Dr. Dominic D’Agostino on Developing a Well-Designed Ketogenic Diet and Harnessing Its Benefits

[Dr. D'Agostino]: But I think where ketones 
shine is using exogenous ketones as a means to   preserve performance resilience in extreme 
environments. There are so many different   factors that need to come into play. When 
you're choosing to do a ketogenic diet,   including monitoring people really need 
to track nutrients, track calories. Some people put, you know, they eat a ketogenic 
diet, but they put the same amount of food on the   plate. And the caloric density of the ketogenic 
diet is like 50% higher.

So you can't eat.   So typically, you know, we have auto feedback 
mechanisms that will tell us when we're satiated   full, but for some people they don't work well. So they do need to count calories 
and macronutrients and track   at least initially. So they have some 
idea of how many calories we're eating. [Dr. Patrick]: Hey, everyone. I'm 
sitting here with Dr. Dom D'Agostino,   who is an associate professor at 
the University of South Florida.   He's also a research scientist at the 
Institute for Human and Machine Cognition.   His research lab focuses on metabolic 
therapies, including ketogenic diets,   ketone supplements among others. I'm super excited 
to have you back on the podcast, Dom. It's been   six and a half years or so, it's been quite 
some time since we had a conversation. And   since then, keto, as it's called, for sure, in 
the popular world, has really…it's exploded   in popularity. I feel like with that explosion 
in popularity, it's lost a little bit of…it's   become a little bit more of a brand in the popular 
mind and less of a distinct metabolic state.

And so I'm excited to have you here 
to talk about the science…to give   us a refresher about the science of 
ketogenesis, ketosis, ketogenic diets,   ketone supplements, and all those things. And 
as someone that has been researching it over   the years who's been practicing ketogenic 
diets personally for also many years,   maybe we can kind of just start with 
a refresher, what ketogenesis is.

[Dr. D'Agostino]: Yeah. I think that gets lost 
in, you know, all the noise because it has been   commoditized, so to speak, and commercialized 
in ways that are not always very good. So,   a ketogenic diet is unique from a dietary therapy 
point of view in that it's the only diet that we   know of that is defined by an objective biomarker. 
So, that's ketones, and you measure that in your   blood, in your urine, and also in your breath, 
right? So there's different ways to do that. If you are not in a state of hyperketonemia, 
elevated ketones, you're technically not on a   ketogenic diet. And what most people don't 
really appreciate is that to really get   higher levels of ketones that are therapeutically 
linked to what it's used to treat, which is like   neurological disorder, seizures, and 
things like that, you really have to   increase the fat…drop the carbohydrates 
especially but moderate the protein and   really consume a really high-fat diet.

And that's 
not always sort of appreciated in the mainstream. And a clinical diet is probably not 
the best choice for a lot of people,   a clinical ketogenic diet. But there are 
variations of the diet from a four to one, which   is a classical ketogenic diet, which is 90% fat 
and one part protein and carbohydrates. And then,   all the way on the other end of the spectrum, 
there's the modified ketogenic diet or modified   Atkins, or low glycemic index therapy or LGIT. 
And that's more of a one-to-one ketogenic diet.   It's personally kind of what I follow, and 
I think you can construct the diet in a way   that produces a mild state of ketosis. I 
think that could be a good lifestyle diet,   but it's far different than the classical 
ketogenic diet, which was used for pediatric   epilepsy.

But they both have, you know, 
therapeutic effects that we can delve into. [Dr. Patrick]: Can you give us an 
example of that type of diet and also   what is defined as being in either mild ketosis 
to actually, you know, basically identify you as   being in a state of ketosis from a ketogenic 
diet or even from other…we can talk about   other ways. Obviously, we've had a lot of 
people in the podcast talking about fasting. [Dr. D'Agostino]: Yeah. So, a ketogenic diet 
produces ketosis by suppressing insulin,   right? And I think of it as almost like insulin 
suppression therapy.

So, when you fast, you   suppress the hormone insulin, you deplete liver 
glycogen, and then that accelerates beta-oxidation   of fatty acids. And it's the oxidation of 
fatty acids in the liver or the over-oxidation   of fatty acids that accelerates production 
of acetyl-CoA, and then that condenses to   acetoacetate and beta-hydroxybutyrate. So that's 
accelerated at a maximal state with fasting,   and you can mimic that state of fasting with a 
classical ketogenic diet, which is like 90% to 80%   fat with a level of carbohydrate 
that almost has no effect on insulin,   really. So in many ways, it mimics fasting 
in that you have a low insulin, low IGF-1,   a little bit…suppression of the 
mTOR because protein is moderated too. And then that diet is used classically for 
epilepsy. That's the four to one ketogenic diet.   In extreme cases, they use a five to one ketogenic 
diet. And then if you move down the spectrum, it's   3 to 1, 2 to 1, and then modified Atkins, which is 
like a 1.5 to 1 ketogenic diet to a low glycemic   index diet.

So what that would mean as far as to 
give an example for me. So yesterday I counted my   macros and I had 200 grams of protein, 150 grams 
of fat, and 50 grams of carbohydrates. So, 200   grams of protein compared to a combination of 150 
grams of fat and 50 grams or 150 grams of protein,   sorry, and 50 grams of carbohydrates. So that 
would be a one-to-one. So I have 200 grams of fat,   150 grams of protein, and 50 grams of carbs, 
right? So it's 200 grams and 200 grams.   You know, that's how it's constructed in the 
world of epilepsy or dietary therapies by grams,   not percentages. So, that's a one-to-one ketogenic 
diet, and that sounds extremely high in fat,   right, 200 grams of fat and 150 grams of 
protein.

But that's actually the very liberal,   more loose version of the ketogenic 
diet that produces a very mild state of   elevated ketones. Whereas a 4 to 1 ketogenic diet 
would be like 400 grams of fat to like, you know,   90 grams of protein and 10 grams of carbohydrates, 
right? So that would be very high in fat. Interestingly, the research over the years have 
shown that they both have anti-seizure effects,   and we're getting a better appreciation for 
a more liberal version of the ketogenic diet   that is not so protein-restricted and not 
so extremely carbohydrate-restricted than   something like a low glycemic index diet, 
which can produce little or no ketones,   it can still have an anti-seizure effect and still 
have benefits, even independent of high ketones.   So that's kind of interesting to me because 
it was always thought of that you needed to   get really high ketones to achieve a therapeutic 
effect, but it looks like you could probably get   many benefits from low ketones.

But you're also 
suppressing insulin and suppressing a lot of other   pathways that are, you know, therapeutic in 
some way, they're altering, I should say,   different pathways. I don't know if I 
answered your question. I'm just trying to… There's variations of the ketogenic diet, 
and I think that over the last 10 years…I   guess it's longer than that. I think in 2008, Dr. 
Eric Kossoff from Johns Hopkins, he worked with   Dr. John Freeman, the late John Freeman, and 
developed a modified Atkins diet or modified   ketogenic diet for adult epilepsy. And then it was 
published that the diet can work for adults too   back in 2007 or '08, I think around that time. 
So, we have many variations of the ketogenic   diet even used clinically. And then when people 
talk about the ketogenic diet in the mainstream,   that could be anything. I mean, typically, it 
means carbohydrate, you know, restriction, and it   could be a carnivore diet. And we can talk about 
that. And there are many different variations. But clinically, what you have is a five to one, 
which is very extreme high fat, four to one,   three to one, two to one, and then a modified 
ketogenic diet or low glycemic index diet.   And all of them are therapeutic in one 
way or another, and they're used for a   variety of different neurological disorders, 
seizure disorders, metabolic disorders.

Some   are more efficacious for others, it depends 
on the individual, it depends on compliance,   on the family, there's a lot to be considered 
when it comes to implementing these approaches. [Dr. Patrick]: For a person who has not done 
the ketogenic diet before, what would be a   good starting point? Like, you know, would you 
want to start with something that's one of the   more like four or five to one? You know, because, 
from my own personal experience, and, you know,   I'm going to be doing another ketogenic diet 
very soon, I just haven't gotten my biomarkers   measured, it was very challenging for me, even 
someone that does a lot of intermittent fasting,   to get into ketosis and to really stay in it.

And 
also what levels if someone's measuring. And we   can talk about, you know, biomarkers and 
measuring things but like, you know, what would   be considered a mild state of ketosis if you're 
wanting to go by ketone levels, for example. [Dr. D'Agostino]: So, very good question. 
It's very context-dependent. So,   if you are using the ketogenic diet to manage 
a metabolic or a metabolically linked disorder   or a brain disorder like epilepsy, right, you 
probably want to start with a clinical ketogenic   diet and be under the supervision of a registered 
dietitian and a neurological team. So this is   what they use in epilepsy. And there used to be 
an induction phase where they would fast you,   and that actually helps facilitate metabolic 
switching, which is the transition into ketosis   from being primarily a glucose oxidizer to 
a fat and ketone utilizer. So you can speed   that with fasting. But then you have…most 
people are doing it as a lifestyle approach.

So, in our clinical trial that we're 
doing using… In non-diabetic people,   they tend to be a little bit on the heavier 
side, but they don't have type 2 diabetes,   they're using it to optimize their metabolic 
parameters and glycemic variability. We transition   them into a ketogenic diet over four to six 
weeks. So, we titrate the carbohydrates down.   And what we have found or my colleague has found, 
Dr. Allison Hull, she's at the Florida Medical   Clinic and has a wellness program, that compliance 
and adherence to the diet and ultimately the   results are better. If you take someone who's 
eating 300 grams of carbohydrates a day, that's   standard, you know, American diet, and you drop 
them down to, you know, 100, and then the 75, and   then 50 at about the four to six-week point, and 
you get a very nice improvement in many different   subjective and objective, you know, biomarkers, 
they feel better, signs of mood are increased,   anxiety using the GAD-7 test, the 
PHQ-9, SSQ. Sleep actually improves. If you were to abruptly start the ketogenic diet, 
you're more likely to get side effects and you're   more likely to get things like sleep disruption, 
lipid abnormalities, elevated triglycerides,   you get a quick spike in LDL.

This can occur if 
you rapidly start the ketogenic diet, especially   in the context of not calorie restricting. When 
you calorie-restrict a ketogenic diet, it sort of   mitigates many of the things that are negatively 
associated with high fat diets. So the transition   is a lot easier if you calorie-restrict with a 
ketogenic diet. So that needs to be appreciated. For a lifestyle, I would recommend, if you're 
not on a carbohydrate-restricted diet, to ease   into it and titrate it over time if you're 
not in a rush, right? So, for me personally,   I follow what would be considered a very 
modified supplemented ketogenic diet that   would be more along the lines of a low 
glycemic index diet. So I have about…you   know, 10% to some days 20% of my diet is 
actually carbohydrates but in the form of fibrous   vegetables, right, essentially non-glycemic 
carbohydrates, so a lot of leafy greens.   The carbohydrates that make up my ketogenic 
diet are on the…like typically have about one   third to almost half of it is fiber and has very 
little impact or actually can improve glycemic   variability or reduce it in that it 
moderates the digestion of protein and helps   delay gastric absorption.

So, the 
nutrients and things that I'm eating   actually get into circulation in a protracted 
way. So the fiber helps to slow digestion. And so fat and fiber together are really important 
for the ketogenic diet, and that's not something   classically that's accepted or considered. But as 
we learn more about ketogenic diets, we have an   appreciation for the types of fats that are in the 
diet and actually incorporating fiber, not only to   improve digestion and protein assimilation, 
but to enhance and preserve the gut microbiome,   which is to be appreciated. So there was a 
lack of that understanding 20 or 30 years ago,   and it came into the conversation about 10 years 
ago. And now it's actually become a major focus   of a lot of these dietary interventions, low 
carb and ketogenic diets.

We need to appreciate   fiber as a part of improving the diversity 
and maintaining the gut microbiome. [Dr. Patrick]: You've just answered 
one of the main questions I had about,   you know, being on a modified ketogenic diet 
and somehow intelligently designing a diet   that include more fiber, you know, your thoughts 
on how fiber would be important. And it's really   interesting to hear you say that because, you 
know, the other thing is that, you know, fiber,   you are making butyrate in the gut when you're 
or your bacteria is, you know, making it, the   microbiome inside your gut. And that is fueling 
the colonocytes, right, giving them energy. When I was doing the ketogenic diet, I did 
find that…I ended up just naturally fasting   more because it is so difficult. Like things I 
could eat, it was like, "Well, I can't eat…"   I would snack on some macadamias.

And after a 
certain point, it was like, "Well, this is like   too much, the ratios of the protein in the…" 
So I'd have to like not eat, and then, you know,   I found that I was basically just doing a lot of 
dietary restriction alongside the ketogenic diet. But I also found that when I would add, like, 
dark leafy greens, the portions really made   a difference for me. Like, for example, cooked 
spinach, like, you don't think about it but, like,   because you're cooking it, it's like a 
lot more spinach than you would think   it is. And so, like, a little serving of 
it looks small, but it's actually quite   a bit. And so I noticed the cooks…if 
I had like a portion of cooked spinach,   you know, it wouldn't totally take me out of 
ketosis, but it wasn't getting me into that   higher level.

So, you know, I would go from 
like 3 millimolar down to, you know, 1. [Dr. D'Agostino]: So you were cooking your 
spinach. Yeah. If you take raw leafy greens,   so the cell walls intact, but 
when you cook green vegetables,   the heat ruptures the cell wall. So you make 
the carbohydrates a little more accessible,   even if it's green leafy vegetables. So that's 
going to impact…

Believe it or not, you know,   in the context of a ketogenic diet, it 
makes a difference. If you have greens   that are raw, the glycemic impact is essentially 
nothing, but if you cook your greens,   you know, it does make it proportionately much 
smaller, so you're more likely to eat more,   but it also makes the carbohydrates accessible 
because the heat is rupturing the cell wall. So   similar to like juicing or a smoothie or something 
like that, right? Although with the smoothie, you   got the fiber and stuff in with it too. So, that's 
a big consideration that people need to consider.

[Dr. Patrick]: Greater. [Dr. D'Agostino]: Yeah. But volume. But 
with a salad like a salad that would…an   example of a salad on a modified ketogenic 
diet or modified Atkins diet would be,   you know, fatty fish like salmon, leafy 
greens like arugula, maybe some spinach and   romaine lettuce and stuff, and extra virgin 
olive oil, lots of that. And I tend to mix it   with MCT oil, so a combination of extra virgin 
MCT, we can get into that, as a ketogenic fat.

Nuts are great, but I don't go too 
crazy with nuts but a little bit of   walnuts. So you have fatty fish, a little bit 
of leafy greens, and a very fatty ketogenic   dressing that's made, you know, with MCT 
and olive oil and herbs and things like that   would fit in well with a ketogenic diet. So 
you get monounsaturated fats, right, and you're   getting polyunsaturated fats and MCTs, which are 
saturated but go to a different…they do not   disrupt the gut microbiome in ways that other 
types of fatty acids do. And that's the kind of   nutrition that would be no effect on a continuous 
glucose monitor. So your glycemic response would   be like nothing, and your ketones would likely 
go up because of the macronutrient ratio but also   because of the MCTs that are in it too. So that's 
a very normal kind of typical diet that I eat. [Dr. Patrick]: So most of your 
greens or most of your carbohydrates   are eaten raw for the most part. 
You generally not cook them. [Dr. D'Agostino]: We do broccoli a lot and 
asparagus, so I lightly steam it or cook it,   but I don't make it to the point where it's 
like mushy.

So I lightly steam vegetables like   cauliflower, broccoli, asparagus. I always have a 
salad with my meal. With a ketogenic diet… When   you wear a continuous glucose monitor, you can 
observe that the order in which you eat your food   will impact the glycemic response. And if 
you're attenuating the glycemic response   by eating foods in a certain order, a certain 
combination, that's also reducing the insulin.   So, you need to continually have a suppression of 
insulin signaling to maintain a state of ketosis. So, if you're in a state of fasting ketosis or 
on a ketogenic diet, and you inject a little   bit of insulin, you'll see your ketones go down, 
there'll be a delayed response. That's because   the reduction in insulin plays a 
big role. When you increase insulin,   it dramatically increases glycolysis, 
you know, translocation of the   GLUT transporters to the membrane and 
things like that. So, you could do that.

Exogenous ketones can actually increase 
insulin if it's too much, and we can talk   about the different variations of that and why 
that could be problematic in some conditions.   But, you know, taking a big hit of protein 
like drinking whey protein will kick you   out of ketosis because you're going to get the 
insulin response from the essential amino acids,   and branched-chain amino acids too can increase 
that. So it's really important to incorporate   fat and fiber with the meal especially up front, 
yeah, to attenuate any kind of insulin response.

[Dr. Patrick]: Right. That's an 
interesting [crosstalk 00:20:33]. [Dr. D'Agostino]: And you learn these things 
as you go. There's a learning curve to the   ketogenic diet. I went right into the classical 
ketogenic diet. I bought the book, you know,   "The Ketogenic Diet for Pediatric Epilepsy" and 
now it's "The Ketogenic Diet for Epilepsy and   Other Neurological Disorders," same author, 
Dr. Eric Kossoff, Dr. Mackenzie Cervenka   from Johns Hopkins, and the team there. They 
advocate for a variety of different types of   ketogenic diets and then adjusting it to the 
patient and their circumstances too is going   to be important in the world of epilepsy. So, it 
remains the only widely accepted application of   the ketogenic diet at this time is really epilepsy 
and metabolic disorders like glucose transporter   type 1 deficiency syndrome, PDH deficiency, 
and things like that. And interestingly,   there are inborn errors of metabolism that are 
contraindicated with a ketogenic diet like,   you know, carnitine transferase activity, CPT1, 
you know, whether it be primary or secondary   too. So it could be deadly. A ketogenic diet 
could potentially kill you if you have carnitine,   you know, transferase deficiency. So that's 
a whole another topic we could discuss.

[Dr. Patrick]: You bring up an interesting 
point with the contraindications because   I'm interested in a few of those aspects, so 
for one, perhaps other genetic variants that   maybe aren't as rare. So, for example, 
you know, APOE4 allele, which, you know,   a quarter of the population has one of those 
alleles. Like how is it known how people with that   polymorphism respond to ketogenic 
diets? And also you mentioned, you know,   briefly about people that sort of race into 
the ketogenic diet without any sort of slowly   carbohydrate restriction and how it can elevate 
some biomarkers like triglycerides, for example.   I'd love to talk about like what biomarkers do you 
think are good to monitor and to see if someone is   favorably or unfavorably responding to a ketogenic 
diet, and at what point would you…? Like how   many times would you do it before you sort of give 
up and sort of modify the diet or change maybe   types of fat? You mentioned the types 
of fat or, you know, things like that.

[Dr. D'Agostino]: Yeah. I think it's important. A 
lot of people jump into the ketogenic diet. And,   you know, just from a standard diet… 
It's important to test the water.   If you're not using it for epilepsy or another 
disorder, you want to titrate the carbohydrates   down and track and monitor along the way. 
You maybe do like cut your carbs in half   or by two-thirds or whatever, and then at the 
four or six-week mark, get blood work again   and look at your glucose response, check 
for hypoglycemia, things like that. So APOE4, you know, that's about one 
quarter, right, of the population.   I get this question a lot, and I don't think it's 
ideal. Even the books on ketogenic diets say that   it's an unnatural diet and it's not healthy and 
it's not sustainable.

So these are from the people   who researched the ketogenic diet who published 
the most on the ketogenic diet who are in the   trenches using this diet as a medical therapy 
for like known conditions that are responsive to   the ketogenic diet. So with that said, you know, 
dietary teams that manage patients for up to 10   years, 20, and even I had some correspondence 
with the team that are measuring people and   cardiovascular parameters too, their heart health 
for 30 years. So, in patients, for example,   with inborn errors of metabolism that need to 
be on, like, a classical type ketogenic diet   for like three decades, and they're still 
doing…all their blood work looks great.   So I think that's a good example that the diet 
is not going to kill you.

It would have done   that a long time ago in these patients that are on 
like a four to one or three to one ketogenic diet. But I think it's important 
to… In the context of APOE4,   extremely high fat is probably not ideal. So you 
want to take probably a more moderate approach   and just restrict carbohydrates. I think 
it's really important to get lots of fiber,   lots of phytonutrients. We know the data on 
fiber is just really, really good. There's   no arguing. And people argue against fiber, but I 
think the data for fiber is really good, not just   for the microbiome, for the phytonutrients, the 
micronutrients. As, you know, there's been a lack   of appreciation for micronutrients and ketogenic 
diets, and that has caused problems like selenium   deficiency, which led to cardiomyopathy, 
and there's case reports where people   have literally…I think one or two where people 
have literally died from cardiomyopathy because   of selenium deficiency associated with the 
ketogenic diet.

So you want to make sure   you supplement appropriately, but you don't 
have to supplement if you formulate the   ketogenic diet appropriately with the right 
types of foods, but it's not always possible. But for APOE…and getting back to your APOE. So a 
diet that's moderate in fat, moderate in protein,   and I think of carbohydrates 
as fiber, so plant-based fiber,   moderate protein, and then fats. 
The types of fats are important. So,   monounsaturated fatty acids as opposed 
to a long chain like saturated fats.   Medium-chain triglycerides are probably 
helpful. There is a study that was done   using a product that is caprylic triglyceride, 
which is MCT. At the time it was called AC-1202   by Accera. It was a product that was designed 
for Alzheimer's disease as an alternative   energy substrate that would be given. And the 
results of the study showed that improvements in   mild cognitive impairment were associated with 
ketones. So there was a correlation with that.   But they did not see the correlation people 
with APOE4, which was kind of interesting.   Although I think a larger study probably 
would have shown like a difference.

But I think the take-home message is that a diet 
that's very…like super-restrictive and high in   fat is probably not ideal for APOE4 patients, and 
adding ketones in the form of exogenous ketones   could probably be ideal. There was a case 
report on a patient that I am familiar with   that…I'm familiar with the wife of the patient 
that had passed away, but he was maintained   on a ketogenic diet and then later on ketone 
esters and exogenous ketones and was…did   quite well in this diet for a long time. 
And it wasn't a restrictive ketogenic diet,   but he did much better with ketone supplementation 
as it means to improve his cognition and different   behavioral parameters too. So I think that 
would probably be the better way to go. I'm very cautious in speculating and giving 
medical advice.

I'm not a medical doctor.   I am a professor and I'm professing that I think 
that a more moderate style Mediterranean-like   low-carb/ketogenic diet with supplementation 
in the form of things like omega-3 fatty acids,   MCT oils. The fatty acids comprising the diet 
should be more along the lines of monounsaturated   fats and not so much heavy saturated fats, 
which in the context of APOE4 is probably   not a good thing to chronically maintain a 
state of ketosis with superhigh saturated fat. [Dr. Patrick]: Yeah. So maybe more avocados, more 
of the nuts, and olive oil, salmon, which is a   good type of polyunsaturated fatty acid.

I mean, 
that's the kind of diet that I was doing and will   try again. And we'll talk a little bit 
more about why I'm so interested in   ketogenic diets. I don't have epilepsy, 
and I'm certainly not someone that eats a   standard American diet either. There are so many 
interesting effects being in a state of ketosis   and having the ketone bodies elevated, 
and that to me are very interesting and,   you know, I think possibly beneficial 
for healthspan, for cognition, and so…

With the supplemented ketones that you keep 
mentioning like with respect to, you know,   having a diet you follow, which is more of 
the low glycemic index, one to one ratio,   with supplemented ketones, it's another really 
big area that's exploded over the past few years.   Can you talk a little bit about, for 
people that aren't familiar, like   supplemental ketones? There's different types of 
supplemental ketones.

You mentioned ketone esters,   salts, and then even MCT oils or powders. So, 
maybe we can kind of jump into that a little bit. [Dr. D'Agostino]: Yeah. I think the question 
is, like, why would you even want to   short circuit the state…? You know, why would 
you want to circumvent the dietary intervention   that produces ketosis, i.e., the ketogenic diet? 
Why would you want to circumvent that? I mean,   the reasons are kind of obvious, and just throw 
ketones into the mix.

Like what's going to   happen physiologically? There are people who are 
unwilling or unable to do the ketogenic diet. So   that was the motivation behind developing and 
testing and ultimately publishing a number of,   you know, articles and studies on exogenous 
ketones. And there are different formulations   and not all types of exogenous ketones 
or formulations of combinations   are applicable to different disorders, right? Some 
conditions are more responsive to ketone esters,   whereas some are more responsive to ketone salts 
or formulations of MCT and ketone salts, right? When I first got into this research in 2008 or 
'09, I believe, I contacted a number of people   who remain to be icons in this field. So, Dr. 
Richard Veach, I like to always, you know,   acknowledge him as being a pioneer in developing 
the rationale and developing ketone esters, you   know, and the rationale for using them and writing 
a number of reviews that actually motivated me   to pursue this path.

Dr. Henry Bruning Grabber 
[SP], George Cahill. Dr. Theodore VanItallie.   I mean, they're all sort of friends and 
collaborators, and they published on this. So,   I was really focused on the ketogenic diet. But 
when you're writing a grant, a federal grant,   and you're trying to sell this approach as 
a means to, you know, reduce seizures or   enhance warfighter performance, resilience, 
and things like that, the high-fat diet   is still looked upon as something that is very 
negative. So, the question was, can you develop   a ketogenic diet in a pill? And essentially, that 
was sort of the path we took with ketone esters. So the ketogenic diet, it was my understanding 
that the body at the time that you need to have   adaptations over time that would change 
your physiology that would change your   brain neuropharmacology that would then have, you 
know, an anti-seizure effect, and that happens.   By changing your systems physiology, you're 
changing your brain neuropharmacology and   your brain metabolism.

So your brain is switching 
from using glucose, and pretty much only glucose,   to using glucose and ketones. It never switches 
completely off of glucose and ketones. So,   the homeostatic mechanisms that maintain your 
blood glucose are very powerful, so your glucose   pretty much stays normal, but insulin 
goes down. So that's a thing that we see. The effects of the ketogenic diet are…and sorry,   it's a long-winded version, but I want 
to kind of provide a framework. You know,   I was educated on the role of ketones as a 
metabolite and also later as a signaling molecule   as a drug-like mediator of the ketogenic diet. 
So, we produce these endogenous metabolites,   and they not only serve as alternative energy 
for the brain and the heart and other tissues,   but then they have signaling effects that mediate 
many of the beneficial effects associated with   being in a state of therapeutic ketosis. 
So that's things like elevating adenosine,   activating various ketone receptors, GPR109A 
receptor, for example, anti-inflammatory pathways. I was really interested in the oxidative 
stress associated with high-pressure oxygen.   So we measured like superoxide anion production 
using ethidium molecule like the fluorescence and   showed that mitochondrial ROS production goes down 
with a beta-hydroxybutyrate and ketone molecules.   So there was all these things that were 
happening as a consequence of the hyperketonemia.   So, undoubtedly, there's things that happen 
with the ketogenic diet that are therapeutic   and very beneficial that don't happen with 
exogenous ketones but there's a lot of overlap.

And then later, as we develop ketone 
esters and ketone salts and used MCTs,   we saw that if we administer these things 
to animals that are not on a ketogenic diet,   we saw remarkable anti-seizure effects, 
anti-cancer effects, we saw changing   the brain neuropharmacology, meaning that the 
GABAergic tone went up. So, GABA is made from   glutamate via an enzyme called glutamic acid 
decarboxylase. So we have glutamate as the most   ubiquitous neurotransmitter in the system in our 
body. And that's an excitatory neurotransmitter   that activates the AMPA receptors and NMDA 
receptors. And then glutamate via the conversion   to GABA through glutamic acid decarboxylase is 
a brain stabilizing, calming neurotransmitter. And I've even measured my own neurotransmitters 
and showed that GABA is like twice as higher   than what would be expected, my GABA to glutamate 
ratio, right? In animal models, we see this too.   We did an animal model of Angelman 
syndrome, which is responsive   to…we knew from case reports that the seizures 
could be silenced with the ketogenic diet. So we   had an animal model of Angelman syndrome, 
and we administered ketone ester with a   standard diet and saw an increase in GAD65 
and 67 and essentially an increase in GABA.   And then that resulted in what we saw, increase 
in learning memory, we saw, you know, anti-anxiety   effects.

And the increasing GABAergic tone likely 
contributes to the anti-seizure effect of that. And many anti-seizure drugs like Vigabatrin 
and other drugs work through GABA. So,   the ketogenic diet works through many different 
mechanisms in synergy, and one of them is GABA.   So we're sort of interested in it 
from that perspective. So you can   replicate and mimic many of the effects 
that I'm interested in from a neurological   perspective, neuroprotective with 
simply administering exogenous ketones   to animals at least on a standard diet. 
So this has actually spawned many… The pre-clinical animal model data was 
so compelling that it has inspired,   not from our lab, from other investigators, you 
know, looking at this too, a dozens of clinical   trials that are ongoing right now. If you just 
go to clinicaltrials.gov and google and just or   just type in ketone supplement, I think you get 
like 30 or 40 clinical trials that are looking   at ketone supplements. And just a few years 
ago, there was none, right? So, there's a lot   of other people instead of us looking at this idea 
of…I guess you could call it a ketogenic diet .

But I think of exogenous ketones are 
calorie-containing molecules that are essentially   in some ways found in nature, some 
of them are, some of them aren't.   But they do elevate a bioidentical ketone 
bodies in the blood and in tissues. So,   in many ways, they're not so much like 
a drug. It's like creatine monohydrate,   right? So you can take…creatine is found 
in meat and it's found in other things.   We can take exogenous creatine, and it has not 
only effect on skeletal muscle but on the brain.   And I think we're getting an appreciation 
for creatine as like a nootropic even. I look at ketones as being kind of the next 
creatine, but it's going to take a while   for the research. I think there's like 700 or more 
trials or studies on creatine, you know, showing   the efficacy and the positive effect, whereas 
maybe there's maybe like 50 to 100 with ketones,   but it's expanding very rapidly. It's very nascent 
literature, but the nascent literature has spawned   many other labs, you know, outside of our lab 
and labs that were doing it well before our lab.   But I became so interested in this idea 
that it…I just changed my whole research   direction away from drugs to look at diet 
and supplements.

Sorry, that was long-winded. [Dr. Patrick]: No, it's fantastic, so much 
information. You mentioned that, you know,   in different contexts, these different types 
of ketone supplements can have, you know,   varying effects or be used for different 
things. If you're just looking at   ketone…you know, beta-hydroxybutyrate levels 
as an endpoint, what would be the difference   in taking a ketone ester versus a ketone salt? How 
long would you see an increase in the, you know,   beta-hydroxybutyrate levels is how transient? 
Is it side effects-wise, you know, with these   different…? And the formulations as well. Like 
there's all kinds of formulations that you see. [Dr. D'Agostino]: So, you can get an elevation 
of ketones for one hour or six to eight hours   depending on the formulation and depending upon if 
you took the ketone supplement with…on an empty   stomach or taken it with food or combined, for 
example, a ketone ester with a ketone electrolyte   salt, right? If you take ketone salts and you 
combine it with medium-chain triglycerides,   the fat delays gastric absorption and pushes the 
pharmacokinetic curve, if you will, to the right.   And this is important.

You get a little bit slower 
elevation of blood ketones, and then you have   a significant sustainment of hyperketonemia 
over time and the decrease in the spike.   So a very rapid spike in ketones 
contributes to a release in insulin. So, if you consume a ketone ester at a large 
dose on an empty stomach, you have a very large   increase in beta-hydroxybutyrate and acetoacetate 
too depending on the formulation. And it's that   rate of change, the relative rate of 
change of metabolites, similar to like   if you have a very rapid, you know, relative 
spike in leucine, it's going to kick on   skeletal muscle protein synthesis, but if 
it's a gradual spike, maybe it won't kick on   the metabolic machinery associated with skeletal 
muscle protein synthesis. The rapid elevation of   ketones can produce a counter-regulatory 
effect, which is a release in insulin,   and then that can shut down your 
own natural ketone production.   So, the way to go about doing it is to formulate 
something that causes a predictable but gradual   rise in ketones and sustains that for a period 
of time and has a predictable decrease over time.

So the way to do that simply is to take…the 
way that I do it on a daily basis is   beta-hydroxybutyrate that's bound to electrolyte 
sodium that has sodium, potassium, calcium,   magnesium in that formulation, so balanced 
electrolytes, more or less like the electrolyte   supplements that are on the market. So, LMNT is 
one. I think maybe Liquid IV or Gatorade or even   these things. So, the higher sodium, you know, 
but you want to match it with some potassium,   calcium, magnesium. And then the electrolytes in 
themselves will actually delay gastric absorption   a little bit. So salt does that. And if you 
combine that with MCT too, that delay it.   The salts can actually delay gastric 
absorption, so it's not so much of a rapid rise. If you take a beta-hydroxybutyrate ester, 
you have 1,3-butanediol typically is bound   to beta-hydroxybutyrate. When you consume that, 
the beta-hydroxybutyrate is quickly liberated,   so it spikes your glucose or your ketones 
up very high.

But in regards to glucose,   actually, that comes down pretty low. And you had 
to ask me that question. Why does glucose drop,   so down into hypoglycemic ranges with a 
single large dose like 30 to 50 milliliters   of like a pure ketone ester, 
something like that, right? Yeah. So, in the beginning, I thought it was 
insulin, and it is insulin. So the threshold   for me at least…I measure insulin quite often in 
response to this, and what I find is that if you   take a ketone supplement and it boosts you 1 to 
2 millimolar like a delta, a change, an increase,   then the elevation of insulin is almost 
imperceptible according to like the assays   that we're using.

But if you were to consume 
a ketone ester and get up into the three,   four, and five range, then that produces 
an elevation of insulin equivalent to   eating…you know, drinking like 2 to 4 ounces 
of OJ or like 10 grapes or like a small orange,   right? So, for me, it goes from like 3 to 6 
or 8 or 10, right, insulin, my blood insulin   levels. And it's equivalent to maybe eating 
about 30 or 40 grams of protein. So you would   get that amount. Whereas if you consume, you know, 
Ketostart or another exogenous ketone supplement,   and you consume it like 10 grams of pure BHB, and 
you get that elevation of about 1.5 millimolar… [Dr. Patrick]: Is that a full packet of Ketostart? [Dr. D'Agostino]: It's kind of like 
double…almost it's like double   dosed in a way. So I usually 
do half a packet and then… [Dr. Patrick]: Which is I'm 
drinking right now, right? [Dr. D'Agostino]: Yep. So, consuming a full 
packet typically I get about 1.5 millimolar,   so I feel the effect. But I've actually consumed 
two packets, and I start to get a bump in insulin,   but one packet, no.

And the bump in insulin 
is relatively small probably because   the mineral load is delaying, you know, the 
absorption into the system a little bit.   So I think that that's really important because 
we know like insulin suppression is also important   for the anti-seizure effects. So we think that a 
reduction in glycolysis is therapeutically part   of the scenario of the anti-seizure effect of 
the ketogenic diet because 2-deoxy glucose has   a pretty strong anti-seizure effect.

And that 
is being advocated and used clinically in some   studies as the ketogenic diet in a drug, so 
a glycolytic inhibitor, 2-deoxy glucose. So,   you consume this drug and it's 
like 25 milligrams per kilogram,   and if you go higher than that, then it becomes 
cardiotoxic. So it's not an ideal approach,   but it inhibits the glycolytic pathway in a way 
that sort of mimics effects of the ketogenic diet. So when we increase insulin, insulin stimulates 
glycolysis, and I think that that could be   a negative thing in the context of maybe cancer or 
seizures or other things that we're interested in   therapeutically managing. There's the ketogenic 
diet and exogenous ketones, and they're not   mutually exclusive. But I actually think they're 
synergistically, you know, when they're combined   together.

So, if you follow a more liberal version 
of the ketogenic diet like a modified Atkins diet   or modified ketogenic diet or low glycemic index 
therapy, which is like a one-to-one ketogenic   diet, and then supplement ketones on top of that, 
then I think what you have in my opinion is an   optimized ketogenic diet for a lifestyle. This 
needs to be studied and validated in clinical   trials. But I think it would also be optimal 
for epilepsy, for cancer, for managing type   2 diabetes, and also for weight loss. So the 
ketones have a satiating effect on the brain. So the ketones are alternative energy substrate, 
and when your brain is metabolizing ketones,   and it actually experiences low glucose, 
it doesn't go into an energetic crisis.

So   it's not signaling that you need to eat. 
And I think that's really interesting.   There have been cases where you could 
produce a hypoglycemic shock that would be   fatal…otherwise fatal. But if your ketones are 
elevated, you're asymptomatic for hypoglycemia.   So that's a remarkable example of the effects 
of ketones on preserving, maintaining brain   energy metabolism, and that has real-world 
effects in the context of everyday living. And if you go on a diet, you inadvertently need to 
go into a calorie deficit. So calories do matter   for one thing, and you have to achieve 
and maintain a protracted calorie deficit   to lose weight and to some extent, sustain that 
weight for a period of time. Then you can go back   to a more eucaloric ketogenic diet or eucaloric 
diet. It will necessitate like low glucose,   low insulin, and you're going to get 
hungry, but if your ketones are elevated,   that's where ketones shine. They really shine in 
the context of calorie restriction or an energy   deficit because you have a better fuel flow to the 
brain in that context, right? So if you're on a   low-calorie diet that's producing a state of 
hypoglycemia, but your ketones are not elevated,   that's going to be a painful 
diet to adhere to and sustain.

[Dr. Patrick]: Right. [Dr. D'Agostino]: Not fun. [Dr. Patrick]: No. And it's funny. Like, 
I absolutely noticed that when I was doing   my ketogenic diet. Like I said, I was doing a lot 
more intermittent fasting, and it was a lot easier   to do. I mean, you do feel…I felt satiated. 
And this kind of gets into another topic,   and I did want to kind of ask you about the 
difference between…you mentioned the diester   for ketone esters, but there's also monoester, 
right? Is there a difference in terms of efficacy,   I mean, if you're just kind of wanting to elevate 
your ketone levels? And again, it seems as though   I prefer…

I've tried all these different types 
of ketone supplements, and I personally am not   a huge fan of the really quick spike and then 
like…like to me, it's kind of crashing because   my glucose levels get so low, and then when the 
ketones wear off, it's like, "Where's my energy?" [Dr. D'Agostino]: So you have, yeah, 
hypoglycemia and hypoketonemia,   and you might also be kicking yourself out 
of ketosis. So it could be a dose thing.   The 1,3-butanediol beta-hydroxybutyrate monoester,   that was developed by…in part by Dr. Richard 
Veach. That was one of the first ketone esters   that we actually…you know, I became interested 
in, and it did not have anti-seizure effects.   I didn't lose enthusiasm because I knew there was 
so many other molecules that could be developed. We worked on a couple different molecules. And 
the next one was the diester. Actually, first,   we had the monoester. 1,3-butanediol-acetoacetate 
monoester had very strong anti-seizure effects.   And then we could do more of a transesterification 
reaction, it's just more or less a stoichiometric   reaction where you just add more ketones, 
in this case, acetoacetate 2-1-3-butanediol.   So it's 1,3-butanediol, which gets metabolized 
in the liver completely pretty much to   beta-hydroxybutyrate.

That molecule with a 
reaction, we can add to acetoacetate molecules. And, you know, both of these things, the 
monoester and the diester, they taste nasty,   they taste like gas. But they have 
very distinctly different effects   at least in the context of the 
anti-seizure effects. So when we developed   the ketone diester, and we used that in our 
animal model of tonic-clonic seizures, which was,   in this case, high-pressure oxygen, but we then 
tested it in various other seizure models too,   it had a very strong anti-seizure neuroprotective 
effect. And then if we use 1,3-butanediol or any   other ketone, it didn't really have 
that profound anti-seizure effect. [Dr. Patrick]: GABA. Is there like a 
difference in the GABA [crosstalk 00:51:19]? [Dr. D'Agostino]: That's an interesting, you 
know, theory, but one of the things that kind   of stood out was elevating acetoacetate seemed to 
be really important. And some of the animal model   work…

It was brought to my attention by people 
who had been studying this for longer than me.   One of them was Dr. John Rowe. He 
was looking at beta-hydroxybutyrate   and acetoacetate saying, you know, there's 
really good literature with acetoacetate and   acetone too having an anti-seizure 
effect. The 1,3-butanediol-acetoacetate   diester elevates beta-hydroxybutyrate and 
acetoacetate more or less on a one-to-one ratio. So we did blood work. We measured blood, 
and we sent it out to mass spec[trometry].   And there's kind of like a nice…there's 
a quick spike up in acetoacetate   and beta-hydroxybutyrate from the 1,3-butanediol, 
and that happens over hours. And we had a 600%   increase in the latency to seizure, which 
means that animals could go 600% longer,   and we published that. And then later, we actually 
combined the ketone ester with MCT and saw a   little bit of a boost, you know. The MCT seemed to 
further elevate ketones and extend the sustainment   of ketosis. So that has been the ester that we 
focus mostly on in our studies at least initially. But then we started tinkering with the ketone 
salts and putting ketone salts and mixing that   with MCT. So, ketone salts alone or mixed with 
MCT seem to have a lot of favorable effects on   glycemic regulation, anti-anxiety effects.

You 
know, they also have an anti-seizure effect,   maybe not as strong as the ketone esters, which 
are just more powerful on a per gram basis. But   I personally would not… I have access to these 
things. Even if ketone esters tasted great,   I would not be consuming them day in 
and day out. Just for the same reasons,   I don't think it's good to spike glucose 
throughout the day. I don't think it's   really favorable to throw a lot of energy in the 
system in a way, especially if ketones get high,   you do get a metabolic acidosis that you can… 
We see pH drop in our animals.

So we measure like,   you know, our pH levels and blood gases and things 
like that, and we see that the pH level will drop   typically when the ketones get above about 3 
millimolar. So that's probably not a good thing. So, I'm of the opinion personally and 
experimentally by…you know, in the idea of   keeping exogenous ketones within like an elevation 
of 1 to 3 millimolar. I think it's pretty optimal   unless you're managing like a very serious form of 
epilepsy, or you have glucose transporter type 1   deficiency syndrome or some other inborn error 
metabolism where having higher ketones can be   favorable because you have a decrease in 
other metabolic pathways or transporters   like in the case of glucose 
transporters deficiency. [Dr. Patrick]: It sounds like though…   For my own personal anecdote when 
I was trying the ketone esters,   you know, at first, it was like, "Oh, maybe more 
is better. I want to get, you know, at least   above 3 millimolar." You know, I got like 3.5 with 
consuming about 30 mils of, I believe the 1-3… [Dr. D'Agostino]: Yeah.

Monoester. [Dr. Patrick]: Yeah, that formulation. Like 
I said, you know, 30 mils, that's a lot. So,   you know, there's people that might be doing that 
like every couple of hours even, and it sounds   like that could potentially be a dangerous 
thing to do, especially if they're getting   in that range where there could be a pH 
change. And if they're not measuring it,   you know, no one's going to 
know. So, it's something… [Dr. D'Agostino]: I don't think we know, and 
I think it's like… If you have like type 2   diabetes, if you have Alzheimer's disease, you 
know, cancer, I think it's better to spread out   the dose too. So, I think from my perspective, 
I'd rather take something that's also delivering   electrolytes that my body can use 
and also that tastes good.

And   the 1,3-butanediol is also a consideration, 
right, because the liver has to work harder,   so it uses the alcohol, the dehydrogenase 
pathway. And I noticed, you know,   playing around with these things over time 
just 1,3-butanediol, which the ketone esters,   if I consume that at a certain dose 
for two weeks and then get blood work,   my liver enzymes are elevated. They're 
still within normal range, but they creep   up into that upper range of normal consuming, 
for example, like 1 gram per kilogram per day.   That's the amount that's needed to sustain 
hyperketonemia equivalent to a ketogenic diet.

I feel intuitively that it's probably better 
to take a more natural form of ketones where   it's just ionically bound to a monovalent 
or divalent cation like electrolytes,   which our body tend to deplete anyway when you're 
on a state of ketosis. So, I use the product   LMNT. But once we got the ketone formulation 
kind of figured out, you can deliver   the same electrolytes that are bound to ketones. 
So I think it's a good adjuvant or a good   supplement to add to a low-carb 
diet to ketogenic diet.

[Dr. Patrick]: How often do you   do…? Is this a daily electrolyte sort 
of supplemental thing that's…? Okay. [Dr. D'Agostino]: Yeah. And I just use maybe like 
a small dose in the morning and I combine it with   like creatine, acetyl-L-carnitine, and a couple 
other like taurine. There's some supplements that   I think are really beneficial with the ketogenic 
diet. They can help boost ketosis. And then, when   you're on a ketogenic diet, you're oxidizing so 
much fat, you tend to be deficient in carnitine,   and we see this like in kids that are on…so 
I think carnitine is like really important.   The selenium, some studies may show 
up that that's really important,   but I think that's more of the type 
of foods that you're consuming. [Dr. Patrick]: I mean, a standard 
multivitamin too also would be…

[Dr. D'Agostino]: Yeah, multivitamin, but I 
think you can get a lot of nutrition from,   you know, a lot of eggs and sardines and fish and 
oysters and things like that that are very rich   and some things that may be depleted in other 
people at least clinically. So I take a little   bit of ketone salts in the morning, and then 
later in the day like midday as a pick me up,   like I'll do the other two-thirds of a packet, 
you know. I feel it [crosstalk 00:58:09]. [Dr. Patrick]: Any other supplements that 
you take or that, you know, encourage? [Dr. D'Agostino]: Yeah. You know, from listening 
to you a lot, the omega-3s, DHA, EPA, carnitine   because that's really important kind of aspect. 
If I wasn't taking ketone salts, I would be taking   more electrolytes, but I 
take magnesium, "Magnesium   3 and 8". And also BiOptimizers makes 
a magnesium breakthrough product,   which is like magnesium in like five 
different forms or six different forms. So   I've measured my blood levels of magnesium, 
and it goes up pretty high with that.

I take vitamin D, which was actually low even 
though I get tons of sun and I was supplementing   4,000 to 8,000 IUs a day. And I got a blood 
test done, and I was on the lower end of normal,   which was really confusing. So I got another 
blood test that confirmed, the other blood test   that I was on a low end of normal. So I got 
prescription vitamin D, which is vitamin D2.   But then I ran out of that, and I was using 
another vitamin D supplement from another   maker. I think it was Mindbodygreen. I 
was supplementing with that. And then   got another vitamin D test after and I stayed 
elevated in the upper range of normal. So maybe   I was using a well-known vitamin D formulation, 
but it was like from Walgreens or CVS. And I was   taking 8,000 IUs a day, and I was still 
in the low end of normal even though I'm   getting a lot of sun exposure. So this was 
probably one of the most weirdest things. [Dr. Patrick:]: It could have 
been a polymorphism or…

[Dr. D'Agostino]: I was thinking about that. Yeah. [Dr. Patrick]: …you know, because there 
are polymorphisms that some people require,   you know, in some cases, two to three times 
the normal dose to actually just bring   you up to like a normal level of 
like 30 to 48 nanograms per mil.   But the other would be that there's been a variety 
of studies now over the years showing if you   just randomly take different vitamin D supplements 
off the shelves like Walgreens, you know,   in grocery stores, that the actual concentration 
of vitamin D3 in each supplement varies so widely   that you'll often get a supplement that says 
it's, you know, 4,000 IU, but it's more like 400   IU.

And it's really a big problem, honestly. So it 
is good to like kind of find some go-to reliable   brands. Maybe third-party sites have tested 
the concentration of the vitamin D3. I know   Labdoor does one, and then ConsumerLab, 
they actually go around and test the actual   concentration of whatever active ingredient, in 
this case, vitamin D3 in a variety of pretty,   you know, readily available supplements. 
That could have been it as well, right? [Dr. D'Agostino]: It really shocked me because, 
I mean, I'm out…we're in Florida. I'm outside,   you know, working on the farm, 
shirt off a lot, and I double dose   on…I'm pushing like the upper limit 
I thought of vitamin D supplement… [Dr. Patrick]: You have enough magnesium 
obviously because magnesium is important. [Dr. D'Agostino]: Yeah, get a ton. Yeah. [Dr. Patrick]: Have you done a genetic test? [Dr. D'Agostino]: Yeah. I did 
23andMe like back in 2010.   So I have all the raw data, 
and I haven't put it into… [Dr. Patrick]: [crosstalk 01:01:16] because we do 
a lot of the vitamin D3 SNPs. There's quite a few,   and, you know, there's several that 
affect your ability to convert…   There's several steps in vitamin D3 
metabolism but particularly vitamin D3…

[Dr. D'Agostino]: I actually 
becoming fascinated with vitamin D. [Dr. Patrick]: Yeah, vitamin D3 converting 
into to 25-hydroxy vitamin D, which is what   is the major circulating form which is what you're 
getting measured when you're getting a blood test.   There's SNPs that affect that. And I've 
had several friends and I've seen…you   know, I looked at the data, but 
I've had several friends that   have had to take like up to 30,000 
IUs a day because they have a SNP.

[Dr. D'Agostino]: And explain 
to me why prescription is D2. [Dr. Patrick]: I don't know 
why it is. And to be honest… [Dr. D'Agostino]: Okay. Yeah. I asked my doctor 
and she didn't know. She was like, "I have no…" [Dr. Patrick]: …I'm not terribly 
thrilled. Maybe it's a cost thing   because you're getting it from like 
plant like mushrooms or something.   I know there's been a couple of studies over 
the years. I don't quite understand, like,   the mechanism and I don't know if it's known 
or how much has been studied. There's some   preliminary data, and I haven't checked back, I 
don't know how much of this has been confirmed.   Supplementation with vitamin D2 seemed to 
like inhibit some of the effects of vitamin D   in muscle. So I was kind of like,   "That's kind of concerning." And I know a lot 
of vegetarians like to take vitamin D2 because,   you know, they want something that's plant-based, 
but you can actually get vitamin D3 from lichen.

[Dr. D'Agostino]: Oh, really? [Dr. Patrick]: Yeah, they produce vitamin D3. 
Yeah, like stuff that grows on rocks and trees. [Dr. D'Agostino]: You can eat it. You can boil 
it. And, you know, it's good nutrition. Yeah. [Dr. Patrick]: You can eat it. Yeah. There are 
companies that…like I know Thorne makes one,   a vitamin D3 for vegetarians 
and stuff from lichen. [Dr. D'Agostino]: In skin wise, if you have 
more olive skin or…

So I form keloids. Like   this was a big…if I get a cut, I form keloids 
like African Americans do with dark skin. So,   I was thinking that there's something, you know, 
biochemically in my skin, although I don't have   like an over-production of melanin, but I have 
aspects of that, of having darker skin, especially   like in forming keloids. So I'm thinking there's 
something in my skin, I'm not synthesizing it. [Dr. Patrick]: That's interesting. [Dr. D'Agostino]: I mean, I tan if I'm outside. I 
mean, it's winter now. Yeah, usually, I'm pretty   dark. Yeah. There have like to supplement and 
double the amount of dose that's recommended   and to be outside all the time and to have low 
levels. Like I got the call and said, "Yeah,   we need to get you on a vitamin D supplement." I 
was like, "No, that's not right. Order another."   And I got it and it was, like, low like super, 
like, right, at the cutoff. But I did take 50,000   IUs of vitamin D2 is the prescription, and three 
or four weeks of that, you just take one per week,   I was on the upper range of normal slightly 
above.

Then I stopped and it went back down   to normal, but I was supplementing…I 
changed to a different brand. Yeah. [Dr. Patrick]: And you've been able to 
maintain levels? What dose do you take? [Dr. D'Agostino]: I think it's like 
back to 5,000, yeah, 5,000 IUs. Yeah. [Dr. Patrick]: Maybe it was the… Yeah. 
Look at your SNPs. That would be like   my [inaudible 01:04:30] SNP. But then 
absolutely could be the actual supplement brand. [Dr. D'Agostino]: Is there anything 
acutely or chronically that you could   have that would use…would deplete 
vitamin D? So that was another thing.   I researched it but really couldn't find 
too much. I figure you would know this. [Dr. Patrick]: There's some 
evidence that like, you know,   being in a state of like inflammation and, 
you know, like illness like which you're not.

[Dr. D'Agostino]: My hs-CRP is, like, usually 
non-detectable or 0.1. And everything else,   you know, micronutrient status is really good. [Dr. Patrick]: I think it mostly comes 
down to the metabolism of it like   forming the 25-hydroxyvitamin D3 and then also 
the brand of supplement. And then there's another   thing about doing, like, a weekly dose versus 
daily. If you're doing a weekly dose that's   really, really high, so if you're doing like 
20,000, 50,000 IU a week, you're much less likely   to have that huge variation in the concentration 
of the vitamin D supplement like for some reason.   It seems to be absorbed a little bit better 
too. But I don't know how much, you know,   how negligible that is in terms of what you're 
experiencing. I would say the SNPs is probably   the big elephant in the room. So, super 
interesting. But I'm going to get back to… [Dr. D'Agostino]: Sure, the answer. [Dr. Patrick]: We're talking about acetoacetate 
and beta-hydroxybutyrate.

I was interested in,   and you kind of already sort of answered some 
of that question, if there's varying effects   of these two…I'm calling them ketones. I 
think acetoacetates or ketone technically,   beta-hydroxybutyrate's ketone body, you don't 
really hear that as much, but anti-seizure.   So that's one. Acetoacetate seems to really be 
important for that. Are there any other known…? [Dr. D'Agostino]: Distinct effects of the two. [Dr. Patrick]: Yeah. [Dr. D'Agostino]: Yeah. There are. Well, we know 
like beta-hydroxybutyrate has epigenetic effects   as far as activating, you know, histone 
deacetylase inhibition. And also there's   something called beta- hydroxybutyrylation, 
similar to lag [SP]. So beta-hydroxybutyrate   can directly interact with the histone 
to cause epigenetic modifications, and   it has become the theme of my Ph.D. students 
dissertation to look at Kabuki syndrome,   which is a rare genetic disease, where the 
ketogenic diet in the lab of Hans Bjornsson   at Johns Hopkins demonstrated that the ketogenic 
diet silenced these neurological abnormalities   associated with this Kabuki syndrome, which is 
a rare genetic disorder, it causes seizures too.   So we want to see if we can recapitulate 
this with ketone therapy using ketones as   an…and metabolite to alter epigenetic effects. 
And so we have those studies going on right now.

So, there's ketone induced epigenetic 
effects specific to beta-hydroxybutyrate,   maybe acetoacetate, but we don't know. 
Acetoacetate on the other hand has effects   at least in muscular dystrophy in regards 
to increasing skeletal muscle regeneration,   and it does it through an ERK-MEK cyclin D, 
I think, mechanism. So it's a very unique   mechanism that was kind of new to me. 
But a pretty good publication came out   using…showing that acetoacetate 
stimulates…so beta-hydroxybutyrate,   I was going to go down the path, and acetoacetate 
too maybe have anti-catabolic effects. [Dr. Patrick]: Let's talk about that. [Dr. D'Agostino]: Yeah. The research that 
we've done uses an ester that elevates both   of them and shown that it works in a model of 
cachexia.

And we know that acetoacetate has   an enhancement, as I said, proliferation or muscle 
regeneration, and beta-hydroxybutyrate as a fuel   undoubtedly has anti-catabolic effects. And 
we know that when we administer, even in human   studies, if we IV administer beta-hydroxybutyrate, 
there's a sharp decrease in alanine, and also a   preservation of branched-chain amino acids like 
leucine is elevated, and it prevents a drop.   So alanine is like your main gluconeogenic amino 
acid that is liberated under conditions of stress,   high cortisol, high gluconeogenesis, glucagon, 
things like that.

We are going to liberate   alanine as a gluconeogenic amino acid. It 
goes to the liver, we make glucose. And   elevating ketones seems to reduce that. That 
could play into the anti-catabolic effects. [Dr. Patrick]: What are your thoughts 
on…? I'm interested in your thoughts on   the anti-catabolic effects of ketones in various 
context of…I mean, I guess in human development   or even, you know, with respect to humans that 
have different lifestyles. So, for example,   people that are physically active, 
more young, athletic versus people that   are older and are battling sarcopenia, you know, 
versus people that are just sedentary.

I mean,   everyone has…they have different protein 
requirements, you know, between these groups.   How can ketogenic diets or 
perhaps supplementing with ketone   supplements sort of…? Can they have 
an effect on muscle mass in some way? [Dr. D'Agostino]: I think so, and I think 
skeletal muscle… And maybe I'm a little bit   biased because I've always been super interested 
in strength training and weightlifting and things   like that. But muscle mass is probably the 
most important factor for healthy aging. And   focusing on building as much muscle as possible 
I think is super important in preserving that   muscle with time. So, ketogenic diets are 
probably not optimal for adding as much   size and strength as possible, right? But I do 
think they are important for preserving muscle   while improving metabolic parameters like 
glycemia, hyperinsulinemia, and things like that.   I do think the ideal strategy in the context 
of a calorie deficit to preserve muscle   under that sort of condition, right? And it 
does it by a number of different pathways.

So, I think the elevation of ketones one of the 
functions is to prevent muscle loss during periods   of fasting, right? So with limited glucose 
availability or limited food availability,   we start liberating fatty acids for fuel, and 
then the body makes ketones, and then the ketones   provide energy flow to the brain, which has very 
high demands for glucose. If we didn't produce   ketones, we would liberate a lot of alanine and 
other gluconeogenic amino acids from skeletal   muscle, and we would quickly waste away and die. 
The fact that we're able to make ketones from   fatty acids as a water-soluble fat molecule that 
could cross the blood-brain barrier, that actually   becomes our safeguard to catabolic processes that 
would allow us…cause us to waste away, right? And we are sort of wasting away in 
the context of a weight loss diet   or in the context of intermittent fasting. So 
then the ketones come into play when we're in   a calorie deficit like I said, but also when we're 
doing time-restricted feeding, I think the ketones   provide an anti-catabolic effect.

But from our 
perspective, we're super interested in ketones   preventing age-related sarcopenia, skeletal 
muscle wasting associated with cancer cachexia.   I think that's important. And 
they're doing it I think not only   providing in the context of a disease phenotype or 
a chronic aging phenotype, the alternative energy   function is there, but the 
anti-inflammatory effects, I think. So with cachexia, for example, you have a high 
elevation of like IL-1 beta, TNF alpha, which used   to be called cachexin I think as inflammatory 
media. So, the ketones then work through   anti-inflammatory pathways that can mitigate the 
inflammation-induced muscle wasting associate. So   we did a study with lipopolysaccharide, LPS. So 
LPS causes massive, you know, muscle wasting and   sarcopenia with time. And in that model too, the 
ketones are protective in some ways by inhibiting   some of the anti-inflammatory…inhibiting 
the inflammatory effects of LPS. [Dr. Patrick]: Do you think that…? People 
that aren't, for example, in a constant state   of ketosis because they're on a ketogenic 
diet, but perhaps they would like to take,   you know, a supplement, ketone salt. Do 
you think that's something that…like the   chronic elevation or the constant constituent 
elevation of these ketones that's important or   little bumps throughout the 
day, you know, or something? [Dr.

D'Agostino]: That's a good question. So I 
get that a lot. And I think chronic ketosis is   probably not natural or not ideal for most people 
unless you're managing a chronic disorder that's   responsive to chronic ketosis like epilepsy and 
other metabolic disorders. But I'm a big believer   in relative changes. So, even with intermittent 
fasting like I think I'm fasting today,   maybe I just had some ketone supplements but 
like yesterday I did. So I only do intermittent   fasting probably two, maybe three times a week 
at the most because, if I did it every day,   I feel that I lose some of the benefits 
of it, I also lose too much weight.

Like   I can't get enough calories. I end up eating 
too many calories at the end of the day. So,   the body works good. You know, relative 
changes are really good to the body. So   you get a lot more…I personally get a lot 
more benefits doing intermittent fasting   if I use it more intermittently, you know, 
right? I feel the benefits a little bit more. So I think the same is true with ketosis. And 
I think Dr. Valter Longo has a great idea,   this idea that… I actually gave it a lot 
of thought. So it was good to see that he   came out, you know, with this idea of the 
fasting-mimicking diet being implemented for   just a one week or five day 
period, right, per month,   and that can have long-lasting metabolic 
benefits even throughout, you know,   weeks to even a month or more after you do that as 
far as resetting insulin sensitivity and improving   different metabolic biomarkers. So I think chronic 
ketosis is probably not ideal for most situations   unless you're doing…you're trying to get your 
insulin managed, you're trying to lose weight and   maintain that weight loss over time, and you've 
had difficulty doing it with other types of diets.

But I think there's so many different factors that 
need to come into play when you're choosing to do   a ketogenic diet, including monitoring. People 
really need to track nutrients, track calories.   Some people put…you know, they eat a ketogenic 
diet, but they put the same amount of food on the   plate. And the caloric density of the ketogenic 
diet is like 50% higher. So you can't eat… So, typically, you know, we have auto feedback 
mechanisms that will tell us when we're satiated   full, but for some people, they don't work 
well. So they do need to count calories and   macronutrients and track at least initially so 
they have some idea of how many calories we're   eating. I know, until I started tracking calories, 
I had no idea how many calories I was eating.   So I thought I was eating more like 3,000, but 
it was more like 4,200 pretty much every day.

[Dr. Patrick]: I want to talk about these 
cyclical ketogenic diets, but before I go there,   since we're talking about muscle and the 
anti-catabolic effects of ketones on muscle, I'm   also sort of interested in exercise performance 
as well like anaerobic exercise versus aerobic   exercise if you are either on a ketogenic diet at 
that…you know, or doing some sort of modified   or cyclical form of it, whatever it 
is, versus supplementation as well,   you know, like how being in ketosis affects, you 
know, some aerobic versus anaerobic exercise. [Dr. D'Agostino]: I get asked that question 
more than any other question, I think.   So, in animal models, when you put them on 
a ketogenic diet…I think one of the first   studies we did published at the Alzheimer's 
Institute at USF, the Byrd Alzheimer's,   we didn't see a big robust effect on amyloid-β 
and tau.

But we started the intervention   after the pathology kicks in in these mouse 
models, so double and triple knockout. Although   I think Dr. Veach and Dr. Mark Mattson, maybe 
they did ketone ester or started earlier in   the ketogenic intervention. But in our study, 
we didn't see any like major changes in   tau or amyloid, but the mice like ran faster. They 
ran like 30% longer and faster on the treadmill,   and it was like remarkable. And I remember one 
of the PIs on the project, a very experienced   Alzheimer's researcher was like, "Yeah, 
we've never seen anything like this."   So that was an MCT supplemented ketogenic diet. 
We've done some research with ketone esters too.

So performance, you know, in animal models, we 
see it in humans, the data is messy and it's hard   to make sense of it. So my general opinion…my 
speculation is that ketones probably have a small   effect on exercise performance in the context of 
aerobic performance. And in regards to strength   performance, my ideas about that have been 
changing over the last couple weeks because   we're giving ketone supplements to some CrossFit 
athletes, and they're breaking PRs. But I think   it could be potentially a placebo effect. Since 
everyone…excluding one person out of dozens of   people, I think there's maybe something more. 
But I think ketones with caffeine, especially   ketone salts with caffeine are a pretty powerful 
ergogenic aid. So I would loosely say that that's   probably a performance-enhancing supplement, the 
combination of ketones caffeine and electrolytes. But I think where ketone shine is using exogenous 
ketones as a means to preserve performance,   resilience in extreme environments.

So that's in 
the context of hyperoxia. So that's what I study.   So, of course, when you're not having a seizure 
and your neurological function is maintained and   preserved in the context of extreme hyperoxia like 
three or four or five atmospheres of high-pressure   oxygen, that's going to be advantageous. But on 
the other end of the spectrum is hypoxia, right?   So a lot of people who are mountain climbing, 
running, cycling at hypoxia. We know   if we put athletes on a treadmill or bike in 
a hypoxic environment and give them glucose,   that the performance-enhancing effects of glucose 
are not observed in hypoxia, which is kind of,   you know, interesting. Whereas it's also shown 
that there may be an inhibition under hypoxic   environments of pyruvate dehydrogenase. There 
might be some PDH deficiency or some snag or   bottleneck in the metabolic pathway associated 
with glycolytic energy production under hypoxia.

And you would think that hypoxia…you know, 
chronically, it activates like HIF-1 alpha, and   you have increase in glycolysis and transporters 
and things like that. But in the context of,   you know, exercise performance under hypoxia, 
carbohydrate supplements don't seem to help.   Whereas there seems to be…and it was 
brought to my attention in a couple of   reviews and also serving on grant committees 
and stuff like that. There seems to be a   good rationale for the use of ketones for 
fueling performance in a hypoxic environment,   and that could be very strategic and beneficial 
in like a military setting or like a space,   you know, setting or altitude, you know, setting.

My general feeling is that ketones have a small 
effect at increasing athletic performance. So   there's only a few things that actually are 
powerful ergogenic aids. So we have caffeine.   We have creatine monohydrate typically. 
There's other forms of creatine.   You know, beta-alanine kind of works 
pretty good. And a few other odds and ends,   but, you know, there's just a pretty short list 
of ergogenic, you know, supplements out there.   I do think that with time as we understand dosing 
and the application of specific types of ketones   in certain settings that ketones will be added 
to that list, but I'm not sure it'll be in the   top tier list. But I do think it would be in 
the top tier list under extreme environments. [Dr. Patrick]: What about swimmers or surfers? [Dr. D'Agostino]: Yeah. I think 
being in a state of ketosis could   be beneficial from the context of like 
brain injury, inflammation, and maybe   just, you know, the stress of being out, 
you know, in certain extreme environments,   or when we're exercising too, we're overproducing 
oxygen-free radicals.

And these impart an adaptive   response to the muscle too. So there could be a 
benefit to increase oxidative stress. I think the   real benefit of ketones are not…I'm talking 
about this in their response, and I think your   question is in the response to an acute setting 
like consume ketones, go exercise, what happens. [Dr. Patrick]: Or be on a ketogenic diet. Yeah. [Dr. D'Agostino]: Yeah. So, where I think 
exogenous ketones will help…and when I   was talking that they would be added to the 
shortlist of ergogenic aids is used chronically   as an adaptive response. So when we exercise, 
a lot of bad things happen, if we pull blood,   you know, there's inflammation reactive oxygen 
species, things like that. If we use exogenous   ketones chronically over time, I think it will 
help to facilitate the adaptive response to   exercise over time, so suppressing inflammation or 
chronic inflammation, which would sort of enhance   or augment adaptive responses to exercise over 
time. I think there's a good rationale for that,   but the science is not there yet.

But science is 
being done now. So like rodent studies are being   done. I'm aware of a couple human clinical trials 
that are studying this. So, [crosstalk 01:23:16]. [Dr. Patrick]: And what about like doing a 
maximum effort like you're doing some kind of   sprint? You know, because you do need… If you're 
going into a state where your mitochondria can't   work hard enough to produce energy, you need 
glucose, right? If you take one of those big   boluses of ketone ester, you drop your glucose, 
what's that going to do for your sprinting? [Dr. D'Agostino]: That's a good point. So, one of 
the criticisms of the ketogenic diet was that it   inhibits the pyruvate dehydrogenase complex. So, 
whenever we're doing carbohydrate restriction,   we're limiting glucose availability but also 
lowering insulin. And by lowering insulin   especially, that inhibits glycolytic enzymes 
like hexokinase. The transporter for glucose   gets internalized into the cell if…you know, 
the glycolytic flux is essentially decreased. But   I think if you follow a ketogenic diet where you 
intermittently add small amounts of carbohydrates   in, you can keep that PDH from being reduced. I've 
seen data to indicate that severe carbohydrate   restriction could decrease the production and the 
activity of PDH.

This is actually what happens   with Alzheimer's disease too. So, with Alzheimer's 
disease, it's pathophysiologically linked to   impaired glucose metabolism. So if you 
do an FDG PET scan, the PET scan shows   glucose hypometabolism in the brain scan. Ketones 
as an alternative energy substrate makes sense. In the context of, you know, athletes, you're kind 
of doing that with chronic ketosis. It decreases   the glycolytic pathway, but your muscles and your 
heart and other tissues actually use fatty acids   for a source of energy, the brain, not so much, 
right? And also, when you're on a ketogenic diet,   then you're feeding ketones to the brain. So 
the brain's kind of like a different story.   But I do think that it gets overblown. I 
think, you know, very severe carbohydrate   restriction will decrease PDH, and then 
that will impair exercise performance   with maximum exertion anaerobic.

It's really 
important that if you do a low carbohydrate,   that you have to train under those conditions. 
Do you know what I mean? You can't implement   a ketogenic diet or low carb and then train and 
expect to maintain the same performance. You have   to put your body into that state of ketosis and 
then train very hard to induce those adaptations   to make it possible for your body to perform 
and maintain your performance in the context of   insulin suppression and low glucose availability. 
So those adaptive processes will then   come to benefit you come game time or performance 
time where you can then titrate the carbohydrates   back in in small amounts. So this is 
just called metabolic flexibility, right? So, train low when your glucose is low and 
your insulin is low in a semi-fasted state,   and that will induce metabolic adaptations, i.e., 
metabolic flexibility that will then benefit you   in the context of the actual event where 
you can add and titrate carbohydrates back   in or mix fuels.

Really, you want to be able to 
optimally use glucose, you know, fatty acids,   beta-hydroxybutyrate, ketone bodies, 
lactate too, which is an important fuel. One of the things that I used to take when 
I was mountain biking was Cytomax, which is   alpha-L-polylactate, which is like lactate as an 
energy zone. My original interest in academia as a   postdoctoral fellow was actually using lactate for 
brain injury like stroke and hypoxia. And I was   tinkering around with that in a hippocampal brain 
slice preparation doing different measurements on   that, and somehow I just got steered towards 
ketones. But I always wanted to revisit the   lactate thing because, yeah, I think there's a 
lot that can be done in formulating more of a   comprehensive multi-fuel delivery system for the 
brain.

And lactate's been a bit under-appreciated   and kind of stigmatized and criticized, 
but I think it's got a lot of potential. [Dr. Patrick]: Yeah. Really, good info, Dom. You 
know, I've been reading some meta-analyses over   the years about training in a fasted state versus 
fed state and how, you know, if you eat before,   you know, you go for a run or something, that, 
you know, a lot of the mitochondrial adaptations   can be blunted somewhat. And, of course, a lot of 
those studies are using high refined carbohydrate   like some toast with jam, you know, where… And 
I've always wondered like, you know, what… And   there is like sort of a cut-off where if 
you're training in a fasted state for longer   than an hour, you're going to have performance 
drop off, right? I've often wondered like if   these studies were done using a more modified 
Atkins diet or some form of a ketogenic diet,   those mitochondrial adaptations that are being 
blunted somewhat with, you know, a high refined   carbohydrate fuel intake prior to exercise, 
I'd wondered, maybe that wouldn't happen.

[Dr. D'Agostino]: Yeah. I think it comes down 
to like nutrient sensing, right? I mean, it's   the whole thing going back to autophagy and like, 
you know…and just entering a state of ketosis,   that if we're in a state where like AMP kinase is 
high, like M2 is low, you know, insulin is low,   that whole pathway is low, when you exercise 
in that state, it may not optimize performance,   but it will optimize the adaptations that could 
serve you later on for performance. And then   when it comes time to… You might want to train 
sort of in a fasted state to induce adaptations   and then tinker around with different fuel sources 
periodically to see if you could further augment   your performance, you know. That's why we need 
to really periodize our training under certain…   There's, you know, training to force adaptations 
and then there's sort of game day nutrition,   which is going to be a little bit 
different than training nutrition   if we want to force that…you know, 
if we want to maximize our performance. But one thing you don't want to do is actually 
radically switch your dietary approach or   supplement approach just prior to…you know, 
you don't want to train for an event and be like,   "Oh, I want to start slamming, you know, MCTs 
and ketone esters and stuff on game day." No,   you want to experiment with it very methodically, 
you know, before you do that.

I do believe that   the health benefits are really important 
when it comes to exercise, you know, and   then…not only the health benefits, but I 
think you're going to get more adaptation   in regard to…maybe not so much for powerlifting 
and strength training and things like that,   but I think for aerobic performance and 
just cardiovascular benefits and just   actually benefiting at the level of the skeletal 
muscle and the nervous system too benefits. [Dr. Patrick]: So speaking of the nervous system, 
this is one area where in my opinion ketosis,   ketogenic diets really shine. What has thoroughly 
convinced me is, you know, just the overwhelming   evidence that you've talked about with the effects 
on the brain and epilepsy and other types of brain   disorders but also some of the preclinical studies 
that have come out of our mutual friend Dr.

Eric   Verdin, and I know John Ramsey also did some 
publications where they fed mice. In the case   of Dr. Verdin's study, midlife, they started a 
cyclical ketogenic diet. And I'd love to get your   thoughts on why…he said the reason they did 
it was because the mice were overeating, which   I found to be interesting because I've always 
been satiated on a ketogenic diet. But anyways. [Dr. D'Agostino]: A lot of 
nuance Eric [crosstalk 01:31:32]. [Dr. Patrick]: Yes. Let's get into that. 
But also the thing that was so striking,   and you know much more about the details of these 
studies than I do, but the effects.

I mean, their   health span was improved. So their median lifespan 
was improved. They were dying less earlier, but   maximum lifespan I guess wasn't affected. But the 
effects on the brain and cognition like he said,   you know, that these…the older mice 
had better cognition than younger mice.   And when he said that, I mean, I 
was, you know, like that's really. [Dr. D'Agostino]:   Things are magnified in rodents. So I'll say 
as far…and especially [crosstalk 01:32:10] [Dr. Patrick]: Yes. So my question is, do you 
think this is going to translate to humans? [Dr. D'Agostino]: Rodent model studies 
are in very, very informative, especially   mechanistically, not always predictive.

Some of 
the nuances is that there's different strains   of rodents that will overeat ketogenic diets. Like 
early studies before, some colleagues were feeding   it and said, "This is not gonna work. They're 
hoarding the food. They're eating. They're getting   blown up." There's like this is obesogenic, you 
know. So the high fat… There's a lot of high-fat   diet research that detractors of ketogenic diet 
will point to and say, "This diet is…you know,   causes all these bad things." But that's a 
westernized obesogenic high-fat diet.

So,   what Dr. Verdin used and Ramsey…so they did 
actually the study that I really wanted to do,   and they probably did it better than I could 
ever do. They have really great molecular   tools and everything, and they did it in a very 
clever way. From my understanding, they did…   And the results were to be expected. You know, 
I think the results are what I would expect. So my understanding is that they did the cyclic 
ketogenic diet because, yeah, they didn't want   them to gain weight, which could negate. So, I 
have to look to see what animal model they used,   but the C57BL/6 mice will eat a ton of the 
ketogenic diet food, and they don't gain weight.   Whereas other…depending upon the strain.

And 
then we have the VMDk mice that we use for our   cancer research, and they tend to… It corrects 
their eating behavior, meaning that if you give   them a standard diet, ad libitum, they just gain 
weight like a couch potato. But a ketogenic diet,   they will lose weight and everything improves. So 
they're like the other end. The C57BL/6 are kind   of like athlete mice, I think, where the other 
models are more like sedentary mice. They are not   as active. But what we found… I have to 
look exactly at the feeding protocol. But when   we did a little bit of calorie restriction…our 
calorie restriction is just putting, you know,   5 or 6 grams of food into it every day, 
and then they eat it within an hour,   and then they essentially fast for 23 hours.

[Dr. Patrick]: [crosstalk 01:34:30]. [Dr. D'Agostino]: So it's kind of more like… 
But you have to individually house the animals,   and then, you know, sometimes if you house them 
together, they'll start, like, fighting and eating   each other because they're kind of hungry. But 
one thing that we saw very consistently early on   is that a mild amount of calorie restriction makes 
these mice like super mice. Like they become…you   know, they're thinking faster. They are really 
thriving in the context of a calorie deficit,   and I think that goes back to human evolution 
too. So, we survive today because we undoubtedly   experience food scarcity and limited food 
availability, and in the context of being hungry,   that enhanced our cognition and even exercise 
performance to be able to acquire resources,   right? So the same thing I think is 
happening in their mice, and it could be…

I have to look at the weights of the mice, but 
a lot of it's kind of like weight dependent and   producing that energy deficit. But you just get 
a whole plethora of things to happen in regards   to suppressing age-related chronic diseases 
with just a little bit of dietary restriction   seems to unmask this probably because, 
with a standard rodent chow-fed ad libitum,   they overeat, and it just basically fuels 
metabolic derangement that contributes to   early-onset age-related chronic diseases and 
also the formation of spontaneous tumors.   And I think in their studies maybe with both 
or at least one…maybe both studies showed   a suppression of spontaneous tumors too. 
So, this has major implications, I think.

We're very interested in actually taking animal 
models that have inducible tumors, for example,   you know, various genes that will kick on at 
200 days and then form spontaneous tumors or a   melanoma model where you subject to UV radiation. 
And if they're fed a ketogenic diet, can you   suppress that? People don't do these studies 
because the NIH doesn't really fund like cancer   prevention research. I feel like these are the 
most important studies that need to be done. You   put a variety of different rodent strains under 
different conditions that are known to like induce   tumors, and you feed them, you know, a low carb 
diet or ketogenic diet that you could actually   feasibly maintain and do. And you see if you could 
suppress these spontaneous tumors.

But that's what   they did in this experiment, and they showed, like 
you said, an enhancement of cognitive and learning   ability relative. The older mice learned better 
than the younger mice [inaudible 01:37:09]. Yeah. [Dr. Patrick]: I know in John Ramsey's   publication. Dr. Verdin mentioned also in the 
podcast when we had him on a few years ago that   they had a time-restricted feeding aspect 
to it because they were feeding the animals   proportions of very specific proportions. 
They were only given their food, you know,   when the people…the scientists were going 
there into the house and giving them the food.   So they had this sort of dietary restriction 
component to it. Whereas Verdin's they were ad   libitum. They were cyclic. They were going on the 
cyclic ketogenic diet. And Ramsey's data was more   pronounced, like you mentioned, the combination 
of the dietary restriction plus ketogenic diet   seems to be like secret sauce in a 
way. But, you know, to me, it was… And again, like you said, you know, the animal 
rodent research isn't necessarily predictive of   what's going to be, you know, occurring in humans, 
but it certainly is promising in my opinion.   It got me very interested in it and, you know, 
I've got nerve degenerative diseases on both   sides of my family, Parkinson's and Alzheimer's. 
So I'm very interested in, you know, any types of   lifestyle…

And I also have genetic factors there 
at play as well. I'm certainly very interested in   any sort of lifestyle factors that can mitigate 
that genetic risk, which as we know there are many   things that you can do in your lifestyle that can 
help. Doing some sort of modified ketogenic diet,   cyclical maybe, you know, because it is for me 
hard to sustainably do it all the time, you know. [Dr. D'Agostino]: That's where intermittent 
fasting kind of comes in too because people   don't have to tinker around with their… I mean, 
the foods that we eat are super important just   like eliminating processed sugar, carbs, things 
like that.

That's going to move the needle, like,   quite a bit. But there are some people that I know 
like family member and [inaudible 01:39:08] There   are just some people who are not going 
to count carbs even to do that. You know,   this is just not going to happen. But eating 
within a predetermined time window is pretty easy   for…that's like a good introduction. Once you 
start doing that, then you start realizing how   good you feel in this mild state of ketosis. And 
then you start maybe…that becomes the entry   point to where you start manipulating your 
food and your macros and things like that. [Dr. Patrick]: So what happened with me totally 
in that very order.

I mean, I'd practice a   lot of time-restricted eating and started to 
notice in the mornings with stuff. It was like   I'm just so much sharper and my anxiety was a 
little bit lower, you know, believe it or not,   while I was not eating. So I decided to experiment 
with ketogenic diet, and while I did do it,   as you mentioned earlier in this podcast, one of 
the most pronounced things I noticed, and this is   totally subjective, was my anxiety level was so 
much lower. I mean, very noticeably. I'm somewhat   of an…I mean, I've got some anxiety, you 
know, that can kind of kick in, and that was… [Dr. D'Agostino]: High performers 
are like that though. So that's   like pretty much [crosstalk 01:40:17] personality.   Yeah, sure. And then you leverage that 
into productivity. Yeah, I think. Yeah. [Dr. Patrick]: I felt like 
it was very noticeable for me   with the anxiety. And then, you know, it's 
like that feeds into if it's affecting anxiety,   what else in the brain is it affecting, you know, 
cognition wise? You know, if you're anxious,   it does sort of limit cognition in a way.

It can 
kind of like, you know, distract you and so… [Dr. D'Agostino]: And you did this back like in 
grad school you started doing this? I started   doing it. Like before big talks, I would chew 
on a propranolol and hold it to get like a   beta-blocker. I like needed this when I was like 
in grad school I think in my early…And then I   realized as I think I got into my postdoc 
and I started tinkering with intermittent   fasting at first and then just carb, I was 
like, "Wow, this is how I feel," you know,   especially when I kind of dieted and brought my 
weight down a little bit, it's like, "Wow, I just   feel like super calm." It's like, "I can't even 
get anxious under certain conditions." So, it… [Dr. Patrick]: Well, I didn't do a ketogenic diet. [Dr. D'Agostino] …like a 
nootropic, it almost too. [Dr. Patrick]: Yeah. Well, I didn't do the 
ketogenic diet until of recent. Like this was like   last summer.

But caloric restriction, I used to 
do a lot of that combined with exercise as well.   So I was kind of like…I was getting in 
ketosis, you know, without having to do… [Dr. D'Agostino]: Yeah. Exercising ketosis. [Dr. Patrick]: Yeah. I mean, I was running…this 
was like even before grad school but like early   in grad school. I was running like 10 miles 
a day, and I was doing that like four to five   times a week. So I was running [inaudible 
01:41:47]. I had gone almost to an extreme   too where it was like I changed my menstrual 
cycle where I wasn't getting it, you know,   because I was very active. I was doing a lot 
of caloric restriction. I felt great. I mean,   I really did. That was actually a long time 
ago, and it wasn't until like sort of…my   time-restricted eating when I had Sachin 
[SP] on the podcast back in 2015, I mean,   that's when I really got hardcore about trying 
to like time my timing with my food intake and   following that really, you know, obsessively 
for the last, you know…

Has it been like   six or seven years? That's really helped. 
But the ketogenic diet was also unique. I   do want to sort of incorporate that into my… 
I want to do some kind of cyclical version of   it. I really want to and I want to, you know, 
measure my biomarkers and all that, which I… [Dr. D'Agostino]: And do them together.
[Dr. Patrick]: And do them together. [Dr. D'Agostino]: So you're still 
going to do intermittent fasting. [Dr. Patrick]: Yeah. And do them 
together, you know, as well. [Dr. D'Agostino]: That's the key. Like 
people think it's one or the other, whatever,   but low carb intermittent fasting, so just a 
modified. Low carb intermittent fasting probably   has more benefits than chronic ketosis, eating 
like throughout the day I think for a normal   healthy person.

And maybe even therapeutically for 
managing…because I'm communicating with adults   that have epilepsy and they're following ketogenic 
diet. They breakthrough seizures. But then they   take the same diet, same calories, and then do 
an intermittent… And this is not promoted in   the world of epilepsy, but when they take their 
ketogenic diet where they're having breakthrough   seizures and they implement time-restricted 
feeding, then they get seizure control again. And I think the people in the trenches know this. 
Like the neurological teams and dietitians, they   realize, "Hey, well, if you can do this." It's not 
part of the medical literature, but they know this   intuitively just because of the information 
people are putting out, all the information   on intermittent fasting.

You know, Mark Mattson 
has been studying this stuff since the '90s, and   I first stumbled upon his stuff in grad school. 
And I always kept his papers with me. I was like   showing people. I was like, "Look at this. Why 
don't people looking at this research? It's like   so important." I haven't read his book yet, but 
he has a new book out to it. [crosstalk 01:44:01]. [Dr. Patrick]: Yeah, he does. Yeah, we have… [Dr. D'Agostino]: He inspired me. I think that's 
how I got inspired into the ketogenic diet,   it was looking at the calorie 
restriction and then fasting,   and then that led me to ketones.

But 
it was Mattson actually that actually   sparked my fire, and then that led 
me to some of the ketone researchers. [Dr. Patrick]: I asked Mark this question when 
he was on the podcast, and I'll kind of ask it   to you in reverse. And that is…you've 
already sort of touched on it, but like   what do you think the overlap between being on 
a ketogenic diet…a modified ketogenic diet   is with intermittent fasting, whether 
we're talking about these epigenetic   changes with beta-hydroxybutyrate being an 
epigenetic modulator, a signaling molecule,   autophagy's one that I'm 
very interested in as well? [Dr. D'Agostino]: Yeah. Two things in my mind, 
insulin and insulin signaling like IGF-1,   you know, activation of AMP kinase, IGF-1, mTOR,   but also the ketones as a drug-like mediator on 
not only alternative energy substrate but also as   a drug-like mediator for all these different 
things like suppression of inflammation,   activating epigenetic effects, and things 
like BDNF, which I think I…

You know,   Mattson's work actually showed that many of the 
benefits of intermittent fasting were associated   with beta-hydroxybutyrate-induced growth factor 
effects on like BDNF and things like that. So I   see there's the hormonal effects of intermittent 
fasting are replicated with the ketogenic diet,   and then the hyperketonemia that's associated 
with intermittent fasting in the ketogenic diet   then have their own effects through 
beta-hydroxybutyrate and acetoacetate. So   that's two main things, but there's a whole…it's 
pleiotropic, right? So the ketogenic diet. I've given talks to pharmaceutical companies 
where I go there and they say, "Well,   let's key in on the mechanisms that we can sort 
of drugify," right? But the end summary slide   is like a dozen or more mechanisms, and there's 
probably many more that are all sort of working in   synergy. And I think that becomes the reason why 
the ketogenic diet works when drugs fail because   you have drugs work through a GABAergic mechanism, 
these drugs work through suppressing glutamate.   You have a variety of anti-epileptic drugs 
that work through different pathways, but   combinations of them used in high dose 
often work initially then they fail,   and then patients are put on a ketogenic diet 
and it works.

So the ketogenic diet is working   through a mechanism independent of what we 
know these pharmaceutical drugs are working.   And that becomes…you know, the complexity 
of metabolism is very…it's like daunting,   right? And to key in on something that's 
really having… And it could be depending… The etiology of epilepsy is largely unknown, and 
the ketogenic diet seems to work through all these   different types of epilepsy, whether it's like 
tonic-clonic, there's Dravet syndrome, there's   different metabolic disorders, absence seizures. 
And the ketogenic diet seems to work across all   these different seizure types probably because 
working through all these different mechanisms. [Dr. Patrick]: What do you 
think about a ketogenic diet   for the treatment of neurodegenerative disorders 
like Parkinson's and Alzheimer's disease? [Dr.

D'Agostino]: I think there are different 
subtypes of Alzheimer's disease. Again,   I think the etiology of Alzheimer's is complex, 
and there is probably a metabolic phenotype that   Dr. Bredesen talks about like in his book. And I 
think that phenotype would be very responsive to   the ketogenic diet where, I don't know, you would 
potentially screen for these patients by doing an   FTG-PET scan. And if you see, you know, there's 
like brain atrophy, but if you see a dim PET scan,   then a metabolic intervention may be 
a good, you know, approach for that. But I can tell you just by communicating 
with hundreds of patients over the years,   the ketogenic diet works remarkably well for 
some patients and has no effect on others.   I don't think it's ever hurt or decreased 
anyone's cognitive, you know, capacity or   anything that I'm aware of. I get biased feedback 
and people are telling me that it's working,   but, you know, I've seen it not work too. Dr. Mary 
Newport was one of the people that really inspired   me in the beginning. I actually brought her to 
University of South Florida, and she actually   gave a lecture.

She used to lecture for some of 
my classes. And at the time…the early times she   would bring her husband, Steve. So I don't know 
if you know that there was a case report written   on the use of beta-hydroxybutyrate ester as a 
therapy. And this case report was her husband. And I witnessed that her husband…she had many 
more years, well, you know, years maybe like   five or six years just from an outsider looking 
in. It seemed like she had that amount of time   extra with her husband to spend because of 
the ketogenic intervention. The early part,   it was just coconut oil, and then she realized 
that coconut oil had medium-chain triglycerides   and then found the patent by Accera, 
AC-1202. And the active ingredient was   caprylic triglycerides. So she went out and bought 
MCTs and then had an effect, but then learned   about the ketone ester and the ketogenic diet and 
was administering that, and that was helping him.

When 2009 she was a guest speaker in my class 
and then we went out to eat, and her husband was   shaking with Parkinson's disease-like symptoms, 
he had Alzheimer's disease. And then he had a vial   of MCT and coconut oil. And when he consumed 
that, within about 15 to 20 minutes the tremor   stopped and he became animated and was commenting 
on our conversation. So when I saw this in 2009,   I realized that he was not really…it wasn't the 
food he was eating. He consumed that supplement,   it elevated MCTs in his blood, which 
can also cross the blood-brain barrier   but produce a state of hyperketonemia, and that 
acutely stopped the tremors he was having and   he became more animated. And that was… Being in contact with her and seeing this and 
witnessing it and also seeing his clock test   and Mini-Mental Status Exam or State Exam   convinced me to go in that direction for 
my research.

So there's no doubt he was   a metabolic phenotype, but he was also APOE4 
positive, so which is very interesting, right,   because we talked about, you know, different 
dietary interventions. So there was no doubt. In the study of Accera in AC-1202, the APOE4 
phenotypes were the ones that were not responsive   to hyperketonemia, but he's APOE4…and he 
was responsive, and I saw it with my own eyes,   and then that motivated me. Actually, the first 
study that we did was an Alzheimer's mouse study   at the Alzheimer's Center. And then I developed 
the ketone ester because the funding agency   did not want to look at the diet per se. So we 
focus on the ester later in the seizure studies. [Dr. Patrick]: It seems like, you know, in 
particular with some of these neurodegenerative   disorders like Parkinson's disease, I mean, 
you mentioned the tremor that, you know, the   standard care of treatment, you know, like 
carbidopa-levodopa [SP], there's a lot of   terrible side effects with time.

And if there 
was another possible either adjunct treatment or   alternative in some way or something, that it 
should really be explored more. For example, if   you could. I mean, ketogenic diets are so widely 
accepted now for epilepsy. Like what about some of   these other brain disorders? Is there any movement 
in research to kind of push to our understanding   of whether or not ketosis is going to be 
beneficial for other types of brain disorders?.

[Dr. D'Agostino]: Yeah. It's so much 
easier to do a ketone supplement as   opposed to a ketogenic diet for a…randomized 
controlled clinical trial is very hard with   a ketogenic diet, right? But with a supplement, 
you can have a control, you can do things. So,   I think those studies are happening, and we 
know that, you know, just by virtue of the   ketogenic diet altering brain metabolism, brain 
pharmacology, we know…I mean, I observe early   on that this is going to be important for many 
different neurological disorders and cancer too. So, that's why we got steered towards, you know… 
So I didn't want to initially, you know, study   cancer, but the data was so compelling that we 
should at least test this. And it became a whole   another track in my research, you know, that we're 
doing in the lab. I think we are, but it's slower   to go in that direction. And we really do need 
clinical trials before we can start prescribing   these things to people, the ketogenic diets or 
the supplements.

I mean, that's happening now. But there's groups of people 
getting together…you   know, there's a group that I'm involved in 
that's associated with metabolic psychiatry,   and they are looking at dietary interventions 
for a broad range of psychiatric disorders. And   that could be depression, that could be bipolar. 
Even eating disorders like anorexia is under the   umbrella of a psychiatric disorder. So there's a 
lot of potential interventions there. And there's   clinical trials, but the data is not there yet 
to, you know, be able to prescribe this to that.

[Dr. Patrick]: I mean, people are out there 
experimenting with ketogenic diets. There's   ketone supplements that you can buy on Amazon. 
There's a certain element of, you know, there are   families out there that are wanting to 
try different lifestyle, dietary changes.   Talking to their physician about them 
is, you know, obviously recommended,   but I mean, they're doing it, they're trying them. 
And I can tell you like so my mother has…she has   the different types of tremors, essential tremor, 
she's got orthostatic tremor, she also gets   migraines.

And she did do the ketogenic diet with 
me. Somewhat she like cheated a lot more than I   did. But I also have given her ketone supplements, 
and it's noticeable. And it's the reason why she   even tried to…was wanting to try the ketogenic 
diet because she's very much addicted to refined   carbohydrates. But it, I mean, noticeably stops 
her essential tremor and somewhat her orthostatic,   which is her legs when she stands still, but 
noticeably the essential tremor and the migraines.

And this is totally anecdotal. So I'd love to 
hear your thoughts on it. She will take a ketone   supplement. Ester has worked for her and ketone 
salts. So she's done the Ketostart, and it totally   takes away her migraine, which is phenomenal 
because I'm not a big fan of the migraine   medicine that she used to take. But she gets 
migraines that are debilitating. Like she can't… [Dr. D'Agostino]: Oh, yeah, good 
rationale for migraines. Yeah. So,   yeah, I get, I mean, a lot of 
emails about that. I try…because   I'm a researcher, I go in the other direction and 
try not to oversell it as much as I can because…

[Dr. Patrick]: Totally. [Dr. D'Agostino]: Yeah, I mean, that's just not 
very academic. So, I get so much feedback and I'm   so excited. I want to cut and paste things and 
put it on social media about responses because   people even send blood work or test results or 
their doctor. But I'm very cautious to do that   because I know the power of placebo, I know the 
power but… I know what I saw years ago. The   stopping of tremors and becoming animated was not 
placebo because the patient at the time didn't   really know that he was…what he was taking, 
really.

I mean, he was pretty far advanced. But in regards to migraines, a Ph.D. student by 
the name of Dr. Elena Gross. So we wrote a review   together, which kind of highlighted many of the 
benefits associated with migraines. So she was a   person who had crushing migraines and discovered 
that the ketogenic diet and then later ketone   supplements could recapitulate that and actually 
help to manage her chronic migraines that she had.   And it was likely just like the ketogenic diet 
for epilepsy is working through multi-modal   mechanisms, so by probably increased 
GABAergic tone, increase brain blood flow. Some people get migraines because of like an 
increase in blood flow in some people because of   vasoconstriction. And we know that the ketogenic 
diet and exogenous ketones increase adenosine.   And from our metabolomic data, adenosine, I 
was not really interested in it at the time,   was like many fold higher 
relative…it was a thing that was   really hot on our metabolomics data.

I was like, 
"Oh, this is very interesting." So, I recognize   adenosine as a very powerful vasodilator 
for cardiovascular, you know, physiology. So, when you fast or even when you go 
on a ketogenic diet, when you fast,   blood flow to the brain can increase by 30%. 
So it's an acute. You can acutely elevate it   and probably through this adenosinergic 
mechanism. So there's adenosine,   there's probably dramatic effects 
on brain blood flow, on, you know,   neurotransmitter systems, energy systems. And 
also neural inflammation can trigger a seizure. I don't like to go to anecdotal evidence but I 
have…a lot of people will contact me that have   like herpes simplex or shingles or different 
things where the virus like attacks their body,   and the first sign that they get is like a 
crushing headache. And then they get like   full-body inflammation, and then they 
get like sores if it's like shingles   or something like that. And they'll 
start fasting or they'll acutely use   ketone esters or ketone salts.

Actually, they've 
been using…I've been recommending it and it's   like, "Okay, please, give me…you know, 
give me feedback." And I've been giving them   recommendations or not recommendations. I've been 
suggesting this as a potential way to mitigate the   inflammatory cascade, and the feedback has been 
pretty remarkable that they can basically stop,   you know, an episode from…you know, 
like shingles or herpes simplex. And the same thing happens. They get crushing 
headaches, and then usually, that's a sign that   the virus is starting to shed, and it produces, 
you know, changes in the brain. Systemic   inflammation contributes to neuroinflammation, 
which contributes to the headache, and then   usually you get the cascade kind of after 
that. So, it has worked through a variety   of different people, and people get headaches for 
different reasons. So I think it's kind of like   Alzheimer's where you're going to get…you know, 
a certain phenotype will be more responsive to… And I probably should mention 
that there's products on Amazon   that people are using, ketone salts, where 
they take it and it gives them a headache.   I think I've taken some of these because, you 
know, I try to test as many things as possible,   and there are supplements out there, 
quite popular ones, where I consume it,   and then I just get like a headache…almost 
like a caffeine headache or something like that   after that.

That's a very reliable sign that 
there's something wrong with that supplement. So,   if you're getting headaches from supplements, 
and I've gotten quite a few emails about this,   so I know there's listeners out there listening 
to this, I would say change the ketone supplement   that you're taking. And it could be the 
electrolytes, it could be contaminants,   purity, potency, tolerability, gut issues. If 
it disrupts your gut, that could contribute   to a headache. But I am firmly of the opinion that 
ketogenic diet and fasting.

Fasting was also used   for headaches. So ketogenic diets, fasting, and 
exogenous ketones can be used to manage migraines. [Dr. Patrick]: The other area that kind of is 
interesting and leads into the carnivore thing,   we mentioned it earlier, and it 
is an interest of mine as well,   is autoimmune disease. And I know there's been 
some preliminary evidence…well, last I checked.   Maybe there's been more since then. So I haven't 
done a ton of reading on that, but with ketogenic   diets actually helping with autoimmune disease. 
I know there's been also a lot of work with   intermittent fasting, fasting-mimicking diets 
helping with autoimmune disease.

And so there,   again, might be some overlap with ketosis 
from either a ketogenic diet or fasting   helping with a variety of types of autoimmune 
disorders. I mean, I know you're not…you're   not going to say ketogenic diets are 
going to help with autoimmune disease.   It seems like a promising area 
to continue to research as well. [Dr. D'Agostino]: Yeah. There's a couple… I 
was just teaching one of my classes. Yeah. So   there's a couple studies on MS and other, of 
course, GI-associated autoimmune, you know,   disorders. And I'm not an immunologist. I mean, 
we do some work, you know, in measuring, you know,   immune factors like cytokines and chemokines and 
things like that. I can say that we know that   dietary interventions…nutritional interventions 
can be powerful modulators of the immune system.   And in some cases, a hypersensitive 
immune system will contribute to   increased intestinal permeability.

So intestinal 
hyper-reactivity is an immune response,   and that intestinal hyper-reactivity will always 
lead to intestinal permeability, which can lead to   impairing…you know, exacerbating an autoimmune 
condition. So I think dietary interventions are   working through that way too and maybe suppressing 
some of the inflammatory mediators, IL-6,   IL-1beta, TNF alpha, things like that. So, the 
ketogenic diet interesting can also augment the   immune system in ways that makes it hyper-vigilant 
and being able to detect things like cancer cells,   right? The ketogenic diet enhances the anti-cancer 
immunity of people that are following it. [Dr. Patrick]: Oh, really? [Dr. D'Agostino]: Yeah. So, a 
colleague of mine, Dr. Adrienne Scheck,   did research with a glioblastoma cell 
line showing enhanced cancer-specific   immune regulation, you know, with a dietary 
intervention. She was also using radiation.   And also I think it needs to be appreciated 
that there's a lot of people who are against   the standard of care, but I think the standard 
of care in the context of the ketogenic diet   is a much more synergistic approach.

So, when 
you give radiation, when you give chemotherapy,   it's stimulating autophagy and it's 
stimulating tumor lysis syndrome.   So you're actually like breaking down…you have 
bits of tumor that are entering circulation. And it's not really talked about. I always think 
about it in this way, when you give someone chemo,   it's killing cancer cells, and then you're 
stimulating autophagy and tumor lysis syndrome,   and then that's stimulating the immune system. 
So, you know, I think chemotherapy, in general,   is carcinogenic, it's bad, but it's also 
stimulating the immune system to then   attack the cancer cell. In the context of a 
ketogenic diet, that a ketogenic diet, especially   if it's calorie restricting, is stimulating 
cancer, it's putting metabolic stress on cancer   cells and actually stimulating autophagy sort 
of in cancer cells, is stimulating cancer cell   death.

And it makes the tumor more sensitive 
to chemotherapy and radiation. So you have   more tumor die off and you're also protecting 
the normal healthy cells. And it's augmenting   the immune system in a way that's actually 
stimulating it more to attack the cancer. So what I'm saying here is probably you 
can't go to any publication, but we just   know from tumor biology that, you know, when 
you stimulate…when you kill cancer cells,   you know, through any means, you can have this 
process called tumor lysis syndrome, which could   kill the patient if you do it too abruptly, 
right? But that's why we're very, you know,   adamant in advocating a more gradual approach, 
which would be like ketogenic diets, maybe   metabolic drugs, and also hyperbaric oxygen 
therapy, or something that we studied. But it needs to be acknowledged and recognized 
that chemotherapy and radiation also work by   stimulating the immune system, and it works 
better in the context of a ketogenic diet,   which makes the immune system more 
hypervigilant to be able to recognize   and attack the cancer cells.

So, there's a 
lot of research being done on that now. And,   you know, I know the Moffitt Cancer Center, which 
is by USF, is very interested in immune-based   therapies and using ketogenic diets to enhance 
like PD-L1 inhibitors like checkpoint inhibitors. A paper just came out in a pretty high-impact 
journal, I forget the name of the journal. But   it showed that PD-L1 inhibitors were greatly 
augmented in the context of the ketogenic   diet. And even metabolic drugs like the PI3 kinase 
inhibitors are remarkably effective and promising,   but they have a counter-regulatory effect at 
increasing insulin. So when we take these things,   they can target tumor metabolism, but there's 
also an increase in insulin. And in the context   of insulin suppression with a ketogenic diet, 
that can unmask and augment and greatly enhance   PI3 kinase inhibitors. So Dr. Lou Cantley is 
really spearheading some of that work. And I've   been in contact with a few of the patients 
in that that are doing like really well.   And they're using a ketogenic diet to enhance, 
you know, the efficacy of that treatment.

[Dr. Patrick]: I know glioma. 
Gliomas are one type of cancer   to seem to be responsible [crosstalk 
02:06:05] evidence suggest, right? [Dr. D'Agostino]: Yeah. That was my first interest 
in…because I started doing hyperbaric oxygen   and I saw some…I saw, like, cancer cells 
exploding under hyperbaric oxygen. So this   got me very interested in cancer, it was that. And 
I didn't know why they were exploding. And we had   a dye that was looking at superoxide 
production in the cytosol and also in   the mitochondria. So what I would see 
is that the mitochondria would light up   really quick. We were doing optical sections 
with a laser scanning confocal microscope,   and I can see that superoxide production was 
ramping up like super-high and super-fast when   we hit it with oxygen. And then I would see 
the mitochondria disappear and then like the   cells would rupture. So they're exploding. So 
we're giving high-pressure oxygen, and the tumor   cells were taking that oxygen, and because the 
cancer cells have defective mitochondria, they   put out proportionally more superoxide 
anion, which then can be converted to,   you know, hydrogen peroxide and more reactive 
intermediates like hydroxyl radical.

And then   that damages membrane lipids and then you get 
rupturing of the cells. So I was like seeing this,   and I was like, "This is very interesting." 
And what it was telling me is that…I didn't   know why it was happening but later found 
out about the Warburg effect where you have   an altered metabolism. Like some people say the 
Warburg effect is the cancer cell sort of changing   metabolism for its own benefit to redirect 
nutrients and biomolecules to the biosynthetic   anabolic production of…you know, for the 
expanding biomass of the tumor.

So that's why. And other people like Warburg said it was damaged 
respiration leads to compensatory fermentation,   so the sugar cell consumes more glucose. But it 
was sort of looking at this effect which got me   very interested in cancer in ways to target 
sort of cancer cells and then manipulate the   substrates. So, that actually was the precursor 
to our cancer work with ketones because I was   using hyperbaric oxygen, and then under different 
conditions, I started growing cancer cells and   feeding them glucose and ketones. And then I 
would take away the glucose and keep the ketones,   and the cancer cells would die.

And then I 
would have glucose, and when I added ketones,   it would decrease proliferation. So this is 
before I ever published anything, but it was   like…it got the wheels turning, and I was like, 
"There's something that needs to be studied here." So I had a few different med students replicate 
each other. So they could replicate it. So   that gave me some confidence. And then a 
Ph.D. student came along, Dr. Angela Poff,   who's hosting Metabolic Health Summit with… 
So she's now a research associate and does   research among other things. And then she 
actually moved this to the animal model,   which was ketogenic diet and hyperbaric oxygen 
and then later ketone supplementation. And that   was a synergistic combination. So, the modified 
ketogenic diet we used was we took out the lard,   and we put like a large percentage of the fat.   Maybe 40% was MCTs and then we also 
used omega-3 fats with flaxseed oil. At the time, I was very interested in MUFAs 
and PUFAs.

We looked at what ketogenic diet   researchers were using. I was like, "Well, 
let's make our own." So, we did like 20%   instead of like 10%, you know, protein. We 
did like 20% or more protein, 20% to 25%.   And then we replaced the fats with essentially 
MCT, flaxseed oil, and then we put some fiber   in there too. And then that became the diet we 
actually use for the Alzheimer's research, and   then we use this diet for our cancer research. And 
our effects were pretty robust, and I often think,   you know, was it because we were using, you know,   a diet high in like, you know, omega-3 oils 
and we just… We also had higher protein,   which I think was a little bit beneficial. But 
we had high ketones.

So we did different diets   and this diet especially with the MCTs gave us 
higher ketones and seemed to work really well. [Dr. Patrick]: Wow, super-interesting. What 
about, you know, the different…? There's   different types of cancer, and I know we were 
discussing this a little bit earlier, you know,   the potential for some types of cancer at least 
in rodent studies to, you know, maybe metabolize   some ketones and use them in a positive way to 
benefit the cancer cell. Is that something…? [Dr. D'Agostino]: There's no doubt they do. 
So there's a little bit of… Cancers are more   heterogeneous than we'd sort of like to believe. I 
think the field at large believes that, and that's   why we have all these different cancer therapies. 
There are some cancers that are very responsive to   the ketogenic diet. But when I think of 
the ketogenic diet as a cancer therapy,   I don't think of it as…I don't think of the 
hyperketonemia treating the cancer cells.

The   therapeutic efficacy of the ketogenic diet is 
through insulin suppression and suppressing the   insulin pathway, limiting glucose availability, 
and also to some extent elevating ketones. We know   this because, if we put exogenous ketones into a 
standard diet, we can extend the life of animals   that have metastatic cancer. So we've published 
that in the "International Journal of Cancer." But   what was happening was when you put the ketones 
in the standard diet food, they probably eat a   little bit less, and it's also lowering blood 
glucose and changing metabolic physiology.   So it may not be… And then the reviewers 
rightly asked, they said, "Well, go do a   calorie restriction group." So we took a 
standard diet and calorie-restricted like 25%,   and we saw an increase in survival, 
but it was nowhere near the increase in   survival from adding the ketones to the 
standard diet. So we did that control. So to get back to your question, 
yeah, I think, you know, brain tumors,   aggressive, you know, solid tumors, endometrial 
cancers, maybe certain GI cancers, maybe   lung cancer, you know, are responsive. 
The cancers that are associated with   metabolic derangement are probably responsive, 
also cancers that are more aggressive or more   glycolytic.

So they're more likely to 
respond. And brain cancers are a good   cancer to study because you get seizures 
with brain cancers and because the tools, the   treatments are so limited. Like glioblastoma we 
just know that standard of care does not work. So   you want to use something. A dietary approach can 
then potentially make the existing drugs work or   augment the many different factors that could make 
the brain cancer more responsive to the tumor. But there are different mutations. There's one 
for melanoma, BRAF V600E mutation, I believe,   which changes the tumor metabolism in a way that 
can actually maybe cause acetoacetate to be used   as fuel. Some cancers may respond to ketones in 
ways that are different than other cancer cells   like the brain tumor cells that we've studied in 
the lab. So, in particular, there's a melanoma   cell line at least that has BRAF V600E mutation, I 
believe.

And those cancer cells have been shown to   use acetoacetate as potentially an energy source 
but also for biosynthetic reactions. And I suspect   there's a variety of different cancer cells 
that can use ketones, not only as a biosynthetic   molecule, but maybe even for energy too. But 
I think largely, cancer cells that are more   aggressive have reverted back to a glycolytic 
phenotype where they're primarily relying   on fermentable fuels, and that includes 
glucose and glutamine are the two fuels. And cancer cells that are more glycolytic and 
very sort of damaged in their respiration due   to the hypoxia of expanding tumor mass. So, as a 
tumor grows, it outstrips its ability to supply   blood flow and oxygen to the tumor. So it 
becomes hypoxic, and that further damages   the mitochondria. So it causes the tumor to 
be more glycolytic and less of the oxidative   phosphorylation pathway.

So, literally, this 
would mean that tumor cells…especially the   core of expanding tumor biomass would not be able 
to use ketones as an energy source because it's a   mitochondrial energy, you know, event. So in that 
way, we think that ketones are not, you know, an   ideal fuel for tumors, and in our model systems, 
you know, it's very clear that they cannot   run…in the absence of glucose, tumor cells 
die, whereas even in the presence of consistent   glucose when we add ketones, there seems to 
be a decrease in proliferation. And we think   that could be due to a ketone-induced decrease 
in hexokinase, which is a glycolytic enzyme.   So there's a lot of potential I think for using 
ketogenic diets as, you know, an adjuvant therapy   and then maybe some potential as using exogenous 
ketones as a means to influence the tumor   microenvironment and also to influence essentially 
the metabolism of the tumor as a whole.

[Dr. Patrick]: And also as you 
mentioned earlier with Dr. Eric,   Verdin, and John Ramsey's co-published 
studies, there was a reduction…I mean,   there's a possible preventative, you know, 
mechanism as well with at least…according   to animal research, there being a reduction 
in spontaneous tumors in these rodents seems   promising to study, you know, as 
well if there's any way we can reduce   cancer incidents. You know, it's always easier 
to not get cancer than to try to treat it. [Dr.

D'Agostino]: Exactly. Yeah. [Dr. Patrick]: So, you know, that's also really 
a sort of interesting and promising field that… [Dr. D'Agostino]: I mean, those results 
were impressive, so suppressing tumor   growth through probably IGF-1 and mTOR and 
just suppressing…keeping inflammation low,   and many other, you know, biomarkers 
I think it's optimizing to do that.   But if we take these ketogenic diets and optimize 
it with specific phytonutrients and we add some   fiber in and we add…then it becomes difficult to 
figure out what's doing what. But I do feel that   there's some synergy in optimizing a 
ketogenic diet with plant, you know, fiber and   phytonutrients that we know have anti-carcinogenic 
effects like curcumin and turmeric and EGCG, and,   you know, there's groups at the Cancer Institute 
that spend their whole life studying just a   handful of these phytonutrients, and they 
show that it has remarkable chemo-prevention   effects. So we should be incorporating these 
into the ketogenic diet [crosstalk 02:17:43] [Dr.

Patrick]: Which brings us to the all meat, 
no carbohydrate diet really briefly, I mean,   the carnivore… There's a lot of people that 
sort of feel like they've done a ketogenic diet,   and they need to graduate somehow to another 
level of zero carb. What are your thoughts on…? [Dr. D'Agostino]: Well, I'm not sure 
if it's like…I think it's going back   towards kindergarten. There's no doubt that a 
carnivore diet is beneficial for some people,   and I think it's therapeutic in some ways. It 
is a form of a ketogenic diet. I followed it,   actually felt pretty good on it subjectively, but 
objectively, my biomarkers were…my LDL I think   almost doubled on it. And then my triglycerides 
started to creep up.

So this was a little bit   of a concern for me. Like if you have…the fat 
pathways were a little bit backed up. For example,   if you have an inborn error metabolism like 
carnitine deficiency either primary or secondary,   a telltale sign is like an elevation of 
triglycerides, hypoketonemia, and then you have   like, you know, a lot of…a cascade of different 
things. Like you're just not metabolizing fat   as well as you should be. Whereas we know that 
certain omega-3 fatty acids can actually increase   the carnitine, you know, transferase and actually 
augment fat oxidation, certain fatty acids can. For me personally, I felt good…I felt fine, 
but my blood work was a little bit concerning.   And when I went back to just adding more fish and 
omega-3 fats and more plants back into my diet,   maybe it was a fiber, maybe it was phytonutrients, 
I felt just as good, but I brought my biomarkers,   especially my triglycerides came back down again. 
But I think, you know, it depends on the type of   meat that you're eating, the amount of food that 
you're eating.

If you're eating the carnivore diet   and creating a calorie deficit while you're doing 
it, I think it could be beneficial. But I don't   think it's something that would be sustainable or 
optimal long-term. So it could be sustainable. It   is for a number of people that I know. But 
I guess the question is, is it optimal? And   I have no science. I'm not aware of any science 
that supports a carnivore diet as optimal   for treating anything. Although I've been in 
communication with people who have benefited   greatly from it. So I'm not going to criticize 
it too harshly. It is a form of a ketogenic diet. [Dr. Patrick]: Yeah. Again, as you mentioned, 
it's like, well, are these people severely   caloric restricting themselves? Are they just 
getting off of a terrible diet that's…?   I mean, there's so many factors. And 
again, it's like, well, you know, to me… [Dr. D'Agostino]: And the lack of fiber.

[Dr. Patrick]: Lack of fiber and, you 
know, the phytonutrients, which… [Dr. D'Agostino]: Which kind of brings it 
back to the fiber issue too, right? Because   it's obvious that we could do well off 
no fiber at all. So the question is like,   you know, is fiber necessary? I don't think 
it's necessary, but I think it's optimal. So   I think excluding it all together is not doing our 
bodies any favor. And I think when we add it back   in…there's just so much good data on fiber that 
it's hard to ignore.

So that's why, you know… [Dr. Patrick]: What do you think 
the colonocytes and like getting   the butyrate from fiber like what 
do you think is happening in the gut   in someone with a no fiber diet? Like the butyrate 
is so incredibly important for gut health. [Dr. D'Agostino]: It is. Yeah. And 
it's a primary fuel for colonocytes. [Dr. Patrick]: It is. [Dr. D'Agostino]: I don't know. I do know that if 
it caused, like, a massive disruption of the gut   microbiome and intestinal permeability, it would 
show up on blood work as like hs-CRP elevation.   Mine trended…it actually went up like from 0.1 
to like point 0.2 or 0.3, but that's like… So I   think humans are omnivores, and they're incredibly 
adaptable to any kind of diet. And I think that   dietary diversity might be a good thing. But 
you have, you know, populations of people   like in Africa or other areas where they 
just eat like one food all the time,   and it could be like some cornmeal or 
it could be whale blubber in another,   and they do perfectly well.

They survive, 
they live a healthy life. It's just   staggeringly remarkable that we have the metabolic 
flexibility and adaptation to eat almost anything. You know, the question is what is optimal? Should 
we even be eating such a huge diversity of things?   And I think that could be beneficial at 
least. You know, it gives us an array of   different things that we can eat and we're 
grabbing nutrients from different areas. But   yeah. I am kind of a little bit neutral on the 
carnivore diet. I think it's beneficial for some,   but I think it's sub-optimal as a ketogenic diet.

[Dr. Patrick]: And as you mentioned, there's 
just a lack of empirical evidence. Like   there's [crosstalk 02:22:49], 
which again is confounded   all the time by many things. But there's 
really not a lot of research that have   been done on…I mean, published and 
peer-reviewed and, you know, actually… [Dr. D'Agostino]: But there are people 
doing it and they're thriving on it and   they've corrected, you know, various…everything 
from autoimmune disorders. You know, there's   superhigh achievers. You have Shawn Baker, 
who's just like a physical specimen,   and he's just eating nothing but 
meat and doing very well and has…I   don't know. I haven't seen his blood work, but 
I think it's okay. I mean, he's smart enough. I   do think that if you're eating a carnivore diet 
and you're getting surplus amount of calories,   which I kind of did because I added just a few 
pounds, and I think that negatively affected   a lot of my blood work. But if you eat a carnivore 
diet and a calorie deficit, then I think it could   be therapeutic and potentially helpful.

So it all 
comes down to calories. People ask me if calories   matter. I think they most certainly do, and I 
think we need to appreciate that because a lot   of the ketogenic diet community, they said 
don't count calories, just count carbs or,   you know, the calories don't matter if you 
eat this way. But calories absolutely matter. [Dr. Patrick]: You mentioned having 
a…you do intermittent fasting sort of   cyclically.

Like how many times a 
week or how many meals a day? Like,   you know, is it something 
that you alternate each week? [Dr. D'Agostino]: My normal pattern is to have 
like a small ketogenic breakfast and then more   or less fast through. Midday I'll have like a 
ketone supplement or maybe a small coffee but not   past 2. And then I eat, we eat dinner typically 
between like 5 and 6. I probably try not to do   a little bit later if I'm working late, sometimes 
it's later. But I consume most of like 80%   of my calories between the 6 and 9 p.m. I know 
9 sounds kind of late, but we go to bed around,   you know, 11.

But I get the bulk of my calories 
probably with dinner, which is around like   five or sixish. A lot of my protein too. But in 
the morning I eat a ketogenic breakfast. Lately,   I've been eating waffles and making waffles. 
There's different ketogenic waffle recipes   that are really, really good. So I've been 
experimenting in the kitchen a bit with my wife. [Dr. Patrick]: What about your exercise routine? [Dr. D'Agostino]: Yeah. I try to do some form 
of exercise every day. I mean, we have some   pretty…we live on a farm, so farm work occupies 
probably about 10 to 20 hours a week of my time   doing…and that's good outdoor activity, getting 
sun, exercise around the cows. We walk our dogs,   you know, usually like twice a day. And then I 
do resistance training no less than twice a week,   but sometimes I try to get four times a week if I 
can.

I like to do a lot of bodyweight exercises.   And I think when you're traveling and you're 
pretty busy, like chin-ups, push-ups, dips.   A lot of…chin-ups are probably like one of my 
favorite exercises, pull-ups, chin-ups. Yeah. [Dr. Patrick]: And then you're 
doing some hot tub therapy. [Dr. D'Agostino]: Hot tub 
therapy. Yeah. So your article on   sauna and just hyperthermia in general. So I did 
some experiments measuring my core temperature and   showed that I can…getting the hot tub to about 
105 to 110, I can get my body temperature up to   about 102 within about 15 minutes. And I really 
believe in looking at the literature, and also   after I do this, I then measure…well, I've 
measured my glucose, and my blood pressure   comes down and it seems to be…I'm like my blood 
pressure is like the lowest it's ever been, it's   like 97 over 60 or something or 58 or something. 
It's really low. And I always trended on the   higher end of systolic especially like 130, 140. I 
think during grad school was like 145 consistently   systolic pressure, always ran a little bit 
higher systolic, although I carried more mass   at the time.

But the one thing that has really 
moved the needle in my blood pressure has been,   not changing anything and just doing what 
I'll call heat therapy with the hot tub… [Dr. Patrick]: That's awesome. [Dr. D'Agostino]: …brought it down 5% 
to 10%. And I was like measuring like   five times a day blood pressure 
throughout the day because I became…I   would love to have a continuous blood 
pressure monitor. That would be really cool.   But my continuous glucose monitor with the 
Levels Health app is very insightful and   gives information, and I can do like a comparison 
of this meal versus that meal and sauna versus,   you know, cold.

I can mark it, time mark it and 
do a CGM comparison with [crosstalk 02:27:26] [Dr. Patrick]: What's the best way to measure 
your actual ketones? Is it blood, breath? [Dr. D'Agostino]: Good question. Yeah. [Dr. Patrick]: Best versus also most 
like easy for people as well. I mean,   they're both kind of important. [Dr. D'Agostino]: Again, 
like people don't like this,   but it depends. So that's my answer to a 
lot of things. So it's context-dependent.   The clinicians that are managing epilepsy 
patients say that urine is great,   and they're not going to change from urine, and 
they're doing…because they don't want to prick   the kid's finger too, right? So I did blood. 
I like using the glucose ketone index. [Dr. Patrick]: What is that? [Dr. D'Agostino]: It's your glucose over ketones 
in millimolar concentration. So, if you're   fasting, it takes me about 72 days…72 hours to 
get…although the guy fasted for 360 or 80 days.   Fasting for 72 hours gets my glucose ketone index 
to one where my glucose comes down to about 3   millimolar and my ketones come up to 3 millimolar. 
So that would be a glucose ketone index of one.   Although I haven't measured LC3 and 
other components of the autophagosome,   it's my belief that achieving and sustaining a 
glucose ketone index of one for 24 hours will   induce and perhaps maximize autophagy.

No 
doubt that you can get more benefits five,   seven days, but then at five days and seven days, 
I see a suppression in testosterone and other   things I don't like. So, for me, three days is 
like the sweet spot. I can achieve a glucose   ketone index of one. And then my breath acetone 
is off the charts. And I think breath acetone   is probably your best ketone to measure if 
you want to lose fat. So, all the carbons   of the acetone you're blowing off essentially 
are from fat. So, when you look at the device   and it's reading like 40, it's like you're just 
like basically exhaling fat carbons from that. Breath acetone is great because with 
beta-hydroxybutyrate I could be at 2   or 3 millimolar and just walk around the house or 
do some activity, and then I'm back down to like   below one. That's because your body is 
using the beta-hydroxybutyrate as fuel.   And if you have a calorie deficit, you have 
high tissue uptake of beta-hydroxybutyrate,   right? Whereas my breath acetone seems to be more 
stable and a better correlate of fat oxidation.   And it's also easier.

So if you're blowing 
into a breath acetone meter five times a day,   that's a lot of money in strips and a lot of 
poking your finger. So I use the Readout Health   Biosense device. And I don't know. I've blown 
into mine like 1000 times, and that would be   cost-prohibitive from a ketone monitoring 
perspective and a lot of finger pricks   associated with that. And it has a pretty cool 
app and also a fasting sort of meter in with it.   I think they collaborate with Zero Fasting. So 
I think there's some collaboration there, but it   can show you if you're doing a fasting and using 
that. Although it's more of a clinical device,   but now it's broken into more mainstream. So it's 
an FDA-approved class 1 or whatever, physical   device…medical device for measuring ketones. And I became interested in acetone because 
it correlates with seizure control.

So,   acetone does. So, I recommend it to parents 
who have kids that are managing and they don't   want their fingers pricked and the urine 
ketone strips are not very accurate. So,   to answer your question, I think both blood 
ketone measurements. If you're just starting   the ketogenic diet, it may be good to just 
use urine to say yes you're in ketosis,   you're not. It's like semi-quantitative. And 
then spend the money to get a ketone meter.   Like the Keto-Mojo device is probably one of the 
best, and then a breath acetone meter is good   for people who are doing fasting and for people 
that are really interested in like weight loss. [Dr. Patrick]: What about using blood 
glucose levels as a proxy? Like is there…? [Dr. D'Agostino]: That's like super interesting. 
Yeah. We had an NIH workshop sort of on this,   and I brought this up as a continuous ketone 
monitoring or continuous glucose monitoring   system.

And now you have the ketone 
monitoring system with app. It has Lingo   device now, which does like glucose, ketones, 
lactate, and also alcohol. But a CGM device   is like the ultimate device to look at dietary 
adherence to a ketogenic diet because it should   be…the trace should be completely flat, and if 
there's big excursions, then that person is not on   a ketogenic diet. I guess if they're under stress 
or they're exercising really hard, you might get   a blip, but generally speaking like a CGM trace 
is a very, very good way to tell if someone is   adhering to a ketogenic diet. So these things 
should be used I think, and generally speaking,   the community also feels that this needs to be 
used. But it's an off-label use at this time. [Dr. Patrick]: Is there like a level 
that's like a range or does it vary?   Like would you…if you were to 
give an estimate guesstimate. [Dr. D'Agostino]: Of what? [Dr. Patrick]: Of blood glucose level to like… [Dr. D'Agostino]: For a ketogenic diet? [Dr. Patrick]: Yeah. To say, like, "I'm probably 
in ketosis because my blood glucose levels are X." [Dr.

D'Agostino]: Yeah. Well, I could show you 
on my… So, what was very interesting when I   woke up this morning, I spiked 40 milligrams per 
deciliter. I've never seen that before like ever.   So my CGM trace typically looks like…oh, 
probably now it's going to be…maybe I'm excited   and maybe it's all over the place, but it's going 
to look like… I added, like, an extra 30 so it   wouldn't go off negative during everything. But 
right now if you subtract 30 from that number,   that's what your CGM trace should look like 
on a ketogenic diet. You've worn a CGM before. [Dr. Patrick]: Yeah. I need to get a new one. [Dr. D'Agostino]: So I'm 74. Yeah. 
But when I woke up this morning,   I had a big…I only had maybe like four 
and a half hours of sleep or something.   So it could be that, it could be the 
different time zone or something like that.

[Dr. Patrick]: Oh, yeah, totally. That was the 
first thing I learned from my CGM was…because   I started wearing it when my son was like 
four or five months old. I was waking up   multiple times to breastfeed. I mean, so my 
sleep was insanely disrupted and fragmented,   and my blood glucose was just…it was just 
going out of control. And it was always on   the nights when I was like waking up multiple 
times and not getting enough sleep. And that was,   like, one of the biggest things I learned 
from my CGM that was surprising to me. [Dr. D'Agostino]: Where were your 
highs? Like how high were your highs?   So mine spiked to almost like 130 or 140, and 
that's unheard of. Like I've never seen that.   But that just could be due to the time change 
and getting about half of the normal sleep   that I get.

I mean, I feel fine now. Okay. 
Yeah. But it was just highly variable. Yeah. [Dr. Patrick]: I can't recall. It's been too many 
years, but they were…yeah. It was something   like that. It was above 120, you know, like 
where it was like, this is postprandial level,   you know, like this is pretty, you know, 
intense, you know, like a robust effect.   High-intensity training. I was doing a lot 
of spin class and stuff like hour-long like   pretty intense spin.

That would help. So if 
I do the spin and then have the disruption   that night after the spin, it was way better. 
Like my glucose was way better. So like the   exercise totally helped negate some of the 
glucose dysregulation that I was having.   I don't know what exactly was happening 
about my glucose spiking so high. So   that was also a learning. I learned so much from 
the CG, and I haven't worn it for a couple of   months because I have to…I think I'm going to 
do Levels because my prescriptions like expired. [Dr. D'Agostino]: Levels is great. [Dr. Patrick]: Now I'm like, "Okay, 
I think I'm going to move to Levels." [Dr.

D'Agostino]: I'm not going to mention the 
other, but I did a couple different companies   and I just wore it. Well, they're in beta now. 
The difference about Levels is that it's kind   of coaching you, and you also have the option 
to…I mean, you could just push and get to a   nutritionist. So I guess that's good for people. 
Maybe not like us but for the average. But it has   so many features built in.

Where I exercise, 
it'll say, you know, "What did you do here? We saw   that you exercised." It learns my body. Even if I 
have a cup of coffee in the morning, it learns my   sort of dawn effect. And I just take a picture 
of my food. It marks it and then it sends me an   email the next day of the picture of my food, 
my average glucose effect, my metabolic score,   and things like that. So it's so easy. 
Otherwise, I mean, you could just buy a CGM   I guess if you had someone prescribe it to you and 
just look at the CGM trace and then make your own   inference. As long as I engage with the app and 
I take a picture of my food and everything, I get   the email the next day, and that tells me what 
happened to my glycemic response the whole day.   And it also gives me a weekly thing.

So all I 
have to do is just engage with the app once a day,   and it sends me like a daily report and also a 
weekly report where I could see like every day. And there's so many features. I don't 
even use like 90% of the features but   I use like 10% of the features and it's very 
useful to me.So we're doing a clinical trial   right now with CGM. And people have app 
fatigue. Not everybody wants to be on an app   all day. But you can engage with it as much as 
you want or just, you know, engage with it two   or three minutes per day is enough to really be 
getting a lot of insight into your own metabolism. [Dr. Patrick]: Just wearing the CGM   without even having to do all the app stuff 
really helped me figure out what foods that   I should be eating and portion sizes and 
all that stuff because it was like…

[Dr. D'Agostino]: What were 
your biggest surprises? [Dr. Patrick]: The cooked spinach was the one 
because I was like, "Oh, the sugar and it has   a low glycemic." But what you said makes 
a lot of sense. That was a big surprise.   And then another really big surprise was like 
a lot of these like cauliflower rice, you know,   like I was traveling on part of this, you know, 
where I was on a ketogenic diet, and so I would   like order food that was like this is keto and 
you get something that says keto. And I'm like,   "This is not keto at all." I'm like, "It's 
like spiking me so high." And then you like   track down the ingredients, and it's like sugar. 
And I'm like, "Really? You're calling this keto   but you actually have added sugar in it." Other 
surprises where I was taking some like collagen   gummy chewables that didn't have any 
sugar allegedly.

And my blood glucose   just went through the roof, and I'm like, 
"What's in this? This is something…" [Dr. D'Agostino]: Same thing. I 
tried some kind of sugar-free gummy,   it shot me off the chart. And all the 
bars that I get sent. So, 90% of the… [Dr. Patrick]: Anything that's keto. [Dr. D'Agostino]: Yeah. The only bar that 
has completely ketogenic is a Keto Brick.   So it's like the brick is 90 grams of fat and 
I think like maybe 30 grams of protein and like   hardly any carbohydrates and it's 1000 calorie 
brick. And that's like truly the only ketogenic,   you know, bar. There's a bunch of bars out 
there, Keto Brick. Yeah. Check them out. [Dr. Patrick]: I mean, if you 
go to Costco now, it's like… [Dr.

D'Agostino]: Yeah. I know, everywhere. [Dr. Patrick]: …like keto everything. 
I have yet to find actually something   when you turn around the back and you 
look at the sugars and the ingredients   that like one of these things that was, like, this 
coconut keto crunch. And my mom loves coconut. She   was doing keto and like ordered it on Instacart. 
And then I came and I'm like, "There's a lot of   sugar in this. This is not keto. Like, how dare 
they call it keto? It's so misleading." Again,   takes us back to the beginning where 
it's like these ketos become…it's   very much become trendy and it's almost like 
this marketable thing. And, you know, I think the   essence of ketosis has been lost somewhat. So, 
it's really been nice having you to talk about   all this. I want to talk even longer, 
but we probably should wrap this up.   Thank you so much, Dom. We're going to have 
dinner tonight and talk more, so that'll be great.   I want to talk to you about all sorts of things. 
But like for people that want to learn more about   your research, they want to follow you, they want 
to learn about Metabolic Health Summit or your   blogs, you know, all those things.

Where's the 
best places to find you on social and all those? [Dr.D'Agostino]: Yeah. Thanks for 
asking. Yeah. ketonutrition.org,   so ketonutrition.org, and we have a blog 
there. Subscribe to the newsletter. When   this podcast comes out, we'll put it in the 
newsletter, of course. And a lot of the other   information that I don't post anywhere else 
is in the newsletter as you do too.

So,   subscribe to your newsletter which I did, and 
it's like an awesome source of information. Metabolic Health Summit which will be happening 
May 5th through the 8th, amazing event. We have   clinicians, you know, basic scientists, 
and entrepreneurs scrambling to this area   and influencers. It's an amazing event in Santa 
Barbara, California. I'm excited to be a co-host   for that. Yeah. Most of the information that we 
promote will be on our blog and on our website.   I personally do not have any 
products. People always ask me,   "Dom, what's your ketone product?" I don't have 
a ketone product, but I do support a number of   different companies and it's on the website.

The 
exogenous ketone product that I use is Ketostart.   Keto Brick is my go-to keto bar. I get 
that question asked all the time. And   Keto Brainz is a coffee creamer that I use, got 
alpha-GPC, theanine, it's got lion's mane in it,   it's also got C8. So, these are three 
supplements that I use pretty much on a daily   basis. Not a huge supplement guy, but these are 
supplements we love and promote on that website.

[Dr. Patrick]: And you're also on Twitter? [Dr. D'Agostino]: On Twitter. Yeah. If you search 
my name. I always forget my Twitter handle,   but on Instagram, Twitter, Facebook, I 
like to share new literature that's out,   our publications, and others in the space. So 
I try to be a resource, not as much as you,   which you put out amazing information, 
and truly appreciate you giving me this   platform to give my information 
to your followers. Thank you. [Dr. Patrick]: Oh, my pleasure. 
Thank you for all your research,   Dom. I'm looking forward to more 
and to a future conversation. [Dr. D'Agostino]: Thank you..

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