Get ready for a heavy-hitting and deeply educational show with Dr. Dominic D’Agostino: neuroscientist, research-scientist, and of the world’s most foremost researchers on the ketogenic diet, especially pertaining to the use of ketone supplements for neuroprotection. 

Dr. Dom brings tremendously extensive knowledge to the table for this episode, having been one of the earliest researchers to focus on identifying the many different uses for ketone supplements. He also worked with the Navy SEALS for over a decade to help address specific issues they were experiencing (like oxygen toxicity seizures), and even offered up his expertise to me back when I was first researching the keto diet for my book, Keto For Life!

In this show, Dr. Dom talks about the wide-ranging benefits that come from following a ketogenic diet, while also offering all the scientific research and evidence to back it up. We talk about the “post-exercise ketosis” that athletes experience and Dr. Dom explains not only why athletes use ketones much quicker than sedentary people, but also why it’s likely that they receive more benefits from ketones as well, plus, many more fascinating facts he has uncovered throughout years and years of research.

Perhaps one of the most singularly valuable insights I ever received from Dr. Dom was to “beware of people who speak in definitives.” The importance of this lies in the fact that real scientists will often say, Well, I don’t know. We don’t know…Well, maybe… In a world where it seems like everyone is trying to sell or convince you of something online, this perspective serves as a practical and helpful reminder. 

Enjoy the show, and connect with Dr. Dom here.


Dr. D’Agostino has researched for years. You are going to learn about the amazing and wide-ranging benefits of ketones on the body. [01:20]

The ketogenic diet has some amazing metabolic benefits that researchers have discovered. [09:28]

Research started because the Navy Seal divers were having trouble using the rebreather. [12:32]

Ketogenic and low-carb diets have been used for a hundred years as a medical treatment for epilepsy. [14:56]

The animals used in research for Alzheimer’s were given ketogenic diets and had remarkably enhanced motor function and exercise performance. [18:56]
If you eat zero sugar and zero carbohydrates, your glucose does not drop to zero. [23:07]

It is difficult to study how a body does in starvation. [27:30]

If you elevate ketones, it provides a remarkable energetic boost to the brain. [32:19]

There are problems with some of the ketone supplements. [40:00]

How do the impurities get into these products? [43:56]

How does one know the dose that works for them? This is for temporary cognitive boost. [45:25]

The ketone salt products come in different forms. [48:52]

Is there some intermittent use of the ketogenic diet as a tool for fat reduction and the peripheral benefits? [52:30]
The blood levels of ketones are a function of ketone production and ketone utilization. 


Breath ketones are a good measure to have during fasting. [01:19:32]

When doing a lot of fasting and carb restriction, it’s technically a stressor to the body. [01:02:37]

How does the ketogenic diet benefit weight loss? First, there is a lot of behavioral modification involved by tracking.  [01:06:39]

Dom did a big deadlifting feat after a long fast. [01:14:29]



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Brad (00:00:00):
Hey listeners, get ready for a very heavy hitting and deeply educational show with Dr. Dom D’Agostino. This guy is something else he’s an all around man. And he is widely regarded as one of the world’s foremost researchers on the ketogenic diet and especially ketone supplements for neuroprotection. He has been working with the Navy Seals for over a decade. One of the earliest researchers on the various use of ketone supplements, especially in the Navy Seal program where they were having problems with oxygen toxicity seizures among Navy seal divers using rebreathers. Rebreathers are the devices that prevent the bubbles from rising to the surface when you’re scuba diving. And it’s very important for the Seals to be able to sneak up on their enemy, target underwater without revealing themselves with the, uh, bubbles rising to the surface and amazingly so this is how the crazy ketogenic diet craze emerged that’s right from research on crazy stuff like this.

Brad (00:02:34):
And Dom was right there at the, uh, the epicenter years ago. He was tremendously helpful to Mark Sisson and I, when we were doing our initial research to write The Keto Reset Diet book that was published back in 2017, and he spent a lot of time with me on the phone. Uh, I remember the interview distinctly because he said, I don’t know so many times that I finally, uh, you know, burst out laughing and I’m like, dude, that seems to be your favorite answer. And he said, oh yes. He said, uh, beware of people who speak in definitives and you’ll notice a real scientist by the number of times they offer up answers such as, “I don’t know,” “maybe”, things like that. And that was a great education for me and kind of recalibrated my awareness when I’m getting hit with expert information from YouTube or on podcasts and people convincing you pointing their finger at the camera saying, this is the way it is.

Brad (00:03:35):
So it’s nice to reflect on how a real scientist will have that open mind and that willingness to reevaluate their positions rather than speak in strong, powerful definitives. So officially Dom is a research scientist at the Institute of Human and Machine Cognition and an Associate Professor at the College of Medicine, Molecular Pharmacology and Physiology at the University of South Florida. On his Twitter account, he calls himself a neuroscientist, believer, self experimenter, and you’re going to hear about some of the crazy stuff he’s done to get his blood glucose levels down below measurable levels, experimenting with the potency of ketone supplements, lucky husband, aquanaut, scuba, space, and nutrition enthusiast. And check out his action over at ketonutrition.org. You will find the most respected and thoroughly researched commentary on the ketogenic diet. So we’re going to get into it in this show. There’s a lot of science.

Brad (00:04:42):
You might be a little bit overwhelmed by some of his commentary because it’s so deep into the science, but I do my best to try to pull out actionable insights and sound bites. And, uh, you may have heard of keto and how you, uh, eat fewer carbs and lose weight. Uh, but you’re also gonna get a basic education on the amazing and wide ranging benefits of ketones in the body. Particularly how they are a cleaner burning fuel source than glucose that reduced free radical production when they’re burned, especially in the brain, which is so sensitive to free radicals. And that’s why the ketogenic diet has been used for over a hundred years in patients with epilepsy, because when they’re in ketosis, it raises the oxygen threshold for seizures in the brain. The brain is getting better oxygen delivery, better blood circulation, and is protective against just like with the Navy seal divers protecting against oxygen toxicity when they’re re breathing.

Brad (00:05:53):
Um, someone with epilepsy has a greater protective benefits when they’re to the ketogenic diet or taking these ketone supplements, which have been invented in recent years. And Dom describes the difference between the ketone salts that we see commercially available and ketone esters, which are much less common, uh, but they’re much more potent. They can rise your blood ketone levels extremely in a short time. And then we kind of cover the important stuff, of great interest to the broad audience, which is the ketogenic diet for weight loss. And this is an important soundbite I’ll tee you up with, that Dom describes how the effectiveness of the ketogenic diet is that it causes an inadvertent, mild calorie restriction due to appetite suppression and a restriction of choice in food. So all of a sudden you are now counting your carbohydrates, trying to keep them under 50 grams a day per the ketogenic guidelines.

Brad (00:06:55):
And so you’re going to have an automatic improvement in the quality of your diet and a reduction in caloric intake because you’re cutting out a lot of the popular junk that we would otherwise throw in there when we’re unregulated. And I think that’s an important distinction between any sort of magic that you’re gonna raise your metabolism or things like that, which are hotly disputed. Uh, you listened to my show with Dr. Herman Pontzer where we got into that in detail. And so a little bit of that, uh, kind of absorbs into this show too. Uh, but when you do make this effort, you can expect, uh, some wide ranging benefits besides the automatic reduction in caloric intake and the improvement in fat burning. And that’s why, uh, Mark and I called the keto diet, a bucket list item for everyone, uh, in the Keto Reset Diet and another book.

Brad (00:07:51):
So if you go to the trouble to, uh, engage in intermittent fasting, uh, carbohydrate restriction, even if it’s for a short duration, even if for, for a six week binge, you’re going to have all these benefits that as Dr D’Agostino describes will stay in place. Even if you transition away from this strict adherence to the ketogenic macronutrient guidelines. We also talk a bit about, uh, the application of the diet to athletes, where I asked him some of my questions and mysteries that I experienced when I was deep into this research and experimenting with the ketogenic diet myself and putting up some low numbers on my blood meter. Even though I thought I was going to be, uh, you know, skyrocketing because I had fasted so long and had a string of ketogenic meals and done a hard workout and how maybe there’s too many stress factors in play there.

Brad (00:08:45):
And so Dom himself talks about how he enjoys a significant amount of carbohydrates in the evening, which helps him recover from his extreme high performing workouts. And wait till you hear what he did after a seven day fast, not eating any calories, and then stepping up to the deadlift bar and performing this magnificent human feat that I think we can track down a video or more details in the show notes. Okay. I think that’s enough tee up. So here we go with Dr. Dom D’Agostino coming to us from his new home on the farm out there in south Florida. Enjoy.

Brad (00:09:28):
Dr. Dom. D’Agostino. I’m so glad to connect with you again, where you are now. What was that five, maybe more than five years ago when I talked to you on the phone to find out about what this whole ketogenic diet thing was. Now, you’re sitting back in your, in your, in your chair and the lab at the University of South Florida, and, uh, have watched it turn into a sensation. So I think part of this show, we’re going to have to set some things straight because, uh, some of it’s gotten out of hand. I’m sure you’re, uh, have some things to shake your head about, but you’ve been doing great research for so long. So maybe the first thing we should start with is you can tell us about the work that you’ve been doing for the past decade and longer. And then, um, um, what is this a ketogenic diet and some of the amazing metabolic benefits that you and the other researchers have discovered.

D’Agostino (00:10:18):
Yeah. Glad to fill you in on that. And, uh, yeah, thanks for having me, Brad. Appreciate it. So it was about, in about 2007 or 2008, I became interested in the ketogenic diet for our work that was funded by the Department of Defense and specifically the Office of Navy Research, which is a component of the Department of Defense. And my role is looking at mitigation strategies for oxygen toxicity seizures, which is a limitation for Navy seal divers using a closed circuit rebreather. So, uh, we developed some unique technologies like microscopes inside hyperbaric chambers, and environmental chambers, and allowed us to look at, look at the effects of metabolism on brain cells. And, um, I was looking at a variety of different things and ketones were a side project that I had because I found out the ketogenic diets use for epilepsy and other seizure disorders.

D’Agostino (00:11:22):
So I thought, you know, maybe it would be good to try it for this. Long story short. We, we, the military, I would say looked at a lot of different drugs and we looked at various drugs and nothing really came close to nutritional ketosis. And then later we develop exogenous ketones and they became a very effective tools for neuroprotection in the context of oxygen toxicity seizures. So that was like over 10 years ago. And we’ve branched off into looking at things like cancer, things like, rare metabolic diseases, wound healing, glycaemic control lowering blood glucose and an exercise performance. So, uh, we’re looking at nutritional ketosis in the context of not only disease processes, but really enhancing and preserving metabolic resilience in extreme environments. And that’s kind of, if I had to describe, you know, the thrust of what I do, it’s really preserving safety and performance resilience in these extreme environments.

Brad (00:12:32):
So it all started the impetus was these Navy Seal divers were having real trouble using the rebreather. Maybe you can describe what that is. And the ketones came in because as a sound bite, they improve oxygen delivery to the brain. So they kind of make it less difficult to struggle, uh, same with the, um, the epileptic seizure patients that have been using the diet for over a hundred years. Right?

D’Agostino (00:12:59):
Yeah. There’s a lot kind of going on with nutritional ketosis and I’ll kind of sum it up. So oxygen in the air that we breathe is that 20%, but a close circuit rebreather like a dragger re-breather is actually a completely closed circuit. And when to avert the enemy seeing you in the water, for stealth mode, there are no bubbles when you’re swimming underwater. So if you can envision swimming across the lake to, you know, sneak up on the end enemy plant a mine, you know, attack a ship, something like that, you won’t see the enemy coming if they’re wearing a closed circuit rebreather, I’m looking out over my pond right now and I can track alligators. I see the bubble trail going across and it just came to mind. I was out on my stand up paddle board yesterday and I was watching bubbles come to me and the alligator is coming to me across, uh, he’s just a small alligator so I wasn’t afraid.

D’Agostino (00:14:00):
But it’s kind of like the same scenario, right? So no bubbles, there’s the stealth component. The disadvantage of using a closed circuit rebreather is that, uh, if you go down to just 50 feet of seawater within 10 to 15 minutes, according to the Navy dive tables, you can have oxygen toxicity. So the rebreathers are typically used, not for deep diving, but for stealth operations, just, you know, 10, 15, 20 feet below. But if the water has high visibility and it’s very clear and you have an overhead and like a helicopter or something like that, you gotta dive down deeper to get out of sight. Right? So, so that’s, that’s a limitation having a seizure under water. It’s not very good for the mission. So, uh, we don’t at this current time. Well, at the time I was researching it, we didn’t how to predict or how to mitigate oxygen toxicity seizures.

D’Agostino (00:14:56):
We’re looking at physiological biomarkers, like, uh, you know, EEG on the brain and things like that. That’s a little bit harder that we can do that in the lab, out in the field. That’s hard, but you can wear a monitor and look at things like, um, heart rate variability. You can look at, you know, breathing patterns. You can look at body temperature. It tends to dip and breathing be kind of becomes erratic before you have a seizure. So we’re looking at physiological biomarkers, we’re looking at biochemical biomarkers and that’s a whole nother aspect of what I do. But the main thrust of what I do is preventing these seizures from happening in the first place. And the ketogenic diet had a super track record. I, I, I went through a nutrition program in my undergrad at Rutgers University and kind of studied nutrition and knew about keto diets and low carb diets.

D’Agostino (00:15:47):
But I did not know that they had a a hundred year history of being used as a medical therapy for epilepsy. So I thought it would be pretty cool. I did my PhD in neuroscience and physiology. I thought it would be cool if I could get nutrition science back into my research program. And essentially that’s what I did, you know, about 12, 13 years ago, and started looking at, uh, different metabolites and altering our metabolic physiology to change our brain energy metabolism. So that’s really what happens with the ketogenic diet is that you’re switching a fuel source. It’s not like you’re switching totally from glucose to ketones, but when you elevate ketones in the blood, by virtue of the metabolic processes that happen, you’re also lowering blood glucose, elevating ketones, and that actually changes the brain energy systems. Uh, and then ketones have anti-inflammatory effects.

D’Agostino (00:16:48):
They affect different signaling molecules. And also, neuro-transmitters so they lower glutamate and they elevate Gabba. And there are it’s multifactorial. The effects of ketones are not just an energy and they do play a role in oxygen too, but they don’t decrease the oxygen or increase the oxygen in the brain. They increase brain blood flow, but what they do, and this was the first observation of ketones is that they reduce oxygen free radicals, which are also called reactive oxygen species. So this was the first observation underneath a microscope where I developed a technique in hippocampal brain slices. The hippocampus is we think where the seizures start, uh, to reduce superoxide antiones. And in the context of high oxygen, you see a big burst of reactive oxygen species. But if you have ketones, you know, in the media then are in the solution that the brain cells are in, uh, there’s a much less, uh, elevation of reactive oxygen species.

D’Agostino (00:17:56):
So this one is the first observation and it was indicative of enhanced mitochondrial function. So essentially what we saw was the preservation of mitochondrial activity and metabolic processes in the context when metabolism typically shuts down and the cell dies. So the cells were able to stay alive and the mitochondria were working with high efficiency as evidence, you know, by reduced superoxide Ana. So that kicked off this whole idea of, Hey, how do we implement the ketogenic diet? The military was not very keen in using a high-fat ketogenic diet. So, uh, we worked on delivering, developing, testing, and ultimately delivering a ketogenic supplement in the form of ketone esters and ketone salts, which we’re really focusing on now. And even things like MCT, which is added to the, the formulations that we’re working on.

Brad (00:18:56):
Wow. So if you’re a, a science student taking notes, now we’ve pulled out some, some tidbits that are extremely important and applicable to everyone. If you can get your mitochondria functioning better, if you can produce less reactive oxygen species, especially in the brain. We’re talking about sailing down the path of life with a minimized risk of cognitive decline, dementia, Alzheimer’s, every day better for focus, mental clarity, all those kinds of things. So this must’ve been exciting when you, uh, kind of move through the path of trying to help the, uh, the divers sneak up on the ships and plant a bomb to, Hey, this could be a, you know, a life-changing thing, especially in the realm of disease. And, and of course also in peak performance, and we’ll talk about weight loss shortly, but, um, it seemed like you were kind of peeling this onion off and probably getting more and more excited in the lab over the, over the decade plus that this stuff was coming out.

D’Agostino (00:19:55):
Yeah, that’s a, that’s a pretty good observation. And, and summary of, of the effects. You know, it does have implications for things like Alzheimer’s and actually the, the, the military that was a bit of a hard pitch to get them to buy into this idea of therapeutic ketosis, because ketones had, there was a lot of negative connotations associated with being in ketosis because it’s diabetic ketoacidosis. Um, but the, I had colleagues at the Byrd Alzheimer’s Institute, which is on the University of South Florida campus. And the Alzheimer’s Association actually funded a project, looking at ketogenesis for preventing, uh, as a therapy for Alzheimer’s disease. So the, I had a PhD student Millennia Brownlow, uh, who’s kind of moved on and doing some really cool things now. But she did her PhD project looking at the effects of ketogenic diets on Alzheimer’s disease model. And, uh, probably the most interesting data that came out of that research funded by the Alzheimer’s Association was that these animals had remarkably enhanced motor function and exercise performance.

D’Agostino (00:21:14):
When we put them on a treadmill like device called a rotor rod, which is like a little wheel that they run on. But they not only have to keep up with the speed of the wheel, they also have to maintain their balance. And the data, when you look at the day, you didn’t even need statistics to sort of say, wow, the, the, you know, the performance was much higher in the Alzheimer’s disease model. We implemented nutritional ketosis in the Alzheimer’s model after they got significant disease processes. So we were not able to reverse the amyloid and the tau because that has already started, but other labs implemented nutritional ketosis earlier and saw that they could delay the accumulation of the, the two proteins that are implicated in the etiology of Alzheimer’s disease, which is the amyloid beta, toxic protein and the tau protein.

D’Agostino (00:22:13):
We didn’t actually see that in our studies because we started a little bit later, but we did see the, the phenotype of the animal was remarkably changed in that it was, it was much more robust energetically from a motor performance point of view. So that was really refreshing because my research with the Navy was just starting up and it was like, you have something that undoubtedly can prevent seizures and is neuroprotective, but you have something that could potentially also enhance performance. So then it became even more interesting and applying a nutritional ketosis to diseases of motor function. So like ALS and, you know, we’re working with a wide variety of different diseases where, uh, impairment of motor function is part of this symptom of the disease. And we’re conducting research on that now.

Brad (00:23:07):
You mentioned some comment about it’s not all or nothing here, so we’re not like switching into this realm of being a ketone burning machine and departing forever from the baseline of, you know, today we’re burning, uh, mostly glucose in the brain because of our diets. But you’re making a transition where you’re, uh, becoming, I guess, predominant in ketones, if you’re really serious about it and strict on the diet versus are we more or less almost entirely burning glucose unless we do some dietary modification?

D’Agostino (00:23:42):
Yeah. That’s a really good point because pretty much everything I see out there when people are pitching the ketogenic diet, or if he found back Shark Tank, Hey, yeah, yeah, yeah, exactly. That you’re switching, you know, a hundred percent from glucose to ketones. If you eat zero sugar and zero carbohydrates, your glucose does not drop to zero. So that’s like a really, and when you fast for even 40 days, like your glucose does not drop to zero. There are very powerful homeostatic mechanisms that maintain blood glucose within very tight regulation in a normal, healthy person between say three millimolar, which is down to like maybe 60 ish to like a hundred milligrams per deciliter. And it’s very rare in a fasting state to be outside of that. Uh, although with, with a really strict ketogenic diet or fasting, you can dip down into the forties and fifties, maybe even occasionally into the thirties with really long, fast.

D’Agostino (00:24:45):
But, uh, and in, in that context with a low glucose, the ketones are elevated and they’re supplying an alternative energy substrate to the brain. So you are, and what’s super interesting in a whole nother field of study, is that in the case of insulin shock or type one diabetes, uh, or hypoglycemia, subjects who, uh, undergo prolonged fasting, if you inject them with insulin to drop glucose down into a level that would be universally fatal, they are asymptomatic for hypoglycemia and they don’t go into a seizure. They don’t go into a coma. Uh, these are studies done by George Cahill at Harvard medical school. Uh, the fellow in the lab at the time was Dr. Oliver Owen and this study, it was published in, uh, 1967, really caught my attention. And I almost didn’t believe it because, uh, it, it contrast it, a lot of things that I thought I knew about the brain, and it sparked a big interest to me that if this was real, then the brain can run on this alternative energy fuel.

D’Agostino (00:26:03):
And it, it, the implications were pretty remarkable that you could provide alternative energy, you know, for Alzheimer’s disease, Parkinson’s disease, ALS, MS. a wide range of metabolic disorders that some of them we study, including glucose transporter type one deficiency syndrome, that’s a mouthful, uh, [inaudible] deficiency syndrome. So actually in those two cases, the ketogenic diet is the standard of care. And without it, the, you know, the patients would die. So actually they need to maintain a certain level of ketones to stay alive and to function and to prevent seizures and things like that. So I was looking at more the broader implications of all these things that people were not studying. And, uh, there seemed to be a pretty good scientific rationale for expanding it beyond the use of epilepsy. And that has become, you know, the major motivation behind what I do, but not what I do per se, because I oversee the research, but what my students do, because they’re really the PhD students, the med students, I have undergrads, I even have high school students. They’re in the trenches doing the research, and they’re really excited about this research and we’re publishing and we’re getting the information out there. So it’s been a real whirlwind trip going down this path. And it’s been very exciting for me and for the people in the lab.

Brad (00:27:30):
Uh, so you mentioned this Cahill study from Harvard back in the sixties. And I know it was highly regarded. One reason being that it’s very difficult to replicate because the people were basically starving for a long time. And so we can go look back, but we can’t be doing this left and right, because of the rules now. But you’ve kind of taken a deep yourself. I heard you mention somebody, some of your personal experimentation, so, let’s, let’s focus on that a little bit about how, how difficult it is to study things like, um, how the body does in starvation or extreme carbohydrate calorie restriction, and then some of the stuff that you’ve pulled out from messing around.

D’Agostino (00:28:09):
Yeah. I, I like to immerse myself in the research that I’m doing and, um, and that typically involves, you know, fasting, ketogenic diets and exogenous ketones and calorie restriction and, you know, all of the above. Uh, so, you know, I come to find out like you, you can’t even do a fasting study where you’re injecting insulin in a fasted state to animals. Although, you know, back in 1967, if, you know, you had a institutional review board and influence. So, uh, you know, professor, you could get this passed, presumably, you know, for a human study. Uh, but in our lab, what we observe is that if you implement a ketogenic diet, you inadvertently usually produce a state of mild calorie restriction. So that further sort of enhances. In rodents and mice and rats. And if you feed them, you know, rodent chow, they like humans, they basically overeat.

D’Agostino (00:29:16):
And then they gain weight as they get older and they become insulin resistant and they just, you know, they put on adiposity, uh, intromental fat, which contribute to metabolic syndrome and things like that. So some of the first observations were that a mild calorie restriction also enhanced like performance. And you had saw like a lot of benefits from that. But, uh, and we saw a benefit even in the context of cancer with mild calorie restriction. But if you calorie restrict a ketogenic diet, then your ketones are elevated and that provides further benefits above and beyond what you’d get from just calorie restriction. And we know like a lot of people will say, well, the ketogenic diet works for weight loss and other things simply because it’s all about calories in calories out.

D’Agostino (00:30:10):
We know from the context of epilepsy research that a lot more is happening with the ketogenic diet than just calorie restriction, right? Because it’s changing the brain energy metabolism, preventing seizure and calorie restriction alone does not do that. Fasting will, but you have to take it to extremes, to control seizures. A well-formulated medical ketogenic diet can control seizures equally or as good as fasting. So, uh, so in our lab, you know, we, we did a variety of things. We developed ketone esters, and there’s a variety of different ketone molecules we could talk about. And then I also became interested in this idea, like you could take a ketone molecule and combine it with an electrolyte like sodium and potassium and magnesium and calcium. Why don’t we develop a balanced electrolyte formulation, you know, similar to electrolyte products that are on the market. But instead of combining the electrolyte with like chloride, like sodium chloride, we do sodium beta-hydroxybutyrate or magnesium beta-hydroxybutyrate.

D’Agostino (00:31:19):
So I kind of had this idea that nobody was doing it. And I had a chemist that was very good, uh, outside of academia, which is a good thing in many ways, because academia is very, very slow when it comes to exploratory science and getting things off the ground and running. So we were able to, you know, develop these ketone molecules that were like new entities. And I started testing them on myself, and I realized that I could be in a very low hypoglycemic state and would be in a fasting. I, you know, I can produce that state through a variety of ways. Maybe some I will not discuss, but what I observed is that, uh, that I could produce, you know, a state of hypoglycemia that would typically put someone into a coma. But if my ketones are elevated, I was not only, you know, not only asymptomatic for hypoglycemia, I felt very lucid and cognitively sharp.

D’Agostino (00:32:19):
So then, you know, we were actually doing funding research, funded research at the time, but I totally bought into this idea, which is come, you know, proven to be true, that if you do elevate ketones, it provides a remarkable energetic boost to the brain. And this has tremendous for disease processes. Yes. But I think also for the everyday person looking to get sort of an edge in regard to cognitive function, preserving, you know, metabolic resilience. There’s a lot of things that happen when you’re doing things like intermittent fasting and the ketogenic diet. You’re shifting your metabolism over to burning fat and ketones. But what we discovered is that if you administer exogenous ketones, my thinking was that you had to first convert your metabolism over and you had to fast for a period of time or use a ketogenic diet to get the benefits of ketones.

D’Agostino (00:33:19):
But this was not the case because we took rats that were eating a standard high carbohydrate diet. And we administered a ketone Ester for our first study that we published. And, uh, they were completely naive to ketones or occasionally diet. And then we put them inside the hyperbaric chamber. We pressurized it to five atmospheres of oxygen, which produces a seizure within five minutes. And I remember the first rat, we’re all standing around the chamber. There’s a little window poured in there and we have a camera set up and we’re also pulling 14 channels of data off the rack because they have biosensors on the rat and on the brain too. And an hour goes by and we’re staring at the rat, you know, in the chamber and it’s grooming itself. It’s acting like normal. And, you know, we had never seen that before. So we’re thinking, you know, this could be a little bit of a backstory.

D’Agostino (00:34:11):
We actually tested a few different ketogenic molecules that didn’t have an effect, but then we developed a particular ketone ester that elevated a acedo acetate, and beta-hydroxybutyrate in a one-to-one combination. And then that particular entity became very anticonvulsant neuroprotective. So, um, you know, we administered this and we did another animal and another animal, another animal, and saw the same thing every time. And, uh, and then we’d wash out the molecule and then we administer water as a control and they’d have a seizure in like five minutes. And, you know, but when they’re in a state of ketosis, you know, there was a, almost a 600% increase and their resilience to this extreme environment where all of those rats would have been dead a long time ago, uh, if they were not in a state of ketosis. So, and that was about, you know, 2010 we observed this and then that kicked off a whole series of different experiments and collaborations and new molecules. Other, other investigators jumped on this opportunity. A variety of different companies jumped on the opportunity, started developing different ketone supplements and things like that. But, uh, I think it was those observations. And then speaking about it on different podcasts and stuff that sparked a lot of interest.

Brad (00:35:32):
So you can get into a state of, ketosis and advanced ketosis as seen by the Cahill study by starving for a long period of time, or taking carbs down to extremely low. You’ve heard people talk about under 50 grams a day, which by most accounts is really low and you can work hard and get there, or you can consume these supplements and immediately experience the benefits like you were discussing with the rat.

D’Agostino (00:36:04):
Yeah, yeah. That, that’s the case. You know, I was a little bit, um, I was skeptical that this would happen. And, uh, the original protocol that I wanted to do was to put the animals on an exogenous ketones for like a week, but we were not able to synthesize enough of it to like, you know, do the original. So I jumped the gun so to speak, and I was like, well, let’s just, let’s just give one dose and put, put the ketones into that five millimolar range and then put the rat in the chamber and see what, see what happens. Um, and you know, I did, I did this with a beta hydroxy buttery, ester, and other molecules. And, uh, and didn’t see an effect including one, three butane dial, which breaks down to ketones. We actually, the molecule that was most neuroprotective was one, three butane dial a seal acid digester, if you want the chemical name.

D’Agostino (00:37:00):
Uh, but now we’ve used a variety of different molecules. Um, we do find that when we combine that molecule with MCT oil, there was a further boost in the, uh, in the neuroprotective effects. And then also more the oil delays, the gastric absorption in a way that extends the pharmacokinetic profile in pharmacology, we say it shifts it to the right, right. So there’s an elevation of ketones. And then that elevation is preserved over hours instead of just like an hour and a half or so. So you get many hours of that. So there’s different formulations that we use too. That would basically the formulation when it’s administered just prior to emission would give neuroprotection over a period of hours, uh, and, and safety and resilience over a period of hours. So, yeah, we, um, I kind of, I talked with the late Dr. Veech and Dr.

D’Agostino (00:37:54):
George Cahill and Dr. Theodore Van Itallie,, all these people were icons remain to remain icons in the field of fasting and the field of ketogenic diets. And Dr. Veech was really the one who was developing and testing ketone esters before I even got into this field. So I like to give credit to him. And Dr. Richard Veech actually worked under, uh, Hans Krebs. The Krebs cycle. So he was a, a student of Hans Krebs, very knowledgeable, uh, and there was also a remarkable individual, uh, Henri Brunengraber at Case Western. And he actually gave me the recipe to synthesize the other ketone ester that we ended up testing and being most efficacious. So, so these ideas, you know, people say I’m the keto king. And I developed these things, but it was really other people and consulting with other people. And many of them were very generous with their time on the phone.

D’Agostino (00:38:54):
Uh, I’ve met with many of them in different, you know, meetings and things like that. Uh, and it’s a good thing I did at the time, because many of them, you know, are, are not here now. So they’re kind of up in their age, but they did this research like years ago and no one really picked up and followed up on it in a very robust way that, and I was thinking, and I think because ketones had a negative stigma to it, but if you just look at the physiology and nowadays, a lot of people focus on nutritional biochemistry. But the people in nutrition nowadays, and I don’t want to make a blanket statement, they’ve may not have an appreciation for metabolic physiology. So physiology is really integrating it all. Instead of medical, like with nutritional biochemistry, it’s like, you know, knowing the pathways of vitamin K synthesis things I said, but with nutritional physiology, you really understand, you know what’s going on.

D’Agostino (00:40:00):
So, uh, that my physiology background gave me an appreciation for the work that these icons did. And it’s like, someone’s got to follow up on it. And I was like, my department is a physiology pharmacology. So it was, uh, a little bit people were thinking it was academic suicide to transition from drug research to, um, to, uh, you know, nutritional high-fat diet research. So there’s some, some eyebrows were raised and saying, this is not a very good field to go into if you want to get tenure at a medical college. So, um, so, but, but it ended up panning out because I knew it would work because it worked experimentally. And if something works and the science is good, eventually a funding agency would recognize it and, um, support your support, my students, you know, to continue doing the research.

Brad (00:40:59):
So the number of people interested in the protective benefits is fewer than those interested in fat loss and all the things that have made keto become this cultural sensation and, you know, the latest dietary trend. And I wonder it kind of, um, you know, your reflections right now on how these divergent paths have gone. I mean, we’re still, uh, you’re still doing great work with the, the, the space group and the Navy Seals and all that. And then we’re also seeing, um, everywhere we look, people slimming up with their ketone pills and they’re this and that. So, um, let’s, let’s see what you think about all that.

D’Agostino (00:41:41):
Yeah, it’s a good, I’m glad you brought that up because there’s a lot of misinformation and a lot of hype behind the ketogenic diet and claims behind certain supplements. So the large majority of ketone supplements that are out there, like the ones you probably see on Shark Tank and things like that are so underdosed. And we say, what do we say? Like fairy dusted with a very small amount of ketones and, and we’ve analyzed some of these things. And there are things besides ketones in their ketone formulation that are things I can’t even identify. So I would say impurities. So they lacked potency, they lacked purity and they lacked tolerability. So this is like the main problem that I see with ketone supplements out there. Uh, there’s really only a few supplements that when people ask me of what I would recommend, uh, there’s a couple of companies that are pretty good.

D’Agostino (00:42:38):
Um, most of them are medical, you know, companies, uh, making it for medical foods that are actually pure, like ketone esters and ketone salts. Audacious nutrition, product Keto Start is very good. Um, and there’s a few others out there that I think are up and coming, but I’d have to do an analysis of the purity and potency and things like that. But some of the things that we got sent to the lab that we did mass spec on, they look kind of scary on paper, cause it was spikes in the mass spec of things that shouldn’t be there. Uh, so I think it’s really important to, uh, if you’re, if you are going to use ketone supplements and they could be a great adjutant to the ketogenic diet, they could help one transition into the ketogenic diet. And the ketogenic diet is a great weight loss tool. And it’s also great for lowering your blood glucose and, you know, achieving body composition alterations that are favorable in the context of weight loss. So we’ve published that. And, uh, but it’s just one tool, you know, that you can use and it doesn’t necessarily have to be a clinical ketogenic diet that used for epilepsy. It just has to have a level of carbohydrate restriction that can produce some of these benefits.

Brad (00:43:56):
Before we go off the supplement topic and then focusing on weight loss, a couple of other questions, one of them is how the heck are impurities getting into the product? I mean the manufacturer or the marketers obviously ordering them from some, uh, supplying laboratory that you would expect has product standards and they’re doing their own mass spectrometry, but is this, I know this is heard this to be a common problem in the supplement industry.

D’Agostino (00:44:25):
Yeah, well, there’s a cutoff for things like heavy metals. And, you know, I found certain, certain products were like borderline on heavy metals, whereas others were just basically non-detectable. So you want, you want, you know, a certificate of analysis that does the complete, you know, analysis of, of that. And the synthesis pathways for ketone esters are a bit more involved. So you could have a variety of different solvents and other things in there that we couldn’t really identify with the ketone esters. Uh, although you could do, we actually do a very simple distillation. We do, uh, uh, you know, I’ll tell you it’s one, three butane dial and turf butyl. Acetol acetate. It’s a, transesterification just high heat and high vacuum. And it’s basically, there’s really not a way to get too many impurities with that way, unless you burn it, something like that, you overcook it. But with a ketone salts impurity, it’s very simple chemistry to make ketone salts.

D’Agostino (00:45:25):
And I’m going in the direction of ketone salts now because, uh, you can formulate a balanced electrolyte formulation with ketone salts that are tolerable and potent and approaching that of the ketone ester. And the big, big thing is that they taste good. So you can make a ketone salt product that actually tastes like, you know, high [inaudible] And, you know, I have ketone esters in the lab. I have them at home, you know, I can take whatever I want, but, you know, and in the beginning there’s like a mystique to it and it’s a novel thing. And it’s like, whoa, look how high and get my ketones. But for someone who’s just using it on a daily basis, it’s like blood glucose. Like you don’t, you’re not trying to achieve a 10 millimolar, uh, blood glucose or, you know, uh, a hundred and, uh, you know, 60 milligrams per deciliter to have more energy, right?

D’Agostino (00:46:18):
There’s a, a point of diminishing returns. And the same thing happens with ketones. If your ketones, my experiences, I feel best at about 1.5 to maybe two, between, I’d say between one and two millimolar and that’s giving your brain a boost. If you look at the physiology between 10 and 20%. So at one millimolar elevation of ketones at about a 10% boost in a available brain energy substrate. So, uh, so that, you know, I kind of think about it like that. Whereas if I push it to five millimolar, that becomes a metabolic acidosis that the body has to deal with. So you’re actually the, body’s working hard to sort of, uh, it’s dumping bicarb in the system through the renal pathway. And it’s like, you have to compensate for the pH shift when you spike your ketones really high. And I think that could be, that could be beneficial for someone who has a metabolic disorder, like glucose transporter deficiency, or epilepsy or things like that.

D’Agostino (00:47:20):
But I actually, you know, we see it can impair performance. It has a negative effect. Whereas if you have a healthy individual or even someone who’s just like, you know, not so metabolically, you know, enhanced or whatever, staying within that one to two millimolar range. And the good news is that this can be achieved with the ketone supplements that are on the market. You just want to be careful in particular with the ones that you choose and medium chain triglycerides are a great MCT Oil are great too, because they are a simple molecule found in nature, and it’s actually getting your body to produce the ketones. But the ideal formulation is like, you know, getting MCT and combining it with the ketone salts. Although I don’t always do that sometimes I just take ketone salts, like during the day. And, uh, and I, you know, experienc a lot of benefits with that and we do this in animal models and we do this in humans and we see nice benefits from that.

Brad (00:48:22):
So you’re doing this for a temporary cognitive boost. And then if the individual’s really interested in going further, they can adhere to the diet protocols where there, uh, for quite a bit of time, the elevating their ketones into that sweet spot. I mean, the cutoff point for actually being a ketogenic would be, is it, is it 0.5 millimolar is that you’re trying to get above to say, okay, now I’m, now I’m getting some, uh, some progress here.

D’Agostino (00:48:52):
Yeah. That’s a clinically, that’s the cutoff 0.5 millimolar blood beta-hydroxybutyrate. And so you know, it would be difficult to achieve that almost impossible with like a standard American diet unless you have a super early dinner and then the next day you eat your, your first meal at about 12 noon. And then you’ll start to get up towards that if you’re exercising or something like that. But and then it’s probably important to mention that the ketone salt products come in different forms, right? There’s the D enantiomer. So there’s like, you know, beta hydroxybutyrate comes and it’s a mirror image. There’s the L and the D form. And this becomes kind of interesting in that the D beta hydroxybutyrate is the primary ketone molecule that the body makes. We do have an enzyme called Aromazyme enzyme that can convert the D to the L a, but when you take most ketone supplements, it’s a combination of the D and the L form. The L form will eventually gradually transition to the D form.

D’Agostino (00:50:07):
So over, over time. And I think of the L form is kind of like a time release form of the D and also the ketones, the D and the L K T a L beta hydroxybutyrate provide energy, but the probably has a more favorable, energetic profile than the L beta hydroxybutyrate. Although the D gets burnt up really quickly for fuel, whereas the L beta hydroxybutyrate sticks around longer because it just gets metabolized a lot slower. But the advantage to that is that it’s hitting a lot of the signaling pathways. So the D and the L for example, suppress the NLRP three inflammasome. So the important thing is that they have anti-inflammatory properties, both of them, but the L sticks around longer so it may have greater anti inflammatory effects. And it also has epigenetic effects that are favorable. So it activates gene pathways that have, can provide the body with resistance to oxidative stress.

D’Agostino (00:51:11):
And now we know of something called beta hydroxybutyerate elation. So beta hydroxybutyrate, the ketone molecule can directly interact with the histones, which play a role in, uh, activating certain, uh, genes, expression, certain genes. And there’s scientific rationale that the L may be doing that to a greater capacity than the D just because it doesn’t get oxidized as fast. So we’re interested in that, and we’re actually looking into doing some experiments to, to look into this. So, um, so I think, so I bring that up because when you measure ketones, you’re only measuring the commercial meters on the market, only measure the D beta hydroxybutyrate. So if you consume a supplement, that’s an anti-America mix of DNL, and you’re getting an elevation of one millimolar, you’re actually getting an elevation of two millimolar of ketones, because you’re only measuring quantitatively. The D beta-hydroxybutyrate, hopefully that didn’t confuse everybody. But, uh, but I think, uh, I think that the important thing is that racemic beta hydroxubutyrate as sold as ketone salts are not a bad thing. And I think they may actually be a good thing. And most of our research has actually used the racemic forms and showed some pretty remarkable effects.

Brad (00:52:30):
So most people are looking to achieve goals like fat reduction, maybe some, some peak performance attributes for the extreme athletes and the endurance athletes, especially limiting their carbs so they can transition over to increased fat burning as we saw in the faster study and so forth. But for the broad listenership and enthusiasts, you described the supplements as sort of a, a helper to help you transition over into ketone burning. But in general, we have to go focus on some dietary modification, and let’s talk about some of the high points of that. And then also sort out some of the confusion about, do I have to do this all the time for the rest of my life, or for the next six months and not miss a single, not binge on any carb, or can there be some sort of, um, intermittent use of the ketogenic diet as a tool for fat reduction and the peripheral benefits.

D’Agostino (00:53:33):
Yeah, there’s a lot to unpack there, but I think what we can say is that to achieve a maximum state of ketosis and keto adaptation, which is shifting your metabolism to oxidizing preferentially more fat and ketones, there has to be a, a reduction in the hormone insulin and a reduction in glucose availability. And that needs to be protracted in a way that augments the liberation of fat from adipose tissue. Uh, so when you suppress the hormone insulin, then you elevate things like glucagon and catecholomines, which are things like adrenaline, and that mobilizes more fatty acids for fuel. So your peripheral tissues start using in a very high capacity. These fast for fuels, same thing happens if you’re fasting, but you can replicate that with carbohydrate restriction. The brain on the other hand does not use fat, very good as an energy source, although it can use a medium chain triglycerides, it can cross the blood-brain barrier, but essentially what happens is that to fill the energetic gap, uh, you have elevated beta oxidation of fatty acids in the liver, and that generates these ketones, that spill into the blood, and then the ketones cross the blood-brain barrier and maintained a high energy in the central nervous system, which is top priority for our physiology.

D’Agostino (00:55:00):
So to the state that I just explained it can happen intermittently, or it can happen in a protracted way. The more, the more you stay in a state of ketosis, the more adaptations will be associated with that. So the more you do it, uh, the faster you’ll transition, the easier it gets, and probably the more benefits you’ll derive from it. One thing I could say is that in our animal models, and I think this applies to humans, that if you take rats and put them on a ketogenic diet, or you do like intermittent fasting and things like that, and get them in a state of ketosis and then put them back on a high sugar, high carbohydrate diet for a couple of weeks, and then put them back on a ketogenic diet, they had a quicker elevation of ketones, something like 30 or 30 to 50% faster.

D’Agostino (00:55:55):
So th there appears to be what I call like a metabolic memory. So if we train our muscles, you know, to get to a certain strength level, for example, on the bench press, you know, and, uh, and it might take like three years to get there. And then we take three months off and we’re back to our starting point. It’s not going to take another three years to get back to that. So I think we can train our metabolism over time, and this involves an upregulation of transport or mechanisms, enzyme mechanisms, and also what I call the catalytic enzymes, which are key, like enzymes within the mitochondria and the cell that actually, uh, play a role in converting the ketones to energy ATP or energy currency. All these things are elevated when we’re on a ketogenic diet. And then there are certain gene pathways that need to kick on and signaling pathways. There, there are many things that we don’t understand, but what we do have an appreciation for now is that when you do it and you maintain it, state of ketosis, and then get out with ketosis, you can get back into ketosis much quicker if you’ve been there before. And I think that’s really important.

Brad (00:57:05):
Oh my gosh. I remember using the term of bucket list in our book, The Keto Reset Diet Mark Sisson and, and I, and you were so helpful with getting us, uh, teed up to, to, to plunge into the subject back in 2017. We described it as a, as a bucket list objective. So everybody at least try to, you know, do some dietary restriction and see, see if you can upregulate fat burning, even if it’s for a short duration or you kind of a trend a little higher than the ketogenic cutoff, but yeah, you’re fine tuning your fat burning mechanisms. And it’s a wonderful experience I should ask you. You know, I went deep into this, doing the book research and was tracking my blood ketones every day. I was getting scar tissue on some of my fingers and writing down all the numbers and seeing how it related to, uh, doing workouts, uh, periods of fasting, uh, the carbohydrate content of the meals.

Brad (00:58:01):
And, uh, I think it was after, after a while I wasn’t getting the, the blood ketone values were, were sort of dropping and it was difficult for me to even get past that 0.5 millimole or cutoff, even know, maybe you can correct me or say, Hey, something was off with your approach. But even though I was saying, going on an 18 hour fast and having a couple of string of ketogenic aligned meals, and then testing my blood, the following day thinking I was going to break records and there, it was at 0.6 or 0.4 or something, I’m going, man, what does the guy got to do to put up some numbers here?

D’Agostino (00:58:40):
Yeah, yeah. Another really good topic you bring up. So the blood levels of ketones are a function of ketone production and ketone utilization. So what we do see, uh, and this actually, uh, Dr. Veech told me this like a long, long time ago, like, well, over a decade ago, uh, that athletes will use ketones much quicker than like a sedentary person. And probably get more benefits too, because an athlete, uh, experiences something called post-exercise ketosis. So there they are essentially fat adapted. They intermittently go into a state of ketosis. And if you do a ketone tolerance test, and I just made up that term because I like it. And I think it, it, it describes actually what’s going on. If you administer a bolus of ketones to a sedentary couch potato person, their ketones are elevated for a long period of time. Whereas if you administer a bolus of ketone esters or salt to an advanced athlete, they clear it very quickly from the blood.

D’Agostino (00:59:46):
So probably because they have more mano carboxylic, acid transporters and things like that. So, you know, you’re an athlete, uh, many people maybe listening to this are an athlete and, uh, many, many athletes that I’ve communicated with hundreds, if not thousands are, you know, sometimes they get, have a problem getting into and sustaining a high state of ketosis and, uh, and come to find out, you know, when you administer ketones, they clear them from the blood pretty quick. Uh, so that said, there’s a couple of things going on that could affect ketone production. One is that some people have a pretty large increase in glucagon. Glucagon is not something we, we measure a lot. We’re measuring it now in our studies. We have a clinical trial and I’m going with Florida medical clinic. And, uh, and I measured, you know, in myself typically what happens, especially in athletes, they’ll have a really large suppression of the hormone insulin, but in elevation and glucagon and glucagon will increase gluconeogenesis.

D’Agostino (01:00:54):
So some athletes will have a persistently elevated. Uh, they won’t have a reduction in glucose, I could say, but their glucose levels will remain like 85, 90, maybe even a hundred percent upon waking, which is something called the Dawn effect we could talk about. But, uh, that’s largely, uh, a result of an elevated. It could be an elevation of cortisol, but more likely contributor is an elevation of glucagon. So glucagon being sustained and elevated glucagon is the sort of counterregulatory hormone with insulin. So you lower insulin, you enhance fat oxidation, fat burning is off the charts, right? One thing that enhances fat oxidation, but also gluconeogenesis is glucagon, which is the counterregulatory hormones. And in athletes, uh, you know, it couldn’t be because they’re just, just really hard charging individuals and they just, they work out a lot or whatever. Uh, you tend to see higher levels of glucagon. And the glucagon is actually making, you know, stored glycogen in the liver, more available. If you’re on a ketogenic diet, you start exercising, you could see a big burst in your blood glucose, and that’s the glucagon, and catecholomines actually liberating the glycogen, but you’re also, you know, liberating and mobilizing fatty acids for fuels. But, um, but I think the short answer is that the reduction in blood ketones that some athletes see is a consequence of higher ketone utilization and also an elevation of the counterregulatory hormones, like glucagon and catecholamines.

Brad (01:02:37):
Right. You don’t need to have this high level of ketones because the glucose is still there to burn thanks to the liberating of the fuel high glucagon and so forth. And that brings up another question. Uh, I was speculating at times with all my experimentation relating to diet, exercise, fasting and exercise, carbohydrate intake and recovery. And so forth that, uh, if I’m doing a lot of fasting and carb restriction, it’s technically a stressor to the body. And then I go do a sprint workout and I come home and instead of slamming a high-performance smoothie that has carbs, that has protein, I’m fasting for more hours, I’m getting a spike in adrenaline, right. Because I got to get the energy from somewhere. And could this be contributory to an excess amount of stress factors that affects my recovery? Oh, I forgot to throw in that I’m 56 years old doing these crazy sprint workouts and high jumping, uh, pretending I’m on the high school varsity team. And so that was one, I, I wondered what your opinion would be on that. And then maybe as a throw in, add on question, um, could ketone supplements come to the rescue here in the recovery period to provide me with this wonderful clean burning fuel source?

D’Agostino (01:03:57):
Yeah. Well, first thing you look great for 56. Wow. Like Mark, you and Mark Sisson, man, you guys are like defying, you know, the age, the normal age. So 56 is a new 25 30 or whatever. But yeah, to get to your point, I think, uh, being in a protracted state of carbohydrate restriction, low glucose, low insulin, high glucagon is probably not favorable. Definitely not clear both for recovery. So, um, what I like to do is just, I save all my carbohydrates for nighttime. So I have a big salad and at nighttime, uh, I do eat at night, not right before bed, but I try to eliminate, you know, two hours before, but I have, I always have berries. Like I can not, I can count on one hand the number of times I had not had berries in the last year. So I have like wild blueberries and raspberries and things like that.

D’Agostino (01:04:50):
And then mix that in with like this little keto pudding thing that I make at nighttime. So I typically have a little bit of fruit and vegetables and maybe upwards of like a a hundred grams of carbs. And for me a high fiber. And for me, that’s enough, I think to enhance recovery. I work out in the evening, typically late afternoon evening. So, uh, then we have dinner and we take the dogs for a walk and we do kind of some more low-intensity activity if you want to call it that. And then at night time, uh, you know, in the early mid evening, you know, I’ll have what will be the majority of my carbohydrates, but during the day I have basically like no carbohydrate. So I think it’s it’s can be advantageous for being fat adapted to, um, to do the exercise in the context of low insulin and, you know, low glucose.

D’Agostino (01:05:42):
And then you’re really tapping into and mobilizing fat for fuel. Uh, it’s good to train that way. Train low. Keep your body hungry for glucose. So that’s, I mean, if I have to stay in one way, you know, keep protein higher, moderate, especially the older we get, the more protein we need protein at about, you know, 1.5 grams per kilogram to two grams per kilogram. So 200 pound guy, like 200 grams of protein. Uh, I that’s, you know, some people will say that’s too high, but, um, for athletes, I think you really do need that too on a ketogenic diet, a low carb diet to preserve and maintain that muscle. And, you know, into that two grams per kilogram range, if you want to build muscle for the average person. If you’re below 1.5, it’s hard to build muscle and hard to even sustain it. You know, if you’re kind of a hard charging athlete. So I think that’s important to consider.

Brad (01:06:39):
So back to the weight loss question and the benefits of the ketogenic diet for weight loss, you’ve said that the, the big ones are, um, suppression of appetite and then restriction of choice of foods. And this seems to be such wonderful advice, but it’s not as sellable as saying, Hey, you can go out and eat all the bacon and butter you want. As long as you cut the carbs, you’re going to lose weight. And by the way, take some of these pills too. So I think we need to clarify this with that comment you made reminded me of, uh, Dr. Herman Pontzer coming on and his, his recent book Burn where he’s saying, look, it’s just, it’s just all about the calories and there’s no, uh, in other words, I think he said, every diet known to mankind is essentially a gimmick and it’s just to get you to adhere to it and get your nutrition. And I think we need to, you know, sort this out from a big picture perspective, but, uh, being able to suppress appetite and enjoy the heck out of your meals is a strong, you know, it’s a strong vote, uh, to do something that’s sustainable and will actually work.

D’Agostino (01:07:49):
Yeah. So there’s a lot of debate on this and a lot of, you know, things firing on Twitter and things like that. So I, I go against the grain if you will by the majority of the low carbs field. And I do believe that calories matter, right? And I believe that the benefit of low carb and ketogenic diets are kind of twofold or threefold, really. So when you take someone who’s eating a standard American diet and really just not tracking anything, and you put them on a low carb diet, then they start tracking. They’ll eat something. They’re tracking carbs. They’re paying attention to labels. They’re more cognizant of what they’re eating and that in and of itself is a behavioral modification that will translate to, uh, to some form of restriction usually. And it’s a behavioral modification that will help assist, uh, weight loss and maintain that weight loss if they continue with tracking. So tracking alone, and it could be any diet just tracking.

D’Agostino (01:08:54):
So that, and then another level of enhancement of weight loss is actually tracking, a diet that is a low carb diet or a ketogenic diet. So, uh, you could calorie restrict a high carbohydrate diet, you know, um, and you know, calorie restrict temporary calorie, restricted, a diet, or relative to a low, a low, a high carbohydrate diet. The hormones are going to be quite different. You know, you will have a suppression of insulin. If you restrict a calorie, restrict a high carbohydrate diet and you’ll have a more robust decrease in insulin and glucose and probably elevation of glucagon and some other hormones that we’re measuring now. The jury is still out. No one really has done and unambiguously perfect study on this. But generally what you see is that like a higher protein, like high protein, low carb, high fat diet has a greater appetite suppressing effect through changing hormones, various hormones in the body, but probably resulting to some extent by reducing glycaemic variability.

D’Agostino (01:10:17):
There is no doubt in my mind that you could take two diets, a high carb diet and a low carb diet, and then calorie restrict it. You’re going to see much tighter reduction in glycaemic variability with the low carb diet. And I think that, you know, at least in type two diabetics, I don’t know why it wouldn’t happen in normal, healthy people, but in type two diabetics that typically translates to a reduction in appetite. You know, there’s an appetite suppressing effect and better cognitive, you know, the facts and more energy and things like that. Uh, the studies on this are not that great, but that’s, that’s the general consensus. Although many people would debate that with me.

Brad (01:11:05):
That’s surprising that there’s not a lot of studies on it and what would be the studies.

D’Agostino (01:11:16):
There’s not a whole lot of good studies that clamp calories, clamp calories. So you have very high attention to, you know, oversight over calorie intake with a low carb diet versus a high carb diet, and to look at hormones and appetite regulation and a variety of other things. But the general consensus is that low carb diets have a mild advantage over that. And, uh, and that’s due to a wide variety. I do think that like my opinion is that a low carb diet is, uh, and I don’t want to put it in a negative context. It’s, uh, it’s some people it’s a low carb diet is hypo palatable and it reduces the hedonic response to eating. So I’m comfortable with saying that, that statement, when you eliminate the combination of sugar and carbohydrates, it’s not triggering that dopamine response. You just do not want to eat as much of a low carbohydrate diet as you would with a high carbohydrate diet.

D’Agostino (01:12:17):
And that in and of itself will reduce total calories over time and improve your metabolic health and many metabolic parameters. So that’s a really important thing. There’s many people, low carb community. We’ll just kind of shrug that off and it’s like, yeah, that may happen. But the big thing is that it’s the hormones, you know, that you’re suppressing the hormone insulin, which happens to a greater extent with low carbohydrate diets, at least acutely in response to a meal. The high carb cant may say, well, you have to look at insulin over a 24 hour period. Not just right after a meal. You know, when I think, you know, we don’t have continuous insulin monitors and then we could do that. So we just have fasting insulin. And I have to say that when I did a higher carbohydrate diet, and then I measured my fasting insulin, it really wasn’t, uh, much different, you know, if I controlled for calories although my insulin would spike quite high, right after a, uh, a high carb meal.

D’Agostino (01:13:24):
And that’s, that’s most certainly shutting off the fat burning process. So I think that’s probably not favorable. But what I would feel if I, you know, carbohydrates in the form of bread or pasta or starches or sugar, is that I feel great, you know, right after the meal, but about an hour to two hours after I would have that dip, I would get a little bit shaky and it would just screw up my whole mental flow. And low carb diets, ketogenic diets, completely abolished that post-prandial dip. And, uh, that pays big dividends. If you’re, you need a four or five-hour stretch to work on a grant, or you’re doing something that involves a lot of cognitive, you know, capacity over time. So, so I’ve learned to just accept this diet, not only steady it in my research, but actually transitioning to actually following the very thing that I’m studying myself.

Brad (01:14:21):
Hey, how about that? That’s it that that’ll help you get tenure. Look at this guy he’s walking his talk here.

D’Agostino (01:14:27):
I think they felt for sure. Yeah.

Brad (01:14:30):
Um, if the listeners don’t know about your extreme athletic achievements and devotion, I think we should, we should touch on that a little bit. And, uh, in the meanwhile you can tell us, tell us about your, your deadlifting feat that you did coming off an extended fast, I guess, to, um, again, walk your talk and, and, uh, show up on the, on the tenure track. But, um, I’m also wondering if there’s an additional variable relating to your training regimen when it comes to cracking that code about dropping excess body fat.

D’Agostino (01:15:05):
Yeah. Uh, well that the deadlift thing, yeah, about like 10 years ago, I became very interested in this idea of fasting and changing, you know, brain energy metabolism. So after a seven day fast, uh, I tested my strength, you know, not with a brutal long workout, but just, you know, uh, I, I warmed up, of course, and just, you know, deadlifted 500 for 10 and then, uh, six plates or another step. So, but that was within like what I was used to doing. And I’ve found that it didn’t feel any, uh, it didn’t feel any heavier after, you know, fasting for, for seven days. Not to say I could, you know, keep doing that workout for a whole hour or two. It was just a test for my overall strength. So I found that to be really unexpected. Uh, and I, I went into it thinking, you know, I was warming up and then 135, oh, that’s easy, 225, 15, 405 and then five plates.

D’Agostino (01:16:06):
And then it’s just like, I just kept going with the reps. And it was just, wow, that this is, this is remarkable. I have not eaten anything for seven days and it didn’t feel that much heavier. Uh, so not, maybe not everybody would have that experience, but a lot do because a lot of heard that and, you know, kind of fasted and, and nowadays I do fasting for three days, maybe every quarter. And I do like a deadlift test at the end and can do you know, the same amount. So, that, you know, that’s, that’s pretty much, I don’t think that fasting is, you know, an ideal tool for putting on muscle, but it just goes to show you that the body can adapt quite well. And I do think that I adapted well to that seven day fasting protocol because I have been in a state of ketosis for a year or two prior to attempting that.

D’Agostino (01:16:56):
I think if you’re on a high carb diet, you’re a high carb athlete, and then you just completely stop eating your body was running on glucose, and you’re going to have a painful transition into that prolonged fasting state. Whereas it was almost effortless. The third day was a little bit hard, you know, uh, but it was more of a behavioral thing. I just enjoy the process of eating. But my blood work looked great. You know, the blood work I did, I tested a bunch of things and, uh, and continued to do really demanding week of writing grants and teaching and things like that. And everything went super smooth. If anything, I was a lot more productive because I didn’t have to prepare meals, clean up, you know, eat the meals. So it saved me a lot of time during that week. So now I, I do it three times, uh, three to four times a year.

D’Agostino (01:17:44):
I do these three-day fasts and I just sort of task load myself, uh, to read a lot of papers and get a lot of, you know, office work done. I don’t task myself with a lot of physical activity during that time, because fasting is, I think of it nowadays is kind of rest, reset, transition the body, and then, you know, ease back into eating and then get back into training once I get back into eating. But I will test my strength at the end of it. And I do low, low cardio, low impact stuff during the actual fast to transition into, uh, a greater degree of ketosis during the actual fast.

Brad (01:18:21):
So your blood ketone levels, I’m sure are rising up to be pretty high, especially at the end of three days, but, uh, is your glucose pretty stable due to, in part due to your athletic commitment and your, your good metabolic function?

D’Agostino (01:18:36):
Yeah, the glucose will typically, uh, by the second day, get down into the mid to high sixties and then the low sixties by the third day that has been pretty consistent with the last couple of three-day fast. And I mean, to get back to that point of beta hydroxy butyrate. My blood ketone levels will, you know, on a normal day, they just stay at about one millimolar, but in the fasting state, they don’t pop up to three, four or five. They actually stay around like two or 2.5 or something like that. So they don’t shoot up very high at all. And in the morning there might be 0.5 or even one in a three-day fasting state. So this is what I see, but what I also see is that my breath ketones, so readout health makes an FDA approved device called the Biosense meter. And, uh, I just, uh, I’m about to do a blog on it.

D’Agostino (01:19:32):
Actually, it had to, it was in our last newsletter description of the Biosense. So the Biosense meter is really a better in the context of a calorie restriction or fasting state is a better indicator of your fat burning and your state of ketosis, your breath ketones. I originally got interested in breath, ketones because breath ketones correlated with seizure control, but the more, and I’ve pricked my finger, thousands of times measuring blood ketones. And I would see during activity, they would go down like after a walk, when they should be going up, I should predict, but I was them as fuel, but my breath ketones would go up and I would smell it on my breath. And I could just feel I was in a high state of ketosis, but it wasn’t showing on the blood meter. And, uh, and the more I looked into this, I realized, you know, the breath ketones in the state of fasting or calorie restriction is a much more fulfilling and accurate assessment.

D’Agostino (01:20:30):
And now the device is quantitative because it gives you a number which correlates. So the breath ketone measurements is actually what I prefer during fasting, or if I’m trying doing a weight loss, uh, and if you’re on a, you caloric diet, which means your calories, you know, maintenance level calories. The blood ketones and the breath ketones correlate well. So there’s breath ketones are measured and Ace’s like levels of acetone, like 10 ACEs Ace’s will correlate to one millimolar of beta hydroxybutyrate. And that’s, that’s very consistent with a eucalyptic maintenance, ketogenic diet. But once you start fasting the breath ketones climbing, climbing, climbing, and the blood ketones kind of stay where they’re at, or they don’t go anywhere. And I knew that that was not, you know, that’s not happening. I know that, but I knew I was in a state of higher state of ketosis, but I was just using more ketones for energy because I had, I was in a calorie deficit state.

D’Agostino (01:21:28):
So I’m just, you know, pulling more ketones out of the blood, if you want to use more energy. Whereas I was blowing off at the tone, the acetone that I could taste it is basically those carbons are all carbons from body fat. So that’s the way I think about it. It’s like when you’re in, you can just taste it. You can smell it. You’re like inner state of ketosis. And, and that acetone is pure fat. Kind of you’re blowing pure fat out of the body. So, uh, I could feel it, but it wasn’t showing on the blood ketone meter. So I’m a big fan. It took me a while to warm up to using this breath ketone device. And I used a couple of ones before I settled on the Biosense, but, uh, now I’m interested in actually doing some research to back up some of these observations.

Brad (01:22:12):
You’re our guy just researching everything, testing everything. Uh, I gotta say, Dom, you, you look good yourself. I mean, you’re a, for an academic, you’re a big strong guy, but you have lost quite a bit of muscle mass on purpose and trimmed down, you look like a different person, but tell us about that journey and how you feel today at a, um, a little more, uh, carrying around a little less muscle.

D’Agostino (01:22:38):
Yeah. Yeah. I lost probably 10 years ago at this time, 2011, I was just looking at a picture. It was right about 235. So right now I’m 216. And I have to say that I do feel better just being a little late. I’m a little bit, I’m over six foot, like six foot, some kind of a tall and maybe somewhat lanky guy, but I have a pretty big frame. And, uh, I do notice I become more interested in my biomarkers of health, like blood pressure, triglycerides, hemoglobin A1C. These are things that I like compete against myself to try to improve these numbers. Cause I’m thinking about longevity. I try to maintain a certain level of strength and the basic compound movements. And I think that’s important for longevity because the muscle is like, you know, I talk about like muscle currency. So there’s more, it’s, it’s really good to have a strength reserve and a muscle reserve.

D’Agostino (01:23:35):
So I make sure that I can like deadlift three times my body weight and bench a certain amount and things like that. So you can’t move the amount of weight that I did when I was heavier for us, but I feel like I can move a certain percentage of my body weight better and do it for more reps than I could when I was heavier. So I think, and also, uh, I’m a big fan of like body weight movements. So it took a year off and didn’t lift any weights, but was doing chin ups and dips and a variety of different ways for pushups and things like that. So I would say about half of my workout routine is actually using my body weight for, I do weighted chin ups, weighted dips, pushups like that, but then I do deadlifts and squats, but that pretty much encompasses all my workout. And I just work out with weights about twice a week. And it’s real quick, like 20 minutes, maybe twice a week.

Brad (01:24:29):
And then in between those pretty, pretty hardcore workouts, uh, you’re walking the dogs and just filling in with, uh, minor bodyweight things or something.

D’Agostino (01:24:39):
Yeah. Yeah. And I do a lot of work around the house too. We live on a farm here and we made a little island out in our lake and this weekend I was literally pulling out the cat tails and it was like, it was, I told my wife, it was like dead lifting for three to four hours. Pulling the cat tails off and then walking up the incline of the, the island and then like putting them on the top. And it was just doing that. And I was like completely exhaust. It was like the biggest work. So I do stuff like that. We have a lot of land, we have cows on the land and there’s a lot of fence like about almost two miles of fence. And there’s always trees falling down and knocking the fence down. So I’m out there with a chainsaw cutting stuff up, you know, repairing the fence doing it’s like usually about 15, 20 hours a week just doing that. And that kind of keeps me in shape. And I do walk the dogs every day, sometimes twice a day. And then I squeeze in to weightlifting workouts a week to just keep that strength, maintenance,

Brad (01:25:42):
Farm life for Dom D’Agostino. Thank you so much for all these insights. It was a, a wild journey through the world of ketones and more. Where can people connect further with you?

D’Agostino (01:25:54):
Yeah, thanks for asking. Keto nutrition.org. So all one word: ketonutrition.org,. Check out our blog, which hits many topics. Everything from the ketogenic diet for cancer, we have guest writers, for example, registered dieticians that work with patients that, you know, have their links to their services there. But we delve into many topics that we discussed here, but in a much deeper way and the blog and sign up for our newsletter to in the newsletter. I usually tell people about what I’m doing, you know, and then a month or two later, I’ll do a blog about it or something like that. So our newsletter, our products that we like, uh, experiments that I’m doing, you know, and usually an important research topic that is sort of, you know, new research that’s coming out. We’ll do, we’ll highlight it and, uh, the newsletter.

Brad (01:26:49):
Fantastic. Thank you Dom. Thank you listeners. That’s a wrap. Thank you for listening to the show. I love sharing the experience with you and greatly appreciate your support please. Email podcast@bradventures.com with feedback, suggestions, and questions for the Q and A shows, subscribe to our email list of Brad kearns.com for a weekly blast about the published episodes and a wonderful bimonthly newsletter edition with informative articles and practical tips for all aspects of healthy living. You can also download several awesome free eBooks when you subscribe to the email list. And if you could go to the trouble to leave a five or five star review with apple podcasts or wherever else, you listen to the shows that would be super, incredibly awesome. It helps raise the profile of the B.rad Podcast and attract new listeners. And did you know that you can share a show with a friend or loved one by just hitting a few buttons in your player and firing off a text message? My awesome podcast player called overcast allows you to actually record a soundbite excerpt from the episode you’re listening to and fire it off with a quick text message. Thank you so much for spreading the word and remember B.rad.




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