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ARI: Welcome to the Less Doing Podcast. Today my guest is Dr. Dominic D’Agostino, an
assistant professor at the University of South Florida. His research involves ketogenic diets,
metabolic syndromes, and some really cool stuff that we’re going to cover today. Dom, thanks
for being on the show.
DOMINIC: Thanks for having me, Ari. Appreciate it.
ARI: Absolutely. Let’s jump right in. Let’s talk about what your focus of research is. I know that
it’s changed a little from what it originally was supposed to be, right? So what’s your focus?
DOMINIC: At the simplest level, we develop and test ketogenic diets and metabolic therapies,
which include supplementation. Under that would be ketone supplementation for a variety of
disorders, including seizures, Alzheimer’s disease, cancer, ALS, wound healing, just to name a
few. But yeah, those are the major ones right now. So basically with an emphasis on diet and
nutritional supplementation for these disorders, and less on drugs. We do a little bit of drug
research, but it’s 90% diet.
ARI: Now, how did you come across – from what you told me before, you originally were trying
to find a better drug. So how did you get on the path of looking at nutrition, and specifically the
DOMINIC: I was funded by the Department of Defense, and under them is the Office of Navy
Research. Divers use a closed circuit rebreathing apparatus, the Navy Seals and Special Ops guys
use that, and the advantage is that it’s very quiet; the disadvantage is that it can create seizures
underwater, and these seizures are resistant to drugs. They’re very powerful, what we call grand
mal seizures, or tonic-clonic seizures. And giving a Special Ops guy or a Navy Seal anti-seizure
drugs is really not a good idea, because it can dull your senses and impair your performance. So I
looked into alternative strategies to prevent this, to test in the lab, and I found the ketogenic diet
was actually more effective than drugs for preventing seizures. It really blew my mind, the
research behind this.
So I focused on the ketogenic diet, not only that, but developing I guess you can say a ketogenic
diet in a pill. The version that we’re testing is a ketone ester, so you take it orally. Within 15
minutes you have a level of ketones above and beyond what you could achieve with a ketogenic
diet. The function of the ketones is that they provide an alternative fuel for the brain, and if the
brain has lots of energy, it can actually withstand the oxygen toxicity that triggers a seizure. And
the ketones themselves also have neuroprotective properties. So it led to that, developing a high
power nutritional supplement based on the ketogenic diet.
And then we found that ketones had all these other applications. Because they function as a very
high, dense source of alternative energy for the brain, that they had applications in Alzheimer’s
disease and in ALS. We’re looking at cancer now. Cancer cells have a defect that prevents them
from using ketones for energy. They basically have dysfunctional mitochondria. The
mitochondria is where the ketones are actually oxidized to make ATP. And wound healing, too.
Ketones increase brain blood flow; they also increase blood flow to the periphery, and we can
observe this. So they have a number of applications that just kind of exploded out of our seizure
ARI: Wow. Without backing up too much, tell me what ketone esters are.
DOMINIC: Your main ketone bodies that your liver produces under periods of carbohydrate
restriction would be acetoacetate and beta-hydroxybutyrate. The function of these ketone bodies
– think of them as like fats that are water-soluble. You stop eating or you restrict your
carbohydrates and you deplete your carbohydrate stores, and your brain is craving some source
of energy, and it can’t really use the fats very effectively because they can’t cross this blood-
brain barrier, we call it. So the fats are converted to ketone molecules, which can get to the brain,
and they provide energy to the brain.
What we’ve done is taken basically the two ketone molecules, beta-hydroxybutyrate or
acetoacetate, and we’ve made supplements out of them, either mineral salts of beta-
hydroxybutyrate, or esters of acetoacetate. Essentially what an ester is is that you take the ketone
molecule and combine it to something that stabilizes it so that when you ingest it orally, your
body can break it down in a controlled fashion and it releases the ketone in a rapid and sustained
fashion so you have elevated levels in the blood. And that ketone body is actually providing a
super fuel to your tissues, and most importantly, your brain and heart.
ARI: The fact that you’ve been able to isolate that – now, how is what you’ve created, the
ketones in a pill, how is that different from taking MCT oil, for instance?
DOMINIC: MCT oil, when you ingest it, it goes to your liver and is processed and broken down
into – it can become ketone bodies through liver metabolism. The elevation of ketones that you
get with MCT oil is relatively modest, maybe half of a millimolar or 1 millimolar, if you’re into
measuring your blood, like I know a few guys out there are. Another problem with MCT is that
you have this issue with tolerability. Some people can tolerate several tablespoonfuls, like me,
actually. So I can get my ketones pretty high, actually, with MCT. Other people can’t even
tolerate a teaspoon. They’re running to the bathroom with a teaspoon. So that’s a limitation. A
fatty acid is something that really needs to be processed by the liver for your body to make
ketones. The advantage is it’s a natural source, it’s cheap, it’s readily available.
Ketone salts, or ketone esters, are kind of like straight up ketones. You take it and bam, you get
rapid elevation of ketones. It might not be one or the other that’s optimal for whatever
application you’re using it for, cognitive or physical performance, but we actually find that when
you combine these things, a ketone salt or ester with an MCT oil, that they work kind of
independently, but synergistically in a fashion that can help elevate and sustain ketones. So it’s
not maybe one or the other, but a combination of the two will likely be your best bet. Depending
on your application.
ARI: That’s interesting. My first question with that then is can you overdose on ketones? Other
than the [inaudible 00:07:38] thing.
DOMINIC: Well, we’re doing studies now in our rodent models where we go very high in
ketosis, and there is a level where you basically start to feel drunk. You feel sedated because
your body’s dealing with – too much of anything will be toxic, right? The ketone bodies will
start to – you’re probably familiar with diabetic ketoacidosis, or alcoholic ketoacidosis?
ARI: Right, the fruity smell.
DOMINIC: Yeah. These are a little different, because with diabetic ketoacidosis, your blood
glucose is really high, like astronomically high, and your ketones are high. The combination of
those two produces an acidic condition in the body. It can cause coma and death, even. Toxicity
with a supplemental ketone would be very, very difficult. You’d have to consume a ton of the
stuff, and your body has a great capacity to eliminate what it doesn’t need, and it would be
expensive. The limitation to toxicity would be your gastrointestinal ability to absorb it and get it
into the system.
People talk about “If I can get my ketones up to 1 or 2 millimolar” – I was just on the line before
you with some researchers who think 1 to 2 millimolar is the sweet spot for performance
enhancement. That’s really not achievable with MCT. You get almost to 1, but with a ketone salt
and a ketone ester, that’s very achievable. But you can also achieve 5 or 6. I believe that 5 or 6
millimolar would be good if you have, for example, severe seizures. But for performance
enhancement, I think it’s putting – ketone bodies are mildly acidic, so at that level, it may be
creating an acidic load that your body has to deal with.
Although the salts of our ketone products are buffered with minerals that are very alkaline, so
they’re kind of pH balanced, you could say. But I don’t think there’s any advantage to going
over 3 millimolar of ketones. Many of the leading researchers would probably support that, like
Jeff Volek, a colleague of mine. He would probably say, yeah, once you get above 3, your
body’s just working to get rid of it, rather than – unless you’re really all-out sprinting or
something like that, or maybe an Ironman athlete. Maybe 2 or 3. But your body’s using it so
much, so it’d probably be hard to get up to that level if you’re in the middle of training or in the
middle of cycling or whatever event you’re doing.
ARI: I’ve done Ironman, and I looked at all sorts of different training methods, and metabolic
efficiency was one that came up a lot. Now, I personally was self-directing, and I was basically
on a diet that was almost 85% carbs at the time. Which was fine for me, honestly, except for the
fact that I was eating every hour, basically.
DOMINIC: That’s a disadvantage right there.
ARI: Exactly. And had to eat on the bike and all that stuff. It was fine. Also, the remnants from
that, because it’s completely different from what my diet is now, is that I got ridiculous sugar
addiction once I stopped eating that level of carbs. And I don’t have an addictive personality. I
know that from years of stuff, and I have legitimately had a battle with a sugar addiction since
I guess there’s two motivations for looking at a ketogenic diet. One would be if you have an
actual disease, something like cancer or some other metabolic syndrome where you really need
to starve your body of glucose.
But then there’s this other side, which is performance-enhancing, cognitive-enhancing and
energy-boosting. Personally, right now, my motivation for having ketones in my body – and I’m
not saying ketogenic, because I’m certainly not. I am not low-carb, I’m not 85% carb. My
current diet is pretty much high fat. My motivation is that my wife and I have a 22-month-old
and twin 6-month-olds, and neither of us sleep very much, and I find that having high fat in my
diet is pretty much the only way that I can not just get through the day, but actually really
function at a high level. But I’m not getting the benefits of the disease-fighting aspect in that
case, because I’m sort of cheating.
DOMINIC: Well, you’re pushing your body from being a sugar burner to a fatty acid and
perhaps ketone burner. I don’t know what your ketone levels are. But whenever you shift away
from a glycolytic or glucose-based metabolism to a fatty acid metabolism, especially with your
level of exercise performance, you’re forcing your mitochondria to be more efficient. You’re
probably stimulating mitochondrial biogenesis. The healthier your mitochondria are, the greater
capacity you have to deal with stress, the more efficient you can convert food into energy. In a
high fat diet, your meal frequency goes way down, you’re satiated.
I used to eat like six to eight meals a day, actually. I eat two now. I eat a breakfast and a dinner,
and they’re spaced 12 hours apart, and I don’t get hungry during the day. I have some bulletproof
coffee during the day, maybe some branched-chain aminos. But it’s extremely more practical. I
cannot even fathom going back to my early pattern of eating, where I look at my watch and I see,
“Okay, two and a half hours went by, I’ve got to eat.” With my lifestyle, I just can’t do that, with
teaching and research and everything else I do. It would be very inconvenient to do that. And I
understand where you’re coming from with being a family guy and juggling a lot of things in
your training. I can see how that can be a very enormous practical advantage. But you probably
are realizing the performance enhancement effects, too, of the high fat intake.
ARI: But not necessarily the disease prevention aspects, right? Like the cancer or – I mean, I
don’t have a seizure issue, but those kind of things.
DOMINIC: Yeah. For cancer prevention, I think generally just a low carb diet is best. You may
want to periodically do a fast, like a short-term fast, three to five days. What that does is, say you
have precancerous cells in your body, if you go into fasting ketosis, it’s putting an enormous
amount of metabolic stress on those cancer cells that are in your body and essentially purging
them from your system through autophagy. Your body can deal with them. I think that was
probably part of our normal evolution. We did that.
But I tell people who don’t want to do a ketogenic diet, just prevention. Just eat low carb and
periodically go into nutritional ketosis a couple times a year. For people who really don’t want to
do a ketogenic diet, I think prevention’s a cure for cancer, and periodically going into ketosis
could be a very effective strategy to prevent it. And just avoiding any kind of processed
carbohydrates and keeping your blood sugar in check, exercise, just kind of the basic things. But
a calorie-restricted ketogenic diet for the rest of your life is not very feasible. I actually think the
body is best when you cycle it. You do periods of maybe overfeeding, if you have a goal to
increase muscle size or strength, and then periods of under-eating is probably the best way the
ARI: I think that’s a very good way to frame it. You mentioned nutritional ketosis. For people
who don’t really know what that is – because that’s not exactly the same as saying a ketogenic
diet. We’re talking about an in between, aren’t we?
DOMINIC: Nutritional ketosis is any nutritional method you use to elevate blood ketones. That’s
my thing. But typically, historically, it’s been carbohydrate restriction. If you restrict
carbohydrates, your glucose goes down, your liver glycogen gets depleted, and your liver starts
pumping out these ketone bodies to replace glucose.
ARI: Right, that’s the distinction that I want to make for everybody. With a ketogenic diet, it’s
more of the idea of eliminating – not eliminating, but restricting severely carbohydrates and
protein due to gluconogenesis for the purpose of cutting out glucose. Gluconogenesis being the
process of your liver turning lean proteins into sugars. Nutritional ketosis is sort of the other side,
where you’re just looking at raising the available ketones in your body. It’s very, very important
to me that people realize this distinction, that you sort of can have your cake and eat it too. As
long as it’s a low-carb cake.
DOMINIC: Yeah. It really depends on what your goal is. If your goal is to manage seizures, you
probably need to be on a strict ketogenic diet to optimize that. Cancer prevention, periodic
carbohydrate restriction to induce ketosis could be optimal. If you are an athlete – this begs the
question about – and I get this a lot in advanced athletes – sprinters, I don’t think should be on a
ketogenic diet. Maybe a targeted ketogenic diet where you throw in carbs during the actual event
just to maintain muscle glycogen.
But for triathletes, I think adding a little bit of carbs in there, like Ben Greenfield does maybe
100 grams a day or 150, just to keep maybe your muscle glycogen topped off, may be optimal.
You might be able to have your cake and eat it. Because I think he even registers ketones with a
relatively high carb intake. If you’re real active, you can get away with it. You can save your
carbs for your dinner. I did that for awhile. When I’m real active, I basically just go ketogenic all
day, work out, go home and eat dinner, and just have a salad, vegetables, half a sweet potato,
something like that.
ARI: And that’s also another good point. My understanding is that triglycerides are a good
indicator of your carb tolerance, right?
DOMINIC: Yeah. I think they’re a great biomarker.
ARI: Which is really cool. And anything under 100, as I understand, is considered to be pretty
good. If you’re going above 100, then you’re probably having too much carbs. You know Jimmy
Moore, cholesterol clarity guy?
DOMINIC: Yeah. Jimmy’s a great guy.
ARI: Jimmy’s awesome, and I had a really cool interview with him. Of course, we had to start
comparing numbers. What I thought was really funny, I think – yeah, this is what it was. When
we had the interview, which was maybe a month or so ago, I had just had a blood test because I
knew I was going to talk to him, and my triglyceride level was 57. Which is great, and I don’t
think I’m low carb, but 57 is really good. I looked back at my blood results when I was 85%
carb, when I was training for Ironman, and my triglycerides were 74. So apparently, I can handle
quite a bit of carbs and still have ketones floating around.
DOMINIC: Yeah. That’s probably because you were – it also depends on your calorie balance. If
you’re in a high carbohydrate diet, but you’re at even a mild calorie deficit, like 10%, 20% for
that week or something like that, your triglycerides are going to be low, because you’re pulling
them from your system and oxidizing them as fuel. But keep in mind, I think one simple rule is
that carbohydrates spare fats. So if you’re giving your body glucose as an energy source, then it’s
going to say “I don’t want to use the fats because you’re giving me glucose.” They’re going to be
spared in the blood and they’re going to register on your blood triglyceride reading.
My triglycerides I think were really low, like 30s or 40s, when I fasted and then did a strict
ketogenic diet. I think now they run around 50; 40 or 50. They’re still pretty low. Really low.
ARI: Yeah, that’s really cool. Another thing I want to talk about, which may be slightly outside
of your realm of research, but I’m sure you’re going to have a little opinion on it. The other
motivation for me personally for being high fat is that I have found that a high fat diet –
avocados, grass-fed butter, those kind of things have been very anti-inflammatory for me as
someone with Crohn’s disease. But obviously, chronic inflammation is at the heart of so many
illnesses. Am I making that up?
DOMINIC: No, I’m glad you bring that up. It’s not something I talk about much, but I think it’s
extremely important, and I think your case reflects it. The application of the ketogenic diet, or a
low carbohydrate, high fat diet with quality foods like you mentioned will have a powerful anti-
inflammatory effect on the body, which will be reflected in low C-reactive protein levels. Mine
actually doesn’t even register, it’s so low. Whereas previous blood reports showed it was pretty
elevated when I was on more high carb.
I think the benefits of that cannot be overstated, and I think that you’re a walking example of
that. I just see so many people who their muscles don’t ache, their GI problems are resolved,
their brain fog is gone. And I think it’s a combination of controlling your blood glucose, and a
ketogenic diet, high fat diet, tends to control your appetite, too, so you’re less likely to just
overeat, and then you’re less likely to binge and less likely to have these blood glucose
excursions, if you will, that go up into the dangerous zone. Which can kick on a whole host of
You eliminate that process in your body, your blood glucose is stable, your body’s antioxidant
mechanisms are more robust and upregulated from the fuel that you’re giving it, and your
mitochondria are more healthy because you’re forcing your mitochondria to burn fat for energy.
If you’re giving glucose, the mitochondria get sluggish, and our metabolic health really is
reflected upon our mitochondrial health, which is much better if we’re on a fat-based, low carb
ARI: It’s really exciting for me to hear that, because for all the time that I’ve been doing the Less
Doing stuff and wellness has been part of that, I never intended to – and I haven’t – created a
diet, but I’m always recommending that people increase good fats. For a couple reasons, one of
which is I feel like most people in the standard American diet simply don’t get enough good fats.
They’re not eating the olive oil and the avocados, and certainly not the grass-fed butter. Simply
increasing that, to me, is already a benefit. And it’s really great to see that there’s research to
back that up.
DOMINIC: Yeah, absolutely.
ARI: What’s next in your research? What are you excited about?
DOMINIC: A lot of things. Actually, everything. But yeah, I have some really great – my
graduate students, my Ph.D. students are the ones driving the research, so it’s kind of a neat
transition when you go from being a Ph.D. student to a postdoc to doing all your research and
then getting more settled in a lab and getting students to do your research. I have research going
on now and I can just pop into the lab and see blood ketones being measured, looking at tumor
growth in one room. I have all these projects going on.
I think I’m most excited about the cancer work, because it was so unexpected. I got into
ketogenic diets, and I stumbled upon Thomas Seyfried’s work with the calorie-restricted
ketogenic diet. We also had an observation that high levels of oxygen make cancer cells explode,
and we didn’t see this with normal cells, so it was like we have to test this idea of combining the
ketogenic diet with hyperbaric oxygen. And when we did, the results were so dramatic. We
recently got that published.
But now that we’ve developed ketone supplementation, ketone supplements tend to lower blood
glucose. We don’t know exactly how it’s working, but we did a study, it’s under review now,
showing that simple ketone supplementation, even to a standard diet with carbohydrates in it, has
a profound anti-cancer effect and increases survival tremendously in a model of advanced
metastatic cancer. So the cancer stuff is really exciting to me.
Another thing is just developing and testing different ketone supplements that can be used for
pathological conditions, but also applied to athletes to enhance performance. Working with
University of Tampa right now in developing a protocol where we’re looking at advanced
athletes, like advanced bodybuilders, and looking at the effect of the ketogenic diet and ketone
supplementation in the form of MCT, and looking at strength and looking at metabolic
biomarkers and looking at body composition. So this will be a really interesting study, because
nothing like it has been done before.
So I have a combination of things I’m really excited about, both rodent models and in human
models. Just a lot of potential for what we call metabolic therapy, and not too many people are
doing stuff like this. It’s kind of surprising. Well, I guess there’s not a lot of research for
nutrition. That’s why I call it metabolic therapy, because if I write a grant and say I’m going to
study the ketogenic diet or low carb diet, the funding agencies just kind of roll their eyes, like
“Ugh, another diet study. This isn’t novel. This isn’t exciting.” But if I repackage it into
metabolic therapy and innovative ways to elevate ketone metabolic substrate – so I have to use
scientific jargon and terminology to win over the hearts of funding agencies, and it becomes kind
of tricky. Luckily, we’ve had some really generous donations come in to the lab to really help
our research along and been really fortunate to have a few generous people donate to our lab.
ARI: That’s great. It’s got to be exciting, too, to be able to do research that you yourself can live,
actually, as far as the diet. Because if you’re testing a new drug or something, you really can’t
just pop that in your vein and see what happens.
DOMINIC: Yeah. Say we do test a number of different drugs and they work, and then you have
to file an investigational new drug report. It’s literally like millions of dollars to get that thing
into the public hands, and like 10 years. And in our hands, I have the ability to test different
things in our rodent model, and basically we’re finding that forcing your body to shift from one
physiological state to another with nutrition has a powerful neuroprotective effect, anti-seizure
effect. It basically is kicking on a genetic program in your body to confer protection against a
number of different things.
By enhancing your metabolism and persevering your mitochondrial function, it makes the
nuclear genome do its thing better. So DNA repair mechanisms are more robust. Even by
enhancing metabolism, it’s actually preserving the fidelity of your nuclear genome and
preserving the function of your cells. I think that’s a real important thing to understand. There’s a
lot of these targeted approaches, especially for cancer, but if you keep the nucleus of the cell
healthy by keeping the bioenergetic state of the cells very robust and healthy, you’re going to
prevent cancer, you’re going to prevent the early onset of many chronic diseases, and it can be
used as an effective treatment, too.
ARI: Wonderful. We’re out of time now. I just want to ask you the last question that I always ask
everybody on the podcast, which is what are your top three personal productivity tips? What
makes you more effective every day?
DOMINIC: Productivity tips. Sleep I think is a big one. Sleep, actually. I just noticed, I went
through a couple days without getting sleep and it taxed my productivity. Diet. A high fat, low
carb diet decreases my meal frequency, and when I do, I have stable blood glucose. I just have
more energy to do what I need to do, and less food preparation and all that stuff. So sleep, diet,
and just downtime, quality downtime. I do walks with my girlfriend, play with my puppy during
the day. I think I really need that downtime to kind of reboot and get my mind back into work
mode where I can attack work. When I wake up in the morning, I just want to attack work like an
animal. But only if I’m well-nourished and have proper sleep and have good downtime.
Sometimes we lose track of those things when life gets busy, and we need to put things in
ARI: That’s absolutely true. Dom, thank you for those. I think those were three great tips. Thank
you for all that really amazing information. Where can people find out more about you and
follow what you’re doing and what you’re eating?
DOMINIC: (laughs) What I’m eating. You know, I keep a website called ketonutrition.org. It’s
mostly because I get hammered with a lot of emails from patients just wanting more information,
so I’ve compiled a lot of information on that ketonutrition, all one word, .org website. I’ve done
a number of podcasts, so if you look at podcasts – I just did a TED Talk last week, so that’ll be
up pretty soon, probably in about a month or so because they’ve got to edit it. Yeah, I would go
there and just look at our research too. I probably have to edit that website and put more things
up. But I really need to develop a website. I’ve been so busy with research, though, I need to
actually do the research and get more studies done so I have something to show on the website.
But we’re in the process of that.
ARI: We’ll link to that in the show notes.
DOMINIC: Okay, cool.
ARI: Okay, again, Dom, thank you so much, and I hope we get a chance to talk to you again in
DOMINIC: Thanks. My pleasure being here.
ARI: Have a good one.
DOMINIC: Appreciate it. Bye.