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Dr. Dominic D’Agostino is an Associate Professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine. He is also a Research Scientist at the Institute for Human and Machine Cognition (IHMC). Dr. Angela Poff is a Research Associate in the Department of Molecular Pharmacology and Physiology at the University of South Florida in Tampa, FL, and Co-Founder of Metabolic Health Initiative. Dr. Latt Mansor and Geoff Woo met Dr. D’Agostino and Dr. Poff in person to talk about the state of the art of ketone research in 2022. Key point topics and studies mentioned:

Role of ketones and the future direction of ketone research in:

  • Athletic performance/ extreme environment
  • Mitochondrial protection in astronauts in space
  • Cancers
  • Metabolic psychiatry
  • Alzheimer’s and dementia

• Optimal blood ketone levels for health benefits
• Keto vs. carnivore vs. plant-based diets

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Transcription

Dr. Latt Mansor:

Hi, this is Dr. Latt Mansor, Research Lead of Health via modern nutrition here on HVMN Podcast. Now, I know we have taken quite a long hiatus, but what a better way to relaunch HVMN podcast with this episode where my co-host, Geoff Woo, and myself interviewed Dr. Dom D'Agostino and Dr. Angela Poff, talking about the current state of ketone research in 2022. In this episode, we covered everything around ketone research, including cardiovascular disease, cancers, psychiatry, neurodegenerative diseases, athletic performance, or even space exploration, so stay tuned. On top of that, most importantly, we also covered a question that most of you guys ask all the time. What is the best level of blood ketones to reach in order to get all the optimal benefit in performance as well as therapeutic targets? Is it higher the better, or is there a Goldilock's zone? Are you curious to find out? Well, tune in and let's get right into it.

 

Geoff Woo:

Hey everyone, this is Geoffrey Woo on the HVMN Podcast. We've been on a super long hiatus, so I can't think of a better opportunity to re-jumpstart the podcast. My cohost, Dr. Latt Mansor, and of course our esteemed guests, doctors Angela Poff and Dom D'Agostino. Maybe just to start off here... I feel like in this group, there's some of the most OG scientists, academics that have really set the field for our modern understanding of metabolic health and ketosis. I always like to start from the beginning. What was the field like... What initially drew you into this specific research area? We'll start there, and then we're just going to fast forward and dive into the cutting edge stuff. But, let's set the foundation and build the context.

 

Dr. Latt Mansor:

Hold on one second, let's close the door.

 

Dr. Dom D'Agostino:

Good idea.

 

Dr. Latt Mansor:

I think I can hear that, because we're [inaudible 00:02:18]. All right, continue.

 

Dr. Dom D'Agostino:

Okay. Going back...I went back in time today to 2008, because occasionally I get emails from people where I recommended the ketogenic diet for things like epilepsy. One person comes to mind, Mike Dancer, who had epilepsy. Just as I was getting into ketogenic diets for oxygen toxicity seizures, I was connected with different people who were benefiting from ketogenic diets and even ketones. Mike Dancer... Google Mike Dancer epilepsy, and you'll find an interesting story, and also Dr. Mary Newport, whose husband was helped tremendously by ketones and kept him active for a number of years with advanced Alzheimer's disease. These things caught my attention in 2008 and 2009, and then the observation that ketones decrease proliferation of cancer cells in culture. Then, Angela joined the lab in 2010, right? A first year PhD student.

 

Dr. Angela Poff:

Yes.

 

Dr. Dom D'Agostino:

She was very highly motivated to study the use of the ketogenic diet and hyperbaric oxygen because we also observed high pressure oxygen killed cancer cells and caused oxidative stress, and that became her PhD project. There was a synergy of things going on between 2008 and 2010. But, the big thing that actually made this research possible in our lab was the Department of Defense created technologies that allowed us to build hyperbaric equipment and also the Office of Navy Research, which they invest in high risk projects, and this was sort of a high risk project. Basically, using synthetic ketones, ketone esters in this project, as a mitigation strategy for oxygen toxicity seizures. I had a little departmental funds, and that kicked off Angela's PhD project. That was 2010, about two years. In 2010, we started trickling, getting in some funding. Then, there was funding in 2009 or '10 from the Alzheimer's Association on a mouse study, and I guess the rest is history. Then, things started happening very fast. Then, Shannon Kessel came in and then she was studying ketones and wound healing, which ended up being an awesome project. Shannon, we have to get that paper published, but she's got a great dissertation.

 

Dr. Angela Poff:

I think she's working on it. I talked to her recently.

 

Dr. Dom D'Agostino:

Okay. That's some of our best data. I mean, Shannon generated that. I've just been super grateful and fortunate to have amazing students come in, not only are they personally motivated, that drives them and they do great science and we just work hard to advance the science into human application. Then, years after that, we had Metabolic Therapeutics Conference, which was really about outreach about what we're doing. Well, I just told you the first two years, and there's many things that I'm missing there, but that's kind of the gist of it. Then, I became very interested in actually doing the diet myself, fasting for a number of days, looking at my strength levels, measuring my ketones. At this time, I was talking with Dr. Veech, Dr. Van Italy, Dr. Sami Hashim, Dr. George Cahill, before he passed away in 2012. I talked to all of the real icons, all the real keto kings in space with Dr. Veech, Cahill, Dr. Sami Hashim and Theodore Van Itallie. I mean, these are the people that really inspired me. Mark Mattson at the NIH. The science was really good and I was like, "Why are people not studying this?" I was early in my career, transitioning into a tenure track position. I was kind of told that this would be academic suicide to transition from studying small molecule antioxidant compounds and drugs essentially to a high fat diet and then these synthetic ketones molecules, and ketones were bad. But, there was a body of literature that convinced me that ketones were nerve protective, anti-seizure properties, and they had remarkable effects on human metabolism and brain energy metabolism. I'm so glad I went down that path and recruited smart people under me to do the research.

 

Geoff Woo:

Angela, did you know how much of it was a "career suicide" before joining to help?

 

Dr. Angela Poff:

I think I was blissfully ignorant.

 

Dr. Dom D'Agostino:

I was kind of like, "This is going to be hard." I don't have a plan, just study what you want to study. I was like, I mean, "We can try it," but I wasn't... I was confident that what we were studying was going to have an effect and it was important.

 

Dr. Angela Poff:

It was important.

 

Dr. Dom D'Agostino:

I think if the scientific rationale was good and I was internally motivated to do it...

 

Dr. Angela Poff:

I remember... When you start a PhD program, a lot of times you go and you listen to pitches from the different PIs about what they're doing in their lab. There's obviously a lot of really cool research going on, but I remember listening to Dom at that time and hearing you talk about the CNS oxygen toxicity stuff and everything, and then at the end you had one final slide and you're like, "How does...?"

 

Dr. Dom D'Agostino:

Oh, at the pitch.

 

Dr. Angela Poff:

The pitch, during the pitch, yes.

 

Dr. Dom D'Agostino:

I pitched my ad to all the incoming PhD students, yes.

 

Dr. Angela Poff:

The new students, yes, if you wanted to join.

 

Dr. Dom D'Agostino:

Then, you reached out quick. You and Shannon, I both got emails at the same time. I'm like, "Oh, okay." I want to join your lab.

 

Dr. Angela Poff:

Yes. But, I just remember that whole day of when you talked on that slide about this idea of a ketogenic diet, which I never heard of anything like it before at that point, as a potential therapy for cancer. I mean, it just really struck me in a way that the other research, while it was exciting of course and what it was, it was just so fascinating from the very get-go and exciting from the idea of a project that felt very novel and just out-of-the-box. I think what spoke to that part of me as a little girl that always wanted to be a scientist to do something novel, cool, and just thinking outside-the-box to make something happen that was truly changing, and to be able to go over the next... I guess it's been 12 years since then, which is kind of nuts.

 

Dr. Dom D'Agostino:

Yes, it's crazy.

 

Dr. Angela Poff:

But, to see how this all has changed since then, going from this field that was quite obscure, niche, and not something that most people really had heard about to fast forwarding and now it's really a part of a major conversation between people and their daily lives, but also wide spectrum of healthcare related conditions. It's been really fascinating to see that journey.

 

Dr. Dom D'Agostino:

Do you remember the project? The project was essentially...

 

Dr. Angela Poff:

We went through a lot of rounds of [inaudible 00:09:43].

 

Dr. Dom D'Agostino:

A ketogenic diet and hyperbaric oxygen with a chlorotoxin conjugated radioactive nano particle. You take chlorotoxin and you conjugate a radioactive nano particle that would decay in a predetermined time-set, and then you take that molecule, it goes to the glioblastoma, applies a pulse of radiation during a time where you put that individual inside a hyperbaric chamber, so you have directed hyperbaric oxygen and the efficacy of radiation therapy is proportional to the PO2 of the tumor. You site specifically apply a small dose of radiation during hyperbaric oxygen in a context of therapeutic ketosis where you drop blood glucose, you drop insulin and elevate ketones, and then that becomes a fairly non-toxic synergistic strategy. I was convinced and I wanted to revisit that, but...

 

Dr. Angela Poff:

It was so cool.

 

Geoff Woo:

This wasn't human?

 

Dr. Dom D'Agostino:

That was kind of the pitch.

 

Dr. Angela Poff:

No, this was in an animal model. But then, we got sidetracked by the ketones because it was...

 

Dr. Dom D'Agostino:

I had all these ideas and that was one of them, and I was like, "What should I say at this thing?" I was like, "Let me pitch this." It was fresh in my mind. I was reading a stack of papers and I was like, "I know this would work. If it's done, it works." I think I can talk about things and sometimes oversell it and over-pitch it, I was worried, "Maybe I'm over-pitching this concept," but in my mind it made a lot of sense, as did the ketogenic diet, as did exogenous ketones. I don't know, I'm glad... I have a lot of ideas and it's just I feel like I'm always jumping out of my skin about all these ideas. I just don't have the time to do it.

 

Geoff Woo:

Tell me about it, I feel like...

 

Dr. Angela Poff:

That's a part of science.

 

Dr. Dom D'Agostino:

Angela took an idea, then applied it and then did the work. We got an animal model that was a very good animal model from Dr. Thomas Seyfried, and then let her run with it. I said, "Here, you give it and you do the work," and she did the work and made it happen.

 

Geoff Woo:

Then, I think from that, if it's circa 2008, 2010, the last 12, 14, 15 years I think has been one of the...

 

Dr. Dom D'Agostino:

What were you doing at that time, 2008?

 

Geoff Woo:

2008, I was...

 

Dr. Dom D'Agostino:

Did you know about ketones?

 

Geoff Woo:

I did not know about ketones. I was studying computer science. I was likely a sophomore, junior studying, probably looking at algorithms and machine learning. I remember the first time Googling ketones was in probably 2014, 2015, and the first result for ketosis was ketoacidosis. Just even from 2014, '15 when I got first interested in human metabolism, going from this is being a diseased state or a very extreme atypical state for type one diabetics where ketones are generated uncontrollably to now a whole field of study. I mean, when I think about why this has exploded as a field of study, I think one attribute is that while the pharmacology, just how potent ketones are as a natural molecule to the regulatory status as being basically considered foods or supplements is a one super powerful attribute that unlocks so much innovation. I think in, I would say, the most cutting edge of human performance, a lot of discussion, a lot of experimental, starting to get into clinic, but still very hard to get scheduled drugs, whether it's CBD, cannabis, now it's psilocybin, other psychedelics. I think we're going to go down that route and I think there's interesting learning from the metabolic health space. But, I think that the fact that you have something very potent but very accessible, even if you diet or through synthetic ketones, is a huge innovation unlock. Then two, I think a lot of credit to what you guys have built with the Metabolic Health Summit and just programs like ours. I remember watching Joe Rogan and some of these big podcasts, just really educating the science... We're also kind of living it. I think one thing that I think is not very accessible to everyday consumers is that scientists, a lot of times, don't actually live the lifestyle of what they're studying. That's likely okay, because you can be academic about something, but to me, life and just real influence or real credibility is not just your academic book-smart, it's the actual application and walking the walk part of the space. I think with metabolic health, using ketogenic diet, experimenting with different types and variants and prototyping a bunch of keto foods and supplements, I think folks like us who can actually walk the walk and actually perform, throw up numbers, and show these blood markers. I think, to me, there's not a lot of science and academic fields that cover those two attributes where you can have an intervention that's super powerful, but it's not like, Hey, we're talking about BMT or LSD, you can actually do it.

 

Dr. Dom D'Agostino:

You can do it. Well, you can do that too.

 

Dr. Angela Poff:

Yes, you can. It's accessible. You can visualize it too or track yourself.

 

Geoff Woo:

You can do it, but you might go to jail, right?

 

Dr. Angela Poff:

Right.

 

Dr. Dom D'Agostino:

It makes it very tangible, and because you can implement it yourself, it makes it very exciting and drives our experiments in the lab. I remember people throwing up... Remember the early ketone salts [inaudible 00:15:26]?

 

Dr. Angela Poff:

I do remember that.

 

Dr. Dom D'Agostino:

Okay, I shouldn't talk too much about that. We were creating molecules and we were testing them, it was like wow. Then, the early ketones meters, which were like 10 bucks a pop, and seeing things go up. Then, when I tried the diet myself, I was like, "Oh, I do feel different. I feel that this is..." That's what's so exciting is that ketones can rapidly change brain energy metabolism and the neuropharmacology of your brain in a way that's neuroprotective and anti-seizure, so that really caught my attention. The science supporting that was indisputable. Then, it became, well how do you develop... Well, what's the optimal diet? What's the optimal ketone formulation? We're talking about the ketogenic diet, the only valid therapy was actually for pediatric epilepsy at the time, or neurometabolic disorders that would be Pyruvate dehydrogenase deficiency syndrome, glucose transporter type one, all these things have very long names and they are actually standard to care for that. But now, we're talking about metabolic psychiatry. I was just communicating with Dr. Chris Palmer this morning, and he's treating patients that have bipolar and schizophrenia and having remarkable success and giving podcasts. He's excited to be on Andrew Huberman's podcast coming up soon. Getting that information out is very important. We can do the science all day long and publish papers, but if people don't know about it... I didn't know if Dr. Veech's... Dr. Veech should have done Joe Rogan, I wish he was still alive today. I would've done everything possible to get Dr. Veech on Joe Rogan. But, I think you can publish in high impact peer review journals, but the lay public really... They don't read these journals. By doing the research, being excited about it, being able to work on something that's tangible and readily implementable and then having a platform like Metabolic Health Summit to bring people together or doing research on this to talk about it, that has been... It's just so exciting. It has made science very exciting, the outreach aspect of it.

 

Dr. Angela Poff:

Yes, and prioritizing that communication to the public. I think scientists are historically very bad at communicating to the public and it's caused a lot of probably unnecessary difficulty in many points in history. Just being able to try to effectively communicate a message, preventing over-hype, under-hype, whatever it is, getting a message across that's clear and evidence based. That's why I think we're very passionate about the education piece of this. That has driven the field forward by giving information to people in a responsible way. We're very protective of the message. I know there's a lot of information out there and I always want to make sure that everything that all the education that we provide through Metabolic Health Summit or stuff that we do with our lab is just very clear, direct, and really honors the science and the legitimacy of the science, because with this field, you don't have to exaggerate. Honestly, it's really the amount of research that's out there is so impressive that we just have to effectively communicate it, and the people want to know because it is, to your point, ketones are basically a food with drug-like properties. There are no pharmaceuticals that have the same type of multimodal, kind of pluripotent response within the cell, different tissues systemically with the ability to impact physiology from the brain to all of systems biology. People are fascinated by this, and it's something that is accessible and can excite people. I think that's why this field has really exploded, because it's put health back into people's hands, and I think that it was taken away for a long time. It felt very like you couldn't touch it.

 

Geoff Woo:

Yes, let's definitely dive into those sectors. But before that, I want to just touch on just the evolution of science because, from my opinion, I think the fact that every person can research PubMed and get the same access to academic literature for maybe 20, 30 years where you had to be at an academic institution to even understand what's being published. I think that there's more open sourcing of data. I think there's just really smart lay people that are, as a technical thought, just even crazier in terms of data analysis than professional researchers. That, to me, is really the true rough and tumble of science, which is not about the infallibility of authority, but just what is a data? Can we debate and learn from good argumentation and good evidence? Do you sense that the way academia is being done is changing? I mean, you guys are within academia, but I would say on the more, arguably, thoughtful on the science communication side where I think a lot of our collaborators, partners probably don't know how to even have a normal conversation on a podcast for more than 10 minutes. They're just scared or they just don't want to say the wrong thing. I mean, do you think that's a good thing? I mean, I think for me it's... If people are funding the science through our government agency bodies, we as researchers should have an obligation to make it translatable.

 

Dr. Dom D'Agostino:

That's a really good point. It got me thinking. I think maybe when you join the lab... the National Institutes of Health, the NIH, tends to fund very mechanistic bottoms-up research. They have a mechanism, then they sort of study that, and then work your way to a clinical trial of some drug that you put in humans. We kind of approach it from a top-down perspective. We knew something worked, the ketogenic thing worked, so let's mechanistically figure out novel innovative ways to induce ketosis, then mechanistically deconstruct and identify the various mechanisms, and then we can reverse engineer or fully understand how we can better augment nutritional ketosis in a way that can enhance the applicability of this physiological state, metabolic state. We actually went into it understanding that this works almost, and let's not only understand the anti-seizure effects of it, but also let's apply this. It's having anti-seizure neuroprotective effects because it's changing brain energy metabolism and changing neuropharmacology, we knew that. We did not know about the anti-inflammatory effects. We did not know about the epigenetic signaling associated with that. But, we just knew brain energy metabolism and then it's GABA was going up or glutamate, we had some idea. But, we understood that if it was doing this, well, why can't we apply it to other neurodegenerative diseases, neurological diseases? Then, our cell experiments were showing effects on cancer too, and that led to Angela's project. We became very interested in applying metabolic therapies, and it doesn't just have to be about ketosis. I mean, we've had... One of my students, Nate Ward, did a project on metformin and dichloroacetate. Then, we look at other, a wide range of metabolic, altering metabolism. It's about altering metabolism, and you can do that with a diet, you can do it with synthetic ketogenic agents, you can do it with natural ketogenic agents like MCTs or ketone salts. You can do it with a big toolbox of metabolic drugs from PI3 three kinase inhibitors, [inaudible 00:23:45], 2-Deoxy-D-glucose, three [inaudible 00:23:48]. I mean, the toolbox is big and expanding. That becomes very exciting from a research point of view, but also from the point of view of a conference on this too, because pharmaceutical companies are very interested in this, they should have emerging interest in this. There was no interest in cancer metabolism, really. There was no mention of the Warburg Effect even in the hallmarks of cancer, but now there is.

 

Dr. Angela Poff:

Yes, that changed quickly.

 

Dr. Dom D'Agostino:

I think a lot of things have changed. You talked about PubMed, very little on PubMed, just do a PubMed search for ketogenic diet and look at the years, it's exploding. Clinicaltrials.gov, 296 clinical trials if you type in ketogenic diet and look. When Angela joined, I think there was four maybe, three or four. Yes, there's an explosion of research that's not only already out there on PubMed, but what's really probably most exciting, it's being done now on registered... It's registered, it's clinical trials on clinicaltrials.gov. It's everything, stuff that you wouldn't even think about. I mean, there's bipolar, there's schizophrenia, there's alcohol use disorder, there's a bunch of exercise studies, there's Parkinson's and Alzheimer's, a lot of cancer studies, maybe about 40 cancer studies, 50 cancer studies. This is very exciting that the research is being done now, and it's only going to add more validity to this. It's going to show what works and what doesn't work. That's really exciting. As we identify what does work, we can further tweak that to apply it to a disease pathology or performance.

 

Dr. Latt Mansor:

I think metabolism has evolved so much from us understanding metabolize just as substrates, just as substance that gives us energy to now, I was just talking to my PhD supervisor back in Oxford, that we were talking about metabolites as signaling molecule. Like you said, it's a macronutrient that has drug-like properties, because it is signaling other parts of metabolism and other pathways that regulate our metabolism. Hence, also realizing the effect downstream, which could be beneficial for diseases, for dysfunctions and how we live healthily and age healthily. To your point as well, it's so true that so many scientists, there is so much disconnect between what we know and what the public knows, and that's exactly why I study science. I wanted to be the bridge between the knowledge, the information, and the public and how we can apply it, like Geoff said. How can we apply it to make sure that people are using that current knowledge and not the outdated knowledge to improve their lives? Thankfully, we have all these platforms now, podcasts, and so many of us scientists now are able to lend our voices to these platforms to make sure that people are educated and know more about what we know about ketones, what we know about glucose, what we know about insulin, how do they work with each other. It's not always a switch on or off sort of situation, it's more about turning up or turning down, dialing up, dialing down, depending on the stimulus, depending on the environment. It's a homeostasis. It's a check and balance system where we can manipulate to get the most optimal results.

 

Geoff Woo:

Let's talk about the state of the art. I think when we had our first taped conversation, I think it was 2016, 2017.

 

Dr. Dom D'Agostino:

Was that in San Francisco?

 

Geoff Woo:

In San Francisco, when we were still at an office in SF, so five, six years. I would say that a lot of the literature and the folks of the time is around athletic performance, ergogenic, acute dosing before endurance exercise. I think we've learned a lot about that specific use case. I think we could probably have an interesting conversation, what we think panned out, what we think was overrated, what we think is underrated and potentially deserves more research, particularly around the recovery side. I think there's also.. I think just opening up the pluripotent, what is a great word? We should also talk about... I think this branding there makes total sense. I think we have an increasing interest in the psychiatry, neurodegenerative, TBI side of the world as well. But, I think we should probably start from an athletic, ergogenic, as well as post exercise recovery perspective. What do we think?

 

Dr. Dom D'Agostino:

I think that's important.

 

Geoff Woo:

What is your perspective, 2022?

 

Dr. Dom D'Agostino:

Because the athletic angle of ketogenic diets, and exogenous ketones were kind of like the hook that got me into this, because I started studying this and a few years later I discovered Jeff Volek and Stephen Phinney's work in the Art and Science of Low Carbohydrate Living. Then, published the Art and Science of Low Carbohydrate Performance with Ketogenic Diets. But then, as I got into exogenous ketones, I was searching around and saw that Darpa was funding a Warfighter Performance program with ketones, so I became even more motivated to apply a ketogenic strategy to what I was funded to study, which was central nervous system oxygen toxicity seizures. I was like, "Okay, they're studying ketones for exercise performance. The ketogenic diets are already the standard of care for drug resistant epilepsy." Then, that led to the Office of Navy research funding, and we started study that. But, the performance and the observation that the military, specifically Darpa, was funding some of the projects with NIH and Oxford on Warfighter Performance, that was actually something that nudged, I felt, our program manager to say, "Okay, we can go down this path because not only do you seem to identify something that had anti-seizure potential, but it's not something that's going to impair exercise performance," because there's a well-funded project on exercise performance. When it comes to exercise performance, I have always thought... I was pretty enthusiastic in the beginning, and I'm still enthusiastic that there's potential there. But, the way the studies are designed, it's like you have athletes, you acutely dose them, then you push them and then the effect is small, but I think it's significantly consistent although small. The change is small, but you have to realize that's in the context of acute administration prior to... Then, some of it's mixed results, some of it's... I mean, but formulation matters, the context matters extremely. But, where I think we just have to take a step back and look to say that the greatest effect of ketones will be as a performance aid over time where you are consuming the molecules over the period of weeks to months to maybe even years where they're benefiting recovery, you're getting epigenetic effects, anti-inflammatory effects where I feel personally, and people that many dozens if not hundreds of people that I'm in correspondence with, are basically using them as performance aids to increase the adaptation to the training stimulus. You go, train, and your body breaks down and needs to repair, you need to have... If you optimize your metabolism, your mitochondria and various metabolic markers, your adaptation to that exercise stimulus will be augmented. I feel that that's one area where ketones could be beneficial. As things like creatine, monohydrate of course, beta-alanine, caffeine pre-workout, things like that, so there are various other things that can help too, and protein of course. But, another performance aspect of ketones is in the context of extreme environments, which we have a lot of work in that, is that a hyperbaric environment, high pressure oxygen... Not a whole lot of people do this, but advanced diving, military operations, altitude, that could be riding your bike on top of the mountain or aviation performance, optimizing the aviators, and also astronauts, which is a very high interest of mine is actually the safety and the performance resilience of astronauts for long term duration of space play, because their mitochondria get a big hit in space. It's going to be very important to protect the mitochondria and optimize metabolic health in space.

 

Geoff Woo:

I think that's nicely summarized. I think a lot of the high altitude stuff that the lab presented at the NMHS I think speaks to that, in terms of especially around reducing reaction time, increasing recall, and increasing accuracy. Hopefully, we publish that in a formal setting soon to help add that literature.

 

Dr. Dom D'Agostino:

People may say, "Well, okay, I'm not doing that. I am at one atmosphere of oxygen." It's great ketones have this effect in these... For using a rebreather, if you are in space... I'm not going to be an astronaut, or some people may say that. But, I think that the rationale is there that these things are improving, bring energy metabolism, signaling and producing resilience. That's what I think we study, resilience, performance resilience, being able to maintain a certain level of cognitive and physical performance in the context of an extreme environment. You could argue that a lot of people are in an extreme environment, their systems are exposed to things that are rather extreme, and that could be an infection, it could be COVID. I don't know if I could say that, but various disease pathologies, environmental toxins, we're subjected to many things that have extreme effects on our body. If you have something that can preserve an optimized mitochondrial function, as we tend to do, then that needs to be studied. We were talking before getting on here of all these things that need to be studied, and I think that these things need to be studied.

 

Geoff Woo:

Let's dive into mechanistically. I think one of the arguments for why ketones... I think this is a mix of metabolism and metabolic biochemistry than bro science is that ketones burn more efficiently or it's super fuel. The way I interpret it from a metabolic biochemistry side is that when the mitochondria is burning ketones, you expand the delta... It gives free energy between the electron transport chain [inaudible 00:35:18], so you have a little bit more efficiency in terms of generating ATP and less electron leakage.

 

Dr. Dom D'Agostino:

We observed this in the lab early on, you have less electrons jumping off to oxygen to make a superoxide in, so superoxide being the precursor oxygen free radical that's generated. In the context of purely glucose metabolism, the generation of superoxide ion is higher relative to beta-hydroxybutyrate. When viewed from that context, very mechanistically, and these are some of the convincing arguments that Dr. Beech had, and I think that does pan out. It doesn't always pan out in every model system, but the scientific rationale is there.

 

Dr. Angela Poff:

Tissue dependent.

 

Dr. Dom D'Agostino:

Yes, tissue dependent heart, being a very... Heart and the brain being the two organs with the highest metabolic capacity, metabolic demands, liver being pretty high too, but, that not being a big, robust user of ketones. But, the heart and the brain, I'm convinced that keto metabolism is superior, but it's not one or the other.

 

Geoff Woo:

That's [inaudible 00:36:36]. I think the bro science-y part is that people talk about sugar burning and then fat burning or keto burning as if it was binary. If you actually look at the substrate mix, even if you're at a five, extremely high levels of ketosis, you're maybe at max 15% burning keto, the rest is primarily fat, or if you're doing a little bit of anaerobic, a little bit of glucose. I think that's one, I would say, misunderstanding of the broad space, where you're always burning a mix.

 

Dr. Dom D'Agostino:

You have to think of flux. Metabolic flux changes considerably in the context of fasting, ketogenic diets, or even acutely consuming a ketone ester or a ketone 1-3 butanediol, or I'm taking a ketone salt right now. This is when consumed in an amount that elevates to a millimolar concentration, I think the estimates were one millimolar can give your brain metabolism an extra 10% boost in available energy. That's going to change not only brain energy but also the energetic pathways, the TCA cycle actually generates not only the reduced intermediates for the electron transport chain, but also the TCA cycle intermediates are alpha-ketoglutarate and [inaudible 00:38:02], all these things, they are the precursors to the neurotransmitters. Glutamate, GABA are these things that are really important. Glutamate is, by far, the most important ubiquitous neurotransmitter system in the body. Without it, we rapidly die, and that's probably why we don't have a lot of drugs that actually modulate glutamate, that block glutamate, because you die. So serotonergic systems, dopaminergic systems, [inaudible 00:38:37] systems are also altered with the ketogenic diet. There's a lot more work that needs to be done on there. But, we do know that the neurotransmitter GABA, which is sort of a yin and yang, glutamate is being excitatory, GABA is more brain stabilizing, inhibitory or brain stabilizing. There's more glutamate to GABA conversion that has been shown with a diet. There's some evidence in certain animal models that happens with exogenous ketones too. That may then support the concept of using not only nutritional ketosis but supplemental ketosis for the field of metabolic psychiatry. I do not think that ketone supplementation, exogenous ketones are necessarily a replacement for a ketogenic diet in that context, in the context of seizures, metabolic psychiatry. But, I do think they're a very powerful means to further augment the ketogenic diet at this point in time. We need to do research to show the benefits of each, and then the additive benefits. There's people who study diet will say, "You can't replicate it with an exogenous ketone. Don't think about that, it's a bad decision," and then people talking about either side. But, I think we need to come together and talk about... There's many different types of ketogenic diets, there are many different types of exogenous ketones, they have different applications and then we will personally respond differently to them. There are available tools, continuous glucose monitors, epigenetic markers. There are a variety of different tools that are available that we need to use to optimize and personalize our approach to not only the ketogenic diet but all diets.

 

Geoff Woo:

I think we all know friends or businesses working on continuous ketone monitors and the continuous glucose monitors.

 

Dr. Dom D'Agostino:

Monitors help, I got to plug that. I'm wearing a Dexcom G6, I'm wearing the Libre. I found these devices and the software especially to be incredibly insightful in understanding my metabolism. My wife, Csilla, is a sugar burner. If we eat the same meals, we have different responses, and we otherwise wouldn't know that if I didn't wear a continuous glucose monitor. I think people wearing these devices can eat the same meal together and have different responses. I think that's going to be part of the future of metabolic health, that companies who have technologies out there, whether it be a continuous monitoring system for glucose, hopefully ketones and lactate and things like that, but also software that takes that data, integrates it, and actually gives you actionable information about what to do, about what to eat, and how sleep integrates with your metabolism too.

 

Dr. Latt Mansor:

Yes, and I was about to point out what Dom said about the heart and the brain, especially on keto and metabolism because we know now from studies that in the heart and the brain, the uptake and utilization of ketones are not gated... Well, we know that they're not gated by insulin, but they're also not gated by the availability of the other substrates. For example, if you keep providing your heart and your brain with ketones, the uptake is proportionate to the availability whereas the other substrates, we can see a plateau that is correlated to the availability of the transporters. Even though we know that MCT, monocarboxylate transporter, is responsible for taking in ketones, but for some reason it can take in a lot of ketones as long as ketones are available. What they have seen in hearts specifically is that the increase in uptake and metabolism of keto is also independent of other substrates, which means that with the availability of keto, you are essentially adding a whole new group of substrate that is available and readily convertible into ATP. Imagine that for your performance, for brain activity, and energy demand.

 

Dr. Angela Poff:

Yes, and that's also with the brain, of course. Dr. Stephen Cunnane has done some really incredible work showing that, as we age, our brains naturally decline in the uptake of glucose as we age and the older you get. As someone develops early cognitive decline that might develop into dementia, that is exacerbated. But, keto metabolism, ketone uptake is retained and normal even in the aging brain, even as someone with cognitive decline, cognitive impairment. It's fascinating, because something like... We know that energy uptake in, for example, something like a dementia is well characterized, but in most neurological conditions, even in things you wouldn't necessarily think about like a traumatic brain injury, there is a glucose hypo-metabolism that occurs following the energy. This characteristic glucose deficit in the brain across neurological conditions, things that are not quite even obvious, seizures as well have periods of glucose hypo-metabolism, traumatic brain injury, stroke, a lot of neurodegenerative diseases, they all have this energy deficit. Dom, you're mentioning maybe it's 10% increase in energy, but that is actually pretty important, especially if you're talking about the brain, which is the most energetically demanding organ and really requires that high energy uptake to maintain neurotransmission. We wrote a review article on this a couple... It came out a couple months ago, it was a really fun article to write. It was titled something about ketones meeting the needs of a brain and an energy crisis. It was really fun to dig into that literature, because it is a very consistent theme in these pathological conditions, but even just in someone aging. This begins in early middle age, it's not just when we're elderly, it starts at my age.

 

Dr. Dom D'Agostino:

I encourage people to go check out that article. I don't want to get too science-y, but what Angela covered was, as we age... Age related dementia, neurodegenerative diseases, and traumatic brain injury, which is kind of like Alzheimer's disease in real time. You have impaired brain energy metabolism because there's a vascular component, so that's something we can discuss to. But also, the impaired glucose metabolism is due primarily to an internalization of the glucose transporter in the brain, that would be the GLUT3 transporter in the brain, and also pyruvate dehydrogenase complex. These are two things that have been pathophysiologically linked to Alzheimer's disease, dementia, and also traumatic brain injury, so the pyruvate dehydrogenase, also the GLUT3 transporter, and also there's vascular components too, so glucose metabolism goes down. Ketones can circumvent the glucose transporter, so they use the MCT transporter, and they can also circumvent a deficiency in the amount and the activity of a pyruvate dehydrogenase.

 

Dr. Angela Poff:

They don't know why it happens.

 

Dr. Dom D'Agostino:

Even for kids that have that enzyme, the standard of care is to use this. As we age, that precipitously goes down, and then ketones can bypass that. That's sort of part of the equation there that we know there's good science to support that.

 

Dr. Latt Mansor:

Also, ketones create [inaudible 00:46:33], which further activate pk, which it is [inaudible 00:46:38], so that all makes sense. Geoff and I, we actually just recently published a review paper on TBI using ketones and lactate as potential intervention. Dom, you're one of our reviewers.

 

Geoff Woo:

I was going to say, "Great minds think alike." I think there's a unification around it. I think one of the goals that people are trying to unify, I think to your point, Alzheimer's and traumatic brain injury, which is very, very acute, there is some metabolic underlying framework.

 

Dr. Latt Mansor:

Metabolic dysfunction.

 

Geoff Woo:

From that level and potentially from an intervention side, ketones have a very similar parallel of lactate, in which they don't meet the glucose transporter to fuel and empower the Krebs cycle. I mean, it's very interesting, because I think obviously I think that, and maybe this goes back to just the loop around I think a lot of the interest was in the physical and performance side and now I'd say that the field is very much focused... I mean, expanded maybe is a better way to say it, to cognition. I was sort of remiss before moving fully to cognition, not to be quantitative around exact normal arranges, because I know that a lot of our audience members are going to be the folks that have levels... I was a SeedInvester, so like Dom, a huge fan of Sam and the team, they've just... Super amazing execution of... I think they are now...

 

Dr. Dom D'Agostino:

They got me hooked on CGMs, the team. Josh Clemente and Casey Means, and the whole team actually was just amazing. I had different options to go with different CGM companies, but I was very inspired by the team at Levels and the underlying desire just to get this information or this technology in the hands of the everyday public, and being able to see the app evolve over time, they're very receptive to feedback, and it's just an amazing product. I'm also excited about the new technologies of these bio-wearables, multi-analyte sensing, that being the future and applying this to some of the research projects that I'm involved in now, I'm very excited about that.

 

Geoff Woo:

100%. I mean, I think it's going to be obvious at some point there will be a continuous ketone monitor, so right now we're all just finger sticking ourselves.

 

Dr. Dom D'Agostino:

Lactate too, I think continuous lactate monitoring with glucose and ketones is super important, not only for the biohacker but also for cancer research in patients. Tumor burden is associated with elevated lactate, it could be a biomarker for that. There's just so many applications for this technology.

 

Geoff Woo:

Let's talk about the ranges, because I think between different types of ketone nutritional compositions whether it's diet, salts, esters, butane dial, other molecules. I think the way that just can conform it in a way is just talk about what ketone blood PHP range are we trying to actually hit. I think there's more or more, at least on the anecdotal side and I think the practitioner side, that just as you can have too little ketones, you can have too much ketones, and that can absolutely backfire.

 

Dr. Dom D'Agostino:

We'll talk about that.

 

Geoff Woo:

I feel like folks like us haven't talked too much about the downside of the high side just because I think we were so much just educating that, hey, ketones can be useful, that we didn't talk about, hey, maybe too much of a good thing is not that great, just like with almost everything. Glucose has its use cases, especially for performance, but do you want to be eating 300 grams of sugar every two hours? Probably not, regardless. With that context, I'd love to get your thoughts on maybe the boundaries, the guidelines, the guide rails, maybe get to specific ranges that you're trying to target, whether it's two to three millimole, five millimole, eight millimole, one millimole.

 

Dr. Dom D'Agostino:

I've been everywhere. I've been to where the meter just doesn't read, it just flashes high.

 

Dr. Angela Poff:

That's probably go to the hospital.

 

Dr. Dom D'Agostino:

I think it's really important to say that higher is not better. I mean, we had a discussion prior to jumping on here that we've put a lot of animals into ketoacidosis experimentally. With exogenous ketones in particular, ketone esters, they're very powerful and I think they have the potential to do harm by causing rapid ketoacidosis, lowering pH.

 

Dr. Angela Poff:

It's all in the dose.

 

Dr. Dom D'Agostino:

It's all in a dose. From my personal, from stuff that we've done in the lab, we know that the anti-seizure effects are very pronounced when you get to two, three, and 4 millimole, so that's actually clinically that's great. When I do that on a daily basis, I don't feel too good because I think you are... If you acutely elevate ketones in that context, then it becomes disruptive to metabolic physiology and it will increase your insulin and start kicking in some counterregulatory mechanisms. Whereas if you increase ketones to two, don't go over two though because I find that insulin starts to get released. But for me, just getting to one millimolar to 1.5 is a nice safe range and I feel very comfortable in that context. I can achieve that with a ketone salt, with 1,3-Butanediol, with a low dose of a ketone ester, all these things will get you there. They're commercially available, it's relatively inexpensive now to do that and to use that amount of exogenous ketones. I think there's real world benefits to that. You can simply just look at your biomarkers. You could wear a continuous glucose monitor, you could eat carbohydrates, and then take it with ketones and actually see that your glycemic variability, your postprandial glycemic excursion if you want to get science-y will be less if you consume your carbohydrates with some exogenous ketones. That could be a salt, that could even be MCT, it could be an ester, it could be 1,3-Butanediol. It's great. There's a lot of different products out there that you can experiment with, so there's that. I think these things can be used to further augment the ketogenic diet. A big problem with the ketogenic diet that I experience, if you want to call it a problem, it's a little bit controversial, is a very high elevation of LDL and LP little A and ApoB2. I mean, I've had these things elevated to where I adjusted the ketogenic diet, started adding some fruit, some vegetables, and some essentially fibrous carbohydrates and found that I could bring the LDL down, the ApoB down, the LP little A down just by adding 50 to 100 a hundred grams or more active [inaudible 00:53:50] of fibrous carbohydrates normalizes my blood lipids, but it does push me out of ketosis to some extent. But then, a low carb Mediterranean diet with exogenous ketones... We were talking before jumping on here, I feel it's optimal for me. I feel that if people are talking about the optimal diet, everybody's going to be different. But. I think it's completely excluding carbohydrates, fruit, and vegetables, to the extent that you do that with a clinical based ketogenic diet is not optimal. I think a more diversified diet with plants, vegetables, fruits, and a diversity of different protein sources with exogenous ketones probably would be optimal.

 

Dr. Latt Mansor:

Now, as a scientist though, Dom, I have to ask, why do you think that anything above two millimolar may spike incident? What do you think is the mechanism around that?

 

Dr. Dom D'Agostino:

I think, mechanistically, when we're on a ketogenic diet and we are producing ketones, our ketones are regulated in a number of different ways. One is ketone uria, we are literally excreting out calories, ketones. If you're on a very high state clinical, it could be about 100 calories, so that's almost wasting calories, so maybe Atkins was right, you are kind of... Ways you got to lose it, but I think it's negligible. I don't think it's very significant. But you also, one way, a counterregulatory mechanism that our body has and very tightly controlled is that as ketones get elevated, it starts to stimulate a pulse of insulin, a small amount of insulin, that reduces beta oxidation of fats in the liver and that will decrease ketone production, also glucagon goes up a little bit, so you start kicking on gluconeogenesis a little bit more. If you take, for me personally... I think I've communicated with a couple people that I said, "Do this, measure insulin, do that." If my ketones are acutely and rapidly elevated above two millimolar, then my insulin level is noticeably higher, so I do get an elevation. But, two millimolar is... You can only really achieve that with a ketone ester, a large dose of 1,3-Butanediol or Ketone-IQ, but you're kind of limited with ketone salts. I'm taking a ketone salt product, KetoStart, and even if I take two packets... Two packets gets me to 2 millimolar essentially, but you're limited by GI tolerability and the mineral load too. But, one thing with a ketogenic diet is that you tend to eliminate a lot of sodium and electrolytes too, so that supplemental could be good to an extent. I think the general view is that more is not better when it comes to ketones. You're getting real world benefits with one millimolar to two millimolar.I think going above two for a normal physiology could start to kick on counterregulatory hormonal effects that could be unwarranted, but this could potentially be helpful for someone with type two diabetes, so maybe a larger dose could help them, maybe a larger dose would help someone with a disease pathology. But, for biohackers out there, taking a ketone ester that shoots you up to three, four, 5 millimolar and doing that every day... I have access to these things, I would not do that. I did that, and I didn't feel well. What I've been doing is just adding additional ketones to my physiology to enhance my brain activity, to improve metabolic biomarkers, and I do that about twice a day. I've incorporated some more carbohydrates into my diet, so instead of 25 grams of carb a day, I'm hitting about 50 to 100 grams a day. I'm getting more fiber, more plants, more a diversity of plants and vegetables, especially this time of year. It's a little bit seasonal, probably less in the winter, but some days I'm completely carnivore. Some days I'll just have steak and eggs or fish. But, when we talk about the carnivore diet, it's not something that I would do day in and day out. Some days I just don't want to eat vegetables or maybe I just avoid a salad, so I'll just have meat and eggs, and I love that and I feel great doing that, but I don't there's benefits to doing that every day. Maybe we can get into the carnivore. That's a good idea.

 

Geoff Woo:

Yes, talk about it.

 

Dr. Dom D'Agostino:

I get a lot of questions about this. I think it's a great diet, but...

 

Geoff Woo:

Hold on, before jumping into it, I want to talk a little bit about...

 

Dr. Dom D'Agostino:

Context and nuance I think it is.

 

Geoff Woo:

Well, just going back into the ranges before moving into the carnivore diet. I generally agree that being super high ketones chronically is not necessarily evolutionary consistent because...

 

Dr. Dom D'Agostino:

It's not natural.

 

Geoff Woo:

When you're eating a ketogenic diet, I think people that are long-term keto aren't that high on ketones, measurable ketones, because their body is so hemostatically efficient that they're just producing enough ketones through ketogenesis to fuel their brain and body. You're just very, very dialed in. I think I'm generally in line with you. If I'm just at the office, I just want to feel kind of sharp at work, I don't need a giant spike, a giant bowl of some ketones through a ketone ester or whatnot. However, is there a use case for ergogenic... like, Hey, I'm trying to win a race, maybe spike me up? This is just super niche, super high end. If you're really getting super high ketones, I think one thing in literature and just in the practice that we've seen is that you really reduce blood pH, you really increase blood acidity, especially with ketone mono-esters, which potentially decrements any potential added benefit of having such high ketones. I think a Belgian group showed that potentially stacking sodium bicarbonate attenuates that decrements, so you kind of have a boost, a negative, and then you boost again where you maybe get some performance benefit, but sodium bicarb is really hard to dose.

 

Dr. Dom D'Agostino:

Or electrolytes. Ketones bound to electrolytes, sodium, potassium, calcium, magnesium, that's one way, but it's also a dose thing. I mean, we saw in our animal models, pH starts to go down, animals start to get sick once you get above five millimolar. That's kind of the threshold for mice and rats, and that's kind of scary when you see that. But I think to your point, I think the drop in pH or the increase in acidity is real, but maybe with exercise it's almost training your body to up-regulate the buffer system.

 

Geoff Woo:

Right, but do you want that in your championship race to stress them more when you're trying to win the Olympics?

 

Dr. Dom D'Agostino:

Yes, you want to buffer it. A ketone salt is buffered, but then you have to deal with the mineral load, the electrolyte load. But, the electrolytes could be favorable in the context of replenishing and restoring up to a certain point. But, I think ideally we want a dual fuel system, we want ketones, maybe some MCTs, glucose, alpha L-polylactate, it's a supplement I took when I was mountain biking, Cytomax, I don't know if it's still available. But, I think a dual fuel system seems to be the ideal approach with ketones being probably the most novel, innovative macronutrient, if you want to call it the fourth macronutrient. Alcohol was the fourth macronutrient... Well, 1,3-Butanediol could be alcohol, so maybe [inaudible 01:01:47] is a fifth macronutrient. But, I think the point is that exogenous ketones are another level of innovation and they are something that should be part of a fueling system for...

 

Geoff Woo:

One of our podcasts is one of the earliest Google-able searches for naming it the fourth macronutrient actually. I was looking at who coined it and people were like... I think it was one of our early conversations literally is one of the first internet results of that, which is pretty cool.

 

Dr. Angela Poff:

That's awesome.

 

Geoff Woo:

I mean, anything else you want to cover on dosing? Basically, I think the practical takeaway is that, one, more's not necessarily better. Just if you're having Gatorade or sugar drinks, you're not trying to just chug 15 bottles of Coke right before your marathon, the same thing with ketones. I think you got to be really smart about dialing it in. I think probably some of the innovations in this space will be around formulations, how some of these different ketone precursors and molecules can provide a personalized PK curve for your specific use case. I think that's going to be an innovation area when you're doing deep sea rebreather diving versus going to space versus trying to do Tour de France versus body building. They're likely going to want different PK curves, so that might be different formulations of variance of different ketone molecules

 

Dr. Dom D'Agostino:

Probably consuming these things in the context of the activity that you are trying to augment. If you train, train, train and then the event comes and then you take a bunch of this stuff without taking it and expect a result. But, if you train up to it and get your body used to the fuel and then you learn how to tweak it and adjust it, but probably more importantly, and we talked about this, is the adaptation to that training stimulus. I think that's where ketones can help improve metabolic biomarkers, glycemic control, maybe some evidence for enhancing insulin sensitivity, which would help with glucose disposal, getting it into tissues to help the energetic processes associated with tissue repair, muscle protein synthesis. It is an energy dependent process and you could further augment that by increasing the bio-energetic capacity of the muscle because you actually... With muscle protein synthesis, it activates... and kinase. In the skeletal muscle, it's actually signaling an energetic deficit because it's a costly event to somebody. I think being able to supply ketones and maybe augmenting glucose uptake. I know Dr. Beech talked about... My first questions to him was like, "Oh, glucose is going down." I was like, "It must be releasing insulin." He's like, "No, it's enhancing insulin sensitivity." I think it's kind of a combination of both. But, if you're increasing insulin, insulin will also increase PDH activity, pyruvate. Insulin may not be a bad thing if you're spiking insulin a little bit with ketones, but it's all very context dependent. But, you don't want to be sitting at your desk spiking insulin with 5 millimolar... I've done that before. It took me a while of doing it to convince myself that this was probably not ideal because I was so gung-ho about ketones.

 

Geoff Woo:

But, close [inaudible 01:05:08] recovery, maybe, stacked with carbohydrate, protein, and [inaudible 01:05:14], maybe that instance is likely going to help you recover better and uptake and glycogen replete.

 

Dr. Dom D'Agostino:

I want to be clear, this is no substitute for nutrition. This is the supplements or the icing on the cake, so to speak. Whole food nutrition, that should be a central focus and optimized. But once you get that dialed in, the ketones and the supplements we're talking about really will make a difference. It's that difference I think that we need to study more and do more research. We can always talk about... The jury, and if you go search this stuff, the jury behind ketones augmenting exercise performance is still out. But, most of those studies have been done delivering an acute dose, which is not always tolerable, and then the investigators are expecting a result. What we have discussed here a little bit and prior to this was using ketones as a training aid, so consuming them over time. I think that's where you probably get the most benefit.

 

Geoff Woo:

I feel like we could just have a master session just really going into every single variant and just our speculations. I think we probably have just our hypotheses of how this stuff actually figures out. If you guys want that, we'll have to do our own session, just dive into how we would use this ergogenically and what are the variants or the formulations.

 

Dr. Latt Mansor:

I mean, the list only goes on. The list has been expanded in the past few years, so much in different use cases. What I've been telling people in my recent podcast is that I have sort of... Yes, ketones provides energy, it provides ATP, but most importantly nowadays with the data that we have so far, we are seeing that ketones, as you said, it aids the adaptation process to whatever stimulus that you are putting your body through, because we have seen ketone does the complete opposite things, it turned on mTOR activation after exercising, giving carbs and protein. But then in aging, ketones turns down mTOR, the same thing with inflammation, generally it turns down inflammation. But, when a bacteria toxin is introduced in vitro, it turns out inflammation because that's the natural adaptation process to the infection. With the presence of ketones, it increases that adaptation process, it aids that adaptation process.

 

Geoff Woo:

I want to talk about diet now. You were talking about a well familiar diet, let's talk about the carnivore diet, and then let's talk about cognition and future research areas. I like you were teasing up ketones as a potentiator for so many different use cases. Now going to diet, it feels like every other year there's a new carnivore celebrity. I don't know if you have had seen Liver King recently, but he's this...

 

Dr. Dom D'Agostino:

Interesting fellow, yes. You can't deny the physique, you can't deny the energy, you can't deny... He's articulate and pretty cool. I would like to meet Liver King, so if Liver King wants to come visit... Or, I'd like to go to Liver King Ranch too.

 

Geoff Woo:

I feel like I've met a lot of these folks. I think there was Sean Baker, [inaudible 01:08:32], all reasonable and just actually well researched. They actually know what they're talking about.

 

Dr. Dom D'Agostino:

They've helped a lot of people too, because I've got people email me that said they did the carnivore... Today, I did the carnivore diet, I've had two thirds of a pound of beef today, that's all I've had today, so today I'm doing the carnivore diet. It's just a situational thing, I just didn't have time to eat anything else, and I feel great.

 

Geoff Woo:

I mean, just what do you make of it? Then, I think you're teasing a little bit about the optimal diet in your perspective is kind of a low carb Mediterranean potentially with ketone enhanced or ketone supplements as part of that diet as a macronutrients. I feel like, to me, it's essentially an elimination diet with high protein, high fat. I've done blocks of carnivore, eight, 12 weeks at a time, I felt great on it. It was interesting to not have to poop a lot, but I just realized... People were asking, "Are you constipated?" It's like, "Well, actually most of your poop is fiber," so you're not eating fiber. Meat actually absorbs quite clean in your small and large intestine, so you just don't produce a lot of poop. I felt actually cut clean. The only reason I stopped was it was literally boring. I was like, "It's boring to eat steak and eggs all the time and maybe some seafood."

 

Dr. Dom D'Agostino:

I love... My favorite foods are eggs and steak, so I'm a perfect person for it, but I miss a big salad, I miss vegetables, I miss some fruit too. I love berries. We have fruit trees in the yard, and I'll grab something. These are things I miss, and I think it's suboptimal. I think carnivore diet is an elimination diet. A lot of the benefits of the carnivore diet are due to you're just simply restricting calories or limiting excess calories, and in that context you're getting a lot of the benefits of calorie restriction, I think there's no doubt.

 

Geoff Woo:

You're definitely going to be in ketosis most likely. You're definitely likely calorie restricted, or at least not overly eating because it's so satiating to eat so much protein and fat.

 

Dr. Dom D'Agostino:

That's why with a ketogenic diet too that's formulated is a bit... It's hypo-palatable I would say and hyper-satiating. It's not hyper-palatable to where you just want to eat excess calories, so it's kind of hypo-palatable, you just get sick of it after a while. Then, the protein and the fat definitely have a satiating effect and an appetite suppressing effect, so you're just far less likely to overeat and get surplus calories. A lot of the benefits are simply by calorie control, calorie modulation.

 

Dr. Latt Mansor:

What do you guys think about micronutrients, vitamins, and minerals that people argue you have to get from fruits and vegetables and all that from the carnivore diet, because there's always going to be those people asking so I'm sure the listeners would love to hear your thoughts on that?

 

Dr. Dom D'Agostino:

I mean, if you just add a little bit of organ meat... I mean, my wife introduced me to hearts and liver. I swear, the day after... We eat liver maybe every week or two, the day after, I always have more energy. This is not placebo. Especially a couple days after eating some chicken or just not getting a real diet diversity, and then she cooks liver and it's like, man, I feel like I'm on some kind of nootropic or something the next day. I don't know. I need to check my nutritional status, but I think a well-balanced ketogenic diet, whatever that is, it's just basically a diversity of fish, beef, organ meats, and then some really green, leafy vegetables too I think you can put in there. You're getting magnesium, you're getting a lot of phytonutrients that you are not getting on a strict carnivore diet. I don't know, with a carnivore diet... I don't see the argument against eating wild berries. When we were in nature, we had access to these things. You just go in the woods and in many areas of the world, I mean, these things are available and people are eating these things. I think the fecal fossils that we find very clearly indicate that early humans were eating upwards of one to sometimes 200 grams of fiber a day. I think it would be a hard argument to say that we are strict carnivores, that we were not eating plants.

 

Geoff Woo:

Yes, I mean, I think to me at least...

 

Dr. Dom D'Agostino:

Geographically, it varies tremendously geographically.

 

Geoff Woo:

I guess if we're going to get on the spectrum of weird diets, at least there's no cultures that have been completely plant based. I think there's been...

 

Dr. Dom D'Agostino:

Yes, eating bugs and things.

 

Geoff Woo:

If you had Liver King and then people, extreme carnivore, but there's also plant based whatever celebrities that are saying, "Oh, humans were evolved as herbivores," and I think that's basically factually untrue. I think it's at least for... You're going to balance that. I think to Latt's point, I think we generally agree that for a carnivore you're going to be I think micronutriently complete if you're eating [inaudible 01:14:00] and organ meats. I think the question and debate is, are phytonutrients necessary or optimal? I think I'm very open to that. It seems...

 

Dr. Dom D'Agostino:

Not necessary. Fiber's not necessary. Like I said, some days I feel better just eating meat, meat and eggs, and I feel great. Sometimes I'll go back to eating plants and fiber and it's like I don't feel too good, maybe it's just too much fiber. I almost add it as a garnish kind of thing, even if I... There are points in time where I feel my body doesn't tolerate the fiber as well. I'm convinced that there are people who just cannot tolerate plants and fiber and things because I've communicated with them enough to know that... They've convinced me that the carnivore diet is for them.

 

Dr. Angela Poff:

That's the biggest thing. It is so individual, everyone is very unique metabolically and people respond to diets completely differently.

 

Dr. Dom D'Agostino:

Females too, so to speak to a female physiology.

 

Dr. Angela Poff:

Oh yes, absolutely.

 

Dr. Dom D'Agostino:

I think females do have a hard time with keto.

 

Dr. Angela Poff:

Absolutely, yes. I do, I agree. I think it depends on menstrual cycle and then also pregnancy and breastfeeding periods too. Everything was different during both those periods for me, and just what I thrived on in those periods and what I could tolerate. I think just listening to yourself, taking your own... Doing these labs, looking at how your body responds, because there's going to be people that do well in all of these different types of diets.

 

Geoff Woo:

I think that's something we can all agree on. Trust your intuition, you understand your own body the best, and have tools that can measure the various analog levels and understand the metabolism, the physiology, and nutrition so you can build what works for you, and then cycle it.

 

Dr. Dom D'Agostino:

ZRT labs, they sell a cardiometabolic kit that you can do at home, you prick your finger and put blood on a blood spot card. They've been great, we use them in our research. Continuous glucose monitors, Abbot, Dexcom, the app Levels health, and also Genova Diagnostics has some incredible tests and tools. These are all companies that people can use their resources. It doesn't have to be super expensive. You could just do this just once a year for a baseline, and usually insurance companies cover, and you can usually talk to your doctor into doing like HSCRP or adding insulin or something like that.

 

Geoff Woo:

If not, get a new doctor, right?

 

Dr. Angela Poff:

Seriously.

 

Dr. Dom D'Agostino:

Yes, routine blood work. I mean, I like to do it a couple times a year, more than that. But at the very least, once a year, and two to four times a year would be optimal probably.

 

Dr. Latt Mansor:

Especially if you're trying all these changes, more often is better.

 

Geoff Woo:

I want to be thoughtful on time, because I know that we could go on for another two hours here. I'm going to ask the last question, which future research areas... I know that cognition psychiatry, what are potential metabolic underpinnings of both the therapeutic side as well as the enhancement side or extreme environment side? What are you currently most excited about, especially as a research area and an exploration area? Maybe throwing a curve ball at the end, I know there's a lot of at least anecdotal exploration stacking psychedelics, psilocybin, plant medicine, Ayahuasca, potentially with ketones as a super biohacker, extra credit experiment. I'm curious to hear all of that as a...

 

Dr. Dom D'Agostino:

You've got a lot of questions. I'll try to keep it as short as possible.

 

Geoff Woo:

The last question is the most complicated in the whole study.

 

Dr. Dom D'Agostino:

I'll keep it short, and then I'll let Angela talk. The three things that kill people are cardiovascular disease, Alzheimer's, dementia, I group them together, and cancer. I think there is tremendous potential for using metabolic based therapies, which include dietary therapies, included in that umbrella would be exogenous ketones. But, I think at the very... Dietary therapies, metabolic based therapies for the three things that are going to kill us, cardiovascular disease, cancer, and Alzheimer's, dementia. I think there's tremendous... I think we need to focus on developing metabolic interventions for these things and optimizing them in a personal way. Then personally, I'm super interested in undersea medicine, enhancing the safety, performance, and resilience underwater and also in space. Space is a very challenging environment that takes a big hit to the mitochondria, and so optimizing, preserving metabolic health and mitochondrial function in space I think is going to be super important for a mission to the lunar surface, to Mars, and to deep space, intergalactic. It's like Interstellar. I mean, that's what's on my mind.

 

Geoff Woo:

Hopefully in my lifetime.

 

Dr. Dom D'Agostino:

But, maybe I'll let Angela talk about some of the epigenetic project you started in the lab.

 

Dr. Angela Poff:

Yes, that's exactly what I was going to say. I'm super interested in understanding why these things work, and in particular the role of ketones, not necessarily the metabolic face of them, which I think is pretty well established, but the signaling side of ketones, which is newer, incredibly interesting, and is applicable to all of these different conditions that we've been talking about. We have some pretty cool projects in the lab right now up and coming that are trying to focus on that. In particular, looking at the signaling roles in terms of epigenetic regulation, so how Beta-hydroxybutyrate influences gene expression and looking at differences between the R versus S, PHV. We have a great PhD student in the lab, Sarah Moss, who is extremely passionate about all things genetic and epigenetic. She's doing a pretty awesome project, starting to look at that in some of these diseases. I love the mechanism side of this stuff, I want to know why this stuff is working. It's fascinating.

 

Dr. Latt Mansor:

No one wants to touch psychedelics and key points?

 

Dr. Angela Poff:

Oh my god.

 

Dr. Dom D'Agostino:

Metabolic psychiatry, that's going to be... I didn't add it to that list, but I think maybe the fourth thing, cardiovascular disease, cancer. I would like to add metabolic psychiatry to that because mental health is a huge problem. Depression, anxiety, bipolar, schizophrenia, these things are... Obsessive compulsive disorder. There is a place for metabolic based therapies, dietary and supplemental in treating these diseases, so that's important. Also, medicinal mushrooms. Food literally as medicine, so mushrooms. First Person, I think they are an up and coming mushroom based company that develops a lot of very unique formulations with a wide variety of different types of mushrooms and different formulations. I use their products. I disclose that I consult for them. I think they're doing some great things, advancing this idea of using mushroom-based compounds for improving brain health. They have a very incredible personal story. Check them out, getfirstperson.com. We connected with them. They were a sponsor of the Metabolic Health Summit. I think there's a big future in medicinal mushrooms, and that could be the psychedelic mushrooms. I believe that these things could largely replace, in some situations, SSRIs and other... I've been in correspondence with a number of people who are using them under guidance, a few of them using them outside of guidance, but still doing very, very well where they basically replaced drugs under guidance to improve and enhance their mental health and wellbeing.

 

Dr. Latt Mansor:

Can I ask a sneaky question?

 

Dr. Dom D'Agostino:

Sure.

 

Dr. Latt Mansor:

Also, regarding the mushrooms. Given just mushrooms are all psychedelics and whatnot, it increases brain energy demand, given that ketones increase energy supply, do you think there is a place for a synergistic effect between those two?

 

Dr. Dom D'Agostino:

Yes. I mean, one of the products that I've used for a while is Keto Brainz, which is Lions Mane, MCT, Theanine, and it's got a great combination of cordyceps, reishi, lions mane. These mushrooms have been around for a long time and they have good science behind them. They're considered adaptogens too, so they help your body cope with stress in different ways. I think that's a very innovative market right now, and I think it's expanding very rapidly. A lot of people, similar to ketogenic diets or keto supplements, are rushing... Entrepreneurs are rushing to get into this space because there's a lot of potential. I do think there's synergy, yes, and especially in the context of brain health, definitely a lot of potential.

 

Geoff Woo:

We leave it for the readers or listeners homework, in terms of reaching out if you guys are experimenting, some of these things are against schedule, likely not legal in many jurisdictions potentially, so not advocating or not advocating. But, I think as a scientist who maybe cares less about arbitrary regulations on naturally occurring mushrooms, I'd love to at least just explore and learn more of how this all works.

 

Dr. Dom D'Agostino:

Yes, absolutely. We are excited to maybe do more research in this area in expanding application and of different formulations. Like I said, lots of potential for innovation, not only in ketogenic diet formulations, but also in ketone supplements and in mushrooms too. I'm excited for the future of this.

 

Geoff Woo:

Awesome. Well, let's wrap this. Really great to re-kick off HVMN podcast with Dom and Angela. Thanks so much. This was an awesome conversation.

 

Dr. Angela Poff:

Thank you.

 

Dr. Latt Mansor:

Thank you.

 

Geoff Woo:

We got to do this more often than every two, three years, because I think every six months, twelve months, there's so much going on in this space. You guys are just at the forefront. We're educating, we're building, so let's learn, build together, and help build this community out, because I think what we're all exploring is not just I think academically, scientifically interesting, but potentially could be so helpful for our civilization, for all the populations. Keep up the good work.

 

Dr. Dom D'Agostino:

Well, thank you for providing this platform and getting, like we said... I mean, you can do all the science, but providing the platform, and for you guys who are not only educated, but creating a platform to disseminate the information is equally or more important. Thank you for doing that and having us on. Appreciate that.

 

Dr. Latt Mansor:

Thank you.

 

Geoff Woo:

Thank you.

 

Dr. Latt Mansor:

I hope you have enjoyed this conversation as much as we did. If you did, please like, share, and subscribe. You can find us on all social media at HVMN, and myself at Latt Mansor. On top of that, I will put all the handles for Dr. Dom D'Agostino and Dr. Angela Poff in the description below. If you have any feedback or suggestions, feel free to leave comments, write to us at podcast@hvmn.com or just contact us on any of these social media platforms. Thank you very much for listening. Until next time.

 

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