By playing, you agree to uListen's Terms and Privacy Policy and YouTube's Terms of Service.
Peter Attia MD#05 - Dom D’Agostino, Ph.D.: ketosis, n=1, exogenous ketones, HBOT, seizures, and cancer
Summaries, chapters, transcripts, and FAQs on this page are made by uListen, not YouTube.
EVERY SPOKEN WORD
150 min read · 30,019 words- 0:00 – 0:04
Intro
- PAPeter Attia
[upbeat music]
- 0:04 – 7:24
Episode Overview and Guest Introduction
- PAPeter Attia
Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. [upbeat music] The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other s- obsessions I've gathered along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] On this episode, I interview my good friend Dominic D'Agostino. Dom, as he is known by, is a professor at the University of South Florida. His PhD is in neuroscience, and that's where he got his background, but Dom is probably most recognizable to people listening to this because he is certainly one of the experts on ketosis, and that's in all variants of it, so starvation ketosis, nutritional ketosis, and in particular, the use of exogenous ketones. Gosh, Dom and I go way back. We met probably a little over five years ago and instantly formed a friendship around our obsessive N of one experiments. Although I will say he is closer to winning a Darwin Award on the basis of his N of ones than I am. Couple notes about this podcast. First, this is highly technical at times, and in fact, we'll timestamp it in the show notes, but I would say roughly the first hour is even a little more technical than I had intended to go. I think part of the issue is just once I get talking with Dom about this stuff, I couldn't stop asking him questions, and I think there were times when I guess we forgot we were recording a podcast, and it was just us getting really technical. I don't think it's too technical to follow if you have some background in understanding of biochemistry, but we'll do our best in these show notes to make sure that we're giving even the recreational user the necessary tools to follow this. Now, that said, if you get 20 minutes into this thing and you're like, "I don't understand what the hell these guys are talking about," do not hesitate to skip ahead. There's a lot of stuff that gets later on into the podcast, and, and this is a long podcast. It's nearly three hours. There's a lot of stuff we get into at the end that I think will be kind of the stuff people really want to know, even if they don't want to get in the gory details. So in particular, we talk very specifically about all of the ketones, and I'm getting a lot of questions about, "Peter, what's the difference between a ketone ester, a ketone salt? What are the monoesters? What are the diesters? Where does MCT fit into this? What about the caprylic acid? And, you know, how many... Should we be using this one versus this one, and what are the advantages of this and advantages?" This is going to be your dissertation level course in that subject matter. The other thing that we get into at the very end, and we almost end on this, but again, look to the timestamps for exactly where it is, is we get into what I consider one of the most interesting discussions I've ever had on what I sort of loosely describe as a metabolic oncologist playbook. So when I asked Dom about this, he had just some of the most interesting insights, and I was really impressed by the breadth and the organization of his thinking around this. Now, I want to point out something here, and I say it in the show, but it's really important for me to caveat this here. This cannot be construed as medical advice. Dom is not a medical doctor. He doesn't pretend to be one on TV. He is a research scientist who focuses on basic and translational research. He collaborates with lots of physicians. He is involved in a number of clinical trials. But ultimately, Dom is not offering medical advice, and frankly, nor is anybody or nor should anybody be on a podcast. So this information I asked because I get asked this stuff a lot, and frankly, I don't know enough about this sort of outreaching and outlying metabolic therapies out there. But I hope that if people are listening to this and they're afflicted by cancer, which statistically speaking is obviously going to happen given that one in six people are going to get cancer in their lifetime, I hope that if some of this stuff does scratch someone's sort of desire to understand more, that they can use some of the resources we're going to link to to potentially identify the right places where either a clinical trial will be taking place, or they could at least pursue some of these things under the appropriate medical guidance. I could go on and on about other knits and gnats in here, but honestly, I think the best thing to do right now is probably pay a little bit of attention, maybe more than usual, to the show notes. Treat this as a little bit like a buffet. Go to the places you want to go to. Of course, I would recommend the entire thing if you really have an interest in this subject matter. And I hope that this podcast is going to answer many of the questions that I see people asking out there. I, I actually learned quite a bit on this, and I tend to know the subject matter reasonably well. So without any further delay, welcome to the podcast with Dominic D'Agostino. [upbeat music] Hey, Dom.
- DDDom D’Agostino
Hey, Pete.
- PAPeter Attia
How are you, man?
- DDDom D’Agostino
[chuckles] I'm doing well. How are you?
- PAPeter Attia
I'm, I'm doing really well, and I'm really grateful for you making the trip all the way up here. I know that in part you're visiting family, but it's great that you've carved out time to come from, uh, New Jersey all the way up to the, uh, lovely city of Manhattan.
- DDDom D’Agostino
I appreciate the invite and love being here. Yeah.
- PAPeter Attia
[chuckles]
- DDDom D’Agostino
Love to visit.
- PAPeter Attia
Well, there's going to be a number of people listening to this today who are already incredibly familiar with who you are, the work you've done. I certainly consider you probably one of the two most authoritative persons on the subject we're going to get into today. But for anybody who's listening to this who is not entirely familiar with you, I suspect by the end of today they're going to want to get a lot more familiar with you. So I actually remember the day we met, and it's kind of funny.
- DDDom D’Agostino
Mm-hmm.
- PAPeter Attia
I was in Florida giving that talk at IHMC.
- DDDom D’Agostino
Yep.
- PAPeter Attia
And I knew of you by name, but I didn't know who you were or what you looked like, so I wouldn't-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... have recognized you. And I gave a talk. This would've been 2011 maybe.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
Maybe 2012.
- DDDom D’Agostino
Yeah. Yeah.
- PAPeter Attia
And at the end of the talk, there was like a Q&A, and you know-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... it was a long Q&A, and it just went on and on and on. And then you asked a question. Now, I wish I could say I remember the question, but I knew from the question that- That guy knows what he's talking about. And then-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... of course, Ken Ford, who knew us both-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... had basically arranged for us to all have dinner that night.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
And so that-
- DDDom D’Agostino
Yeah. Mm-hmm
- PAPeter Attia
... was the night we met.
- DDDom D’Agostino
Yeah.
- 7:24 – 16:36
Hyperbaric Microscopy and Cancer Cells Under Oxygen Stress
- PAPeter Attia
So you did your PhD in neuroscience, correct?
- DDDom D’Agostino
Yeah, yeah.
- PAPeter Attia
So what were you-
- DDDom D’Agostino
In physiology too.
- PAPeter Attia
In physiology. So you're finishing your PhD, and you're what, planning to do a postdoc?
- DDDom D’Agostino
Yep. I did it in the neural control of autonomic regulation, so the brain stem mechanisms sort of sense O2, oxygen, and CO2 and modulate respiratory rhythm generation and also cardiovascular sympathetic tone to the heart, like those neurons and how they sense oxygen. During my PhD, I got interested in diving physiology, and it was amazing to me that we don't really understand how our brains and our physiology functions in extreme environments as it pertains to elevated hyperbaric pressure, elevated oxygen, CO2, anesthetic gases, for example. We know the anesthetic potency of a gas is proportional to its lipid solubility.
- PAPeter Attia
Mm-hmm.
- DDDom D’Agostino
But w- we don't really know what that means, like why... What's happening at the level of the membrane or the mitochondria? So my postdoctoral fellowship was actually developing technologies to study that, and that would be hyperbaric atomic force microscopy, and that was like, that's what I just delved into for three or four years.
- PAPeter Attia
So how does that work? So I know what hyperbaric means.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
I know what microscopy means. Tell me about the part about the force.
- DDDom D’Agostino
Yeah. [laughs] The first term for atomic force microscopy was, uh, scanning probe microscopy.
- PAPeter Attia
Okay.
- DDDom D’Agostino
And instead of using light or electrons, it uses a, a very sharp-tipped probe that's can be so sharp it, it's monoatomic, and it, it essentially raster scans across the sample and can detect very subtle changes in the topography of the sample that you're scanning, right? So it actually spawned the whole nanotechnology world. So this particular instrument was used to characterize materials and really helped develop Silicon Valley i- in many ways. And it's a microscope that we took basically an off-the-shelf atomic force microscope that gives you the scanning resolution of an electron microscope but also has the capacity to image living cells and took this technology and put it inside an environmental chamber, a hyperbaric chamber. And part of my project was doing the electrical, the fluid, and the gas penetrations to make the thing functional and also doing a series of studies and calibration tests to determine that we could reliably make hyperbaric atomic force microscopy measurements inside this chamber. And with this technology, it gives us insight at the nanoscopic level of what's happening to the mitochondria, to the cell membrane. So I got a grant through the Department of Defense, which they give these equipment grants to develop this technology, and also a grant to use it, and then later another grant to put a confocal microscope. You might have heard of a laser scanning confocal.
- PAPeter Attia
I, I, I actually used a confocal microscope in my undergrad thesis to, to do-
- DDDom D’Agostino
Oh, did you? Okay
- PAPeter Attia
... optional, optical sectioning of, uh-
- DDDom D’Agostino
Tubes?
- PAPeter Attia
Uh, no, 'cause I was an engineer, so we were-
- DDDom D’Agostino
Oh
- PAPeter Attia
... I was interested in a question of did the direction of extrusion that you put on a tibial plateau... So when you do joint replacements-
- DDDom D’Agostino
Uh-huh. Yeah
- PAPeter Attia
... does the direction in which you extrude what's called ultrahigh molecular weight polyethylene, does that predict its fracture?
- DDDom D’Agostino
Uh-huh.
- PAPeter Attia
And it turned out it did.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
But the tool to help us measure that was this confocal microscope. So that was my introduction to high-end microscopy.
- DDDom D’Agostino
It's an amazing tool. Yeah. So the second grant I-
- PAPeter Attia
E- everyone should have one, really
- DDDom D’Agostino
... Yeah. You got to. It... They're the toys that we have in the lab. So that was the next phase of sort of my experiments, was installing a laser scanning confocal so we could optically section individual cells and look at the mitochondria-
- 16:36 – 20:18
Oxygen Toxicity Seizures and Hyperbaric Oxygen Therapy
- PAPeter Attia
So I want to come back to that, because that now makes sense for why diving could increase-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... that risk, because if you're using an oxygen rebreather, you're getting a higher concentration of oxygen, and then you're under multiple atmospheres of pressure.
- DDDom D’Agostino
Exactly.
- PAPeter Attia
You've now basically-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... replicated in an, in a person-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... what you were seeing in a cell. But going back to the cell thing for a sec, do the free radicals that get generated destroy other cells beyond the cell that is generating the free radical? Or is the problem largely contained to the cell?
- DDDom D’Agostino
It's a dose-dependent phenomenon, right? And we were studying cells in this particular experiment in a Petri dish or on a coverslip. So you have a sort of like an intact neural network or cellular network, so the cells are literally connected to one another, unlike a, a tissue slice where you have an intact cytoarchitecture, which that's a little bit different. But the oxygen free radicals and the substances that the cells produce do actually influence other cells adjacent to it or juxtaposed to it. That's obvious from some of the experiments we do in cell signaling. You know, if one cell becomes permeable and we could detect cell death with various molecules like ethinium homodimer 1, when that cell dies, it can stimulate excitotoxic events in the surrounding cells. Same thing happens with the cancer cells. It's obvious that cancer cells use reactive oxygen species for growth and proliferation, and I know this is something that may be contradicting to many people. We view free radicals as something that's damaging that the cell needs to get rid of, but they're very powerful signaling molecules, especially for cancer cells and growth and proliferation and in normal tissues.
- PAPeter Attia
And do you mean nuclear signaling?
- DDDom D’Agostino
In nuclear signaling and activation of transcription factors, basically there are many... I study, as neuroscientist, I study redox-sensitive ion channels. So the redox state of an ion channel can dictate the permeability and the gating functions of that ion channel, which is intimately linked to cellular excitability by influencing the resting membrane potential. So as a neuroscientist, you know, you can study a very particular... And cells have hundreds of thousands of ion channels, specific ion channels that are redox regulated. But what was obvious is that cancer cells have elevated rates of reactive oxygen species that they use for growth and proliferation. It also fuels metastasis and invasiveness of cancer cells. And because they overproduce oxygen free radicals in the context of high oxygen, you can push the cells above their antioxidant potential and then trigger apoptosis. So it's like a double-edged sword.
- PAPeter Attia
So it's a, it's basically a U-shaped curve, or inverted, depending on how you want to think about it, where-
- DDDom D’Agostino
Exactly
- PAPeter Attia
... the cancer cell is not only optimized to survive, it's optimized to thrive at a certain-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... level of-
- DDDom D’Agostino
Elevated reactive oxygen species.
- PAPeter Attia
Yeah, an elevated level.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
But if you go too far, it becomes counter.
- DDDom D’Agostino
Yeah. So they have elevated endogenous antioxidant capacity, right? But because- Their mitochondria are defective in many ways, and there's... That term is kind of controversial. Some people think the Warburg effect definitely endows the cells many benefits, but the aberrant activity of the mitochondria is creating this excess free radicals, and hyperbaric oxygen and chemotherapeutic drugs that augment oxidative stress are therapeutic modalities that can be used. It was very apparent to me seeing that in a hyperbaric chamber, looking at a microscope, looking at these cells, and, uh, no one had seen it before because no one had hyperbaric oxygen therapy.
- PAPeter Attia
Nobody had the tool.
- DDDom D’Agostino
Yeah.
- 20:18 – 48:09
From Ketones in the Dish to Cancer Metabolism and the Warburg Effect
- DDDom D’Agostino
And that kind of stim- at the same time, I was growing these cells under different conditions. I was very interested in lactate, and I became interested in, in ketones too, just not for this reason. I was not yet interested in the ketogenic diet. I was, I was looking at it for a different reason, actually. But I noticed that the cancer cells were not growing as rapidly as they should in the context of one, two, and five millimolar of beta-hydroxybutyrate, which I was growing them in. And I thought the lab tech may have been doing something that was influencing, but she assured me it wasn't, so we would pull the media off and put regular media on without the ketones, and the, the cancer cells would start growing rapid again.
- PAPeter Attia
Why were you using ketones in the media?
- DDDom D’Agostino
Well, I was looking at a variety of different substrates back in 2008 and '09, uh-
- PAPeter Attia
I see. So you were just saying-
- DDDom D’Agostino
Glucose. Yeah
- PAPeter Attia
... lactate, glucose, BHB.
- DDDom D’Agostino
Yeah. 2-deoxyglucose. Yeah, lactate. I was using a variety of different... And ketones were like, "Well, let's just see what ketones do." You know, that ketones were something that the body would produce in fasting. But I didn't, I didn't even know the anti-seizure properties of the ketogenic diet. I just thought of it as like, what do brains... And a couple odd papers that came out, like ketones could be used as fuel. I was very interested in alpha L-polylactate, various forms of lactate that could be used to preserve brain energy metabolism in the face of oxidative stress, and the ketones just, they sort of shined. So basically, what they were able to do was allow the neurons to preserve their membrane potential and normal cellular function, even in the context of extreme oxidative stress. And it made sense, right? Because the ketogenic diet... You know, I started looking more into this and discovered that the ketogenic diet was a very effective anti-seizure strategy, even when drugs fail. About two-thirds of patients-
- PAPeter Attia
Right
- DDDom D’Agostino
... respond favorably. You get, you know, 10 or 15% are super responders that never have seizures again. You can get them off your, your meds. And it was probably working through a mechanism independent of any anti-seizure compound because the ketogenic diet worked when drugs failed, you know, suggesting it was working through a different mechanism or many mechanisms kind of in, in synchrony. So the tools that we developed really sort of started to allow us to understand from a cellular and molecular mechanism how ketones were working, and I was looking at other compounds at the time, but it's just as I kept studying, I was looking at sigma receptor agonists. I was looking at other antioxidants, many different antioxidants and combinations of antioxidants that were catalase mimetics, uh, superoxide dismutase mimetics. You know, all these things that were, in theory, they should work really well, but nothing was really working as well as ketones. And it also motivated me because when I discovered the ketogenic diet was a grossly underutilized anti-seizure strategy, I was like, "Wow, I could go back to my nutrition roots." 'Cause when I was an undergrad, I majored in nutrition science, but I didn't pursue a PhD in nutrition because nutrition was not like a real science. Like, there was no jobs in nutrition. [chuckles] And, and the '90s was the decade of the brain, so it was like, "Let me try to get into a cellular neuroscience program." So I kind of just left nutrition, and this was my opportunity to bring nutrition back into my research projects into the lab. But my-
- PAPeter Attia
Going back to that BHB in the media-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... did you have the same amount of glucose in as you had in the BHB-free media?
- DDDom D’Agostino
Yeah. So we did everything in the context of the same amount of glucose, usually about five millimolar.
- PAPeter Attia
In other words, the benefit was from the addition of BHB-
- DDDom D’Agostino
Yep
- PAPeter Attia
... not the reduction of glucose.
- DDDom D’Agostino
Absolutely. Yep. And as I started to get into the literature and read into this a little bit more, we started doing glucose subtraction a- and adding ketones and saw that normal, healthy neurons functioned and thrived in a low-glucose environment if the ketones were present, but the cancer cells would die, and this was also replicated and published in various neuroblastoma cell lines. And I think Skinner was one, a person that published, and I found that he was at University of Florida, but he was a do- he was a fellow and just had left the, the school at the time. And then I went up there and gave a talk, I think, in 2010, and that further... That got me more and more interested in studying cancer, even though I was not funded to do so. It was like this pet project that was completely very intellectually stimulating to me and something that I could not just shelf and come back to at a later time. I had to... I felt like the environment was kind of hot for this, so I just kept reaching out to different scientists and showing them my data and asking them to explain it, like top-level cancer biologists, and then I stumbled across Tom Seyfried, actually.
- PAPeter Attia
Speculating, why do you think Tom was one of the few people that latched onto this? Was it simply because he'd already been thinking the same things? Or... Because it's really, it is interesting when you think about how many really interesting and impressive people in cancer have not sort of come around to thinking about this stuff. Now, in 2009, uh, I think it was 2009, y- and I'm sure you know, have read this paper a thousand times. It's sort of... I think it was the first obvious mainstream view of this, was the Matt Vander Heiden, Lou Cantley-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... Craig Thompson science paper.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
Was that '09? That sound about right?
- DDDom D’Agostino
Yeah, which reminded me of they had a couple papers around that time. Which one was it?
- PAPeter Attia
Well, this is the one that offered an explanation for the Warburg effect.
- DDDom D’Agostino
Yeah, yeah, yeah.
- PAPeter Attia
It was basically an energy-
- DDDom D’Agostino
More of a biosynthetic-
- PAPeter Attia
That's right
- DDDom D’Agostino
... directing it-
- PAPeter Attia
It was-
- 48:09 – 1:02:20
George Cahill's Starvation Experiments and Brain Fuel
- PAPeter Attia
Let's get into ketosis a little bit. I want to come back and talk about cancer. I want to come back and talk about the exogenous ketones, both the salts, the esters, and, and even different molecules. But one of the most interesting experiments we've seen in the physiology of ketones, like, you know, as far as old school experiments, was the George Cahill starvation experiments-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... right? So-
- DDDom D’Agostino
I was highly motivated by that study.
- PAPeter Attia
We're gonna link to it here, but let's-
- DDDom D’Agostino
Yeah. Okay
- PAPeter Attia
... uh, why don't you give people the Reader's Digest version of what George Cahill did that could probably never be done again?
- DDDom D’Agostino
Yeah, yeah. And I was, I was very lucky to connect with him, uh-
- PAPeter Attia
Before he died
- DDDom D’Agostino
... he passed away in 2012, but I connect with him a few years before that.
- PAPeter Attia
Mm-hmm.
- DDDom D’Agostino
And just to, to figure out, you know, did he really do this, these studies?
- PAPeter Attia
[laughs]
- DDDom D’Agostino
And there was a lot of studies that also didn't get published that were pretty remarkable too, uh, that somehow they got past ethics review at Harvard Medical School. But essentially what he did, a very elegant study to look at brain energy metabolism, the AV difference in, in blood and metabolites in subjects that fasted for 40 days. And most of the subjects were, uh, divinity students, I believe, or maybe conscientious objectors to the war or something like that. But each person had, like, a different story behind it.
- PAPeter Attia
Mm-hmm.
- DDDom D’Agostino
And he fasted these subjects for 40 days and determined-
- PAPeter Attia
And just to be clear-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... this is water and mineral only.
- DDDom D’Agostino
Water, no calories.
- PAPeter Attia
Yeah, yeah.
- DDDom D’Agostino
So no calorie hydration.
- PAPeter Attia
But they took minerals, right? They had magnesium-
- DDDom D’Agostino
Uh, yeah
- PAPeter Attia
... and sodium.
- DDDom D’Agostino
They did. Uh, yep, I think they took a mineral supplement. And they also were... They weren't lean subjects, so they were subjects who, from their perspective, were overweight, if not obese subjects, so they had some weight to lose. And it was very well documented and well controlled study where they monitored free fatty acids, insulin, glucose, beta-hydroxybutyrate, acetoacetate, and acetone, and lactate.
- PAPeter Attia
And let's... I'll just pause you there for a moment-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... for the listener. We'll come back to this 'cause I want you to explain the difference-
- DDDom D’Agostino
Yeah
- 1:02:20 – 1:16:50
How the Body Makes Ketones: Biochemistry and MCTs
- PAPeter Attia
So let's tell everybody how we make ketones, and then we'll tell them what an MCT is for those that don't know.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
So let's talk about starvation ketosis.
- DDDom D’Agostino
Yep.
- PAPeter Attia
And then if there's differences between that that are worth highlighting with nutritional, that would be great. But evolutionarily, I'm going to deprive you from eating for a few days. How do you survive?
- DDDom D’Agostino
[chuckles] Well, you start burning up your liver glycogen for the most part.
- PAPeter Attia
Okay, so 24 hours later, you've got that down to about half of its-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... half to le- about a quarter of its supply.
- DDDom D’Agostino
Mm-hmm. Through the suppression of the hormone insulin, we start mobilizing fat from adipose tissue, which our cells, pretty much all cells in the body, especially muscle and heart cells, burn fat like a superior energy source. Long-chain fatty acids don't effectively cross the blood-brain barrier, so through accelerated fat oxidation, beta oxidation of fats in the liver, that stimulates the accumulation of acetyl-CoA, which forms acetoacetate and ultimately beta-hydroxybutyrate. So you start spilling these ketone bodies through accelerated fat oxidation in the liver. The liver lacks succinyl-CoA transferase, so it does not actually use the ketone bodies for fuel, and they become available for your brain, your central nervous system, and peripheral tissues.
- PAPeter Attia
So the liver is secreting beta-hydroxybutyrate
- DDDom D’Agostino
Yeah
- PAPeter Attia
And, uh-
- DDDom D’Agostino
And acetoacetate to some extent.
- PAPeter Attia
Okay. So is the BHB being made and then being converted into acetoacetate, or is the liver making both?
- DDDom D’Agostino
Acetoacetate first and then beta-hydroxybutyrate. And it's interesting that some people have a ratio of beta-hydroxybutyrate to acetoacetate of 2:1 and some people 5:1. Generally speaking, about 4:1. So acetoacetate is unstable in that it can spontaneously decarboxylate to acetone, which is volatile and we blow it off in our breath.
- PAPeter Attia
Does it have metabolic activity? Can we...
- DDDom D’Agostino
It, it was thought that it didn't, but more recent work is suggesting that it, the carbons of acetone do find their way into sort of lipid biosynthesis-
- PAPeter Attia
Hmm
- DDDom D’Agostino
... and some other things. But it's kind of rare for that to happen.
- PAPeter Attia
But it's not a great ATP source.
- DDDom D’Agostino
Not, no. Not, not really. It has some effect on neurons. So it has an anticonvulsant effect through, I believe, opening a potassium channel which could hyperpolarize the membrane potential and actually help attenuate some, uh, hyperexcitability in the brain. So there are people that study, you know, the effects of acetone as a subnarcotic levels of acetone, right? Acetone can be pretty narcotic and be problematic. But acetone levels that are 0.5 millimolar and even upwards of one millimolar can have a neuroprotective effect. Once you get above one millimolar, you start to dissolve some of the membranes and you can have sort of, uh-
- PAPeter Attia
That doesn't sound very good.
- DDDom D’Agostino
Yeah, you can have problematic... You know, acetone is a, is a pretty powerful solvent, right?
- PAPeter Attia
Yeah.
- DDDom D’Agostino
It's a nail polish remover. But small levels of acetone are neuroprotective, and that's actually something that we study.
- PAPeter Attia
So how do acetoacetate and beta-hydroxybutyrate enter the Krebs cycle? In other words, where do we get ATP from them?
- DDDom D’Agostino
It depends on the, the cells. So different cells have different, and we're looking at this now, different ketolytic enzymes, right? So they can feed in through a number of different pathways. Like I said, the liver is the production site of beta-hydroxybutyrate. And when it comes to skeletal muscle, they have a range of ketolytic enzymes that can allow them to enter the Krebs cycle at different, different areas. So succinate, for example. So you can replenish TCA cycle intermediates with succinate. You can-- Acetoacetate can break down and provide acetyl-CoA-
- PAPeter Attia
Mm-hmm
- DDDom D’Agostino
... for the Krebs cycle. So what we're finding is that the Krebs cycle is not the simple cycle that we thought it was, especially as it relates to cancer cells. So it's almost like we can't even look at the biochemistry book and kind of pinpoint different pathways. With substrate-level phosphorylation, there are a number of different pathways like the malate aspartate shuttle that are associated with cancer cells if we go back to, to those pathways.
- 1:16:50 – 1:25:42
Ketones, Seizures, Insulin and Glucose Lowering
- PAPeter Attia
Do you know Elizabeth Thiele at-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... Boston Children's?
- DDDom D’Agostino
Yep.
- PAPeter Attia
So I, I remember having breakfast with her about six years ago and asking her a question that at the time I don't think she knew the answer to, and she was gracious enough to explain that, and she was there with someone else in her lab, so it was a very spirited, awesome discussion. But I wonder if the answer is known today. The question was basically, do you believe that the anti-seizure properties of a ketogenic diet are more the result of the brain having another fuel to displace glucose, or due to the reduction in glucose that invariably accompanies ketogenesis? And at the time, she shared with me very compelling data that would... could argue either of those points-
- DDDom D’Agostino
[laughs]
- PAPeter Attia
... potentially suggesting it was the combination of them. Do you have a point of view on this, or is there more information today that steers you one way or the other?
- DDDom D’Agostino
Well, I know she's done some work with the low glycemic index diet, and that has been-
- PAPeter Attia
So, so carbohydrate reduction, but without the production of ketones.
- DDDom D’Agostino
Yeah. So a reduction... It's carbohydrate restriction, but only to the effect of maybe 20 or 25%, you know.
- PAPeter Attia
Yep.
- DDDom D’Agostino
Low. And then carbohydrates that are low glycemic index.
- PAPeter Attia
And, and what are the results of that intervention?
- DDDom D’Agostino
For different types of seizures, it can have a positive effect, and for certain, certain types of seizures. That's not the first line of therapy for, you know, very powerful tonic-clonic seizures in pediatrics.
- PAPeter Attia
Mm.
- DDDom D’Agostino
You wanna go right to the classical ketogenic diet. But it does have a number of applications for different types of seizure disorders.
- PAPeter Attia
And what about if you take someone on a fully carbed diet who's having recalcitrant seizures-
- DDDom D’Agostino
Mm
- PAPeter Attia
... and you give them ketone, exogenous ketone? Does that have anti-seizure benefit?
- DDDom D’Agostino
Yeah. So those studies have not been done yet, and there's a study being, recruiting right now for something called Angelman syndrome, which is a rare genetic disorder that has seizures where the exogenous ketones are the therapy independent of the diet, so they're just being added on top of the diet. There are people out there, because exogenous ketones are commercially available, that are using this in place of the ketogenic diet because the families are either unwilling or for various reasons unable to use the ketogenic diet, and they, you know, use... are using exogenous ketones. And the feedback that I'm getting could be biased, but it does seem to have an effect. It obviously has an effect in animal models.
- PAPeter Attia
Mm.
- DDDom D’Agostino
The animal models that we work with, we give exogenous ketones on top of a standard rat chow, which is high-carbohydrate chow, and it, uh, it works very well for, uh, CNS oxygen toxicity, but also for things like fentanyl and tetrazole, uh, seizures, uh, PZT seizures. Even for absence seizures, we use a particular animal model with absence seizures-
- PAPeter Attia
Hmm
- DDDom D’Agostino
... or absent seizures-
- PAPeter Attia
Yeah
- DDDom D’Agostino
... which are, it works for that. So it works for a variety of different seizure models independent. We are circumventing sort of the dietary restriction that's typically associated with getting into therapeutic ketosis and just simply giving exogenous ketones and elevating exogenous ketones. But a consideration is that exogenous ketones lower blood glucose, so you have... And in some cases, it lowers it really low. Like, the high-dose ketone esters that we do in our rat models, it pushes... In rats typically maintain a glucose of around 140 to 150, and it'll push it down to 40, so milligrams per deciliter.
- PAPeter Attia
Yeah.
- DDDom D’Agostino
Yeah. And that's approaching the maximum tolerable dose of the ketone ester. And it's interesting when we go above the maximum tolerable dose, we actually see glucose levels spike up, and this is a phenomenon that we see. It's almost like it's stressing out the liver or dysregulating the liver in some way. It's data we're trying to figure out. But if you titrate in ketone salts or ketone salt MCT combination or various ketone esters, it's inversely proportional to as you elevate ketones, you have a very predictable, reliable decrease in blood glucose that's above and beyond the decrease in blood glucose that you'd observe with something like metformin. And we use metformin, uh, for many, many studies i- in the lab. I mean, we've, we have a lot of experience with that.
- PAPeter Attia
So what do we think... You know, it's funny, I was up in San Francisco like a month ago, and I was talking with Steve Phinney, who, you know, at the outset I said, "You're one of the people who I would say knows more about ketosis than anyone alive." And, and certainly Steve would have to be in that category, so I would... if I were gonna just guess, I would say that-
- DDDom D’Agostino
For sure, yeah
- 1:25:42 – 1:38:06
Measuring Ketones and NASA NEEMO Self-Experiments
- PAPeter Attia
So just for listeners and stuff, how do we measure ketones? I mean, people talk about urine strips-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... versus blood. What are you measuring in each, and breath for that matter? You've got three ways-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... to theoretically measure these things. Which one do we prefer and why?
- DDDom D’Agostino
For a newbie getting into this, I think the urine ketone strips will at least tell you if you're in ketosis or not in ketosis.
- PAPeter Attia
What is it measuring? A urine strip-
- DDDom D’Agostino
It's measuring-
- PAPeter Attia
... you're peeing on it, and what does it tell you?
- DDDom D’Agostino
... urine acetoacetate is measured. And now there's a urine beta-hydroxybutyrate kits that are available, so you could do that. So the Abbott Labs Precision Xtra and the Keto-Mojo are two devices that will measure basically an assay, a home assay kit for beta-hydroxybutyrate. And we have used both of those things and, and kind of measured it against various assays in the lab and, and, uh, blood that we send out for analysis, and it's pretty close. Pretty close, plus or minus maybe 10 or 15%.
- PAPeter Attia
What does the urinary level, even though it's a qualitative assay, but you know-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... everybody says, "Hey, my urinary ketone thing lit up bright purple."
- DDDom D’Agostino
Mm-hmm.
- PAPeter Attia
Can we infer anything from that about the blood level of BHB or acetoacetate?
- DDDom D’Agostino
Usually, you know, unless you're running kind of dehydrated, [chuckles] you know, if you have a normal hydration state and your urine acetoacetate is 40 milligrams per deciliter or above, you are probably hitting 1 millimolar or above. If you're anywhere between 40 and 80 to I think 160 milligrams per deciliter, so you're in a state of ketosis. I would... If you're at 15, that's like light pink or something, you're usually probably not in a state what I would say keto... That might be a normal state if you wake up in the morning, in sort of a fasted state, you might be hitting that. But generally speaking, you need to be at about 80 milligrams per deciliter on the urine ketone strip.
- PAPeter Attia
And the one thing I didn't do, rather, when I was doing my sort of long foray into ketosis is I didn't use the urine meters at all. I was just, you know, I was-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... I was keeping Abbott in business basically by how many of those Precision Xtra strips I was going through. So I don't know if My urinary excretion actually declined over time when my body became better and better at retaining this potentially preferred fuel.
- DDDom D’Agostino
Mm-hmm. Mm-hmm.
- PAPeter Attia
Have you done anything on that, either personally or in the lab?
- DDDom D’Agostino
So what we use in the lab is the Clinitek Status device, and that device takes the Siemens 10 SG kit, so the Multistix. So you can buy for a s- similar cost as the KetoStix, you could buy the Siemens 10 SG Multistix, and that measures 10 things, including urine acetoacetate, and you could take that urine strip and stick that in a device that will give you more of a quantified number.
- PAPeter Attia
I see. So that's how you were giving me quantitative information on the urine-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... 'cause I've only seen the-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... qualitative stuff.
- DDDom D’Agostino
Well, [chuckles] it's a color change on the strip that's measured-
- PAPeter Attia
Right
- DDDom D’Agostino
... in the device.
- 1:38:06 – 1:59:53
Ketone Salts vs. Esters and the D/L Enantiomer Question
- PAPeter Attia
So let's talk about ketone esters, salts, et cetera.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
So to your knowledge, what's the first exogenous ketone that was ever manufactured? Is that the Vitaly one or?
- DDDom D’Agostino
Exogenous ketone manufactured. So 1,3-butanediol has been around a long time, since the 1950s. Actually, MIT did some, uh, research as a space fuel, so that got... There was a publication in 1975 where they were trying to identify an alternative energy fuel for long duration space flight, and the best candidate was 1,3-butanediol, which is sort of a synthetic compound that breaks down completely to beta-hydroxybutyrate.
- PAPeter Attia
Meaning the liver is not required to transform it into BHB?
- DDDom D’Agostino
The liver is required.
- PAPeter Attia
Oh.
- DDDom D’Agostino
Yeah, through a couple simple steps. So sodium beta-hydroxybutyrate would be the first sort of ketone, exogenous ketone that was used clinically, and that, there was a number of papers that utilized that for rare metabolic disorders actually. So that would be the first one, and a lot of the IP and, you know, sort of, uh, patents that came out were sodium beta-hydroxybutyrate. And then-
- PAPeter Attia
Maybe explain for people what the difference is between a salt and an ester.
- DDDom D’Agostino
Sure.
- PAPeter Attia
So we'll leave acetoacetate out of that for a moment.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
But if you talk about beta-hydroxybutyrate-
- DDDom D’Agostino
But you can have acetoacetate salt too, so I can mention that. So it-
- PAPeter Attia
I didn't know that. I thought it was only-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... a diester. So that's, we'll definitely-
- DDDom D’Agostino
Yeah, yeah
- PAPeter Attia
... wanna hear about that.
- DDDom D’Agostino
Okay, yeah.
- PAPeter Attia
So on the BHB front-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... people are sort of inundated with Ketone salts, ketone esters, and then a whole bunch of complete, like, weird stuff like-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... raspberry ketones and stuff. But-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... let's just leave the nonsense-
- DDDom D’Agostino
Not that
- PAPeter Attia
... off the table.
- DDDom D’Agostino
Yeah.
- 1:59:53 – 2:11:35
A Metabolic Playbook for Cancer: The Press-Pulse Approach
- PAPeter Attia
So I'm gonna caveat my next question with a really serious caveat, but it's also a very serious question and I was sort of on the fence about whether I'd ask you this or not. But I, I'm gonna say screw it and I'm gonna ask you anyway. I'm gonna caveat this by giving the disclaimer, which is you're a Ph.D. scientist, you do basic research, you are not an MD, you are not an oncologist, and nothing you say is gonna be construed as medical advice. So with, with that said, I still have to ask you a question, which is if tomorrow you, your wife, someone you cared about deeply was diagnosed with cancer, and it was a cancer for which all standard therapies had been exhausted, and you are now left to the best insights you have with respect to your knowledge of cancer metabolism, tell me what pulling out all the stops looks like. And again, what I'm-- this is in the context of you've taken and you are complying with all chemotherapeutic radiation therapy-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... hormonal therapy, surgical therapy, et cetera, but you're losing, right?
- DDDom D’Agostino
Mm-hmm.
- PAPeter Attia
So something else needs to be done. What, what does that combination of that something look like?
- DDDom D’Agostino
So I guess, I mean, when we think about the worst cancer, worst case scenario, we'd have pancreatic's pretty bad, but probably glioblastoma would top the list of things, right?
- PAPeter Attia
And would your answer be different if I was asking you about pancreatic adenocarcinoma versus GBM?
- DDDom D’Agostino
I think, you know, it would be... There's things like with pancreatic cancer can make it hard for someone to follow the ketogenic diet, right? 'Cause... And, and liver cancer and things like that.
- PAPeter Attia
Mm-hmm.
- DDDom D’Agostino
So they need to approach it a little bit different, and you can have a lot of unexpected consequences, metabolic consequences by someone with liver cancer if they have heavy liver mets or-
- PAPeter Attia
So let's make it simpler
- DDDom D’Agostino
... pancreatic mets and brain cancers.
- PAPeter Attia
Let's talk about GBM and metastatic breast cancer.
- DDDom D’Agostino
Okay.
- PAPeter Attia
Okay. So start-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... with GBM. Your loved one or you have GBM.
- DDDom D’Agostino
Yeah. I would say it would be useful, not necessarily ne- you know, absolutely necessary, to ask for an FDG PET scan. Do a PET CT. And especially, I mean, with GBM, it's gonna light up like there's no tomorrow.
- PAPeter Attia
Right.
- DDDom D’Agostino
I mean, yeah.
- PAPeter Attia
So just for the listener, so FDG PET means you take glucose, you label glucose with a molecule-
- DDDom D’Agostino
Radioactive label.
- PAPeter Attia
Yeah. And then when you do the PET scan shows by lighting up anything that absorbs that and the most rapidly metabolizing tissues-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... of glucose light that up, which is almost-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... always any cancer, and then a brain normally lights up. So a brain with cancer takes that to another level.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
So you, you're doing that to document that this is a high g- glycolytic tumor.
- DDDom D’Agostino
Yeah.
- 2:11:35 – 2:27:21
The Pulse Protocol: Hyperbaric Oxygen, IV Vitamin C and Glycolytic Inhibitors
- PAPeter Attia
So what is in your pulse protocol then?
- DDDom D’Agostino
The pulse protocol can be varied. So hyperbaric oxygen therapy.
- PAPeter Attia
At what frequency?
- DDDom D’Agostino
Three... Generally speaking, so with a GBM, you have to-- So a consequence of a GBM could be seizures, right? So getting hyperbaric oxygen therapy with a GBM is a bit tricky.
- PAPeter Attia
You gotta be careful.
- DDDom D’Agostino
So yes, you have to start very low, probably like somewhere around one point five ATA, and then work up gradually from there based on the individual person. But generally speaking, the research that we did showed that not five days a week, which is typically used for wound healing, but I do think there needs to be a day off for adaptive effects to happen. So three days a week, two point five atmospheres for sixty minutes, three times a week, and that produces... well, reverse tumor hypoxia, for one thing. So hyperbaric oxygen increases tissue oxygenation, not by hyperoxygenating hemoglobin, but it actually gets oxygen into the plasma. And that's a very important thing because-
- PAPeter Attia
Meaning you solubilize oxygen within the plasma.
- DDDom D’Agostino
Yes. So-
- PAPeter Attia
'Cause you can't really supersaturate the hemoglobin that much more.
- DDDom D’Agostino
No, no. Hemoglobin-
- PAPeter Attia
You're at the top of the curve.
- DDDom D’Agostino
Yeah, you and I are sitting here, I don't know with this air here, but [chuckles] the, but your, your hemoglobin is essentially saturated.
- PAPeter Attia
Yeah.
- DDDom D’Agostino
You know, probably ninety-six, ninety-eight percent. But the hyperoxygenation that occurs with hyperbaric oxygen therapy, and this is why oxygen therapy does not work independent of an increase in pressure, right? So the increase in pressure is needed to drive the oxygen into the plasma. And once it's in the plasma, tumors have erratic vasculature, right? And then the red blood cells get caught inside the capillaries and the vas- and the oxygen doesn't get into the tissue inside the tumor. But if the oxygen is in the plasma, it can get past and all into the nooks and crannies of the tumor and then reverse tumor hypoxia, which is... Tumor hypoxia is driving HIF-1 alpha and VEGF and causing oncogenic activation.
- PAPeter Attia
Oh, that's so interesting. So ironically, you're taking something that's, is initially a deficit of cancer-
- DDDom D’Agostino
Mm-hmm
- PAPeter Attia
... which is its hypoxia-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... but then it utilizes it as it's an advantage-
- DDDom D’Agostino
Yes
- PAPeter Attia
... by saying, "Hey, I'm gonna work around this. It's gonna make me more resilient. It's gonna allow me to increase my vasculature."
- DDDom D’Agostino
Exactly. Yeah.
- PAPeter Attia
Boom. And you're saying, "Hey, buddy-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... that little advantage you had that was a disadvantage-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... we're gonna reverse it. We're gonna hyperoxygenate you now.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
We're gonna take away your hypoxia." Do you also increase free radicals?
- DDDom D’Agostino
And it turns off oncogenes. Yes. So you have a dual effect, right? So you are silencing the oncogenes. You're turning off some of the oncogenes. And also by hyperoxygenating a tumor, which its baseline is to be in a, in a state of hypoxia, by supersaturating the tumor with oxygen, and that tumor tissue has damaged mitochondria, 'cause hypoxia damages the mitochondria. So basically, you're hyperoxygenating a whole bunch of damaged mitochondria, and essentially what that does is skyrockets superoxide anion, which then through Fenton chemistry, so when you have a lot of free iron and all, you got a whole bunch of heme and stuff that's being broken down in the tumor. So you have a lot of free iron driving the Fenton reaction, and which is producing hydroxyl radicals, and that causes a massive oxidative stress specifically to the tumor. And you're delivering a massive oxidative stress to the tumor while it's relatively non-toxic to healthy cells that have normal metabolism, right? Because the tumor is thriving in a low oxygen environment-
- 2:27:21 – 2:32:01
Dom's Seven-Day Fast and Resilience in Ketosis
- DDDom D’Agostino
And, and I know... So, I mean, what I didn't talk about when I did the seven-day fast, like years ago, I brought my glucose levels down really low, and I got to a glucose ketone index of one or maybe even a little bit lower than one.
- PAPeter Attia
So you were about, what, three to four on each of them?
- DDDom D’Agostino
Yeah. Well, my ketones were about four or five, and my glucose got down to three. So that was the lowest I ever, like, captured, you know?
- PAPeter Attia
And that was just a seven-day fast?
- DDDom D’Agostino
Yeah, after a seven-day fast. You know, after a brisk walk at the end. See, I never got like ketones seven or eight.
- PAPeter Attia
Yeah.
- DDDom D’Agostino
Like, I got at, like, four, you know, after, like, a long fast. But then I did, inspired by the Cahill study, I used various strategies to bring my glucose level down, you know, pharmacological strategies, and I, I did it slowly. [laughs] And, uh-
- PAPeter Attia
Just do me a favor, Dom.
- DDDom D’Agostino
Yeah.
- PAPeter Attia
I really would be kind of pissed off if you, like, offed yourself doing-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... dumb shit because I think the world kind of needs you to stick around. So-
- DDDom D’Agostino
Yeah. Yeah, yeah
- PAPeter Attia
... uh, see if you can just maybe get an IRB to do this in the mice or something.
- DDDom D’Agostino
Yeah, yeah.
- PAPeter Attia
There'd be nothing that would break my heart more than getting a call from your wife saying, uh, "Yeah, Dom died of some freak hypoglycemic-"
- DDDom D’Agostino
Yeah, yeah
- PAPeter Attia
... crazy accident. What's the longest fast you've ever done?
- DDDom D’Agostino
Well, that was it, actually.
- PAPeter Attia
Seven days?
- DDDom D’Agostino
So yeah. And I was pretty adapted, and the point I was kind of getting to that I brought my glucose down to where it was not even measurable, but with exogenous ketones-
- PAPeter Attia
Geez
- DDDom D’Agostino
... I was... The meter didn't even read it. So that, to me, and I did that years ago, that motivated me more to basically focus on this area of research as sort of like my life research 'cause it validated to me that this should not be happening, and ketones are an alternative energy source that can be utilized in these metabolic-based therapies that can be game changers for, for v- And we also study glucose transporter type 1 deficiency syndrome-
- PAPeter Attia
Mm-hmm
- DDDom D’Agostino
... right? Which is a inability... And people who have GLUT1D don't get cancer, to my knowledge. I've talked to the doctors, and they've never came across anyone with glucose transporter. So that's kind of motivating too, [laughs] to, that you can create a-
- PAPeter Attia
Yeah. This is-
- DDDom D’Agostino
... a therapy for that that could sort of be a magic, magic bullet.
- PAPeter Attia
Well, what's interesting is this is sort of in many ways old school science, right?
- DDDom D’Agostino
Mm-hmm.
- PAPeter Attia
Where scientists would begin by sort of experimenting on themselves, identifying unnatural or extreme physiologic conditions that are not predicted by the current understanding.
- 2:32:01 – 2:41:33
Ketones as Epigenetic Signals, Kabuki Syndrome and Closing Resources
- PAPeter Attia
You've been so generous with your time. I, I wanna sort of let you get on your way. I know you've got a long drive potentially tonight. But I wanna ask you a question or a couple maybe. What do you believe today to be true that five years ago you did not believe to be true? Let's keep it within the purview of your ketogenic life. What today do you think?
- DDDom D’Agostino
Things that really-- I would say when I got into this field, I was really fascinated and immersed in this idea as ketones as an alternative energy source, so as even, like, space food, you know? And we're-
- PAPeter Attia
Mm-hmm
- DDDom D’Agostino
... still working on that front. But then over the last five years, the observation that beta-hydroxybutyrate is a powerful endogenous metabolite that's also a signaling molecule through its HDAC activity, histone deacetylase activity.
- PAPeter Attia
Mm-hmm.
- DDDom D’Agostino
More recently, we've been working with an organization that-- The name of the organization is called All Things Kabuki. So there's a, there's a rare genetic disease called Kabuki syndrome, which is a gene defect in the KMT2D, which is essentially an acetylase enzyme. And a defect in that gene or that protein creates an imbalance between gene expression and gene repression, right? And in the mouse model of Kabuki syndrome, two things have worked in this mouse model. One is a histone deacetylase inhibitor, HDAC inhibitor, called AR42, which restores neurons in the dentate gyrus and kind of silences the pathological features in this mouse model. And another thing is nutritional ketosis. So nutritional ketosis functioning as a histone deacetylase inhibitor basically salvages or rescues the phenotype of this and circumvents this gene mutation, the KMT2D mutation. The animals have a normal neuronal density in the dentate gyrus, and even from a behavioral characteristic, it enhances sort of, uh, learning and memory. So this idea that an endogenous metabolite can epigenetically sort of control gene transcription. So I, I believe it's probably not unique to beta-hydroxybutyrate. I think m-metabolites, we know that's true for acetyl-CoA and other things, are epigenetic drivers, and I think they are really-- they call the shots. So you can even take a step back and say the mitochondria kind of call the shots too, right?
- PAPeter Attia
Mm-hmm.
- DDDom D’Agostino
'Cause I think mitochondrial health and mitochondrial vitality would be the ultimate tumor suppressor. So if the bioenergetic capacity of a cell in tissues are maintained to a high degree, that bioenergetic efficiency is going to preserve genome stability and be far less likely to trigger oncogenes at the level of the, of the DNA. So when it comes to something like Kabuki syndrome, you have a persistent molecular genetic pathology that's silenced by the elevation of beta-hydroxybutyrate functioning in a metabolic-
- PAPeter Attia
On HDACs
- DDDom D’Agostino
... in-independent way. Yeah.
- PAPeter Attia
Yeah.
- DDDom D’Agostino
Through their-- its HDAC activity. So that, to me, is, like, mind-blowing, and I think that's the direction kind of our lab is going into now. I'm always fascinated with developing alternative energy substrates and alternative fuels as a form of nutrition for tactical applications, space applications maybe. But this idea that you could develop and even engineer nutrition to have powerful effects on gene transcription and epigenetic regulation is something I would have never predicted.
- PAPeter Attia
That's an amazing answer actually because... And, and I know that was probably a little hard for some people to follow. So y- what you're basically saying is, look, five years ago you were completely intrigued and blown away by the metabolic properties of these ketones.
- DDDom D’Agostino
Mm-hmm.
- PAPeter Attia
Primarily as an alternative energy source, and with that comes a lot of interesting stuff we've talked about. But at this HDAC pathway, this inhibition of something that can result in epigenetic change or activation of, in this case, you can basically-
- DDDom D’Agostino
Mm
- PAPeter Attia
... take a germline acquired mutation-
- DDDom D’Agostino
Yes, exactly
- PAPeter Attia
... and silence it with an epigenetic overlay-
- DDDom D’Agostino
Yeah
- PAPeter Attia
... that seems to be signaled by something as simple as ketones. And Dr. Verdin at the Buck Institute, uh, has spoken quite a bit about this as well. I mean, it, this really is one of those moments where you think, "Holy cow, we are really at the, just at the cusp of learning about this stuff." And if there's one reason to make sure we don't off ourselves with self-experiments, it's to make sure we can stick around long enough to do this. Dom, where can people follow you socially, and then m- maybe more importantly, see what you're doing from a research perspective?
- DDDom D’Agostino
Sure. So the site I maintain for informational purposes would be ketonutrition.org. It's a .org, not .com. And on that website I have, uh, a list of, you know, podcasts, there's nutrition consultants, resources like the Charlie Foundation, which is an incredible resource that I've helped them do some educational work. And, and Jim Abrahams of the Charlie Foundation has really created an amazing resource there. I have a blog and we test various ketone supplements, ketogenic foods. I'm self-experimenting and have collected a lot of data, and will be putting some of that data in the blog. So I think that would be sort of like the one-stop shop website for anyone interested in hearing more about what I talked about. I'd also like to mention that our lab, in collaboration with Epigenics Foundation, is sponsoring the Metabolic Health Summit that's occurring in January 30th to February 3rd in, uh, Long Beach, California. And it's gonna have an amazing array of basic scientists. For example, like Luke Cantley will be there, be a keynote speaker, Thomas Seyfried. There's gonna be clinicians there, influencers there, and a lot of entrepreneurial people will be there representing companies that are really changing the shape of this industry. So I'm very interested in technologies and foods and supplements that can make nutritional ketosis accessible for people that want to use it, not only therapeutically for metabolic management of a disorder, but maybe also for prevention or longevity or just as a lifestyle. So you're gonna find there's something for everybody [laughs] at the Metabolic Health Summit. From basic science will be sort of what our lab is focused on, but from clinical application to moving the science into human application is really the theme o- of that.
- PAPeter Attia
And can people register for that already?
- DDDom D’Agostino
Yes. I think you can go to the website and register. If you want to be a sponsor, I think you can sort of download the sponsorship package. There's gonna be a lot of high-profile representation there that would bring sort of more, uh, awareness and more reach to your product if you have a product there, so we're looking for sponsors. And I think we've nailed down most of our speakers. But if you're interested in speaking too, it might be good to contact us through the website.
- PAPeter Attia
Got it. And on Twitter you're pretty active. What's your handle?
- DDDom D’Agostino
Yeah. Before I realized how important it is to have a, a n- like, a handle you can remember. It's dominicd'agosti2. [laughs]
- PAPeter Attia
We'll link to it, but uh-
- DDDom D’Agostino
Yeah, we'll, yeah, link to it. It's not the easiest to remember. And also Facebook, I'm fairly active. Dominicd'agostino1, I think that's my handle on, uh, Facebook too. So I kinda cross-post on each. And try to use Instagram a little bit more, 'cause they tell me I gotta use it more, but, uh, not too active on that. But-
- PAPeter Attia
All right. Well, we'll, we'll make sure we link to all of those things. I want to thank you again. I owe a lot of what I know in this space to you. And, uh-
- DDDom D’Agostino
I can say the same. Thank you. Yeah.
Episode duration: 2:43:20
In the uListen app, the transcript lights up word by word as you listen. Get uListen
Transcript of episode q7kOs6bS1Hg
