Dr. Dominic D'Agostino | What Ketones Actually Do to Your Body

August 05, 2026
In this episode of the Health Optimization Medicine Podcast, Dr. Scott Sherr sits down with Dr. Dominic D'Agostino to explore:
Why has interest in keto faded while the scientific research on ketone metabolic therapy continues to grow exponentially, and why is it far more than just another diet trend?
What is the difference between a ketogenic diet, ketone supplements, and ketone metabolic therapy, and when should each be used for health optimization?
Are ketone supplements a replacement for a ketogenic diet, or do they serve a completely different role in supporting metabolism, cognition, and resilience?
What does the latest research reveal about ketone esters, ketone salts, MCTs, and 1,3-butanediol, and why are some formulations raising concerns about liver toxicity and long-term safety?
How do ketones improve mitochondrial function, reduce oxidative stress, and provide a more efficient fuel source for the brain and heart?
Why might ketone therapies work synergistically with hyperbaric oxygen therapy (HBOT) to support traumatic brain injury recovery, neurological health, and cellular resilience?
Can ketone supplements actually improve exercise performance, or is their greatest benefit found in recovery, cognitive function, and extreme environmental stress?
What does current evidence suggest is the optimal level of therapeutic ketosis, and why can "more ketones" actually become counterproductive for healthy individuals?
Who is Dr. Dominic D'Agostino?

Dr. Dominic D'Agostino is a tenured professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida and one of the world's leading researchers in ketogenic metabolic therapies. His work focuses on understanding how ketones influence cellular metabolism, mitochondrial function, neurological health, cancer metabolism, aging, and human performance.
For more than two decades, Dr. D'Agostino has investigated the therapeutic applications of ketogenic diets and exogenous ketones, pioneering research that began with improving resilience in military divers and has expanded into neuroprotection, traumatic brain injury, metabolic health, and healthy aging. His work has helped shape the modern understanding of ketone metabolic therapy and continues to influence both clinical research and real-world applications.
In addition to leading research initiatives, Dr. D'Agostino is an educator and science communicator dedicated to advancing evidence-based metabolic health. He is the founder of KetoNutrition, co-founder of the Metabolic Health Initiative, and host of The Metabolic Link podcast, where he shares the latest research on ketosis, metabolism, and precision health.
What did Dr. Dominic and Dr. Scott discuss?

00:00 - Beyond the Keto Fad: Ketone Metabolic Therapy Explained
02:11 - Ketogenic Diet vs. Ketone Supplements
06:28 - The Truth About Keto, Cholesterol & Statins
10:37 - Metformin, Mitochondria & Why Ketones Matter
16:18 - Ketones, Hyperbaric Oxygen & Brain Health
18:30 - Ketone Esters vs. Salts: Benefits & Risks
21:00 - The Hidden Risks of 1,3-Butanediol
30:33 - Hyperbaric Oxygen + Ketones: A Powerful Combination
36:17 - Ketones for Recovery, Performance & Longevity
43:03 - Therapeutic Ketosis: How Much Is Actually Beneficial
Full Transcript:

[00:00:00] Dr. Dominic D'Agostino: We use the terminology ketone metabolic therapy, and that's much better because there are many types of ketogenic diets. And for all intents and purposes, you wouldn't want to use the, the original clinical ketogenic diet anyway. Right, right. We use highly modified versions. Right. Higher in protein. You know, it's got fiber in it.

[00:00:16] Dr. Dominic D'Agostino: It's got a certain fatty acid profile. And it's essentially like, uh, an engineered, personalized, prescriptive metabolic therapy. It's far different than the original diets used for epilepsy.

[00:00:31] Dr. Scott Sherr: All right, Dom, good to see you, my friend 

[00:00:34] Dr. Dominic D'Agostino: Great to see you again, Scott. 

[00:00:35] Dr. Scott Sherr: So actually, Dom, you were one, one of our first guests at the formerly known as the Smarter Not Harder podcast. And now, as we are now the Health Optimization Medicine podcast, and I really wanted to bring you back because you are the premier researcher, the guy that knows more about the world of the ketogenic diet, ketogenic metabolic therapies more than anybody.

[00:00:55] Dr. Scott Sherr: And I think what was super interesting is that, you know, it became like this fad [00:01:00] thing, as you and I know. Like three or four years ago, everything was like keto everything. Keto ice cream, keto pizza. And like we know how things go with fads. They go up, and they come back down. But it doesn't mean that the, the research is any less relevant because it's not as popular, right?

[00:01:12] Dr. Scott Sherr: And, and actually we have something-- we've seen something similar with, with methylene blue recently at Troscriptions where huge spike in 2025, and now it's, and it's come back down to earth on some level. But it still doesn't mean that there isn't significant amounts of potential with this particular compound.

[00:01:29] Dr. Scott Sherr: So i- I'm really happy you've been out there on the airwaves, you know, doing your thing and talking. And, and today what I wanted to do is that, like, personally, I've been confused with all the types of ketogenic products that have been on the market. You know, there's, there's the, the beta-hydroxybutyrates.

[00:01:44] Dr. Scott Sherr: There's acetoacetates. There's, there's the 1,3-butanediol. So I think maybe in the beginning before we get into, you know, the details and, and talking about some of the cool things that you're doing in research, maybe kind of define or just give, give us the lay of the land, Dom. Like, what's happening in the world of a ketogenic supplementation and, and then, you know, maybe if you want, what we can do as a starting point, we can define what ketone metabolic therapies are, and then from there kind of talk about the lay of the land as it is now.

[00:02:11] Dr. Dominic D'Agostino: Yeah. I'm glad you brought up sort of, uh, I guess you're referring to, like, the Google Analytics on keto. Yes. Yeah Kind of exploded maybe about 10 years ago or something. So I pay far less attention to the Google Analytics, but my attention is typically paid to PubMed. Hmm. So if you look at PubMed, which is peer-reviewed literature on ketogenic diets and ketone supplementation, and if you look on clinicaltrials.gov, which is registered clinical trials doing research on ketogenic diets or ketone supplements, that growth has been exponential and has actually gone up significantly in the last five years, like exponentially.

[00:02:49] Dr. Dominic D'Agostino: Hmm. 

[00:02:49] Dr. Scott Sherr: Mm-hmm. 

[00:02:49] Dr. Dominic D'Agostino: But I think Google Trends have their mind of their own depending upon what influencer is talking about them. Yeah. So from my perspective as a research scientist, yeah, I get-- I'm more excited now than ever because the [00:03:00] trajectory of ketone research is, is growing exponentially. Hmm. So we use the term ketone metabolic therapy or ketogenic metabolic therapy to describe, uh, a ketogenic diet and different versions of that, but also exogenous ketone supplementation, which there are many forms of that in the form of exogenous electrolyte salts, ketone salts, uh, ketone esters, diols, 1,3-butanediol is a precursor.

[00:03:26] Dr. Dominic D'Agostino: MCT is considered, uh, a ketogenic, uh, supplement. And, you know, we've kind of, um, I mean, on paper we have like 30 different com- compounds, right? That are very ketogenic, that kind of will be bioactive in some way when they're orally consumed. So that's a pretty big category that's emerging in sort of the innovative aspect of a ketone.

[00:03:45] Dr. Dominic D'Agostino: And these things are not mutually exclusive. So you have ketogenic diets, and then you have ketone supplementation, and things like intermittent fasting, which can produce ketosis. So these things can be used situationally, you know, in combination or as a standalone kind of [00:04:00] therapy, right? 

[00:04:00] Dr. Scott Sherr: Right. I mean, I, I think certainly the, there's a very much of difference between being in the research world and seeing what's going on versus the popular, you know, the, the popular world of fads.

[00:04:10] Dr. Scott Sherr: And, and that's wh- I can imagine why you have to avoid the word diet, is because obviously fad and diet are very much combined in popular culture, right? And there's a significant difference as well when we're talking about, you know, the ketogenic diet versus ketone supplementation, right? And, and I think that, you know, what, what's happened a lot over the last several years is that you know what?

[00:04:30] Dr. Scott Sherr: You don't have to follow the diet. All you need to be is on the supplements, right? But I think that's a little bit of a Not exactly correct idea. So how do you typically, um, piece that out for people when you say, "You know what? Like, you should be on the ketogenic diet," or, "Maybe you should be on supplementation to help ketones"?

[00:04:45] Dr. Scott Sherr: It very much depends on the person, I would imagine. How do you think about that? 

[00:04:47] Dr. Dominic D'Agostino: Yeah. It's, it's, it's a good topic, uh, a good topic of discussion, 'cause I think people that market ketone supplements, uh, talk about it as a replacement to a diet. Uh, and that's [00:05:00] not... So there are definitely overlapping physiological and metabolic similarities- Mm-hmm

[00:05:07] Dr. Dominic D'Agostino: with ketones, but a clinical ketogenic diet would involve a level of carbohydrate restriction that significantly shifts your metabolism to fat, fatty acid oxidation and ketone metabolism. Right, right. So that, that's a big... And when you, if you are on a high-carb diet and you're take exogenous ketones, you are shifting metabolism more towards ketone metabolism, but not necessarily fatty acid metabolism.

[00:05:33] Dr. Dominic D'Agostino: So, uh, although ideally, I mean, my approach, what I do is like a low-carb, if you wanna call it, I don't like the term Mediterranean-ish diet- Mm-hmm ... but sort of a, a higher protein ketogenic diet that has a mix of, you know, vegetables and fruits and things like that. Mm-hmm. But it's, it's restricted enough in digestible carbohydrates that I maintain like a, a low level of nutritional ketosis, bouncing around 0.5 to one [00:06:00] millimole later in the day, and then I, you know, supplement periodically, situationally when it's, when it's, you know, beneficial.

[00:06:06] Dr. Dominic D'Agostino: Yeah. And, and also, you know, on some days I, I won't have the first meal until like noon or 2:00, and if I have a heavy workload in the morning- 

[00:06:12] Dr. Scott Sherr: Yeah ... 

[00:06:13] Dr. Dominic D'Agostino: I just tend to be a little bit more lucid and, and quick with my thinking and, and everything. So that's an important, like, sort of consideration. The problem with a ketogenic diet will always be, uh, for, for many people, the high fat.

[00:06:27] Dr. Scott Sherr: Yeah, 

[00:06:28] Dr. Dominic D'Agostino: for sure. So it is hard for, especially for people who have a, you know, high metabolism, to consume that amount of fat, and consuming that amount of fat every day, all day, every day, uh, can produce some abnormalities in blood work that- Yeah, yeah ... are maybe not perceived as, like, optimal Although my metabolism, you know, d- was pretty quick to shift over to fat and ketones, uh, I did have a remarkably elevated LDL cholesterol and ApoB, and I think the jury's still out on that, whether that sustained [00:07:00] super hyper-elevation.

[00:07:01] Dr. Dominic D'Agostino: Uh, I err on the side of caution, and I'm not willing to take a statin, but my genetics are such that I, I am a hyper-absorber. 

[00:07:10] Dr. Scott Sherr: Right. 

[00:07:11] Dr. Dominic D'Agostino: And I do have a mutation in the MPC1 L1 transporter that in the gut, you know. So a tiny dose of ezetimibe, actually I just split it in half, and, uh, will drop my ApoB and LDL in half, and that was like...

[00:07:24] Dr. Dominic D'Agostino: I thought it was very unique to me, but I talk to other people that have that, although my, my mutation is particularly unique. Hmm. Uh, but it also d- lowered my triglycerides a bit, and I don't really have any- Hmm ... side effects associated with taking that drug. It works very specific, very mechanistically, and what I would be concerned about is taking a statin, especially a lipophilic statin that crosses the blood-brain barrier And decreases cholesterol synthesis in the muscles and in the brain especially because the brain...

[00:07:56] Dr. Dominic D'Agostino: I mean, cholesterol is amazing and it does- Yes, 

[00:07:59] Dr. Scott Sherr: it is. Yeah ... [00:08:00] benefit 

[00:08:00] Dr. Dominic D'Agostino: from a neuroscientist perspective. Yeah. And also from a, if you're exercising, the tissue remodeling associated with skeletal muscle protein synthesis following resistive training has a high requirement for cholesterol. So you do not want to be globally, you know, inhibiting the synthesis of cholesterol.

[00:08:17] Dr. Dominic D'Agostino: So that's, like, an important... These are things- Yeah ... like, really not discussed by statin enthusiasts. 

[00:08:22] Dr. Scott Sherr: Yeah. Yeah. This is, it's an important point, and may- and maybe we can harp on it for a minute because, I mean, y- I was just talking to another patient of mine yesterday, um, and they're trying to get his LDL below 55.

[00:08:33] Dr. Scott Sherr: Like, that's the newest of these recommendations. And, you know, it sounds like... I mean, I worry about this too from a, from a lot of different reasons. Yeah. I mean, certainly the lipophilic ones are getting into the brain. But, you know, what you, what you see in some of the studies too, like, and which is interesting, that statins sometimes can have pleiotropic effects for as an anti-inflammatory.

[00:08:51] Dr. Scott Sherr: I mean, using- Absolutely ... in anticancer protocols as well. So I guess I kind of come to hear is that it's not a one-size-fits-all. It really depends on the situation. But I do worry about, you know, [00:09:00] driving people's LDLs down to, to 50 and using really high-dose statins to do it for, for the reason you just mentioned, along with its effect on the mitochondria as well.

[00:09:08] Dr. Dominic D'Agostino: Yeah. And the dose is important. You know, the side effects come, you know, when you're pushing, you know, 20, 40, 60 milligrams of the stuff. But, you know, my parents are on, you know, baby dose of statins. And, and in certain contexts, I think, I think it's totally okay because you do have the pleiotropic effects.

[00:09:24] Dr. Dominic D'Agostino: So- Yeah, yeah ... if you're not getting the benefits from the LDL lowering, there are other benefits you are deriving from it. And I do think the, the, the negative effects are highly dose-dependent. I remember my mom took the, a pretty big dose, and it really made her sick. Hmm. Very much sick. And I think she had to change to another one, but taking a tiny fraction of the original dose.

[00:09:44] Dr. Dominic D'Agostino: And I, when I was in, uh, these drugs came out in, like, used ex- uh, they gained popularity in the, like, the mid-'90s. And I was- Yep ... doing, like, landscaping and, and work outside on the farm and all that. And I worked with a, a guy that was pretty active, and he started using it, and it crippled him. [00:10:00] Like- Yeah, yeah

[00:10:00] Dr. Dominic D'Agostino: I think he had crippling pain and things like that. And I remember it 'cause I think the original, you know, statins were prescribed at a pretty high dose. And I think now we know that- Yeah ... you know, that's not a good thing to do. 

[00:10:12] Dr. Scott Sherr: The Health Optimization Medicine Conference is happening. Two days of events, October 2nd and 3rd, Chicago, Illinois, at the Drake Hotel.

[00:10:19] Dr. Scott Sherr: CMEs available to practitioners who need them. Just 150 people with amazing speakers on the cutting edge of health and wellness. This is a community. It's not your average conference. If you're interested, go to homehope.org and save 25% on your ticket by using conference25 at checkout I hope to see you there.

[00:10:37] Dr. Scott Sherr: Yeah, speaking of, I mean, gr- on the, on the topic, did you see the recent study on metformin and VO2 max? Uh, that was kind of crazy, too. Yeah, the quick and dirty of it is that, you know, metformin is an anti-diabetic drug that's been around forever, right? But, but it's also a complex one inhibitor in the mitochondria.

[00:10:51] Dr. Scott Sherr: Yeah. So it, it actually causes more oxidative load, and the, the, the goal of this drug, at least on some level, is to have you, to force you make, make more mitochondria to, to keep up, you [00:11:00] know, as a result. Yeah. Um, it also has, uh, you know, uh, decreasing blood sugar. But they found that if, if you were using it with exercise, your VO2 max increases were 50% less than those were, that were not using metformin.

[00:11:12] Dr. Scott Sherr: Yeah. Yeah. So a, a big deal, right? And I think we, we always have to remember that there's always gonna be, like, a risk versus benefit, and there's always a network effect on this. And even with statins, like, we, we see people's hormones drop to the tank, right? We see their testosterone level go down. We see, you know, some of their DH- their other adrenal hormones go down.

[00:11:28] Dr. Scott Sherr: If you're not compensating for these things, you know, it's... And, and that's what... The, the main aspect of the study was, like, if you're taking m- metformin and you're metabolically relatively healthy, you should not be taking metformin. 

[00:11:39] Dr. Dominic D'Agostino: Yeah. We studied it in the context of cancer cells. So my former- Oh? ... PhD student, Nathan Ward, he has a lab now at the Moffitt- Yeah

[00:11:46] Dr. Dominic D'Agostino: Cancer Center. Oh, yeah, yeah. But, um, yeah, I mean, we published over 10 years ago and showed that that superoxide production was elevated in response to that. So it, it's functioning as a weak mitochondrial toxin, and when you're taking [00:12:00] metformin, your liver, it's kind of de-energized in a way that doesn't, you know, do the Cori cycle too well.

[00:12:06] Dr. Dominic D'Agostino: So- Hmm. Yes ... you're making lactic a- that lactic acid goes back from the muscles to the liver. It's also because you're kind of, uh, de-energizing the liver in a way. You're decreasing gluconeogenesis, so that has the glucose-lowering effect. But it impairs, you know, various aspects of, of liver function through, you know, increased reactive oxygen species, you know, uh, complex I.

[00:12:28] Dr. Dominic D'Agostino: Mm-hmm. Uh, and we measure that with dihydrero thium, and it was very clear that you can, you can kind of see that with metformin. And I experienced, when I was experimenting with metformin, I stopped a long time ago, but really intense exercise made me dizzy and kind of, like- Yeah ... really tanked me. 

[00:12:44] Dr. Scott Sherr: I saw this with some of my patients as well- Yeah

[00:12:46] Dr. Scott Sherr: you know, when they were using it. Had a couple patients that were on it off-label in the beginning, and then I saw how terrible they felt after exercising. I'm like, there's something, something going on here. So that, that signal's been around for a while. Yeah. I mean, maybe as a quick primer on how the [00:13:00] ketones work in the mitochondria would be helpful here because there's obviously multiple different types.

[00:13:03] Dr. Scott Sherr: Like, we talk about oxidative phosphorylation, we talk about the complexes, like the people that are listening on this podcast, we talk about these science in a very deep- Yeah ... you know, sort of into the electron transport chain a lot. Like, if you're thinking about ketones itself, why are they potentially more efficient than glucose, for example, when we are trying to make energy, uh, in the mitochondria?

[00:13:22] Dr. Dominic D'Agostino: Mm-hmm. Yeah. So ketones can be an energetic substrate, you know, in the brain and the mitochondria. And when ketones are metabolized in- metabolized to generate ATP, our energy currency, right? They have a unique capability, and this was first shown by, I think, by Dr. Richard Veech, who published- Hmm. 

[00:13:40] Dr. Scott Sherr: Mm-hmm ... 

[00:13:40] Dr. Dominic D'Agostino: in the, in the heart, and we are assuming this also happens in the brain.

[00:13:45] Dr. Dominic D'Agostino: And there's like cell-based studies, but his-- He had a very unique model. He had a working heart preparation where he can actually measure the hydraulic efficiency of the heart, like the pumping- Wow. Okay ... of the heart. Okay. In the context of like glucose and, and insulin and then [00:14:00] insulin, you know, without insulin, they would give ketones, and essentially showed that the hydraulic efficiency of the heart was remarkably enhanced when it metabolized ketones relative to glucose And that hydraulic efficiency, Sato was the first author, it was like 1995 they showed this, was primarily due to oxidizing Q.

[00:14:19] Dr. Dominic D'Agostino: So you had less leak of the electrons at the level of, you know, complex one and two, the semi- Right. ... ubiquinone site. So- Yep. But yeah, by oxidizing Q you have basically tighter electron flow, and so tighter electron flow- Less leakage. Yeah. You get a generation of more reduced intermediates to drive the, the, you know, the electron transport chain, so through the TCA cycle.

[00:14:40] Dr. Dominic D'Agostino: And the reduction in superoxide, which is a precursor to more reactive intermediates, so that goes to hydrogen peroxide and then can go to like hydroxyl radical, and then that's very, very damaging- Yep. Mm-hmm ... to membrane lipids and proteins and nucleic acids. But superoxide in and of itself is not super reactive, but it gets broken down to other [00:15:00] things.

[00:15:00] Dr. Dominic D'Agostino: What ketones do, it reduces superoxide production overall, and we see that. I spent my whole postdoctoral fellowship, uh, developing ways to measure ROS production, um, using dihydroethidium and many different ROS dyes. That was like, I spent years doing that. Mm-hmm. So that was very apparent in cell-based systems and also like brain slices and tissue slices and things like that.

[00:15:23] Dr. Dominic D'Agostino: So you're making less superoxide, but it's also enhancing production of antioxidant, endogenous antioxidant mechanisms from, you know, superoxide dismutase to catalase to glutathione, things like that, uh, Nrf2. Like these things are all... And it's doing that through a number of different mechanisms, some of them even epigenetic, we know now through beta-hydroxybutyration.

[00:15:45] Dr. Dominic D'Agostino: So there's multiple mechanisms through which ketones can be energetically favorable but also reduce ROS production and endogenous ROS production and also enhance endogenous antioxidant capacity [00:16:00] of the cells. And it can vary between tissues too. So a lot of- Mm ... what I'm talking about from my experience is the brain, but it- Right

[00:16:06] Dr. Dominic D'Agostino: happens, uh, uh, presumably like in the muscle and other areas. I've not studied muscle, but mostly what we study is the brain. Mm-hmm. And it does happen in, in brain cells for sure, and then other investigators have looked at the heart. 

[00:16:18] Dr. Scott Sherr: Right. And this is, this is direct correlation to some of the research that you were initially doing with the Office of Naval Research and looking at- 

[00:16:24] Dr. Dominic D'Agostino: Yeah

[00:16:25] Dr. Scott Sherr: preventing Navy SEALs from having seizures at, at pressure, right? 

[00:16:28] Dr. Dominic D'Agostino: Yeah. Yeah, 'cause as you know, like, the limitation of hyperbaric oxygen therapy or diving- 

[00:16:34] Dr. Scott Sherr: Mm-hmm ... 

[00:16:34] Dr. Dominic D'Agostino: especially with a closed circuit rebreather, is central nervous system oxygen toxicity. And if you stay down too long, even if you don't get CNS ox tox, if that duration is very long, you sort of get pulmonary oxygen toxicity.

[00:16:46] Dr. Scott Sherr: Mm-hmm. 

[00:16:46] Dr. Dominic D'Agostino: So that'll happen even without pressure. I mean, you're in a room with 100% oxygen, within, like, a day or two you'll get... You know, you'll die of pulmonary oxygen toxicity. 

[00:16:53] Dr. Scott Sherr: Yes. Yeah. So- Continuous people on, on, on ventilators, we see this all the time. Yeah. Right? So yeah. 

[00:16:57] Dr. Dominic D'Agostino: Yeah. 

[00:16:57] Dr. Scott Sherr: Yeah. Yeah. 

[00:16:58] Dr. Dominic D'Agostino: So these are considerations.

[00:17:00] Dr. Dominic D'Agostino: Ketones t- tend to help both, in both situations, but they do by providing the brain an alternative form of energy from a bioenergetic perspective and also an antioxidant perspective. It's working through that. And also it's activating, uh, systems like glutamic acid decarboxylase, and that converts more glutamate to GABA.

[00:17:19] Dr. Dominic D'Agostino: Right. Uh, so there's a benefit there. And we've shown that in various, like, animal models of diseases, but the wild type animals, which, you know, animals that don't even have diseases also, you, you get more glutamate to GABA. So, so I think the... And then we've studied adenosine and the NLRP3 inflammasome, and there's multiple mechanisms.

[00:17:38] Dr. Dominic D'Agostino: I, I thought it would be sort of easy and we'd identify, like, a single mechanism that was- Sure ... the driver. But it does not. It seems to be very context-dependent, in some cases tissue-dependent, and, like, situationally sort of different too. But, but- Yeah ... that's metabolism, right? So metabolism- That's 

[00:17:53] Dr. Scott Sherr: right.

[00:17:53] Dr. Scott Sherr: Everything's all connected, right? There's all these- 

[00:17:55] Dr. Dominic D'Agostino: Everything... Yeah ... different hubs throughout the network, and you can kind of hit the, the network in different [00:18:00] ways. And I think of- Right ... you know, w- the physiological system is like, you know, our bodies are basically networks and, uh- 

[00:18:08] Dr. Scott Sherr: Yeah, yeah ... 

[00:18:08] Dr. Dominic D'Agostino: hubs that are more relevant and context-dependent than other hubs.

[00:18:13] Dr. Scott Sherr: And this is what we talk about all the time, right, at, at Health Optimization Medicine, whereas everything is all networked together. If you move one node in the system, things are going to compensate. There's feedback loops everywhere. This is why the classic is go get TRT Everything else is gonna go down, all your other hormones, if the testosterone's going elevated, right?

[00:18:30] Dr. Scott Sherr: Yeah. And so your thyroid's gonna go crazy. And so it's, it's such an important thing to know. And like, you know, always, you've always seen those diagrams, like of the spaghetti-looking stuff on the wall. That's all the diagrams of everything that's happening for energy metabolism. When you're thinking about exogenous ketones specifically and how to utilize these most effectively, you know, what are, like, the best use cases here?

[00:18:49] Dr. Scott Sherr: Like, what's the dosing expectations we might have for, like, certain types of various types of performance like, you know, cardiomet- cardiometabolic. You talked about the heart, for example, stress resilience, mood. Like, are there particular types of [00:19:00] ketones that are better than other ketones for particular situations?

[00:19:03] Dr. Scott Sherr: Or how do you think about this, Dom? 

[00:19:05] Dr. Dominic D'Agostino: Our research program sort of got spearheaded by looking at ketone esters because they were, like, sort of the, the most potent ketogenic agents. Right. So I just went right to the top, you know? Right. So the first one was a beta-hydroxybutyrate monoester, and that did not have anti-seizure effects.

[00:19:21] Dr. Dominic D'Agostino: Uh, although the NIH and Oxford had studied it for exercise performance and seemed to be a signal there, although that's kind of debatable. Right. I think it's v- I think it's... There's a, there's an, an performance enhancement under certain environmental conditions and under stress or conditions like if you're really sleep-deprived, hypoxic 

[00:19:38] Dr. Scott Sherr: or hyperoxic.

[00:19:38] Dr. Scott Sherr: Specifically with the esters you mean? Or- 

[00:19:40] Dr. Dominic D'Agostino: Yeah, with the esters. Okay. Okay. I think they do have certain use applications, especially for military and extreme environments. Ab- Hmm. Absolutely. Okay. Although the, the beta-hydroxybutyrate monoester did not prevent seizures, so we sort of developed with the late Patrick Arnold, that we developed a 1,3-butanediol diester with acetoacetate.[00:20:00] 

[00:20:00] Dr. Dominic D'Agostino: And it d- you know, it generates in the blood a beta-hydroxybutyrate and acetoacetate, which was really important for seizure, pr- pr- preventing seizures. 

[00:20:09] Dr. Scott Sherr: Hmm. 

[00:20:10] Dr. Dominic D'Agostino: And some of the reasons for that is that it maintains a redox balance. Hmm. If you get a, a big dose of BHB, that can cause reductive stress kind of.

[00:20:20] Dr. Dominic D'Agostino: And, and it- Yes, right. 

[00:20:21] Dr. Scott Sherr: It's a reverse stress, yeah. Yeah 

[00:20:22] Dr. Dominic D'Agostino: But the, the b- you know, the ratio of acetoacetate, the beta-hydroxybutyrate would kind of mimic that which was found in the diet. So that was, like, something that was interesting. And then the acetoacetate spontaneously decarboxylates to acetone. Right.

[00:20:37] Dr. Dominic D'Agostino: And acetone sort of had interesting effects on the, on the receptors and has like a, a, like subnarcotic levels of acetone seems to dampen hyperexcitability. Hmm. Okay. So there's like, you know- Hmm ... there's a lot more to unpack there. But d- you know, just different ketogenic agents You know, different-- But what we didn't know at the time, but we did a study with rats where we fed them [00:21:00] 1,3-butanediol and the esters that were derived from 1,3-butanediol, and if we give them high doses chronically, we saw some liver abnormalities and see some abnormalities maybe in the blood work too a little bit.

[00:21:12] Dr. Dominic D'Agostino: Yeah. Uh, but with the histology- We can talk to you ... you start to see, uh, sinusoidal, like, dilation. Like, and you start to see, like, fat droplets, and you start to see pre-necrotic effects, like, in the liver that- Okay ... were concerning to me. And also, with the human randomized controlled studies that just came out in the last two years The, the maximum dose of 1,3-butanediol is 34 grams, I think, and when subjects consume that, 40% of them got dizzy.

[00:21:40] Dr. Dominic D'Agostino: And these were healthy, robust subjects. Could-- imagine giving that, that dose, which is not really that high, to, to subjects that are, like, you know, older or to have cognitive... So 1,3-butanediol is an alcohol. Right. It's a di-alcohol technically. Right, right. Yeah. It has to go through alcohol dehydrogenase and, and aldehyde dehydrogenase, and it kicks off a BHB [00:22:00] aldehyde.

[00:22:00] Dr. Dominic D'Agostino: It's short-lived, but in-- if you take a lot of it, then it's, can stick around, and aldehydes are not good to have. 

[00:22:06] Dr. Scott Sherr: Yeah. So- Those, those rat studies that you're talking about when you had the elevated liver enzymes in them, was it a dose that would be relevant to humans at all? Or was it something-- and you talked about how long they were taking it as well.

[00:22:16] Dr. Scott Sherr: Maybe those would be helpful, 'cause I know there's, there's a lot of controversy here, so. 

[00:22:19] Dr. Dominic D'Agostino: The dose with the 1,3-butanediol specifically would be a dose that would keep a human at two millimolars ketones throughout the duration of the day. Okay. So for me, like someone like me, that's like, that's like 100 milliliters per day.

[00:22:34] Dr. Dominic D'Agostino: That's a lot. But that's what you need to do to be in like therapeutic ketosis just to keep that one to two to three. And that's 1,3-butanediol. And now the beta-hydroxybutyrate monoester is technically 1,3-butanediol esterified to BHB. Okay. It's 51% molar concentration, 51% chemically 1,3-butanediol. So when you take that, you are delivering 1,3-butanediol too.

[00:22:56] Dr. Dominic D'Agostino: And I think the take-home message is that there are-- like [00:23:00] these molecules have been around since the '50s and '60s, like 1,3-butanediol, you know? And now there are definitely like new molecules that are equally or more potent that have no toxicity. So, you know, we've inadvertently killed quite a few animals with these agents just trying to figure out how to dose them when we first got them.

[00:23:18] Dr. Scott Sherr: Right, right, 

[00:23:18] Dr. Dominic D'Agostino: right. And that created a lot of confusion and, and sort of, you know, pain on our end, uh, to do that, to really titrate the dosages down. But when we're working with like the glycerol triester of aceto- or the glycerol triester or various ketone salts- Yeah ... uh, the racemic salts seem to be, you know, very, especially when you combine them with MCT, and then we have a whole catalog of different agents.

[00:23:41] Dr. Dominic D'Agostino: We never get any toxicity in agents, in ketogenic agents that are not 1,3-butanediol or 1,3-butanediol, you know, associated molecules. They have their place, and I think, you know, they were a big part of our original research, but now we like to pivot it away towards molecules that don't [00:24:00] have any long-term toxicity or cr- you know, with chronic use.

[00:24:03] Dr. Dominic D'Agostino: Right. Also, 1,3-butanediol because it is an alcohol, it can create dependency and also withdrawal symptoms- Hmm ... when you're, if you're taking it and you get off of it. So solid evidence, you know, with that too. Uh- Is 

[00:24:14] Dr. Scott Sherr: the dosing super high for that too as far as how much you're taking? Or c- or you're not really sure at this point?

[00:24:19] Dr. Dominic D'Agostino: Same dose as ethanol, so actually a little bit lower. You get the withdrawal and the chronic... But it would be equivalent to like Three shots per day. Three 30 milliliter shots a day. Someone my size, you know, 100 kilos 

[00:24:32] Dr. Scott Sherr: And now 30 ML shots of, of 1,3-butanediol you're talking about, right? Yeah. Yeah. Yep, yep. Is it common?

[00:24:37] Dr. Scott Sherr: I, I just don't under- I don't, maybe I just don't know. Is it common for people to be using that much on a regular basis, do you think, at this point? Or is it not that common overall when people are using these? Well, 

[00:24:45] Dr. Dominic D'Agostino: you know, the shots, I think they're Well, the shots that I w- was taking, it, I don't know, I'd have to figure out the dosage.

[00:24:53] Dr. Dominic D'Agostino: It's like- Yeah, yeah ... 10 to, 10 to 30 milliliters, I think. You know, one product is 30 milliliters, I think maybe in one shot or [00:25:00] whatever. 

[00:25:00] Dr. Scott Sherr: Gotcha. Okay. 

[00:25:01] Dr. Dominic D'Agostino: Uh, the, the point is, like, the amount that's needed to produce a level of ketones that's therapeutic- 

[00:25:07] Dr. Scott Sherr: Right. 

[00:25:07] Dr. Dominic D'Agostino: Yeah ... is the amount that actually causes- 

[00:25:10] Dr. Scott Sherr: Causes the liver stress

[00:25:11] Dr. Dominic D'Agostino: you know, uh- Yeah. 

[00:25:11] Dr. Scott Sherr: Yeah ... 

[00:25:11] Dr. Dominic D'Agostino: the liver stress, but also over time, and we're talking like months, used every day chronically. Uh- Dependence potentially ... so, so that's sort of the issue there. Yeah. With 

[00:25:19] Dr. Scott Sherr: that 

[00:25:19] Dr. Dominic D'Agostino: said- 

[00:25:19] Dr. Scott Sherr: And that's the dependence piece, right? Yeah, yeah. 

[00:25:21] Dr. Dominic D'Agostino: Yeah. With that said- Yeah ... I think- Yeah ... I think some of these molecules work really well in formulations, right?

[00:25:25] Dr. Dominic D'Agostino: So w- so we saw that toxicity, animals died, they become, uh- Yeah ... ketoacidosis. So what we did, and actually Chilla, my wife, published a paper where we just simply took the ester and mixed it a 50% MCT- Mm-hmm ... with the ester, and that worked. Everything that I'm talking about here is in context of acute administration.

[00:25:44] Dr. Dominic D'Agostino: Sure. So you're still getting that, like, toxicity associated with it, and that concerns me. So, uh, so if you are gonna use like 1,3-butanediol or the ketone esters, think about formulations, and we've done, had did some nice work with the ketone salt and ketone ester [00:26:00] formulations for seizures. 

[00:26:01] Dr. Scott Sherr: Mm-hmm. 

[00:26:01] Dr. Dominic D'Agostino: And then, uh, also when you deliver an exogenous ketone, whether it's an ester or salt with MCT, which is a ketogenic fat, that significantly delays gastric absorption.

[00:26:13] Dr. Scott Sherr: Right. 

[00:26:13] Dr. Dominic D'Agostino: And then the MCT generates endogenously, like your own ketones- Right. Right ... and then MCT can cross the blood-brain barrier and be used as fuel. So these... And, and then- Right ... you're also slowing the digestion, uh, and you're also slowing the metabolism of 1,3-butanediol in a way that's sort of doesn't produce as much of that BHB aldehyde and, and stress the liver.

[00:26:34] Dr. Dominic D'Agostino: Yeah. So, so I think it- That, that's helpful. Yeah ... it's sort of a formulation issue. Yeah. However, you know, there's things that are available, things in the pipeline. Like if for everyday use, you wanna use a BHB electrolyte. So I think that would be... However, for use applications, you might want to use the esters, and you can formulate it in the ways- 

[00:26:52] Dr. Scott Sherr: To 

[00:26:52] Dr. Dominic D'Agostino: make it a little bit safer for you

[00:26:52] Dr. Dominic D'Agostino: and then you have the different enantiomers of BHB, right? So- Right. 

[00:26:55] Dr. Scott Sherr: Yeah, right, yeah ... 

[00:26:56] Dr. Dominic D'Agostino: the market share has really focused on D, beta-hydroxybutyrate, [00:27:00] 'cause our body makes mostly that. Although, if you're on a ketogenic diet and you were to take out somebody's heart, 30% of that is L-BHB, believe it or not. So there's a, there's a, a metabolic pathway that's producing the L.

[00:27:14] Dr. Dominic D'Agostino: And L-BHB delivered as a supplement produces a cardiac output that's five times higher than the D. So this was published- Hmm ... in the Journal of American Heart Association and also in the American Heart Association journal called, uh, Circulation. And w- w- the-- We don't know why, but it decreased peripheral vascular resistance.

[00:27:34] Dr. Dominic D'Agostino: And there's some speculation that it could be nitric oxide, um- Hmm The endothelium gets relaxed with BHB, with the LBHB, just because when you consume the LBHB, it's resistant to ketolysis, so it stays circulating more, so it's hitting all the different- 

[00:27:49] Dr. Scott Sherr: Interesting. Okay ... 

[00:27:50] Dr. Dominic D'Agostino: ketone signaling, and that could be the GPR109A receptor, could be adenosine.

[00:27:55] Dr. Dominic D'Agostino: Like our adenosine signal is really high- Hmm ... in our metabolomics. We have not published that [00:28:00] yet. Yeah. So adenosine is sort of, you know, ATP, adenosine triphosphate. If a- adenosine is simply part of normal metabolic processes- Right ... and it builds up during the day. Mm-hmm. And the most important thing to remember is, in regard to adenosine, is that it is a very potent vasodilator.

[00:28:18] Dr. Dominic D'Agostino: Yes. Like if you give ade- ade- you could like, if you give someone a shot of adenosine, I think they just die. Like they just you would- Well, 

[00:28:24] Dr. Scott Sherr: it depends on the shot. We actually, we use it, we use it- Yeah ... therapeutically for somebody in ser- super ventricular tachycardia because it- 

[00:28:30] Dr. Dominic D'Agostino: Absolutely. 

[00:28:31] Dr. Scott Sherr: Yeah ... it, yeah.

[00:28:32] Dr. Scott Sherr: Because it, it 

[00:28:32] Dr. Dominic D'Agostino: blocks- It's potent. I mean- 

[00:28:33] Dr. Scott Sherr: Yes. Yeah ... 

[00:28:33] Dr. Dominic D'Agostino: my point is that it's very potent- Yeah ... and it's a potent vasodilator. And you, when you're in ketosis, when you deliver an exogenous ketone, the adenosine levels go up quite high, and that could maybe give a little bit of the, a little bit of sedating effects, especially with the esters that are a little bit higher.

[00:28:50] Dr. Dominic D'Agostino: Some people- Mm-hmm ... get a little bit sleepy. Uh- 

[00:28:51] Dr. Scott Sherr: Maybe the dizziness as well that you mentioned too? 

[00:28:53] Dr. Dominic D'Agostino: Maybe. I don't... Yeah. Yeah. Maybe dizziness. 

[00:28:55] Dr. Scott Sherr: Okay. 

[00:28:55] Dr. Dominic D'Agostino: Uh, but it also has neuroprotective effects, and adenosine, there's a book this thick written [00:29:00] by Dr. Susan Masino on adenosine, and she's a friend and colleague of mine, and it's just the adenosine receptors and, and metabolism- Yeah

[00:29:07] Dr. Dominic D'Agostino: is a very interesting area. But I think importantly, like if your ketones are elevated by virtue of fasting, diet, or supplementation, adenosine and adenosine signaling is gonna be higher. That's going to cause vasodilation, and that could increase brain blood flow and blood flow to peripheral tissues. So I think it, there's a strong rationale for ketone supplementation for recovery, so enhancing that blood flow to peripheral tissues, to your brain, and just can overall enhance it.

[00:29:39] Dr. Dominic D'Agostino: And we've seen that in our wound healing model. I mean- Right ... there's plenty of publications out there, like 20 or 30% increase in brain blood flow with acute administration of ketogenic agents. So that's something not, not quite talked about, but you have, you know, American Heart Association journals have like published.

[00:29:56] Dr. Dominic D'Agostino: And when you... It seems to be you could give [00:30:00] DBHB and LBHB, but DBHB gets burned up as energy quickly, and that's a good thing, and the LBHB stays in circulation longer and may convey or endow like the system with, with more of this vasodilation effect, this reduction in peripheral vascular resistance. And I think that's really important to me.

[00:30:20] Dr. Dominic D'Agostino: We have not done the elegant studies to show that. We just showed the effect, like with a Doppler blood flow measurement. 

[00:30:26] Dr. Scott Sherr: Sure. 

[00:30:26] Dr. Dominic D'Agostino: But we have mech- not mechanistically dissected that. And I don't, I don't think anyone has, but I'm aware of a few publications that should be out soon. 

[00:30:33] Dr. Scott Sherr: This actually brings up an interesting point of the dovetailing of you and I many years ago, which is hyperbaric oxygen therapy, right?

[00:30:39] Dr. Scott Sherr: Yeah. And because when, when you and I talked about traumatic brain injury and hyperbaric oxygen therapy, you started talking about this vasodilatory effect, which potentially could be very helpful in the post, you know, concussion optimization of, you know, getting them better, right? And I, and I know you've been very involved in, in hyperbaric medicine for many years in your, in your lab, [00:31:00] and how do you think about the combination of, of hyperbaric therapy and ketones in general in, in, in various ways?

[00:31:07] Dr. Dominic D'Agostino: Yeah. I, I do think there's a synergy there with hyperbaric oxygen and ketone therapy. Uh, I mean, that was what got us funded is that- Yeah ... ketosis prevents oxygen toxicity seizures, but I was studying the negative effects of hy- hyperbaric oxygen, really- I know. I remember. ... like in sheep and mammals, right?

[00:31:25] Dr. Dominic D'Agostino: Yeah. And, uh, but by doing those studies, basically you realize, oh, okay, so hyperbaric oxygen is very therapeutic for, like, you know, 14 different FDA-approved applications. Then there's these emerging applications that are actually more interesting that is just ongoing research on that, like traumatic brain injury, PTSD recovery, and things like that.

[00:31:46] Dr. Dominic D'Agostino: And then with ketones, the ketones are sort of mitigating that potential oxidative stress issue that you- Right ... would get with, like- Right ... too much hyperbaric oxygen, right? Mm-hmm. And it's also, you [00:32:00] know, our brain's capacity to function is limited by two things, oxygen and substrate for energy, glucose or ketones.

[00:32:08] Dr. Dominic D'Agostino: So with hyperbaric oxygen, by re-oxygenating the brain and also giving ketones at the same time, that's a stimulant that happens, you know, in the context of when you're in the hyperbaric chamber, but then you get that pulse of oxygen, and also reactive oxygen species to some extent- But just the cycling of oxygen- Mm-hmm

[00:32:29] Dr. Dominic D'Agostino: can actually have long-term effects too, and activate genes and, and other adaptive mechanisms that, that we call. But I think the, the benefits that you can derive from hyperbaric oxygen therapy can be augmented if you're giving, uh, an alternative fuel that can further enhance cell metabolism and energy before, during, and after that, I think in all contexts.

[00:32:50] Dr. Dominic D'Agostino: But I think from our perspective and from military operational perspective, it makes high concentrations of oxygen more tolerable and also more safe, and it makes [00:33:00] the, the war fighter more resilient. And that can be achieved, you know, with fasting. Well, that's what-- They fasted rats and you know- Sure, sure, sure

[00:33:06] Dr. Dominic D'Agostino: that caught my attention, and I was like, oh. There was a number of inve- And then, you know, then the, the diet had a great track record for seizures, and Office of Navy Research didn't wanna really fund ketogenic diet studies, so they said, "Well, try to investigate, you know, the diet in a pill." So I was like, reluctantly, I was like, "Okay, I'll try it.

[00:33:23] Dr. Dominic D'Agostino: That seems like a big, tall order." But through testing a number of different compounds, we, you know, settled on the ones that, that work, and I think we're kinda just scratching the surface, and it's a very, it's a very nascent field, even though we've been at it for, you know, like 20 years. I, I think there's just, there's, there's many different molecules.

[00:33:42] Dr. Dominic D'Agostino: We don't know the dosage, timing, and scheduling, and then there's very d- you know, different use applications. Mm-hmm. We just know that ketone... It's almost like creatine. When creatine came out The data was pretty compelling. And in 1995, in my exercise science, we had to write, you know, uh, about three ergogenic aids, and, and I wrote [00:34:00] about creatine, and it failed because there was like, there's...

[00:34:03] Dr. Dominic D'Agostino: The, the professor was like, "I've never even heard of this." You know? "There's no evidence behind it." You're, you're 

[00:34:06] Dr. Scott Sherr: 30 years too early there, Dom. Yeah, yeah. 

[00:34:08] Dr. Dominic D'Agostino: I was reading Muscle & Fitness and, and a couple... It was, like, MuscleMag Internet. They were talking about it. Yeah. And I was a little bit overenthusiastic, but now we have, like, 1,000 randomized controlled trials, right?

[00:34:18] Dr. Dominic D'Agostino: On creatine. Right. Sure. I see ketones as sort of there's a parallel there. I think ketones will explode and be the next creatine. It's already gaining- It's already there ... traction. Coming there, yeah. But I do think we need to have a high bar on the rigor of the science. So there's a lot of research being done that's driven by industry.

[00:34:36] Dr. Dominic D'Agostino: Yeah. And I, I don't think the dosage, timing, and scheduling. And, and I think that could involve a whole research project that we're working on, is actually, like, pulling the data to figure out, you know, were the, were the right tests done? Were the, you know, the dosages right? And I think there's a lot that we need to get right in for the foundation of understanding this before we start applying this to, [00:35:00] like, big federally funded research projects, and I think that's gonna save a lot of time, effort, and taxpayers' dollars 

[00:35:06] Dr. Scott Sherr: Yeah

[00:35:06] Dr. Dominic D'Agostino: if we do that. And, um, yeah, and I, I'm really excited to le- you know, kind of leading a group to, to do that. That's great. And we're just in the initial stages of planning it, but, but that's a big project that I'm working on. 

[00:35:17] Dr. Scott Sherr: I look, I look forward to the controversy that you will bring, bringing that such- And because- I think it 

[00:35:22] Dr. Dominic D'Agostino: will be a little controversial, yeah.

[00:35:23] Dr. Scott Sherr: Yeah, I mean, and, and that's okay, like, because you're coming at it from, like, the research side, from the, the rigor of looking at all the data, and that's really what matters the most. I think, you know, for me, as you know, Dom, always it's, it's the clinical application, right? And, and that's what's... And which you've been working on so hard is, like, you've had been doing animal studies on, you know, with ketogenic diets for a long time, and now it's about, and it has been for a while, like, how did this actually work in humans?

[00:35:45] Dr. Scott Sherr: Like, what are we seeing in humans? And, and there's only so much you can know from an animal model. And, and I remember just going back a little bit, you talking about the adenosine system and blood vascular dilation, and we were talking about wound healing, and, like, we'd, we'd love to do a study where we did combination of hyperbaric oxygen with, you know, exogenous [00:36:00] ketones for healing diabetic foot ulcers.

[00:36:02] Dr. Scott Sherr: But it's, it's very difficult to get this stuff approved and done because- Yeah ... again, there's a lot of money that's involved. But looking at this mechanistically and the things that you've been doing has just been transformative, you know, for my practice, right? Because as somebody that's involved in hyperbaric medicine, I use ketones when somebody has a concussion.

[00:36:17] Dr. Scott Sherr: I use ketones when somebody comes with an acute injury. I also- Yeah ... use other things, too, but it's for all the reasons you just mentioned, along with the actual... The other part of it where, you know, there's s- something about recovery here that I wanted to kind of go into, right? Where, like, you mentioned recovery a little bit with ketones and, and there was a study that you were a part of not too long ago talking about exercise and k- ketones specifically.

[00:36:40] Dr. Scott Sherr: Maybe we can go into that because there was, there was a lot of thought, at least in, like, the The fad time of ketones that everybody needed to be taking ketones to perform better from an exercise perspective. You mentioned the ester is maybe under certain duress overall. You could, you know, you can talk about that again if you want, but maybe talk about that study a little bit and what you guys found maybe that was underwhelming and [00:37:00] maybe more compelling than people realize.

[00:37:01] Dr. Dominic D'Agostino: Yeah. Well, we've done numerous studies, and I can give, like, the punchline and the take-home messages from different ones. Yeah. And I think, you know, ketone salts and ketone esters and, and probably MCT too, but we haven't studied that. But exogenous ketones elevating, you know, blood levels to one millimolar, actually getting a little bit higher creates, like, a little bit of an acidic load, I think, and the body has to...

[00:37:23] Dr. Dominic D'Agostino: You know, there's renal and respiratory compensation. So, so- Sure. 

[00:37:25] Dr. Scott Sherr: Sure, 

[00:37:26] Dr. Dominic D'Agostino: yeah ... I think, you know, people out there listening, I, I do- I do-- higher's not better. I've been higher before and got into situations where I could just tell you higher's not better. When-- If you're achieving a one millimolar, that's a significant amount of energy, like, for your cells and your brain to use.

[00:37:41] Dr. Dominic D'Agostino: And, and so, like, one to two is, is pretty, pretty significant. And then also the level that, that you're measuring is not taking into account ketone utilization. So athletes have-- They're dumping a lot of ketones into their tissues. Sure. So that one millimolar is almost like spilling over in surplus reserve, right?

[00:37:59] Dr. Scott Sherr: Okay. '

[00:37:59] Dr. Dominic D'Agostino: Cause your tissues [00:38:00] are quickly sucking it up. So the level in your blood is a, you know, ketone production, ketone utilization, or ketone consumption if it- it's exogenous, and that gets taken up far faster in someone who's, like, an athlete even at rest, right? So- 

[00:38:13] Dr. Scott Sherr: Even somebody that's not fat adapted or anything.

[00:38:15] Dr. Scott Sherr: We're talking about, like, a regular athlete- Yeah ... no matter who they are, right? So- 

[00:38:18] Dr. Dominic D'Agostino: Yeah, yeah, yeah. 

[00:38:18] Dr. Scott Sherr: Right. 

[00:38:19] Dr. Dominic D'Agostino: Yep. But I think, you know, I guess exogenous ketones really got spearheaded by DARPA, and that was, like, a, a NIH Oxford project under the DARPA Warfighter Dominance program, Warfighter Optimization. Mm-hmm.

[00:38:34] Dr. Dominic D'Agostino: And that was in the early 2000s. You know, that was funded, and it looked at rowers, and it looked at exogenous ketones under situations looking at power output and things like that, and there was definitely a signal there. It's like 2% or 3% from the original data, and these were elite rowers, so that's, that's, you know, significant and- 

[00:38:50] Dr. Scott Sherr: Right.

[00:38:50] Dr. Scott Sherr: Sure ... 

[00:38:50] Dr. Dominic D'Agostino: subjects who are at the top in their field. But it is not really translated out into the peer-reviewed randomized controlled trials, right? There's a, a [00:39:00] weak signal there- And I would always... I would say that the benefits of exogenous ketones on exercise performance are really underwhelming. I do think there's a benefit there, but I think we wanna think of like dual fuel.

[00:39:14] Dr. Dominic D'Agostino: Like it's not just keto, it's like- Dual fuel, yep ... ketone, glucose, MCT, like, you know, lactate- Lactate ... lactate. Alpha L-poly lactate. That was used in a product called Cytomax. I think we should think about a variety of different fuels that could enhance- Sure ... anaphoresis, like energy production in general.

[00:39:31] Dr. Dominic D'Agostino: However, ketones have the unique ability to preserve brain energy metabolism and then just general mitochondrial function under periods of oxidative stress and metabolic stress. So that's where ketones really shine. And I think creatine works that way too, like when the system gets overload- loaded, creatine can donate the phosphate.

[00:39:51] Dr. Dominic D'Agostino: Creatine phos- creatine monohydrate gets converted to creatine phosphate, and that can, you know, uh, generate ATP in the context of getting a couple extra reps out [00:40:00] But ketones have a remarkable ability to sort of provide that alternative energy. And from our perspective, it, it tends to work better in the context of stress.

[00:40:11] Dr. Dominic D'Agostino: That could be sleep- Right ... deprivation. It could be- Sure ... hi- it could be hyperoxia, which we've studied, or hypoxia, which we also studied, or limited glucose availability in the context of a calorie deficit, right? You can preserve energy by just, you know, enhancing metabolic flux with ketones. So but if the normal healthy athlete that is just doing their day-to-day events and consuming ketones, I think they're gonna be a little bit disappointed if they're using- Right

[00:40:36] Dr. Dominic D'Agostino: ketones. However, they might, from a muscle performance energetic... However, I think they are in some ways enhancing the central nervous system in a way that could be contributing to red- reduction in perceived exertion and, you know, maintaining CNS function and optimization. Although the signal's pretty weak.

[00:40:56] Dr. Scott Sherr: Okay. 

[00:40:57] Dr. Dominic D'Agostino: So, and the si- that, I have to say that because I have [00:41:00] been on, you know, studying this and it, and it... The signal is there in the context of a stressor. So that could be physical fat- fatigue, mental fatigue, you know, environmental stress, and things like that. So I'm making a very broad statement, but if, you know, the systematic reviews, meta-analysis, like that looks at like ketone augmentation or ergogenic effects in exercise, it, it's still, the jury's still out.

[00:41:24] Dr. Scott Sherr: Understood. Right. 

[00:41:24] Dr. Dominic D'Agostino: And however, if you were to look at, you know, the effect of ketones in the context of extreme environments, then that's where the signal is- Yeah ... you know, there. And that, that's, you know, that's was the appropriate, you know, use case in regard to like military operations and things like that.

[00:41:42] Dr. Dominic D'Agostino: Yeah. Uh, and we still do not know the optimal formulation, dosage, timing. So that's like data even derived from formulations that are probably far from optimal. Sure. And, and in many cases, they're always testing a single, like monotherapy, a single agent. Yes. Where the [00:42:00] real benefits come from, like combining different things.

[00:42:03] Dr. Scott Sherr: And that's always the hardest thing to, to study is combined therapies together. But you also mentioned there might be some additional, maybe more positive signal on the recovery side from exercise as well, right? 

[00:42:13] Dr. Dominic D'Agostino: Yeah. Yeah. And I think, so a lot of these things have been tested You know, almost like caffeine.

[00:42:18] Dr. Dominic D'Agostino: You give a dose and look at power output kind of thing. And, you know, we, we kind of did that i- in, you know, in different anecdotal things where you look at power output and oxygen consumption, you get more power output if you're, like, fueling with ketones. 

[00:42:31] Dr. Scott Sherr: Yeah. 

[00:42:32] Dr. Dominic D'Agostino: Uh, but I think the real thing or the real benefits will be using ketones chronically over time to enhance the adaptive responses to exercise by reducing systemic inflammation, augmenting blood flow, peripheral...

[00:42:48] Dr. Dominic D'Agostino: reducing peripheral vascular resistance- Mm-hmm ... you know, augmenting cardiac output, reducing, you know, the inflammasome activation, and reducing oxidative stress in general. Makes sense. Yeah. So [00:43:00] I think that's where, like, the real, the real benefits are gonna be. 

[00:43:03] Dr. Scott Sherr: Yeah. Well, I- you mentioned a couple times therapeutic ketosis, and I think we-- I would-- I think before we finish up, I have a couple more things, but b- just to kind of talk about this, right?

[00:43:11] Dr. Scott Sherr: When we talked about, like, keeping the, the esters up at two millimolars, that's gonna g- cause liver toxicity in patients, right? You mentioned that giving more energy at one millimolar is typically good for you, how you feel, and how a lot of people are gonna feel. Mm-hmm. Uh, when you talk about the range, the range matters, of course, and it also depends on the person.

[00:43:30] Dr. Scott Sherr: How do you think about therapeutic ketosis at this point now, given all these years that you've been doing this? Because that, there's a huge range. I just thought it may be helpful to kind of go over that briefly. 

[00:43:39] Dr. Dominic D'Agostino: Yeah. I, I think the optimal approach for, like, overall wellness and longevity and things like that would be a low-carb diet that's, like, skirting right on the edge of ketosis, 'cause that means you're optimizing fat oxidation.

[00:43:51] Dr. Dominic D'Agostino: Right. Right, right. So where, like, you're, you know, like, right before a meal, your s- your ketones go up a little bit. So that means, like, you're keeping your body hungry for glucose. That insulin sensitivity is [00:44:00] high. And then periodically, you know, one, two doses a day, three, three doses, uh, do supplemental ketosis, I think would be kind of beneficial.

[00:44:08] Dr. Dominic D'Agostino: And that doesn't have to be chugging an ester. That could be, like, a ketone salt, uh, ideally a DL beta-hydroxybutyrate salt, you know, with, with electrolytes, and you don't have to... You know, similar electrolytes to a common electrolyte supplement. 

[00:44:21] Dr. Scott Sherr: Sure. 

[00:44:21] Dr. Dominic D'Agostino: Sure. So you're getting the electrolytes. You're getting, uh, the salt, and you're, you are boosting the, the ketones in circulation.

[00:44:28] Dr. Dominic D'Agostino: And, you know, I think- We're talking about 

[00:44:30] Dr. Scott Sherr: levels of, like, what here? What, what... If I... On millimolar concentration, what would you s- what would you kind of range there for, like, this kind of person? 

[00:44:36] Dr. Dominic D'Agostino: Yeah. I mean, there's data coming out showing that, like, two or three grams of a BHB salt or BHB is enhancing.

[00:44:46] Dr. Dominic D'Agostino: I'm trying to think. There was a Japanese study that used two or three grams, and it really augmented sleep in a way that improved, uh, deep sleep. 

[00:44:53] Dr. Scott Sherr: Mm-hmm. 

[00:44:53] Dr. Dominic D'Agostino: So there's this sleep study by Japan, and I recently talked with them. Yeah. And, yeah, they're just using two or three [00:45:00] grams a day. And then another study published by the icon in, in protein, Jose Antonio, very well known in the, you know, ISSN and different...

[00:45:09] Dr. Dominic D'Agostino: on protein metabolism. He, he published a study looking at the D and the L beta-hydroxybutyrate showing in- increased reaction time with LBHB, and it was only, like, three grams. So I, I used to always think more is better. Yeah. Yeah. 

[00:45:22] Dr. Scott Sherr: And I 

[00:45:22] Dr. Dominic D'Agostino: think this saves people money. It saves... They can use relatively small doses that you can acquire through ketone salts- 

[00:45:29] Dr. Scott Sherr: Right

[00:45:29] Dr. Dominic D'Agostino: and avert the, the, the taste and the cost of the esters. 

[00:45:32] Dr. Scott Sherr: Right. 

[00:45:33] Dr. Dominic D'Agostino: Uh, and more is definitely not better. I could tell you that from a scientist. Sometimes when levels get into that two, three range, unless you're treating something with an overt pathology. But- 

[00:45:43] Dr. Scott Sherr: Right ... 

[00:45:44] Dr. Dominic D'Agostino: normal healthy subjects, once you get into that three to five millimolar range, then you're basically making them sick.

[00:45:50] Dr. Dominic D'Agostino: You're creating a, a acidic load that needs to be- Yep ... mitigated and then- Then closer to ketoacidosis, yeah ... you know, it's like, it's like energy surplus, right? Yeah, yeah. It's like you're putting more energy into the system and creating- Yeah ... an energy [00:46:00] surplus. 

[00:46:00] Dr. Scott Sherr: So, so from like a millimolar concentration level, we're talking about somewhere around one, you know, is like i- and, or maybe even lower than that, having significant benefit.

[00:46:09] Dr. Scott Sherr: And then three grams of, of a beta-hydroxybutyrate salt is, may not even get you that high, right? But you could- Yeah ... still get significant benefit from that is really what you're grabbing at, right? So- 

[00:46:18] Dr. Dominic D'Agostino: Yeah, yep. 

[00:46:19] Dr. Scott Sherr: Okay. Yeah, that, that's what I was thinking, you know, because I, I've been thinking more and more about this in the range.

[00:46:23] Dr. Scott Sherr: Like, when, when you and I first met many years ago, we were talking about the ketogenic diet with the, with cancer and cancer patients. We're talking about glucose ke- ketone indexes of one, like super low glucoses, super high, you know, ketone levels. But, you know, f- and I think that's a very different subset of people, right?

[00:46:40] Dr. Scott Sherr: We're really talking- Oh, yeah ... what we're talking about here is that we're talking about people that are looking to be optimized and keep them meta- metabolically healthy, metabolically flexible. So that range seems to be a more optimal range for people, like, i- in that capacity, right? 

[00:46:52] Dr. Dominic D'Agostino: Yeah, for sure. Yep. 

[00:46:54] Dr. Scott Sherr: I, I think that, you know, to wrap up here, Don, just a couple more things.

[00:46:57] Dr. Scott Sherr: You know, I know that you're always sort of on the cutting [00:47:00] edge of research and, and doing lots of really interesting novel things in here. So what is on-- what, what are you most excited about in the next six months to a year that either you're working on or other people are working on in the field that you're really kind of, kind of, really excited to see what the results look like?

[00:47:14] Dr. Dominic D'Agostino: Well, we're working on a couple different NIH grant proposals. Okay. And one, if it's funded, it will be... nowadays kind of hard to get NIH funding, but it will be basically looking at ketone metabolic therapy in people that do not have any overt pathology, but just looking at their cardiometabolic biomarkers- Okay

[00:47:33] Dr. Dominic D'Agostino: and, and how that and other factors, objective biomarkers and subjective, and also things like strength and a number of different things, how that changes over time and can mitigate the cognitive decline that's typically associated kind of with aging. So we're thinking about doing, you know, uh, proposing to do long-term studies.

[00:47:54] Dr. Scott Sherr: Nice. 

[00:47:55] Dr. Dominic D'Agostino: Nice Like, you know, years studies, and then tracking with a very high level of [00:48:00] granularity and precision, a number of cardiometabolic biomarkers, cognitive, mental health, like, you know, do the GAD7 test, PHQ9, we look at sleep, DEXA scans and things like that to basically an intervention for healthy aging is what we're kind of targeting.

[00:48:18] Dr. Dominic D'Agostino: I dig it. Yeah. Because if you have someone with metabolic syndrome but not, like, overt type 2 diabetes, that's the time to intervene- Absolutely ... to prevent them from being, you know, uh, a big strain on the medical or getting all the comorbidities that's associated with, you know, sliding into that category of overt diabetes.

[00:48:38] Dr. Dominic D'Agostino: And then the NIH does have a call for proposals. It's not fully out yet, but we're hoping to target that, and this will be a, a relatively larger sort of proposal. 

[00:48:48] Dr. Scott Sherr: Wow. 

[00:48:48] Dr. Dominic D'Agostino: That's great. I'm excited about that and a number of other projects, you know, DoD related too, so. 

[00:48:53] Dr. Scott Sherr: Yeah. I know you have one on hyperbaric therapy and traumatic brain injury.

[00:48:55] Dr. Scott Sherr: Maybe you can talk about that- Yeah ... briefly, you know. 

[00:48:57] Dr. Dominic D'Agostino: Yeah. So that's like a state-funded project [00:49:00] through the university, $28 million project, like total, total grant size, and that project is almost halfway through. It's blinded, so we don't know, but it's the use of hyperbaric oxygen for traumatic brain injury with or without PTSD, without a ketogenic intervention for this initial study.

[00:49:18] Dr. Dominic D'Agostino: But it answers, it's the biggest hyperbaric, you know, therapy study that has ever been done. It will be at least the most costly and most comprehensive scientifically wise. Yes But it actually uses a valid control or sham where subjects get into a hyperbaric chamber and they feel a pressure difference, but we pop the pressure up initially in the beginning to make them think they're undergoing pressure, but we stay at one atmosphere, and it makes them think that we pressurize- Tricky, tricky

[00:49:42] Dr. Dominic D'Agostino: the chamber. Yeah. Yeah. And that's really important, 'cause previous studies, as you know, use hyperbaric, hyperbaric air- Right ... and that's not good either, so you wanna keep it one atmosphere. Right. So we have the proper shams. We have, you know, a number of different PIs getting blood work, e- every possible biomarker you can think of.[00:50:00] 

[00:50:00] Dr. Dominic D'Agostino: So we'll have a lot of data to analyze over the, the course of that. And I'm just a consultant on the project. I was the guy studying the negative effects of, you know, hyperbaric oxygen, but this is a really, really well-designed study, and I think it's going to definitively answer the question, uh, you know- 

[00:50:18] Dr. Scott Sherr: Yeah

[00:50:18] Dr. Dominic D'Agostino: for this particular use case scenario. 

[00:50:20] Dr. Scott Sherr: Yeah. I, I'm very selfishly asking you that question so that you can tell everybody about what's happening. I know it's not the direct things that you work on, but all the years in hyperbaric medicine and all the support you've given has been gigantic for the field, and this particular study is a really great one.

[00:50:34] Dr. Scott Sherr: And, and I know we're not using the ketogenic diet in this one, but in the real world, this is what we do, right? Yeah, yeah. Which is we, we combine the ketogenic diet or ketogenic supplementation- Yeah ... with patients that have traumatic brain injury, with PTSD- Exactly ... and see dramatic, dramatic changes. Yeah.

[00:50:48] Dr. Scott Sherr: And Dom, it's always great to have you and to... I mean, we just obviously scratched the surface. I have, like, another 75 topics that I wanted to ask you about. But as we wra- wrap up, where can people find more information about what you're doing? How [00:51:00] can they support your work? Because again, what you're doing should be supported, and it's such great stuff.

[00:51:04] Dr. Dominic D'Agostino: Yeah, thanks for asking. Well, Metabolic Health Initiative, that platform, so we have... That's an ACCME accredited educational platform. You can get CME credits for that. 

[00:51:14] Dr. Scott Sherr: Right. 

[00:51:15] Dr. Dominic D'Agostino: Ketonutrition.org is my information website. I do not, I don't sell anything. Like, I don't have any company or sell anything. But we have, you know, products on there that I've tested.

[00:51:23] Dr. Dominic D'Agostino: There's a blog on there. Mm-hmm. Mm-hmm. Various resources. The Metabolic Link Podcast too, which you're familiar with. You've been on- 

[00:51:28] Dr. Scott Sherr: Yes, I've been on ... the podcast. Yes, yeah. Yeah, that's been great. Well, Dom, I wish you a great rest of your day, and keep up the good work. And, uh, oh, the last thing I want to mention to everybody is that Dom is actually going to be one of our speakers at the Health Optimization Medicine and Practice conference October 2nd and 3rd in Chicago, Illinois.

[00:51:46] Dr. Scott Sherr: So if you haven't gotten a ticket, you can go to homehope.org, and you can go to our Events page. You'll find Dom's gonna be there. We're gonna have a lot of great speakers. We're gonna have myse- I'll be speaking. Dr. Ted Achacoso, who's the founder of Health Optimization Medicine. We'll have Kiran Krishnan, who's the founder, former founder [00:52:00] of Microbiome Labs.

[00:52:01] Dr. Scott Sherr: We're gonna have JJ Virgin. We'll have Dr. Elizabeth Jurith, who's at, at the Bold Longevity Institute here. She's fantastic. So check it out at homehope.org. And Dom, what are you gonna speak about? You just gave me your title in the message. What w- what are y- what's your topic gonna be? 

[00:52:12] Dr. Dominic D'Agostino: Oh, yeah. Like, science and application of ketone metabolic therapy- Yeah

[00:52:16] Dr. Dominic D'Agostino: and then associated testing that is being done in research and being done, like, personally. So yeah. 

[00:52:21] Dr. Scott Sherr: Nice. And maybe we can get Joey to bring some, uh, some ketones with you so we can have some ketones to fuel us. But everybody, thanks for listening to this, another episode of the Health Optimization Medicine podcast.

[00:52:30] Dr. Scott Sherr: If you like this, don't forget to like and subscribe below, and we'll see you next week