How to Use Ketosis for Enhanced Mood, Cognition, and Long-Term Brain Protection — Dr. Dom D'Agostino

1. 0:00 – 0:49

   Preview.

   1. DDDr. Dominic D’Agostino0:00

      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. 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 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.

2. 0:49 – 5:50

   Ketosis benefits: Quieting the mind, GABA elevation, metabolic psychiatry.

   1. TFTim Ferriss0:49

      Dom, happy holidays. Nice to see you.

   2. DDDr. Dominic D’Agostino0:51

      Great to see you, Tim. Thanks for connecting.

   3. TFTim Ferriss0:54

      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, "You know, 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 Dr. 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, uh, first, let's just give some of the, let's, I'll 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?

   4. DDDr. Dominic D’Agostino2:20

      There are many benefits to being in ketosis, and a ketogenic diet, if we're gonna go there, kind of has the benefits of fasting and are f- you know, for millennia we know the benefits of fasting without the, without the baggage, without the metabolic baggage, you know, the muscle loss, the fatigue. Obviously, you can't live in a, you know, 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, you know, from centuries we knew this, and now over the past decades, this has been, like, a term kind of used. And it, 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 you know, that's why people gravitate towards alcohol, right? The GABAergic-

   5. TFTim Ferriss3:30

      Mm-hmm

   6. DDDr. Dominic D’Agostino3:30

      ... 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-

   7. TFTim Ferriss3:44

      Mm-hmm

   8. DDDr. Dominic D’Agostino3:44

      ... sort of quiet it down. And that I think really echoes its broad application for metabolic psychiatry, which is-

   9. TFTim Ferriss3:53

      Mm-hmm

   10. DDDr. Dominic D’Agostino3:53

       ... everything from major depression to bipolar to schizophrenia to anxiety disorders to anorexia nervosa. So that, that's a very interesting and rapidly expanding application of ketosis that's being funded largely by the Baszucki group-

   11. TFTim Ferriss4:09

       Yeah

   12. DDDr. Dominic D’Agostino4:09

       ... that you just interviewed.

   13. TFTim Ferriss4:11

       Had David on.

   14. DDDr. Dominic D’Agostino4:11

       Yeah.

   15. TFTim Ferriss4:12

       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?

   16. DDDr. Dominic D’Agostino4:34

       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. 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-

   17. TFTim Ferriss5:26

       Mm-hmm

   18. DDDr. Dominic D’Agostino5:26

       ... 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 [chuckles] has developed and there's 160 or more registered clinical trials on exogenous ketones on clinicaltrials.gov. And I could go into each of the applications individually if we want to go

3. 5:50 – 9:53

   My Lyme disease story: Pseudo-dementia reversed in 3-4 days of ketosis.

   1. DDDr. Dominic D’Agostino5:50

      there.

   2. TFTim Ferriss5:50

      Well, [chuckles] as we talked about before recording, and I have to act as a bit of a referee for my audience because I know you can go as deep as, as we want down the rabbit hole into the 17th dimension of Biochemistry. So if you get possessed by the, the organic chemistry demons [laughs] and start speaking in tongues, I'll rein 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 gonna 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. You can arrive at some similar places, but like you said, 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 [chuckles] 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 diet.

   3. DDDr. Dominic D’Agostino7:09

      Yeah.

   4. TFTim Ferriss7:10

      So we're gonna 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, 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 tick-borne disease-

   5. DDDr. Dominic D’Agostino7:59

      Wow

   6. TFTim Ferriss7:59

      ... and was credibly diagnosed. So the second time I had Lyme, I got to a point, because I, 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 f- I really felt like I was operating at 10% 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% of my calories from fat, and keeping my, 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

4. 9:53 – 13:33

   Spirochetes are glycolytic: Starve the bug, boost the immune response.

   1. TFTim Ferriss9:53

      I recommended that, and this is not a randomized controlled trial, but over the years, 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 tick-borne disease. And, you know, 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, right? In brief, do you have a theory or an explanation for why that would work?

   2. DDDr. Dominic D’Agostino10:45

      [chuckles] Yeah. I'm glad you brought that up because quickly, dozens if not hundreds of people with tick-borne diseases, including Lyme disease and all the tick-borne diseases, have communicated with me. And one of the patients is actually Deanna Tidone, who was diagnosed with ALS in-- prior to 2010, and has basically been stabilized, given three years to live. So I realized that it's underdiagnosed. The, the tests to do that are kind of controversial, you know, with the CDC testing, the two-tier testing, and IGeneX. So I know I'm going off track a little bit here, but I think it's important to say that the spirochete Borrelia, that spirochete is essentially 100% glycolytic.

   3. TFTim Ferriss11:29

      Mm-hmm.

   4. DDDr. Dominic D’Agostino11:29

      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, you know, they're doing CAR T therapy and, and checkpoint inhibitors because of the ketogenic enhancement of the adaptive immune response. So and 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, is inflammatory, but people who have shingles and herpes simplex and things like that, I have an inbox full of people [chuckles] 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-

   5. TFTim Ferriss12:40

      Mm-hmm

   6. DDDr. Dominic D’Agostino12:40

      ... to keep the spirochete in a dormant stage or maybe eradicating it in-

   7. TFTim Ferriss12:46

      Mm-hmm

   8. DDDr. Dominic D’Agostino12:46

      ... in some contexts.

   9. TFTim Ferriss12:47

      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, 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 [chuckles] you know, 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 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, of various

5. 13:33 – 15:07

   Ketosis and cancer: Slowing glycolytic tumors, enhancing standard care.

   1. TFTim Ferriss13:33

      types. 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?

   2. DDDr. Dominic D’Agostino13:47

      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, you know, 20, 22, something like that, a eucaloric, meaning like keeping stable caloric level to maintain your weight is gonna 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, 'cause there's people studying ketosis for chemo brain, like reversing chemo brain-

   3. TFTim Ferriss14:37

      Mm-hmm

   4. DDDr. Dominic D’Agostino14:37

      ... and, like, managing that. So it has a broad array of applications, not just targeting-- It's targeting the tumor growth and putting a brake on it, not-- it's not a cure for cancer, and I cringe when people talk about that online, the ketogenic diet curing cancer. It does slow it down, especially if it's highly glycolytic, which 80% of cancers are. And it enhances and augments the response to the standard of care. That's radiation, chemo, and immune-based therapies. We know that now.

6. 15:07 – 17:40

   My 18-day keto experiment: Mood stabilization, Alzheimer’s prevention hopes.

   1. TFTim Ferriss15:07

      All right. So why have I been in ketosis for 18 days, and why am I doing it a, 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 [chuckles] from Dom because this is very self-interested. But what I have found is that for mood stabilization, and you mentioned metabolic psychiatry, I've had-- and you made the introduction, I believe, Chris Palmer out of Harvard on the podcast to discuss this. But there are certain conditions, whether it's depression, but even more squirrely 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 are no longer meet the criteria, right, 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, 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 protective carryover, right? And I also find it much easier now that I started doing intermittent-- I've been 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. Like, 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, completely revolutionized, I mean, that's an overused word, but completely polished my insulin sensitivity and metabolic

7. 17:40 – 21:39

   Metabolic memory: Carryover effects and Valter Longo’s fasting mimicking research.

   1. TFTim Ferriss17:40

      health on a bunch of levels. Like, my labs have never been better. My oral glucose tolerance test has never been better.

   2. DDDr. Dominic D’Agostino17:45

      Mm-hmm.

   3. TFTim Ferriss17:46

      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 y- 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 just, I don't know if there's a there there. But what are your thoughts?

   4. DDDr. Dominic D’Agostino18:23

      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-

   5. TFTim Ferriss18:38

      Mm-hmm

   6. DDDr. Dominic D’Agostino18:38

      ... 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.

   7. TFTim Ferriss18:53

      In his case, this would be the fast mimicking diet, so a few-

   8. DDDr. Dominic D’Agostino18:56

      Yeah

   9. TFTim Ferriss18:56

      ... hundred calories a day?

   10. DDDr. Dominic D’Agostino18:57

       Yeah, like 600, you know, using his protocol of various foods, kind of gravitating towards more of a plant-based, uh, lower protein-

   11. TFTim Ferriss19:06

       Mm

   12. DDDr. Dominic D’Agostino19:06

       ... 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. 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. You know?

   13. TFTim Ferriss19:44

       Yeah.

   14. DDDr. Dominic D’Agostino19:44

       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, you know, gene programs, epigenetic regulation that comes to play. So-

   15. TFTim Ferriss19:58

       Mm-hmm

   16. DDDr. Dominic D’Agostino19:58

       ... first and foremost, it's changing our mitochondrial function and mitochondrial capacity. So the number of mitochondria increase, and then when you take a break and then get that stimulation again, that mitochondria is kind of there and it responds very rapidly. So-

   17. TFTim Ferriss20:14

       Yeah. Thank you for that. And I want to bookmark, maybe we come back to this, but if people are trying to think about this, understanding that the, the science right now is maybe provisional or, you know, hypotheses worth disproving at this point, but that it seems to make sense, right? From an evolutionary perspective-

   18. DDDr. Dominic D’Agostino20:32

       Yep

   19. TFTim Ferriss20:32

       ... that both muscle memory and metabolic memory would be a thing. Otherwise [laughs] it makes sense your body would want to adapt to be prepared for the next famine or whatever it might be, right?

   20. DDDr. Dominic D’Agostino20:45

       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, same scenario. They take time off, and then that VO2 max quickly establishes again. And-

   21. TFTim Ferriss20:59

       Mm-hmm

   22. DDDr. Dominic D’Agostino21:00

       ... it's muscle, but it's, it's metabolic. So I like to use the term metabolic memory.

   23. TFTim Ferriss21:04

       Metabolic memory.

   24. DDDr. Dominic D’Agostino21:05

       Yeah.

   25. TFTim Ferriss21:05

       Okay. Yeah, [chuckles] metabolic memory. Just so people know where I am at, at the moment, and actually, yeah, I'll just tell people, like, 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

8. 21:39 – 23:49

   Intermittent fasting as keto on-ramp: My 2-8 p.m. eating window.

   1. TFTim Ferriss21:39

      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, uh, 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?

   2. DDDr. Dominic D’Agostino22:55

      Mm-hmm. Yep.

   3. TFTim Ferriss22:56

      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 takes, it took me about a week and a half for my body to, 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 it seems to be pretty remediated or, 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

9. 23:49 – 28:12

   Dom’s budget keto meal: Canned mackerel, MCT oil, apple cider vinegar.

   1. TFTim Ferriss23:49

      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 [chuckles] of canned mackerel with about two tablespoons, 30 milliliters of MCT oil, plus, uh, apple cider vinegar with some salt and pepper. It's actually delicious. I just love mackerel. Oh, there it is. Yeah, you've got your apple cider vinegar right there.

   2. DDDr. Dominic D’Agostino24:16

      Cheap stuff you can get on Amazon, so.

   3. TFTim Ferriss24:18

      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?

   4. DDDr. Dominic D’Agostino24:27

      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.

   5. TFTim Ferriss24:38

      Yep.

   6. DDDr. Dominic D’Agostino24:39

      So $1.50 for almost a pound of mackerel that you can get that for.

   7. TFTim Ferriss24:43

      [laughs]

   8. DDDr. Dominic D’Agostino24:43

      Like, you can't... And the omega-3s are off the charts. The heavy metals are low. You know, I consume pounds of this stuff, and I've gotten my blood and my hair heavy metals tested, and it's like, like super low, like non-detectable, so I wouldn't worry about that. People have questions about cost and heavy metals, and that's a non-issue, you know, for me.

   9. TFTim Ferriss25:02

      And maybe you could mention, I'll put links in the show notes as well, but d- since we're on the topic, any, any brands that you default to, that you like? And that chub mackerel piece, for folks, that detail is important 'cause there are mackerel of m- many different sizes.

   10. DDDr. Dominic D’Agostino25:17

       Yeah, king mackerel is kind of high. This is Chicken of the Sea, so if you wanna do the budget, you buy it by 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, just chub mackerel or jack mackerel, so they're both small fish. And I kinda like the King Oscar brand too.

   11. TFTim Ferriss25:41

       Yep.

   12. DDDr. Dominic D’Agostino25:42

       Just a little bit more pricey. And Season's brand is pretty good too, but, I mean, it's, like, as cheap as dog food. [laughs]

   13. TFTim Ferriss25:50

       [laughs]

   14. DDDr. Dominic D’Agostino25:50

       I mean, we buy some pretty fancy freeze-dried. We don't buy the kibble stuff. But when you run the numbers-

   15. TFTim Ferriss25:56

       It's very inexpensive

   16. DDDr. Dominic D’Agostino25:57

       ... we buy cases of eggs for, like, 120 per... You know, if you do, like, eggs, fish, beef, and also turkey, you can get turkeys for under a dollar a pound, the whole turkey.

   17. TFTim Ferriss26:07

       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. Like, there's more that you can eat.

   18. DDDr. Dominic D’Agostino26:18

       Yes.

   19. TFTim Ferriss26:18

       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 damn thing. You're just swapping out default meals. So my first meal is something typically pretty small, like the, the mackerel 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, right? And later on I might have, like, a rib eye 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 I'm a little, let's say [laughs] lower performance when I'm, 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, right, 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.

   20. DDDr. Dominic D’Agostino27:51

       Mm-hmm.

   21. TFTim Ferriss27:52

       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-

   22. DDDr. Dominic D’Agostino28:05

       Mm-hmm

   23. TFTim Ferriss28:05

       ... 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.

10. 28:12 – 31:42

    My ketone measurement paradox: Feeling sharp at 0.2 mM readings.

    1. TFTim Ferriss28:12

       So I'm gathering all of this, but then I notice something really weird, which I've texted you about 'cause I, 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, 'cause you do have to often calibrate these things, right? Don't assume that your continuous monitors are accurate, and you wanna 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 'cause I didn't hear it, and it was like, "Critical medical alert" or whatever-

    2. DDDr. Dominic D’Agostino28:50

       [laughs]

    3. TFTim Ferriss28:51

       ... the code red was because my glucose was 69, I suppose. It's gotten quite a bit lower on ketosis but, you know, usually hovers somewhere between, like, 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, you know, between 1.2 and 2 millimolars is anxiolytic, right? 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? [laughs]

    4. DDDr. Dominic D’Agostino29:52

       [laughs]

    5. TFTim Ferriss29:52

       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?

    6. DDDr. Dominic D’Agostino30:01

       I would definitely say you're running lean. And I think what you've done in your OGT test is really good. I think you had messaged that.

    7. TFTim Ferriss30:09

       And the OGT 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.

    8. DDDr. Dominic D’Agostino30:19

       Yeah, the biggest metabolic lever would be you have enhanced insulin sensitivity.

    9. TFTim Ferriss30:25

       Mm-hmm.

    10. DDDr. Dominic D’Agostino30:25

        And I think that has been the focus. For example, Ben Bikman wrote a book on this and s- you know, doing hundreds of podcasts on insulin resistance, reversing insulin resistance and low carb ketogenic, you know, 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, you know, in older rats where we like gavage, where we tube feed the rats and they're older, the ketones get to toxic levels, whereas like 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, you know, with high metabolic fitness. And that's due in part to ketolytic enzymes. The-- you upregulate the MCT transporters. That could be two or, in rodents, two or three times higher. We-- 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.

11. 31:42 – 33:34

    The carburetor analogy: Ketone production vs. utilization explained.

    1. DDDr. Dominic D’Agostino31:42

       Also, I-- if you're in a caloric deficit, there's less spillover. I just bought like 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 like kind of pouring out the carburetor. So there's spillover of fuel, right? So [laughs] but when I'm running it, it's running lean because I'm using, I'm using the fuel that's kind of going to the carburetor. And kind of the same analogy here is that, you know, 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 like your ketones spike up.

    2. TFTim Ferriss32:20

       Yeah.

    3. DDDr. Dominic D’Agostino32:20

       So I remember some of my highest ketone levels ever is when I consumed [laughs] carbohydrates after I was fasting or in a state of keto. It like jumped up to five, six, seven. I was like, "What is going on here?"

    4. TFTim Ferriss32:31

       Yeah.

    5. DDDr. Dominic D’Agostino32:31

       But the glucose in that context is ketone sparing. But the glucose will also shut off ketogenesis, so it'll tank-

    6. TFTim Ferriss32:38

       Yeah

    7. DDDr. Dominic D’Agostino32:39

       ... you know, after, but.

    8. TFTim Ferriss32:40

       Afterwards. 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-

    9. DDDr. Dominic D’Agostino33:05

       Yeah

    10. TFTim Ferriss33:06

        ... the finger prick might pick up all 10 of those units. I, 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-

    11. DDDr. Dominic D’Agostino33:25

        Yeah

    12. TFTim Ferriss33:25

        ... very, very simplified description?

    13. DDDr. Dominic D’Agostino33:27

        And you're not measuring tissue levels of ketones, which we have done too, even in the brain.

    14. TFTim Ferriss33:31

        Yeah.

    15. DDDr. Dominic D’Agostino33:31

        And that can shoot up like really high.

12. 33:34 – 34:40

    Breath ketones vs. blood ketones: Better indicator in caloric deficit.

    1. DDDr. Dominic D’Agostino33:34

       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 like really low in the blood.

    2. TFTim Ferriss33:44

       Hmm.

    3. DDDr. Dominic D’Agostino33:44

       Low is like one to two, but we're like really deep into fasting, whereas our breath ketones were maxing out the meters. [laughs]

    4. TFTim Ferriss33:52

       Fair.

    5. DDDr. Dominic D’Agostino33:52

       We kind of 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-

    6. TFTim Ferriss34:08

       Mm-hmm

    7. DDDr. Dominic D’Agostino34:08

       ... uptake into the tissues.

    8. TFTim Ferriss34:10

       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.

    9. DDDr. Dominic D’Agostino34:19

       Acetone.

    10. TFTim Ferriss34:19

        Acetone.

    11. DDDr. Dominic D’Agostino34:20

        Yeah.

    12. TFTim Ferriss34:20

        Goddammit. All right. I knew I was close. That was-- it was a 50/50.

    13. DDDr. Dominic D’Agostino34:25

        Comes from the spontaneous decarboxylation of acetoacetate. Like we'll spit out about 20% of the acetoacetate will kick off to acetone, and then you can measure it.

    14. TFTim Ferriss34:35

        I got it.

    15. DDDr. Dominic D’Agostino34:35

        We've measured blood levels of each, and it's very tricky to do that, but we've done it in the lab.

    16. TFTim Ferriss34:39

        All right.

13. 34:40 – 37:52

    Gluconeogenesis fears: Fat, fiber, and salt to slow protein absorption.

    1. TFTim Ferriss34:40

       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 like 200 and 240 grams of protein a day, something like that? Is that roughly-

    2. DDDr. Dominic D’Agostino34:59

       Yeah, on active days. On like less active days, if I'm just behind my computer all day, maybe closer to 180, 200. But yeah, generally speaking.

    3. TFTim Ferriss35:07

       And people might have picked up when Dom was casually throwing around like, "You know when you've been squatting 400 and you take a break, and then you go back and you only could squat 300 pounds [laughs] '" Tom's a pretty big guy who's also deadlifted 500 pounds for like [laughs] 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 [laughs] 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?

    4. DDDr. Dominic D’Agostino36:12

       If you were to consume protein in the form of liquid, for example, like whey or something like that, then the, 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 stomach-

    5. TFTim Ferriss36:34

       [laughs] Talking dirty, Dom. [laughs]

    6. DDDr. Dominic D’Agostino36:36

       Pyloric sphincter is where your stomach connects to your small intestine. If you have a very fatty, salty, f- high fiber meal, that little-- that entryway, we call that the sphincter, it's the pyloric sphincter, will remain shut until like the contents of your stomach become Isotonic, which means that your body has to kind of 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 s- 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, you know, 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 like a fatty steak and MCT oil and then fiber, and that could be insoluble fiber is pretty good too, soluble and insoluble, that can slow the entry of amino acids and essentially buffer the gluconeogenic response.

14. 37:52 – 41:38

    The bunless double cheeseburger question: 80 grams of protein in one sitting.

    1. TFTim Ferriss37:52

       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.

    2. DDDr. Dominic D’Agostino38:04

       Yeah.

    3. TFTim Ferriss38:05

       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, like 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 like 80 grams of protein.

    4. DDDr. Dominic D’Agostino38:29

       Hmm.

    5. TFTim Ferriss38:30

       But plenty of fat, certainly. Tons of fat. Salty AF, plenty of salt. 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?

    6. DDDr. Dominic D’Agostino38:43

       I think you need to measure. So I'm kind of default back to like everybody's a unique metabolic entity. But if you eat that and kind of your activity level is high and you're in a bit of a caloric deficit, and you were to have that and sort of 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 over-satiated feeling, so we have, we have neurons, we have neuronal pathways to and from the liver and to and from the gut. We call that-

    7. TFTim Ferriss39:14

       Mm-hmm

    8. DDDr. Dominic D’Agostino39:15

       ... afferent and efferent signaling, right? And 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 kind of kicking you out of ketosis, but there's also like this when you have stretch receptors and you have a 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 like we're talking adrenaline, epinephrine, things like that, that can further augment and enhance gluconeogenesis. So-

    9. TFTim Ferriss39:53

       Okay. Let me just translate that for a second. So people wake up, cortisol's developed this like bad reputation among a lot of like online influencers, but it's like you really need cortisol, right? So [chuckles] when you wake up in the morning and you see a bit of a glucose spike, like 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, right, outside of how people think about digestion, blood sugar, insulin, et cetera, that just based on stretching your stomach, et cetera, right, with these mechanoreceptors taking the inputs, that that signals to the brain it's go time, so let's basically get things moving with, with these hormones, and that could in and of itself then trigger the liver to produce more glucose or liberate more glycogen, I guess?

    10. DDDr. Dominic D’Agostino40:52

        It can if it's above and beyond what you normally eat.

    11. TFTim Ferriss40:56

        Yeah.

    12. DDDr. Dominic D’Agostino40:56

        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 sort of kind of bifurcates, but then the parasympathetic nervous system is sort of relax, digest, rest and relax, digest. So that kind of comes in after. So you might see a blip and sort of might feel kind of stimulated. Also, all the salt, if it's a salty meal, it's gonna 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.

15. 41:38 – 43:35

    Post-meal walking and GLUT4 activation: Timing your glucose disposal.

    1. DDDr. Dominic D’Agostino41:38

       So it's always good to go take a walk after a big meal.

    2. TFTim Ferriss41:42

       Yeah. I do that.

    3. DDDr. Dominic D’Agostino41:43

       Not like a strenuous, not like go squat and deadlift, but just, yeah, even a 10, 15, ideally like a 20-minute brisk walk is really good after a big meal.

    4. TFTim Ferriss41:52

       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. 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?

    5. DDDr. Dominic D’Agostino42:32

       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?

    6. TFTim Ferriss42:38

       Independent of the walk.

    7. DDDr. Dominic D’Agostino42:39

       Okay. So you're not walking, but you see the rise 60 to 90 minutes later.

    8. TFTim Ferriss42:43

       Yeah.

    9. DDDr. Dominic D’Agostino42:43

       So I'm, I'm saying that you might not see that rise 60 or 90 minutes later-

    10. TFTim Ferriss42:47

        If you did it right after the meal?

    11. DDDr. Dominic D’Agostino42:49

        Yeah, just because a little bit goes a long way. So just like walking, actually doing like some stretching and walking too, it, uh, activates the Glucose 4, the GLUT4 transporters.

    12. TFTim Ferriss43:01

        Yep.

    13. DDDr. Dominic D’Agostino43:01

        That's insulin independent, so less insulin is dumped, greater glucose uptake, and you're also using sort of the sympathetic nervous system mobilization of glucose through gluconeogenesis during that walk. So it then attenuates the buffering of ketogenesis. A very short walk can go a long way.

    14. TFTim Ferriss43:20

        Okay, cool. Yeah. The, is it GLUT4 or GLUT4? How do you pronounce that? I don't know. How do people say that?

    15. DDDr. Dominic D’Agostino43:25

        I say GLUT. I say GLUT4.

    16. TFTim Ferriss43:26

        All right. GLUT4.

    17. DDDr. Dominic D’Agostino43:27

        People say GLUT.

    18. TFTim Ferriss43:28

        Yeah. For the OGs in the audience, go back and look for GLUT4 in The 4-Hour Body.

16. 43:35 – 50:41

    CGM and ketone monitor limitations: When your devices gaslight you.

    1. TFTim Ferriss43:35

       It's in there. So the other measurement question I want to ask you about, which is, you know, these continuous glucose and ketone monitors are not designed for someone like me, right? They're developed, presumably, I don't know about the ketone monitor, but in the case of glucose, to help people with serious conditions not end up in very serious situations. So when I am looking at my ketone levels, right, like right now, I feel very sharp. I had some Keto Start [laughs] , you know this well, exogenous ketone salt-based product not too long ago. It's 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% of the time. There are a few outlier cases. If I'm just doing like a YOLO, you know, as many grams as possible exogenous ketone party, then maybe I could goose it, but we can talk about this. Like, o- 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, you know, right now I'm 0.4 millimolars of concentration on the PsyBio, and as we've talked about, maybe, maybe the Precision Xtra would give me an extra 0.1 or 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, is 103, right? Which is, which is higher than the week prior.

    2. DDDr. Dominic D’Agostino45:40

       Mm-hmm.

    3. TFTim Ferriss45:40

       But it goes around. It moves around. 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. I guess what I'm saying is, if my device is telling me, as it is right now, right, 0.4, "Fat not burning. You're almost not burning [laughs] fat at the moment. Not in ketone." Like, it's very chastising.

    4. DDDr. Dominic D’Agostino46:05

       [laughs]

    5. TFTim Ferriss46:05

       So if I'm to believe this by the letter of the law on the screen, I'm failing at ketosis. Any thoughts on how to kind of read the tea leaves here?

    6. DDDr. Dominic D’Agostino46:14

       I would kind of ignore that. I think that's sort of an app in the process of being sort of developed [laughs] the fat to me.

    7. TFTim Ferriss46:24

       Yeah.

    8. DDDr. Dominic D’Agostino46:24

       So you would need, like, 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 like in athletes, especially more advanced athletes, that, and we do a very strict keto macros and everything, that basically with a bunch of athletes, 0.8 is about as high as we get, and that's the average across. Sometimes you get guys like 2.5, 2.6 like every day, and the same guy with the same, you know, essentially metabolic phenotype will be running 0.4, 0.3. He could potentially just have greater ketone-

    9. TFTim Ferriss47:01

       Utilization

    10. DDDr. Dominic D’Agostino47:02

        ... utilization. So I think it would be important to measure your blood, so a continuous ketone monitor measures interstitial-

    11. TFTim Ferriss47:10

        Stitial, yeah

    12. DDDr. Dominic D’Agostino47:11

        ... ketones. That can be different. The PsyBio, I think it's a great device. It's very versatile. I can kind of, you know, jump in and out of saltwater. The thing stays on me. It's, I, almost like more reliable than a CGM. But I did notice, and I've probably used about 50 of these devices-

    13. TFTim Ferriss47:27

        [laughs]

    14. DDDr. Dominic D’Agostino47:27

        ... 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, the enzyme-based sensor system tends to just de... And you could get around that conceivably just by having the ability in the app to calibrate it.

    15. TFTim Ferriss47:48

        Mm-hmm.

    16. DDDr. Dominic D’Agostino47:48

        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. [laughs]

    17. TFTim Ferriss47:59

        Mm-hmm.

    18. DDDr. Dominic D’Agostino48:00

        So they acknowledged that at the company, and they said, "Yes, we realize that would fix the problem," but that's not a feature of the app yet.

    19. TFTim Ferriss48:08

        They do have in events, they have blood ketone on the bottom right. I don't know if it actually calibrates it. It may just record the blood ketone at this point.

    20. DDDr. Dominic D’Agostino48:17

        It does not have the ability to calibrate it, to my knowledge.

    21. TFTim Ferriss48:22

        I inputted one measurement on the, the Keto-Mojo, and it didn't seem to change it, right? The number stayed the same.

    22. DDDr. Dominic D’Agostino48:27

        No.

    23. TFTim Ferriss48:27

        So I think it's just logging it. Because you can do that with a glucometer.

    24. DDDr. Dominic D’Agostino48:32

        Well, you can do it with Dexcom.

    25. TFTim Ferriss48:33

        Dexcom.

    26. DDDr. Dominic D’Agostino48:34

        But not Abbott.

    27. TFTim Ferriss48:34

        Yeah. Okay.

    28. DDDr. Dominic D’Agostino48:35

        So 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 like 130.

    29. TFTim Ferriss48:42

        Yeah.

    30. DDDr. Dominic D’Agostino48:42

        But I measure, I'm like 80. It's literally like 50 because-
17. 50:41 – 58:16

    Rabbit starvation and protein-veggie days: Why your body won’t bankroll its own ketosis.

    1. TFTim Ferriss50:41

       But I do have a question for you, which I've never really been able to answer to my satisfaction, and it kind of relates to rabbit starvation. [laughs] 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 will 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 sort of dampens insulin response, 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 like moderate fat or low fat protein based keto diet if your goal in part is to lose body fat, or does that backfire?

    2. DDDr. Dominic D’Agostino52:33

       Yeah, just not indefinitely. So when I was... Did the ketogenic diet for a year, I was cruising about three hundred to three hundred and twenty grams of fat, sometimes three hundred and fifty grams of fat per day. And then just experimenting, I would throw in, uh, two days per week of protein veggies-

    3. TFTim Ferriss52:50

       Mm

    4. DDDr. Dominic D’Agostino52:51

       ... with about fifty to a hundred grams of fat. And in those days of dropping to three hundred plus grams of fat to fifty to a hundred grams of fat, after two days, like I swore, like I lost like a 2% body fat. Like and that-

    5. TFTim Ferriss53:04

       [laughs]

    6. DDDr. Dominic D’Agostino53:04

       ... 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.

    7. TFTim Ferriss53:18

       Huh.

    8. DDDr. Dominic D’Agostino53:18

       And if I kept that going, I could get pretty dramatic, like almost scary lean-

    9. TFTim Ferriss53:23

       [laughs]

    10. DDDr. Dominic D’Agostino53:23

        ... 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 gut health, and I would do that twice a week and it's pretty dramatic.

    11. TFTim Ferriss53:41

        Why not do it seven days a week? What happens when you try to do it for more?

    12. DDDr. Dominic D’Agostino53:45

        If the idea is to stay in ketosis, it was really hard for me to stay in ketosis if I do protein veggies. Like after two days I would kind of be out, but my metabolism would be cranking.

    13. TFTim Ferriss53:56

        Mechanistically, why is that the case? Why doesn't your body just break down more body fat?

    14. DDDr. Dominic D’Agostino54:00

        Well, it's taking body fat exogenously and endogenously, and I think the more fat going to the liver, you know, and the more fat that's in circulation, it gets sort of shuttled to the liver and then that's sort of stimulating beta oxidation in the liver. You just have a greater fat pool. But actually, I think the day that I would do t- protein veggie days and then the day I would jump back into ketosis, I would see this big ramp up i- in ketones like that day. Whereas if I did like a cheat day and just ate a lot of carbohydrates, it took me like two or three days to get back into ketosis. But if I just did like protein and veggies-

    15. TFTim Ferriss54:40

        Hm

    16. DDDr. Dominic D’Agostino54:40

        ... and cruise back into ketosis, then I would rapidly get back into ketosis and just gave my body a break from, from the fat. But I think-

    17. TFTim Ferriss54:48

        Hm

    18. DDDr. Dominic D’Agostino54:48

        ... just that short amount of time really stimulates mobilization of fat from your body because your body's 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.

    19. TFTim Ferriss55:06

        Yeah.

    20. DDDr. Dominic D’Agostino55:07

        And then shifting back into ketosis on that third day, I always had probably the best, you know, ketone numbers for the week.

    21. TFTim Ferriss55:14

        I don't want to beat this dead horse too long, but- I'd love f- 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 not enough protein to satisfy all of your resting metabolic rate, right? 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, you know, 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?

    22. DDDr. Dominic D’Agostino56:13

        3,600. Yeah.

    23. TFTim Ferriss56:14

        All right. So 3,600 calories. That's a decent amount of calories, right? And for, for somebody who's, let's just say you're 150 pounds, 10% 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 gonna be really annoyed with me dragging this out so long, but why is dietary fat so important?

    24. DDDr. Dominic D’Agostino56:50

        Because, I mean, that's the fuel that, 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. [laughs]

    25. TFTim Ferriss57:04

        Right. Right.

    26. DDDr. Dominic D’Agostino57:05

        That's a pretty big bolus of protein.

    27. TFTim Ferriss57:07

        That's a lot, yeah.

    28. DDDr. Dominic D’Agostino57:08

        And if one was to go 100 grams of protein or whatever and then bump it up to, like, 170 or 200 or something, they may not, you know, kick out of ketosis. But I remember just lower ketones, but not out of... I was still in ketosis.

    29. TFTim Ferriss57:22

        Yeah.

    30. DDDr. Dominic D’Agostino57:23

        But typically how-- I think I did it, my protein veggie days were following, like, a heavy deadlift or squat workout.
18. 58:16 – 1:02:15

    Alzheimer’s prevention: Biomarkers, B12, hsCRP, and metabolic health.

    1. TFTim Ferriss58:16

       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, is it plausible 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?

    2. DDDr. Dominic D’Agostino58:51

       I think that's a question we don't have an unambiguous answer to.

    3. TFTim Ferriss58:55

       Yeah.

    4. DDDr. Dominic D’Agostino58:55

       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 hs-CRP below 0.6 and then optimize your hemoglobin A1c, your glucose, and I think also, and I've talked about this with Rhonda Patrick and, 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 gonna end up in standard blood work because it's so compelling, the data behind it.

    5. TFTim Ferriss59:42

       Mm-hmm.

    6. DDDr. Dominic D’Agostino59:42

       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, so... and that could be reversed 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, you know, obviously one of them is Alzheimer's. So the level of inflammation, hs-CRP now is probably more atherogenic than LDL. Like-

    7. TFTim Ferriss1:00:19

       Hmm

    8. DDDr. Dominic D’Agostino1:00:19

       ... there are probably people selling statins that don't wanna hear that, but we know that the data is emerging on that now. So lower insulin, lower inflammation.

    9. TFTim Ferriss1:00:27

       And that's an inflammatory marker, right? The C-reactive protein.

    10. DDDr. Dominic D’Agostino1:00:30

        Yeah.

    11. TFTim Ferriss1:00:30

        What does the HS stand for or what is that?

    12. DDDr. Dominic D’Agostino1:00:32

        High sensitivity C-reactive protein.

    13. TFTim Ferriss1:00:34

        High sensitivity.

    14. DDDr. Dominic D’Agostino1:00:35

        So it measures in that lower range, and I used to trend to, like, two to two to three, like, my early CRP, hs-CRP when I was, like, on a high carb. I only had it measured twice when I was on a high carb diet. But, you know, since I've been keto, it's either non-detectable or, like, 0.2, or when I did extreme environment research on myself, you know, [laughs] then I could bump it up a little bit, and when I had a bacterial or viral gastroenteritis, it shot through the roof, so 'cause it-

    15. TFTim Ferriss1:01:07

        Mm

    16. DDDr. Dominic D’Agostino1:01:07

        ... activated your immune system. But generally, that hs-CRP is a big driver. I used to laugh at it and be like, "Ah, it's this non-sensitive thing," but now, like, all the data's 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-

    17. TFTim Ferriss1:01:27

        Mm-hmm

    18. DDDr. Dominic D’Agostino1:01:28

        ... to Alzheimer's disease, your magnesium levels. But also just in general, like exercise

    19. TFTim Ferriss1:01:34

        Yeah

    20. DDDr. Dominic D’Agostino1:01:34

        ... 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.

    21. TFTim Ferriss1:01:44

        Mm-hmm. Yep.

    22. DDDr. Dominic D’Agostino1:01:45

        I was doing once a year, but now I end up doing like three or four times a year 'cause I do these mini experiments to see how acutely some of the things are impacting my body composition.

    23. TFTim Ferriss1:01:55

        Mm-hmm.

    24. DDDr. Dominic D’Agostino1:01:55

        'Cause I, I just get antsy for like an answer to that.

    25. TFTim Ferriss1:01:58

        Mm-hmm.

    26. DDDr. Dominic D’Agostino1:01:58

        It's a long-winded explanation to just basically say that your, your metabolic health is tightly linked to your brain health-

    27. TFTim Ferriss1:02:05

        Mm-hmm

    28. DDDr. Dominic D’Agostino1:02:05

        ... and can dramatically delay the onset of Alzheimer's disease. Not that you're gonna get it or reverse it altogether-

    29. TFTim Ferriss1:02:13

        Yeah

    30. DDDr. Dominic D’Agostino1:02:13

        ... before something else kills you in the end.

19. 1:02:15 – 1:05:55

    My family history: Letrozole, metabolic dysfunction, and rapid cognitive decline.

    1. TFTim Ferriss1:02:15

       The metabolic health piece, just to underscore that, I mean, one of my relatives in question, APOE33, I understand that's not the only risk factor, but there's something just seemed to be missing, right? 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. I'm APOE34, again, recognizing there are other factors at play. But when she just kind of disintegrated, a few things, 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, 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.

    2. DDDr. Dominic D’Agostino1:03:15

       And her body weight and just general, like, composition?

    3. TFTim Ferriss1:03:19

       Poor body composition. Yeah. Poor body composition, very little exercise, despite my best efforts. Misbehaves horribly dietarily. Not morbidly obese, but certainly-

    4. DDDr. Dominic D’Agostino1:03:30

       Smoking, alcohol, other drugs?

    5. TFTim Ferriss1:03:32

       No smoking or alcohol.

    6. DDDr. Dominic D’Agostino1:03:33

       Okay.

    7. TFTim Ferriss1:03:34

       But here's the other piece. 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.

    8. DDDr. Dominic D’Agostino1:04:01

       Guys too-

    9. TFTim Ferriss1:04:02

       Yeah

    10. DDDr. Dominic D’Agostino1:04:02

        ... by the way. Guys.

    11. TFTim Ferriss1:04:03

        Yeah, guys too.

    12. DDDr. Dominic D’Agostino1:04:04

        Guys that take aromatase inhibitors, you know, for like-

    13. TFTim Ferriss1:04:07

        Yeah

    14. DDDr. Dominic D’Agostino1:04:07

        ... TRT and things like that. It's, it's-

    15. TFTim Ferriss1:04:08

        Yeah

    16. DDDr. Dominic D’Agostino1:04:09

        ... not a good thing to do.

    17. TFTim Ferriss1:04:10

        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 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, 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, 'cause I've got a lot of people on it for all of my relatives, but it's just to say that 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. Like, I don't find it to be the most diverse diet in the world. I don't really wanna do it all year round. I also have some maybe compromising cardiac elements. Um, I'm a cholesterol hyperabsorber, so I do, I use r- uh, 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 Nexletol, but that might end up being redundant, the bempedoic acid with

20. 1:05:55 – 1:11:41

    Minimum effective dose: 80% of benefits from low-carb Mediterranean.

    1. TFTim Ferriss1:05:55

       the Repatha. That is a, a long way of saying, like, I gotta keep an eye on the heart stuff because neurodegenerative disease and cardiovascular disease is what's kills everybody in my family. So for a lot of reasons, I don't wanna do keto all year, but I'm trying to figure out, like, what is the sort of minimal effective dose that... Uh, and I know we're gonna have to probably take a couple of speculative leaps here, but just as a working hypothesis, right? 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? 'Cause I don't know what the durability of kinda 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... You know, 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?

    2. DDDr. Dominic D’Agostino1:07:02

       Well, I think in your context it's hard to say, like, you know, to give absolutes, but I would say you can get 80% of the benefits with a low-carb diet.

    3. TFTim Ferriss1:07:13

       Mm-hmm.

    4. DDDr. Dominic D’Agostino1:07:13

       Low carb meaning, you know, 100 grams a day, just fibrous, non-starch, non-sugar carbs, low-carb Mediterranean, if you wanna call it that. And then periodically, maybe one, one week out of a month, get into a deeper state of ketosis, and, uh, 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, 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, you know, neurometabolic diseases and, and some of the things that we actually study need to be in the two to three millimolar, and, and oxygen toxicity needs to be, like, four to five 'cause it's, uh, 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 [laughs] to eat. Broccoli, asparagus, salads, you know, 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.

    5. TFTim Ferriss1:08:50

       Really?

    6. DDDr. Dominic D’Agostino1:08:50

       Yeah. Lentils seems to, like, skyrocket other people that I know. I'm, like, completely flat.

    7. TFTim Ferriss1:08:56

       I'm, like, somewhere in between.

    8. DDDr. Dominic D’Agostino1:08:57

       Okay.

    9. TFTim Ferriss1:08:57

       Yeah, I'm somewhere in between.

    10. DDDr. Dominic D’Agostino1:08:58

        It's, 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-

    11. TFTim Ferriss1:09:03

        Yeah

    12. DDDr. Dominic D’Agostino1:09:04

        ... no bump at all in my CGM. And I think that's where CGM comes into play and w- we can do a personal precision engineered diet, if you will. [laughs]

    13. TFTim Ferriss1:09:13

        Mm-hmm.

    14. DDDr. Dominic D’Agostino1:09:14

        And it gives us insight into the types of foods and the amount of foods that we can eat, and I think that's gonna be really important information. And I know there's a lot of people harping on, 'cause another study came out on CGMs provide no benefit at all to the non-diabetic.

    15. TFTim Ferriss1:09:28

        Yeah.

    16. DDDr. Dominic D’Agostino1:09:28

        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, around the table and just saying, "If you're a Type 2 diabetic, when you were diagnosed, what, like, three years ago, if you were to be given 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.

    17. TFTim Ferriss1:09:51

        Mm.

    18. DDDr. Dominic D’Agostino1:09:52

        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 overt 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, so I think a CGM's gonna be important for delaying Alzheimer's disease, and if you have loved ones, Tim, in 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, you know, we're talking about diet here.

    19. TFTim Ferriss1:10:25

        Yeah.

    20. DDDr. Dominic D’Agostino1:10:26

        But [laughs] 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.

    21. TFTim Ferriss1:10:34

        Mm.

    22. DDDr. Dominic D’Agostino1:10:34

        But muscle is like an endocrine organ that produces, you know, hormones and various molecules that are neuroprotective, and muscle is tightly linked to brain size. [laughs]

    23. TFTim Ferriss1:10:46

        Mm-hmm.

    24. DDDr. Dominic D’Agostino1:10:47

        And of course, your, 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 gonna get a DEXA scan," and every year, like I do, I just kind of like to create, like, a lot of stress for myself to, like, beat my DEXA scan every year.

    25. TFTim Ferriss1:11:01

        [laughs]

    26. DDDr. Dominic D’Agostino1:11:01

        And get their friends involved. Make it like a social event. Everybody goes and gets their DEXA.

    27. TFTim Ferriss1:11:06

        Yeah.

    28. DDDr. Dominic D’Agostino1:11:06

        And then every year you go back and just try to beat-

    29. TFTim Ferriss1:11:09

        Beat your scores.

    30. DDDr. Dominic D’Agostino1:11:10

        Yeah. These are low-hanging fruit kind of things people should be doing.
21. 1:11:41 – 1:16:07

    One week per month protocol: Aggressive calorie cut to ramp ketones.

    1. TFTim Ferriss1:11:41

       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, right, most of the time, with a, like, lower carbohydrate Mediterranean diet, let's just say? Okay. One week per month every three months or three weeks, contiguous weeks, once a quarter. Do you feel like one of those is superior to the other?

    2. DDDr. Dominic D’Agostino1:12:18

       Not really. I think whatever pattern works best, I think you would gain benefits for both. That would be an interesting experiment to do.

    3. TFTim Ferriss1:12:26

       I'm just thinking about the lead time to get into a, like, a properly ketogenic state if I'm going from some carbohydrate to ketosis. I mean, we could talk about things that might accelerate it, but, like, 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-

    4. DDDr. Dominic D’Agostino1:12:42

       Mm-hmm

    5. TFTim Ferriss1:12:42

       ... these are things running through my mind. I'm just curious to get your take.

    6. DDDr. Dominic D’Agostino1:12:46

       The one-week intervention for the month, my kind of opinion is that it could be pretty aggressive. Like, you cut calories 50% the first two days and then cruise into it so you're really cranking ketones by the end of the week.

    7. TFTim Ferriss1:12:58

       Mm-hmm.

    8. DDDr. Dominic D’Agostino1:12:58

       And then you're also cruising into it from what should be, like, a low-carb diet.

    9. TFTim Ferriss1:13:02

       Mm.

    10. DDDr. Dominic D’Agostino1:13:02

        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, to ramp up ketones. Alternatively, if your schedule permits and, like, you know, you work and 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 am 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 [laughs] and cause food noise, then that can really, you know, hamper your compliance to that. But you want to prepare the house [laughs] before. If you're going into a one-week or you're going to a three-week, prepare the house-

    11. TFTim Ferriss1:14:12

        Mm-hmm

    12. DDDr. Dominic D’Agostino1:14:12

        ... and just make sure that you could do-- Of course, you could just call Uber Eats and get anything delivered, but you want to kinda have the house prepared for that, and mentally prepared for it.

    13. TFTim Ferriss1:14:22

        So for you personally, if you had some hereditary gnarliness, right? 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 a bit of both, who knows, would you be more inclined to do the one week per month, just for you personally, or-

    14. DDDr. Dominic D’Agostino1:14:41

        I would.

    15. TFTim Ferriss1:14:42

        Yeah. One week per month.

    16. DDDr. Dominic D’Agostino1:14:43

        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, kinda 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 ch- 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 other 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.

    17. TFTim Ferriss1:15:48

        Mm-hmm.

    18. DDDr. Dominic D’Agostino1:15:48

        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 kinda getting.

    19. TFTim Ferriss1:15:57

        Hmm.

    20. DDDr. Dominic D’Agostino1:15:57

        Whereas if you do three weeks and then take a period of time off, I'm not totally convinced that those benefits are gonna span that amount of timeframe. That's my

22. 1:16:07 – 1:28:57

    GKI sweet spot: Target 1-4, aim for 1-2 during intensive weeks.

    1. DDDr. Dominic D’Agostino1:16:07

       thinking.

    2. TFTim Ferriss1:16:07

       And you mentioned people can find calculators out there, and actually, a lot of the devices will try to provide this to you. Well, actually, is that, is that true? I guess they would have to have both data streams, so probably not, but the GKI. 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? Not known for my quick mental arithmetic [laughs] on, on the podcast.

    3. DDDr. Dominic D’Agostino1:16:58

       Yeah.

    4. TFTim Ferriss1:16:58

       But what would a GKI of, say, one or two look like in terms of the readout on the glucometer and the readout on the finger prick for the millimolars for ketones? What would be a, a, an example?

    5. DDDr. Dominic D’Agostino1:17:11

       So if people are like, "Don't wanna do the millimolar concentration of glucose," if your glucose is 80 and then your ketones are two millimolar, you are right into that one to two. The glucose ketone index of one to two, you're between that level. If you could bring your glucose down to, 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.

    6. TFTim Ferriss1:17:41

       Mm.

    7. DDDr. Dominic D’Agostino1:17:42

       Yeah, I think what's totally feasible is getting your glucose down to, like, 80, 80 to 85, in that range, and getting your ketones, you know, at the end of the one-week fast up to two-

    8. TFTim Ferriss1:17:54

       Okay

    9. DDDr. Dominic D’Agostino1:17:54

       ... and maintaining that. So that would be kind of achieving that GKI of two.

    10. TFTim Ferriss1:17:59

        I think I'm probably saying what I wish to be true [laughs] which is that my insulin sensitivity has improved a lot in the last certainly year in particular, and that is to explain in part the, 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. 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?

    11. DDDr. Dominic D’Agostino1:19:15

        Let me look real quick 'cause I got a lot of, like, little gadgets around.

    12. TFTim Ferriss1:19:19

        Dom is looking into his Santa's workshop of [laughs] various metabolic devices.

    13. DDDr. Dominic D’Agostino1:19:24

        I have a lot of different devices. So one is the Keto-Mojo device.

    14. TFTim Ferriss1:19:30

        Yep, that's the one I have. Yeah, I've got the Keto-Mojo.

    15. DDDr. Dominic D’Agostino1:19:32

        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.

    16. TFTim Ferriss1:19:44

        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 gonna fail, right? 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. [laughs]

    17. DDDr. Dominic D’Agostino1:20:15

        Mm-hmm.

    18. TFTim Ferriss1:20:15

        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, the regular math work?

    19. DDDr. Dominic D’Agostino1:20:49

        One to two is a high bar, I guess. A, 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, in the cancer community, The Society for Integrative Metabolic Oncology is a group that we're discussing the GKI, and Thomas Seyfried's very adamant about getting to one to two. But I give pushback and say one to four. If you look at the published literature, one to four is absolutely 100% 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-

    20. TFTim Ferriss1:21:42

        Mm-hmm

    21. DDDr. Dominic D’Agostino1:21:42

        ... if you don't have the glucose calibration for that, or that would be a GKI of four. And it would be really rare, if not impossible, for anyone in the general population to even achieve a GKI of five to 10.

    22. TFTim Ferriss1:21:55

        Mm-hmm.

    23. DDDr. Dominic D’Agostino1:21:56

        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% available energy for your brain. And also, the Keto-Mojo device is measuring D beta-hydroxybutyrate, and if you're doing supplementation with racemic D and L, then you're not picking up the L.

    24. TFTim Ferriss1:22:21

        Mm-hmm.

    25. DDDr. Dominic D’Agostino1:22:21

        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 L beta-hydroxybutyrate takes about four to five times longer to metabolize. So that's in circulation more.

    26. TFTim Ferriss1:22:37

        Mm-hmm.

    27. DDDr. Dominic D’Agostino1:22:37

        And also, if you're on a ketogenic diet for reasons we don't fully understand, and we are to rip out the heart, [laughs] about 34 to 40% of the ketone in the heart is L beta-hydroxybutyrate.

    28. TFTim Ferriss1:22:49

        Huh.

    29. DDDr. Dominic D’Agostino1:22:49

        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.

    30. TFTim Ferriss1:23:06

        Right.
23. 1:28:57 – 1:31:58

    Exogenous ketones 101: Palatability, tolerability, pharmacokinetics, toxicity.

    1. TFTim Ferriss1:28:57

       So Dom, you know, a few things have come up that I would love to chat about 'cause I get these questions all the time which relate to exogenous ketones. And people have heard this term exogenous, endogenous. It's, it's very fancy talk in a tuxedo for outside the body, in the body, right? So 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 are taking from outside and putting inside. People always ask, and I know you kind of have a dog in the fight here, so I, I want to recognize [laughs] that too. Uh, 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. [sighs] I think there's probably no biological free lunch if people are gonna 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?

    2. DDDr. Dominic D’Agostino1:30:07

       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 gonna consume it. I would, but most people won't. [laughs] 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 gonna spike up in 30 minutes and be out of your system in, like, an hour or two.

    3. TFTim Ferriss1:30:42

       Yeah. Pharmacokinetics is like the stock chart for something you put in your body, right? In this case.

    4. DDDr. Dominic D’Agostino1:30:47

       Yeah.

    5. TFTim Ferriss1:30:47

       Right? [laughs]

    6. DDDr. Dominic D’Agostino1:30:48

       And that's kind of 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 then 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, you know, an energy deficit in the brain.

    7. TFTim Ferriss1:31:15

       How long does that last for you?

    8. DDDr. Dominic D’Agostino1:31:16

       It lasts in the context of consuming, for example, a ketone ester by itself.

    9. TFTim Ferriss1:31:20

       Yeah.

    10. DDDr. Dominic D’Agostino1:31:21

        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.

    11. TFTim Ferriss1:31:42

        Mm-hmm.

    12. DDDr. Dominic D’Agostino1:31:43

        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.

24. 1:31:58 – 1:47:13

    1,3-Butanediol warnings: Liver toxicity, NAD depletion, dependency risk.

    1. TFTim Ferriss1:31:58

       Let's talk about toxicity first.

    2. DDDr. Dominic D’Agostino1:32:00

       Toxicity is probably the most important too.

    3. TFTim Ferriss1:32:02

       Yeah.

    4. DDDr. Dominic D’Agostino1:32:03

       Yeah.

    5. TFTim Ferriss1:32:03

       And let's, for the time being, not talk about the acute medical delivery.

    6. DDDr. Dominic D’Agostino1:32:07

       Okay.

    7. TFTim Ferriss1:32:07

       Let's talk about recreational slash, better said, layperson use, right?

    8. DDDr. Dominic D’Agostino1:32:14

       Mm-hmm.

    9. TFTim Ferriss1:32:14

       This is as a dietary supplement.

    10. DDDr. Dominic D’Agostino1:32:16

        Yep.

    11. TFTim Ferriss1:32:16

        Could you speak to the toxicity piece?

    12. DDDr. Dominic D’Agostino1:32:18

        What we observed, like, about 10 years ago was that formulations that contained 1,3-butanediol, that includes an ester I have a lot of patents on [laughs] 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.

    13. TFTim Ferriss1:32:50

        How is it toxic? What are its toxic effects?

    14. DDDr. Dominic D’Agostino1:32:53

        Well, alcohol dehydrogenase uses NAD, consumes NAD as its function, right? So it, 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, 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, signs that are kind of scary, right? And this could be inflammation of the liver, TNF-alpha, 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% of a ketone monoester is 1,3-butanediol. So it hydrolyzes in the liver, gets into circulation. Still, over 50% 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% 1,3-butanediol. So I see these as, as potentially problematic.

    15. TFTim Ferriss1:34:38

        The diester is what percentage?

    16. DDDr. Dominic D’Agostino1:34:40

        A ketone diester, which would be 1,3-butanediol with two ketones on it, we use acetoacetate on each. That's 35% of that molecule is 1,3-butanediol in circulation.

    17. TFTim Ferriss1:34:53

        I got it.

    18. DDDr. Dominic D’Agostino1:34:53

        And then the beta-hydroxybutyrate monoester is 51% 1,3-butanediol in circulation.

    19. TFTim Ferriss1:35:00

        Mm-hmm.

    20. DDDr. Dominic D’Agostino1:35:00

        So this can become problematic when it's used as, like, a supplement and a lifestyle thing, like, day in and day out.

    21. TFTim Ferriss1:35:06

        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?

    22. DDDr. Dominic D’Agostino1:35:17

        Yep.

    23. TFTim Ferriss1:35:17

        Do you think it translates? And this might be just, like, a precautionary measure. It's like, well, like, pending [laughs] 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?

    24. DDDr. Dominic D’Agostino1:35:39

        So there is a paucity of data. [coughs] There's a deficiency of data on the use of these agents, 1,3-butanediol, and 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 [laughs]

    25. TFTim Ferriss1:35:54

        Mm.

    26. DDDr. Dominic D’Agostino1:35:55

        Study that used 25 grams.

    27. TFTim Ferriss1:35:56

        25 grams.

    28. DDDr. Dominic D’Agostino1:35:58

        25 grams per day, yeah, and that produces, like, 0.1 to one 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 gonna say I, you know, 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. We've done this in animals and fed it at a pretty high level, and we did not see transaminases going up.

    29. TFTim Ferriss1:36:52

        So transaminases are what people could think of as liver enzymes on their blood panels, right?

    30. DDDr. Dominic D’Agostino1:36:57

        Liver enzymes, yeah.
25. 1:47:13 – 1:52:04

    Intermittent fasting vs. ketogenic breakfast.

    1. TFTim Ferriss1:47:13

       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, your Leydig cells are pretty smart. That's the reason your balls turn into Raisinets-

    2. DDDr. Dominic D’Agostino1:47:50

       [laughs]

    3. TFTim Ferriss1:47:51

       ... is because [laughs] it's like, "Cool, we don't have to make that anymore." So I th- I thought, uh, 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 kind of becomes its opposite, right? It becomes a hindrance and makes it problematic. Is that fair to say?

    4. DDDr. Dominic D’Agostino1:48:12

       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, the rapid elevation of ketones seem to have an insulin effect that can double or triple insulin. Even if we elevate ketones to the same level with the salt, we don't see that spike up in insulin. So that could be coming into play with your low ketones if that's, if you are consuming the monoester.

    5. TFTim Ferriss1:48:46

       Not much. Every once in a while, like, before exercise, because I, I might not mind the spike.

    6. DDDr. Dominic D’Agostino1:48:50

       Yeah.

    7. TFTim Ferriss1:48:51

       But I'm not consuming a ton.

    8. DDDr. Dominic D’Agostino1:48:53

       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.

    9. TFTim Ferriss1:49:11

       Yeah.

    10. DDDr. Dominic D’Agostino1:49:11

        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 and... But then again, some people, me included, like, my mind is not as sharp when I have a big breakfast.

    11. TFTim Ferriss1:49:33

        That's the thing, right? I would say that, I mean, for 15 years, right, 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 wanna do three hours of writing, I do not wanna have food immediately prior to that.

    12. DDDr. Dominic D’Agostino1:50:05

        Yeah.

    13. TFTim Ferriss1:50:06

        But I would say I'm also at a point, I think, where throwing up really heavy weight and, uh, for me, right? And [laughs] getting as big and strong as possible is just not, it's less of a priority, right? [laughs] Than it once was, after shoulder surgeries and elbow surgeries and various things. Not that I wanna be the s- you know, skinniest guy in the room, but 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?

    14. DDDr. Dominic D’Agostino1:50:40

        It can be, and I suspect it is, and I've kind of, you know, proven kind of with myself that's the case, but it also can be mitigated in part by taking it with a meal or taking it with MCT. It is metabolized, like 30 milliliters of 1,3-butanediol is kind of like 30 milliliters of ethanol.

    15. TFTim Ferriss1:50:56

        Yeah.

    16. DDDr. Dominic D’Agostino1:50:56

        And then 1,3-butanediol can create dependence, and it also can create, you get withdrawal.

    17. TFTim Ferriss1:51:03

        Oof.

    18. DDDr. Dominic D’Agostino1:51:04

        So it's established in the 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.

    19. TFTim Ferriss1:51:21

        What are the symptoms of that? I mean, I imagine you don't get like DT, right? You're not getting like shakes or anything, are you? But I mean, like what happens?

    20. DDDr. Dominic D’Agostino1:51:30

        I mean, it's like classical kind of ethanol withdrawal, maybe not quite as dramatic, but the glycols or diols do have a GABAergic effect, so you're, you know, doing that. I mean, it's well-established, 1,3- is a, has narcotic-like properties, and that kind of stymied its use as a, as a synthetic food for space flight.

    21. TFTim Ferriss1:51:52

        Mm-hmm.

    22. DDDr. Dominic D’Agostino1:51:52

        Well, I think the palatability also factored into that, but also in the literature it notes, you know, a narcotic effect of this and then the animal studies and really showed dependency and withdrawal.

26. 1:52:04 – 1:56:14

    My accidental intoxication story.

    1. TFTim Ferriss1:52:04

       Just to give a reiteration of that, I mean [laughs] , you know, the 1,3-butanediol-based stuff is also sold as an alcohol replacement. So of course, being the idiot that I am, not an idiot, just like I'm, I'm eager to experiment here and there if it's not gonna kill me. And so I thought, "You know what? I don't want to drink tonight." This was in, 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 a drink, and then I wanted to be able to say, "Hey, I already had this ahead of time. Don't worry, like 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.

    2. DDDr. Dominic D’Agostino1:52:38

       Mm.

    3. TFTim Ferriss1:52:38

       Six ounces, eight ounces. And I felt like I could barely walk to the bathroom. Like, I was smashed. It was, uh, like almost knocked the glass off the table. I was like, "Holy shit. I did [laughs] not do this sort of risk assessment properly."

    4. DDDr. Dominic D’Agostino1:52:54

       Yeah.

    5. TFTim Ferriss1:52:54

       Like, thank God I'm not about to get into a car, 'cause it, it took a little while to wear off. So that narcotic effect, it's not always subtle.

    6. DDDr. Dominic D’Agostino1:53:02

       I made Jell-O shots. I made 1,3-butanediol Jell-O shots and before we made the ketone esters in 2009, Patrick Arnold and I like kind of-

    7. TFTim Ferriss1:53:09

       [laughs]

    8. DDDr. Dominic D’Agostino1:53:09

       ... formulated the-

    9. TFTim Ferriss1:53:10

       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 [laughs] any of that stuff, [laughs] anyway, Patrick's got some stories.

    10. DDDr. Dominic D’Agostino1:53:22

        Yeah. [laughs]

    11. TFTim Ferriss1:53:23

        But so the Jell-O shots, so what happened with the Jell-O shots?

    12. DDDr. Dominic D’Agostino1:53:26

        Well, that was the way to get it down, 'cause 1,3-butanediol's so nasty, right?

    13. TFTim Ferriss1:53:29

        Yeah.

    14. DDDr. Dominic D’Agostino1:53:29

        So you could basically just warm up pure 1,3-butanediol in a pot and then add cherry flavored sugar-free Jell-O and then stir it up and then pour it into like a cookie pan and then cut it into cubes, which you get-

    15. TFTim Ferriss1:53:44

        [laughs]

    16. DDDr. Dominic D’Agostino1:53:45

        ... 20 milliliters per Jell-O shot and make it pretty strong so it's like firm Jell-O, and I would just hit two or three of them and just be buzzing. And you know, 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.

    17. TFTim Ferriss1:53:59

        Yeah.

    18. DDDr. Dominic D’Agostino1:53:59

        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 y- many years ago. But I actually do think it could be part, you know, used by people if they could transition off of ethanol, potentially use that, but there are other ways [laughs] 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. It's gonna make you potentially fall, break your hip.

    19. TFTim Ferriss1:54:39

        Mm-hmm.

    20. DDDr. Dominic D’Agostino1:54:39

        And then when you're older, your ability to detoxify alcohol at an 80-year-old only has like 20 or 30% 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, like as we age, right? And, and people note that. As you age, you just can't tolerate the same amount of alcohol.

    21. TFTim Ferriss1:55:02

        Yeah.

    22. DDDr. Dominic D’Agostino1:55:02

        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.

    23. TFTim Ferriss1:55:18

        Mm-hmm.

    24. DDDr. Dominic D’Agostino1:55:19

        I say that not only as a scientist but because of the volume of emails that I get-

    25. TFTim Ferriss1:55:23

        Yeah

    26. DDDr. Dominic D’Agostino1:55:24

        ... [laughs] on that of people who are like, "I got super buzzed. I didn't know what happened." And some people are very sensitive to it. Like I gave my wife a sh- just she can't tolerate alcohol at all, and she took a shot glass of the stuff, and she like 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 if you're sensitive to alcohol, you're gonna get overly buzzed. And my concern is that, hey, if you want to use it for recreational, like 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 the potential for just getting drunk, just straight up drunk. And Dr. Veech told me that a long time ago, 'cause I was trying to get the ester from him, and I was like, "What if I just use 1,3-butanediol?" And he's like, "You'll get drunk." So [laughs] it's like he instilled that, that do not do that.

27. 1:56:14 – 1:57:58

    Dr. Veech tribute: Student of Hans Krebs, ketone ester pioneer.

    1. DDDr. Dominic D’Agostino1:56:14

       That's what he said.

    2. TFTim Ferriss1:56:15

       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?

    3. DDDr. Dominic D’Agostino1:56:28

       DARPA.

    4. TFTim Ferriss1:56:29

       DARPA, and then patented at Oxford. Is that right? Am I getting my facts straight, or am I getting things mixed up?

    5. DDDr. Dominic D’Agostino1:56:35

       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. Dr. Veech was the student of Hans Krebs.

    6. TFTim Ferriss1:56:50

       Krebs of Krebs cycle?

    7. DDDr. Dominic D’Agostino1:56:52

       Krebs cycle, yeah.

    8. TFTim Ferriss1:56:53

       That's wild. [laughs] Wow.

    9. DDDr. Dominic D’Agostino1:56:54

       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 was, had an amazing mind. 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 Brüne-Graber and some other people, Sammy 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.

    10. TFTim Ferriss1:57:31

        Yeah.

    11. DDDr. Dominic D’Agostino1:57:32

        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, in some experiments. I published some really nice data on 1,3-butanediol, actually even in cancer studies too. So but at the same time, I realized that the negative effects, and I'm, I can pivot away from that. We have other molecules, like, in development now.

    12. TFTim Ferriss1:57:57

        So I know as I'm

28. 1:57:58 – 2:02:37

    Fiber on keto: Wild blueberries, broccoli, apples, walnuts.

    1. TFTim Ferriss1:57:58

       watching, things get dark [chuckles] on the East Coast for you. [laughs]

    2. DDDr. Dominic D’Agostino1:58:02

       [laughs] Yeah.

    3. TFTim Ferriss1:58:02

       That we'll wrap up in just a few minutes, but in brief, you mentioned fat, salt, fiber, right, as things that can be helpful for slowing, I guess, gastric emptying of these, 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?

    4. DDDr. Dominic D’Agostino1:58:24

       Whole food form, I like broccoli. I buy broccoli florets, and then I cut the tip of the floret off, [laughs] and I have, like, a bowl of that, and I give the stalk and stuff to my dogs, and I chop it up for, for their fiber. So that's, that's something that I do. I don't know, just to get a higher dose of, of broccoli. But broccoli, and then wild blueberries. It 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.

    5. TFTim Ferriss1:58:54

       Mm.

    6. DDDr. Dominic D’Agostino1:58:54

       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-

    7. TFTim Ferriss1:59:06

       Mm

    8. DDDr. Dominic D’Agostino1:59:06

       ... or whatever. But wild blueberries, just green vegetables in general, but I like broccoli, and apples are pretty much something I have every day.

    9. TFTim Ferriss1:59:14

       Now, the wild blueberries, I just wanna really [chuckles] underline wild for people [laughs] because that is not what you're necessarily gonna get at your local grocery store that's been optimized to be [chuckles] as sweet as possible.

    10. DDDr. Dominic D’Agostino1:59:29

        They're in Publix, so I can get them-

    11. TFTim Ferriss1:59:30

        Oh, okay

    12. DDDr. Dominic D’Agostino1:59:31

        ... in Publix down here, and I think, I don't know, actually I think they're in Walmart too.

    13. TFTim Ferriss1:59:36

        Oh.

    14. DDDr. Dominic D’Agostino1:59:36

        I think you can go to Walmart, and I think you might have to, like, sneak around for them, but there's a brand. They have wild raspberries and blueberries and blackberries together.

    15. TFTim Ferriss1:59:44

        Okay.

    16. DDDr. Dominic D’Agostino1:59:45

        I forget the name of the brand, but they come in, like, big two or three-pound bags too, so.

    17. TFTim Ferriss1:59:49

        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-

    18. DDDr. Dominic D’Agostino2:00:15

        Mm

    19. TFTim Ferriss2:00:15

        ... and, like, you're, 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 on the macadamia nuts, you can rack up the carbs after a while. What about apples and berries? Where's your cutoff point for yourself?

    20. DDDr. Dominic D’Agostino2:00:38

        Macadamia nuts actually have that 3:1 to 4:1 ratio of fat to... So, so they are pretty high in fat, but cashews and then almonds and other, other nuts. I like walnuts too. I forgot to mention. So I have walnuts, small organic apples we buy, wild blueberries, and broccoli pretty much every day.

    21. TFTim Ferriss2:00:58

        Mm-hmm.

    22. DDDr. Dominic D’Agostino2:00:59

        And all that together ends up being about 60 to 70 grams of carbs.

    23. TFTim Ferriss2:01:03

        Mm.

    24. DDDr. Dominic D’Agostino2:01:03

        But one-third of the carbs is fiber.

    25. TFTim Ferriss2:01:06

        Yeah.

    26. DDDr. Dominic D’Agostino2:01:06

        So it's essentially nonglycemic. And then I tend to... Like, I haven't had any of that today, but I tend to have that at dinner and then my snack at nighttime.

    27. TFTim Ferriss2:01:14

        Mm-hmm.

    28. DDDr. Dominic D’Agostino2:01:15

        So everything that I just mentioned, the carbs. But I don't think about it as undoing ketosis.

    29. TFTim Ferriss2:01:19

        [laughs]

    30. DDDr. Dominic D’Agostino2:01:20

        My glucose tank is always maybe 10 or 20% full, so I'm always running kind of low-
29. 2:02:37 – 2:05:46

    The tainted gummies incident: Dom’s forensic investigation underway.

    1. DDDr. Dominic D’Agostino2:02:37

       hard.

    2. TFTim Ferriss2:02:37

       But you found the addition of the carbohydrates to be beneficial, that slightly higher quantity of carbohydrates.

    3. DDDr. Dominic D’Agostino2:02:44

       I've added the more carbs back in over the years, and that has helped me maintain my body weight, and I just, I like eating those foods. I enjoy those foods. I think they have beneficial fiber, phytonutrients-

    4. TFTim Ferriss2:02:55

       Mm

    5. DDDr. Dominic D’Agostino2:02:55

       ... other micronutrients that I think are beneficial. And I can maintain a level of ketosis about, you know, .5 to 1.5 day in and day out, eating those foods every day.

    6. TFTim Ferriss2:03:07

       Yeah.

    7. DDDr. Dominic D’Agostino2:03:07

       And I do titrate in, like, the MCTs, and I get, like- One or two packets of KetoStart a day, maybe up to three if I'm traveling.

    8. TFTim Ferriss2:03:15

       Mm.

    9. DDDr. Dominic D’Agostino2:03:15

       But that's my normal protocol, and that's has optimized all my biomarkers. Actually got full blood work today, kind of waiting for that to come back to see. It should be interesting, as inadvertently took something that I thought was laced with something, some gummies I told you about. But, uh [laughs]

    10. TFTim Ferriss2:03:30

        People are gonna assume [laughs] when people hear gummies, they assume it's THC, but this was what? Theanine and magnesium? It should've been really innocuous, right? Is that right?

    11. DDDr. Dominic D’Agostino2:03:40

        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." She's... 'Cause sometimes I give her stuff.

    12. TFTim Ferriss2:03:52

        [laughs]

    13. DDDr. Dominic D’Agostino2:03:52

        I tried to get up, fell flat on the floor. Both of us could not walk. We were both, like, 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 it was something. I'm still buzzed.

    14. TFTim Ferriss2:04:10

        Wow, really?

    15. DDDr. Dominic D’Agostino2:04:11

        So if I don't seem like myself, because I'm still buzzed 48 hours later.

    16. TFTim Ferriss2:04:15

        That is wild.

    17. DDDr. Dominic D’Agostino2:04:17

        We had the spinnies, and even this morning I woke up, I had the spinnies, like walking. 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.

    18. TFTim Ferriss2:04:35

        Yikes. That's terrifying.

    19. DDDr. Dominic D’Agostino2:04:37

        My wife does not drink. She doesn't use any drugs, so she was pretty much, you know, really floored by this.

    20. TFTim Ferriss2:04:43

        Wow. Did you go back and buy some more of them to, like, send off to get analyzed?

    21. DDDr. Dominic D’Agostino2:04:48

        Well, I had... 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 like, you know, doctors involved in all this now, so.

    22. TFTim Ferriss2:05:00

        Wow. They dosed the wrong guy. [laughs] Or the right guy-

    23. DDDr. Dominic D’Agostino2:05:04

        Yeah

    24. TFTim Ferriss2:05:04

        ... because you imagine, like, what if that had been a 80-year-old woman sleeping on the second floor? I mean, that's dangerous.

    25. DDDr. Dominic D’Agostino2:05:12

        Absolutely. I just took two, and I'm a pretty, you know, big guy and everything, but if a little kid took two or four or five.

    26. TFTim Ferriss2:05:19

        Yeah.

    27. DDDr. Dominic D’Agostino2:05:19

        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 kinda know what TH- but this is... We're talking 48 hours later-

    28. TFTim Ferriss2:05:32

        Yeah

    29. DDDr. Dominic D’Agostino2:05:32

        ... and I'm still kinda feeling that.

    30. TFTim Ferriss2:05:34

        That's wild.
30. 2:05:46 – 2:08:56

    Thanks to Dr. Boz and Medifoodz.

    1. TFTim Ferriss2:05:46

       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?

    2. DDDr. Dominic D’Agostino2:05:55

       I don't think so. I mean, we talked a lot about, like, sardine fasting and everything, I think, before.

    3. TFTim Ferriss2:06:00

       In the prior conversation, yeah.

    4. DDDr. Dominic D’Agostino2:06:01

       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 like 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 sort of and secured, like, my knowledge. Yes, okay, these benefits are... And now she's been on Diary of a CEO podcast, I think, and some other podcasts, so. I'd also like to mention I'm, 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.

    5. TFTim Ferriss2:06:45

       Mm-hmm.

    6. DDDr. Dominic D’Agostino2:06:46

       And for years, there's no whole food-based ketogenic diet prescription foods.

    7. TFTim Ferriss2:06:51

       Hmm.

    8. DDDr. Dominic D’Agostino2:06:52

       So I have no association with the company. I'm just testing their product. But they're called Medifoodz.

    9. TFTim Ferriss2:06:56

       How do you spell that? M-E-T-I?

    10. DDDr. Dominic D’Agostino2:06:58

        M-E-D-I-F-O-O-

    11. TFTim Ferriss2:07:01

        Medi. I got it. Medifoodz.

    12. DDDr. Dominic D’Agostino2:07:04

        Yeah, Medifoodz with, with a Z. And I gotta tell you, these are like gourmet foods, and then they hit the macros of like a modified ketogenic diet. And we talked about if someone says the ketogenic diet is not palatable, they have to see these foods.

    13. TFTim Ferriss2:07:21

        Hmm.

    14. DDDr. Dominic D’Agostino2:07:21

        They're prescription whole food. There's other companies that tried to do this, and they even got... The packaging is, is compostable. It looks like plastic, but I could throw it in my garden and it breaks down.

    15. TFTim Ferriss2:07:34

        Hmm.

    16. DDDr. Dominic D’Agostino2:07:34

        I'm very impressed with this.

    17. TFTim Ferriss2:07:35

        Yeah.

    18. DDDr. Dominic D’Agostino2:07:35

        I just mentioned that because I just got these foods yesterday and I was really impressed, but other companies have not been so impressive.

    19. TFTim Ferriss2:07:44

        [laughs]

    20. DDDr. Dominic D’Agostino2:07:44

        So Medifoodz is, 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.

    21. TFTim Ferriss2:07:53

        Mm-hmm.

    22. DDDr. Dominic D’Agostino2:07:53

        But I like the idea of a prescription whole food ketogenic diet that potentially a doctor could write a prescription, and these, a week of foods could be sent to the patients. I've been questioning why this, someone has not done this, but I know the margins are very small, like in the food world. So it's hard to, you know, kinda get that up and running, so.

    23. TFTim Ferriss2:08:13

        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, you sell in the beginning-

    24. DDDr. Dominic D’Agostino2:08:23

        Mm-hmm

    25. TFTim Ferriss2:08:23

        ... for much higher price to people who are willing to pay that. You use that to subsidize-

    26. DDDr. Dominic D’Agostino2:08:28

        Yeah

    27. TFTim Ferriss2:08:28

        ... 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? [laughs] And I'm, I wouldn't say totally price insensitive, but I'm willing to pay for convenience-

    28. DDDr. Dominic D’Agostino2:08:45

        Mm-hmm

    29. TFTim Ferriss2:08:45

        ... 'cause 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.

    30. DDDr. Dominic D’Agostino2:08:53

        Yep.
31. 2:08:56 – 2:10:53

    Parting thoughts.

    1. TFTim Ferriss2:08:56

       Medifoodz. Let's see. Dom, are you active on social anywhere? Should people find you anywhere online?

    2. DDDr. Dominic D’Agostino2:09:01

       Yeah. I'm not too active, but I try to jump on about, you know, once or twice a week. I cap my social to maybe an hour a week.

    3. TFTim Ferriss2:09:10

       Yep, smart man.

    4. DDDr. Dominic D’Agostino2:09:11

       But I try to respond back to things, yeah, kinda delete the, the apps from my phone or some of them. But I do repost things and try to acknowledge some questions and stuff people have on this.

    5. TFTim Ferriss2:09:20

       Mm-hmm.

    6. DDDr. Dominic D’Agostino2:09:20

       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 you can get CME credits from it. So that has been a project, you know, that we're working on and trying to advance everything we're talking about into human application through that.

    7. TFTim Ferriss2:09:38

       Beautiful. Well, trying to think of any other links. Is there, are there any other links that you want to mention? And we'll stick these all in the show notes as well for people.

    8. DDDr. Dominic D’Agostino2:09:46

       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-

    9. TFTim Ferriss2:10:00

       Mm-hmm

    10. DDDr. Dominic D’Agostino2:10:00

        ... the three biggies I think, so.

    11. TFTim Ferriss2:10:02

        Beautiful. We will link to all of those things for people listening as well as [laughs] God save the people who help me do the show notes. They're gonna have a lot to dig through. But-

    12. DDDr. Dominic D’Agostino2:10:16

        Yeah

    13. TFTim Ferriss2:10:16

        ... 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. Um, and we may have some in the future [laughs] , so you'll find it. And Dom, thank you so much for taking the time, man. Always great to see you.

    14. DDDr. Dominic D’Agostino2:10:32

        My pleasure. Thank you, Tim, for having me. Appreciate it. Good seeing you.

    15. TFTim Ferriss2:10:36

        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. [laughs] All right, take care everybody.

Episode duration: 2:11:04