Please enjoy this transcript of my interview with Dr. Dominic D’Agostino (@DominicDAgosti2), a tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine and a Visiting Senior Research Scientist at the Institute for Human and Machine Cognition. His research focuses on the development and testing of nutritional strategies and metabolic-based therapies for neurological disorders, cancer, and human performance optimization.
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Tim Ferriss: Dom, happy holidays. Nice to see you.
Dominic D’Agostino: Great to see you, Tim. Thanks for connecting.
Tim Ferriss: So I suggested — definitely — I suggested we hop on the phone because I have been harassing the living hell out of you with so many questions via text message. And I thought, this must be pretty annoying. So rather than answer me once, why don’t we hop on and record a bunch of the details because the details are so fascinating. And for people who are just tuning in who might not know the good doctor, D’Agostino, “Dom” Dominic, we should establish some basics. And I at this point have been quote-unquote in ketosis for 18 days now.
And we’ll dig into a lot of questions around that, tactical practical questions. But before we do, why would someone — and we can talk about what it is and so on, but first let’s just give some of the — let’s call it established benefits ideally in human studies, but could extend to animal models. And then, if there’s anything on the horizon, say in the next few years, because you’re at the cutting edge, if you think there’s anything that might plausibly be established as a benefit, what could that be?
So what would you put on the bullet list of benefits of intermittently or for extended periods of time, being in ketosis?
Dominic D’Agostino: Yeah, there are many benefits to being in ketosis and a ketogenic diet, if we’re going to go there, kind of has the benefits of fasting. And for millennia, we know the benefits of fasting, without the baggage, without the metabolic baggage. The muscle loss, the fatigue, obviously, you can’t live in that level of caloric deficit. But in regards to the practical applications of it, we know that being in a state of ketosis really quiets the mind. And I think that has major implications. And this was from centuries we knew this. And now over the past decades, this has been like a term kind of used.
And it’s backed up by experimental data to show that there’s an elevation of GABA. Obviously, it’s silencing a broad array of seizures independent of the etiology, temporal lobe seizures. Lennox-Gastaut syndrome, Dravet syndrome, rare forms of epilepsy. The ketogenic diet just quiets the brain, lowers glutamate, and elevates GABA, a brain stabilizing, calming neurotransmitter. And that’s why people gravitate towards alcohol, right? The GABA-ergic effects of alcohol and benzodiazepines.
So you can sort of, in a very gentle way, transition your physiology to a state of ketosis, which changes the neuropharmacology of your brain to sort of quiet it down. And that, I think, really echoes its broad application for metabolic psychiatry, which is everything from major depression to bipolar, to schizophrenia, to anxiety disorders, to anorexia nervosa. So that’s a very interesting and rapidly expanding application of ketosis that’s being funded largely by the Baszucki Group.
Tim Ferriss: Yeah. Had David on. And on the physical side, some folks, if they’re old enough, may remember the Atkins diet. Not saying that is what we should hold up as the necessarily the end all be all of any sense, but why would someone go on this for benefits outside of the cognitive psychiatric? Are there any other benefits that you could list off?
Dominic D’Agostino: Yeah, I think first and foremost, it’s weight loss. So it’s very satisfying to go into a state of ketosis because you do see the scale change pretty dramatically, and that’s due in part to some fluid loss associated with a reduction of fluid volume. So it does have a diuretic effect. Ketosis does, ketogenic diets and obviously fasting, and also a natriuretic effect where you dump out some sodium. Your plasma volume, your blood volume will contract a little bit.
So if you have high blood pressure, that will likely go down. So if you’re on blood pressure medication, you have to think about that. But first and foremost, it’s an effective way to get your body to lower the hormone insulin, if you have insulin resistance, and shift your metabolism to burning fats. And as we burn more and more fat, that stimulates the production of ketones, ketogenesis. And ketones have a broad array of applications, metabolic signaling epigenetic that have real world applications.
And that’s why the whole field of exogenous ketones has developed and there’s 160 or more registered clinical trials on exogenous ketones, on clinicaltrials.gov. So yeah. And I could go into each of the applications individually if we want to go there.
Tim Ferriss: Well, as we talked about before recording, and I’ll have to act as a bit of a referee for my audience because I know you can go as deep as we want down the rabbit hole into the 17 dimensions of biochemistry. So if you get possessed by the organic chemistry demons and start speaking in tongues, I’ll reign you in a little bit. However, let me perhaps provide a personal example first for folks because some of this will be familiar to people who’ve listened for a long time, maybe to other episodes of the two of us.
But a lot of it’s going to be new. But I want to establish some priors just so people are aware of what this might look like in practice. So I have experimented with the ketogenic diet, also extended fasting, and you can arrive at some similar places, but like you said, Dom, there can be some pretty heavy taxes to pay with extended fasting. The ketogenic diet, I’ve experimented with all the way back to the ’90s. Some of you weren’t even born probably who are listening, but some of you will remember the ’90s.
And I was using it specifically for mood stabilizing. This was towards the end of college, but also to lean out while building muscle on something called the cyclical ketogenic or ketogenic diet. So we’re going to get to that later in the conversation, but it was effectively, let’s call it six days of focusing on a ketogenic diet with one day or a half to three quarters of a day of glycogen depletion and then, loading with more carbohydrates, lower fat, et cetera.
The reason that the ketogenic diet became doubly interesting to me is that when I had Lyme disease the second time, which came with all sorts of co-infections like babesiosis and so on. And this isn’t chronic fatigue or depression searching for a diagnosis that is external. I feel like sometimes the cottage industry of diagnosing and treating people for quote-unquote Lyme disease can be shady at best. But in this case, I’m coming from Long Island. Everybody in my family has had tickborne disease and was credibly diagnosed.
So the second time I had Lyme, I got to a point — because I did not see the bullseye rash, assumed I did not have it, which is a mistake because sometimes you don’t see the dermatological response and you nonetheless have contracted something like Lyme disease. I ended up weeks later slurring my speech, took me minutes to get out of bed because my joints hurt so much, forgetting friends’ names. And my assistant said, “Tim, you really need to see someone. This isn’t fatigue. I’ve seen you sick. I’ve seen you tired. This is something else.”
And suffice to say, that turned into several months, even post antibiotic treatment, which I do think is important, of we could call it pseudo dementia. I mean, I really felt like I was operating at 10 percent cognitive capacity. And basically at my wit’s end, I said, “Well, what can I control? Because a lot has not done the job.” And I went into strict ketosis. What does that mean? That means that I’m consuming moderate protein, probably getting at least 50 percent of my calories from fat and keeping my carbohydrates to less than 20 grams a day probably at that point.
And within three or four days, I’d probably say around day three or four, because I wasn’t very fat adapted at the time. My body wasn’t well-trained to use fat because I wasn’t doing intermittent fasting, which we’ll come back to. And within three or four days, effectively, all of my cognitive symptoms disappeared. And I stayed in that state through nutritional ketosis for a few weeks, had complete remission of any of the cognitive symptoms plus the joint pain symptoms, and those never came back.
And I recommended that, and this is not a randomized controlled trial, but over the years, as due to various factors, we’ve had ticks growing in population, also expanding to the coasts and on the West Coast that is, and elsewhere, had three friends replicate this with ketosis after suffering various symptoms from tickborne disease. And we were texting, maybe even talking about this, but I never had a great explanation for why it worked.
I said, “I don’t know the exact mechanism. Maybe I have faulty glucose metabolism that was somehow — maybe something was impaired by the ticks and therefore I’m giving my brain this alternate fuel that it really likes ketones,” but it didn’t explain, necessarily, the durability of the changes. In brief, do you have a theory or an explanation for why that would work?
Dominic D’Agostino: Yeah. I’m glad you brought that up because quickly dozens, if not hundreds of people with tickborne diseases, including Lyme disease and all the tickborne diseases have communicated with me. And one of the patients is actually Deanna Tedone, who was diagnosed with ALS prior to 2010, and has basically been stabilized given three years to live. So I realized that it’s underdiagnosed, the tests to do that are kind of controversial with the CDC testing, the two-tiered testing, and IGeneX.
So I know I’m going off track a little bit here, but yes, I think it’s important to say that the spirochete, Borrelia, that spirochete is essentially 100 percent glycolytic. And when you limit glucose availability and glycolysis, you are targeting the energy systems of that microbe. So that’s one thing to think about. And it’s well established now. It wasn’t three years ago, but a ketogenic diet in particular, beta-hydroxybutyrate elevated in the blood, stimulates the adaptive immune response.
And that’s essentially your body’s ability to target foreign invaders and neutralize them. And that has become a rapidly growing area of interest. University of Pennsylvania, just — they’re doing CAR-T therapy and checkpoint inhibitors because of the ketogenic enhancement of the adaptive immune response. So I think that plays a role. And situationally, I have observed that you go into ketosis if you have an inflammatory process and Lyme disease is inflammatory.
But people who have shingles and herpes simplex and things like that, I have an inbox full of people that do that. And I would like to experimentally go down that direction to understand why. But I think there’s two reasons you’re targeting the energy systems and you’re augmenting the immune response to keep the spirochete in a dormant stage or maybe eradicating it in some context.
PREROLL?
Tim Ferriss: It’s really incredible on a whole lot of levels. And I’m just lucky that I had the prior experience with the ketogenic diet to even have it occur to me as a last ditch effort. And for people just to — if it wasn’t clear, I mean, you explained it clearly, but glycolytic, I’m simplifying here, but it means that something needs to eat sugar or metabolize carbohydrates to survive, right? And there are also, Dom, correct me if I’m wrong, but particular cancers that are very sensitive to being starved of glucose as well.
And for people who want more on sort of fasting ketosis as it relates to cancer, we may come back to it also, but we’ve had prior conversations about this and the benefits, some of the incredible effects of fasting prior to cancer treatments of various types.
PREROLL
So is it fair to say, do you think most of the benefits that someone would derive from fasting prior to cancer treatments, they could also get from ketosis or is it dialed back to a smaller percentage of effect?
Dominic D’Agostino: Yeah, that’s a good question. I think it requires a nuanced answer that we probably don’t have time for. But if you are overweight and your BMI, for example, is like — as many cancer patients tend to be like 28, 30, 32, a fasting or a calorically restricted ketogenic diet is the way to go. If a patient is trending towards being lighter, like a BMI, 20, 22, something like that, a eucaloric, meaning like keeping stable caloric level to maintain your weight is going to be important.
And then elevating beta-hydroxybutyrate will be important to get some of the anti-inflammatory effects and also the immune boosting effects and the neuroprotective effects going into cancer therapy because there’s people studying ketosis for chemo brain, like reversing chemo brain and like managing that. So it has a broad array of applications, not just targeting — it’s targeting the tumor growth and putting a break on it.
It’s not a cure for cancer, and I cringe when people talk about that like online, the ketogenic diet curing cancer, it does slow it down, especially if it’s highly glycolytic, which 80 percent of cancers are. And it enhances and augments the response to the standard of care that’s radiation, chemo and immune-based therapies. So we know that now.
Tim Ferriss: All right. Why have I been in ketosis for 18 days and why am I doing it a few times a year? Well, part of how I implement this does hinge and will continue to hinge on some of the answers in this conversation, because this is very self-interested. But what I have found is that for mood stabilization, and you mentioned metabolic psychiatry, and you made the introduction, I believe, Chris Palmer out of Harvard on the podcast to discuss this.
But there’s certain conditions, whether it’s depression, but even more squirrelly when you’re dealing with something like schizophrenia, for instance, or different types of bipolar, people who’ve been on dozens of medications who go into, let’s call it remission, or they no longer meet the criteria for the diagnosis of some of these things after being treated on a ketogenic diet, of one type or another.
It is astonishing. And so for my own mental health, I’ve noticed complete stabilization and without subduing the highs, right? I’ve never had mania necessarily, I’m not talking about that, but I’m not muted. I feel just calm, stable, sharp and that’s one reason in and of itself to do it for periods of time, but I seem to feel a carryover effect, also have Alzheimer’s and other neurodegenerative diseases in my family.
I have three relatives with rapidly advancing Alzheimer’s at the moment. So maybe we could talk also to how these things might intersect. But my feeling is possibly, and I’d love your input here, if I follow a ketogenic diet for a number of weeks or maybe a month and a half or something like that, I’d love to know the timing you might recommend. Let’s say I do that two or three times a year, that there could be enduring effects that have sort of a protective carryover, right?
And I also find it much easier now that I started doing intermittent — I’ve been in intermittent fasting pretty much every day for the last six months, which means I’m eating between typically 2:00 p.m. and like 8:00 or 9:00 p.m. and having two meals a day, that’s it. Not hungry at all. I haven’t eaten today, it’s 12:30 my time, I will not be hungry for another two, two and a half hours. That by itself completely revolutionized. I mean, that’s an overused word, but completely polished my insulin sensitivity and metabolic health on a bunch of levels.
My labs have never been better. My oral glucose tolerance test has never been better. And one question I have for you, which is just for Timmy, Tim, Tim, but will apply to other people is, is there an argument to be made, and maybe I’m totally off base, but that if you follow a ketogenic diet and make it work for a multi-week period of time, that you’re changing your metabolic machinery or just your body in some way that has carryover effects, even after you stop the diet, or is that me just doing some hand wavy fancy footwork as a muggle? I don’t know if there’s a there, there, but what are your thoughts?
Dominic D’Agostino: Yeah, I would say absolutely. I think the science is still working to clarify that and make it less ambiguous, the benefits that we are deriving from that. But that is kind of like one of the pitches for the fasting mimicking diet by Dr. Valter Longo, who was one of our keynote speakers at Metabolic Health Summit, and he’s presented some really compelling research on that, that opened my eyes to that five days of fasting can have — I think he presented a time, even three months of effects on sort of cardiometabolic biomarkers.
Tim Ferriss: And in his case, this would be the fast mimicking diet, so a few hundred calories a diet, of — yeah.
Dominic D’Agostino: Yeah, like 600, using his protocol of various foods, kind of gravitating towards more of a plant-based lower protein strategy. And I think that it’s promoting metabolic flexibility and ramping up fatty acid oxidation enzymes. And much like muscle memory, I think there’s a metabolic memory. So the more you stay in ketosis, the easier it gets and the more benefits you derive from it and the more that you shift your body to being more fat adapted, just like you can build your VO2.
When you build your VO2 max or you build up to like a 400-pound bench press and you take like months off and you go back and you can only do like 225 for a couple reps, it only takes like two or three months to get back, but it took you 10 years to get there. That muscle memory snaps back quick and everybody agrees that there’s this metabolic memory and I think there’s a lot of things at play, including gene programs, epigenetic regulation that comes to play.
So first and foremost is changing our mitochondrial function and mitochondrial capacity. So the number of mitochondria increase, and then when you take a break and then stimulate, get that stimulation again, that mitochondria is kind of there and it responds very rapidly.
Tim Ferriss: Yeah, thank you for that. And I mean, I want a bookmark, maybe we come back to this, but if people are trying to think about this, understanding that the science right now is maybe provisional or there’s a little bit, hypothesis worth disproving at this point, but that it seems to make sense from an evolutionary perspective that both muscle memory and metabolic memory would be a thing. Otherwise, it makes sense your body would want to adapt to be prepared for the next famine or whatever it might be, right? If there is a —
Dominic D’Agostino: I just want to say muscle memory is metabolic memory. So someone — I gave the analogy of like lifting weights, but someone who runs marathons, it’s the same scenario. They take time off and then that VO2 max quickly establishes again and it’s muscle, but it’s metabolic. So I like to use the term metabolic memory.
Tim Ferriss: Metabolic memory. Okay. Yeah, metabolic memory. So just so people know where I am at the moment and actually, yeah, I’ll just tell people what I’m doing because I know they’re probably getting itchy for some just like, what does this look like in practice? And then, I want to talk a bit about how ketosis or the ketogenic diet may or may not be helpful for maybe not treating, maybe treating. I’ve certainly seen some interesting effects in some of my relatives when I give them exogenous ketones where suddenly their sentences are three or four times longer, 30 minutes later, which is wild to see.
But in terms of prevention or staving off the onset of some of these diseases, I’d love to hear your perspective. But let me tell people what I’ve been doing for the last few months, and especially in the last 18 days. So for the last whatever it is, I think I mentioned six months, I’ve been doing intermittent fasting. And that was after hearing a conversation between Dr. Rhonda Patrick, who I’m a big fan of, and Mark Mattson, M-A-T-T-S-O-N, who’s done a lot of research related to intermittent fasting.
And the key piece for me, because you see all of these different types of intermittent fasting, all of these different ways to do time restricted feeding, and I am going to paraphrase here. So Mark, I apologize if I’m getting this wrong or oversimplifying, but in effect, it’s important that you fast, this means no calories, or we could talk about pure fat, but let’s just assume you’re not consuming any calories for 16 hours because you want to deplete your liver of glycogen. And once you deplete your liver of glycogen, your body experiences this metabolic switching.
And I’ve certainly felt this just doing intermittent fasting where my meals contain carbohydrates later, that around the end of that fasting period, boom, something switches and my mind is sharper, right? And then when I got to the point of going into the ketogenic diet this time and also a few months ago, because I was doing the intermittent fasting, and it took me about a week and a half for my body to get comfortable with that, at which point it was no problem.
But I was a little pissy, a little irritable for a little while, a little foggy. And then when I went into the ketogenic diet this time, it was the easiest transition I’ve ever had. I did not have any fogginess, I did not have low energy, I did not have what some people might call the kind of keto flu adaptive period, which seems to be pretty remediated or addressed with electrolytes for a lot of people, but it was incredibly easy.
Just straight into the ketogenic diet with no problem because I was already doing the intermittent fasting.
And then for 18 days, I’ve been having two meals a day and you’ve recommended a few that sound frankly pretty disgusting, but that are actually really easy, like two cans of canned mackerel with about two tablespoons, 30 milliliters of MCT oil plus apple cider vinegar with some salt and pepper. It’s actually delicious. I just love mackerel.
There it is. Yeah, you’ve got your apple cider vinegar right there.
Dominic D’Agostino: Cheap stuff you can get on Amazon. Yeah.
Tim Ferriss: Yeah. For people who might think, “Oh, wow, this is what for fancy people who can do all sorts of expensive things in their diet,” we’re talking about like, how much does that meal cost, three bucks?
Dominic D’Agostino: Yeah, a dollar a can for that Chicken of the Sea. And literally you get almost a pound of mackerel, and this is like third-party tested very low chub mackerel, the little mackerel, less —
Tim Ferriss: Yeah.
Dominic D’Agostino: So yeah, you got like a $1.50 for almost a pound of mackerel that you can get that for. And the omega-3s are off the charts, the heavy metals are low. I consume pounds of this stuff and I’ve gotten my blood and my hair heavy metals tested and it’s like super low, like non-detected. So I wouldn’t worry about that. People have questions about cost and heavy metals and that’s a non-issue for me.
Tim Ferriss: Yeah. And maybe you could mention, I’ll put links in the show notes as well, but since we’re on the topic, any brands that you default to, that you like. And that chub mackerel piece for folks, that detail is important because they’re a mackerel of many different sizes.
Dominic D’Agostino: Yeah. King mackerel is kind of high. This is Chicken of the Sea. So if you want to do the budget, you buy the case, the more you buy and then Amazon subscription and then, it goes on sale. You can actually get it for like less than a dollar a can. And I do the same with Chicken of the Sea jack mackerel or yeah, just chub mackerel or jack mackerel. So they’re both small fish. And I kind of like the King Oscar brand too.
Tim Ferriss: Yeah.
Dominic D’Agostino: That’s a little bit more pricey and Seasons brand is pretty good too, but I mean, it’s like as cheap as dog food. I mean, we buy some pretty fancy like freeze dry, we don’t buy the kibble stuff, but when you run the numbers and we buy —
Tim Ferriss: It’s very inexpensive.
Dominic D’Agostino: Cases of eggs for like 120 per — if you do like eggs, fish, beef and also turkey, you can get turkeys for under a dollar a pound, the whole turkey.
Tim Ferriss: Yeah, and just for people who are like, “Oh, my God, I can’t believe you guys are eating mackerel mixed with oil and vinegar in a dog bowl.” That’s not all you can eat. There’s more that you can eat. You can have, like, chicken with cheese on it. You can have vegetables. There are certain things you have to watch out for, so you’re not whacking yourself out of ketosis. But in my particular case, I don’t mind — and the fact of the matter is when I wrote The 4-Hour Body, people were like, “Oh, my God, you want us to repeat the same meals over and over again?”
I’m like, “What did you have for breakfast the last five days?” And they ate the same thing. You’re just swapping out to fall meals. So my first meal is something typically pretty small, like the macro I explained, and then I have a big meal. I might have some more protein in between, but it’s like yesterday I had lamb chops that were delicious with some vegetables made in an air fryer, no problem. And later on, I might have a rib eye on a big — chopped up on a big gigantic salad with some other stuff added to it.
But that’s about it. You have to be careful with the macadamia nuts. Those things will creep up on you. But that is in effect the diet, right? And I’m doing my training, I’m doing my rehab, I’m doing my zone two. I do find them a little, let’s say lower performance when I’m in ketosis, but what I wanted to talk about is maybe a false negative that I’ve experienced and I’ll explain what that is. So how do you know if you’re — and I keep putting this in quotation marks like quote unquote in ketosis, right?
Because most people are, or maybe all people are producing some level of ketones. So there are different concentrations that you can measure with a finger prick just like you would look at glucose. And at least with the finger prick, I think that’s measuring what you mentioned earlier as being so beneficial in a lot of studies, the beta-hydroxybutyrate, BHB. I also have — because I wanted to run this tracking, a G7 Dexcom continuous glucose monitor on one arm and then a SiBio.
Apologies if I’m not pronouncing that correctly, continuous ketone monitor on the other arm, and I’m wearing an Oura ring when I sleep to see how all of this affects my sleep architecture and everything else.
So I’m gathering all of this, but then I noticed something really weird, which I’ve texted you about because I keep feeling like I’m failing at keto. I feel great. I feel sharp. And yet when I look at not just the continuous glucose monitor, but even with the finger prick, because you do have to often calibrate these things, right? Don’t assume that your continuous monitors are accurate. You want to calibrate them.
But I’m looking at the numbers. And for instance, my girlfriend freaked out the other night because my phone started screaming. I had earplugs in because I didn’t hear it. And it was critical medical alert or whatever the code red was because my glucose was 69, I suppose.
It’s gotten quite a bit lower on ketosis, but usually hovers somewhere between 65 and 80. And my ketones were 0.2 millimolars. Now, when we’ve talked in prior conversations about what kind of target you might aim for, it seems like between 1.2 and two millimolars is anxiolytic, lowers anxiety and then you’re looking for this ratio.
You could talk about this, but the GKI, there’s a ratio of glucose to ketones. And I look at those numbers and I’m like, “This makes no sense to me because I’m not getting enough glucose to function well.
And if I’m basing it off of the Keto-Mojo finger prick, even the Precision Xtra from Abbott or my continuous ketone monitor, I’m not getting any ketones either if you’re taking it at face value. So how am I functioning?
How would you answer that? Because I don’t think I’d be the only person who feels like they’re doing something wrong if they run into this, but how would you interpret this?
Dominic D’Agostino: Yeah, I would definitely say you’re running lean. And I think what you’ve done in your OGTT test is really good. I think you had messaged that.
Tim Ferriss: Yeah, and the OGTT for folks is just that oral glucose tolerance test where you drink a bunch of dextrose water and then they take your blood every 30 minutes for two hours to see how you’re responding to it.
Dominic D’Agostino: Yeah. The biggest metabolic lever would be you have enhanced insulin sensitivity. And I think that has been the focus. For example, Ben Bikman wrote a book on this and doing hundreds of podcasts on insulin resistance, reversing insulin resistance and low carb ketogenic being effective for that.
So that, first and foremost, your insulin sensitivity is very high. Your fat oxidation is really high and your glucose disposal is high. And if you’re in a caloric deficit, your ketone uptake is very high. We see this quite convincingly.
In older rats where we gavage, where we tube feed the rats and they’re older, the ketones get to toxic levels. Whereas a younger metabolically fit rodent will dispose of it very quickly. Same with a couch potato human, same with an elite level athlete. So you have very rapid —
So when you measure ketones in the blood, that’s a function of ketone production and ketone utilization. And you could have two to five times higher ketone utilization with high metabolic fitness. And that’s due in part to ketolytic enzymes, you up-regulate the MCT transporters, that could be two, or in rodents, two or three times higher.
I haven’t done that personally and we have some data in humans we haven’t published yet, but that is a real thing and I think that you’re experiencing. Also, if you’re in a caloric deficit, there’s less spillover.
I just bought an antique motorcycle and it’s got a carburetor and the float sticks a little bit and it always drips out the carburetor when I’m running it. And when I stop and it’s pouring out the carburetor. So there’s spillover of fuel, right? But when I’m running it’s running lean because I’m using the fuel that’s going to the carburetor.
And the same analogy here is that if, for example, it might be good to just sit in one spot and relax and maybe eat a little bit of surplus calories or even eat a little bit of carbs. And what you’ll see often is your ketones spike up.
So I remember some of my highest ketone levels ever is when I consumed carbohydrates after I was fasting or in a state of ketone. It jumped up to five, six, seven, and I was like, “What is going on here?” But the glucose in that context is ketone sparing, but the glucose will also shut off ketogenesis so it’ll tank afterwards.
Tim Ferriss: Yeah, afterwards. Yeah, okay. So it sounds like then because of probably the intermittent fasting in large part, I would think, if my insulin sensitivity is high enough, that can be paired with higher ketone utilization.
So if on the assembly line of my body, right, they’re producing 10 units of ketones. If I didn’t have good ketone utilization and it was my first rodeo with ketosis, let’s just say, or a ketogenic diet, the finger prick might pick up all 10 of those units.
I’m simplifying here, right? But if I have high ketone utilization and my body’s quickly using eight of those, especially in a caloric deficit, then it’s only measuring two and I’m getting the false negative that I’m not actually producing ketones in the first place.
Is that a fair, very, very simplified description?
Dominic D’Agostino: Yeah. And you’re not measuring tissue levels of ketones, which we have done too, even in the brain, and that can shoot up really high.
So that’s also, and I’ve done this with Peter Attia too, we were measuring blood and then breath, and it seems like when we were in a caloric deficit fasting, our ketones were really low in the blood.
Low is one to two, but we were really deep into fasting, whereas our breath ketones were maxing out the meters. So the breath ketones in this — we concluded that after a lot of testing that the breath ketones were almost a better indicator of ketosis, a more accurate, I guess you could say, in a caloric deficit.
Because when you’re in a caloric deficit, you just have very high ketone disposal uptake into the tissues.
Tim Ferriss: It looks like a breathalyzer, right? So is that measuring, what is it, acetoacetate? No, I’m just trying to repeat words that I’ve heard once or twice, but it’s not BHB.
Dominic D’Agostino: Acetone.
Tim Ferriss: Acetone. God dammit. All right. I know I was close. It was a 50/50.
Dominic D’Agostino: It comes from the spontaneous decarboxylation of acetoacetate. We’ll spit out about 20 percent of the acetoacetate will kick off to acetone and then you can measure it.
Tim Ferriss: I got it.
Dominic D’Agostino: We’ve measured blood levels of each, and it’s very tricky to do that, but we’ve done it in the lab.
Tim Ferriss: All right. Here’s another practical, tactical question for you because I’ve gone back and forth on this and Uncle ChatGPT has confused the shit out of me so maybe you can help resolve it. Gluconeogenesis and protein intake, right? So you consume, what is it, between 240 grams of protein a day, something like that? Is that roughly?
Dominic D’Agostino: Yeah, on active days. On less active days, if I’m just behind my computer all day, maybe closer to 180, 200, but yeah.
Tim Ferriss: And people might have picked up when Dom was casually throwing around like, “When you’ve been squatting 400 and you take a break and then you go back and you only can squat 300 pounds.” Dom’s a pretty big guy who’s also deadlifted 500 pounds for 10 reps before, after fasting for a week.
So he and I are not the same size, but nonetheless, I’m trying to figure out on one hand how much protein I can eat without my liver taking excess protein amino acids and turning it into glucose, right?
And depending on what I look at, and I have looked at sources outside of ChatGPT, on one hand, there are folks who say, “Don’t worry about it. If you’re consuming enough fat, you really don’t have to worry about it.”
And then there are other folks who are like, “Watch out, watch out. If you consume more than X number of grams at a given meal, you can very easily knock yourself out of ketosis,” which would, if that’s true, be maybe an alternate explanation for why I’m getting these low readings, if I’m having a small meal around 3:00 and then a gigantic meal later on.
How should I and how should listeners think about this?
Dominic D’Agostino: Yeah. So if you were to consume protein in the form of liquid, for example, like whey or something like that, then the rapid entry of amino acids into your bloodstream from your small intestine will shut off ketosis.
So fat and fiber and salt, because your pyloric sphincter will basically be pretty tight until your —
Tim Ferriss: Talking dirty, Dom.
Dominic D’Agostino: Pyloric sphincter is where your stomach connects to your small intestine, if you have a very fatty, salty, high fiber meal, that entryway, we call that the sphincter, it’s the pyloric sphincter, will remain shut until the contents of your stomach become isotonic.
Which means that your body has to give up water and it’s got to churn it and break it down. So you could delay gastric absorption simply with fat, fiber, and salt is pretty good too. You could do ketone salts or just salt electrolytes.
So that will delay the entry of amino acids or protein into the small intestine and thus amino acids into the bloodstream. And that’s the major regulator of ketosis having an impact on insulin and also having impact on gluconeogenesis to that rate of entry. And if you can slow that down, you see nothing on the CGM and your ketosis levels can basically stay.
You could further augment that by using MCT oil with the protein and the fiber. And so if you have long chain fats from a fatty steak and MCT oil and then fiber. And that could be insoluble fiber is pretty good to soluble and insoluble, that can slow the entry of amino acids and essentially buffer the gluconeogenic response.
Tim Ferriss: So let’s say I was stuck in San Francisco late. I’m just taking a rare trip over here, which is a pretty exciting time to be here with all of the mania with AI going on. But I mean, everyone’s kind of drunk on the Kool-Aid, but that’s a separate story.
I got trapped downtown because didn’t want to deal with traffic and blah, blah, blah, blah, blah. So I ended up having a huge bunless double cheeseburger. Gigantic, this thing, I did not expect it to be as big as it was, right?
And so I go online to try to figure out what the protein content of this thing might be. And it’s 80 grams of protein, right? But plenty of fat, certainly. Tons of fat, salty AF, plenty of salt, right? Not a lot of fiber, we’ll give that one a pass. Should I be worried about something like that knocking me out of ketosis?
Dominic D’Agostino: I think you need to measure. So I’m default back to everybody’s a unique metabolic entity, but if you eat that and your activity level is high and you’re in a bit of a caloric deficit and you were to have that and not overdo it on the total calories.
I know my body. I know my body, I could stay in ketosis, but if you have that oversatiated feeling — so we have neurons, we have neuronal pathways to and from the liver and to and from the gut. We call that afferent and efferent signaling in the enteric nervous system.
And a big meal will basically tell your brain that you had a big meal. And independent, I talked about the amino acids going into the bloodstream kicking you out of ketosis. But there’s also this, when you have stretch receptors and you have the big full meal in your gut, then that could actually tell your brain to activate the sympathetic nervous system.
And then that, by virtue of spilling out catecholamines can basically, we’re talking adrenaline, epinephrine, things like that, that can further augment and enhance gluconeogenesis.
Tim Ferriss: Okay. Let me just translate that for a second. So people wake up. Cortisol has developed this bad reputation among a lot of online influencers, but you really need cortisol, right? So when you wake up in the morning and you see a bit of a glucose spike, it’s actually important to get your ass up and moving.
If you’re in ketosis, it’s a different thing, right? So if I’m hearing you correctly, outside of how people think about digestion, blood sugar, insulin, et cetera, that just based on stretching your stomach, et cetera, with these mechanoreceptors, taking the inputs, that that signals to the brain, it’s go time.
So let’s basically get things moving with these hormones and that could in and of itself then trigger the liver to produce more glucose or liberate more glycogen, I guess.
Dominic D’Agostino: Yeah. It can. It’s above and beyond what you normally eat. If you train your body to that size meal, but it also activates other gut hormones like cholecystokinin, that’s called CCK, and other things that can then activate the parasympathetic nervous system that comes in a little bit after.
At the same time, it bifurcates, but then the parasympathetic nervous system is relax, digest, rest and relax, digest. So that comes in after. So you might see a blip and make you feel stimulated.
Also, all the salt, if it’s a salty meal, it’s going to expand your plasma volume. Your blood volume will increase and that can increase your blood pressure a little bit and that can activate your sympathetic nervous system.
So it’s always good to go take a walk after a big meal.
Tim Ferriss: Yeah. I do that.
Dominic D’Agostino: Not like a strenuous — not like go squat and deadlift, but just yeah. Even a 10, 15, ideally a 20-minute brisk walk is really good after a big meal.
Tim Ferriss: Yep. Now let me ask you this on the walk timing. So when I have a big meal, and I will say, I think I have trained my body to have big meals. What the exact response is, I can only give you subjectively what I feel and I can give you what the monitors show, right? But I typically feel pretty good.
However, if I have a big meal, whether this is in ketosis or otherwise, I don’t see the biggest spike until something like, depends on the meal, right? But 60 to 90 minutes later, that’s when I see the spike. So should I do the walk at 60 to 90 minutes, or should I do the walk right after the meal? When should I actually time the walk?
Dominic D’Agostino: So you eat a meal, you go walk, and then you see the rise 60 to 90 minutes after, or is that independent of the walk?
Tim Ferriss: Independent of the walk. Yeah.
Dominic D’Agostino: Okay. So you’re not walking, but you see the rise 60 to 90 minutes later. So I’m saying that you might not see that rise 60 or 90 minutes later because —
Tim Ferriss: If you did it right after the meal?
Dominic D’Agostino: Yeah, just because a little bit goes a long way. So just like walking, actually doing some stretching and walking too, it activates the glucose four, the GLUT4 transporters. So that’s an insulin independent. So less insulin is dumped, greater glucose uptake.
And you’re also using the sympathetic nervous system mobilization of glucose through gluconeogenesis during that walk. So it then attenuates the buffering of ketogenesis, and a very short walk can go a long way.
Tim Ferriss: Yeah. Okay, cool. Is it GLUT4? GLUT4? How do you pronounce that? I don’t know. How do people say that?
Dominic D’Agostino: I say GLUT. I say GLUT4.
Tim Ferriss: Okay. All right, GLUT4.
Dominic D’Agostino: People say GLUT. Yeah, yeah.
Tim Ferriss: Yeah. For the OGs in the audience, go back and look for GLUT4 in The 4-Hour Body. It’s in there.
So the other measurement question I want to ask you about, which is these continuous glucose and ketone monitors are not designed for someone like me, right? They’re developed presumably, I don’t know about the keto monitor, but in the case of glucose to help people with serious conditions not end up in very serious situations, right?
So when I am looking at my ketone levels, like right now I feel very sharp. I had some KetoStart, you know this well. Exogenous ketone salt-based product not too long ago, just in hot water with a little bit of MCT oil. This was, I guess, an hour, hour and a half ago, but I’m at 0.4 millimolars.
And I guess what I’m saying is whether I have a huge meal or I’m fasting as I am right now, my range is basically 0.1 to 0.4 95 percent of the time. There are a few outlier cases. If I’m just doing a YOLO, as many grams as possible exogenous ketone party, then maybe I can goose it, but we can talk about this.
Once it gets past a certain point, then I might spike insulin and have a subsequent crash. But I guess what I’m trying to say in brief is my range for the most part is 0.1 to 0.4, regardless of whether I’m fasting or eating a gigantic double cheeseburger. So I’m not really sure how to determine what effect it’s having.
I can watch the glucose, but right now I’m 0.4 millimolars of concentration on the SciBio. And as we’ve talked about, maybe the Precision Xtra would give me an extra 0.1 or 0.2, but they’ve been pretty close so far.
And then ever since my cheat meal, we had this experiment, right? I wanted to see if I did a workout and then had one or two cheat meals last Saturday. It is now Thursday, but my glucose right now is 103, right, which is higher than the week prior, but it goes around. It moves around, right? Last night it was probably 70 something.
Do you have any suggestions for how to read the tea leaves or is it mostly just subjective feel? I mean, still thinking about the size of the meal, right? But I guess what I’m saying is, if my device is telling me as it is right now, 0.4, fat not burning. You’re almost not burning fat at the moment, not in ketone. It’s very chastising.
So if I’m to believe this by the letter of the law on the screen, I’m failing at ketosis, right? Any thoughts on how to read the tea leaves here?
Dominic D’Agostino: Well, I would ignore that. I think that’s an app in the process of being developed, the fat —
Tim Ferriss: Yeah.
Dominic D’Agostino: You would need whole body metabolomics to really answer that question if you’re in fat burning or do metabolic cart and look at respiratory quotient or whatever. But subjectively, if you feel good —
We have seen an athlete, especially more advanced athletes that, and we do a very strict, strict keto macros and everything that basically with a bunch of athletes with 0.8 is about as high as we get, and that’s the average across.
Sometimes you get guys 2.5, 2.6 every day. And the same guy with the same essentially metabolic phenotype will be running 0.4 or 0.3. He could potentially just have greater ketone utilization. So I think it would be important to measure your blood. So a continuous ketone monitor measures interstitial — that can be different. The SciBio, I think it’s a great device. It’s very versatile. I can jump in and out of salt water. The thing stays on me. It’s almost more reliable than a CGM. But I did notice, and I’ve probably used about 50 of these devices that the first week, is pretty accurate and then it tapers off, the sensitivity.
And this is a known limitation of the technology is that essentially the enzyme-based sensor system tends to just — and you could get around that conceivably just by having the ability in the app to calibrate it.
So if you were to measure it and the continuous ketone monitor is measuring 1.0, but your blood ketones is 2.0 that you should be able to calibrate it like you can with a Dexcom. So they acknowledged that at the company and they said, “Yes, we realize that that would fix the problem,” but that’s not a feature of the app yet.
Tim Ferriss: They do have in events, they have blood ketone on the bottom right. I just don’t know if it actually calibrates it. It may just record the blood ketone at this point.
Dominic D’Agostino: It does not have the ability to calibrate it to my knowledge.
Tim Ferriss: I inputted one measurement on the Keto-Mojo and it didn’t seem to change it, right? The number stayed the same. So I think it’s just logging it because you can do that with a glucometer.
Dominic D’Agostino: Well, you can do it with Dexcom, but not Abbott.
Tim Ferriss: Dexcom. Okay.
Dominic D’Agostino: That’s a problem with the Abbott FreeStyle too. And that’s the feedback I gave them because I put these devices on, it’s reading me 130, but I measure I’m like 80, literally 50. Because —
Tim Ferriss: Wow.
Dominic D’Agostino: — if you are lean and it’s stuck in your muscle instead of your adipose tissue, the glucose levels are going to be higher, especially when —
Tim Ferriss: Wow.
Dominic D’Agostino: — you work out and stuff. So I’ve noticed this and that’s for me, so that’s why the Dexcom is very nice because I can calibrate it too, and I consistently show that. And that was a major issue I had.
Tim Ferriss: Let me hop in also and just tell folks this is not going to be very quantifiable, but for what it’s worth. Part of my reason I avoided intermittent fasting for so long is that I thought I would not be able to get sufficient protein or caloric intake and that I would lose a bunch of muscle mass.
I was dead wrong about that. I was very, very wrong. If anything, it seems to have enhanced my ability to put on muscle per calorie or per gram of protein ingested. And so I admit I was totally wrong about that.
Furthermore, on this ketogenic diet where I’ve historically found it pretty hard to put on muscle or — I mean, I shouldn’t say keep muscle because I’m only doing it for a few weeks, but I have been astonished by having one small meal. I’ll have some oxtail soup after this with some veggies and obviously oxtail. It’s a whole separate story.
And then I’ll go out and have another meal probably in three or four hours, which will be a much bigger meal. And just with that, and I am watching some of the grams of protein intake and so on, but I have not, looking in the mirror and looking at the weights that I’m putting up in the gym, I don’t feel like I have lost any muscle and I feel like I have leaned out.
Some of that’s losing fluid, but I’ve been really impressed with how little relative to what I used to do in college, taking weight gainers and just all this garbage, how little it actually takes to at least maintain muscle mass.
But I do have a question for you, which I’ve never really been able to answer to my satisfaction, and it relates to rabbit starvation. So for people who don’t know what that is, you could probably give a better description, but if you’ve ever watched the show Alone, Alone is probably the only reality TV show that I love to watch.
seasons six and seven in particular are outstanding for folks. But what you’ll notice is that if people are trying to survive in the wilderness to outlast everyone else, that’s what the show is. You get to pick a handful of items, you get dropped off, you don’t get to choose where you’re dropped, and then you just need to survive for as long as possible.
Sometimes it’s 100 days, sometimes it’s last man or woman standing. If somebody is only eating lean protein like rabbits, they will waste away. They will not last. They will have to get yanked out for medical reasons, and that might seem strange to people.
My question though is on a ketogenic diet specifically, can you just consume leaner protein and then rely on body fat for the fat? And some people are like, “Yeah, everybody knows that doesn’t work.” But I really want to understand why that’s the case, right?
Because I understand dietary fat dampens insulin response, right? Or at least that’s my understanding. Maybe there’s a rate limiting step in how much body fat you can break down and use, right? And who knows if that’s mediated by the kidneys or who the hell, liver, I don’t know, right?
I guess it would probably be liver, but I’d love to hear your take on it, right? Because certainly in the past, I and lots of people reading The 4-Hour Body have been able to lose more body fat than they are told they are capable of losing, as measured through DEXA scans and other things.
Can you do a moderate fat or low fat protein-based keto diet if your goal in part is to lose body fat, or does that backfire?
Dominic D’Agostino: Yeah, just not indefinitely. So when I did the ketogenic diet for a year, I was cruising at about 300 to 320 grams of fat, sometimes 350 grams of fat per day. And then just experimenting, I would throw in a two days per week of protein veggies with about 50 to 100 grams of fat.
And in those days of dropping to 300 plus grams of fat to 50 to 100 grams of fat, after two days, I swore I lost two percent body fat and I would just transition back. So I would just periodically throw in protein veggie days. I would cruise on keto and then periodically titrate in the protein veggie days to assist body composition alterations.
So if I kept that going, I could get pretty dramatic, almost scary lean to where it happened very fast. It’s almost keto trains your fat metabolism and then if you just start titrating in, it’s just pulling fat out.
And I think my body really liked throwing in the veggies with the fiber seemed to help with the gut health and I would do that twice a week and it’s pretty dramatic.
Tim Ferriss: Why not do it seven days a week? What happens when you try to do it for more?
Dominic D’Agostino: If the idea is to stay in ketosis, it was really hard for me to stay in ketosis if I do protein veggies. After two days, I would be out, but my metabolism would be cranking.
Tim Ferriss: Mechanistically, why is that the case? Why doesn’t your body just break down more body fat?
Dominic D’Agostino: Yeah, because, well, it’s taking body fat exogenously and endogenously and I think the more fat going to the liver and the more fat that’s in circulation, it gets shuttled to the liver and then that’s stimulating beta oxidation in the liver. You just have a greater fat pool.
But actually, I think, the day that I would do protein veggie days and then the day I would jump back into ketosis, I would see this big ramp up in ketones that day. Whereas if I did like a cheat day and just ate a lot of carbohydrates, it took me two or three days to get back into ketosis.
But if I just did like protein and veggies and cruised back into ketosis, then I would rapidly get back into ketosis and just give my body a break from the fat. But I think just that short amount of time really stimulates mobilization of fat from your body because your body is used to getting it exogenously, and then you’re pulling more fat off.
But yeah, I think on the protein veggie days, I’m getting higher amounts of calories from protein. So that has a bit of an anti-ketogenic effect. And then shifting back into ketosis on that third day, I always had probably the best ketone numbers for the week.
Tim Ferriss: Yeah. I don’t want to beat this dead horse too long, but I’d love to just hear you riff on this a little bit more because I guess in my mind I’m thinking, well, on your protein veggie-only days, if you’re getting enough protein, not enough protein to satisfy all of your resting metabolic rate, like you’re hypocaloric, but you’re getting enough protein to not lose muscle, why wouldn’t the body just break down the fat that it needs to continue producing ketones, right?
So I’m trying to avoid the gluconeogenesis problem where you’re having like 200 grams at a meal with no fat to offset it, but if you’re having smaller amounts that are slowly digested, but it’s just enough to keep you from losing muscle mass, maybe you’re doing some weight training to help with that or whatever, then I guess what I’m trying to figure out is why the dietary fat is so important? Because I think of the body, right? It’s like each pound of stored body fat is what?
Dominic D’Agostino: 3,600.
Tim Ferriss: All right. So 3,600 calories, that’s a decent amount of calories, right? And for somebody who’s, let’s just say you’re 150 pounds, 10 percent body fat, okay, you got 15 times 3,600, you got plenty of body fat to go around.
So it would seem to be enough to do a few weeks of ketosis that is low fat, higher protein, but not enough protein to necessarily be hammering your liver with gluconeogenesis if you’re dividing it up, slowly digested protein. Some people are going to be really annoyed with me dragging this out so long, but why is dietary fat so important?
Dominic D’Agostino: Because I mean, that’s the fuel that you are using, you coax your body into using. And I should probably add a little bit of context to my protein veggie days. So I would go from like 125 grams of protein to like 300 grams of protein.
Tim Ferriss: Right, right.
Dominic D’Agostino: That’s a pretty big bolus of protein.
Tim Ferriss: That’s a lot, yeah.
Dominic D’Agostino: And if one was to go a hundred grams of protein or whatever, and then bump it up to like 170 or 200 or something, they may not kick out of ketosis. But I remember just lower ketones, but not out of — I was still in ketosis, but typically how I think I did it like my protein veggie days were following like a heavy deadlift or squat workout.
So the thinking was that I’m recovering for those two days and the extra amino acids and proteins and mTOR activation is sort of assisting in recovery and regeneration and skeletal muscle protein synthesis. And then I would kind of go back. I calculated it in that way. So yeah, I like double the protein on the protein veggie days, but my calories were about the same or maybe a little bit lower.
Tim Ferriss: Yeah. I need a SiBio if you’re listening, please allow me to calibrate this with a finger prick because I need a little more range. I need a little more range than 0.01 to 0.04 for me to be able to read this type of thing effectively, right? Because technically, if I’m reading this as it is, I’m never in ketosis. I shouldn’t say never, that’s not true. But in any case, it would not be nice to be able to calibrate.
Let’s come back to something I promised that I would ask about, which is neurodegenerative disease, Alzheimer’s, et cetera. Could the ketogenic diet benefit people with these conditions? And just as important, certainly for me personally, could this, is it plausible that there’s a mechanism by which the ketogenic diet regularly done could help delay the onset of any of these diseases? Or am I just Pollyanna hoping for a pie in the sky?
Dominic D’Agostino: Yeah. I think that’s a question we don’t have an unambiguous answer to, but I think all the science points into the direction that if you improve upon and optimize your cardiometabolic — I like to say cardioimmunometabolic biomarkers, instead of cardiometabolic biomarkers because if you can lower, for example, your insulin and keep that between two to six, and if you lower your hsCRP below 0.6 and then optimize your hemoglobin A1C or glucose. And I think also, and I’ve talked about this with Rhonda Patrick and other people, too, that if you measure your omega-3 fatty acids and look at your omega-3 to 6 ratio, I think that’s going to be a biomarker that’s probably going to end up in standard blood work because it’s so compelling, the data behind it.
And you also measure your B12, too. I think that’s important. People coming into the Alzheimer’s center that can present as flat-out Alzheimer’s disease and then you correct their B12, a B12 deficiency will cause brain atrophy, and that could be reverse with B12.
So the things that if you’re following ketone metabolic therapy, it’s impacting the things that we know are driving age-related chronic diseases, and then obviously one of them is Alzheimer’s. So the level of inflammation, hsCRP now is probably more atherogenic than LDL. There’s probably people selling statins that don’t want to hear that, but we know that the data is emerging on that now. So lower insulin, lower inflammation —
Tim Ferriss: And that’s an inflammatory marker, right? The C-reactive protein. What does the HS stand for or what is that?
Dominic D’Agostino: High-sensitivity C-reactive protein.
Tim Ferriss: High-sensitivity.
Dominic D’Agostino: Yeah. So it measures in that lower range. And I used to trend to like two to two to three, like my early CRP, hsCRP when I was like on a high carb, I only had it measured twice when I was on like a high-carb diet, but since I’ve been keto, it’s like either non-detectable or like 0.2. Or when I did extreme environment research on myself, then I could bump it up a little bit. And when I had a bacterial or viral gastroenteritis, it shot through the roof because it activated your immune system. But generally that hsCRP is a big driver.
I used to laugh at it and be like, “Ah, it’s this nonsensitive thing.” But now like all the data is pointing to the direction that we need to add that to that.
And your omega-3 status, your B12, make sure you don’t have any deficiencies because that could lead to sort of rapid progression to Alzheimer’s disease, your magnesium levels.
But also just in general like exercise, the biggest metabolic lever and your body weight, body composition.
Get DEXA scans. I know it might be good for you to do a DEXA scan with your keto experiments, too. So I was doing once a year, but now I end up doing like three or four times a year because I do these mini experiments to see how acutely some of the things are impacting my body composition because I just get antsy for like an answer to that.
But it’s a long-winded explanation to just basically say that your metabolic health is tightly linked to your brain health and can dramatically delay the onset of Alzheimer’s disease. Not that you’re going to get it or reverse it altogether before something else gets you in the end. Yep.
Tim Ferriss: Well, I mean, the metabolic health piece, just to underscore that, I mean, one of my relatives in question, APOE 3/3, I understand that’s not the only risk factor, but there’s something just seemed to be missing because the decline was so precipitous. It didn’t map to any patient data or clinical data that a number of doctors, who are also researchers I was working with, had seen. Also because this person, this relative had been assessed four or five years prior and did not show any indication of predisposition to a rapid decline.
And I’m APOE 3/4, again, recognizing there are other factors at play, but when she just kind of disintegrated, there are a few things that came to light. Number one is her local GP had basically missed severe metabolic dysfunction for years. And I can’t remember the reference range, but like insulin, let’s call it upper bound of 12. I’m making this up, but you’ll get the idea. And she was like 43, right? It was just absolutely atrocious.
Dominic D’Agostino: And her body weight and just general composition?
Tim Ferriss: I mean, poor body composition. Yeah. Poor body composition, very little exercise despite my best efforts, misbehaves horribly, dietarily, not morbidly obese, but certainly —
Dominic D’Agostino: Smoking, alcohol, other drugs?
Tim Ferriss: No smoking or alcohol.
But here’s the other piece that, so she had been diagnosed with stage one breast cancer, had a lumpectomy, was removed, late 70s was put on an estrogen, I think it’s an estrogen blocker called letrozole.
And I looked at this and I spoke to a friend of mine who was a radio-oncologist and she said it is very poorly tolerated by most women from a cognitive perspective, like they get smashed by and large.
Dominic D’Agostino: Guys, too, by the way. Guys who take —
Tim Ferriss: Okay. Yeah, guys do.
Dominic D’Agostino: — aromatase inhibitors, yeah, for like TRT and things like that. It’s not a good thing to do.
Tim Ferriss: Yep, yeah. So I was looking at it and I mean, it’s upsetting that I’m the one who has to kind of find these things, but it’s like, okay, well, we think about the oncologist’s role. It’s to prevent my mom from dying of cancer. That’s the directive, right? But if she were 30 and had later stage cancer that was really aggressive, it’s one thing, but she’s late 70s, stage one, all cancer removed, and so got her off of the letrozole with the cooperation and after discussions with doctors and almost saw an immediate turnaround within a handful of weeks after the washout period and everything.
But it seems to, I mean, look, I’m not an MD. I don’t play one on the internet, but it seems to have done some real damage. I mean, there’s the metabolic piece that is very non-trivial, but the acceleration of decline was just so absurd over the course of a handful of months, terrifying to see.
But I guess I’m laying this all in, not necessarily to explore this particular case because I’ve got a lot of people on it for all of my relatives, but it’s just to say that my — like I am not going quietly into the night with something like Alzheimer’s, right? And so what I’m trying to figure out for myself, I’d be curious to hear your perspective.
I will be honest, I find keto pretty goddamn boring. I don’t find it to be the most diverse diet in the world. I don’t really want to do it all year round. I also have some maybe compromising cardiac elements. I’m a cholesterol hyper-absorber, so I do use — again, guys, talk to your doc. Don’t just copy me, but it’s like I’m using Repatha, taking ezetimibe. I have been also taking Nexlizet, but that might end up being redundant, the bempedoic acid with the Repatha.
That is a long way of saying I’ve got to keep an eye on the heart stuff because neurodegenerative disease and cardiovascular disease is what kills everybody in my family. So for a lot of reasons, I don’t want to do keto all year, but I’m trying to figure out what is the sort of minimal effective dose that — and I know we’re going to have to probably take a couple of speculative leaps here, but just as a working hypothesis, what does a minimum effective dose of following a strict ketogenic diet look like for me?
Assuming the rest of the time I’m still doing intermittent fasting, I’m not eating a lot of refined carbohydrates, but how might you suggest that I think about that? Because I don’t know what the durability of kind of keto memory, like metabolic memory is. So I’m trying to figure out like can I get away with two, three to four-week periods a year where there’s some carryover of like cancer-protective — our last conversation we kind of talked about thinking about ketones as hormones, but in terms of neuroprotective, anti-inflammatory, yada, yada, yada, what are your thoughts?
Dominic D’Agostino: Yeah. Well, I think in your context it’s hard to say, like to give absolutes, but I would say you can get 80 percent of the benefits with a low-carb diet. Low-carb meaning 100 grams a day, just fibrous, non-starch, non-sugar carbs, low-carb Mediterranean, if you want to call it that.
And then periodically, maybe one week out of a month, get into a deeper state of ketosis and at higher is not better. We know that from the research. When ketones get into that two, three, four, five millimolar range, that creates energy toxicity and something we call reductive stress, and that is not good.
I did not know this before getting into this kind of research, but the sweet spot seems to be between one and two for therapeutic ketosis, unless you’re metabolically managing a disorder that’s highly responsive to a ketogenic diet like neurometabolic diseases.
And some of the things that we actually study need to be in the two to three millimolar. And oxygen toxicity needs to be like four to five because it’s a — very powerful seizures. But one to two seems to be the sweet spots for metabolic management of many different things and also just general metabolic health.
And I think what you’d be doing, just doing low-carb and periodic ketosis is just enhancing your metabolic flexibility and maybe increasing the diversity of food that you’re eating to prevent micronutrient deficiencies, too.
I am of the opinion that plants are good for you to eat broccoli, asparagus, salads, colorful vegetables, things like that, that kind of fit into a pattern of eating that we’ve known. Even things like lentils are probably good. Lentils actually have like zero CGM response to me, but I —
Tim Ferriss: Really?
Dominic D’Agostino: Yeah, lentils seems to like, skyrocket other people that I know. I’m like completely flat.
Tim Ferriss: I’m like somewhere in between. Yeah, I’m somewhere in between.
Dominic D’Agostino: Okay. Like completely flat. I don’t know. Maybe it’s the time of day that I have them at dinner, then I always go take a walk, but it’s like no bump at all in my CGM.
And I think that’s where CGM comes into play and we can do a personal precision engineered diet, if you will, and it gives us insight into the types of foods and the amount of foods that we can eat. And I think that’s going to be really important information.
And I know there’s a lot of people harping on, because another study came out on CGMs provide no benefit at all to the non-diabetic. And I’ve had this conversation with people actually at a big event and people that were type 2 diabetics and I asked them just flat-out, I just went around the table and just saying, “If you’re type 2 diabetic, when you were diagnosed like three years ago, if you were to be giving a CGM five years before that, or even one year before that, do you think you would’ve been diagnosed with type 2 diabetes?” And they said no.
They said once they got type 2 diabetes and got a CGM, it gave them the awareness. I mean, you can ask anyone who has flat-out over type 2 diabetes and just ask them the question, “Hey, if you were given a CGM a year or two in advance and you understood the impact of foods.” So I think a CGM is going to be important for delaying that Alzheimer’s disease. And if you have loved ones, Tim and your family, that I think you would encourage them to slap on a CGM and get some insight into what they’re eating.
But it’s also forcing them to exercise because we’re talking about diet here, but just getting out and doing a brisk walk 20, 30 minutes a day can go a long way. Resistance exercise, I’m a little biased towards that, but muscle is like an endocrine organ that produces hormones and various molecules that are neuroprotective and muscle is tightly linked to brain size and, of course, your waist and your visceral fat.
I would also encourage them to get a DEXA scan and gamify it and say, every year I’m going to get a DEXA scan and every year like I do, I just kind of create a lot of stress for myself to beat my DEXA scan every year and get their friends involved, make it like a social event. Everybody goes and gets their DEXA and then every year you go back and just try to beat your scores. But I mean, these are low-hanging fruit kind of things people should be doing.
Tim Ferriss: Yeah. Let me, I think probably fair to say, make sure you consistently hydrate for any of these things like a DEXA scan.
I do have a follow-up question. So also on the exercise piece, people can look up something called klotho, K-L-O-T-H-O. There’s a lot more that comes of exercise like BDNF and all these various things. There’s a book called Spark that covers some of it, but it’s very outdated, but check out klotho. There are a lot of good reasons to exercise. Thinking of muscle like an endocrine organ, that’s a really good way to put it.
My question to you was, you mentioned, say, one week per month going to more of a lower carb or ketotic state. How would you think about the benefits of one week per month? Assuming that the rest of the time I’m behaving, most of the time with a lower carbohydrate Mediterranean diet, let’s just say, okay, one week per month, every three months or three weeks, like contiguous weeks once a quarter. Do you feel like one of those is superior to the other?
Dominic D’Agostino: Not really. I think whatever pattern works best, I think you would gain benefits for both. That would be an interesting experiment to do.
Tim Ferriss: I’m just thinking about the lead time to get into a properly ketogenic state. If I’m going from some carbohydrate to ketosis, I’m just — we could talk about things that might accelerate it, but if it takes me two days to get there or three days and then I only have kind of four days in the sweet spot, these are things running through my mind. I’m just curious to get your take.
Dominic D’Agostino: Yeah. The one-week intervention for the month, my kind of opinion is that it could be pretty aggressive. Like you cut calories 50 percent the first two days and then cruise into it, so you’re really cranking ketones by the end of the week. And then you’re also cruising into it from what should be like a low-carb diet. So you should have that metabolic flexibility to kind of seamlessly transition into that ketosis state. And you could do intermittent fasting with mild caloric restriction for the first two days to ramp up ketones.
Alternatively, if your schedule permits and like your work schedule, you have like three weeks where you need to really dig deep into a research project or something and ketosis seems to give you that cognitive flow or boost, then that might situationally fit into your schedule. And I definitely have periods of time where I do that, especially like if my wife is traveling or something like that, or on a research project or something, I just like, okay, I clean the house of certain foods and then I just prepare.
I mean, simple things like that, too, I know just from the clinical ketogenic world is that if you have a family member that stocks the shelves with certain foods that can trigger and cause food noise, then that could really hamper your compliance to that. But you want to prepare the house, or if you’re going into a one week or you’re going into a three week, prepare the house and just make sure that you could do. Of course, you could just call Uber Eats and get anything delivered, but you want to kind of have the house prepared for that and mentally prepare for it.
Tim Ferriss: So for you, personally, if you had some hereditary gnarliness, if you look back at your family tree and you’re like, ooh, whether it’s a bunch of cancer or a bunch of neurodegenerative stuff, maybe bit of both, who knows, would you be more inclined to do the one week per month, just for you personally or yeah, one week per month?
Dominic D’Agostino: Yeah. And I would shoot to get a glucose ketone index of like one to two for at least three days out of that week. So really do a fairly aggressive ketone metabolic therapy intervention, kind of even think about it as like a prescription intervention, just like Valter Longo’s diet is a prescription medical therapy, right?
So I would shoot to achieve a glucose ketone index of one to two for three days. And everything that we’ve seen in the lab that I’ve seen sort of on paper, of course, people aren’t out there measuring the autophagosome like P62 and other things, but that you are achieving a level of autophagy and that’s also stimulating many of the benefits of ketosis, not just ketones as an energy source, but you’re getting many of the robust signaling effects and really adapting your metabolism to fat and ketone sort of oxidation that has long-term benefits that can go at least three weeks.
So I’m convinced of that. So you get benefits for three weeks, reset one week, benefits for three weeks, reset one week so you’re always kind of getting — whereas if you do three weeks and then take a period of time off, I’m not totally convinced that those benefits are going to span that amount of timeframe. That’s my thinking.
Tim Ferriss: And you mentioned people can find calculators out there and actually a lot of the devices will try to provide this to you. Actually, is that true? I guess they would have to have both data streams, so probably not, but the GKI.
So the glucose ketone index, you can find calculators for this, but fact-check this, since this is AI overview from Google, I wanted to just take a look at it. Divide your blood glucose level by your ketone level. If your glucose is milligrams per deciliter, common in the US, you first divide it by 18, this is an important step, to convert it to millimolars per liter, matching the ketone units, then perform the division. So you can figure this out very easily. And that is the GKI that you were mentioning of a one to two.
What might that look like just offhand? I’m very not known for my quick mental arithmetic on the podcast, but what would a GKI of, say, one or two look like in terms of the readout on the glucose, on the glucometer and the readout on the finger prick for the millimolars for ketones? What would be an example?
Dominic D’Agostino: If people are like don’t want to do the millimolar concentration of glucose, if your glucose is 80 and then your ketones are two millimolar, that would be, you are right into that one to two kind of the glucose ketone index of one to two, you’ll be between that level.
If you could bring your glucose down to like 18, so like 68, 70 and get your ketones up to three, so that would be a GKI of one. So that’s pretty hard to achieve, but relatively definitely doable with exogenous ketones and MCT and things like that. I think what’s totally feasible is getting your glucose down to like 80, 80 to 85 in that range and getting your ketones at the end of the one-week fast up to two and maintaining that. So that would be kind of achieving that GKI of two.
Tim Ferriss: I think I’m probably saying what I wish to be true, which is that my insulin sensitivity has improved a lot in the last certainly year in particular, and that is to explain in part, or maybe wholly, the lower readout on the ketone meters.
But part of the reason I have confidence in that is that I’m using the same devices that I used to use. And back in the day, I would have much higher millimolar readouts.
Of course, I have new strips. I did, at least to the extent that I can, for the continuous monitors, I’ve done calibration for the CGM at least, the glucose monitor, but that presents a problem. Even if that is, “Good news, Tim Ferriss, you’re not failing at keto. You’ve actually just made yourself a lot healthier with intermittent fasting and other things,” it still presents a problem for me to figure out if I am in that GKI sweet spot.
So how would you suggest I try to figure that out? Is there a way to measure my ketone uptake and, therefore, modify the equation such that I factor that in somehow? Like there’s a multiplier of the readout on the finger prick or something like that? How would you handle that?
Dominic D’Agostino: Yeah. Let me look real quick.
Tim Ferriss: Dom is looking into his Santa’s workshop of various metabolic devices.
Dominic D’Agostino: Yeah. So I have a lot of different devices. So one is the Keto-Mojo device here.
Tim Ferriss: Yep, that’s the one I have. Yeah, I’ve got the Keto-Mojo.
Dominic D’Agostino: Okay. So that, I mean, you could just calibrate it such that it reads in millimolar concentration in glucose and ketones, and it actually gives you, this is the GKI version. It’ll just spit out the GKI.
Tim Ferriss: Oh, you know what? I do have the GKI because you’re right, the Keto-Mojo also measures glucose.
I guess what I’m asking for myself is since my readouts are so low, presumably as a placeholder due to improved insulin sensitivity and ketone utilization, I’m going to fail if I’m just using the glucose and the ketone strips for the Keto-Mojo. Because right now, if it’s telling me that I’m at 0.4 millimolars, and I can tell you subjectively, I do not feel like I’m at 0.4. I feel like I’ve got a lot more juice and a lot more gas in the tank.
Is there a way to, whether it’s on paper or otherwise, account for the increased ketone utilization? I mean, it’d be great for me just to verify that somehow, but then whether I can verify it or not, if I wanted to try to determine during that week, like if I’m hitting my target GKI, how would you suggest that someone like me do that if I’m just not getting the numbers necessary to make the regular math work?
Dominic D’Agostino: So one to two is a high bar, I guess, a GKI of one to two. And I think we’ve had this conversation back and forth with this group that we’re working with in the cancer community.
The Society for Integrative Metabolic Oncology is a group that we’re discussing the GKI, and Thomas Seyfried is very adamant about, like, getting to one to two. But I give pushback and say one to four is if you look at the published literature, one to four is absolutely 100 percent therapeutic across not only cancer, but also like seizures and everything. So I’m going to expand that range to a one to four.
So what does that mean? That would mean that your glucose level can be upwards of 80. And so you could have a glucose level of 75 to 80, and then get your ketone levels to one, and that would be a GKI of one essentially if you don’t have the glucose calibration for that. Or that would be a GKI of four, rather. And it would be really rare, if not impossible, for anyone in the general population eating to even achieve a GKI of like 5 to 10. So that’s indicative of high fat oxidation, ketone production, and I think that you’re getting a lot of therapeutic benefits. Also, a millimolar concentration of one in your blood represents a 10 percent available energy for your brain. And also the Keto-Mojo devices measuring D-beta-hydroxybutyrate. And if you’re doing supplementation with racemic D and L, then you’re not picking up the L. So that could be a factor too if you’re using racemic ketone salts.
And there’s a number of publications that have already happened and some in the pipeline basically showing that elevate hydroxybutyrate takes about 4 to 5 times longer to metabolize. So that’s in circulation more. And also like, if you’re on a ketogenic diet for reasons we don’t fully understand and we are to rip out the heart, about 34 to 40 percent of the ketone in the heart is elevate hydroxybutyrate. And we don’t know why it converts the D to the L, but it serves a function that — the groups that have done the research are convinced it’s not an energetic, but it’s actually impacting cardiac output and reducing peripheral vascular resistance, maybe at the glycocalyx. So I don’t want to go down that rabbit hole. But basically, it’s like if your heart is pumping against pressure and think of it as like a garden hose and you take the kink out of the garden hose, the elevate hydroxybutyrate is taking the kink out of the garden hose of your vascular endothelium and then that’s also in your brain. So you have better blood flow to your brain.
I mean, there’s tons of data out there showing an increase in brain blood flow with beta-hydroxybutyrate and the L trends better to increasing that blood flow. We do a Doppler blood flow measurement on various wound healing things that we’ve done in the lab. I mean, a lot of people have vascular dementia, right?
Tim Ferriss: Yep.
Dominic D’Agostino: So there’s different types of dementia, and it might be not like completely one or the other. And the metabolic phenotype of dementia could be vascular. You get a restriction of oxygen and energy to the brain. My point is that one millimolar of beta-hydroxybutyrate in circulation has an energetic effect and it also has a pronounced effect on the vascular endothelium to increase blood flow and circulation. So you are getting a benefit.
Tim Ferriss: I’ve never had this experience in ketosis before where these levels have been this low. It’s so bizarre. And yet, let’s say, back in the day before the intermittent fasting, and it’s pretty much the lever that I pulled that I think changed things. Prior to that, I could tell you probably within 60 minutes of hitting 0.7 millimolars on the precision extra. Like I knew when my brain clicked past that point. And I did years and years and years of this stuff. I think as much as I like to measure things, I should just assume, right? If I’m having a bowl of mackerel dog food with MCT oil and apple cider vinegar and salt and pepper, then having a meal later that effectively has close to zero carbohydrates, if I’m doing that for almost three weeks, there doesn’t seem to be a physiological option C for failure, right?
It’s like, what’s my body going to do? It has to be doing something because I’m not getting the dietary carbohydrate, and I’m not just mainlining whey protein isolate all day. So, I think I’ll probably just have to trust in the process because if I do have the increased ketone utilization and I’m just somewhere between 0.2 and 0.4 millimolars, for the most point, or for the most part, I just don’t think that the math might be really hard even to hit the GKI of four. But it’s like, if you’re following the process, I guess you’re following the process, right?
Dominic D’Agostino: I say trust the process and also think about — I’m talking about like blood biomarkers, but let’s talk about physical metrics that could be considered biomarkers, right?
So for me, it’s all about the numbers. Like my lab books and stuff like that have numbers in the lab, but also training. It’s like, I know exactly what I’m going to do going into the next workout and it’s all about X amount of weight for X amount of reps. So you can also do that with various brain training apps where you can do reaction time. So for our NASA NEEMO experiments where we’re in an extreme environment and we’re working with astronauts, we’re assessing reaction time, decision making, risk taking, where like this balloon blows up and you don’t know when it’s going to blow up, but you have to stop. It’s like a weird risk game.
So we have this whole metric of testing cognitive function, reaction time and things like that. So there are things that you could do even with an app-based thing to assess that, and I think that would be a good thing. We have a massive NIH grant at University of South Florida on brain training games and assessing performance on that. Alzheimer’s was in my family, I would basically be doing everything possible, physical training, dietary metabolic training with nutrition, supplementation, and also brain training.
And brain training games, and we use Joggle, the NIH Toolbox, I mean, we have like about six or eight different types of tests that we do to get a very objective measure of cognitive function. And I think it would be good to establish that now and then get your baseline just like we’re doing a DEXA for body composition, and then test that every six months. And then do it in the absence and presence of being in ketosis. So I would suggest something like that.
Tim Ferriss: Yeah. I have time blocked out in my calendar this Friday to do a whole battery of cognitive testing. And again, this is not super precise, but having tracked myself for so long and developed a water fuel for certain types of performance, zone two feels a lot easier right now, a lot easier than usual. And coming back to your prior comments. And then, I would say, I’m using software right now. At some point I’ll be able to talk more about this, but to basically train my visual processing to compensate for presbyopia, it is crazy, some of the effects that this stuff has. But it also is very much indirectly a measure of reaction speed, and they see some really cool carryover effects. And my speed in terms of time to completion for four bouts, like modules of tasks has just gone up and up and up since I’ve sort of been in extended ketosis. Again, that’s very easy for me to see. So folks who are listening, I’ll have more to share on that later, but it’s pretty mind-blowing stuff.
So Dom, a few things have come up that I would love to chat about because I get these questions all the time, which relate to exogenous ketones. And people have heard this term, exogenous, endogenous. It’s very fancy talk and a tuxedo for outside the body, in the body, right? I’m simplifying here, but the easy way to remember exogenous is exoskeleton, right? It’s like a skeleton on the outside of your body. Exogenous ketones, ketones that you’re taking from outside and putting inside. People always ask, and I know you have a dog in the fight here, so I want to recognize that too. But how should people think about supplemental ketones? And are there any warnings or disclaimers that you want to add to that, right?
Because this is a topic du jour. I think there’s probably no biological free lunch if people are going to be mainlining fruity pebbles and eating tons of carbohydrates, maybe not a great idea to eat tons of exogenous ketones. I don’t know, I’d be curious to get your take on that. But what’s the good, the bad, and the ugly of exogenous ketones? Where should people go? How should they think about it?
Dominic D’Agostino: The things to consider would be when you’re thinking about a ketone supplement to think about palatability. If it doesn’t taste okay, you’re not going to consume it. I would, but most people won’t. Palatability, tolerability, if it gives you disaster pants or it makes you nauseous or something. So palatability, tolerability, and then the next one, the third one would be the pharmacokinetics. So you want something that when you consume it, that it has an ideal pharmacokinetics, meaning it’s not going to spike up in 30 minutes and be out of your system in like an hour or two.
Tim Ferriss: Yeah. Pharmacokinetics is like the stock chart for something you put in your body, right? In this case, right?
Dominic D’Agostino: Yeah, yeah. And that’s important because if you have a very rapid rate of rise of ketones, that can trigger an insulin response. And what I’ve observed, if I’m cruising in ketosis and I take a large dose of a ketone ester, it shoots my ketones up real high and it’s back down within like two hours, but it also kicks out insulin and that shuts off my own ketone production. Then I’m hypoketotic and hypoglycemic from the insulin. And that can create an energy deficit in the brain.
Tim Ferriss: How long does that last for you?
Dominic D’Agostino: And it lasts in the context of consuming, for example, a ketone ester by itself. But if you consume the ketone ester with MCT, if you could tolerate that, you could buffer that response to some extent, or you take it with food or something, or you could avert that by different ketone formulations and we could talk about that. But I just want to move down, so you got palatability, tolerability, pharmacokinetic properties, and you also have toxicity. So that would be the four things that you need to consider when sort of selecting an exogenous ketone. And those things differ depending upon if you’re using it acutely, like in a medical situation, or it’s like a daily thing that you want to take every day for prevention, right?
Tim Ferriss: Yeah, let’s talk about toxicity first.
Dominic D’Agostino: Toxicity is probably the most important too.
Tim Ferriss: Yeah. Let’s, for the time being, not talk about the acute medical delivery. Let’s talk about recreational/better said layperson use, right? This is as a dietary supplement. So could you speak to the toxicity piece?
Dominic D’Agostino: Yeah. Well, what we observed about 10 years ago was that formulations that contained 1,3-Butanediol, that includes an ester. I have a lot of patents on and I have actually ongoing experiments with 1,3-Butanediol by itself is a ketogenic agent and that can have toxicity when used chronically. 1,3-Butanediol is an alcohol dimer and it gets metabolized through alcohol dehydrogenase and aldehyde dehydrogenase. Aldehyde dehydrogenase kicks out a beta-hydroxybutyrate aldehyde that can be toxic.
Tim Ferriss: How is it toxic? What are its toxic effects?
Dominic D’Agostino: Yeah. So alcohol dehydrogenase uses NAD, consumes NAD as its function, right? So it can basically deplete the liver of NAD. And aldehyde dehydrogenase also consumes up NAD and it rapidly depletes, for example, the liver, the hepatocytes of ATP. So we know that there’s a paper coming out that’ll show that in our lab we’ve seen therapeutic effects in certain contexts, but when delivered acutely. But when consumed chronically, when we go beyond our experimental window and give these things chronically as like a lifestyle, exogenous ketone. And then we sacrifice the animals and then we do blood work and we look at the liver, we see signs that are scary, right? And this could be inflammation in the liver, TNF-α, sinusoidal dilation, sort of like gaps in the liver, fatty liver, a number of different things start to surface. And that’s pretty much just due to metabolizing something that’s considered a toxin to the body, 1,3-Butanediol.
It’s a very versatile drug. 1,3-Butanediol by itself is more toxic than 1,3-Butanediol based ketone esters. So you have the ketone monoester, which is technically the millimolar concentration. You have 51 percent of a ketone monoester is 1,3-Butanediol. So it hydrolyzed in the liver, gets into circulation. Still over 50 percent of that is 1,3-Butanediol. That kind of needs to be detoxified, but 1,3-Butanediol does get broken down to beta-hydroxybutyrate. The diester is about 35 percent 1,3-Butanediol. So, I see these as potentially problematic.
Tim Ferriss: The diester is what percentage?
Dominic D’Agostino: A ketone diester, which would be 11,3-Butanediol with two ketones on it. We use acetyl acetate on each, that’s 35 percent of that molecule is 1,3-Butanediol in circulation.
Tim Ferriss: I got it.
Dominic D’Agostino: And then the beta-hydroxybutyrate monoester is 51 percent 1,3-Butanediol in circulation. So this can become problematic when it’s used as like a supplement and a lifestyle thing like day in and day out.
Tim Ferriss: Can you translate from the animal models to humans, do you think, right? Because we all know, humans are not just big furry mice, right? Do you think it translates, right? And this might be just like a precautionary measure where it’s like, “Well…” Like pending additional studies, let’s hit pause in a sense. But if it were to translate, do you have any idea what type of dosing per day or per week with which we might see this toxicity in humans, right?
Dominic D’Agostino: Yeah. So there is a paucity of data, and there’s a deficiency of data on the use of these agents 1,3-Butanediol that are long-term studies. The only study that I’m aware of is a case report with Dr. Mary Newport’s husband, Steve, and then there’s a 28-day study that used 25 grams.
Tim Ferriss: 25 grams.
Dominic D’Agostino: 25 grams per day, yeah.
Tim Ferriss: Oh, shit.
Dominic D’Agostino: And that produces like 0.1 to 1 millimolar. But what I have done is I took the R-1,3-Butanediol and then the racemic 1,3-Butanediol at different time points. And I basically dosed it for two weeks to keep my ketone levels at two millimolar, which would be like a therapeutic. And when you do that, what you will see, and I — well, I was going to say, I tell people that go ahead and do it, but maybe don’t do this. But when you take something like 1,3-Butanediol at a dose, which for me requires 30 milliliters three times per day to keep at two millimolar throughout the course of the day. If you do that for two weeks and then you test your transaminases, so that would be AST, ALT, and GGT, they will go up, so that’s a clear indication that — so we’ve done this in animals and fed it at a pretty high level, and we did not see transaminases going up.
Tim Ferriss: So transaminases are what people could think of as liver enzymes on their blood panels, right? ALT. Is GGT typically tested?
Dominic D’Agostino: GGT is like the wild carb, but what’s good about GGT is it’s the canary in the coal mine. It will go up before ALT and AST. If you expect someone has a problem with alcohol and they say they’re not drinking and you want to figure out if they’re drinking or not, say, “Hey, can I see your blood work and make sure the doctor adds GGT just to get a better,” and that’s elevated and your AST are not. The only things that’ll really shoot up GGT is like alcohol. And also the size of the red blood cell too can be if they’re like larger, that’s an indication like someone’s drinking too much alcohol. And it could be just like two or three glasses a day, but that will elevate GGT. So we observed that transaminases actually didn’t go up in our animals fed. The ketone esters or 1,3-Butanediol chronically, but when we pulled the livers out and then looked at the livers, then we saw things that concerned us. And we published this recently.
And it’s good to know when someone has non-alcoholic fatty liver disease, they can have normal transaminases but have a necrotic liver.
Tim Ferriss: Yuck. I did not know that. It’s terrifying.
Dominic D’Agostino: Yeah, yeah. I mean, you look very closely at ALT longitudinally and that creeps up, but you basically have to do like a CT scan or a high resolution ultrasound of the liver. And basically, you could just take a subset of the American population that trends to be overweight and you do some liver scans and you find that they can have overt fatty liver disease and have completely normal transaminases are just trending up, right?
Tim Ferriss: Mm-hmm.
Dominic D’Agostino: So my liver enzymes tend to trend a little bit higher just because I eat a lot of protein. So with 1,3-Butanediol and 1,3-Butanediol based ketone esters, you have a problem with tolerability, palatability, potentially feasible pharmacokinetics and also toxicity. So it almost like checks all the boxes in a negative way. So the field is trending towards non 1,3-Butanediol based exogenous ketones, and that could be free acids, it could be a triester with glycerol and also the ketone electrolyte salts, but you could also avert part of this just by formulation. The issue is that companies have one molecule and then they test that one molecule, but you could — I think formulation is the way to go. And companies don’t want to hear that because they have all their IP in one molecule. But we’ve always been a formulation kind of based lab, and always saw that these things always have drawbacks when used as a monotherapy, but when you start combining them together, that’s when you get better therapeutic effects.
Tim Ferriss: Got the hounds out there. Hopefully, not next to the gators. We won’t spend any time on this, but I just wanted to tell people that before we start recording, you’re telling me that you caught a 10-foot alligator that was trying to eat your dogs and then you pinned it down and taped its mouth and then measured its glucose and ketones. Turns out that alligator had a pretty good GKI, but that’s a story for another time. So only in the things that Dom would do category that stand out, but we’re talking about a lot of terms that are likely unfamiliar to folks. I don’t want to throw anybody under the bus here, but people should do their homework. 1,3-Butanediol is very, very, very common. It’s very inexpensive, or relatively inexpensive to produce. So just keep an eye out for 1,3-Butanediol. If this is of interest to you, I have no investment in any ketone supplement company or anything.
I do not have a stake in this, but I would like to ask a couple of things. So I have experimented, as you know, with ketone monoester, diester, ketone salts, I’ve played with everything, and I’ve found the diester to cause quite a bit of intestinal discomfort, to put it mildly, at least the first one or two times. I will say for folks, if at first you don’t succeed, meaning you have to run to the toilet. You may acclimate to it, which I did in that case, but I felt subjectively less and less effect. I seem to develop tolerance very quickly. I don’t know why that would be the case, but I seem to experience it. The ketone monoester, which is the 1,3-Butanediol bound to BHB, if I understand it correctly, right? I do like that. I like the subjective feeling of it, but if that’s only at about 11 milliliters.
If I take 25 plus, speaking to your pharmacokinetics, right? Like the stock pops and then it drops and then I feel very tired and often feel more anxiety. It seems to prompt in me more anxiety. I mean, look, we got to talk about this. Not that it invalidates what you’re saying in any way, but your wife runs a company that sells ketone salts, which I also I’ve been using most consistently. Keto’s Therapy, people can check it out. But on the ketone monoester, what I’m wondering is if I’m only taking, let’s say, 11 milliliters once or twice a day, and I’m taking it alongside MCT oil, where would you put the risk analysis on something like that?
Dominic D’Agostino: I would say, the risk is very minimal for a healthy person. So I have a super healthy liver. I even take N-acetylcysteine, alpha-lipoic acid, all these things. So I was surprised to see sort of liver climbing. What we see in our older animals is that they are selectively vulnerable to 1,3-Butanediol toxicity from acutely and also chronically. So for a normal healthy person, especially someone that’s sort of really good metabolic health and liver function and they don’t drink or drugs that compromise the liver, I would say upwards of 1,3-Butanediol 20 to 20 milliliters a day is probably where you want to cap it and maybe not do it every day. 1,3-Butanediol based ketone ester would do that, but you can also probably achieve and maintain the same level of ketosis with a ketone salt, a beta-hydroxybutyrate salt.
And I do like the idea of a D and the L, the two enantiomers, which is a conversation that you may or may not want to have. So the L is basically like, it’s packaged beta-hydroxybutyrate in the time release form and it has some signaling effects. And then you have free acids too that are coming up on the market, and various liposomal formulations. I’m not sure if they’re commercially available yet, but these are some things in the pipeline. But yeah, 1,3-Butanediol based monoester, I think there’s good data behind it. I think the science that’s published is biased under the direction because that was the molecule that a lot of companies associate with, and then they test that molecule in and of itself as a monotherapy. And I am of the opinion that things are definitely optimized. You could avert a lot of the problems just by formulation.
Tim Ferriss: How does the MCT oil help? I guess basically it makes the ramp up more gradual. Is that the effect that the sort of co-consumption of the MCT oil has?
Dominic D’Agostino: Yeah. It delays gastric absorption for one thing, but it’s also stimulating your endogenous production. So the MCT goes to the liver, not through like chylomicrons, it goes right to the liver and stimulates your body’s ketone production. And I think that’s important. It’s almost like training your liver to ramp up fat oxidation, and it’s almost like exercising your liver to stimulate it. What we’ve also observed, and we published on that, like a large dose of MCT, when you take the liver out and look at it, there’s globules of fat all in the liver.
Tim Ferriss: Oh, that sounds bad.
Dominic D’Agostino: Well, we see a fatty liver, but we did not see evidence of necrosis, but we did see some inflammatory markers.
Tim Ferriss: Necrosis is dead tissue, dead cells.
Dominic D’Agostino: Yeah. Yeah, we did not see that, but we saw signs. We saw sinusoidal dilation and TNF-α was elevated and some other things to suggest that large doses of MCT. And if you do the human equivalence, it would be like me taking upwards of like 80 to 100 milliliters per day. So that’s a lot.
Tim Ferriss: Although, it’s not that much though, right? I mean, because 30 milliliters is like two tablespoons, is that roughly, right? So it’s like six tablespoons. If you’re just squirting it into your coffee, it’s not hard to necessarily get above a hundred. It’s actually pretty easy. So where would you recommend capping MCT consumption? I’ll get rid of my camel back with the MCT oil in it, but where would you recommend capping the MCT consumption?
Dominic D’Agostino: The studies that were done showing benefits is like 20 milliliters per day, but they only did a single dose, which is weird, but that was the old Axona studies. And like 80 percent of people tolerated that, 20 percent didn’t. But I’m of the opinion that 20 milliliters twice per day would be perfectly fine for essentially most people that can tolerate that. And you’re going to have probably about 30 percent or more that can, but MCT is much more tolerable when you take it with a meal. So if you take MCT on empty stomach, prepare to be closer to a bathroom, right? So yeah.
Tim Ferriss: Yeah. Of all the disgusting things that I have consumed in my life, and I’ve had a lot, right? I mean, I’ve tried early prototypes of some of the esters and all sorts of stuff. I’m not going to say it was a Piña Colada, but I was fine with it. MCT oil to this day, I just find so absolutely revolting. I don’t know if it’s the neutrality and the mouth feel, but mixed with the mackerel and that apple cider vinegar, it sounds so disgusting. My friend almost puked in his mouth yesterday when I was describing it. It’s actually really good. I’m just a sucker for mackerel. I’ll take mackerel over sardines all day long, but — let’s see here… So I think we’ve covered a lot of the exogenous ketones. I’ll just pull this from our text thread because I think it might be a question on some people’s minds.
As I was trying to troubleshoot my apparent failure mode with ketosis because of my low numbers, I asked you, is there any argument to be made that I should have a ketogenic breakfast instead of intermittent fasting? Could it be that I’m causing problems with exogenous ketones, right? Am I delaying potentially the onset of my own ketosis? Is it like TRT, right? If you’re taking exogenous, remember that word, if you’re injecting or rubbing on or swallowing testosterone, it’s like your Leydig cells are pretty smart. That’s the reason your balls turn into Raisinets is because it’s like, “Cool, we don’t have to make that anymore.” So I thought, am I shooting myself in the foot by taking exogenous ketones? And it sounds like a little bit goes a long way, but like most things, in excess, it becomes its opposite, right? It becomes a hindrance and makes it problematic. Is that fair to say?
Dominic D’Agostino: Yeah. We’ve only seen the anti-endogenous ketosis effect with 1,3-Butanediol or 1,3-Butanediol-based ketone esters, and that is due in part to their potency and also the rapid elevation of ketones seem to have an insulin effect that can double or triple insulin. And even if we elevate ketones to the same level with a salt, we don’t see that spike up in insulin. So that could be coming into play with your low ketones if you are consuming the monoester.
Tim Ferriss: Not much. Every once in a while, like before exercise, because I might not mind the spike, but I’m not consuming a ton. Yeah.
Dominic D’Agostino: But the breakfast, I’m of the opinion that protein loading in the morning, actually when you first wake up, and I think Donald Layman and maybe Stu Phillips would also agree with this, and maybe Layne Norton too, the protein guys in the camp, is that protein in the morning kind of amps up your metabolism throughout the rest of the day. And I think if you abstain from eating during the day, you tend to get the munchies later in the day and you tend to overeat, whereas if you have a protein-heavy meal in the morning with high fat, then that can sort of rev up your metabolism for a good part of the day. But then again, some people, me included, my mind is not as sharp when I have —
Tim Ferriss: Well, that’s the thing. That’s the thing, right?
Dominic D’Agostino: Yeah.
Tim Ferriss: Yeah, I would say that, I mean, for 15 years, the sort of 30 grams within 30 minutes of waking up has been this sort of easy to remember heuristic that I’ve recommended for folks and that, if I am not intermittent fasting, that’s also what I do, but I’ve become so addicted to the mental sharpness that it’s just like, man, I know that if, for instance, if I want to do three hours of writing, I do not want to have food immediately prior to that.
Dominic D’Agostino: Yeah.
Tim Ferriss: But I would say, I’m also at a point, I think, where throwing up really heavy weight for me and getting as big and strong as possible is just not — it’s less of a priority than it once was, after shoulder surgeries and elbow surgeries and various things. Not that I want to be the skinniest guy in the room, but —
Okay. It sounds like the pharmacokinetics are maybe to blame with the associated spike in insulin for some of the issues you might run into if you’re taking the 1,3-Butanediol-based products.
Dominic D’Agostino: It can be, and I suspect it is, and I’ve kind of proven with myself that’s the case, but it also can be mitigated in part by mixing, taking it with a meal or taking it with MCT. But then you get the — it is metabolized, like 30 milliliters of 1,3-Butanediol is kind of like 30 milliliters of ethanol.
Tim Ferriss: Yeah.
Dominic D’Agostino: And then 1,3-Butanediol can create dependence and it also can create — you get withdrawal. So it’s establishing literature. There’s several publications just showing that with 1,3-Butanediol will produce dependency, and when you abruptly stop 1,3-Butanediol after consuming it for a period of time, there’s essentially alcohol withdrawal from that.
Tim Ferriss: What are the symptoms of that? I mean, imagine you don’t get DT, right? You’re not getting shakes or anything, are you? But, I mean, what happens?
Dominic D’Agostino: Yeah, it is, I mean, it’s like classical kind of ethanol withdrawal, maybe not quite as dramatic, but the glycols or diol alcohols do have a GABAergic effect, so you’re doing that. And yeah, I mean, it’s well established it has narcotic-like properties and that kind of stymied its use as a synthetic food for space flight. Well, I think that the palatability also factored into that, but also in the literature, it notes a narcotic effect of this and then the animal studies and really showed dependency and withdrawal.
Tim Ferriss: Just to give a reiteration of that, I mean, the 1,3-Butanediol-based stuff is also sold as an alcohol replacement. So of course, being the idiot that I am, not idiot, just like I’m eager to experiment here and there if it’s not going to kill me, and so I thought, “You know what? I don’t want to drink tonight.” I remember where I was. I was in Upstate New York, about to go to a restaurant with a friend. I knew he would want to drink, and then I wanted to be able to say, “Hey, I already had this ahead of time. Don’t worry. We’re on the same level.”
And I chugged a small can. It wasn’t, in terms of liquid volume, a lot, right? I don’t know, six ounces, eight ounces. And I felt like I could barely walk to the bathroom. I was smashed. It was, like almost knocked a glass off the table. I was like, “Holy shit, I did not do this risk assessment properly. Thank God I’m not about to get into a car,” because it took a little while to wear off. So that narcotic effect is really, it’s not always subtle.
Dominic D’Agostino: I made jello shots. I made 1,3-Butanediol jello shots. And before we made the ketone esters in 2009, Patrick Arnold and I kind of formulated this.
Tim Ferriss: Patrick Arnold. So people who don’t recognize Patrick, listen to my conversation with him from years ago, but if you know BALCO or remember when Barry Bonds grew a few head sizes or any of that stuff, anyway, Patrick’s got some stories.
Dominic D’Agostino: Yeah.
Tim Ferriss: So the jello shots, so what happened with the jello shots?
Dominic D’Agostino: Yeah. Well, that was the way to get it down because 1,3-Butanediol is so nasty, right? So you could basically just warm up pure 1,3-Butanediol in a pot and then add cherry-flavored sugar-free jello and then stir it up and then pour it into like a cookie pan and then cut it into cubes, which you get 20 milliliters per jello shot, and make it pretty strong so it’s like firm jello, and I would just hit like two or three of them and just be buzzing. And I talk about it, like 1,3-Butanediol can be fun and it’s a lesser of two evils when we’re talking about ethanol. So I actually tried to file a patent for the use of 1,3-Butanediol for alcohol withdrawal and things like that. But actually, there was some prior art on that, and this is many years ago, but I actually do think it could be part used by people if they could transition off of ethanol, potentially use that, but there are other ways to get off alcohol. I’m not advocating for that.
But my concern, is why I’m talking about it now too, is that I know there’s older people out there with dementia, perhaps Alzheimer’s disease, that if they’re consuming 1,3-Butanediol as a ketogenic supplement, it’s going to make you dizzy. It’s going to decrease your stability, like it’s going to make you potentially fall, break your hip. And then when you’re older, your liver, your ability to detoxify alcohol, an 80-year-old only has like 20 or 30 percent of the capacity to do that. So the same amount of 1,3-Butanediol for a 20-year-old is going to be like three to five times harder on your liver as we age, right? And people note that, like as you age, you just can’t tolerate the same amount of alcohol.
Tim Ferriss: Yeah.
Dominic D’Agostino: So I think these things, the 1,3-Butanediol-based supplements, the straight up 1,3-Butanediol and 1,3-Butanediol-based ketone esters are problematic for the age population that I think some of these products or companies are targeting. And I say that not only as a scientist, but because of the volume of emails that I get on that. People were like, “I got super buzzed. I didn’t know what happened.” And some people are very sensitive to it, like I gave my wife — she can’t tolerate alcohol at all and she took a shot glass of the stuff and she could not believe that it was a legal supplement to sell.
And now this will probably interest a lot of people, so they’ll probably go out and buy it, but I’m just saying like if you’re sensitive to alcohol, you’re going to get overly buzzed, and my concern is that, hey, if you want to use it for recreational, that’s your thing and maybe it’s better than alcohol, but for older people, a large dose of 1,3-Butanediol is problematic from a narcotic, from just the potential for just getting drunk, just straight up drunk. And Dr. Veech told me that a long time ago, I was like, because I was trying to get the ester from him and I was like, “What if I just use 1,3-Butanediol?” It’s like, “You’ll get drunk.” So it’s like he instilled that, that, “Do not do that.” That’s what he said.
Tim Ferriss: And Veech was the co-inventor, is that fair to say, of the bonded monoester that was funded in part by, was it the DOD or DARPA?
Dominic D’Agostino: DARPA.
Tim Ferriss: DARPA and then patented at Oxford. Is that right? Am I getting my facts straight or am I getting things mixed up?
Dominic D’Agostino: Yeah. Well, Oxford sort of acquired the IP and made a company out of it, but we have to credit Dr. Richard Veech, who passed away a few years ago, for the conception of a ketone ester for just — Dr. Veech was the student of Hans Kreb.
Tim Ferriss: Kreb of Krebs cycle?
Dominic D’Agostino: Krebs cycle, yes.
Tim Ferriss: That’s wild. Wow.
Dominic D’Agostino: Yeah.
I went to Dr. Veech’s lab at the NIH. I saw the whole ketone process, I tested different things. We were in communication, and I think he was a very colorful character and he had an amazing mind. We disagreed, we agreed to disagree on some things, but I consider him a mentor of mine, and I think we all owe a lot. I don’t think exogenous ketones may even not exist. Well, Henri Brunengraber and some other people, Sami Hashim developed the triester. So there was other people in this space, but he really advanced the science and ultimately the application of exogenous ketones and I think has written extensively about it. I mean, these things were around for a long time, and I think as science advances, we have more information and then we can — I have pivoted away from these things, although we still use them in some experiments. I published some really nice data on 1,3-Butanediol, actually even in cancer studies too, but at the same time, I realized that the negative effects, I can pivot away from that. We have other molecules in development now.
Tim Ferriss: So I know as I’m watching things get dark on the East Coast for you that we’ll wrap up in just a few minutes. But in brief, you mentioned fat, salt, fiber as things that can be helpful for slowing, I guess, gastric emptying of these meals that I’m having. And I’m curious for you, on a ketogenic diet, what are your favorite sources of fiber, supplemental or in whole food form?
Dominic D’Agostino: Whole food form. I like broccoli, and I buy broccoli florets, and then I cut the tip of the floret off, and I have a bowl of that and I give the stalk and stuff to my dogs and I chop it up for their fiber. So that’s something that I do, I don’t know, just to get a higher dose of broccoli. But broccoli, and then wild blueberries that has about half of the sugar and more fiber. They’re about a quarter of the size of like the huge blueberries you buy at, like, Walmart. But so wild blueberries, I like apples because they have a certain fiber called pectin in it. Some people that have a problem with fiber can’t digest pectin or they get gassy, so it’s on the FODMAP list or whatever. But wild blueberries, just green vegetables in general, but I like broccoli, and apples are pretty much something I have every day.
Tim Ferriss: Now, the wild blueberries, I just want to really underline wild for people because that is not what you’re necessarily going to get at your local grocery store that’s been optimized to be as sweet as —
Dominic D’Agostino: No. They’re in Publix. So I can get them in Publix down here. And I think, I don’t know, actually I think they’re in Walmart too. I think you can go to Walmart, and I think you might have to sneak around for them, but there’s like a brand, they have wild raspberries and blueberries and blackberries together. I forget the name of the brand, but they come in like big two or three-pound bags too.
Tim Ferriss: How much can you eat of apples or berries before undoing all the good metabolic work that you’re doing in ketosis, right? Because even, for instance, we’ve talked about how easy it is, and it really is easy as long as you’re pretty simple to please dietarily, to, say, travel for keto, right? So you just pack a bunch of canned sardines, mackerel, maybe some oysters, and macadamia nuts, and you’re kind of good to go, like these things are pretty calorically dense. But the macadamia nuts, I was looking at the bag the other day because it’s one of the few kind of crunchy things that I feel like I can eat aside from some of these vegetables, and I was like, “Wow, if you go whole hog in the macadamia nuts, you can rack up the carbs after a while.” What about apples and berries? Where’s your cutoff point for yourself?
Dominic D’Agostino: Well, macadamia nuts actually have that three-to-one to four-to-one ratio of fat to — so they are pretty high in fat, but like cashews and then like almonds and other nuts. I like walnuts too, I forgot to mention. So I have walnuts, a small organic apples we buy, wild blueberries, and broccoli pretty much every day, and all that together ends up being about 60 to 70 grams of carbs, but one third of the carbs is fiber, so it’s essentially non-glycemic. I haven’t had any of that today, but I tend to have that at dinner and then my snack at nighttime. So everything that I just mentioned, the carbs. But I don’t think about it as undoing like ketosis, and I do think my glucose tank is always like maybe 10 or 20 percent full, so I’m always running kind of low on glucose, and on some days I’m more active.
Tim Ferriss: What’s your height and weight, Dom, at the moment?
Dominic D’Agostino: Six foot, 220, and I’ve been, give or take, five pounds for years now, yeah. So just always cruise at like 220. Yeah.
Tim Ferriss: Yeah. I mean —
Dominic D’Agostino: 100 kilograms.
Tim Ferriss: Yeah, good body composition. That is a lot of muscle for people who are not watching the video. I’m just trying to set the maybe context for what your tolerance might be for grams of carbohydrates.
Dominic D’Agostino: I have pretty good tolerance for carbs now, but I think I have good tolerance more now because I’ve titrated some carbs back in, because I did go probably at least five years on like very low, like clinical ketogenic. And I did end up losing like almost like 18 pounds of like lean body mass, and then I took a year off in 2018, when we bought our farm. I was very busy on the farm. Then I bought weights and just have it on the farm. And then I’ve been doing DEXA. My last DEXA, it was 218, but under — I was like 9.8 percent body fat, like still under 10 percent. But I gained muscle when I got back into lifting and just did the heavy compound movements again. I don’t go super crazy on the weight, but I do train hard. But —
Tim Ferriss: You found the addition of the carbohydrates to be beneficial, that slightly higher quantity of carbohydrates?
Dominic D’Agostino: Yeah. I’ve added more carbs back in over the years, and that has helped me maintain my body weight. And I like eating those foods. I enjoy those foods. I think they have beneficial fiber, phytonutrients, other micronutrients that I think are beneficial. And I can maintain a level of ketosis about 0.5 to 1.5 day in and day out eating those foods every day. And I do titrate in like the MCTs and I get like one or two packets of KetoStart of day, maybe up to three if I’m traveling, but that’s my normal protocol and that has optimized all my biomarkers. I actually got full blood work today. Kind of waiting for that to come back to see. It should be interesting. I was inadvertently took something that I thought was laced with something, some gummies I told you about, but —
Tim Ferriss: People are going to assume. When people hear gummies, they assume it’s THC, but this was what, theanine and magnesium? It should have been really innocuous, right? Is that right?
Dominic D’Agostino: Yeah. Theanine and magnesium, my wife bought it at Marshalls. We both took two. We woke up in the morning and she says,” I’m dizzy.” She’s asking me, “What did you give me last night?” I was like, “I didn’t give you anything.” Because sometimes I give her stuff. I tried to get up, fell flat on the floor. Both of us could not walk. We were both completely incapacitated. I called the Poison Control Center. And yeah, so basically I’ve been running around to different labs, and now I’m doing forensics, so do something. I’m still buzzed —
Tim Ferriss: Wow. Really?
Dominic D’Agostino: — so if I don’t seem like myself, because I’m still buzzed 48 hours later. So we took something —
Tim Ferriss: That is wild.
Dominic D’Agostino: We had the spinnies, and even this morning I woke up, I had the spinnies walking to — so whatever it was, it was pretty powerful. And I have a little bit of a back injury from about a week ago, and I don’t have any pain from that. So I think whatever it is, I’m thinking potentially a fentanyl derivative or something, but —
Tim Ferriss: Yikes, that’s terrifying.
Dominic D’Agostino: My wife does not drink, she doesn’t use any drugs, so she was pretty much really floored by this.
Tim Ferriss: Wow. Did you go back and buy some more of them to send off to get analyzed?
Dominic D’Agostino: Well, I have it. Yeah. So I collected my urine, my wife collected her urine, and then I’m doing the necessary blood work, and I’ve contacted a forensic lab, and we have doctors involved in all this now.
Tim Ferriss: Wow. Dosed the wrong guy. Or the right guy, because you imagine like what if that had been a 80-year-old woman sleeping on the second floor. I mean, that’s dangerous.
Dominic D’Agostino: Absolutely. Yep, absolutely. I just took two and I’m a pretty big guy and everything, but if a little kid took two or four or five — so obviously, I don’t know, the company, and the company you can find it on Amazon, mixed it up and it’s laced with something or they just put high concentration THC and I kind of know what, but this is, we’re talking 48 hours later and I’m still feeling it.
Tim Ferriss: That’s wild.
Dominic D’Agostino: I’m super curious with my blood work, so I’m waiting for that to come in. Be careful, people out there because —
Tim Ferriss: Be careful of those gummies, folks.
Dominic D’Agostino: Yeah. Not regulated.
Tim Ferriss: Yeah. Dom, is there anything else you would like to mention or anywhere you’d like to point people before we wind this to a close?
Dominic D’Agostino: I don’t think so. I mean, we talked a lot about like sardine fasting and everything, I think, before.
Tim Ferriss: In the prior conversation, yeah.
Dominic D’Agostino: Yeah, yeah. I’d like to credit to Dr. Annette Bosworth, Dr. Boz, because, I mean, I’ve kind of came up with this idea, but it got traction, and I think she has — a lot of people that email me about sardine fasting heard it from Dr. Boz, and she’s amplified the message with millions of YouTube followers. But she kind of took an idea and actually put it into practice and amplified it through a lot of people, and then those people emailed me about it, so that amplified and secured my knowledge. “Yes, okay, these benefits are…” And now she’s been on like Diary of a CEO podcast, I think, and some other podcasts.
So I’d also like to mention, I’m testing today even, there’s a company coming out, I don’t know if I can mention or not, but I will, Medifoodz. And for years, there’s no whole food-based ketogenic diet prescription foods. So I have no association with the company, I’m just testing their product, but they’re called Medifoodz. And
Tim Ferriss: How do you spell that? M-E-T-I? M-E-T —
Dominic D’Agostino: M-E-D-I-F-O-O-
Tim Ferriss: Oh, Medi. I got it. Medifoodz.
Dominic D’Agostino: Yeah, Medifoodz. With a Z. And I got to tell you, these are like gourmet foods, and then they hit the macros of a modified ketogenic diet. And we talked about if someone says the ketogenic diet is not palatable, they have to see these foods. They’re prescription whole food. There’s other companies that tried to do this, and they even got like the packaging is like compostable, like it looks like plastic, but I could throw it in my garden and it breaks down. I’m very impressed with this. I just mentioned that because I just got these foods yesterday and I was really impressed, but other companies have not been so impressive. So Medifoodz is pretty impressive. And Quest Nutrition tried to do this a while back and I think their foods were good, but they got a new CEO and just phased it out.
But I like the idea of a prescription, whole food, ketogenic diet that potentially a doctor could write a prescription. And a week of foods could be sent to the patients. I’ve been questioning why someone has not done this, but I know the margins are very small in the food world, so it’s hard to kind of get that up and running.
Tim Ferriss: I mean, they could take the approach that a lot of companies take, a lot of tech startups take, like Uber, Tesla, et cetera, you sell in the beginning for much higher price to people who are willing to pay that. You use that to subsidize the R&D or the scale necessary to then offer, right? Instead of Uber Black, you have UberX, and similarly for a lot of companies. I mean, I would pay for this, right? And yeah, I wouldn’t say totally price-insensitive, but I’m willing to pay for convenience because there does come a point where I’ve had enough canned mackerel and salads with rib eye that I would love to have something else in any case. So I will check out Medifoodz.
Let’s see. Dom, are you active on social anywhere? Should people find you anywhere online?
Dominic D’Agostino: Yeah, I’m not too active, but I try to jump on about once or twice a week, and I cap my social to maybe an hour a week.
Tim Ferriss: Yep. Smart man.
Dominic D’Agostino: I try to respond back to things, yeah. Kind of delete the apps from my phone or some of them, but I repost things and try to acknowledge some questions and stuff people have on this, and then I collect questions and then — we have our own podcast, the Metabolic Link Podcast. And we have a Metabolic Initiative Platform which has ACCME accreditation, so it’s like you can get CME credits from it. So that has been a project that we’re working on and trying to advance everything we’re talking about into human application through that.
Tim Ferriss: Yeah. Beautiful. Well, I’m trying to think of any other links. Are there any other links that you want to mention? And we’ll stick these all in the show notes as well for people.
Dominic D’Agostino: Yeah. Ketonutrition.org. No products. I don’t sell anything. So ketonutrition.org information website, the Metabolic Link Podcast, and the Metabolic Health Initiative Education Platform are like the three biggies, I think.
Tim Ferriss: Beautiful. We will link to all those things for people listening as well as — God save — People who help me do the show notes, they’re going to have a lot to dig through, but we will link to everything that we can find a link for at tim.blog/podcast. Just search Dominic, and this will be the most recent episode. I mean, we may have some in the future, so you’ll find it.
And Dom, thank you so much for taking the time, man. Always great to see you.
Dominic D’Agostino: My pleasure. Thank you, Tim, for having me. Appreciate it. Good seeing you.Tim Ferriss: Yeah. And everybody, as per always, thanks for tuning in, and until next time, be just a bit kinder to others and also to yourself, especially if you might be self-flagellating yourself over not hitting your GKIs, like yours truly. All right. Take care, everybody.
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