39

        Ex- exactly. I mean, that's the same thing with MCT, right? You're limited by your ability to, you know, transport it a-across the gut. Uh, so the mineral load that you would get from [clears throat] the KetoCaNa product would, um, would, you know, cause an osmotic, you know, uh, issue in the gut. And, uh, it's great, you know, if you wanna stay regular. So it's, it stimulates peristalsis in the gut. Um, so you'll, you'll, um, get that side effect probably if you exceed. For me, I could probably do up to five or six servings a day and, and be okay. Um, but as far as toxicity, and this is where we can draw off some of the, the rat studies we're doing, we just finished a 15-week, uh, study in rats, and it's like equivalent to like, you know, a year or two years in humans, where we fed a variety of ketone supplements from esters to the salts to combinations thereof at 25 grams per kilogram, uh, per day.

    14. TFTim Ferriss2:17:41

        [laughs]

    15. DDDr. Dominic D'Agostino2:17:42

        Uh, so [laughs] that's, that's, that's really high, right? So we did that. This is part of the, um, toxicology studies that we are doing, you know, to get FDA approval for different things. And, uh, so they actually just required 2.5 grams per kilogram per day. Well, I was like, "Well, let's, let's increase that tenfold," [chuckles] and we, we formulated it. I come at this from-- The FDA, you know, may see this as a drug, but I see ketones as a, a, a fourth macronutrient, right? You have, [chuckles] you have fats, you have proteins and carbs. Ketones are an energy containing, uh, molecule, and, uh, they're like water-soluble fat molecules. So we formulated them into the diet and we fed it. We fed, uh, our rodent models this, and we did clinical chemistry. We were doing metabolomics. We do histology. We do, uh, we did, we had-- We did actually some, um, some anxiety studies where-

    16. TFTim Ferriss2:18:43

        What is his- uh, histology? I'm sorry.

    17. DDDr. Dominic D'Agostino2:18:45

        Oh, histology is where we, at the end of the study, we harvest all the organs, right, like the kidneys, the liver, and, and heart and everything, and we weigh them out. And then we take the organs, and then we, um, we basically treat them in a way where we can section them and make slices of them and look at the cells. So we can look at the liver, for example, or the kidneys, and then we can examine at the level of the mitochondria inside the cells. We can examine these cells to determine whether the agent that we administered caused any, uh, toxicity to the animal, to the organs.

    18. TFTim Ferriss2:19:22

        Got it.

    19. DDDr. Dominic D'Agostino2:19:23

        And, you know, if there was toxicity, we would be able to pick it up most likely in the clinical chemistry, which we've done that, and we've also, on top of clinical chemistry and the histology, we also looked at all the, about 27 different types of cytokines. Um, and we, we didn't see anything relative to the control, whether relative to the standard rodent chow, there were no abnormalities and, um, to indicate liver or kidney stress. And, uh, on top of that, we did kind of parallel to this in the same group, we did some s-

    20. TFTim Ferriss2:19:58

        And that was at the, that was at 25, what was it? 25 grams per kilogram?

    21. DDDr. Dominic D'Agostino2:20:02

        25, 25 grams per kilogram.

    22. TFTim Ferriss2:20:04

        [laughs]

    23. DDDr. Dominic D'Agostino2:20:04

        So ins- [laughs] instead of delivering it like they do in drug studies with the one dose, we formulated it into the diet. So we figured out like how much, how much, how many grams of food the animal ate, and then-

    24. TFTim Ferriss2:20:17

        Mm

    25. DDDr. Dominic D'Agostino2:20:17

        ... we took that and we formulated it in a way that we know that if they ate this amount of grams for food a day, they would be getting this amount. So instead of getting it at a big dose once a day, they would eat it, they'd nibble on it throughout the day.

    26. TFTim Ferriss2:20:30

        Got it.

    27. DDDr. Dominic D'Agostino2:20:31

        And, uh, it was, you know, and that's kind of a more realistic way to give it instead of doing like most drug studies or even food studies are done with food additives.

    28. TFTim Ferriss2:20:40

        So-

    29. DDDr. Dominic D'Agostino2:20:40

        They just give it in a, a bolus

    30. TFTim Ferriss2:20:41

        So is the, uh... Oh, sorry
23. 2:22:45 – 2:41:33

    Foods and beverages that spike ketone levels

    1. TFTim Ferriss2:22:45

       any unusual foods or beverages or anything that increase ketone levels dramatically in animals or humans that you've seen? So for, I'll give you an example, and this could be complete, uh, this could be complete... Well, it is speculation, but it could be com- just completely erroneous. So, um, I've gotten a bunch of my friends kinda hooked on using the Precision Xtra device to track their, their millimolar levels, and some of them-

    2. DDDr. Dominic D'Agostino2:23:16

       Mm

    3. TFTim Ferriss2:23:16

       ... have really gone kinda nuts where they're, they're taking five to 10 readings a day and so on. Uh, and one of them observed, this is Kevin Rose, [laughs] that artichokes seemed to spike ketone levels. Uh, and he replicated it for himself, uh, I think two or three times. I've been doing some experimentation with it, but I was like, "Huh, interesting," because, you know, artichoke extract, I've seen it used, uh, as a, uh, what is it, PDE4 inhibitor, um-

    4. DDDr. Dominic D'Agostino2:23:50

       Uh-huh

    5. TFTim Ferriss2:23:50

       ... to, uh, 'cause PDE4 breaks down cyclical AMP as far as I understand, blah, blah, blah. And, uh, but is there any, I mean, you could talk to artichokes specifically, I don't know if you've ever looked at it, but is, are there any foodstuffs or things that people can use to jack up ketone levels besides exogenous ketones or, you know, MCT oil, et cetera?

    6. DDDr. Dominic D'Agostino2:24:15

       Hmm. Yeah, that, that's an interesting observation, um, with the artichoke. Artichoke's, you know, mostly fiber really, and-

    7. TFTim Ferriss2:24:22

       Yeah

    8. DDDr. Dominic D'Agostino2:24:22

       ... I guess that, that could lead into the next question, right? Soluble fiber breaks down into short-chain fatty acids, which are ketotic. Uh-

    9. TFTim Ferriss2:24:33

       Oh, interesting

    10. DDDr. Dominic D'Agostino2:24:33

        ... that, you know, they... So I, [laughs] I was actually at, um, at NASA a few weeks ago, and it was brought to my attention by, uh, a former astronaut, uh, Rick Linnehan, who's also a vet, that cows are ketotic and that they, um, and this gets back to your sort of the thing we were talking about, about short-chain fatty acids being, uh, formed from the breakdown of soluble fiber. And short-chain fatty acids, uh, can, uh, can be, you know, a form of ketones, uh, can, can contribute to ketogenesis. And, and also, uh, also the generation of butyrate in the gut, so which can enhance and, um, contribute to, uh, our gut microbiota. So, um, yeah, so I think that needs to be appreciated that we were talking about foods that-

    11. TFTim Ferriss2:25:32

        Right

    12. DDDr. Dominic D'Agostino2:25:32

        ... could enhance, um, ketosis. And I think that one could formulate a ketogenic diet with, uh, the intention to further enhance ketosis by adding certain types of Fiber, uh, soluble fiber that are broken down into short-chain fatty acids, which are potentially ketogenic. Like your friend that had the artichoke and had a big bump in ketones, that's really interesting. Uh, I lo- I love artichokes, and maybe that's why [laughs]

    13. TFTim Ferriss2:26:02

        [laughs]

    14. DDDr. Dominic D'Agostino2:26:04

        I get levels of... So I'm, I'm looking at the macronutrient profile of artichokes now, and I see that, yeah, they're primarily carbohydrate, but mostly fiber.

    15. TFTim Ferriss2:26:13

        Hmm.

    16. DDDr. Dominic D'Agostino2:26:13

        And that, that fiber is, uh, can be ketogenic. And fiber can also assist in helping us stay in ketosis by being a buffer when you're eating with protein, 'cause it helps slow the digestion, assimilation, and utilization of protein. So you get less of a spike in amino acid levels, which can help. Uh, a spike, a quick spike in amino acid levels can, like, shut off ketogenesis, and if you attenuate that spike, it can help promote your body into staying in that, in that, that state of ke- ketosis longer by-

    17. TFTim Ferriss2:26:53

        Does, is this... I'm sorry to interrupt. Is the spike knocking you out of ketogenesis because the liver is using gluconeogenesis to convert those amino acids into glucose, or is it something else entirely?

    18. DDDr. Dominic D'Agostino2:27:06

        Mm-hmm. Yeah, it's, uh, if you get too many amino acids getting into the liver as a source of fuel for gluconeogenesis, but also protein can stimulate, uh, a release of insulin, and insulin is, uh, very anti-ketogenic. So it's the combination of, of attenuating the rise in, uh, in amino acids, which will attenuate the rise in glucose, which will attenuate the, uh, bump in, in, uh, insulin that you could potentially get from that.

    19. TFTim Ferriss2:27:41

        Yeah.

    20. DDDr. Dominic D'Agostino2:27:41

        So, so fibers are pretty... Fiber is actually really useful, um-

    21. TFTim Ferriss2:27:45

        What would be good sources of fiber that aren't going to, that are gonna have very low net carbs?

    22. DDDr. Dominic D'Agostino2:27:52

        Mm-hmm. Yeah. Uh, I think the staple ones that I like are... Actually, artichoke is on that list. Uh, spinach, kale, uh, broccoli, uh, asparagus is probably at the top of my list.

    23. TFTim Ferriss2:28:07

        Mm-hmm.

    24. DDDr. Dominic D'Agostino2:28:08

        Uh, celery a little bit. Um, so any kind of green leafy vegetables, like salad. I have a salad every night, and with mixed greens and, um, a lot of olive oil. Uh, and, you know, take your, always eat your, your vegetables with a source of fat. I think it helps promote that you're getting the most nutrition out of vegetables. Um, and also if you mix your food so you're eating your protein with, you know, obviously high fat and fiber will definitely help you stay in ketosis. Because, um, if you just bolus protein, uh, a lot of people say they're on a ketogenic diet just by eating, like, no carbs, but, uh, like, a, a chicken breast will quickly kick you out of ketosis. [laughs] But a chicken breast cut up into a green leafy salad with a lot of olive oil and maybe some feta cheese and, you know, and, uh, and some Bulletproof coffee or something like that combined will, will not kick you out of ketosis.

    25. TFTim Ferriss2:29:19

        Okay.

    26. DDDr. Dominic D'Agostino2:29:20

        You can just stay cruising in ketosis. So th- this is, I think needs to be appreciated if you're-

    27. TFTim Ferriss2:29:26

        So, so I, just to fill in the blank f-

    28. DDDr. Dominic D'Agostino2:29:29

        Yeah

    29. TFTim Ferriss2:29:29

        ... the, the blanks for your sort of typical day then, if your breakfast is, uh, sardines, half a can of oysters, four eggs, and then some asparagus or some other green, what are the rest of your meals for a, a typical day?

    30. DDDr. Dominic D'Agostino2:29:47

        Okay. Uh, I do get a lot of, uh, MCT [laughs] in, in the day. And, uh, so-
24. 2:41:33 – 2:43:13

    Top resources

    1. DDDr. Dominic D'Agostino2:41:33

       thinks this is really good, so.

    2. TFTim Ferriss2:41:34

       Cool. I'll try it out. So I, um, would love to ask some rapid-fire questions. I know we're wrapping up. We could talk for many more hours, but-

    3. DDDr. Dominic D'Agostino2:41:42

       Yeah

    4. TFTim Ferriss2:41:42

       ... uh, w- if for people who want to-

    5. DDDr. Dominic D'Agostino2:41:45

       Mm-hmm

    6. TFTim Ferriss2:41:45

       ... dig into ketosis further, give it a shot, what resources should they start with or books should they start with?

    7. DDDr. Dominic D'Agostino2:41:55

       Yeah, I think probably the best place to go would be Ketogenic Diet Resource, and that's a website. Uh, Ellen Davis has that website, and literally that's the name of it, ketogenicdietresource.com. And, um, it's, like, a ton of information on there, pretty much every question you'd ever want on there. We even, she, uh, put together a book for ketogenic diet and cancer, one for the ketogenic diet for type 2 diabetes. It was co-authored by a doctor, uh, that's actually in my area that has type 1 diabetes that uses the ketogenic diet for that. So that's a incredible resource.

    8. TFTim Ferriss2:42:34

       Excellent.

    9. DDDr. Dominic D'Agostino2:42:35

       Uh-

    10. TFTim Ferriss2:42:35

        Ellen Davis.

    11. DDDr. Dominic D'Agostino2:42:36

        Yeah, Ellen Davis, Ketogenic Diet Resource, definitely one of the go-to places. I have a website, ketonutrition.org, and I, I've, basically it's like a skeleton website, has compiled a lot of, um, useful links that I thought, and her website's on there, her book's on there. Um, so that's ketonutrition.org.

    12. TFTim Ferriss2:42:59

        Awesome. What, um, what is the book you've given most as a gift? Not necessarily related to ketosis, just any book that you've given often or given before as a gift.

    13. DDDr. Dominic D'Agostino2:43:12

        Oh, that's a

25. 2:43:13 – 2:50:18

    Most gifted books

    1. DDDr. Dominic D'Agostino2:43:13

       good question. Um, yeah, I would have to... Well, going back in the college days, I would say [laughs] uh, Anthony Robbins, I listened to his stuff when I was my senior year in high school.

    2. TFTim Ferriss2:43:26

       Mm-hmm.

    3. DDDr. Dominic D'Agostino2:43:26

       And, uh, I listened to, like, this 30-day tapes back when we-

    4. TFTim Ferriss2:43:30

       Oh, the Personal Powers?

    5. DDDr. Dominic D'Agostino2:43:31

       ... listened to tapes. Yeah, Personal Power.

    6. TFTim Ferriss2:43:32

       Yeah.

    7. DDDr. Dominic D'Agostino2:43:32

       So I bought the book too, and then I liked it so much, like, I bought it and I gave it to all my lifting buddies, you know. And, and they, and then I didn't, you know, they went off to college and everything, and years later, like, two of them contacted me and they're like, "You know that book you gave me? It changed my life. You know, I did better in college and everything." So I would say- Anthony, you know, going way back, Personal Power, Anthony Robbins' book-

    8. TFTim Ferriss2:43:54

       Yeah

    9. DDDr. Dominic D'Agostino2:43:54

       ... was, was kind of influential from, you know, back in the day. And, uh, and then as I, you know, got into science and became a scientist and my advisor was, uh, funded by the NIH, and I was always told that I needed NIH funding to be a career scientist. And, uh, then I met the NIH director, Francis Collins, at Society for Neuroscience meeting, and I was like, "Well, I should understand the mind of Francis Collins and understand, you know, what is the director of basically the President of Science thinking [laughs] ?" So I, I went to try to find some biographies on him, and when I did a search, I found a book, uh, The Language of God, and I thought, you know, that was really... I didn't, I had no idea of his sort of, uh, his spirituality or his kinda worldview besides outside of science. I knew he spearheaded the Human Genome Project and was pretty instrumental in finding the gene for, uh, cystic fibrosis. But, so The Language of God, like, it's, it really ins- inspired me because I had no idea that a scientist, uh, of his stature was, you know, could be, have such a devout faith. And, and that kind of influenced me and it got me to reread some older books I read, uh, by C.S. Lewis.

    10. TFTim Ferriss2:45:17

        Mm-hmm.

    11. DDDr. Dominic D'Agostino2:45:17

        Uh, The Screwtape Letters.

    12. TFTim Ferriss2:45:18

        The Screwtape Letters is great.

    13. DDDr. Dominic D'Agostino2:45:19

        Yeah, yeah. The Screwtape Let- Letters is really good. So, uh, and I, I don't think I've given that [laughs] to... But I, I gave the, The Language of God to, uh, some of my friends, and they really enjoyed it. So that would be one. Uh, and then a required reading for my students would be Tom Seyfried's book, Cancer as a Metabolic Disease.

    14. TFTim Ferriss2:45:38

        Hmm.

    15. DDDr. Dominic D'Agostino2:45:38

        So that, that's a really... I mean, I think it's sold pretty well on Amazon. Uh, and it's highly, highly technical, and it's, unfortunately it's, like, really expensive. [laughs] So it's about 100 to 130 bucks, I think.

    16. TFTim Ferriss2:45:52

        Wow.

    17. DDDr. Dominic D'Agostino2:45:52

        Maybe you can get it cheaper. You can get used versions for probably, like, 50 bucks online. But if you want a really good kind of description of, I guess, m- cancer as a metabolic disease, the science, the history, I mean, it's really well-written. Tom, uh, did... He's a c- he's a collaborator of mine. He, he worked a, a lot on that book, and it's, it shows. So that book. Um, and, oh, another book by a guy that I'm actually working, uh, on a project with him now. Uh, his name is Travis Christofferson. He wrote a book called Tripping Over the Truth.

    18. TFTim Ferriss2:46:34

        Hmm.

    19. DDDr. Dominic D'Agostino2:46:35

        So tripping-

    20. TFTim Ferriss2:46:36

        I, I like the name, yeah.

    21. DDDr. Dominic D'Agostino2:46:37

        Yeah. And he wrote a precursor to the book. He wrote an article that was appeared on, uh, Rob Wolf's blog. And, uh, I'm actually, I have an article written with him that's gonna appear on the blog on, uh, Thursday. It's about the history of the ketogenic diet, and I think Rob's gonna put it on the blog on, on Thursday, I believe. But, uh, Travis is a brilliant, he's probably one of the most gifted writers I've ever known. So Tripping Over the Truth is basically the story of, uh, uh, the story of cancer, really. I mean, it's a, it's a great history of, uh, the story of cancer that's comes at it from a different perspective from the M- Mukherjee book, uh, which is, uh, the biography of cancer that, uh, is pretty popular with New York Times bestseller. It's been on, uh, The Emperor of All Maladies is actually the name of the book, the biography of cancer. Uh, that book is, kinda talks about the history of cancer. Tripping Over the Truth is similar to Mukherjee's book, but viewed from the perspective of understanding cancer as more or less a metabolic disease and how we could, uh, develop therapies, you know, to target it from a metabolic perspective. So, and, and I've given that book, probably bought seven or eight copies of that book over the last year and given it away, and everybody has come back to me and said that book was fantastic. I mean, not only is it informative, but Travis is, like, an unbelievable gifted writer.

    22. TFTim Ferriss2:48:15

        Awesome. Let me, let me ask you one... I have, I have one more question, and, uh, then maybe we'll do a round two if, if people demand it by, uh [laughs] popular request.

    23. DDDr. Dominic D'Agostino2:48:26

        Sure.

    24. TFTim Ferriss2:48:26

        But, um, you mentioned Rob. So Rob and I are friends, Rob Wolf, and we've talked about-

    25. DDDr. Dominic D'Agostino2:48:32

        Yeah

    26. TFTim Ferriss2:48:32

        ... Lyme disease on and off for a while now because I was, I was out of commission for about nine months, or at least operating at about 10% capacity-

    27. DDDr. Dominic D'Agostino2:48:40

        Yeah

    28. TFTim Ferriss2:48:40

        ... after contracting Lyme disease on Eastern Long Island. And the, the, what appears to have made the biggest difference for me in terms of getting back to feeling like myself and having the cognitive function that I had pre-Lyme disease was the ketogenic diet.

    29. DDDr. Dominic D'Agostino2:49:00

        Mm-hmm.

    30. TFTim Ferriss2:49:01

        And I was very puzzled by this, and I wasn't sure exactly why that would be the case, and so I, I just ha- hypothesized that perhaps, uh, either Lyme disease or the, the subsequent antibiotic treatment caused some type of, uh, carbohydrate metabolism dysfunction. And I was chatting with Rob about this because I, I didn't know the mechanism, but I had recommended to a few people with Lyme that they test ketosis, and literally 100% of them, if they entered ketosis properly and stayed there for more than a week or two, reported the same results. And, uh, Rob sent me an interesting, um, research abstract which showed how, uh, antibiotics such as dox- doxycycline could cause mitochondrial dysfunction-
26. 2:50:18 – 2:53:18

    Fighting Lyme Disease with the ketogenic diet

    1. TFTim Ferriss2:50:18

       investigating that?

    2. DDDr. Dominic D'Agostino2:50:20

       Well, I, I'm from New Jersey, uh, so [laughs] Lyme-

    3. TFTim Ferriss2:50:24

       Yeah. Lyme country

    4. DDDr. Dominic D'Agostino2:50:24

       ... Lyme disease is really, you know, I knew a lot of people, especially growing up in a family that, you know, was hunters, and knowing most of my friends were hunting and in the woods. I, I grew up in the woods. Uh, somehow I, I, I s- didn't get Lyme disease. Um, never been tested for it, but never really had any symptoms for it. So, Lyme's disease really produces pretty profound inflammation, and, uh, the spirochetes can cause, you know, everything that you describe, fatigue, and, and, uh... But I think they can cause, um, you know, from a neurological perspective, they can cause encephalopathy, and that essentially is resulting from neuroinflammation. And ketones, uh, the ketogenic diet, and ketones in particular, have pretty profound anti-inflammatory effects, and especially in relation to the nervous system, uh, since ketones are freely permeable to the blood-brain barrier and, and kind of bathe our nervous system. Um, so I think that may have something to do with also the spikes in blood glucose, higher insulin levels all can contribute to inflammation and inflammatory processes, so putting a dampening on that situation with a ketogenic diet and, you know, having elevated levels of ketones could impact the, uh, the primary, uh, malady that's causing the symptoms, which would be the inflammation, the, the encephalopathy, uh-

    5. TFTim Ferriss2:52:07

       Right

    6. DDDr. Dominic D'Agostino2:52:08

       ... the, uh, the, you know, the inflammation of the white matter, I think. There's, you know, memory, uh, attention, uh, you know, cognitive, emotional states are altered in people, and I think it can just help bring your nervous system back to a state of homeostasis, uh, similar to what it's doing for other disorders. But i- inflammation is really... Did, did you happen to get blood work and look at, uh... 'Cause the, the spirochete, really, that's how it wreaks havoc in your system. I mean, by activating your immune system-

    7. TFTim Ferriss2:52:44

       Oh, yeah

    8. DDDr. Dominic D'Agostino2:52:44

       ... but also just wreaking havoc, you know, as far as causing systemic inflammation in the body.

    9. TFTim Ferriss2:52:50

       Yeah, I could go back. You mean looking at things like C-reactive protein or whatever?

    10. DDDr. Dominic D'Agostino2:52:54

        Mm-hmm. Yeah.

    11. TFTim Ferriss2:52:54

        Yeah, or cyt-

    12. DDDr. Dominic D'Agostino2:52:55

        Or cytokines or something like that

    13. TFTim Ferriss2:52:56

        ... or cytokines. I'm sure I have the blood work. I mean, my, I, uh, the inflammation was so clear to me that I didn't really need the blood work to confirm it. I mean, my, my knees were so swollen that I could barely get up in the morning, and I was s- had very slow, almost slurred speech, um-

    14. DDDr. Dominic D'Agostino2:53:12

        Mm-hmm

    15. TFTim Ferriss2:53:13

        ... and, uh, felt like I had early onset dementia. It was really scary as an experience. What

27. 2:53:18 – 2:55:53

    The effect of ketosis on mitochondria

    1. TFTim Ferriss2:53:18

       effect does ketosis have on mitochondria, if any?

    2. DDDr. Dominic D'Agostino2:53:24

       Yeah. So, uh, ketones are very efficient metabolic fuel, and, uh, and in studies that were done in animal models and were, you know, um, looking at some, the muscle biopsies too, uh, shows that if you're in a state of ketosis relative to a higher carbohydrate diet, that it can increase mitochondrial biogenesis and mitochondrial efficiency. Uh, at the level of the cell, uh, when we talk about efficiency, um, I don't want to get down into too much specifics, but there's the, the electron transport chain is kind of how our cells, the mitochondria, make energy, and there's, if there's a, a site between complex one and complex two and complex three, called the semiquinone site, and a few ketones have the ability to, um, oxidize Q [laughs] basically, and that can prevent, uh, by, by, uh, ketone metabolism can enhance the energetic flux through the mitochondria to produce ATP, our energy currency. And at the same time that it's enhancing, uh, the bioenergetics of the mitochondria, it's also preventing the formation of superoxide anion, which is a oxygen free radical-

    3. TFTim Ferriss2:54:53

       Mm-hmm

    4. DDDr. Dominic D'Agostino2:54:53

       ... or reactive oxygen species, and that's the precursor to more reactive oxygen species like, uh, hydroxyl radical and peroxy nitrate and things like that. So by f- kind of fundamentally, you know, turning down the generation of superoxide anion by enhancing mitochondrial efficiency, not only do we make more ATP, uh, through ketone metabolism, but we're also enhancing the flux of, of substrate utilization and energy production from that substrate, uh, even, even glucose substrate-

    5. TFTim Ferriss2:55:29

       Huh

    6. DDDr. Dominic D'Agostino2:55:31

       ... uh, d- by, by en- en- enhancing mitochondrial bioenergetics. And the ketones, we know, can do that through, uh, a variety of mechanisms that I can get into. But, uh, but basically, yeah, I mean, there, you can, you can derive more energy, uh, per oxygen molecule-

    7. TFTim Ferriss2:55:51

       Got it

    8. DDDr. Dominic D'Agostino2:55:51

       ... uh, with,

28. 2:55:53 – 2:57:51

    Healing from use of antibiotics

    1. DDDr. Dominic D'Agostino2:55:53

       uh, with ketone metabolism.

    2. TFTim Ferriss2:55:55

       Is it, uh, conceivable that ketosis could aid... It sounded like the answer is yes. You mentioned biogenesis. If one had damaged- ... their mitochondria through eight to 12 weeks of doxycycline or even using harder antibiotics for longer periods of time, is it conceivable that ketosis could help repair that damage?

    3. DDDr. Dominic D'Agostino2:56:17

       Yeah. Yeah, I think so, especially, uh, in certain tissues. You know, we know muscle is incredibly plastic. Uh, but if you're exercising and in a state of ketosis, that you can, you can build up your mitochondria, and you'll do that more efficiently if you're on a ketogenic diet. And I think even in the central nervous system, which may have taken a big hit from doxycycline or Lyme disease, uh, the central nervous system is running more efficiently, uh, in a state of ketosis, I believe, especially if you can dampen, uh, some of the neuroinflammation that's associated with, uh, with the disease.

    4. TFTim Ferriss2:56:58

       Right.

    5. DDDr. Dominic D'Agostino2:56:58

       And I think, and I think that would ultimately, you know, contribute to... I don't know how you would quantify that or, uh, but we... I'm trying to think of studies that we've done sort of in parallel. We did some work when an Alzheimer's model, and I think that the, the Lyme's has been associated with tau and amyloid plaques and neuroinflammation that can contribute to those plaques. And I think being in a state of, uh, ketosis, uh, even there's some work with exogenous ketones and calorie restriction or even intermittent fasting type things, uh, can limit, uh, the, um, the accumulation of some of these plaques that are associated with, um, with neuropathology, such as Alzheimer's disease, the amyloid, and the tau plaques.

Episode duration: 3:06:34