#117: Dom D'Agostino on Fasting, Ketosis, and The End of Cancer

Dr. Dominic "Dom" D'Agostino (@DominicDAgosti2 https://twitter.com/DominicDAgosti2) 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 (IHMC). He has also deadlifted 500 pounds for 10 reps after a seven-day fast. He's a beast and — no big surprise — he's a good buddy of Dr. Peter Attia http://fourhourworkweek.com/2014/12/18/peter-attia/, my MD friend who drinks "jet fuel" in search of optimal athletic performance. The primary focus of Dom's laboratory is developing and testing metabolic therapies, including ketogenic diets, ketone esters and ketone supplements to induce nutritional/therapeutic ketosis. D'Agostino's laboratory uses in vivo and in vitro techniques to understand the physiological, cellular and molecular mechanism of metabolic therapies and nutritional strategies for peak performance and resilience. His research is supported by the Office of Naval Research (ONR), Department of Defense (DoD), private organizations and foundations. Show notes and links for this episode can be found at www.fourhourworkweek.com/podcast http://www.fourhourworkweek.com/podcast. This podcast is brought to you by Audible http://audible.com/tim. I have used Audible http://audible.com/tim for years and I love audio books. I have 2 to recommend: The Graveyard Book http://www.audible.com/pd/Teens/The-Graveyard-Book-Full-Cast-Production-Audiobook/B00LXHQO22/?tag=offsitoftimfe-20 by Niel Gaiman Vagabonding http://www.audible.com/pd/Travel-Adventure/Vagabonding-Audiobook/B00GCHWZHG/?tag=offsitoftimfe-20 by Rolf Potts All you need to do to get your free audiobook and a free 30-day trial is go to Audible.com/tim http://audible.com/tim. Choose one of the above books, or choose between more than 180,000 audio programs. That could be a book, a newspaper, a magazine or even a class. It's that easy. Go to Audible.com/Tim http://audible.com/tim and get started today. Enjoy! This podcast is also brought to you by 99Designs http://99designs.com/tim, the world's largest marketplace of graphic designers. I have used them for years to create some amazing designs. When your business needs a logo, website design, business card, or anything you can imagine, check out 99Designs. I used them to rapid prototype the cover http://99designs.com/tim for The 4-Hour Body, and I've also had them help with display advertising and illustrations. If you want a more personalized approach, I recommend their 1-on-1 service http://99designs.com/tim, which is non-spec. You get original designs from designers around the world. The best part? You provide your feedback, and then you end up with a product that you're happy with or your money back. Click this link http://www.99designs.com/tim and get a free $99 upgrade. Give it a test run… Enjoy!

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Tim Ferriss?

  Quick sound check. What did you have for breakfast this morning?

• 0:03Speaker 01

  Eggs and sardines and oysters.

• 0:07Tim Ferriss?

  Eggs and sardines and oysters. Did you just throw that?

• 0:09Speaker 01

  And broccoli, a little bit of broccoli.

• 0:11Tim Ferriss?

  You just throw it in a Vitamix?

• 0:17Speaker 02

  At this altitude, I can run flat out for a half mile before my hands start to shake. Can I ask you a personal question?

• 0:23Speaker 03

  No, we're just sitting in a broken time.

• 0:27Speaker 02

  I'm a cybernetic organism, living tissue over metal and metal.

• 0:38Tim Ferriss?

  This episode is brought to you by Audible, which I've 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 Four Hour Work Week. 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

• 1:21Tim Ferriss?

  180,000 audio programs. So that could be a book, that could be a magazine, that could be a newspaper, it could be a class. It's that easy. Go to audible.com/tim. That's audible.com/tim, and grab a book. Enjoy.

• 1:38Tim Ferriss?

  This episode is brought to you by 99designs, your one-stop shop for all things graphic design related. I've used 99designs for everything from banner ads to book covers, including sketches and mock-ups that led to The Four 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 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

• 2:23Tim Ferriss?

  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.

• 2:40Tim Ferriss?

  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 guvenetos 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 Tsatsoulin 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

• 3:25Tim Ferriss?

  the University of South Florida Morsany 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. He is a beast, both physically and intellectually. He has published or co-authored many different fascinating papers, research papers. And no big surprise, he's a good buddy of Dr. Peter Attia, whom I mentioned shortly ago. Now Pete, of course, drinks so-called jet fuel in search of optimal athletic performance,

• 4:08Tim Ferriss?

  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 aspects, theories, and practical

• 4:51Tim Ferriss?

  implementations of research that is at the forefront right now. So, please enjoy my conversation with Dom D'Agostino.

• 5:02Tim Ferriss?

  Dom, welcome to the show.

• 5:04Speaker 01

  Thanks for having me, Tim. Appreciate it.

• 5:06Tim Ferriss?

  Of course. I have my notebook out, always, when I'm on the phone with you, walking around. I'm struggling to find paper in my pockets or record notes, so I have all of my materials ready. I've spoken with our dear friend, Pete Attia, to sort of plot the arc of questions that I would ask you, mostly out of pure self-interest. But for those people who are unfamiliar with you, when someone asks you, "What do you do?", how do you answer that question?

• 5:34Speaker 01

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

• 5:50Tim Ferriss?

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

• 5:59Speaker 01

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

• 6:22Tim Ferriss?

  Very cool.

• 6:22Speaker 01

  It's kind of sums up, yeah.

• 6:24Tim Ferriss?

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

• 6:37Speaker 01

  Wow, I imagine you get a range of responses from that.

• 6:44Speaker 01

  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 it just happened to conclude, right before I had to give a lecture, kind of on the topic. And I went into it, you know, with my glucose in the mid, maybe 30s, low 40s, and my ketones up there at about 5 millimolar or so.

• 7:11Speaker 01

  And then I did go to the gym, yeah, I deadlifted 500 for 10. And I, and I finished off with a one rep of 585, six blades, so that's... I haven't done that since, I haven't done anything that extreme since, but I just felt like, I was inspired by George Cahill. He was a researcher at Harvard Medical School, and he did a fascinating study that, that really, where he fasted people for 40 days, actually, and 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.

• 7:52Speaker 01

  So, yeah, I did that, and 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, 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, 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.

• 8:26Tim Ferriss?

  What was the time, what was the year, roughly, when was this?

• 8:30Speaker 01

  Uh, this was 2010.

• 8:34Tim Ferriss?

  Got it.

• 8:35Speaker 01

  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.

• 8:49Tim Ferriss?

  It's, it's funny to me that 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 go beyond, you know, one to three days.

• 9:07Speaker 01

  Oh, yeah. Yeah. That's, that's good. You know, I, I serve on the, the university institute for animal care and use committee. It's called IACUC. It's just, it's like the animal IRB. And, uh, yeah, they, they, the committee usually has like a reactionary response to anything under 25% calorie restriction, you know? 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. So, yeah, I am, I am amazed that some of the stuff, you know, got, got approved. I think the IRB was probably on vacation or something.

• 9:49Tim Ferriss?

  Can you?

• 9:50Speaker 01

  Yeah, IRBs are a little different now.

• 9:52Tim Ferriss?

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

• 9:58Speaker 01

  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 allowing, it's a committee of people that have kind of, uh, a broad range of expertise and, and they review the, uh, the reason why the study is going to 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. You know, you can use an outside IRB that's outside of the institution.

• 10:41Speaker 01

  And 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 minutes from here that ran a, a ketogenic diet study in advanced lifters for us. And the IRB was approved in like two weeks.

• 11:06Tim Ferriss?

  Which is, which is fast.

• 11:09Speaker 01

  Very fast, yeah. Like two or three weeks. So in other IRBs, I think I did one 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 I mean, it's just giving it as a single dose. Kind of more or less a bio identical 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 IRB, which is less, you know, less restrictive in many cases. So they can be a big hurdle to an investigator.

• 11:47Tim Ferriss?

  Yeah, the, uh, especially if, if the 25% or more loss is deemed cruel and unusual punishment.

• 11:57Speaker 01

  Oh, okay. For the animal study, yes. So in, uh, in, yeah, in these human studies, it's, you know, there's, there's pretty, uh, pretty stringent criteria on, on the humans and stuff.

• 12:08Tim Ferriss?

  What was the, what was?

• 12:09Speaker 01

  But yeah, the, the animal studies are pretty bad.

• 12:12Tim Ferriss?

  What was this, the, 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?

• 12:19Speaker 01

  Uh, yeah, that's under review right now.

• 12:22Tim Ferriss?

  Ah, got it.

• 12:23Speaker 01

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

• 12:43Tim Ferriss?

  What was that percentage, just out of curiosity?

• 12:46Speaker 01

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

• 12:56Tim Ferriss?

  Got it.

• 12:56Speaker 01

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

• 13:00Tim Ferriss?

  Got it.

• 13:00Speaker 01

  So it was pretty, it would be, uh, it would be like me, let me see, squatting, you know, for.

• 13:08Speaker 01

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

• 13:11Tim Ferriss?

  Yeah, these are very.

• 13:12Speaker 01

  It's pretty significant.

• 13:12Tim Ferriss?

  Yeah, significantly advanced trainees.

• 13:15Speaker 01

  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 moderate fat. And the ketogenic diet had roughly seventy five to eighty percent fat, restricted carbohydrates to about twenty to twenty five 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.

• 13:58Speaker 01

  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 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

• 14:43Speaker 01

  it's 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. And did some follow up work with it.

• 15:03Tim Ferriss?

  Now, what is your, uh? What is your hypothesis, or maybe you already know, but 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 with different growth factors and whatnot? And I had a conversation, I want to say it was with Stephen Finney, very short conversation, and I asked him this because I'd been in a ketotic state for two or three weeks and had experienced a non-trivial amount of muscle growth, and I was really surprised by it. And he explained in terms that I can't recall, but how the ketogenic diet might have a,

• 15:48Tim Ferriss?

  I guess, like a branched-chain amino acid sparing effect of some type. But is it possible to get very big and powerful on a ketogenic diet? If so, what's the mechanism in the sort of absence of higher spiking insulin levels? If that is the parent anabolic hormone, and I'm not saying it is, but a lot of people view it that way?

• 16:11Speaker 01

  Yeah, so, you know, there's insulin and insulin signaling, right? Certain diet, like when you calorie restrict a rodent, or even, you know, humans or any mammal, you will enhance insulin sensitivity, right? So you will be more sensitive to a given amount of insulin. And I think we're seeing some of that in the athletes. I mean, exercise itself enhances insulin sensitivity. So, and guys that are 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.

• 16:52Speaker 01

  You know, he would probably not be a good candidate 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 in 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, no, it's 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 we can fast for 40 days and the ketones have an anti-catabolic protein

• 17:35Speaker 01

  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 situation where you're at a, at a caloric deficit, I think that's where ketones can shine. You

• 18:18Speaker 01

  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 what ketogenic diet we're talking about. But I don't think a purely ketogenic diet as it's kind of 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

• 19:03Speaker 01

  Johns Hopkins group that developed the classical ketogenic diet. And it's really that, that protein level is important. So growing on a classic ketogenic diet would 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 drug resistant seizures when they're putting 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.

• 19:35Speaker 01

  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 to metabolically manage seizures. And I think that sort of diet can be used pretty successfully in the performance world and specifically for bodybuilders. I think with that amount of protein, you'd 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 and,

• 20:16Speaker 01

  and drive anabolic processes. Uh, but a lot of times people, when they follow ketogenic diet, because ketones have a really good appetite suppressing effect, that they will inadvertently restrict calories and may not even know it after a while and, uh, and maybe losing weight without even trying. And that's, I mean, that's one of the benefits, 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.

• 20:47Tim Ferriss?

  And the, 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, I guess we could talk about nutritional, uh, and sort of fasting ketosis, but what is ketosis exactly? And what are ketones?

• 21:12Speaker 01

  Okay. Uh, I kind of like to start out with fasting, right?

• 21:16Tim Ferriss?

  Sure.

• 21:17Speaker 01

  So we're, 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.

• 21:28Speaker 01

  Right, and 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, we'll be depleting 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, while you're suppressing the hormone insulin, you'll upregulate beta-oxidation of fatty acids in the liver. And an accumulation of products from fatty acid oxidation will start forming ketone bodies.

• 22:09Speaker 01

  And these ketone bodies are, they're more or less like water soluble fat molecules. And they're small molecules that can readily cross the blood-brain barrier and get inside cells into the mitochondria. And as we fast, within about 24 to 48 hours, we'll start registering ketones to the level that clinically is defined as being in ketosis.

• 22:34Tim Ferriss?

  I was gonna ask you about that.

• 22:35Speaker 01

  Which is above 0.5 millimolar typically. Yeah, so a person on a high carb diet would probably take about 24 to 48 hours to start even getting into mild ketosis. 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 admitted into a place like Johns Hopkins, the old protocol was to fast them. They're not exactly sure if that's absolutely necessary with things like more with ketogenic diets have MCTs and stuff. But you can, fasting has classically been the fastest way to get into ketosis.

• 23:17Speaker 01

  So the ketogenic diet has a macronutrient ratio. It's high in fat, typically 90 to 70.

• 23:25Tim Ferriss?

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

• 23:29Speaker 01

  Yeah, yeah. And maybe ketones could be the fourth macronutrient, maybe, if you talk about exogenous ketones. So a ketogenic diet has a macronutrient ratio 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 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

• 24:09Speaker 01

  that occur with that, epigenetic changes. You know, we know that, that beta hydroxybutyrate, which is a ketone body, can have a, you know, interesting effects on gene expression.

• 24:20Tim Ferriss?

  What types of effects?

• 24:22Speaker 01

  Uh, well, there was a science paper showing that beta hydroxybutyrate is an HDAC, class one and class two inhibitor, and can activate genes that play a role in enhancing 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 enhances the robust kind of protective mechanisms that the cell has that can preserve the genome stability. So

• 25:05Speaker 01

  maybe being in a state of ketosis and maintaining that can protect your DNA from damage. So that's the implications. Also anti-inflammatory. So we, we published a, a paper, our colleagues actually did it at Yale. I developed the diet for them and sent it up to them. It was exogenous ketone, but the paper demonstrated that it, it 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

• 25:44Speaker 01

  chronic age-related diseases. And it was independent of the ketone's effect on metabolism. So they teased out, they did a lot of studies to tease out the mechanism and, and demonstrated that, that the effect Of it, you know, suppressing inflammatory pathway was 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 HDAC inhibitor. How do you spell that?

• 26:23Tim Ferriss?

  I apologize. The HDAC?

• 26:25Speaker 01

  Oh, yeah. Histone deacetylene inhibitor. So HDAC would be H D A C.

• 26:32Tim Ferriss?

  Got it.

• 26:32Speaker 01

  And then there's class one, two, three, I think four. So class one and two, HDAC inhibitors are a big, big, 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 companies focusing on histone deacetylene inhibitors for, as targeting specific pathways to, for cancer therapy. So, so you have an endogenous HDAC inhibitor, you know, with beta hydroxyl.

• 27:05Tim Ferriss?

  Not, not to interrupt, but just for people who want to keep endogenous and exogenous straight. I've always found, thinking of exoskeleton as sort of outside, as an indicator of outside. So if you're taking exo, please correct me if I'm getting this, if I screw this up in any way, Dom, but if you're taking exogenous ketones, that means you are, you are consuming ketones from outside of your body. And endogenous is something you're producing yourself.

• 27:31Speaker 01

  Yes.

• 27:32Tim Ferriss?

  The, so in, in a case, for instance, with cancer, I have a friend who recently went through chemotherapy and he would fast for three days prior to his chemotherapy. And in the same group, almost everyone was, aside from him, everyone else was laid out for days after chemotherapy, really unable to function. And he was able to go for 10 mile runs, for instance. And it's been, it's been, I've been very fascinated by looking at the implications of combining fasting with, for instance, chemotherapy and the treatment of cancer. Does, if you were, say, advising someone with a

• 28:18Tim Ferriss?

  Her family history of Alzheimer's and Parkinson's, which I have. So I don't know if those fall into the age-related issues that you were talking about, but are there implications for fasting or nutritional ketosis or exogenous ketones for helping to prevent or mitigate the onset of those type of neurodegenerative diseases?

• 28:44Speaker 01

  Yeah, and you know, fasting has to be done, you know, under, you have to know your body, right? And fasting should probably be done under a pretty strict medical supervision.

• 28:56Tim Ferriss?

  Sure.

• 28:56Speaker 01

  To some extent, yeah. So someone would have to do a little research on it. And it would depend on, you know, the particular person. If, so if you have a cancer patient that it's a woman with breast cancer, say, and she has a BMI of 28, you know, and it's going in for chemo, I think it's a good idea for them to fast before they go in.

• 29:18Tim Ferriss?

  BMI, body mass index.

• 29:20Speaker 01

  Oh, body mass index, yeah.

• 29:22Tim Ferriss?

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

• 29:26Speaker 01

  Yeah, that would make her kind of a little pudgy, I guess, and have some, some extra weight to lose. So, so we know, we know that getting chemo in a fasted state, there's a couple of reports out there showing that it could, it sensitizes, it can sensitize the tumor to the therapeutic effects of the agents. And also, there's some evidence showing that, that it could prevent some of the side effects associated with chemotherapy agents, specifically things that, you know, cause cell damage. So, so being in a state

• 30:05Speaker 01

  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 the, of the chemotherapy agent. So that's, and you'd want to 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, you'd want to do it in a very cautious way. But I I definitely think, you know, this is something that should be implemented, you know, in our oncology wards.

• 30:42Tim Ferriss?

  Yeah.

• 30:43Speaker 01

  That fasting before chemo definitely has some real benefits that we should be utilizing.

• 30:48Tim Ferriss?

  No, it's so fascinating. And so cecexia, man, you are a treasure trove of vocabulary. So is that the, is that the, 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 what is cecexia?

• 31:08Speaker 01

  Yeah, so cecexia would be defined as, actually investigators are trying to get a clear definition of it and understanding of it, which our lab, I have, one of my students is just studies cancer, cecexia. Cecexia is defined as, in cancer, as you're in a physiological state where your body is releasing factors like tumor necrosis factor alpha and inflammatory cytokines that inflammatory mediators that are metabolizing your muscle tissue, your lean body mass.

• 31:48Tim Ferriss?

  And just, I apologize, I just wanted, for people who are unfamiliar with the vocab, so anabolism would be building tissue in general and catabolism would be breaking down tissue? Is that fair? Or is it?

• 32:00Speaker 01

  Exactly. Like anabolic steroids are building and catabolic processes are the breaking down of things.

• 32:06Tim Ferriss?

  Okay. Sorry to interrupt.

• 32:08Speaker 01

  Oh, no, that's great. So you're, yeah, you're in a state where you're, you're basically wasting lean body mass, you're wasting, you know, tissue. And a lot of cancer patients succumb to cancer cecexia and its mortality is closely intimately related to that. So as you lose lean body mass from being in a state, say for example, someone has advanced metastatic cancer, that they

• 32:38Speaker 01

  Well, 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 you get this situation where you have an older patient that gets cancer, like seventy year olds, and you have age-related sarcopenia, right? They're already losing muscle. Right. Uh, compounded with cancer cachexia, which increases lean body mass loss due to the the pathology on top of chemo-induced cachexia. Oh, wow. So chemotherapy is a pretty powerful destructive agent to lean body mass

• 33:20Speaker 01

  on top of 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 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.

• 33:59Speaker 01

  Uh, and we're, we want to 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. Yeah. There's not a whole lot 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. Because once they lose their mobility, once they get weak enough where they just can't move around, I mean, their whole psychology just deteriorates. I would imagine. You know? Yeah, so there's, there's a lot of.

• 34:41Speaker 01

  Reasons that we should be looking into keeping patients as strong and preserving their muscle as much as possible.

• 34:49Tim Ferriss?

  Is, are there any 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.

• 35:00Speaker 01

  Yeah.

• 35:01Tim Ferriss?

  Are there people out there who have, who believe that there's a role of anabolic agents, whether steroids or otherwise, in those types of circumstances with, say, cancer patients? And I don't, and I'd be really interested to hear your thoughts, just because we, there are also a lot of people who are trying to, say, minimize IGF-1, among other things, for longevity purposes, or even for anti-cancer purposes, but how do you, how do you think about that, or how do other people think about that?

• 35:33Speaker 01

  Well, I, I think it's a little outside of mainstream cancer kind of world that I'm linked in with, but I think it should be. And I think, you know, we want to develop a pretty solid program here in our lab to, to look into this. 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. Pretty sure the literature says that there are specific androgen receptor modulators

• 36:16Speaker 01

  out there, they're called SARMs, 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 testosterone and other anabolic steroids without the androgenic or the hormone effects.

• 36:37Tim Ferriss?

  Right.

• 36:38Speaker 01

  And they are actually developed specifically for cancer cachexia.

• 36:44Tim Ferriss?

  Oh, really?

• 36:45Speaker 01

  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. We're looking at branched-chain amino acids right now, which we think are, are pretty important, too. 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 per week, say, you start to increase systemic IGF-1 levels. And if you go up to about 600 milligrams a week, which would put you

• 37:26Speaker 01

  at a supra-physiological level, about twice or three times that of a normal male, at least, that causes the liver to increase IGF-1 release. So your systemic IGF-1 will go up. But a dosage of, say, 100 to 200 milligrams a week does not increase, to my knowledge, factors, hormones, growth factors that would cause cancer to grow and spread. And I think at that dosage, especially with a lot of male cancer patients, that would have a

• 38:06Speaker 01

  pretty remarkable protein-sparing effect. And we know that, you know, anabolic agents can be life-saving drugs for HIV patients.

• 38:15Tim Ferriss?

  Absolutely.

• 38:15Speaker 01

  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 the physicians and the doctors that treat their patients, that are familiar with these agents and know how to intelligently prescribe them and administer them, they will tell you that, you know, they save lives. So, and I think that application may be useful in cancer. So, but I think the SARMs are kind of an interesting compound that's coming out. And I think there's definitely some potential for some drugs out there.

• 38:53Tim Ferriss?

  Now, is the advantage of SARM, a SARM over, say, a high anabolic, low androgenic steroid like a nandrolone or a oxandrolone, for instance, which is very popular with 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 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, you know, anabolic agents that are, that are low androgenic.

• 39:36Tim Ferriss?

  And just so, so people understand, 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, in so much as they have anabolic, i.e. tissue building, muscle building effects, and then they have androgenic effects, which can, can accelerate the development of secondary sex characteristics, whether that's like a, a square jaw, male characteristics, or a, you know, deeper voice and development of the vocal cords, more hair, acne, et cetera, that kind of stuff. So, in the case of someone with, say, wasting disease, particularly if they are female instead of male,

• 40:19Tim Ferriss?

  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, 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 SARMS, SARMS over pre-existing low androgenic anabolic therapies.

• 40:46Speaker 01

  Yeah, okay. So SARMS are designed with the intention in mind to minimize the androgenic component down to nothing, you know, that, that's really the goal.

• 40:59Speaker 01

  And I think they're pretty close to doing that. The, the problem is, I don't, 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 anabolic steroid counterparts or cousins. But the, the advantage is, you know, is that if you have a guy with prostate cancer, or all males, you know, probably get prostate cancer in, in time. So, you can, high testosterone could drive the, the growth of your prostate and prostate cancer. And, and anabolic steroids could obviously have major side effects for women. I mean, we see this in women's bodybuilding, right?

• 41:45Speaker 01

  We see the side effects are pretty real and, and pretty non-reversible. So, a, a selective androgen receptor modulator can have the advantage of, you know, potentially...

• 42:00Speaker 01

  Giving the protein sparing anabolic properties of the agents, you know, without the side effects. So there's not, there's research going on, but it's, I don't think it's moving as fast as what we had initially anticipated as far as them being super potent anabolic agents that would make anabolic steroids obsolete.

• 42:26Tim Ferriss?

  Got it.

• 42:27Speaker 01

  So 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 of years.

• 42:39Tim Ferriss?

  Yeah, I want to chat with you separately about how to marshal resources to do a lot more studies because 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 distributed studies potentially. Anyway, you and I would love to chat more about that. But in the case, coming back to the chemotherapies, I love looking at cancer and 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, you know, I suppose

• 43:21Tim Ferriss?

  I would include myself in that, although normal is kind of pushing it. The, is it possible, or to what extent is it possible to mimic the benefits of fasting pre chemotherapy with exogenous ketones?

• 43:38Speaker 01

  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.

• 43:49Tim Ferriss?

  Right.

• 43:51Speaker 01

  They're energy that your liver only produces under certain circumstances of

• 43:57Speaker 01

  What's considered a kind of strange metabolic physiology, like a fasted state.

• 44:04Tim Ferriss?

  Right, duress sometimes, yeah.

• 44:06Speaker 01

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

• 44:51Speaker 01

  output of glucose. So your liver is the master regulator of your blood glucose, really. And it's, so the drug metformin in type 2 diabetics will decrease hepatic gluconeogenesis. So the liver's ability to make glucose and put it into the bloodstream. We think that ketones are doing this also. And I think 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 also, a big dose of ketones could potentially cause a small release of insulin. And that's kind of how we regulate our endogenous ketone production, is that if our ketone

• 45:36Speaker 01

  levels get too high, that ketone will cause a very tiny release of insulin from the pancreas. And that will signal the liver to kind of turn down or turn off hepatic ketogenesis. And it's a, 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.

• 46:01Tim Ferriss?

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

• 46:20Speaker 01

  Yeah, I think it's pretty rare to see over five millimolar in kids, you know, with kids that have a disorder called glucose transporter type one deficiency syndrome. 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. 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 kind of going to fluctuate throughout the day. So if you measure and you hit seven, I wouldn't panic or anything. I mean, because it's probably a little peak that you're getting.

• 46:58Tim Ferriss?

  Or you're on a pedi diet doing a cycling workout.

• 47:02Speaker 01

  Yeah, yeah, there's that, you know, you have post-exercise ketosis where guys that are on a high carb diet, after four, 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 naturally just going to be in ketosis. So their, their body is used to seeing ketones, you know, because of the exercise that they do. 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

• 47:42Speaker 01

  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, you know, health benefits, longevity benefits, performance, resilience. I think there's some real world benefits to staying in that, that range. And you'd be hard pressed to find any potential adverse effects that could be, you know.

• 48:11Speaker 01

  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.

• 48:26Tim Ferriss?

  Right.

• 48:26Speaker 01

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

• 48:37Tim Ferriss?

  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 ketosis experiments myself with exogenous ketones. So I have two jugs of exogenous ketones in my fridge. Then I have some powdered 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? Calcium potassium? Am I getting that right?

• 49:10Speaker 01

  Calcium sodium.

• 49:11Tim Ferriss?

  Jesus, ah, Ferris. So bad. Anyway, I try. I try hard. I'm like Avis. The so I have the powdered, the powdered 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 diet 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, upon waking. How could I use?

• 49:55Tim Ferriss?

  Can I accelerate 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?

• 50:18Speaker 01

  Yeah.

• 50:21Speaker 01

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

• 50:46Tim Ferriss?

  Yeah, you feel grumpy and shitty.

• 50:48Speaker 01

  Yeah, you have glucose withdrawal. I mean, your brain goes through glucose withdrawal, and it uses glucose to, not only for energy, but to make neurotransmitters, to your brain homeostasis, is your glucose levels are basically telling your brain that it's happy, it's in a homeostatic state. So if you feed your body, your brain ketones, it is preserving more or less that neurophysiological homeostasis, I think. And you're not going to have a, maybe a stress reaction. So if you fast, and this is in subjects that just kind of go cold

• 51:32Speaker 01

  turkey and fast, within the first 24 hours, they, you know, it's a stress response, their cortisol level spikes, your sympathetic nervous system is activated, their immune system could be suppressed. 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, sustained nutritional ketosis, without some of the bumps along the way.

• 52:02Tim Ferriss?

  Got it.

• 52:03Speaker 01

  And I think that you could probably reap some of the performance benefits. And I think it 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?

• 52:19Tim Ferriss?

  Yeah.

• 52:20Speaker 01

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

• 52:31Tim Ferriss?

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

• 52:42Speaker 01

  Yeah.

• 52:43Tim Ferriss?

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

• 52:50Speaker 01

  Yeah, where, you know, in 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.

• 53:05Tim Ferriss?

  Right, right.

• 53:05Speaker 01

  So you could be, could be 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, 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, because it is very restrictive.

• 53:29Tim Ferriss?

  It is.

• 53:29Speaker 01

  And you could do like a modified Atkins, which is kind of the way I think we should eat anyway. I mean, just eliminating all processed carbohydrates and just, you know, protein, fat, veggies is kind of 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. And I think it would allow us to optimize the therapeutic effects of the ketogenic diet 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 the ketogenic diet, too. And I think that's, that's possible. But a lot of people just want something in a pill.

• 54:14Speaker 01

  And we kind of, we did that study. Well, we're, we're doing those studies now and we are, I'm a big fan of the ketogenic diet and I'm actually pretty impressed and, and even not shocked as in the world, but we're getting, we're getting results better than I expected just by giving pure ketones. Then I thought 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. We showed that really in our first study.

• 54:49Tim Ferriss?

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

• 54:57Speaker 01

  Yeah, it is in our animal models and we think it is in humans right now. So we have some studies approved. We're going to be looking at that in humans, looking at the metabolic effects. But the first study that we did is a rat study where we did an acute feeding. 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

• 55:36Speaker 01

  they probably weren't. So they've never really seen ketones before. And in this study that we did, we acutely, you know, gave them 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.

• 56:01Tim Ferriss?

  And the bolus was, I mean, a high dose, single?

• 56:05Speaker 01

  Yeah, ketone ester.

• 56:07Tim Ferriss?

  And what was the ketone ester?

• 56:09Speaker 01

  It was, you want the chemical name?

• 56:13Tim Ferriss?

  Maybe I should take a different approach. What is a, for people listening, what is a ketone ester?

• 56:19Speaker 01

  Okay, so your body makes, you know, primarily two ketones that it uses for fuel. One is acetyl acetate, and another is beta hydroxybutyrate. And they're both kind of interchangeable, and they're converted to one another in the body. Beta hydroxybutyrate actually has to break down to acetyl acetate, you know, to be used for energy. But the beta hydroxybutyrate tends to be the primary, 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 acetyl acetate. So a ketone ester is taking one of these, acetyl acetate, or beta hydroxybutyrate, or both.

• 57:02Speaker 01

  And taking those molecules and attaching it to something and with an ester bond that functions is like more or less a carrier to it. So you can esterify a ketone with a wide range of things. You could use glycerol. You can use, we use what something called 1,3 butane dial. And you can attach ketone molecules to this with a trans esterification reaction. And when it's ingested in the body, there's various enzymes, we have hydrolytic enzymes that will, esterases that will break off the ketone and you'll get, when you ingest

• 57:42Speaker 01

  it orally, you will 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. 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

• 58:25Speaker 01

  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. And in the rat study that I was describing, they are quickly put into ketosis. And then in that particular study, we would dive them 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 down to 132 feet of seawater, breathing 100%

• 59:08Speaker 01

  oxygen on, in a rebreather that they use called a Drager rebreather.

• 59:14Tim Ferriss?

  And the purpose of that, of course, is so that they don't give away location by having bubbles come out of their system.

• 59:21Speaker 01

  Yeah, so there's a definitely a stealth component to a closed-circuit rebreather. If you're using it and you're in the middle of a pond, in the middle of the jungle, 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 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. So with a, with a rebreather, there is a, a big advantage, a stealth component. The disadvantage is, obviously, you know, if you go down to just 50 feet of seawater, you're at the risk of getting what's called oxygen toxicity seizures within like 15, 10 to 15 minutes.

• 1:00:06Tim Ferriss?

  Wow.

• 1:00:07Speaker 01

  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, you're, you gotta, you gotta dive down the plana mine on a bridge or a ship. It's not always easy to do. So, we developed these things for, you know, providing resilience and safety and performance.

• 1:00:30Tim Ferriss?

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

• 1:00:33Speaker 01

  Yeah, that's, they're developed, you know, originally with that application in mind, with, with sort of a, a defense application in mind, military application. And that's, that's how my project originally got started.

• 1:00:47Tim Ferriss?

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

• 1:00:54Speaker 01

  Yeah, yeah, that was, the original idea for this was, I got turned on to the ketogenic diet because it was used for drug-resistant seizures. And my program officer, 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, you know, I remember the first time we did it, we, you

• 1:01:35Speaker 01

  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're standing there and it's like thirty minutes has gone by, forty minutes, and we're up to an hour. And everybody's just kind of like looking at one another. Whoa. This is unbelievable. I wasn't getting excited. I was like, okay, calm down. Calm down. This could be like a major outlier or something. 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 five hundred

• 1:02:16Speaker 01

  and seventy-five percent. And that sort of blows away any anti-comulsant drug out there. 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. Yeah. University is for kids with drug resistant seizures. And in the studies published, the original studies by John Freeman, published showed that in 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,

• 1:03:01Speaker 01

  like or like ninety-five percent reduction in seizures. So it made sense. So I was actually thinking that, well, the original study design was to feed ketone esters for a week and then diet them. But my source was only making like a little bit at a time. And the chemist that I got to make the product for me, so I had, you know, little tiny vials of it. And it's like, well, I don't know, I was just kind of impatient. And I was like, instead of getting enough to feed it for a week, I was like, let's just try to give it one dose and see what happens. And when it worked, it was just, we were just blown away. So we did like three or four rats. And I was like, okay, I'm convinced, but completely unscientific, right? I mean, this, you know, you usually got to do like in, you know, twelve and do stats and everything and do controls. But I was completely, because

• 1:03:46Speaker 01

  we dove like four rats and they all went way beyond. Yeah. You know, any other rat we've ever seen. So I was like, I have to move on this fast. Or someone Is gonna kind of take this idea or something. I think we gotta, we gotta move on this finding as fast as possible.

• 1:04:02Tim Ferriss?

  Well, it seems, it seems also, I mean, and just, just like my, my ridiculous potassium instead of sodium remark earlier. Definitely club, like verbally club me over the head if I do anything like that, but it, it seems like. I mean, when you're evaluating the statistical significance of a given study, the sort of civilians, like non scientists. Will say, oh, well, how big was your sample size? And it's like, oh, it was six or 10. They're like, oh, well, it's that's so small, you know, kind of. And they'll say it should be 100 or it should be 1,000. And they really don't know about science and I'm, I should probably put myself in that category too.

• 1:04:41Tim Ferriss?

  But if you have a huge magnitude of effect that is consistent across a smaller subject size, it can still be statistically significant, can it not?

• 1:04:51Speaker 01

  Yeah, it depends on your sample population, you know, what kind of statistical power you have. Or the likelihood to that the study will detect an effect, you know, is the statistical power. And that you really have to sit down with a statistician and look at, you know, the probability of making a type two error. Or concluding that there's no effect, you know, and so this, and I'm, I know just the, you know, I had took the basics to stats class. And, but I still consult, you know, with a statistician when we're designing, you know, a study for a proposal or something like that. And you kind of, you need to run it by it because if you don't do it beforehand, the reviewers that are reviewing your paper.

• 1:05:37Speaker 01

  There's always, there's always that statistician that, that's, you know, part of the review committee who will ding you on it and be like, nope. You were not passing it. You gotta go back and do two more animals for this group. And then it's like, ah, they could set you back, you know, like a year and a half.

• 1:05:51Tim Ferriss?

  Sure.

• 1:05:51Speaker 01

  Publish study. So, so you always want to do that upfront.

• 1:05:54Tim Ferriss?

  Yeah. I mean, especially I was looking at with some mutual friends of ours, looking at a. Study involving beet juice intake and endurance gains and they were using a small sample size of extremely high level endurance athletes. And if you were to take the results, it was like, you know, a 2% performance increase or whatever and try to convey it, it sounds extremely unimpressive, but the study, the entire study was underpowered in some fatal ways. But the question for you, so I enjoy scuba, but scuba can be dangerous, right? Who knows, like you get snagged on something or let's say you're, let's just take a different scenario.

• 1:06:37Tim Ferriss?

  So instead of using a rebreather with pure oxygen, right? So in excess of oxygen, you risk a running out of oxygen, right? Or excessive CO2 levels. Let's say you're a freediver and trying to break records. Would taking a sort of single large dose, like a bolus of exogenous ketones or ketone esters before a record attempt be, would that be a rational sort of insurance policy? Or would that in any way help mitigate potential damage?

• 1:07:12Speaker 01

  Yeah, that's a really good question. And so our lab, in addition to looking at oxygen, we also look at what's called hypercapnia, which is high CO2 levels. Because if you're in a spaceship that's headed to Mars or you're in a submarine, the level of CO2 that you're experiencing is about on an order of 10 times higher. So that's something that we're looking at. But when it comes to oxygen utilization, I guess one of the studies you could refer to is Peter Attia's blog where we look at, we've kind of set the work. Peter took a ketone salt that we had and kind of a crude version of it.

• 1:07:56Speaker 01

  And I commend Peter for his bravery in downing this.

• 1:08:00Tim Ferriss?

  This is the jet fuel that made him dry heave in the kitchen?

• 1:08:03Speaker 01

  Yeah.

• 1:08:05Speaker 01

  So yeah, if you if you look at his blog there, yeah, and I think the title is Jet Fuel. And you look at the oxygen consumption for a given work output. In his case, it was on a bike at 180 watts. He had roughly, you know, five to eight percent decrease in oxygen consumption for a given work output. So showing that your oxygen utilization, you know, was lower. And so your oxygen, your metabolic efficiency. So that that's kind of the the take home is that you you can enhance, potentially enhance metabolic efficiency.

• 1:08:43Speaker 01

  So I can tell you that when I fasted for one week, I do a lot of snorkeling and a lot of diving and just kind of water sports. And out of curiosity, I was swimming around in the pool at my house. And I noticed I could stay under longer. And I told my girlfriend, now my fiance, it's like, I want to do an experiment and and measure. I I knew what my breath hold time was. And then in a fasted state, I had never checked it before. So I was able to stay down for three and a half minutes, I think, almost four minutes, which is like well beyond double my my breath hold time. And it was it was really remarkable.

• 1:09:28Speaker 01

  So being in a state of pretty, pretty intense ketosis allowed me to to withstand levels of hypoxia. So

• 1:09:40Tim Ferriss?

  What was your millimolars at the time?

• 1:09:42Speaker 01

  And there's Yeah.

• 1:09:44Tim Ferriss?

  Or roughly?

• 1:09:45Speaker 01

  I was running, yeah, I was running between four to five and a half.

• 1:09:51Tim Ferriss?

  You're up there.

• 1:09:52Speaker 01

  But I'm a good ketone user too. So I would be, if I'm sitting at my desk, so that's what I would, I would kind of be registering. But if I got up and took a brisk walk around campus or around my place or something, that would drop down to like two. Because I think your peripheral uptake of ketones would be higher, but

• 1:10:13Tim Ferriss?

  You also have a lot of, you have a lot of mass you're walking around with.

• 1:10:17Speaker 01

  Yeah, so, and I think we build our transport and mechanisms of ketones with time. So the mono, it's called the monocarboxylgasec transporter, sort of the, the, the protein that gets the ketones across the membrane and allow cells to use it, is upregulated over time. So the longer you're on a ketogenic diet, the more benefits you could potentially derive from it because you, your body is adapting to that state of ketosis by upregulating transporter mechanisms. And a few of my colleagues study this. And, and at least in a rodent model, in about, takes about four weeks, and you could actually double the protein

• 1:11:02Speaker 01

  level, uh, which, you know, the actual subunits of the proteins that are part of the transporter, goes up about 50% at, when you, when you transition an animal to a ketogenic diet for four weeks. So that's a pretty remarkable increase in the potential, you know, of utilizing ketones as an energy source. So, and I think some of the work by Jeff Bolick, I just had the opportunity to visit him at Ohio State, uh, just last week. And he's done some remarkable work just showing between, you know, fat-adapted athletes and carb-adapted athletes, and they're both at elite levels. If you look at substrate utilization between these two groups, it's

• 1:11:43Speaker 01

  like night and day. I mean, the, even the, the best carb-adapted athletes, they're the ones that are using fat at the highest level, are using much less fat than the fat-adapted athletes, than the guys that are on the ketogenic diet. I mean, they're literally using about two to three times more fat for, during, during exercise. And, and I think that's what happens. I, I think resting and just kind of being in a calm state and letting your sympathetic nervous system kind of chill out and having a, a good, and diving is a lot, a lot of mental preparation goes into diving. But I found that, you know, if I could

• 1:12:25Speaker 01

  just kind of calm my body down, and, and if I'm in the state of nutritional ketosis, fasting ketosis, I could increase my breath hold time by like three times, like 300%. And that's, that blows my mind. So I need to study this.

• 1:12:41Tim Ferriss?

  I've also replicated that myself in two different, uh, two different experiments. I mean, it's an N of one, but um, the, yeah, the magnitude of difference. I mean, it's kind of like your rat swimming around for an hour instead of 25 minutes or 15 minutes rather. Double or triple breath hold time at uh, even low ones like 1.3 millimolars. Um, I don't, uh, I even, uh, even on a very strict chlor- uh, calorically restricted ketogenic diet. I, I very rarely get past uh, three, uh, unless I'm ingesting stuff that facilitates it. Meaning supplemental ketones, MCTU, et cetera. But the, a question for you on the, the adaptation.

• 1:13:24Tim Ferriss?

  I'm so interested in this. So for instance, people talk about muscle memory, right? Where people regain weight faster, muscle weight after uh, they've gained it once before. Even if they lose, say 50, 60 pounds like Casey V8 or did at one point and then regained it. And they're like, oh, well, that's muscle memory. And some people, at least based on reading I've done, attribute that to, you know, satellite cell growth and so on. That happened the first time around that facilitate this kind of regrowth. So there's a persistent benefit to that one time event. Is there, uh, what is the persistence of the upregulation after four weeks of being on keto? So let's say you stay on a stick, a strict keto diet for four to six weeks.

• 1:14:10Tim Ferriss?

  You upre- you upregulate these, these proteins and therefore sort of the uptake or transport by 50%. If you stopped that and didn't follow a ketogenic diet again for another six months. Is there a persistence of effect or if you had to guess, what would you say?

• 1:14:29Speaker 01

  Yeah, anecdotally, I would say yes. I mean, there's some memory going on here. And yeah, if you just, you know, if you use ketone levels as kind of an index for this, like your body's ability to make ketones, it's definitely better. Like if you're on a ketogenic diet and you break ketosis and go eat sushi for a couple of days and come back, I can get into ketosis real quick relative to the big learning curve I had when I started doing this, you know? So I would say, yeah, and I'm not sure we've studied it to that extent I think you're referring to, but that brings up a good question, you know, because a lot of people want to go in

• 1:15:14Speaker 01

  and out of ketosis, like, can I just use this intermittently? Can I eat ketogenic but just throwing carbs during my workout?

• 1:15:23Speaker 01

  You know, and people say, well, should I be on a ketogenic diet all the time? Should I always be in nutritional ketosis? And I tend to be in that state because I just feel better, generally in a moderate state of ketosis. But I think it's probably good, too, to have metabolic flexibility for your body to be able to use all sorts of, you know, food for energy. So going in and out of ketosis may be optimal, like to get your body in and out. And I do that from time to time, depending on, you know, I'll be traveling, I'll be in Europe the next two or three weeks, actually, so trying different foods. So I'll probably get out of ketosis.

• 1:16:05Speaker 01

  But I actually travel with ketone supplements, too, so I kind of cheat along the way.

• 1:16:09Tim Ferriss?

  So if you go to, like, Italy and you're eating bread and pasta, what are the main benefits? I'm making that assumption, but that's what I would do because I'm a glutton and love carbs when it comes down to it. But 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?

• 1:16:35Speaker 01

  Okay, uh, depends on, you know, kind of the person, what you wanted to, uh, if you were working out or whatever, uh, just, but just for general health and energy.

• 1:16:45Tim Ferriss?

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

• 1:17:00Speaker 01

  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. And I'm kind of, it's not on the market yet, but I just kind of have it. And, uh, and I use the Keto Kena product 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.

• 1:17:35Tim Ferriss?

  And that's a combination, and that's the combination of the MCT powder and the Keto Kena, or Keto Kana? God, I need to, it's like Gym Kana, like that horrible but awesome movie I saw ages ago.

• 1:17:46Speaker 01

  Yeah.

• 1:17:47Tim Ferriss?

  All right. Keto, Keto Kana? Is that how you guys say it?

• 1:17:49Speaker 01

  Keto Kana, yeah.

• 1:17:51Tim Ferriss?

  So do you combine those two when you first get up and take it with water?

• 1:17:55Speaker 01

  I do sometimes, not all the time. Sometimes I'll just take the straight MCT powder. It just kind of depends on my mood or whatever. But, uh, but I always take, uh, MCTs are so versatile and they're so cheap and so readily available. Uh, traveling with MCT oil is not like really that good. But so the powder is something that I've been testing and I really love it. And the powder, the huge advantage of an MCT powder, especially caprylic triglyceride, is that with straight MCT oil, I'm running to the bathroom, you know, when I, on an empty stomach, or if I try to get my levels up to above one millimolar, above whatever

• 1:18:37Speaker 01

  baseline I'm at. Whereas the MCT powder that I'm working, you know, that's being formulated and tested, uh, is sort of spray dried with a probiotic fiber that's healthy for your microbiome and, uh, has some interesting properties in and of itself. But it allows you, uh, the powder. Increases tolerability at least double or triples it.

• 1:19:00Tim Ferriss?

  Wow.

• 1:19:00Speaker 01

  And so it allows you to kind of cruise along at an extra two millimolar and stay there. And then, you know, you could take that powder and then add some Ketokana to it. And or some other, you know, ketone salt products that we're developing. And basically, I mean, you're approaching the potency of a ketone ester. The ketone esters will probably always be the most potent molecules out there. It'll be hard to touch that. But some of the the more palatable ketone salt products that are being developed and tested now. Uh, we're working really hard to make them tolerable and, you know, palatable. Are will be able to approach the the potency of the esters that are developed for military applications, which I think is really exciting.

• 1:19:44Speaker 01

  Cause I mean, they're they're going to taste, they're actually, you'll look forward to tasting them. Uh, they're that good and they can put you into that that mild ketosis range, that one to three millimolar independent of carbohydrate restriction or fasting. So you will, you know, you'll have the ability to derive a lot of the benefits, whether it be health, longevity, performance of ketosis, of higher levels of ketosis than you could otherwise get with any kind of MCT oil out there or any anything out there. Uh, so I will bring that with me when I travel. And, um, so I'll be in Budapest and Belgium and a few other places along the way.

• 1:20:28Speaker 01

  And I will probably not be eating keto. I'll be eating low carb, but not keto. But I'll be cruising around at, you know, probably two to three millimolar. Uh, kind of more or less off of a ketogenic diet, low carb, but not ketogenic.

• 1:20:43Tim Ferriss?

  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?

• 1:20:52Speaker 01

  Uh, this morning, uh, I had, uh, eggs. I usually have four eggs and some kind of fish. I'm a big believer, I've 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. Why is that? 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, uh, they're really high in micronutrients like selenium and, uh, which are, you know,

• 1:21:37Speaker 01

  things that are maybe hard to get from other sources out there, but, uh, but I think, I just like the taste of them too. So. Right. Um, so sardines are really good to travel with. 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. Uh, so that's what I had for breakfast, but before I eat breakfast, I always kind of

• 1:22:20Speaker 01

  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 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

• 1:23:05Speaker 01

  put, uh, MCT powder in it on top of the butter. So it's very ketogenic. And the macronutrient ratio of my breakfast is always about about seventy to eighty percent fat and with the balance being, you know, protein and a little bit of carbs from whatever green vegetables I have.

• 1:23:24Tim Ferriss?

  And the BCAAs, what brand are you using?

• 1:23:30Speaker 01

  Yeah, I use Scivation.

• 1:23:32Tim Ferriss?

  How do you say that?

• 1:23:34Speaker 01

  Yeah, it's short for science and innovation. So S I, oh, S C I V A T I O N, right? Yeah, Scivation. So Scivation has been an incredible supporter of our, our cancer research program. So, 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.

• 1:24:11Tim Ferriss?

  Right.

• 1:24:12Speaker 01

  The CEO of Scivation's is a close friend of mine and 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 Extend 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 it's actually the product that we're using in our cancer studies. 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 high amount of glutamine in it. So I said, you know, I want to study this, but let's remove the glutamine and just do

• 1:24:57Speaker 01

  pure branched-chain amino acids. And I think he replaced the glutamine and put some taurine in it or whatever. And we, we started with that and we added.

• 1:25:08Tim Ferriss?

  Is that because the glutamine is glucogenic or what was the reason for removing the algalutamine?

• 1:25:14Speaker 01

  Yeah, I should describe. So cancer cells in 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 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 source of energy. 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

• 1:25:54Speaker 01

  and the aggressiveness of a tumor in imaging, in 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, by cancer cells. So, and we call that glutamine lysis. So cancer cells can use glucose, primarily glucose, but they can also use glutamine. And there's, this is understood now and kind of well-defined in the literature. So, but we know that glutamine,

• 1:26:34Speaker 01

  I mean, some formulas actually promote, or hospitals will promote giving IV glutamine or oral glutamine to cancer patients. 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 from the extend product, at least for our studies.

• 1:26:57Tim Ferriss?

  Right.

• 1:26:57Speaker 01

  And we want to go back and do a parallel study with the glutamine, actually, to see.

• 1:27:01Tim Ferriss?

  And the IV glutamine in the hospitals is for waste to, for an anticoptic catabolic purpose? Or is it for some type of recovery purpose? Why are they doing that in the first place?

• 1:27:13Speaker 01

  Yeah.

• 1:27:14Tim Ferriss?

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

• 1:27:17Speaker 01

  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. I'm not sure how much glutamine you're actually getting to the muscles when you do that.

• 1:27:28Tim Ferriss?

  Right.

• 1:27:28Speaker 01

  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. Glutamine is also a, an important amino acid for maintaining your immune system. So it plays a, I would say if you're deficient in glutamine, it can compromise your immune system. So you want to 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're a burn patient, you know, you're going to want, you might want glutamine.

• 1:28:08Speaker 01

  Although we don't, we want to, we're testing a hypothesis that we want to metabolically starve cancer cells in our experiment and preserve muscle at the same time. So the Extend product that's out there by Cyvation 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 going to take it. So the Cyvation, branched-chain amino acids, they taste really good, but they're also,

• 1:28:50Speaker 01

  you know, very tolerable and very, you know, palatable. But they, you know, this particular product had glutamine. So we removed it from 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 looked at survival of mice with, with advanced metastatic cancer. And 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 the animals were

• 1:29:35Speaker 01

  maintaining their, their weight better 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 mTOR has been associated with driving, a major driver for cancer growth and proliferation.

• 1:29:58Speaker 01

  But, you know, and, and there's cancer biologists out there that would say, well, if you give leucine, you're just going to drive cancer because you're stimulating a, an anabolic process that can drive cancer growth and proliferation. But I would kind of argue that that's not the case here. We definitely don't see it in this model and some of the other studies out there do not show that branched-chain amino acids cause cancer to grow faster. And some of it shows the opposite, actually. But I, I think branched-chain amino acids have their effect on anabolic processes are relatively specific to skeletal muscle.

• 1:30:43Speaker 01

  And I think that's, that's really important to understand is that stimulating anabolic processes is not a global effect. It's that, it's kind of similar to anabolic steroids, right? So there's specific receptors on the muscles. We think that, that the...

• 1:31:02Tim Ferriss?

  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 because your...

• 1:31:11Speaker 01

  Yeah, yeah.

• 1:31:12Tim Ferriss?

  Your, your intestines are the size of your forearms. Yeah.

• 1:31:16Speaker 01

  Yeah. IGF-1 is great for like growing your skin and your organs. Yeah. So it has a pretty global systemic anabolic effect. Whereas, 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, and to look at this, you know, we're gonna, you know, feed animals 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 assay is and everything to look at the, the signaling and the, you know, insulin signaling, the

• 1:32:00Speaker 01

  metabolomics, the growth factors and whatnot. So and compare it to the groups without the branched-chain amino acid. So we're really delving mechanistically into this.

• 1:32:09Tim Ferriss?

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

• 1:32:20Tim Ferriss?

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

• 1:32:31Speaker 01

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

• 1:32:39Tim Ferriss?

  Right.

• 1:32:40Speaker 01

  And, and my, who would you call, 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, you direct me to labs that are doing interesting nutrition science research. And there wasn't a whole lot going on. I mean, I like Rutgers and everything, but there just wasn't a whole lot of stuff going on there that really interested me. And the more people I talked to, I was kind of going the pre-mid route. And, and people were like, well, yeah, you should probably, you should probably major in biology too. So I double majored in nutrition, biological sciences. And, but I really had a passion

• 1:33:22Speaker 01

  for nutrition. And then when I went into a PhD program, it was neuroscience because I was really fascinated with the brain, but also did physiology. And I studied the neural control of autonomic regulation. So how the brain controls our body, our physiology. And then, you know, I started, did my postdoc in, you know, looking at physiological resilience and the oxygen toxicity thing. And it brought me back full circle.

• 1:33:49Tim Ferriss?

  Yeah.

• 1:33:50Speaker 01

  Because when I started, you know, 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 realized 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 warfighter, you know, and basically put them into a coma. And it's not very...

• 1:34:11Tim Ferriss?

  Not the ideal way to prevent seizures.

• 1:34:14Speaker 01

  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, ah, 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'd be, I was like, you know, I realized this was grossly underutilized. And if I could harness the power of this,

• 1:34:55Speaker 01

  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, which was always there. I always even, you know, throughout grad school and postdoc, I was totally into working out on nutrition and understanding, you know, different diets and trying lots of stuff on myself. It, it, it allowed me to, you know, kind of come full circle 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

• 1:35:40Speaker 01

  drugs.

• 1:35:41Tim Ferriss?

  Well, and a lot of, I mean, you mentioned metformin as sort of a regulator of, you know, liver glycogen, hepatic glycogen. There are plenty of folks who take metformin. Is it still called glucophage, the, glucophage, I'm not sure the, the brand name, but the metformin prophylactically, I mean, these are otherwise, we consider healthy people who are taking it primarily to prevent cancer growth, if I'm not mistaken. I mean, is that fair to say? Or are they using it for other purposes?

• 1:36:12Speaker 01

  Yeah, you can use it for a variety of reasons. You could use it as kind of a metabolic prophylactin to prevent you from getting type 2 diabetes down the road. But when it comes to cancer, yeah, it definitely activates 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 activate various downstream signaling processes, it mimics in many ways calorie restriction and fasting, the same processes that would be activated.

• 1:36:56Speaker 01

  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. We don't really, the cancer, the cancer, 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

• 1:37:40Speaker 01

  by its ability to regulate hepatic glucose output or 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, and I got blood work. And the only thing I saw was that my testosterone was lower. So that was, I think that's a side effect. I have since got off of it and I rechecked and my testosterone levels like are back into the normal range that we're. Did you feel? That's the only thing I. No, I didn't. And I, well, I felt, I don't know how to describe it, a little, maybe a little

• 1:38:24Speaker 01

  less anxious, a little bit, kind of like you're, you kind of set the governor, like my highs weren't as high and it's 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, because that would be my bigger meal. So I'd kind of dose them at the form and according to my food intake, which I think is important. 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. So I, I backed down.

• 1:39:01Tim Ferriss?

  Now, now, so to gut tolerance, meaning to disaster pants, like, is that, I mean?

• 1:39:09Speaker 01

  Not, not the MCT effect, not, not what I'd describe as the MCT effect, but I would, it's kind of like a dull, kind of aching feeling in the stomach. But yeah, there was like loose stools a little bit. And then I, I just kind of, the next day I backed off and I played around with it for probably two or three weeks. And then I, I realized, okay, one gram is about what I can do, um, you know, safely and comfortably, I thought. And, uh, yeah, I did that for three months and I tried to like, take nothing else at the time, I wasn't experimenting with any other things. And, um, and I took that and my testosterone went down. That's the, but my, my

• 1:39:48Speaker 01

  other market, like my triglycerides were the lowest ever. My HDL was like 98. It bumped up from like 80 to 98. Uh, and other things, like my C reactive protein wasn't even measurable. And I, and I did, I tried not to calorie restrict or even change my diet at all. So some things went in the positive direction, but, but I was, I, I really thought that it suppressed my testosterone. And there was a couple of publications that would indicate that it does that. You know, maybe if I took 500 grams a day, I wouldn't, or 500 milligrams a day, I wouldn't have that effect. But I felt like I get a gram a day. And, um, I had like a powdered version. So it was probably like one point, you know, one to 1.5 grams a day. I was kind of measuring out with,

• 1:40:32Speaker 01

  with a powdered version. Uh, so it was at least one gram a day I was taking.

• 1:40:39Speaker 01

  So that's my experience with it. And I know, I know a few people out there. If cancer runs in your family and you are concerned that, you know, you may be at risk or maybe had cancer in the past, I think it's a pretty safe drug to take. One of my students is PhD student and his entire PhD dissertation is on metformin. So we're looking at it, you know, very deep, kind of, understanding of metformin as much as, you know, you can in a PhD dissertation. So we delve over the literature, we're running studies in individual cells in isolation, in advanced cancer models. And, you know, we have a pretty

• 1:41:23Speaker 01

  good understanding of what it does and what it doesn't do. And in our metastatic cancer model, we have survival times increased almost forty to fifty percent increase in survival.

• 1:41:37Tim Ferriss?

  Now metastatic.

• 1:41:38Speaker 01

  And we have to give a pretty big dose.

• 1:41:39Tim Ferriss?

  Is that with some, you're talking about metformin?

• 1:41:42Speaker 01

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

• 1:41:59Tim Ferriss?

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

• 1:42:12Speaker 01

  Yeah.

• 1:42:13Tim Ferriss?

  Is that also, do you still see the forty to fifty percent?

• 1:42:15Speaker 01

  Yeah. So it's interesting. So 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 isolated cell cultures of these cells that are metastatic and very aggressive. And they're transfected with a gene that makes that, that makes the protein luciferase. So it basically makes the cells glow in the presence of luciferin. So, not to get too complicated, but if we

• 1:43:00Speaker 01

  take these cells in culture, right, we harvest them and we implant them inside the flank of the animal or underneath the skin. It, uh, the cells 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. Right. 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.

• 1:43:44Speaker 01

  It's a really, really good book. Uh, it's like required reading for all my students, but, uh, he developed this model and 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, convenient model to use because when you implant the

• 1:44:27Speaker 01

  cells, the experiment goes real fast, right? Because, 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 rachael and we formulated it. Into into the food, so it would be equivalent to a person taking about 2.5 grams a day.

• 1:45:10Speaker 01

  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. Would be the human equivalent to that. The animals lived about about 50% longer, any about 45 to 50% longer survival time. So instead of living, you know, 21 days, they lived like almost 40 days.

• 1:45:37Tim Ferriss?

  That's amazing.

• 1:45:38Speaker 01

  And so so what we're doing now, and so we have to like tediously test all these things in isolation. And then we have to do different dose ranges too, right? So we got to do a variety of dose ranges and make all these dose curves and everything. But I'm I just want to jump right into it, you know? I want to do a calorie restricted ketogenic diet with ketone supplementation and metformin and hyperbaric oxygen. Yeah, I want to jump right to it, but and we're kind of doing some of these things as pilots. But but we're testing, I think it's really important to get a handle on what each of these things do.

• 1:46:15Tim Ferriss?

  Now here's.

• 1:46:15Speaker 01

  At different dosages.

• 1:46:16Tim Ferriss?

  No, definitely. I let me, I apologize for interrupting, but if you and you would find this, you would figure 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 calorie restricted ketogenic diet. So I'd love to hear.

• 1:46:43Speaker 01

  Yeah.

• 1:46:44Tim Ferriss?

  What calorie restricted means, right? You mentioned metformin, you mentioned hyperbaric oxygen treatment. You mentioned exogenous ketones. We talked earlier about fasting, but let's just say you found out, oh, shit. I'm in a bad situation here and this is a very, very aggressive cancer. Putting aside the chemotherapy and some of the other therapies that that you might have administered of the toolkits that we've been discussing, like what would you what would you do?

• 1:47:17Speaker 01

  Okay, well, you know, so I'm not the kind of person, 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 leukemia, or lymphoma, there's a variety of cancers, you'd be crazy not to do the standard of care. Sure. So, when I talk about this, 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. For sure. Which we plan to do. So, say, you know, worst case scenario, like glioblastoma, right?

• 1:48:02Speaker 01

  A glioblastoma is, in some ways, it's 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's almost, you know, if we do a study with glioblastoma patients, it's almost like you have historical controls that you can refer to. Right. So, the ketogenic diet, I think, would be, would be absolutely like your base therapy, right? And it would be not just a macronutrient ratio, it would be the sources of the macronutrients itself. Like, you would have to, you would do a macronutrient ratio that would put you into ketosis, but

• 1:48:43Speaker 01

  take extra care to get, you know, fish that was from a natural source, or grass-fed beef. 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 a salmon that's farm-raised 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, 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.

• 1:49:28Speaker 01

  So, you'd have, so your single meal would be like a dinner? Uh, it would be dinner. Yeah, you would eat probably within a window of, you know, four hours, like slowly. 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 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

• 1:50:11Speaker 01

  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 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.

• 1:50:52Speaker 01

  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. So exogenous ketones.

• 1:51:07Tim Ferriss?

  What type, like for you personally, what would, how, how, how much would you take? When would you take them?

• 1:51:12Speaker 01

  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 1.5, 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, MCT powder, which will be available soon. The Keto Cana product, there's some, there'll be some products coming out pretty soon, ketone salt products that'll taste really

• 1:51:55Speaker 01

  good and will be, will allow you to easily achieve this.

• 1:51:59Tim Ferriss?

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

• 1:52:12Speaker 01

  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. But I think it's okay to not continuously, you know, provide an exogenous source of ketones, but maybe just use them when you need them, if you need to boost in energy.

• 1:52:35Tim Ferriss?

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

• 1:52:39Speaker 01

  Yeah.

• 1:52:39Tim Ferriss?

  Two to three times a day?

• 1:52:40Speaker 01

  I would do, I would do two to four times a day, probably because 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 tumor suppressor effects that you get. So, um, yeah, I would, I would use them to the extent where I was pretty much constantly, 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

• 1:53:25Speaker 01

  boosted, an additional one to two millimolar.

• 1:53:28Tim Ferriss?

  Got it.

• 1:53:29Speaker 01

  Minimum.

• 1:53:30Tim Ferriss?

  And, um, what, what about other things that you might do?

• 1:53:33Speaker 01

  Yeah. Uh, the metformin, uh, I would.

• 1:53:37Speaker 01

  I would titrate metformin into where it starts causing side effects and then back off from there.

• 1:53:44Tim Ferriss?

  Titrate, meaning you just start low and increase the dosage?

• 1:53:47Speaker 01

  Yep, even, you know, you can get it 250 mg tablets or break the tablet in half and keep, you know, start out one week, maybe start at 500 and then go up to 750 and then to a gram and then bump it up to where, you know, you start to get some GI discomfort and then back it off and then stay there.

• 1:54:05Tim Ferriss?

  Mm-hmm.

• 1:54:06Speaker 01

  Metformin's pretty, pretty cheap, pretty remarkable drug in our hands and I think it would synergize with the other things that I'm describing. So DCA is another, another drug that we're looking at and one could simply get on Google and do a search for dicloacetate, DCA in cancer and find a lot of interesting information. I think there's, uh, there's clinical, registered clinical trials going on right now with glioblastoma. And we think it may synergize with some of the things that I'm talking about, even metformin.

• 1:54:43Speaker 01

  So DCA activates a particular enzyme metabolic pathway, pyruvate dehydrogenase complex and for reasons we don't completely understand, it can cause cancer cells to, it, it kills them. It triggers apoptosis in, in cancer cells by reasons we don't completely have a, a handle on yet. But it's used clinically for lactic acidosis. So, and lactate can drive, or, you know, in the microenvironment, lactate can drive tumor growth. So DCA can actually, uh, make your body more alkaline, right? I mean, it's used clinically for that application. And maybe its therapeutic effects may have to do with that, but we know that if we just

• 1:55:27Speaker 01

  grow cancer cells, you know, in isolation, like a dissociated cell prep and put on DCA, the, the cancer cells start to die. And at, at levels that are relatively non-toxic to healthy cells. Uh, so dicloacetate adds...

• 1:55:46Speaker 01

  You know, I don't like to give recommended, but if I was to

• 1:55:48Tim Ferriss?

  No, this is for you and theoretical, yeah.

• 1:55:51Speaker 01

  Yeah, I would start at like 10 milligrams per kilogram, you know, and I'm a little over 100 kilograms or whatever. So you could do the math on that. And so I would start to 10 milligrams per kilogram and probably not go higher than 50 milligrams per kilogram. Uh, because once you get above 50 milligrams per kilogram of DCA, you start to get peripheral neuropathy. And this, we see this in our animal models and it's also reported in patients. If you could go onto the forums of patients that have glioblastomas, they'll report tingling in the fingers and the toes at like, you know, once they start reaching about 50 milligrams per kilogram.

• 1:56:33Speaker 01

  Uh, I think the clinical trials use 20 milligrams per kilogram, if I'm not mistaken. Uh, so, so DCA activates pyruvate dehydrogenase complex. So that complex makes the mitochondria, it activates the mitochondria. And if you activate the mitochondria of cancer cells, which have defective mitochondria, it, it like causes the mitochondria to like explode and the cancer cells to, it triggers apoptosis. So it probably triggers the release of cytochrome C from the mitochondria, which is part of the apoptosis pathway.

• 1:57:08Tim Ferriss?

  apoptosis, meaning cell death.

• 1:57:10Speaker 01

  Yeah, programmed cell death.

• 1:57:11Tim Ferriss?

  Programmed cell death.

• 1:57:12Speaker 01

  Yep. So, and that's, that's kind of like a theory that I'm throwing out there, but it's based on kind of what we know, what we see in the lab and what we know from the literature. Uh, but it's relatively, you know, a non-toxic drug. I mean, relative to the chemotherapeutic agents that are, chemotherapy is, are highly carcinogenic. So when you're giving chemotherapy, you're giving a highly carcinogenic substance. So it doesn't make sense to treat cancer with something that we know is a powerful carcinogen? So it, it doesn't. In some cases it does. Like I mentioned, some of the

• 1:57:47Tim Ferriss?

  Testicular cancers.

• 1:57:48Speaker 01

  Some of the cancers I mentioned before, yeah. And there's, there's application for it, but, um, but I think we have to view it this in perspective. DCA, I don't think you can patent it. It's like a really simple molecule, di-chloroacetate. Right? You can kind of visualize it if you're a chemist. It's pretty small, simple molecule. And it has a pretty powerful metabolic effect. And again, it works, it works well by itself with a high carbohydrate diet. So just think about how it may synergize with a ketogenic diet. Exogenous ketones, you know, metformin, intermittent fasting. You know, it's working, it has, it's working through overlapping mechanisms.

• 1:58:27Speaker 01

  So you are further compromising sort of the, the energetic state of the, of the cancer cells by adding it to the mix.

• 1:58:39Tim Ferriss?

  And if you had, if you had this, you're using this portfolio of techniques, right? So you're on a, you're in a ketogenic diet, you're intermittent fasting, you're consuming exogenous ketones two to four times a day, enough to jack up your sort of ceiling by one to two millimolars. You're, you're perhaps taking metformin in combination with DCA. Is, would fasting be additive to this or would it be redundant in your mind?

• 1:59:11Speaker 01

  I think it has its place, you know, and you may not want to do, depending on your overall health, like my health, I can tolerate fasting pretty much every day. Intermittent fasting would be no problem. But I think you could derive benefits by fasting, you know, two or three times a week, even once a week, you know, I think could be beneficial. Uh, but I would try to do it, you know, some people do every other day fasting, but I think one meal a day is one way to go about doing it. Uh, or alternatively, if that's too stressful, you could eat, you know, two or three meals one day and then, you know, Monday, Wednesday, Friday, do, uh, do one meal per day.

• 1:59:51Speaker 01

  Uh, but I think that, that gap in time, that 20 plus hours that you're not eating and that you have, you know, metformin in your system, you have DCA in your system and you have exogenous ketones kind of flooding your, your bloodstream. I mean, it's, it's putting your physiology, it's putting your metabolic physiology into a state that's

• 2:00:15Speaker 01

  Compromising the tumor tissue. And I always, you know, and I had to discuss this with my colleague, Tom Safrid. He thinks that if you don't have cancer and you do a therapeutic fast, you know, once or twice a year, or maybe three times a year, if it's a shorter fast, that it would purge any precancerous cells that may be living in your body. So if you put your physiology into a state of fasting ketosis, that puts tremendous metabolic stress on cancer cells that are highly dependent for survival and growth on, you know, high levels of glucose and insulin.

• 2:00:51Tim Ferriss?

  Yeah.

• 2:00:51Speaker 01

  By subtracting them of those growth needs, they can trigger apoptosis, autophagy, and you could potentially purge yourself of some precancerous cells.

• 2:01:01Tim Ferriss?

  Precancerous cells, which pretty much everybody has by age thirty-five, forty, right? I would imagine.

• 2:01:06Speaker 01

  Pretty much, yeah. Our immune system is kind of a surveillance mechanism that detects them and takes care of them. You know, in our animal models, the cancer cells are kind of, they've evolved to evade the immune system. So that's one of the hallmarks of cancer, right? That it can metastasize, evade the immune system. You know, now in 2011, they finally added that it has an aberrant metabolic phenotype, but they ignored the whole metabolic thing for a while. But yeah, so the immune system, our immune system kind of becomes overwhelmed or declines in its capacity with age. So that surveillance, that immune system surveillance over our bodies of these potential neoplastic cells is, can be overlooked.

• 2:01:50Speaker 01

  And I think one way to reset our body and even stimulate our immune system is to do therapeutic fasting.

• 2:01:59Tim Ferriss?

  Definitely.

• 2:02:00Speaker 01

  And I think it can build us up in ways that we're just really starting to understand.

• 2:02:04Tim Ferriss?

  So I'm trying to, or I'm not trying, I am fasting at least once per quarter. And the question of duration is one I'd love to ask you about because I can go seven days if need be. I've done that already. Last time I wanted to see what it would be like, just from a starvation standpoint, you know, crashing an airplane, going from high carb intake to no food, which I would not do again.

• 2:02:36Tim Ferriss?

  I would induce ketosis as quickly as possible nutritionally and then do it. But because I had excruciating lower back pain, I mean, I just was like in a fetal position with, I think my uric acid levels were just through the roof, among other things. So I'd like to avoid that. That was really shitty. But my question is, if the therapeutic fast is, say, two to three times a year, what duration might those fasts be? What is the sort of minimum effective dose in your colleague's mind? Or your, I'm not sure if it was a colleague or student, but.

• 2:03:09Speaker 01

  Yeah. If you want to do it kind of hardcore.

• 2:03:13Tim Ferriss?

  Yeah, it's got kind of my MO.

• 2:03:16Speaker 01

  Yeah, yeah. Okay. So, 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 there, the back pain, some, you know, your body goes into kind of more or less a stress.

• 2:03:32Tim Ferriss?

  Shitty, shitty sleep, like horrible. Like, I guess that's, 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 had been doing it for two weeks, three weeks, four weeks, or, or so. And, but everyone reported horrible insomnia and like tachycardia, you know, like rapid heartbeat when they're trying to sleep.

• 2:03:55Speaker 01

  So, yeah, 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 will trigger brain fog, it'll trigger headache, it'll trigger activation of sympathetic immune system. 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 pressure will drop, and that'll contribute to your headache and you're just feeling crappy.

• 2:04:32Tim Ferriss?

  Dizziness when you stand up and all that.

• 2:04:35Speaker 01

  Yeah, I've seen several women, it seems to be more pronounced in women that try this, that they faint and they, they, you know, I had a couple of them like calm me up and just, it just made them go crazy. Like, they thought they were gonna die. So if you can get past that.

• 2:04:53Speaker 01

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

• 2:04:58Tim Ferriss?

  Yeah.

• 2:04:58Speaker 01

  Uh, I've got reports as early as the end of the first day, but I think they're kind of wimps. But usually the second and third day, 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. So if you're giving your body, even kind of cheat through that. 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.

• 2:05:39Speaker 01

  Uh, I think five days is, 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.

• 2:06:09Tim Ferriss?

  I was like, wow, this is a real interstellar moment. You're like really doing some funny stuff with time. Okay. Yeah. No, the.

• 2:06:15Speaker 01

  Yeah. Sorry. Yeah.

• 2:06:16Tim Ferriss?

  No, no, no.

• 2:06:16Speaker 01

  Per year, I think would be something to do. And you'd wanna, you know, I, I would kind of say, you know, time it so it would fit into your schedule. But when I fasted, I did it like right in the middle of writing grants and teaching and all this other stuff. And it didn't, I think it increased my productivity because think about all the time that you spend, you know, preparing food, eating food, cleaning up, eliminating and shopping for food. And all these things associated with our fixation on food.

• 2:06:50Tim Ferriss?

  It's a lot.

• 2:06:50Speaker 01

  And, and that, that's kind of time that you save. And, uh, I also realized that I was, prior to doing this, and this goes back like five, six years ago, I had a preoccupation with food. Like I was, I thought, and even going back maybe a little bit longer, I, I thought I had to eat like five or six meals a day. And I would prepare my food, like all my food on a Sunday and put it in bags and Tupperware and have it in there and have it labeled. And I was kind of neurotic about it and, you know, and that, that's okay. If you're into that sort of thing, and I think it's good, but I just. And actually maybe more efficient throughout the week. And you know, no, no offense against people who do that. But, uh, but I find that, uh, not doing that makes me more, more productive.

• 2:07:34Speaker 01

  And I find that eating a ketogenic diet also sustains me, uh, sustains my energy levels to where I just get more out of life. I'm more productive. I'm not fixated on food because I don't have to eat as frequently, but, uh, but because my energy levels more stable. So I can spend the time doing the things that I think, uh, are more productive. And I'm, you know, I'm in the process, you know, as we speak, uh, this is like the week that I'm submitting everything for my tenure, you know? So it's like been super crazy as far as, you know, 18 hour days, uh, preparing for all this and traveling and stuff on top of that. And I can't imagine doing that, you know, living the way I used to live, eating like

• 2:08:18Speaker 01

  five, six meals a day and having it timed and everything. I just, I just couldn't do it.

• 2:08:23Tim Ferriss?

  Yeah, it is, it is very liberating to realize that you 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. Uh, I was astonished, I mean, when I went through my very unpleasant, like plane crash simulation of starvation, um, I was miserable from, uh, miserable is exaggerated. I was 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, I felt fantastic. I mean, I went for long walks. I felt extraordinarily, um, cognitively sharp.

• 2:09:06Speaker 01

  Yeah.

• 2:09:06Tim Ferriss?

  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. Has that, have you observed that in other people or is that just a? The Tim thing.

• 2:09:39Speaker 01

  Yeah, I have. I've gotten emails about that. I found a couple, you know, kind of articles on discussing that. And I found that in myself that like last night I got to bed at 2 a.m. I try to get to bed at like midnight and I woke up at 6:37. So I'm running off four and a half, maybe five hours. And I feel totally fine. I've been pretty productive today. Did a lot of work in the morning. And I typically run better, best on about six hours as opposed to maybe seven or eight that I felt I required. And that depends on, you know, my activity level and kind of what's going on. But generally, I feel

• 2:10:19Speaker 01

  like I need about one or two hours less sleep, that my requirement for that is less now. And, and I think there's different reasons for that. And I think when we're in a state of nutritional ketosis, we have better fuel flow to our brain without the fluctuations in glucose throughout the day. And I think that we're, our astrocytes actually kind of spare, our astrocytes.

• 2:10:48Tim Ferriss?

  What is an astrocyte?

• 2:10:49Speaker 01

  Oh, I'm sorry. There's different brain cells, neurons and glia cells, and among glia would be astrocytes. And it's thought that astrocytes are, they actually store glycogen, 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 can actually build up their glycogen levels. So there's a couple of studies 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.

• 2:11:31Speaker 01

  And I think that process is more, is enhanced, or is 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 able to restore homeostasis of our, our brain chemistry. And I think that, that. Metabolic, so enhancing global brain metabolic activity or preserving brain homeostasis, 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

• 2:12:15Speaker 03

  What does etiology mean?

• 2:12:16Speaker 01

  Oh, etiology is like independent of the cause of the disease. 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 has an energy source. So if, if a child has glucose transporter deficiency, the only therapy that, that's offered is the 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,

• 2:13:01Speaker 01

  and we know the cause, we've identified the gene, 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, of glucose or, um, of, of 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 cerebral, um,

• 2:13:43Speaker 01

  fluid of the, of the brain and 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 phenybuty 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.

• 2:14:19Speaker 01

  But I do think that being in a state of ketosis and getting, having ketones elevated and having them available for your brain can enhance your restorative processes that occur when you're sleeping in the brain.

• 2:14:37Tim Ferriss?

  So I am looking to shift gears a little bit. I'm looking at some goodies that I'm making a cocktail with in front of me. And 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 so I, inspired by our conversation, I have Keto Sports Keto Cana, calcium and sodium beta hydroxybutyrate. And the label says dietary ketone supplement for enhanced physical and mental performance. This one is not for resale for R and D use only. So this must be an early one. And then I have the branched chain amino acids.

• 2:15:19Tim Ferriss?

  And then I have a Perillo MCT oil cap try, which is the caprylic acid. Now, on the side of the calcium and sodium, sodium beta hydroxybutyrate, the Keto Cana, 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 want to ask you about the, the risks or toxicity of consuming exogenous ketones. And, 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

• 2:16:04Tim Ferriss?

  combination to me, but I could be totally off. So I'd love for you to just to talk about the, the toxicity risks or other risks associated with exogenous ketones.

• 2:16:14Speaker 01

  Okay. 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 biological intolerance that you'll get.

• 2:16:34Tim Ferriss?

  So your body will stop you through diarrhea before you get close to anything that'll hurt you, is that?

• 2:16:39Speaker 01

  Exactly. I mean, that's the same thing with MCT, right? You're limited by your ability to, you know, transport it across the gut. So the mineral load that you would get from the KinoKana product would, you know, cause an osmotic, you know, issue in the gut. And it's great, you know, if you want to stay regular. So it stimulates peristalsis in the gut. So you'll, you'll get that side effect probably if you exceed, for me, I could probably do up to five or six servings a day and be okay. But as far as toxicity, and this is where we can draw off some of the rat studies we're

• 2:17:19Speaker 01

  doing, we just finished a 15-week 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 per day. So that's, that's really high, right? So we did that. This is part of the toxicology studies that we are doing, you know, to get FDA approval for different things. And so they actually just required 2.5 grams per kilogram per day. Well, I was like, well, let's, let's increase that tenfold.

• 2:18:04Speaker 01

  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, you have fats, you have proteins and carbs. Ketones are an energy-containing molecule, and they're like water soluble fat molecules. So we formulated them into the diet. And we fed it, we fed our rodent models this and we did clinical chemistry, we were doing metabolomics, we do histology, we do, we did, we did actually some, some anxiety studies.

• 2:18:42Tim Ferriss?

  What is histology, I'm sorry?

• 2:18:45Speaker 01

  Oh, histology is where we, at the end of the study, we harvest all the organs, right, like the kidneys, the liver and heart and everything, and we weigh them out and then we take the organs and then we, 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 toxicity to the animal, to the organs.

• 2:19:22Tim Ferriss?

  Got it.

• 2:19:23Speaker 01

  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. And we, we didn't see anything relative to the control, whether relative to the standard rodent chow, there were no abnormalities in, to indicate liver or kidney stress. And on top of that, we did kind of parallel to this in the same group.

• 2:19:58Tim Ferriss?

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

• 2:20:01Speaker 01

  25 grams per kilogram. So instead of delivering it like they do in drug studies with 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 we took that and we formulated it in a way that we know that if they ate this amount of grams per 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.

• 2:20:30Tim Ferriss?

  Got it.

• 2:20:31Speaker 01

  And 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. They just give it in a bolus.

• 2:20:41Tim Ferriss?

  So is the

• 2:20:42Speaker 01

  And I didn't see anything.

• 2:20:43Tim Ferriss?

  So, okay.

• 2:20:44Speaker 01

  There was no negative effects.

• 2:20:45Tim Ferriss?

  So you haven't observed any toxicity then? No known toxicity? Like, there's no, there's no, like, LD-50 of, um, sorry, lethal dose 50, like, a dose that'll kill 50% of the subjects or anything like that, or produce some nasty effect. You guys just haven't observed it?

• 2:21:03Speaker 01

  Not when administered that way. So in taking a step back, if we were to give 25 grams per kilogram as a single dose of our most potent ketone ester, that would cause ketoacidosis in the rats, for sure.

• 2:21:18Tim Ferriss?

  Got it.

• 2:21:19Speaker 01

  Because we, you know, got, and then they would, uh, that would be hard to reverse, actually. But that would be such a, I don't even think that volume is, is possible. I think, uh, the Ayakook wouldn't even allow us to administer that dose because the volume would be so high for the stomach.

• 2:21:37Tim Ferriss?

  Right.

• 2:21:37Speaker 01

  You know what I mean? So I don't, so it would be really, really high. So we haven't seen any, any side effects at doses that would even approach, you know, kind of what's on the label there. And, uh, and you have to figure, when these things are ingested, it's bio-identical to what our body makes anyway. And even if we eat, uh, an egg or a piece of, if we eat, you know, muscle from an animal that's in ketosis, we're getting ketones, you know, exogenous ketones. We're just not getting it at the level that would really put us into ketosis. Although, I think milk, there's some, there's some ketones in milk and different products that could kind of boost your, uh, your ketone levels a little

• 2:22:22Speaker 01

  bit. So we, we sort of looked into that when, uh, we were trying to understand for FDA regulations, are ketones in, in our food? And yes, they are in our food if an animal's in ketosis and we're eating, we're drinking milk from an animal or the meat from an animal that's in ketosis. We're technically consuming exogenous ketones.

• 2:22:43Tim Ferriss?

  So the, the, are there any unusual?

• 2:22:47Tim Ferriss?

  Foods or beverages or anything that increase ketone levels dramatically in animals or humans that you've seen. So I'll give you an example, and this could be complete. This could be complete. Well, it is speculation, but it could be just completely erroneous. So I've gotten a bunch of my friends kind of hooked on using the precision extra device to track their their millimolar levels. And some of them have really gone kind of nuts where they're they're taking five to 10 readings a day and so on. And one of them observed,

• 2:23:26Tim Ferriss?

  this is Kevin Rose, that artichokes seemed to spike ketone levels. And he replicated it for himself, 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 as a, what is it, PDE4 inhibitor, to, because PDE4 breaks down cyclical AMP, as far as I understand, blah, blah, blah. And but is there any, I mean, you could talk to artichokes specifically, but I don't know if you've ever looked at it, but are there any foodstuffs or things that people can use to jack up ketone levels besides

• 2:24:11Tim Ferriss?

  exogenous ketones or MCT oil, etc.?

• 2:24:14Speaker 01

  Yeah, that's an interesting observation. With the artichoke, artichokes, you know, mostly fiber, really. And I guess that could lead into the next question, right? Soluble fiber breaks down into short chain fatty acids, which are ketotic. So I was actually at NASA a few weeks ago, and it was brought to my attention by a former astronaut, Rick Lenahan, who's also a vet, that cows are ketotic, and that they, and this gets back

• 2:24:53Speaker 01

  to your sort of the thing we were talking about, about short chain fatty acids being formed from the breakdown of soluble fiber. And short chain fatty acids can

• 2:25:07Speaker 01

  Can be, you know, a form of ketones can contribute to ketogenesis. And also, also the generation of butyrate in the gut, so which can enhance and contribute to our gut microbiota. So, um, yeah, so I think that needs to be appreciated that we're talking about foods that could enhance ketosis. And I think that one could formulate a ketogenic diet with the intention to further enhance ketosis by adding certain types of fiber, soluble fiber that are broken down into short

• 2:25:52Speaker 01

  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. I love artichokes and maybe that's why I get levels of, I'm looking at the macronutrient profile of artichokes now. And I see that, yeah, they're primarily carbohydrate, but mostly fiber. And that fiber is, can be ketogenic. And fiber can also assist in helping us stay in ketosis by being a buffer when you're eaten with protein, because it helps slow the digestion, assimilation, and utilization of protein.

• 2:26:31Speaker 01

  So you get less of a spike in amino acid levels, which can help, 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 ketosis longer by.

• 2:26:53Tim Ferriss?

  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?

• 2:27:05Speaker 01

  Yeah, it's, if you get too many amino acids getting into the liver as a source of fuel for gluconeogenesis, but also protein can stimulate a release of insulin. And insulin is very anti-ketogenic. So it's a combination of attenuating the rise in.

• 2:27:31Speaker 01

  In amino acids, which will attenuate the rise in glucose, which will attenuate the bump in insulin that you could potentially get from that.

• 2:27:41Tim Ferriss?

  Yeah.

• 2:27:42Speaker 01

  So fibers are pretty, fiber is actually really useful.

• 2:27:45Tim Ferriss?

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

• 2:27:52Speaker 01

  Yeah, I think the staple ones that I like are, actually artichoke is on that list. Spinach, kale, broccoli, asparagus is probably at the top of my list.

• 2:28:10Speaker 01

  Celery, a little bit. So any kind of green leafy vegetables, like salad, I have a salad every night and with mixed greens and a lot of olive oil.

• 2:28:23Speaker 01

  And, you know, take your, always eat your, your vegetables with a source of fat. I think it helps promote that you getting the most nutrition out of vegetables. 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 if you just bolus protein, a lot of people say they're on a ketogenic diet just by eating like no carbs, but like a, a chicken breast will quickly kick you out of ketosis.

• 2:29:02Speaker 01

  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 some bulletproof coffee or something like that combined will, will not kick you out of ketosis. You can just stay cruising in ketosis. So this is, I think, needs to be appreciated if you're.

• 2:29:26Tim Ferriss?

  So just to fill in the blanks, the blanks for your sort of typical day then, if your breakfast is 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 typical day?

• 2:29:47Speaker 01

  Okay, I do get a lot of MCT in the day and so.

• 2:29:53Tim Ferriss?

  Those are just tablespoons of MCT oil or the powdered MCT oil?

• 2:29:58Speaker 01

  I have the, I have the powder and the oil sometimes and I cook in coconut oil. And I'll cook with a combination coconut oil and butter. So I'll put a pad of butter with like a spoonful of oil in a pan and cook my eggs in that. And, and I will, the sardines, if I have sardines in the morning, it's packed in extra virgin olive oil, which I, I like a lot of. I was eating a lot of dairy fat and I noticed my LDL went like really high and my LDL particle number went up. And that's kind of like a whole nother conversation, but I was kind of doing an experiment on myself.

• 2:30:38Speaker 01

  So I haven't phased out dairy completely, but I backed off on it a little bit and been using more coconut cream in place of regular cream. So yeah, so in the morning, I kind of described my breakfast already, but at nighttime,

• 2:30:56Speaker 01

  what I like to have would be, I always have a salad.

• 2:31:01Tim Ferriss?

  So you don't, so you're skipping breakfast and having intermittent MCT oil instead? Or I'm sorry, you're skipping lunch and having.

• 2:31:07Speaker 01

  Yeah, yeah. And when I have my breakfast, I will make, I'll have a cup of coffee, but I have a thermos that I bring with me to work. And in that thermos, I cut a stick of butter in half and throw it in it and then I, and then I put a scoop or two scoops of MCT powder. And then I pour the rest of my coffee that I make in French press in that and I just kind of shake it up or zip it up. So it's all mixed up and then I bring that with me to work and that's the coffee that I sip on throughout the day. And it's basically, I make like three cups of coffee. It's not super strong, probably less strong than like Starbucks coffee or something.

• 2:31:48Speaker 01

  But I have like, you know, one cup in the morning and then like two equivalent cups in my thermos. And sometimes I'll brew a, a cup of coffee, you know, at work or I have a product that my friend makes. It's called Utopian. It's a really good product by D-NOVO Nutrition. I'll do that instead of coffee and then I'll.

• 2:32:08Tim Ferriss?

  What is Utopian?

• 2:32:10Speaker 01

  Oh, Utopian. Oh, there's a company. My friend has a company called De Novo Nutrition.

• 2:32:15Tim Ferriss?

  How do you spell that?

• 2:32:16Speaker 01

  Uh, De Novo is spelled D E N O V O.

• 2:32:21Tim Ferriss?

  Oh, that's okay. Got it.

• 2:32:23Speaker 01

  Yeah, like made De Novo, you know. Um, so De Novo Nutrition makes, uh, some really interesting products, uh, and I'm really particular about products that I use. And the one product that they have is called Utopian and, uh, they also sell probably the highest, you know, quality, uh, whey protein too. But Utopian is a product that I use sparingly. I have it packed in my bag now because I'll be traveling in Europe. Uh, and it's, it's basically like a cognitive enhancement agent that also promotes

• 2:33:01Speaker 01

  sort of a well-being and you might call it a, you know, it's a mild nootropic and a mild stimulant. And it's just got some standard things in it like Cooperazine. You might be familiar with that.

• 2:33:14Tim Ferriss?

  Yeah, the acetylcholinesterase inhibitor, right?

• 2:33:16Speaker 01

  Yeah, yeah, like it has that. It's got like five ingredients that are formulated really well that, uh, enhance acetylcholine transmission, enhance dopamine. Uh, there's a, just enough caffeine to give like a stimuli, I think about a hundred milligrams of caffeine. And it's just, it's a good product to, that I keep on hand. Uh, and it's, it's form, a lot of thought went into the formulation of it. So with the ratios of things. So, uh, so I definitely, it's if you're looking for a, a, a lift, a boost, sort of a nootropic, uh, Utopian is definitely something that I keep at the corner of my desk and I use it kind of sparingly, but I'll use it a couple of times a month.

• 2:33:59Tim Ferriss?

  And then, uh, what is, and dinner is a large salad. What is a, a large salad? What does the salad composition look like for you?

• 2:34:07Speaker 01

  Yeah, um, I usually get like mixed greens, uh, like two or three different types of salads. Uh, like usually spinach, a mixed green and two different types of mixed green bag salads. And I mix them together and, uh, I get like a good quality extra virgin olive oil. And uh, and I will, uh, what else did I put in it? Uh, artichokes, actually. Uh, avocado, artichokes, uh, olive oil, and I make, I put MCT oil on as salad dressing too. And so I'll make a salad and maybe a little bit of uh, Parmesan cheese on it or feta.

• 2:34:51Speaker 01

  And we have typically like uh, chicken, you know, which would have the skin on it, beef or fish. And it's usually like the fattiest versions that we can get. And uh, and, and I don't go too over, too overboard on the protein like I used to. Uh, so pretty moderate amount of protein, maybe about fifty grams of protein and then uh, some kind of Fifty, five zero. Yeah, like fifty grams. That would be like my bolus, like probably the, one of the larger protein meals. And if I work out, if I happen to work out, which I did yesterday, I would probably eat a little bit more, maybe about sixty

• 2:35:32Speaker 01

  or, or like seventy or eighty grams of protein. And that'll be kind of like my larger meal of the day. And uh, and then for, I'll have a salad, some kind of fatty protein. And uh, last night I cooked uh, Brussels sprouts and I kind of cut them in half, face down and cooked them in butter and olive oil. No, butter and coconut oil. So they suck it up. And so it's, I think of vegetables as like a fat delivery. So uh, same thing with like collard greens or asparagus, like they're usually cooked in a lot of butter, olive oil, coconut oil.

• 2:36:12Speaker 01

  And I'll have that. So I'll have some kind of fatty protein, some kind of vegetable cooked in fat and um, and salad. Got it. And then I always have dessert. That's kind of unique, actually. It's uh, I call it my I don't know keto mousse or keto ice cream. And uh, what it essentially is, is uh, it could be sour cream or coconut cream. And I take sour cream. So the easiest thing, take sour cream or coconut cream. And take maybe about a cup of it or two cups, cup and a half. And then I put a tablespoon of dark chocolate baking powder in it, some cinnamon, a pinch of salt and stevia.

• 2:36:55Speaker 01

  And stir it up until it's like a, a thick mousse and then I stick it in the freezer. And then I go kind of do my things and you know, shower, get ready for the day or whatever. And then I take it out and um, at the freezer or refrigerator and it, it's basically like ice cream to me and.

• 2:37:12Tim Ferriss?

  So it's sour, one cup sour cream, one tablespoon dark chocolate powder.

• 2:37:18Speaker 01

  Yeah.

• 2:37:19Tim Ferriss?

  A pinch of salt. How much stevia?

• 2:37:23Speaker 01

  Stevia, uh, just sweeten it to whatever you like. I mean, I put, I have the super concentrated stevia. So I just put like, uh, like literally a pinch of it in there.

• 2:37:35Tim Ferriss?

  What brand do you use? Do you know, offense?

• 2:37:37Speaker 01

  Uh, I have to go back and look at the brand, but you can get it on Amazon. If you just go to bulk stevia powder and it comes in like a two pound or one pound container. And it's uh, yeah, it's kind of like the generic. I've tried like every brand of stevia and this is, it's powder. It's, it's pretty good. It travels well and everything too.

• 2:37:56Tim Ferriss?

  Cool.

• 2:37:57Speaker 01

  Uh, yeah, a bit of cinnamon and it's like a fat bomb. So, so people ask like, where do you get all your, your, your fat? You know, there's a lot of, a lot of fat to eat to get in about 300 grams of fat a day um, for the diet. So yeah, so that, that's like a fat bomb. It's about 300 grams of fat, I think. And you know what? If I eat that at nighttime and if I work out or if I haven't gotten like any carbohydrates during the day, I usually put in uh, like a third of a cup or even a half cup of a wild blueberries, which are like higher in fiber, not real sweet, but higher in fiber. And I stir that into it and, and sometimes I'll do like, you know, like it'll be a pretty big bowl. I'll do like two cups of coconut cream or two cups of sour cream.

• 2:38:42Speaker 01

  So I was doing a lot of, I would, I have a, a whipped cream maker that I put heavy cream in. And uh, and I would put whipped cream on top of that and I would. In my whipped cream maker, I would put the heavy cream in and I put stevie in. So I'd sweeten the whipped cream a little bit, you know, shake it up and charge it with a little, little things that they have and make my own whipped cream. And I'd put whipped cream on top of that. Like a hundred gram fat bomb.

• 2:39:09Tim Ferriss?

  Wow.

• 2:39:10Speaker 01

  And, uh, and I was getting in extra fat throughout the day with heavy cream. And I did an experiment because I wanted to determine what, what happens if you have surplus amount of calories in the form of dairy fat. And if I did that for two weeks, so I got like a thousand extra calories per day, 500 to a thousand extra calories per day for two weeks. Then I went in and got like an, an NMR, you know, lipidomic profile of, of everything. Um, and it really shot up some things remarkably, like my LDL P particle. And I'm still analyzing that right now. I'm kind of still doing experiments on myself, but I, I went back and I did, I cut out the

• 2:39:54Speaker 01

  dairy and I replaced it with coconut cream and all those numbers came back down. Um, so I've, I've, but I still get, uh, I still get dairy in form of butter and I just don't go too overboard with it. Uh, cause people ask me that question a lot, like, can I have dairy? And, and I do have dairy every day, but I, I've switched out my, um, my, my nighttime snack, uh, switched out the sour cream to either a mix of sour cream and coconut cream together. And sour cream is really not sour, right? I mean, especially if you ha- I buy the, uh, dark chocolate baking cocoa, the extra dark, and it's a little bit bitter. And if you add it to it, it's sort of neutralizes any remote little sourness that sour cream

• 2:40:39Speaker 01

  has, and it makes a really delicious chocolate mousse.

• 2:40:44Tim Ferriss?

  I'll have to try that.

• 2:40:45Speaker 01

  And it's like purely ketogenic. And oh yeah, I also will take a tablespoon of coconut oil. And especially if it has the frozen blueberries in it and if I drizzle it around and stir it up, the coconut oil will sort of harden and make these little crunchy chocolate things. So it actually tastes like you have chocolate chips in there, if that makes sense.

• 2:41:05Tim Ferriss?

  Yeah.

• 2:41:06Speaker 01

  Coconut oil. Yeah. So, and then so my fiance is totally not ketogenic. I mean, she has an enormous carbohydrate tolerance and she just thinks what I do is really strange. But if I make this, and she's a big fan of regular like Breyer's or Haagen Dazs chocolate. And if I give this to her, she thinks it's incredible. So even someone who's not, not ketogenic and doesn't eat this way and has a sweet tooth, thinks this is really good. So.

• 2:41:34Tim Ferriss?

  Cool. I'll try it out. So I would love to ask some rapid fire questions. I know we're wrapping up. We could talk for many more hours, but if for people who want to dig into ketosis further, give it a shot. What resources should they start with or books should they start with?

• 2:41:55Speaker 01

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

• 2:42:34Tim Ferriss?

  Excellent. Ellen Davis.

• 2:42:36Speaker 01

  Yeah, Ellen Davis, Ketogenic Diet Resource. Definitely one of the go-to places. I have a website, keto nutrition.org. And I've, basically it's like a skeleton website is compiled a lot of useful links that I thought and her website's on there, her book's on there. So that's keto nutrition.org.

• 2:42:59Tim Ferriss?

  Awesome. What, 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.

• 2:43:12Speaker 01

  That's a good question.

• 2:43:15Speaker 01

  Yeah, I would have to, well, going back in the college days, I would say Anthony Robbins, I listened to his stuff when I was my senior year in high school. And I listened to like this 30 day tapes.

• 2:43:30Tim Ferriss?

  Personal Power?

• 2:43:31Speaker 01

  Yeah, Personal Power. 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 I didn't, you know, they went off to college and everything. And years later, like two of them contacted me and 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, going way back, Personal Power, Anthony Robbins book.

• 2:43:54Tim Ferriss?

  Yeah.

• 2:43:54Speaker 01

  Was, was kind of influential from, you know, back in the day. And, and then as I, you know, got into science and became a scientist and my advisor was funded by the NIH. And I was always told that I needed NIH funding to be a career scientist. And 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? So I, I went to try to find some biographies on him. And when I did a search, I found a book, The Language of God.

• 2:44:38Speaker 01

  And I thought, you know, that was really, I didn't, I had no idea of his sort of, his spirituality or his kind of worldview besides, outside of science. I know he spearheaded the Human Genome Project and was pretty instrumental in finding the gene for cystic fibrosis. But, so The Language of God, like it really inspired me because I had no idea that a scientist 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 by C.S. Lewis, Screwtape Letters.

• 2:45:18Tim Ferriss?

  Screwtape Letters is great.

• 2:45:19Speaker 01

  Yeah, yeah, Screwtape Letters is really good. So, and I don't think I've given that. But I gave the the language of God to some of my friends and they really enjoyed it. So that would be one. And then a required reading for my students would be Tom Seyfried's book, Cancer as a Metabolic Disease. So that that's a really, I mean, I think it's sold pretty well on Amazon. And it's highly, highly technical and it's unfortunately, it's like really expensive. So it's about a hundred to a hundred and thirty bucks, I think. Maybe you can get it cheaper. You can get used versions for probably like fifty bucks online.

• 2:45:56Speaker 01

  But if you want a really good kind of description of, I guess, cancer as a metabolic disease, the science, the history, I mean, it's really well written. Tom did, he's a collaborator of mine. He worked a lot on that book and it's, it shows. So that book. And, oh, another book by a guy that I'm actually working on a project with him now. His name is Travis Christopherson. He wrote a book called Tripping Over the Truth. So tripping. Yeah. And he wrote a precursor to the book.

• 2:46:40Speaker 01

  He wrote an article that was appeared on Rob Wolf's blog. And I'm actually, I have an article written with him that's going to appear on the blog on Thursday. It's about the history of the ketogenic diet. And I think Rob's going to put it on the blog on Thursday, I believe. But 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, the story of cancer, really. I mean, it's a, it's a great history of the story of cancer that comes at it from a different perspective

• 2:47:20Speaker 01

  from the Mukherjee book, which is the biography of cancer that is pretty popular, New York Times Bestseller. It's been on. The Emperor of All Maladies is actually the name of the book, The Biography of Cancer. That book is, kind of 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 develop therapies, you know, to target it from a metabolic perspective. So, and I've given that book, probably bought seven or eight copies of that book over the last year and given it away.

• 2:48:05Speaker 01

  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.

• 2:48:15Tim Ferriss?

  Awesome. Let me, let me ask you one, I have, I have one more question. And then maybe we'll do a round two if, if people demand it by popular request. But you mentioned Rob, so Rob and I are friends, Rob Wolf. And we've talked about 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 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.

• 2:48:59Tim Ferriss?

  And I was very puzzled by this and I wasn't sure exactly why that would be the case. And so I, I just hypothesized that perhaps either Lyme disease or the, the subsequent antibiotic treatment caused some type of 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 Rob sent me an interesting research abstract,

• 2:49:43Tim Ferriss?

  which showed how antibiotics such as doxycycline could cause mitochondrial dysfunction. Or degradation because it My understanding is that mitochondria are very similar to bacteria. And the, how would you explain ketosis making me and these other people feel better after Lyme disease? And I don't know if you're familiar with Lyme disease, but is it, is it a, it is, how would you approach thinking about that and investigating that?

• 2:50:20Speaker 01

  Well, I, I'm from New Jersey. So Lyme, Lyme 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 grew up in the woods. Somehow I, I didn't get Lyme disease. Never been tested for it, but never really had any symptoms for it. So Lyme's disease really produces pretty profound inflammation and the spirit heats can cause, you know, everything that you described fatigue and, but I think they can cause, you know, from

• 2:51:00Speaker 01

  a neurological perspective, they can cause encephalopathy and that essentially is resulting from neuroinflammation. And ketones, the ketogenic diet and ketones in particular have pretty profound anti-inflammatory effects and especially in relation to the nervous system. Since ketones are freely permeable to the blood brain barrier and, and kind of bathe our nervous system. 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

• 2:51:44Speaker 01

  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, 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

• 2:52:24Speaker 01

  just help bring your nervous system back to a state of homeostasis, uh, similar to what it's doing for other disorders. But inflammation is really, did, did you happen to get blood work and look at, uh, cause the, the spirit key really, that's how it wreaks havoc in your system. I mean, by activating your immune system, but also just wreaking havoc, you know, as far as causing systemic inflammation in the body.

• 2:52:49Tim Ferriss?

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

• 2:52:53Speaker 01

  Mm hmm. Yeah.

• 2:52:54Tim Ferriss?

  Or cytokines or something. These cytokines. I'm sure I have the blood work. I mean, my, I, 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, had very slow, almost slurred speech, uh, and felt like I had early onset dementia. It was really scary as an experience. What effect does ketosis have on mitochondria, if any?

• 2:53:22Speaker 01

  Yeah. So, uh, ketones are very efficient metabolic fuel and, uh, and in studies that were done in animal models and we're, you know, um, looking at some of 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,

• 2:53:57Speaker 01

  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 site between complex one and complex two and complex three called the semi ubiquinone site, and if you ketones have the ability to oxidize Q, basically, and that can prevent by by ketone metabolism can enhance the energetic flux through the mitochondria to produce ATP, our energy currency. And at the same time that it's

• 2:54:39Speaker 01

  enhancing the bioenergetics of the mitochondria, it's also preventing the formation of superoxide anion, which is a oxygen-free radical or reactive oxygen species. And that's the precursor to more reactive oxygen species like hydroxyl radical and peroxynitrate and things like that. So by kind of fundamentally, you know, turning down the generation of superoxide anion by enhancing mitochondrial efficiency, not only do we make more ATP through ketone

• 2:55:18Speaker 01

  metabolism, but we're also enhancing the flux of of substrate utilization and energy production from that substrate, even even glucose substrate, by by enhancing mitochondrial bioenergetics. And the ketones, we know, can do that through a variety of mechanisms that I can get into. But but basically, yeah, I mean, there you can you can derive more energy per oxygen molecule.

• 2:55:51Tim Ferriss?

  Got it.

• 2:55:52Speaker 01

  With with ketone metabolism.

• 2:55:54Tim Ferriss?

  Is it 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 the ketosis could help repair that damage?

• 2:56:17Speaker 01

  Yeah, yeah, I think so, especially in certain tissues, you know, we know muscle is incredibly plastic, 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, the central nervous system is running more efficiently in a state of ketosis, I believe, especially if you can dampen some of the neuroinflammation that's associated with, with the disease. Right.

• 2:56:59Speaker 01

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

• 2:57:35Speaker 01

  type things, can limit the accumulation of some of these plaques that are associated with, with neuropathology such as Alzheimer's disease, the amyloid and the tau plaques. And, and this can be shown in animal models that are genetically kind of predisposed to accumulating those plaques. And, and I think that would be, you know, you could probably draw some parallels from that work with.

• 2:58:08Speaker 01

  With the neuroinflammation and the neurotoxic effects that Lyme's disease kinda has. And that's what, you know, I'm not, Lyme's disease is not something that I study, but I just come across it a lot because hyperbaric oxygen has been used to sensitize sort of the bacteria to the antibiotics. So a lot of people ask me questions and I have to, and I have to go. I've been staying up on top of the literature, kind of in a peripheral sense, because it's not my kind of core of study. But everything that I read really

• 2:58:46Speaker 01

  focuses on the neuroinflammation that's resulting from the spirochete.

• 2:58:54Tim Ferriss?

  Got it. Well, Dom, this is so much fun. There's so many other things that we could talk about. The hyperbaric oxygen treatment, the brilliant Patrick Arnold we didn't have a chance to get into.

• 2:59:07Speaker 01

  Yeah.

• 2:59:08Tim Ferriss?

  And, I mean, not to mention your own training and the approach that you no doubt bring to that. So I will, I want to let you get going. And if fans enjoy this, then maybe we can do a part two sometime. But what is the best, what is the best way for people to find you online in terms of websites, social media, if they want to say hi to you online? What's the best way to do that?

• 2:59:33Speaker 01

  Okay. I think probably the best way would be the keto nutrition website.org. And I have that. And yeah, Facebook. And I probably use that more than Twitter.

• 2:59:46Tim Ferriss?

  What are you on Facebook?

• 2:59:47Speaker 01

  Uh, my Facebook handle, you mean?

• 2:59:52Tim Ferriss?

  Yeah, your Facebook handle. I could pull that up too. I can put that in the show notes if you don't recall it offhand.

• 2:59:58Speaker 01

  Yeah, I will. Yeah, it should be obvious, right?

• 3:00:04Tim Ferriss?

  I think it's, oh wait, here it is.

• 3:00:06Speaker 01

  Dominic, Dominic dot D'Agostino dot one.

• 3:00:10Tim Ferriss?

  Got it. All right. So I will link to this, guys. So Facebook is facebook.com forward slash Dominic period D A G O S T I N O period one. And I will link to all this as well as your USF page in the show notes for so everyone listening can find links to many of the things that we talked about in this episode and more at fourhourworkweek.com/podcast, all spelled out, or just go to fourhourworkweek.com and click on podcast. But Dom, I really appreciate the time. I always love chatting. And how much do you weigh these days?

• 3:00:52Speaker 01

  Weigh? Man, I haven't weighed myself in a while, but about two, I always stay between two twenty and two thirty, probably about two twenty-two.

• 3:01:01Tim Ferriss?

  Is that ever a challenge? I found when I, like, for every additional millimeter of neck diameter that I have, my, the perceived IQ that people have of me drops by like five points. Do you ever have trouble being taken seriously by, by people who are not sort of a nerd wrapped in a meathead body?

• 3:01:22Speaker 01

  I don't have that problem too much now, just because, you know, I have my diet under control and, but yeah, I think sometimes I face that resistance a little bit. But generally, you know, it was a little bit more apparent when I was a younger scientist, but now that I'm, you know, working my way up and have a, have a lab, I think people are starting to take some of this stuff seriously. I am in a totally oddball area of research, though, as far as, you know, being in a pharmacology department, doing this weird hide fat diet stuff, it raises some eyebrows. So I feel like I kind of have to prove myself still.

• 3:02:01Tim Ferriss?

  Well, I think I would like to collaborate more in the future. We'll talk more about that. But this is enough for, for one big session. So Dom, I really appreciate you taking the time. So thank you.

• 3:02:15Speaker 01

  Thanks for having me, Tim. Appreciate it. It was fun.

• 3:02:17Tim Ferriss?

  This is a good time. And to everyone listening, as always, thank you for listening. And until next time, experiment, be well, check out the ketogenic diet.

• 3:02:33Tim Ferriss?

  Hey guys, this is Tim again. Just a few more things before you take off. Number one, this is Five Bullet Friday. Do you want to get a short email from me? Would you enjoy getting a short email from me every Friday that provides a little morsel of fun before the weekend? And Five Bullet Friday is a very short email where I share the coolest things I've found or that I've been pondering over the week. That could include favorite new albums that I've discovered, it could include gizmos and gadgets and all sorts of weird shit that I've somehow dug up in the world of the esoteric as I do. It could include favorite articles that I've read and that I've shared with my close friends, for instance. And it's very short.

• 3:03:16Tim Ferriss?

  It's just a little tiny bite of goodness before you head off for the weekend. So if you want to receive that, check it out. Just go to fourhourworkweek.com. That's fourhourworkweek.com all spelled out and just drop in your email and you will get the very next one. And if you sign up, I hope you enjoy it. This episode is brought to you by 99 Designs, your one-stop shop for all things graphic design related. I have used 99 Designs for everything from banner ads to book covers, including sketches and mockups that led to The Four 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.

• 3:04:00Tim Ferriss?

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• 3:04:37Tim Ferriss?

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• 3:05:21Tim Ferriss?

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