#825: Dr. Dominic D’Agostino — All Things Ketones, How to Protect the Brain and Boost Cognition, Sardine Fasting, Diet Rules, Revisiting Metformin and Melatonin, and More

Dr. Dominic D’Agostino (@DominicDAgosti2 https://x.com/DominicDAgosti2) is a tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine and a Visiting Senior Research Scientist at the Institute for Human and Machine Cognition. This episode is brought to you by: Helix Sleep https://helixsleep.com/tim premium mattresses: https://HelixSleep.com/Tim https://helixsleep.com/tim (27% off all mattress orders) Momentous https://livemomentous.com/tim high-quality creatine: https://livemomentous.com/tim (code TIM for up to 35% off) AG1 https://drinkag1.com/Tim all-in-one nutritional supplement: https://DrinkAG1.com/Tim https://drinkag1.com/Tim (1-year supply of Vitamin D plus 5 free AG1 travel packs) Timestamps: [00:00:00] Start. [00:14:43] Why I'm interested in ketogenic strategies for neurodegenerative prevention. [00:16:18] Mary and Steve Newport's ketone-linked temporary cognitive improvements. [00:18:18] A mechanisms overview for Alzheimer's/dementia. [00:21:25] The immune system as longevity's "fifth horseman" — and why metabolic control is key. [00:22:04] How to measure ketones and GKI. [00:23:00] Fasting vs. ketogenic diet. [00:24:18] There's nothing fishy about sardine fasting. [00:28:32] My hiatal hernia discovery and increased cancer risk concerns. [00:30:04] HSCRP as a superior biomarker to LDL for cardiovascular risk. [00:31:57] Glucose tolerance testing revelations and CGM importance. [00:31:57] Upgrading the metabolic machinery through keto without getting bored. [00:42:07] What do do if you, like Dom and me, are among the 30% who suffer from cholesterol hyperabsorption. [00:43:42] Dom's day-to-day diet regimen. [00:45:56] How Dom optimizes his aging dogs with ketones, SARMs, and supplements. [00:51:30] Supplementing for sleep disruption while fasting. [00:55:41] Why Dom doesn't have misgivings about melatonin. [00:59:15] Shingles prevention through fasting protocols. [01:00:15] Immune system modulation: Innate vs. adaptive, vegan vs. ketogenic. [01:03:54] Dom at 50-something: Current meal timing and composition. [01:05:57] Blue zone observations: Greek and Sardinian longevity habits. [01:08:16] Ketogenic diet initiation tips: MCT, electrolytes, and fasted cardio. [01:15:18] Ketone metabolic therapy for cancer. [01:18:15] The metabolic psychiatry revolution. [01:22:10] The soothing effects of hyperbaric oxygen and ketosis on seizure sufferers. [01:28:27] Metformin vs. berberine. [01:31:43] The low-dose neuroprotective potential of GLP-1 drugs. [01:34:58] NAD research: MIB-626 and stabilized forms for mitochondrial health. [01:39:48] Idebenone, CoQ10, and the Deanna protocol for ALS. [01:42:05] Dom's supplement short list: CoQ10, creatine, ketones, vitamin D, melatonin. [01:44:43] KetoNutrition.org, Metabolic Health Summit, Audacious Nutrition, veteran-focused research protocols, and other parting thoughts. * Show notes for this episode: https://tim.blog/2025/09/03/dr-dominic-dagostino-all-things-ketones/ For show notes and past guests on The Tim Ferriss Show https://tim.blog/podcast, please visit tim.blog/podcast https://tim.blog/podcast/?utm_source=podcast&utm_medium=podcast&utm_campaign=podcast-description. For deals from sponsors of The Tim Ferriss Show https://tim.blog/podcast, please visit tim.blog/podcast-sponsors https://tim.blog/podcast-sponsors Sign up for Tim’s email newsletter (5-Bullet Friday) at tim.blog/friday https://go.tim.blog/5-bullet-friday-1/. For transcripts of episodes, go to tim.blog/transcripts https://tim.blog/transcripts. Discover Tim’s books: tim.blog/books https://tim.blog/books. Follow Tim: Twitter: twitter.com/tferriss https://twitter.com/tferriss Instagram: instagram.com/timferriss https://instagram.com/timferriss/ YouTube: youtube.com/timferriss https://www.youtube.com/timferriss Facebook: facebook.com/timferriss https://www.facebook.com/TimFerriss/ LinkedIn: linkedin.com/in/timferriss http://linkedin.com/in/timferriss See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Tim Ferriss?

  Hello, boys and girls, ladies and germs. This is Tim Ferriss. Welcome to another episode where it is yet again my pleasure, after more than a decade, to deconstruct world-class performers from all different disciplines, to tease out the news you can use, the tactics and specifics that you can apply to your own life. My guest today is a very popular and repeat guest on this show, Dr. Dominic D'Agostino. He is a tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida, Morsany College of Medicine, and a visiting senior research scientist at the Institute for Human and Machine Cognition. He's also one hell of an athlete, and if you were to ask me to name one person to

• 0:42Tim Ferriss?

  ask any question related to ketosis, exogenous ketones, in other words, supplemental ketones, anything at all related to the ketogenic diet, metabolic psychiatry, if I had to choose someone who was a decathlete of the highest order across all of those, it would be Dominic or Dom. He teaches medical neuroscience, physiology, nutrition, and neuropharmacology, and his research focuses on the development and testing of nutritional strategies, we'll talk about that, and metabolic-based therapies for neurological disorders, whether it's depression or chronic inflammation, cancer, and human performance optimization. He has served as a research investigator and crew member on NASA's Extreme Environment

• 1:23Tim Ferriss?

  Mission Operations, and his research has been supported by the Office of Naval Research, the Department of Defense, the National Institutes of Health, and nonprofit foundations, among others. We get into a lot in this episode, we get very much into the weeds, so I thought I would do something that I rarely do and just share a few of my takeaways, and these are just a small sampling, but I wanted to mention a few things. For instance, I've been taking various types of supplemental ketones, and they come in many different types. You have ketone salts, sometimes combined with electrolytes, you have ketone esters of different types. There are many different types of supplemental ketones you can take. A ketone is not a ketone is not a ketone.

• 2:07Tim Ferriss?

  And I learned, for instance, that if I am consuming- Something like Keto Start, which is a keto and salt that also includes electrolytes. Or if I'm consuming, say, a mono ester or something like that, that I should add MCT oil to the mix, which you can get as an oil or you can get it powdered. Now, why would you want to do such a thing? Well, straight from Dom, we had a lot of texts before and after this conversation. Exogenous BHB, that's beta hydroxybutyrate, plus MCT increases BHB higher than either one taken alone. MCT sustains the elevation of BHB salts and esters by slowing absorption. So you want to take them together. The beta hydroxybutyrate is what is measured when you do, at least with most devices, a finger prick test for ketones.

• 2:52Tim Ferriss?

  Now, why should you care about ketones or the ketogenic diet at all? Let me give you a couple of reasons, and these are straight also from my notes with Dom from past and this conversation. So ketones are not just something your body produces when you're on a ketogenic diet, which was used for a very long time, a very long time ago, for epileptic children. You also run into ketosis if you're, say, in a starvation state where your body begins to pull from body fat and use that as fuel, which the brain and the heart love, for instance. But why should you care about them otherwise? Couple of reasons. If you think of some common neurodegenerative conditions, such as Alzheimer's, which is sometimes referred to as type 3 diabetes, you have an energy problem.

• 3:36Tim Ferriss?

  And if your glucose, right, sugar, the carbohydrates, the normal stuff that people depend on, is compromised, you can sometimes circumvent that and help to mitigate a lot of problems by using ketones. And ketones can furthermore be thought of as hormones, in a sense, or at least signaling molecules. And so let me just read straight from my notes. So Dom explains that ketones are far more than just fuel, even though they are really, really interesting fuel, especially if you're doing training, like zone 2 training and so on. Citing a key paper, he states that beta hydroxybutyrate, that's the BHB I mentioned before, is an HDAC class 1 and class 2 inhibitor. We won't get into that, it's histone deacetyls, but a pathway of great interest to the pharmaceutical

• 4:20Tim Ferriss?

  industry for cancer therapy. So what does this mean? By inhibiting these enzymes, ketones can activate genes that enhance the body's own antioxidant and cellular defense mechanisms. And Dom and I have talked at length in the past about the application of the ketogenic diet, or ketones to different types of cancer. Dom goes on to describe a paper from colleagues at Yale, for whom Dom's lab developed a diet protocol showing that ketones have a direct anti-inflammatory effect. This is really important, and this is why I'm also paying so much attention to this. They were shown to inhibit a specific inflammasome. Okay, that's a word you should look up, inflammasome, linked to many chronic age-related diseases, not just something like Alzheimer's. This effect was demonstrated to be completely independent of the ketones' role as a metabolic

• 5:05Tim Ferriss?

  fuel. So it's a lot more than just an alternate fuel that you run into when you say fast for a few days, or go on a ketogenic diet, or a fast-mimicking diet. Other things we talk about. We talk about some risks of common ketone supplements that are on the market. And I'm going to try to get the wording very carefully crafted here. And the way I'll put it is that there is potential for liver toxicity when certain types of supplemental ketones are used chronically. So I'm being very delicate in how I word that. But if you're taking anything with, say, 1,3 butane-dial-based ketone esters, those are very, very common.

• 5:48Tim Ferriss?

  Chances are, if you get something at retail, or if you just search around casually and find something that it's based on 1,3 butane-dial in some fashion, if you use that chronically, and not at super-high doses either, let's just say that's above 100 milliliters a day. Now, if you're taking, like, high-performance ketones, and you're training as a cyclist, that's not actually a crazy amount. If you look at certain case studies where people have taken monoesters for Alzheimer's, let's just say, in the hopes of mitigating symptoms, you get up to that level. So, got to be careful with the ketones that you are taking, and, as always, cycling off on occasion. And moderation, I think, are the keys to success. As is true of so many other things.

• 6:33Tim Ferriss?

  Otherwise, for instance, looking at the much touted and discussed metabolic zone with respect to ketones. This can be done through fasting or the ketogenic diet, where you pull in something... Called the glucose ketone index, GKI. And sure, one to two might be ideal. One to five is still great. And what Dom and I discussed a little bit is that the Goldilocks amount of ketones, let's just call it 1.2 to 2 millimolars, and you measure that with finger pricks, for instance, there are other ways to do it, is anxiolytic. It reduces anxiety. But what I've noticed is that if I take a lot of exogenous ketones and have it spike

• 7:15Tim Ferriss?

  far above that, that I actually have significantly increased anxiety. Rut row, don't want that. And a subsequent crash, which may or may not be related to insulin and its effects on insulin. So let's look at a couple of other things. And I'll just emphasize again that some people are transitioning away from using 1-3 butane dial, which is a dial alcohol, and 1-3 butane dial-based ketone esters because of these potential liver toxicity effects with chronic use. And that's going to be coming out in publications in the not-too-distant future, I would expect. All right, looking at a few other things, some other usable tidbits. Dom explains that soluble fiber in foods like artichokes is fermented by gut bacteria

• 7:59Tim Ferriss?

  into short-chain fatty acids like butyrate, which are themselves ketogenic. So here's a little-known fact, that cows are naturally cattotic due to this fermentation process. So when you're on the ketogenic diet, why not have some artichokes? There's one. And then I would say another technology that I've implemented based on conversations with Dom is hyperbaric oxygen treatment, HBOT. There's a lot of literature on this. There are a lot of fly-by-night kind of bullshit operations out there. But if you're using a hard-shell, medical-grade HBOT facility that can get you up to, let's just call it 2.4 or higher atmospheres, ATA, then you can apply it to all sorts of things.

• 8:43Tim Ferriss?

  And I'm using it right now to hopefully enhance surgical recovery after elbow surgery. And one of the enhancements you can add to hyperbaric oxygen treatment is taking ketones beforehand. Taking supplemental ketones to reduce the potential for oxygen toxicity and there are a host of other benefits. So Dom is, as I mentioned before, a real decathlete across so many different fields that are touched by ketones, by his knowledge of training. We even talk about, I believe, the use of androgens or anabolic agents in cancer, believe it or not, which would be very counterintuitive, I think, to a lot of folks. We get into the weeds.

• 9:26Tim Ferriss?

  So if you are listening, you're like, oh, my God, I cannot make sense of all this terminology. Just skip ahead five minutes and chances are something will pop up that you can certainly apply. And that is, I want to say, maybe the longest intro I've done, but I'm going to make it just two minutes longer because I noticed a few things that I've written down. One is that Dom has taken a pretty substantial doses of melatonin nightly for ages. And I was always concerned, based on some animal studies showing endocrine disruption. And we discussed that. And long story short, I'm back on melatonin after having that conversation. And he also tells the story of Dr. Fred Hatfield and sardine fasting.

• 10:10Tim Ferriss?

  So using one can of sardines per day for a week of each month, which is very similar to, in some respects, the work of Walter Longo and the fast mimicking diet. But apparently, and I'm pulling this from memory, since I recorded all of this about a few weeks ago, that Fred was able to extend his runway after a serious cancer diagnosis by years following this protocol, which was one week per month of what he called sardine fasting. So we get into all of that. We discuss lots of different takeaways, different brands of X, Y, or Z that Dom trusts. And I will leave the rest to Dom. For God's sake, that's a long enough intro.

• 10:53Tim Ferriss?

  So without further ado, maybe just a few words from the sponsors to make this possible. Please enjoy a very in-depth conversation with the one and only Dr. Dominic D'Agostino.

• 11:04Tim Ferriss?

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• 11:47Tim Ferriss?

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• 12:30Tim Ferriss?

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• 13:12Tim Ferriss?

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• 13:55Tim Ferriss?

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• 14:20Speaker 01

  At this altitude, I can run flat out for a half mile before my hands start shaking. Can I ask you a personal question?

• 14:26Dr. Dominic D'Agostino?

  Now would be the soon appropriate time.

• 14:30Speaker 01

  I'm a cybernetic organism, living tissue over metal endoskeleton.

• 14:42Tim Ferriss?

  Dom, nice to see you again. It's been a few years. Thanks for making the time.

• 14:47Dr. Dominic D'Agostino?

  Yeah, it's great to see you, Tim. Yeah, we've stayed in contact here and there with texting, but yeah.

• 14:51Tim Ferriss?

  Lots of texts and why not? This is one of the text threads I could probably actually make public in my life without some type of mutually assured destruction with many of my friends. I have been revisiting everything ketogenic and certainly looking at exogenous ketones for a number of reasons. And one of which, we were chatting a little bit before recording, is that I have a number of relatives who are deteriorating from neurodegenerative disease. Including Alzheimer's and one of them is APOE 3.3. And my siblings and I are APOE 3.4, which would seem to indicate we would have potentially

• 15:32Tim Ferriss?

  a, let's just call it two and a half X higher probability of developing something like Alzheimer's, even though data might change, who knows? Nonetheless, I'm looking to throw as much possible at this from a preventative perspective. What data do we have? And if there's a little bit of speculation involved, I'm fine with that too, in terms of future directions for research and what might come up for applications of, say, the ketogenic diet and/or exogenous ketones to something like Alzheimer's, whether it's from a preventative perspective, a mitigation of slowing of progression of symptoms or anything else.

• 16:13Dr. Dominic D'Agostino?

  Yeah, that's a rapidly emerging area of research. And I think you're aware, we talked kind of previously of the case reports that are out there that kind of got, put this on everybody's radar. I would say, you know, the early adopters of this idea were the people who understood that brain energy metabolism was pretty central to Alzheimer's disease.

• 16:36Tim Ferriss?

  Sometimes called type 3 diabetes if I'm getting that right.

• 16:40Dr. Dominic D'Agostino?

  Yeah, that was coined back in 2005 or 06, I think. And that was brought to my attention actually by Dr. Mary Newport and her husband, Steve Newport, was the subject actually in the case report for the use of the beta hydroxybutyrate monoester for that. And Dr. Richard Veitch of the NIH was also on that. And Mary was near and dear to my heart. I actually coincidentally hosted her for dinner last night at the house and had her over here and she's a close friend of mine. We co-teach together. At USF, she's a guest teacher. Interestingly, you know, I saw Steve Newport in 2008 or nine. I witnessed the observation. He is a three, four. He has Alzheimer's. He was three, four for APOE four.

• 17:25Dr. Dominic D'Agostino?

  And he also had, he had Lewy body dementia, but confirmed Alzheimer's disease too. When they looked at the brain, I was questioning this idea of ketones rescuing the brain in the context of Alzheimer's disease. Symptomatically, there was no doubt in my mind that it did because he wasn't using the ketone ester at the time, but we quickly transitioned to that after a meeting. But he was taking coconut oil and MCT oil and he would bring these little shot glasses. Mary taught my class. We went out to dinner. He did the shot glass. His, his tremors stopped. He became animated and he talked and after about four hours, he started to decline and started getting fine tremors again. And then he would become reanimated upon increasing his ketones to about one to two,

• 18:08Dr. Dominic D'Agostino?

  which we'd give him like a 30 milliliter shot of MCT plus coconut oil that was mixed in there. So she was really, and doing that three to four times a day with meals. So that was my, you know, first observation and it was clear to me that there was at least a metabolic within the Alzheimer's spectrum. I just liked Alzheimer's is kind of a fuzzy diagnosis. Sure. Very fuzzy. I'd just kind of like to call it, you know, dementia, cognitive dementia. There's vascular dementia and there's A beta and tau. And my wife was working on tau at the Alzheimer's center when we met. She was working under a guy who studied tau. Then there was people at there who studied amyloid beta.

• 18:48Dr. Dominic D'Agostino?

  And there was like the tauists and the beta, and there was kind of like an argument as to what was more profound. But a universal feature of Alzheimer's is amyloid plaque accumulation. But also now we know that glucose hypometabolism is central to that. And as we age, our ability to use glucose as an energy source decreases over time due to, they thought maybe vascular reasons, but come to find out it's a constellation of things, including the glucose transporter. The glut three is on neurons, pyruvate dehydrogenase complex, which is like really the governor or the rate limiter of glucose metabolism in neurons. That's PDH, pyruvate dehydrogenase complex and.

• 19:32Dr. Dominic D'Agostino?

  If you look at that protein for that, that decreases over time, as does the sort of catalytic activity of that enzyme over time. So we know that. And then there's neuroinflammation, there's a vascular component. So all these things kind of contribute to metabolic dysregulation, but also a big driver is neuroinflammation. And I do believe, as does Dr. Mary Newport, who is the author of that paper, kind of with a case report and a number of other leaders in the field, including, I'm blanking on his name, the Chair of Neurology at Harvard, just gave an NIH seminar on infection as an etiological agent for Alzheimer's disease.

• 20:12Dr. Dominic D'Agostino?

  So Epstein-Barr virus, cytomegalovirus, herpes simplex virus, HPV, you know, can contribute to things like- So we're probably talking about if, I mean, 50, 60% of the population having one of these things. Sure. Yeah. Well, Steve Newport, the subject in that case report, had bouts of herpes, HSV, around the eyes and got hit pretty hard with that. But also people who have shingles, I think they're at risk too. We know like Epstein-Barr virus, you're four or five times more risk for things like MS, you know, it's triggering the immune system. So I think there's a renewed interest in looking at Alzheimer's disease, you know,

• 20:53Dr. Dominic D'Agostino?

  looking at the root cause. And I think metabolism is central, but the metabolic hit that may be contributing to dysregulated metabolism and neuroinflammation could be an infection. And I think there's accumulating evidence for that. I was skeptical 10 years ago, probably when we talked. However, this kept putting on my radar. And then I was in a NIH sponsored workshop on this, you know, looking at various aspects. And the data presented by a number of different labs was very compelling for this. So what does that mean? Our immune system is, there's the four horsemen, right, that our friend Dr. Peter Tia talks about. I think the fifth horseman is really the immune system. I like to add the sixth horseman

• 21:38Dr. Dominic D'Agostino?

  as our physical form, our skeletal structure, our bones, you know, and that that will give over time too. But the immune system is really central to longevity and the metabolic control of epigenetic regulation and metabolic control of immune system function is of very high interest. I know the Buck Institute has kind of refocused on that. And many longevity clinics are now looking at that.

• 22:03Tim Ferriss?

  What is your preferred device for measuring ketones these days?

• 22:06Dr. Dominic D'Agostino?

  For publications, we've used the Abbott Precision Extra because historically we've used that. However, when I recommend a meter to people, I generally recommend the Keto Mojo device because that

• 22:19Tim Ferriss?

  Keto Mojo.

• 22:20Dr. Dominic D'Agostino?

  The glucose ketone index. And so the glucose ketone index is the millimolar concentration of glucose over ketones. And the strips are about nowadays, still less. I was gonna say, I don't know, a few years ago, they're about half the price. And we've tested the Keto Mojo. So we have a human clinical trial where we did breath, we did urine, and we did Precision Extra and Keto Mojo. All together. And then subjects go into the chamber and we did metabolomics and everything else. The Keto Mojo consistently gives us numbers that are more in line with our biological assays that we run in the lab, like the alliances on that. Yeah.

• 22:59Tim Ferriss?

  Well, let me just tell you what I'm up to. And you can tell me how ridiculous I am and off base or fact check as needed. Can you remind me of how to pronounce this? Dr. Thomas, is it Seyfried? Am I getting that right?

• 23:12Dr. Dominic D'Agostino?

  Yeah, he's a good friend and colleague, Doc, Tom Seyfried, man.

• 23:15Tim Ferriss?

  Tom Seyfried. All right. So in terms of fasting, we've talked quite a bit about fasting. It still is very interesting to me. And I'm wondering, just in brief, if you could, without getting too, too much in the weeds, but I'm wondering what the ketogenic diet does that exogenous ketones do not achieve. And then I'm wondering what fasting does that the ketogenic diet does not do. But the way I want to get to that is to ask you, because for a long time I was doing a one week, we could call it a water only fast, but let's call it a calorie free fast, black coffee and black tea and stuff I was consuming. But a week long, water long fast a year, and I was doing maybe a three day fast every quarter.

• 24:01Tim Ferriss?

  I couldn't quite, didn't really want to do like three to four week long fasts a year. Just didn't want to do it. But in terms of potentially purging precancerous cells and so on, I was like, you know what? I like the aesthetic practice. Seems like a bit of autophagy and cellular cleanup is a good thing. Why don't I do that? Do you do any fasting anymore? Or is that something that you have omitted from the current version of Dom's schedule?

• 24:27Dr. Dominic D'Agostino?

  Yeah, I do it situationally. And I think there's situations where I think I'll benefit from fasting or from just inducing a state of an energy deficit, right? So you could do caloric restriction, time restricted feeding, dietary restriction, you could do a restricted ketogenic diet, cyclic ketogenic diet, modified supplemented ketogenic diet, I guess, which is what I do. I like to do what I call, I mean, I kind of coined it. It's like sardine fasting. And I had a cancer patient, a long time, one of the first that I sort of engaged with, actually, his name was Dr. Fred Hatfield. So he was like, kind of a famous-

• 25:05Tim Ferriss?

  Is this Dr. Squat?

• 25:06Dr. Dominic D'Agostino?

  Yeah, yeah, Dr. Squat.

• 25:08Tim Ferriss?

  Back in the day, wow.

• 25:09Dr. Dominic D'Agostino?

  Yeah, we were good friends. He was a mentor to me in many ways, but he had advanced metastatic prostate cancer and it went to the bones where they did like a PET. And I was just getting into this area of research and I was like, here's what I would do. And I would go to his house and I'd bring him things and he was testing things and he loved sardines. So he, I think he steered me onto sardines in like, maybe 2007 or eight or something like that. That was my love for sardines kind of was probably from him. But he would do low carb, he called it ketogenic, but I think it was just more of a low carb diet. And then he would do five days, he would do a fasting mimicking diet that Walter Longo has advanced, but he has more of a plant-based approach. But Dr. Hatfield

• 25:51Dr. Dominic D'Agostino?

  would do, Fred would do like one or two cans of sardines, like maybe one can of sardine per day for a week. So we called it like sardine fasting. And that was just as I was getting into this. And essentially what happened is that he went into rapid remission and the doctors didn't really know. Fred ended up passing away, maybe eight years later of something completely unrelated to his cancer.

• 26:15Tim Ferriss?

  As a non oncologist, I have to pause and just say, I mean, it seems like prostate, for a lot of people, they hear that, they think death sentence, metastasized prostate cancer. They think, no way, you're done. Am I exaggerating? I mean, how- Frequent is it that people have complete remission of something like that? Maybe I'm exaggerating things.

• 26:34Dr. Dominic D'Agostino?

  Yeah, there's a lot of factors like the Gleason score and his was, you know, not good and a number of factors. So he was given, I think he told me like three months to live. I mean, but he went years and years after that and he was like, no evidence of disease.

• 26:49Tim Ferriss?

  How often was he doing the sardine fasting? Was that once every month? What did his cadence look like?

• 26:55Dr. Dominic D'Agostino?

  He stayed ketogenic and then I would go over there and encourage him to do that. And he loved to do it. He was like, okay, I do this and now I feel better like when I'm doing. Fred also surprisingly would smoke a little bit and I got him to maybe stop that. We got him to dial back on some other behaviors and maybe he would drink a little bit too, but not that much. But his health improved dramatically when he adopted a low carb and then ketogenic diet. And then for years he did the sardine fasting and we communicated and I just encouraged, hey, keep sending me your medical reports and maybe there is something to this. So that actually steered me into, we did, started Alzheimer's research because of Dr. Mary Newport. I studied seizures because of Mike Dancer.

• 27:39Dr. Dominic D'Agostino?

  Just Google Mike Dancer epilepsy and you'll find some remarkable stories. I kind of steered him to the ketogenic diet and it, and it was remarkable. He got off all meds and it worked way better than the meds. But that was prostate cancer, but then I started engaging with other patients and then connected with Thomas Seyfried.

• 27:57Tim Ferriss?

  How frequently was Fred doing the week-long sardine fasts? If you had to guess.

• 28:03Dr. Dominic D'Agostino?

  Once a month. Sorry. Yeah. I meant to, yeah, it's analogous to the fasting mimicking diet. I think Volta Longo can do that, you know, he advises patients based on situationally, their situation. But I encouraged Fred to do it every month and his feedback to me was that he would do it once every month to two months. He enjoyed doing it. So it was something that he kind of like looked forward to doing.

• 28:25Tim Ferriss?

  Sardine fast. I can't wait for that to become a thing. That's going to spread. I don't want to gloss over what you personally do. So for you, for instance, I found out recently and everybody get your checkups, right? Do not skip colonoscopies, do not skip. In my case, I got an endoscopy because I was having some trouble swallowing every once in a while. I thought it was like, ah, maybe it's just like I'm eating too quickly with dried chicken or something. And suffice to say, putting that aside, that was sort of the symptom that catalyzed it. But I end up having very unexpectedly, a hiatal hernia. Hiatal, I think also related to the word hiatus etabbiologically. But basically, I'm going to get the definition wrong, I'm sure. But basically, from your esophagus to your stomach, typically, there's

• 29:10Tim Ferriss?

  a nice kind of sphincter or ring. And basically, the stomach is kind of pushed out of that ring. And there's actually a lot of scarring in my throat from acid. So I was told that, you know, maybe not this bluntly, but that that puts me at some increased risk of throat cancer or esophageal cancer, some type of cancer. And I was like, shit, that's not typically what kills people in my family. Usually, it's the cardiac stuff. And I feel like I have that. My lipid profile is very well under control. And which is why going back and doing research for this conversation, and I've also done fasting over the years, I've thought, okay, well, in addition to taking the proton pump inhibitors and everything so that I'm not accumulating

• 29:54Tim Ferriss?

  more scarring, yeah, is there a place for doing the fasting, since I don't mind doing it anyway, just to further hopefully decrease the risk? And you were saying you fast episodically? Was that the word that you used?

• 30:08Dr. Dominic D'Agostino?

  Situationally episodic.

• 30:09Tim Ferriss?

  Situationally, situationally. What does that mean?

• 30:12Dr. Dominic D'Agostino?

  If my wife is traveling and I, you know, prevents me from being antisocial, and I have a lot of work to do, and I have to, I have a grant deadline, it's five days away. Okay, I'm starting fasting for five days until I get this grant submitted. If I'm traveling by myself, I'll do it if I get for any reason occasionally, you know, I'll get like sort of an inflammatory flare up and I don't know what it's, I'll feel a little bit off like brain fog or my joints or something like that. It's pretty rare now because my HSCRP is like non-detectable, right? Before I did, it was always like one or two to on a higher carb diet.

• 30:49Tim Ferriss?

  Yeah. So people might recognize CRP, right?

• 30:52Dr. Dominic D'Agostino?

  Yeah.

• 30:52Tim Ferriss?

  I mean, C reactive protein is a marker of inflammation. I mean, if you get your annual blood test or whatever, chances are it's on there somewhere.

• 31:00Dr. Dominic D'Agostino?

  Yeah, I'd like to draw attention to that real quick because HSCRP is a better indicator of cardiovascular disease than LDL cholesterol. Like we know that now, like if you, someone said that like 10 years ago, there's like, I think you're crazy. But yeah, HSCRP is what we call a cardiometabolic biomarker, including, you know, triglycerides and insulin and things that should be included. But that is a really important biomarker, I think, to keep low for Alzheimer's and for cancer and all the other, I call it six horsemen now. So things that I mentioned. Yeah. So occasionally I'll use it situationally just if I feel my body, if I feel like something is coming on, like I'm getting a flu. But

• 31:42Dr. Dominic D'Agostino?

  the sardine fasting is, and I advise it for cancer patients, I want them to avoid a water only fast in the context to prevent cancer cachexia.

• 31:53Tim Ferriss?

  Yep. Muscle loss or muscle wasting.

• 31:55Dr. Dominic D'Agostino?

  Yeah. And omega-3 fatty acids are very potent mitigators of cancer cachexia. So you have the omega-3s and basically you have everything your body needs, especially like nutrition wise in sardines. You might want to add a little bit of vitamin C or magnesium or something, but essentially it's like you have adequate nutrition and then you have, you create a caloric deficit, you create caloric restriction. And then with caloric restriction come a whole host of beneficial things. The protein's low enough that you're suppressing insulin, mTOR, and probably activating AMP kinase. And if you do that in a protracted way and you can achieve a glucose ketone index of one to two for about three to five days, the constellation of things that if you measure that would

• 32:40Dr. Dominic D'Agostino?

  sort of correlate with inducing and maximizing autophagy. So that was sort of the rationale for me to do that. And a lot of people talk about autophagy and it's kind of a nebulous term. We measure it. We look at the autophagosome. So we're like a lab that actually does kind of look at things like that. And there's like P62 and other things that you can measure, but there's no commercially available. I think the best way to measure that suggests you're in autophagy is a glucose ketone index.

• 33:09Tim Ferriss?

  Yep. Which Keto Mojo will do automatically. It'll do the calculation for you. I did have a quick question. When I compared my Keto Mojo to a oral glucose tolerance test where I was having blood drawn every 30 minutes, the glucose readings I got from the Keto Mojo were substantially higher than the blood test, than the blood draw itself. And I was wondering if that's something you've observed. I mean, who knows? Maybe it's a bad device. Maybe I had too much alcohol still on the finger and I didn't dry it properly. I mean, who the hell knows? But maybe it doesn't matter so much, but it seems to matter, right? Because a regular spikes above a certain kind of nanogram per deciliter seem to be

• 33:53Tim Ferriss?

  indicative of all sorts of things. Have you run into any issues with the device or any caveats related to specifically the glucometer side? What I do like that's nice about is it does give you that glucose ketone index, the GKI, as a readout right there on the device, or in the app at least that accompanies the device.

• 34:11Dr. Dominic D'Agostino?

  Are you talking about measuring glucose at the exact same time point that a phlebotomist pulled the blood?

• 34:17Tim Ferriss?

  That's exactly what I'm talking about.

• 34:18Dr. Dominic D'Agostino?

  Okay. And what was the difference between what was measured?

• 34:23Tim Ferriss?

  Let's say the peak at 30 minutes out after drinking this not so delicious dextrose water. It's something like this. Like I was bumped up to probably 140 on the phlebotomist drawn blood and it was like 165 on the Keto Mojo. And the return was much faster and much better on the phlebotomist drawn blood than it was on the Keto Mojo device, which is not to throw them under the bus because it could be operator error or just a single bad device. And I have friends who have used it very successfully on the ketogenic diet, which is why I ended up buying it because Precision Extra is kind of a pain in the ass to get a hold of, at least on Amazon. So that was my experience. And I was like, okay, well.

• 35:08Tim Ferriss?

  Tricky, tricky, tricky. Cause I, you know, if I'm really trying not to pop above a certain level, if the device I'm using day to day is 20 points above where maybe it should be, then that's a problem, right?

• 35:21Dr. Dominic D'Agostino?

  What's your hemoglobin A1C?

• 35:24Tim Ferriss?

  I'd have to go back and look. It's trending down, but I would have to go back and look.

• 35:28Dr. Dominic D'Agostino?

  If you wear a CGM, you're under maybe a hundred, like with the CGM. So the meters tend to trend a little bit high, like about 10% high. The keto mojo was 10% higher than our assays and the precision extra was 20% higher than our, the assays that we do when we pull blood from the animal. So if that helps, you want to look at your insulin levels, your hemoglobin A1C.

• 35:54Tim Ferriss?

  Yeah, we, we, we got it all. And just for people, public service announcement, do an oral glucose tolerance test, ask your doctor, talk to them, get your insulin measured because my relatives metabolic dysfunction was missed for a very long time, in part because they were looking at fasting glucose and you can get really lucky with fasting glucose, depending on when you get that snapshot. And I mean, the docs weren't great to begin with, who were tracking these relatives. But as soon as we looked at OGTT, the oral glucose tolerance test and insulin, oh my God, it was like sky high, out of range.

• 36:31Dr. Dominic D'Agostino?

  Yeah. Or put a CGM on them. That's what motivated me to be, I guess, you know, one of the first advisors for levels and I've worked with them on a research front. I think you've interviewed Sam, right? But levels, I mean, that's, yeah, Sam, I mean, that's like the ultimate kind of, you know, metabolic optimization platform. I mean, there's others emerging too, but simply wearing, I mean, now they have the Stella solid device that came out. So CGMs are over the counter now. But the analytics from that and also the biomarkers that if you're part of that program that you can measure, which include, you know, many things that we can talk about, but that would capture your relatives if your relatives

• 37:12Dr. Dominic D'Agostino?

  put a CGM on, you know, that's really important. But what you observed is pretty normal and not to probably be of concern.

• 37:21Tim Ferriss?

  Okay. Cool. Yeah. I just wanted to check it out.

• 37:26Tim Ferriss?

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• 38:08Tim Ferriss?

  industry. So check them out. Subscribe today to try the next gen of AG1. Listeners will also get a free bottle of D3K2 and AG1 Welcome Kit and five of the upgraded AG1 Travel Packs with your first order. So start your journey with AG1's Next Gen and experience the difference firsthand. Simply go to drinkag1.com/tim. That's drinkag1.com/tim.

• 38:39Tim Ferriss?

  If someone uses, just to tie this up for me and I maybe just missed it, if someone is using exogenous ketones on a continual basis, are there longer term adaptations? And part of the reason I'm asking is that in the most recent sort of kind of set of experiments, let's just say, I was strict keto for three weeks and then frankly just got bored to death of the diet. It's hard. I did like, yeah, I did three weeks of, let's just call it kind of textbook protein, also quite low, like 10 to 15%, let's say. So maybe I bump it up next time, but just got so bored of it after three weeks. But I want to do enough that there might be some upgrade of the metabolic machinery and we could talk about that because I know for athletes, it might be

• 39:21Tim Ferriss?

  like six months to 12 months. But went from that to then 16/8 intermittent fasting, still in ketosis for maybe a week. So 16 hours off, eating between, let's say 2pm and 10pm.

• 39:36Tim Ferriss?

  And then I went to a more paleo-ish diet, let's just call it, within that feeding window. And I'd say, did that for a few weeks, then started layering in exogenous ketones in my fasting state, typically 11 a.m., 1 p.m. if I'm doing podcast recordings and things like that. And part of what I'm trying to figure out is, given I'm APOE 3,4, scared to death of Alzheimer's, and maybe there's nothing to be done about it, but if there is something to be done, in addition to exercise, right, and kicking out the clotho and BDNF and all that good stuff, from a dietary perspective, trying to figure out, like, okay,

• 40:19Tim Ferriss?

  how long does keto memory last if there is a expiration date? And if you were in my shoes, how you would think about not just the exogenous ketones, but fasting and ketogenic diet? Do you have any thoughts on that?

• 40:38Dr. Dominic D'Agostino?

  Well, yeah, you're doing a lot of stuff there. And I would recommend following a protocol that you could do kind of day in and day out that should ideally almost be effortless and kind of mesh with your schedule, which may be variable if you have podcasts and things like that. But I also, I'm of the opinion that, you know, you could follow like a baseline diet, which is a low carb Mediterranean-like diet. Mediterranean's kind of a fuzzy term, I hate it, but low carb Mediterranean-style diet that essentially keeps biomarkers in check and then situationally go into ketosis now and then to just optimize it. But you want to follow an approach therapeutically that keeps your GKI into that 1 to 4 range.

• 41:23Dr. Dominic D'Agostino?

  Tom Seifert is very adamant about 1 to 2, but the normal GKI of a person in the US is like 50, right? 25 to 50. So just living in a state of having a GKI of even 5 would be, I think, trending towards being more metabolically flexible, having greater fat oxidation. And then you want to, as it sounds like you're doing, just keeping check of your metabolic biomarkers. So comprehensive metabolic panel, CBC, of course, if you're using You know, different agents on that, but insulin, HSCR, P hemoglobin A1C, triglycerides, ApoB, you want to measure to LP little A, it's good to know. So unfortunately, 30% of

• 42:08Dr. Dominic D'Agostino?

  people, and this is probably important when navigating what protocol to use. I have a mutation. I did GB Health Watch, which looked at my genetics for dyslipidemia. So GB Health Watch, Dr. Spencer Nadolsky reached out to me because he was, I was posting my numbers online and he was like, hey, you need to do this test. So he's a very smart, aggressive or proactive kind of guy and suggested this test. He's like, I think you're a hyperabsorber. And it's like, isn't like 1% of the population a hyperabsorber? But come to find out about 30% of the population, hyperabsorb cholesterol. That's me too. I'm in the same boat. Okay. I have an MPC1L1 receptor mutation. That's a gain of function mutation. So I

• 42:51Dr. Dominic D'Agostino?

  use azetamide monotherapy for that. So azetamide was sold as Zetia and I can get by with half of a tablet, which is five milligrams and it half my ApoB. It put my ApoB, it cut it in half and also half my LDL. So I can follow a ketogenic diet and I had the skyrocketing LDL ApoB, but then I put that back in check. I am of the opinion that I need more data to come out. There's a group of people that think, you know, LDL in the context of optimal metabolic biomarkers that it's not to be concerned about, but that data is emerging and there's groups of people that I believe are credible and then working on that front, looking at the lipid energy model. With the lipid energy model, LDL and ApoB is sort

• 43:35Dr. Dominic D'Agostino?

  of a carrier for fat to peripheral tissues, but we don't have to go there. Yeah, let's dodge it for now. Yeah. Yeah. If your LDL pops up, then a pescatarian Mediterranean like diet that's low carb, that ideally under 100 grams of carbohydrates per day, that's no sugar, no starch, fibrous vegetables and fruits. So my rule of thumb is 25% of what carbohydrate you consume should be fiber. And then that'll essentially kind of make it non-glycemic. What percentage did you say? So what I do personally is about 50 to 100 grams of carbs a day and ensuring that the carbohydrates that you're consuming, about 25% of that carbohydrate is fiber. So for example,

• 44:21Dr. Dominic D'Agostino?

  Broccoli, you know, asparagus, of course cauliflower, green leafy vegetables, but even fruits, like I trend towards wild blackberries, raspberries, blueberries and buy them like in combination. And then wild blueberries are about half the size and they have more fiber, less sugar. So I have like a cup of that per day. That's probably my carbs come from mostly broccoli, wild berries, dark chocolate, and maybe a few other.

• 44:48Tim Ferriss?

  Where do you get wild berries? Is that something you can buy? Or do you have to go out and steal from your neighbor's patch?

• 44:55Dr. Dominic D'Agostino?

  Surprisingly, blueberries grow great in Florida, but we have a blueberry farm right by us and they make, it's a winery. So they make, they grow blueberries and then make blueberry wines and things like that and have huge festivals, but we get from there. But yeah, you can go to Walmart and get, you know, the Walmart blueberries, which are like the size of grapes. And then next to that now Costco and Sam's and even Walmart now have the wild blueberries.

• 45:20Tim Ferriss?

  Oh, no kidding. Okay. So just because you mentioned LDL, I might be hallucinating this, so please correct me if I am, but didn't you at one point dramatically cut down your LDL labs by swapping dairy out? I think maybe heavy cream and using coconut cream or something else in its place? Or am I making that up?

• 45:42Dr. Dominic D'Agostino?

  I took out heavy cream, but put sour cream back in, but maybe about half of the sour cream, but also just switched out the eggs. I think the eggs were getting to me because eggs have a lot of cholesterol and I was eating like a dozen a day. So when I prepare my food in the morning, my dogs get my food. So I, I'll make 10 eggs, but I will do, I'll have like three yolks and then I divide the other yolks between my two dogs. And then I also, instead of like ground meat, which I was eating a lot of, I get chub mackerel. I do sardines, occasionally tuna fish, but I get cases of chub.

• 46:17Tim Ferriss?

  Chub, like the insurance companies? C H U B B? No. How do you spell it?

• 46:21Dr. Dominic D'Agostino?

  Yeah, a C H U B. So a chub, unlike a king mackerel, which are bigger, chub mackerel are small fish.

• 46:28Tim Ferriss?

  Yeah, they don't bioaccumulate as much garbage.

• 46:31Dr. Dominic D'Agostino?

  Yeah. So they're really low on the, on the, uh, the heavy metal list, which I, I tend to check because I eat so much of it. So one can is almost a pound and there's three fish in each. I take a fish and give my two dogs each a fish. Then I pour, it's got a lot of fatty water in it full of omega threes. I pour that on their food. And they love it.

• 46:51Tim Ferriss?

  Where do I sign up to be reincarnated as one of your dogs?

• 46:54Dr. Dominic D'Agostino?

  Yeah, yeah, yeah, they get, yeah, this morning they got, my wife, audacious, has an audacious canine supplement. So we give them, and that's got spirulina, ketones, and a few other things. We give them that creatine monohydrate.

• 47:06Tim Ferriss?

  Hold on, I can't skip over that. Why give ketones to your dogs?

• 47:10Dr. Dominic D'Agostino?

  Well, the brain boosting effects, the anti-inflammatory effects, the nerve protective effects, and the anti-cancer effects. So these are all things I worry about with my dogs. They are fixed. I do give them a SARM.

• 47:23Tim Ferriss?

  This is an anabolic, right?

• 47:24Dr. Dominic D'Agostino?

  I do, yeah. I transitioned. They got attacked by a big pit bull and they, you know, kind of immobilized for a while. So it was like, I was going to use it for a cancer cachexia study. And it's Ostarine, I think. So I, yeah, started giving it to them and it seems like, yeah, they are leaner, stronger. We have a Great Dane that's 12 years old. That makes them like 90 to 100 human years, and he runs 35 miles per hour. Like he has like no sign of slowing down. Yeah, he's like, he's a Great Dane that should have passed away years ago, and he's just like a machine.

• 47:56Tim Ferriss?

  You mentioned audacious nutrition, just for the purposes of transparency. You do have family in the business involved with audacious, right? Just to confirm.

• 48:04Dr. Dominic D'Agostino?

  Yeah, I can't have any company. I don't sell anything personally, but yeah. My wife decided to create a product that sort of used the ketones that we actually used in research. So evolved out of that was various salts. And the idea was that if that product was created, then we can use it for research. And that was the initial part. And that's kind of what I, I was using it anyway. I was like, well, why don't you just make a product out of this? I can't do it. But it actually was an ICORPS NSF program through the university that got that started.

• 48:35Tim Ferriss?

  Question, do you give rapamycin to your dogs or would you, or to yourself? Do you currently or take or give your dogs rapamycin?

• 48:44Dr. Dominic D'Agostino?

  I've went back and forth. I follow Matt Cameron's work, you know, pretty closely and go back and forth. And I've decided not to just because of the immune suppression. And I got about a handful of people that use it. And I would say half of them get sores in the mouth. Yeah, that's super common, the mouth sores. Yeah, the date is too early for that. And I think the same thing can be achieved. A bigger lever would be sardine fasting, for one thing. And just beta hydroxybutyrate, you know, and a well formulated, low carb supplemented ketogenic diet. By definition, a diet that elevates ketones and exercise, right? So exercise and a whole host of other lifestyle things.

• 49:28Dr. Dominic D'Agostino?

  I'm not ready to pull the rapamycin trigger. Anything I do with my dogs, excluding the SARM, I haven't used that. But seeing the effects and looking at their blood work, it looks perfect. So there are no, no side effects with that. And it seems to be helping. Can you take just a paragraph, explain what this SARM refers to for people? Yeah, there's a specific androgen receptor modulator that is sort of hits the androgen receptor, but doesn't have the androgenic like qualities. It's not going to give you a third Adam's apple, but it'll help with muscle growth. It helps to stimulate skeletal muscle protein synthesis.

• 50:10Dr. Dominic D'Agostino?

  And then the context of this drug also bone metabolism. And both of our male dogs are fixed too. So we have discussions with various vets that are of the opinion, they're more progressive, that your dog should be on like TRT if they're fixed, because that will increase the quality of their life, especially as they age. I can't detect any loss of skeletal muscle mass, even when I look at pictures. For clarity, your dogs are all male? Yeah, we have two male dogs and both of them are considered advanced age. And the, the black lab is showing it a little bit. He has hardware in his two back legs. We had two knees put in with him, but he was a little bit heavier.

• 50:51Dr. Dominic D'Agostino?

  And now we've dropped his weight with what I feed him now, which is essentially fish, meat, eggs, ketones, and we give him a mushroom supplement that's lion's mane and a reishi.

• 51:04Dr. Dominic D'Agostino?

  Maybe cordyceps and a few other things. And then I give them creatine monohydrate. So they get, yeah, they're pretty optimized as dogs. And I think the big thing is that we live on a farm and they get a lot of activity too. They get two non-negotiable walks every day. And that's, I do that for, for me too. That's part of like my creative downtime is to do a non-negotiable walk like morning and night. So, and they get a lot of that and they chase our animals around too. So.

• 51:30Tim Ferriss?

  What are your current feelings on, let's just say on the sardine fast? When you're doing a week long sardine fast, and maybe you're so adapted at this point that you don't experience this, but certainly when I've done water fasts, and even if I'm doing a lower calorie ketogenic, following a lower calorie ketogenic diet, I can have a really tough time sleeping, at least for a handful of days. Have just kind of rapid heart rate. I don't know if that's trying to compensate for lower blood pressure because I'm just losing so much water and electrolytes. Who knows? I have found supplemental electrolytes to help a bit with that. But what type of supplementation do you take or advise people take if they are trying a ketogenic diet for the first time or fasting? Maybe the

• 52:15Tim Ferriss?

  answers are different. Let's just say it's a sardine fast, like a man, Falter Long, coming for you with the sardine fast. So what supplementation makes this easier or more productive? Just from an adaptation perspective?

• 52:34Dr. Dominic D'Agostino?

  I will use sardines and also Keto Start, which is essentially, you know, the electro-sodium, potassium, calcium, magnesium, beta-hydroxybutyrate. And that will be used like two to three times per day. At nighttime, yeah, when you go with a caloric deficit, your sympathetic nervous system is activated a little bit, especially with a water only fast. So you get a little bit hyper or dysphoric even for some people.

• 52:59Tim Ferriss?

  Yeah, feel like you just ran up three flights of stairs when you're trying to go to sleep. Yeah, it's unpleasant.

• 53:03Dr. Dominic D'Agostino?

  Yeah. So that's less with a sardine fasting instead of like zero calories. So the sardines would then be eaten at nighttime typically. I remember doing this repeatedly and what I would do is take a little bit of GABA at night and on one or two fasts, I took just 25 milligrams of diphenhydramine.

• 53:25Tim Ferriss?

  I think that's the exact or close to the exact dose of one or two Benadryl, right? I'd have to look at it, but isn't diphenhydramine?

• 53:31Dr. Dominic D'Agostino?

  Yeah, diphenhydramine is histamine. It tends to be lipophilic, which means when you take diphenhydramine, it quickly crosses the blood brain barrier. You could be a little bit groggy the next morning. The studies show that 50 milligrams of diphenhydramine can decrease, you know, memory recall if taken acutely, but 25 milligrams, there's no effect of that. So I'm comfortable with taking 25 milligrams of diphenhydramine at night and then giving a lecture the next day in the morning. I feel razor sharp and because also it reduces sleep latency. So I get better sleep. I would not use it more than like once a month or something. And I do think diphenhydramine and these over the counter sleep aids used every night by various people that are emailing me, I mean, is creating dementia.

• 54:16Dr. Dominic D'Agostino?

  I think, I think the data is pretty clear on that. You have an older person getting 50 milligrams every night, every week is bad. So melatonin, magnesium, a small dose, I guess for my size, it would be a half dose of diphenhydramine and then GABA. So you could take GABA in the form of GABA that you can get over the counter or there's also phenybuty GABA. So, which I have, but tend to haven't used in a while. Phenybuty, I would just want to put out there can be a really nasty drug for people. It could be addictive. You build a tolerance real fast and coming off of phenybuty can be very problematic for people. I mean, it's like coming off of GHB, I think. But it could be a tool in the toolbox because, I mean, we're talking about taking like two,

• 54:57Dr. Dominic D'Agostino?

  three grams of phenybuty can give you euphoria and you have, it's like a benzodiazepine kind of, but if you take 250 milligrams or 200 milligrams of phenybuty, which is a small dose. I mean theoretically, you could take that two or three times per week and never really build a tolerance or get, but I would not advise people do that. But if you're going to fast, like say, once a month, one way to avert that, and I get the same exact thing, I get super hyper and my brain just goes on fire when I did the first day of fasting. Yeah, a little bit of GABA, orphaned but diphenohydramine, magnesium. I've always done melatonin, five to 10 milligrams of melatonin.

• 55:37Tim Ferriss?

  Oh, that's a solid dose.

• 55:38Dr. Dominic D'Agostino?

  Yeah, we went on vacation and I forgot it.

• 55:41Tim Ferriss?

  Do you still use melatonin continually? Because I remember there was some conversation floating around the ether and never looked too closely into it because I don't use melatonin all the time about some possibility of endocrine disruption.

• 55:54Dr. Dominic D'Agostino?

  Yeah, I've been using melatonin, probably when I started using creatine in 1993, the old phosphagen when I was in high school.

• 56:02Tim Ferriss?

  Oh, man, back in the day.

• 56:04Dr. Dominic D'Agostino?

  Yeah, yeah.

• 56:04Tim Ferriss?

  EAS, is that?

• 56:05Dr. Dominic D'Agostino?

  It was, I was a beta tester for that. Yeah, I was a beta tester and then phosphagen came out in 1993, I think I started using creatine. I was like an early adopter of creatine. But yeah, to get to your question in melatonin, I've studied melatonin on the hippocampus, on brain slices. You can slice the brain like a piece of bread and it applied melatonin and looked at, you know, reactive oxygen species and things like that. We use it for oxygen toxicity. It wasn't good for that because it did make the rats sleepy. Melatonin doesn't really make me sleepy. It kind of makes me more calm than anything else. So I went on a vacation where I forgot melatonin and I slept like a baby, probably because I was up every morning, you know, sun is the ultimate circadian synchronizer.

• 56:46Dr. Dominic D'Agostino?

  So I got off of melatonin to check my endogenous melatonin and there was no suppression. Melatonin in animals that are hibernating, like little gerbils and things like that, if you give them melatonin, it can suppress endocrine function, including testosterone production. Huberman talked about, I love Huberman, because I was following him and he was talking about melatonin. And so I went to the primary literature and I was like, man, he's right. It is an endocrine disruptor and suppressor. But then I dug into the literature more and it was not the case for humans. So there was no evidence in human, and I think when he talks about. I don't think he references like a human study, but he does reference legit studies and Andrew Huberman is an amazing scientist and he puts out awesome information out there.

• 57:27Dr. Dominic D'Agostino?

  But it did get me concerned about it. So I got off of melatonin and then I confirmed that my body does make normal amounts of melatonin. So I measured that. I also confirmed that five milligrams of melatonin. If I go and measure the next day, my melatonin is off the charts, meaning that I take five milligrams at night. The next day in the morning at nine o'clock or 10 o'clock in the morning, my melatonin is like super physiological.

• 57:53Tim Ferriss?

  Is that good or bad?

• 57:55Dr. Dominic D'Agostino?

  I think it's good. So I take melatonin not to sleep, but as a neuroprotective agent that has a whole host of beneficial effects for the brain, also Alzheimer's disease, also cancer, especially breast cancer. So use it for that. I also mega dosed 20 or 30 milligrams and then checked my LH and FSH.

• 58:17Tim Ferriss?

  Milligrams?

• 58:18Dr. Dominic D'Agostino?

  Yeah.

• 58:18Tim Ferriss?

  Okay.

• 58:18Dr. Dominic D'Agostino?

  Yeah.

• 58:19Tim Ferriss?

  Yeah. So 20 to 30 milligrams.

• 58:20Dr. Dominic D'Agostino?

  10 milligram tablets are like the gorilla tablets for melatonin.

• 58:24Tim Ferriss?

  Yeah.

• 58:25Dr. Dominic D'Agostino?

  I chewed a bunch of them and then held it under my tongue. And I didn't really feel any more sleepy. I just slept like normal, you know, my Oura ring was like normal, but then I went and I got lab work done. And I did testosterone, LH, FSH, and there was no suppression. Actually, my LH and FSH were trending like high end of normal. Which is another topic that I can get into, but the thing is that it did not trigger an endocrine response in me. I do not think there's any data in humans, although specific animals are very sensitive to melatonin. And if you give it to them, it can cause endocrine suppression, some sex hormones. So it is a hormone.

• 59:04Tim Ferriss?

  Well, that's good to know because I actually benefit from taking melatonin. But I've largely cut it out because of some of the murmurs, but I do, it does help me sleep. Is this a true statement that you do not do any? Fasting currently, or like pure water fasting, but instead do this situational sardine fasting? And I mean, is that sort of 99% of the bang for the buck? And there isn't really any reason to go beyond something like that as a fast-mimicking diet? Or are there benefits that you think are compelling of doing a more restrictive, say, water-only fast where you're allowed black coffee and a few other things perhaps? But are otherwise really not consuming calories?

• 59:50Dr. Dominic D'Agostino?

  For me personally, it's very context-dependent. I was talking to someone the other day that was getting shingles. As soon as this first sign of tingling, which is like the precursor of getting shingles, they start fasting and it never actually surfaces. So only when they situationally pull the trigger and start water-only fasting, does it completely mitigate? It's a massively effective countermeasure for herpes simplex flares or things like that.

• 1:00:15Tim Ferriss?

  Yeah, I was gonna ask, I don't know anything about shingles. So what's happening there? Do like endogenous ketones and therefore could you just take a bunch of shots of exogenous ketones? Or like, what's actually happening to have that suppression?

• 1:00:29Dr. Dominic D'Agostino?

  I think we're augmenting metabolic control of immune regulation in the context. So you have the innate immune system, which is always kind of running around. And then work we're doing now with the Moffitt Cancer Center is basically using ketone metabolic therapy to augment the adaptive immune system. So the adaptive immune system is more specific. It's kind of like, you know, that B-cell and T-cell, like augmenting the B-cell and T-cell things where it's like, the adaptive immune system is like the Navy SEALs. And there was a human study that used a vegan diet versus a ketogenic diet. And this got put on my radar by numerous people who then wanted to research this. A vegan diet actually augments and enhances the innate immune system.

• 1:01:15Dr. Dominic D'Agostino?

  And a two-week ketogenic diet, and this was published in Nature Medicine, augmented the adaptive immune system, partly through the gut and partly just through changing metabolic physiology. This happens when we fast. If we're fasting, our gut is like relaxing. I think it's restoring or preventing, you know, when we eat something, we have things going into circulation that's keeping our immune system kind of active, right? So if we're not eating anything, our immune system becomes hyper vigilant and then in a way that it becomes hyper vigilant to attack things, but at the same time it's suppressed. So inflammatory markers go down. The immune system is like an army. You have like a hundred thousand guys like in an army

• 1:01:59Dr. Dominic D'Agostino?

  in the immune system and then they're all working. If you're eating and you're stressed and environmental toxins and things like that. When we fast, we allocate more of that immune system to be more vigilant to attack things, but at the same time, our general inflammation state goes down. It just becomes more vigilant, but inflammatory cytokines, chemokines kind of go down. So I think that's part of it in that it's stimulating, I think, cancer specific immunity, but also just generally suppressing inflammation. And that's happening for a number of different reasons, in part due to elevating beta hydroxybutyrate, which is an endogenous metabolite that plays a role in inflammasome suppression. I know guys

• 1:02:42Dr. Dominic D'Agostino?

  like maybe Eric Verden and like the guys at the Buck Institute kind of looking at that. And then our colleagues, Dr. Deep Dix at Yale, I sort of formulated a diet to specifically elevate BHB because he had showed previously that fasting suppresses the NLRP3 inflammasome and the metabolite that's off the charts with beta hydroxybutyrate. So the next study was giving that as a supplement with a normal diet to see if that could then also suppress the inflammasome and it did. And that was published in Nature of Medicine 2015. So I formulated the diet like for that study and I'm kind of like a middle author on that. So I think that plays a role in that, but I think it's multifactorial and I think it's

• 1:03:25Dr. Dominic D'Agostino?

  like, it's one of these things that needs to be studied because it's kind of universally accepted.

• 1:03:31Dr. Dominic D'Agostino?

  That it's kind of happening, but you also have to be in a good, healthy state. If your nutritional status is low, it depends on kind of your baseline characteristics, your therapeutic response to fasting. And I think that's really important, especially for people who have cancer, maybe getting chemotherapy where they have compromised nutritional state in some ways, then have to approach it very cautiously.

• 1:03:53Tim Ferriss?

  How many meals per day do you eat now?

• 1:03:56Dr. Dominic D'Agostino?

  How old are you, Dom? Uh, 50s. Yeah. I just turned Yeah, 50s. In my 50s. Yeah.

• 1:04:01Tim Ferriss?

  All right. Well, congrats. What does your diet look like now? Just like a kind of the, the set it and forget it version of Dom's diet. What does that look like?

• 1:04:11Dr. Dominic D'Agostino?

  It's situational, but always probably three meals per day.

• 1:04:15Tim Ferriss?

  Yep. And you weigh about how much at this point?

• 1:04:17Dr. Dominic D'Agostino?

  I just did a DEXA this weekend, actually. I did a DEXA two weeks ago and I did another one after I got off creatine and then did another one. So I just hover it at 218 to 220. And body fat last was 9.4.

• 1:04:32Tim Ferriss?

  You got some muscle to feed. All right. So three meals a day. What does it look like?

• 1:04:37Dr. Dominic D'Agostino?

  Uh, this morning it was eggs and chub mackerel and that's it. So basically it does protein and fat. For lunch, I typically have, you know, beef, chicken or fish, usually fish. Lately I've been eating a David bar. Peter sent me some of those and I've been, I've kind of like mixed opinions about it. It pops up on the CGM a little bit, but I think it's kind of an interesting direction to go into. I enjoy them. They taste really good. Right? So I've been doing that. And then for dinner, we went out for Mexican the other night and last night hosted Mary Newport and usually have like beef, chicken or fish with a vegetable, like always broccoli. I'm a huge fan of broccoli. I could eat like

• 1:05:19Dr. Dominic D'Agostino?

  three pounds of broccoli as no gas or bloating effect for me at all. So somehow my body is just, my body loves broccoli. So our dogs do too. So I give them a little bit of that salads, but usually about a pound of beef, chicken or fish at dinner. So that's my big meal. And over the years, we have transitioned, instead of eating at seven, we eat at like five, five or 5:30. So we eat earlier and then I do physical activity after that. If it's squats or deadlifts, I have to do it before I eat, but for like pressing movements and activity I do after that. And I do farm work for like an hour or two. In the evening after that, and I typically have like every other night, like wine. So I'll have like, I do have

• 1:06:01Dr. Dominic D'Agostino?

  a bit of wine, lower alcohol, non-sugar dry farm wines, which has like less than one gram of sugar per. I would never drink wine without doing like some kind of activity after, like wine at nine o'clock and then try to go to bed. Like, I would never do that because I see that on my aura. But if I do like a glass of wine and some form of physical activity, we always do an evening walk. And I think I sleep better. I think I don't do two glasses, but I just do one glass. And I know the current consensus on alcohol is that it's but I would push back because none of that is specifically studying wine. If you go to the studies on wine, it actually shows the first one that came up is actually decreasing cancer risk.

• 1:06:42Dr. Dominic D'Agostino?

  And then I noticed that when I take wine and measure my blood, it's less viscous. So wine also decreases platelet aggregation. So it makes your blood less viscous. So, and that is well known. I observed it and it was like, something's going on here. And then I went to PubMed and it's actually well known. I didn't know it at the time that it decreases platelet aggregation. So less potential for clotting, for stroke and things like that. So I think that may factor into, we just got back from Greece. And they had the Uzo and everything. And I just like all the, we went to, then we went Sardinia. So we went to these blue zones and they just, you know, at night after their dinner, the males will do like a shot of alcohol, usually wine, but sometimes Uzo.

• 1:07:27Dr. Dominic D'Agostino?

  And they're all like in their nineties and like hundreds, right? They're in the blue zone. So it's a universal characteristics.

• 1:07:34Tim Ferriss?

  Well, that's, that's my protocol. Yeah. There may be a genetic component too. I remember there was this book that was like, why French women don't get fat or something. And way back in the day, I remember before his passing, I was talking to Charles Poliquin. He's like, yeah. MTHFR, he's like, that's why it's none of the other stuff in the book. And he mentioned a couple of other things, like, who knows? But the Yeah, I mean, I think

• 1:07:56Dr. Dominic D'Agostino?

  Activity, yeah. Living by the water, activity and social. So the social interaction is probably the biggest lever. I mean, I just see them, they're all out and about, walking around. And yeah, that's probably the biggest lever and getting sun. So they're outside in the sun, everybody, you know, it's multifactorial, but it doesn't seem to be hurting them. Let's put it that way.

• 1:08:16Tim Ferriss?

  If someone is, let's just say they want to test out the ketogenic diet. And certainly they will note, they'll be like, wow, Dom doesn't eat a lot of vegetables, except for a pound of broccoli.

• 1:08:27Dr. Dominic D'Agostino?

  I can tolerate that, but I have like, probably like, it comes out to 30 to 40 grams of fiber a day, which is pretty high, but that's broccoli. And I usually have a small apple too. Sometimes we have apples and then a cup of wild blueberries. So it comes out to

• 1:08:42Tim Ferriss?

  Oh, right. Okay.

• 1:08:43Dr. Dominic D'Agostino?

  About 30 grams. That's maybe a higher, sometimes 10 or 20, but I try to shoot for about 30 grams of fiber.

• 1:08:50Tim Ferriss?

  Yeah, got it. Okay. If people want to kickstart the ketogenic diet, any tips for kind of getting over the hump in the beginning? People tend to, it can sometimes have a bit of a hard time before they kind of click over. I'm not sure. For me, it's like, once I'm above 1.2 millimolars, I feel totally fine. That's just me on a precision extra. But for people who are looking to give it a shot, maybe haven't given it a shot, any tips for novices?

• 1:09:21Dr. Dominic D'Agostino?

  I would do fasted, low intensity cardio. For me, that would just be going for a long walk. You know, waking up in the morning and if you're going to start your ketosis experiment or whatever you're doing that morning, getting out in the sun, staying well hydrated. You could take MCT and also ketone electrolytes like Keto Start or something like that. And then that will ease the transition because it takes a little while for your ketogenesis to ramp up. Due to you got to deplete liver glycogen and ramp up beta oxidation fat enzymes. And then you have, as ketones get in the circulation, Over the period of a couple of weeks, you're going to upregulate the ketolytic enzymes,

• 1:10:01Dr. Dominic D'Agostino?

  which are basically the enzymes in the tissues that are able to utilize and leverage those ketones for energy over time.

• 1:10:08Tim Ferriss?

  How long does that adaptation take, would you say?

• 1:10:12Dr. Dominic D'Agostino?

  You know, I don't know if anyone has unambiguously answered this question in humans, but in rodent models, you could see the MCT transporter, not to be confused with MCT oil, but the monocarboxylic acid transporter, now there's one, two, three, and four. That protein is 50% higher after two weeks, like in a rat, for example. I think the point is, for most people, is that if you start fasting or ketogenic diet, and to avert the keto flu, you want to hydrate, get in electrolytes, and also elevate ketones as much as possible. And to do that with MCT, if you can tolerate it, or ketone electrolytes. I would not be guzzling a ketone ester because you're going to spike ketones up,

• 1:10:57Dr. Dominic D'Agostino?

  you're going to inhibit your own ketone production. It's a dose-dependent thing, but my advice would be low-intensity cardio, hydrate electrolytes, and then small amounts of ketone electrolytes with MCT. So MCT will stimulate your own ketone production, too.

• 1:11:14Tim Ferriss?

  Now, are you just taking tablespoons of liquid MCT? Are you using a powder and mixing it in? What do you personally do? Or what would you recommend?

• 1:11:23Dr. Dominic D'Agostino?

  For the liquid, sometimes what I do, like if I'm eating tuna fish, which is like packed in water, I'll pour the MCT on the tuna fish and stir it up, and then deliver it that way. If I'm having coffee, I can put in the MCT powder in the coffee and mix that up, and that would be, you know, 10, 20 upwards of 30 grams. And work by Stephen Kunnane actually showed that if you take MCT in the context of caffeine or coffee, you can boost your ketone production by like 20 or 30%. So there's a bit of a ketogenic synergy. When you deliver caffeine with MCT, it's stimulating lipolysis and also fat oxidation in the liver.

• 1:12:03Tim Ferriss?

  What type of powder do you like to use?

• 1:12:06Dr. Dominic D'Agostino?

  People send me things, but I actually, the powder that I have is actually, it's Keto Brains. It's MCT powder, Alpha GPC theanine, and it has lion's mane mushroom. It goes under the brand name of Keto Brains, and that's the MCT powder that I use. The base of it is MCT, but then it has sprinkled onto that theanine, which has a nice calming effect, which probably good to use like on the first day of fasting. Alpha GPC, if I take too much of it, it gives me a headache. So I only do like one or two.

• 1:12:38Tim Ferriss?

  I gotta be careful with Alpha GPC. I also get a headache.

• 1:12:41Dr. Dominic D'Agostino?

  Yeah. Oh, really? Okay. So you're like the first one. I don't know if I was correct, but yeah, I did. You know, when I first got Keto Brains, I did like six scoops and I was like, oh my God, I got it. Had a bad headache.

• 1:12:51Tim Ferriss?

  I love that your first go was six scoops.

• 1:12:55Tim Ferriss?

  If I just wanted off the shelf MCT oil, cause I just like, I feel like there's, there's only so many medicinal mushrooms that I can cram into my diet also. But no, no offense to the mushrooms, but I actually have some interesting thought on some of them additional mushrooms. Some of them are very strongly antiviral and immunomodulatory. And so when I've talked to a number of very credible mycologists, they're like, yeah, it's probably best not to take that stuff every day. Like you should cycle on and off, but if I just wanted MCT for purposes of travel, right? Cause MCT liquid can create such a goddamn mess when you're traveling.

• 1:13:31Dr. Dominic D'Agostino?

  And in your pants too. Yeah.

• 1:13:33Tim Ferriss?

  And in your pants too. Yeah. And for people who are novices, do not do creatine, caffeine, and MCT oil out of the gate. You gotta prove to yourself that you can handle that.

• 1:13:43Dr. Dominic D'Agostino?

  Unless you're constipated.

• 1:13:45Tim Ferriss?

  Depends on the airplane. Yeah. What other just MCT oil powders might you recommend or have you used?

• 1:13:53Dr. Dominic D'Agostino?

  Quest MCT powder. I think you can get that in like CVS and Walgreens now too, and Amazon, just the NutriCost. So I bought just straight up MCT. They also have like a C8 powder and I've tested both of them wearing a continuous ketone monitor. Yeah. And I saw a nice elevation over time and then I combined that MCT powder with Keto Start. And basically I was in ketosis for half the day. So just dosing twice a day with that.

• 1:14:19Tim Ferriss?

  I mean, I'm going to break my own rules here, but I've done enough test drives. I'm about to go to not super high altitude, but I'll be coming from. Sea level to about 8,000 feet on average and we're going to be doing a lot of intense exercise. So maybe my morning dose of coffee, which I'm sure will be some shitty instant coffee, but it's going to taste delicious when you've been freezing your balls off all night. Maybe I'll add some Keto Start and MCT powder to that because those would be easy to travel with, I would imagine. I'm not sure how Keto Start tastes in coffee.

• 1:14:52Dr. Dominic D'Agostino?

  No, no, don't do that. No, they have Keto Spike coffee. So Audacious Nutrition has Keto Spike cocoa, coffee and tea. So in the afternoon, I don't do caffeine after 12, so I will brew, I'll just boil hot water and just put, and the Keto Spike coffee is like a good Colombian coffee and it just has, you know, the BHB electrolytes in it. So I've been doing that.

• 1:15:15Tim Ferriss?

  All right, cool. I'll check that. I'm just trying to figure out, because I went back through all of our conversations, which covers a lot of technical detail, as you would imagine. And I'm just wondering what you are most excited about. And right now, I, I mean, just to volunteer this, I'm very interested in neuroinflammation and the inflammasome, the interplay with the microbiome and how the microbiome can seemingly influence or mediate some of, for instance, the anti-seizure effects of the ketogenic diet, right? If you get rid of acromansia or a few other strains, low and behold, doesn't really

• 1:15:55Tim Ferriss?

  work. And I'm wondering if that applies to other conditions that metabolic psychiatry might be applied for, like schizophrenia and others, I don't know. But seems interesting as a question. What types of questions or projects or realizations, findings, anything have captured your interest or excitement these days?

• 1:16:15Dr. Dominic D'Agostino?

  Just quickly go down the list. Ketone metabolic therapy for cancer, so is one. And we have a pretty comprehensive review that describes the framework for ketone metabolic therapy.

• 1:16:28Dr. Dominic D'Agostino?

  For glioblastoma, which is a cancer that's largely resistant to the standard of care. So way too much to talk about. It was actually like a 200 plus page paper that was going to be submitted and we had to like, basically put a lot of data and things as supplementary figures. I think there's like six supplementary figures that tell specifically all the different metabolic drugs that target glucose, glutamine, GKI calculator and a lot of things. So yeah, just Google like ketone metabolic therapy framework for glioblastoma and it's open access. So that has stimulated research at different places, but I'm excited about research that we're doing with Amophic Cancer Center, which is the largest cancer center or one of the

• 1:17:09Dr. Dominic D'Agostino?

  largest in Florida, tier one cancer center where we've got various projects, glioblastoma, maybe a breast cancer, but also lung cancer, with specifically using ketone metabolic therapy to augment immune therapy, specifically the checkpoint inhibitors. And that has to do with what I described about ketone metabolic therapy, specifically beta hydroxybutyrate, activating the adaptive immune system and making checkpoint inhibitors, which is a class of drug that's, and CAR T therapy. So now they actually have a study with CAR T therapy and checkpoint inhibitors. So ketones tend to expand the T cells that are associated with CAR T therapy.

• 1:17:53Dr. Dominic D'Agostino?

  So just kind of enhancing that therapy. And with the checkpoint inhibitors, it tends to just enhance cancer specific immunity that is augmented by PD1 inhibitors. So they're specifically studying that. So I'm excited about that. So that's on the cancer front. And then we can jump. If you have no questions, I could jump to other, the Alzheimer's, the metabolic psychiatry and.

• 1:18:14Tim Ferriss?

  Yeah, let's talk about those. Let's hop to the Alzheimer's and metabolic psychiatry. Would love to dive into that because that's.

• 1:18:22Tim Ferriss?

  Front of mind for me. And just as a, as I'm not sure if I made this clear, doing the couple of weeks of strict ketosis, segueing to a 16, eight ketogenic diet and then moving to kind of a paleo-ish diet, has produced some of the best labs I've ever had. And also the best oral glucose tolerance test that I've ever logged. And from a mood stability standpoint, I am also, for at least the last few weeks, supplementing with the monoester and a diester, the sort of Q I T O N E. But all of those things combined, I gotta say, psychologically, from the standpoint of sustained

• 1:19:06Tim Ferriss?

  focus and mood, has been just kind of mind blowing, to be honest. So I, yeah, I'd love to hear any and all thoughts on Alzheimer's metabolic psychiatry front.

• 1:19:18Dr. Dominic D'Agostino?

  So metabolic psychiatry, I would encourage people to listen to Chris Palmer, who you, I kind of put on your radar. I don't know if you remember, I sent you the link to your metabolic.

• 1:19:27Tim Ferriss?

  Yeah.

• 1:19:28Dr. Dominic D'Agostino?

  So it's like, you gotta watch this, Tim. It's going to change sort of the landscape of psychiatry.

• 1:19:34Tim Ferriss?

  Yeah, I remember you used that. That was a recording from a conference, I believe, where he was interviewing one of his patients on stage.

• 1:19:41Dr. Dominic D'Agostino?

  The Metabolic Health Summit. Yeah, the Metabolic Health Summit. So which is part of Metabolic Health Institute, which is, you can get educational credits through that. So yeah, we brought Chris in and it was such a compelling story. He treated Matt Bazooki. So Matt Bazooki is the son of Jan and David Bazooki. And they, because he quickly went into durable remission.

• 1:20:05Tim Ferriss?

  Who are well known from Roblox.

• 1:20:07Dr. Dominic D'Agostino?

  Well known from Roblox. Yeah. Sort of billionaire philanthropists that are changing sort of the, actually, ultimately maybe the standard of care for psychiatry. And I think they.

• 1:20:20Dr. Dominic D'Agostino?

  Kind of single-handedly are funding metabolic psychiatry with Sabani Sethi. She's at Stanford, Chris Palmer at Harvard, and I work with them closely as an advisor. There's at least a dozen other institutes that are doing metabolic psychiatry research for schizophrenia, bipolar, major depression, anorexia nervosa, which is a psychiatric disorder that kills more people than any other disorder, and a range of different things and anxiety disorders and alcohol use disorders, alcohol withdrawal syndrome. So they're doing research on that. So with metabolic psychiatry, there's a lot of pilot studies, mostly bipolar, looking at a range of different things, ADHD too. And then there's apps that are emerging like

• 1:21:04Dr. Dominic D'Agostino?

  MetSci, metsci.com. That's a collaboration with Ally Houston, he's at Oxford, and Georgia Ead, who might be good to have on the show. She's from Harvard, psychiatrist. So that app is more of a comprehensive app that incorporates ketogenic therapy, but also lifestyle stuff and then coaching. So metabolic therapy coaching for mental health.

• 1:21:29Tim Ferriss?

  How do you spell the name of the app?

• 1:21:32Dr. Dominic D'Agostino?

  MetSci is M E T P S Y, right?

• 1:21:36Tim Ferriss?

  Because they're better at the size than the branding.

• 1:21:40Dr. Dominic D'Agostino?

  Yeah, yeah. M E T P S Y dot com at sci. So I think they have their website up. So they're basically like in their onboarding phase. So they should go live pretty soon. But I'd like to add that the Bazookas, I remembered that they are funding a big study at Oxford right now, and the Bazookas will match dollar for dollar, like any donation and spearheading sort of that, using the app and using ketogenic therapies in combination with, you know, lifestyle therapies. Metabolic psychiatry is rapidly emerging. And this ties into work we did, I guess my wife did, I was on the paper, but she ran the study. We were doing seizure studies with exogenous ketones. And the most efficacious one for

• 1:22:23Dr. Dominic D'Agostino?

  this application was the racemic ketone salts in the MCT. So we were gavaging them.

• 1:22:30Tim Ferriss?

  What does gavage mean?

• 1:22:31Dr. Dominic D'Agostino?

  Oh, it's basically like tube feeding the animal. So instead of Mixing the ketones in with the rat chow, they eat it. And so it's taking a syringe and based on the weight of the animal, you pull in the amount of ketone ester, or this case, it was MCT and ketone salts. We did the esters too, and it did have an anxiolytic effect, anxiety reducing effect. And then you administer that to the animal. And what we were doing is, you know, we do seizure studies, put them inside a hyperbaric chamber and we go two to three times more normal and it induces a seizure. But what we observed when we put the animals in ketosis is that instead of them trying to bite us and kill us and not wanting to be held,

• 1:23:11Dr. Dominic D'Agostino?

  they were very chill and calm. So it was just, well, this is great. We can handle the animals easier and get them into the chamber without them trying to bite us. And my wife's a behavioral neuroscientist and she was like, well, we should do some behavioral studies because I think there's something here. So we did elevated plus maze. So in this case, the animals can go inside a closed little cave, or it can come out into the open arm in the elevated plus maze, which is exploratory behavior, like they're more extroverted if they come out and more introverted and kind of like, you know, their fear response if they go into the cave. So we got results that we published. The title is like anxiolytic effect of ketone supplementation, you know, we published,

• 1:23:56Dr. Dominic D'Agostino?

  I think, three papers and showed like the mechanisms and stuff too. So that was an early paper and over like 10 years ago, just basically showing that inducing acute ketosis with this formulation and doing the elevated plus maze produces an effect that was analogous to a dose of benzodiazepine. Like if you look at like, you know, I don't know, Xanax or other things in elevated plus maze, it was like, yeah, 20 or 30% more time in the open arm. So they're less fearful to be in environment and making them. More like a social lubricant, maybe like, you know, benzo or something. So it had that effect in the animals. And when we look at the blood work and even to take out the hippocampus

• 1:24:37Dr. Dominic D'Agostino?

  and the brain, the levels of GABA to glutamate are higher. And then in another study we did with Angelman syndrome, we looked at the mechanism of that. And there's an enzyme called glutamic acid decarboxylase. And a lot of anti seizure drugs kind of target that. So that the protein levels were higher, essentially showing that your brain converts more glutamate, which is anxiety evoking, like wakefulness enzyme, it's converting more glutamate, which is excitatory to GABA, which is brain stabilizing. That's like your chill, or you know, like alcohol. It's what you take before bed. Yeah. Yeah. Yeah. So that was, you know, in a variety of different studies, we also looked at adenosine receptor signaling. That's a little bit more complicated to describe, but

• 1:25:21Dr. Dominic D'Agostino?

  there's a number of different effects contributing to that. So there's a clear rationale, I think, for depression. If you do an FDG PET scan on someone that's depressed, it shows glucose hypometabolism. One thing to mention, I think an important thing to mention in the context of bipolar, you can have a hyperglycolytic effect. And Dr. Ian Campbell from Edinburgh University has published some elegant reviews and is doing some work on that front and sort of describing the research there. But I think it's important because some of the feedback coming out, and I think you even mentioned too, when ketones get really high, what we observed, if ketones get too high, that can cause an anxiogenic effect. Yeah.

• 1:26:04Dr. Dominic D'Agostino?

  But there seemed to be a sweet spot, maybe one to two, I wouldn't go above three, probably 1.5 to 2 millimolar range. That seems to be a level of ketones that safely does not produce a metabolic acidosis. So what we do see that when you get above three, it starts to change blood pH. So it seems to maybe overwhelm the respiratory and renal compensation and your kidneys put out bicarb. And then there's respiratory and renal compensation that kind of regulates your blood pH. But the animals that succumbed to ketoacidosis and died from the ketone esters that we gave them in early

• 1:26:43Dr. Dominic D'Agostino?

  studies had to do with the acidification of the blood. So it was just an overwhelming because ketones are acidic. And when you deliver it into an ester form, there's nothing to buffer that. When you give a ketone salt, the electrolytes are kind of like a buffer for that, right? So you have the metabolic effect, you have the changing of the brain neuropharmacology. And in bipolar, you throw anti-epileptic drugs at bipolar patients and it's largely ineffective. So it makes sense that a ketogenic therapy would kind of work for that. And the neuroinflammation too. So things that trigger neuroinflammation and that could be, that could be an infectious agent, that could be a virus, that could be, you know, T. gondii.

• 1:27:26Dr. Dominic D'Agostino?

  I mean, it could be like a bacteria. There are various things that could cause psychiatric disorders. Various infectious agents create that neuroinflammation. And then when someone has a seizure too, the inflammatory state of the brain gets much higher. So I think ketogenic therapies are working through multiple mechanisms, more or less like in synergy to produce that. It's not one mechanism. When we published the NLRP3, I got requests from Genentech and various pharmaceutical companies to go there and give a talk on the mechanism so they could drugify. And I would throw up like a big flowchart of all these mechanisms and I think they would get frustrated. And it was like, well, what, tell us the mechanism so we can make a drug out of this.

• 1:28:09Dr. Dominic D'Agostino?

  But I think the beauty of ketogenic therapies is that it's pleiotropic, which means it's many mechanisms working in synergy. You could say metformin, GLP-1 drugs are working through metabolism and they're kind of pleiotropic also. Do you use either of those? I've experimented with metformin and that is a way for some patients to increase their ketone levels. So we've published on metformin from the context of that. It increases mitochondrial oxidative stress. It's a weak toxin to the liver. Most people didn't know that when we were studying

• 1:28:47Dr. Dominic D'Agostino?

  that. And I think metformin can enhance, increase AMP kinase, maybe increase insulin sensitivity, and has a very weak effect at reducing blood glucose if you have a normal glucose, but it does tend to increase ketones a little bit. And I think there is about 150 studies on clinical trials.gov right now on metformin as a means to augment cancer therapy. So I think that could be a tool in the toolbox for some people. When I take it and I do really intense, if I do an intense workout, I felt sick. An issue with metformin is it could produce lactic acidosis. It's producing lactic acidosis because it is a toxin to the liver. So it's sort of de-energizing

• 1:29:30Dr. Dominic D'Agostino?

  the liver. But also, when I took it up to two grams per day, I had a photosensitivity. So when I went outside, the sun gave me a rash.

• 1:29:38Tim Ferriss?

  You mentioned on your wrists. Are you making that up?

• 1:29:41Dr. Dominic D'Agostino?

  Yeah, yeah. It tended to correlate with that. And then I got off of it. And then I experimented with it again. And I'm in Florida and it was like May. It's like when the sun's really starting to crank. And then I just go outside all day. And it's like, where is this rash coming from? So it's a photosensitivity reaction that I got. And that kind of concerns me. So I never, I have it, but I don't use it.

• 1:30:01Tim Ferriss?

  May I ask you a quick question just related to metformin for a second? I was looking back on notes on prior conversations, and I think you mentioned Dr. Dale Bredson on an episode of STEM Talk, but specifically for folks with the ABOE4 genotype, like yours truly. Do you think metformin may be more interesting?

• 1:30:21Tim Ferriss?

  But let's assume, in my case, let's call me metabolically healthy. So maybe yes, maybe no. I remember a long time ago, having a chat with Navchandall, I want to say. I might be getting the name slightly wrong from Northwestern. And he was like, ah, if you're doing a bunch of exercise and getting your diet straight. He's like, I don't think that you're going to see a lot of benefit, but he didn't have the APOE for information on me. And then berberine, I have written down for some reason. I'm just wondering if there's anything to either of those for APOE for specifically.

• 1:30:53Dr. Dominic D'Agostino?

  Yeah, berberine is kind of like the, is pretty similar to metformin's glucose lowering effect. So that's something that you can consider if you don't want to take metformin. I'm of the opinion that for the general population, eating a standard American diet that, you know, is kind of averse to like working out and just trying to really modify their diet. Metformin, I think, is a very potentially effective drug for longevity. It's going to reduce blood glucose, since most people are prediabetic or, you know, have type 2 diabetes that are in their 40s, 50s and 60s. And it will reduce your incidence of cancer, specific kinds of cancers like pancreatic cancer.

• 1:31:34Dr. Dominic D'Agostino?

  I think the data is kind of good on that. And I think it'll shift metabolic biomarkers that we have historically good data on in the right direction.

• 1:31:44Tim Ferriss?

  Does metformin do anything that taking a GLP-1, like terzepatide or something, doesn't do? I mean, I guess I'm just wondering if there's an additive effect.

• 1:31:55Dr. Dominic D'Agostino?

  Well, they're totally different drugs, but people who take metformin and one gram to two gram dose, two grams is kind of high. But when they do that, they tend to eat less calories. So it does create like a little bit of, for me, a GI issues, maybe a little bit loose stools in the beginning. And that could, you know, be factoring in there. So it does tend to improve metabolic biomarkers across the board. If you're trending towards metabolic dysregulation or metabolic syndrome. A GLP-1 works essentially through caloric restriction and just decreasing appetite through, in part, a mild gastroparesis and decreasing.

• 1:32:32Dr. Dominic D'Agostino?

  Gastric emptying time, but also works on the brain and I think has

• 1:32:37Tim Ferriss?

  Yeah.

• 1:32:37Dr. Dominic D'Agostino?

  A wide range of beneficial effects. I think it's, it's a game changing drug that's going to change the whole landscape of metabolic therapies.

• 1:32:44Tim Ferriss?

  Yeah, it seems to have a, from what I've read, and maybe I don't want to over interpret here, but potential neuroprotective effects, right? So that's the main reason I would be looking at potentially low dose GLP-1.

• 1:32:59Dr. Dominic D'Agostino?

  I like that you preface it with low dose because I think higher doses are not studied enough long-term to avert potential side effects that we don't know about, but.

• 1:33:10Tim Ferriss?

  Do you take berberine or is it superfluous because you, of the diet, you don't really need anything to lower glucose?

• 1:33:18Dr. Dominic D'Agostino?

  Yeah, I, I've experimented with it and it did decrease my glucose in response to a meal. I did dihydroberberine, which is a more potent version of berberine. But interestingly, after about a week, I started to get a headache and then I got off. I don't know if it has a vasodilat or maybe it impacts liver metabolism in a way that was, who knows, maybe making, decreasing my caffeine metabolism. I mean, that's, these are things that come into mind.

• 1:33:46Tim Ferriss?

  You still consume quite a bit of coffee, yeah?

• 1:33:49Dr. Dominic D'Agostino?

  I do, I fill this up. So this is metabolic mind.

• 1:33:54Dr. Dominic D'Agostino?

  Actually metabolic mind is part of the Bazookas group metabolic psychiatry. So they have.

• 1:33:59Tim Ferriss?

  All right. So you're, you're holding up.

• 1:34:00Dr. Dominic D'Agostino?

  I do one of these per day. Yeah.

• 1:34:02Tim Ferriss?

  What is that? That's like 16 to 20 ounces?

• 1:34:05Dr. Dominic D'Agostino?

  24.

• 1:34:05Tim Ferriss?

  Something 24 ounces. Yeah. Okay. It's a metal, it looks like a thermos basically.

• 1:34:10Dr. Dominic D'Agostino?

  Yeah.

• 1:34:11Tim Ferriss?

  Okay. Got it.

• 1:34:12Dr. Dominic D'Agostino?

  Yeah, relatively strong coffee. I do, you know, I do that and pour one cup and I usually finish it like about now and no caffeine. Yeah. Caffeine at four or five P M. It's probably going to disrupt sleep latency and. Sleep timing, but yeah, GLP-1, amazing class of drug. We're covering that now at med school in our nutrition courses we're teaching. And then the SGLT2 inhibitors are also a pretty interesting class of drug that I think has a lot of potential. So if someone trying to bring their glucose levels down, for example, trying to get that, these are prescription drugs. So of course, go to your doctor. But that's the pretty good lever to pull, especially if someone's like, resistant to dropping their carbs, if they're eating some carbs. And the GLP-1 and SGLT2 are great.

• 1:34:58Tim Ferriss?

  Well, this is also, you know, a tool in the toolkit with, let's just say elderly patients who are, even if they wanted to comply, may not have the mental faculty to comply with ongoings. And you can't have necessarily 24/7 supervision, prevent them from eating bagels. But maybe you can do just like all the meds in the morning and then one injection a week or whatever it might be. Do you take any supplements or medications for mito with the explicit goal of mitochondrial health? Or maybe just the side effect of mitochondrial health?

• 1:35:32Dr. Dominic D'Agostino?

  Yeah, well, I think ketones shine there, both the D and the L beta hydroxybutyrate. So that's like first and foremost. And we are doing research with NAD.

• 1:35:43Tim Ferriss?

  These injectables?

• 1:35:45Dr. Dominic D'Agostino?

  Well, I can't talk about, you know, the research that we're doing in depth, but we're working with Metro International Biotech. So they have phase two and phase three trials for like Alzheimer's. There's NR, nicotinamide ribosine, nicotinamide mononucleotide. So the problem with those is that they're kind of, the liver is pretty greedy and takes a lot of that. And then the muscles are kind of, so a lot of it's maybe not getting to the brain. But if people just Google like MIB626, so that's one of their drug forms of NAD, that's a stabilized form of NAD. And then they have a whole suite of NAD molecules that most people don't know about, but are in experimental trials. And we're doing some

• 1:36:25Dr. Dominic D'Agostino?

  of those preclinical animal model work in our lab. So I do think for certain applications, we didn't see an effect, but at the same time, they are for applications like, you know, non-alcoholic fatty liver disease, maybe Alzheimer's, maybe inflammatory disorders improving if used for a long period of time.

• 1:36:47Dr. Dominic D'Agostino?

  Markers of mitochondrial health, I think, improve. So NAD, people may know NAD is basically like a substrate for like the sirtuins and various enzymes. There's like 500 different enzymes. Yeah, so a class of proteins that are called sirtuins rely heavily on NAD. So this is like an important thing to consider.

• 1:37:09Tim Ferriss?

  And the sirtuins, just for folks who are like, have I heard that before? I want to say back in the day when risvertrol was everywhere in the news and super mouse and all you have to do is drink wine, but maybe 20 cases of wine. I mean, that, you know, all of that stuff with transirisvertrol, that's where the sirtuins popped up.

• 1:37:26Dr. Dominic D'Agostino?

  Yeah.

• 1:37:27Tim Ferriss?

  Yeah.

• 1:37:27Dr. Dominic D'Agostino?

  The sirtuins are really heavily reliant on NAD. And NAD is involved in everything that we study, right? So like 500 to 600 metabolic enzymes need NAD for fuel. So that's important to consider. And DNA repair is exclusively tied to NAD levels. So remember I mentioned like reductive stress with D beta hydroxybutyrate? Reductive stress means that the NAD to NADH ratio would drop. So you get more NADH relative to NAD. And that could be problematic because the availability for NAD may not be there for sirtuins and other, so that, you know, a redox balance formulation. So that kind of feeds back.

• 1:38:12Dr. Dominic D'Agostino?

  I don't want to get too far into that, but I think it is impacting the redox balance, which is getting us to revisit the various ketogenic formulations and to study this in cell-based systems, animal models. It's hard to do in humans. You could do like a 31 phosphorus MRS if you have like a four or seven Tesla system like Harvard has. So this is one way to look at like phosphocreatin, ATP, pH, and also NAD to NADH ratios. So this is one way. Actually, we do have that at our Alzheimer's center and that's on the list of to-dos. To look at this reductive kind of stress thing. So NAD, I'm just throwing that out there

• 1:38:55Dr. Dominic D'Agostino?

  because I think there's some, a lot of criticism towards NAD now that happens from time to time because moving science from cell-based systems to animal models to humans, there's a massive learning curve there. We're learning that with some of the ketogenic agents. We're, we're just at the cusp of really understanding the dosage, timing, scheduling, and form of exogenous ketones that's optimal. And it's going to vary depending upon the situation that you're trying to treat and also individually, I think people are going to have. So that opens up this whole personalized, precision ketogenic metabolic therapy, or the NIH is throwing a lot of money on personalized medicine based on genetic markers and based

• 1:39:39Dr. Dominic D'Agostino?

  on biomarkers that, some of them that you can measure in real time, like continuous ketone monitoring, continuous glucose and maybe lactate monitoring.

• 1:39:47Tim Ferriss?

  Yeah, that's very cool. One last supplement question because I'm looking back at past notes, and I'm probably going to mispronounce this, but idebenone, sort of more observable version of CoQ10, maybe that's a fair description, maybe it isn't. Do you still take that or no longer?

• 1:40:05Dr. Dominic D'Agostino?

  I think CoQ10 is on the shortlist of five supplements that I would recommend to people, although I don't take it. I do get quite a bit from the foods that I eat. I eat a lot of heart, liver, animal products that have kind of like CoQ10 in it. But if you're like on a statin, if you're on like metformin and other drugs, they could potentially deplete you. And then CoQ10 has a solid track record for like cardiovascular health. So idebenone is kind of a drug stabilized form of that. And then when I discussed that on your podcast, that was in the context of something called the Deanna Protocol. The Deanna Protocol is after Deanna Tadone. She has ALS, she was diagnosed. Well, over a decade ago was given, you know, two or three years to live. She's alive and well today.

• 1:40:50Dr. Dominic D'Agostino?

  We're just like emailing yesterday. So the antidone had advanced ALS and then has been stabilized using the Diana protocol, which included at the time iDebinone, but I think it became a drug. So iDebinone became the standard of care for Friedrichs ataxia. And then you couldn't get it like on Amazon, but I think ubiquinol or CoQ10, it would be a good substitute for that. And I don't use it myself, but I think that's if you're older in age and you have cardiovascular heart problems like in your family. However, with that said, we actually did ubiquinol. We did high doses in our animal models and we saw some like kidney toxicity.

• 1:41:30Dr. Dominic D'Agostino?

  We had some animals die and we didn't know, but that was in rodent models and we use, again, we use like really high dose for oxygen toxicity. We've looked at everything under the sun, but it was this unexpected side effect. And then I went to the literature and showed that it's such a powerful antioxidant in some ways. And it maybe it was concentrating in the kidneys. So there was a couple of papers came up and then we think that that's why, you know, the animals may have died. We were using a mitoQ, like various forms that are like more mitochondrial specific. We're using like more potent forms of the CoQ10. So it may not be to similar to the commercially available forms.

• 1:42:06Tim Ferriss?

  What are the other supplements on that shortlist? You said four or five supplements. What are the other ones?

• 1:42:10Dr. Dominic D'Agostino?

  That I take? Yeah. So creatine monohydrate would be kind of the staple thing that I've used, you know, since I was, I don't know, a teenager. First and foremost, exogenous ketones and the data is emerging on that. I think that's going to be like the next creatine for that. But creatine for Alzheimer's disease, we didn't talk about it, but a dosage of 10 to even if you're larger 20 grams, and that's not a misspeak there, 20 grams of creatine. Spread out, you know, maybe five grams, three to four times a day for advanced Alzheimer's, if you can tolerate it. Micronized form.

• 1:42:43Tim Ferriss?

  I'm taking 20 grams today just because I didn't get very good sleep last night. I just find it to help with recovering from, let's call it sleep deprivation. But yeah, gotta watch the split dosing.

• 1:42:56Dr. Dominic D'Agostino?

  Vitamin D, but you have to measure that like in your lab. So you want that to be, you don't want it like over a hundred, right? So you want vitamin D levels that are probably like 60 to 80 would be a good level of vitamin D on and getting that checked. But I think you should check it first. It's weird. I live in Florida, get tons of sun, but if I'm not supplementing vitamin D, I trend to be like low 30s. It could be trend. But so when I supplement it, I basically stay in the mid 60s to 70s. So vitamin D and melatonin, I think is a great neuroprotective antioxidant supplement to take at nighttime. And I don't take omega-3 supplements, but just

• 1:43:39Dr. Dominic D'Agostino?

  because I did Rhonda Patrick, you know, connected me with the omega-3 guy and I tried the omega quant and my DHA levels and EPA levels were off the charts. Out of curiosity, I got off of fish for like a month or so and it went down to normal ranges. And then I tried Nordic Naturals, which it was a company that reached out to me and I was like, okay, well, I'll remove omega-3s from my diet and then add it back in with a dose and it popped me back up to a level similar to if I'm eating like tons of sardines per day. So if you don't like sardines and you don't like eating a lot of fish, I think Nordic Naturals is probably like one of the go-to brands, you know, I'm not paid to say that or anything, but they're legit. But you could do the omega-quant

• 1:44:22Dr. Dominic D'Agostino?

  test. And I think there's so much data on EPA and DHA that I think ultimately the omega-3 levels will be part of standard blood work. Like there's so much data emerging on that that I think probably within the next 10 years, like when you get comprehensive metabolic panel, CBC, like that DHA and EPA will probably be added to that.

• 1:44:43Tim Ferriss?

  All right, Dom, well, we could go for many more hours, I am sure, but let's start to land the plan for this round. And I do want to ask, of course, if there's anything else that you'd like to mention or point people to, anything you'd like to recommend, formal complaints you'd like to lodge, people you'd like to secure in front of a large audience. No, I'm kidding. But anything that you'd like to say or point people to, any resources, anything that you're up to, where they can find you, anything at all?

• 1:45:15Dr. Dominic D'Agostino?

  Yeah, I just want to mention Keto Nutrition, that's our informational website, ketonutrition.org. We've hosted a conference where many people you know, Dr. Walter Longo, Rhonda Patrick, who's been keynote speakers, that's the Metabolic Health Summit. That's been the conference, and that is run by Metabolic Health Initiative. So I direct people to Metabolic Health Initiative, and it's kind of run by three of us, my colleagues, Dr. Angela Poff and Victoria Field, sort of run that show. I kind of tag on for the ride. But that's an ACCME accredited medical education platform. So everything that we're talking about here, we have speakers and we create a medical education platform

• 1:45:56Dr. Dominic D'Agostino?

  so people can learn about metabolic psychiatry, people can learn about metabolic-based therapies and metabolic drugs, like GLP-1 drugs and hormone optimization, things like that. So I'd mention that. The brand of ketones that I use that I often get asked is Audacious Nutrition Keto Start. So that evolved out of our work with cancer, neurodegeneration and seizures. We're doing work at, you know, BIRD Alzheimer's Center on probably 20 or more ketogenic compounds in development that are mostly alcohol-free. So I think all of them are actually, and we have some really interesting studies on Alzheimer's and a lot of other. So hopefully in the next year, be able to share some of that preclinical animal model work.

• 1:46:38Dr. Dominic D'Agostino?

  Hyperbaric oxygen, so we have a $28 million study. That's huge. Yeah, at the University of South Florida, I am just peripherally involved in that, or just know people running that, and it's essentially evolved out of the DoD work that looked at the muddy waters of hyperbaric oxygen therapy for that.

• 1:47:00Dr. Dominic D'Agostino?

  It's a good way to put it, the muddy waters. Yeah, I have been part of reviewing grants and also manuscripts, and I think there's a lot of interesting studies that's going to emerge by the time this airs. I think they will be on PubMed, essentially showing that hyperbaric oxygen therapy protocols, more mild hyperbaric oxygen, 40 to 60 sessions, in people that had traumatic brain injury. A decade ago can enhance cognitive function, reaction time, and a wide variety of metrics associated with brain function. So I think this work coming out of Israel, I would like to see it replicated. I would like to see the work that's different at the

• 1:47:42Dr. Dominic D'Agostino?

  University of South Florida is that it's very innovative and that it's using a sham. Instead of using hyperbaric air as the control, they basically pulse pressure in the beginning to make people think they're being pressurized and at the end, so their ears pop a little bit. And, you know, I don't know, it's blinded, you know, people don't know even what they're getting. If you question them, they don't know if they're getting hyperbaric oxygen. But I do think that oxygen is a powerful drug and I'm excited about that research. If you ask me, I'm excited if it proves it or disproves it, you know, I think we're going to get an unambiguous answer to this question about hyperbaric oxygen for traumatic brain injury in people with and without post-traumatic stress syndrome. So my thing

• 1:48:25Dr. Dominic D'Agostino?

  is that if they put patients on ketone metabolic therapy, that would augment and enhance hyperbaric oxygen therapy and decrease the potential for risk of an oxygen toxicity seizure, which goes up, right? If you've had a traumatic brain injury, your risk of oxygen toxicity seizure would increase.

• 1:48:45Tim Ferriss?

  Now, this is pretty specific to military or what are we talking about?

• 1:48:49Dr. Dominic D'Agostino?

  They're all vets and if they do find out that they get a beneficial effect from that, then after the experiment, they'll be able to get that for free service. So there's six quarter to half a million dollar hyperbaric chambers. So the hard shell chambers, you know, there's six of them in this facility and it's the most elaborate hyperbaric oxygen therapy study that has ever been done. So it'll answer the question about the efficacy. So that's ongoing now and I'm excited about that. I'm also excited about potentially using that facility because it's next to the Moffitt Cancer Center for patients that are undergoing various cancer treatments that could be enhanced with hyperbaric oxygen therapy because it augments the immune system and it's actually an FDA-approved application

• 1:49:33Dr. Dominic D'Agostino?

  for radiation necrosis. So if you've had radiation, then your insurance would actually cover it. But it can enhance certain therapies that we're working on.

• 1:49:41Tim Ferriss?

  Yeah. Amazing. All right. Well, we will link to all of those things in the show notes as always, and I encourage people to check all of those out. I'm going to check all of them out. And

• 1:49:54Tim Ferriss?

  Dom, thanks so much for the time, as always. I took a ton of notes. I have even maybe even more questions on top of that for more text messages. Sorry in advance. And so nice to see you again.

• 1:50:07Dr. Dominic D'Agostino?

  Yeah, you too, Tim. Yeah, thank you for having me on. I appreciate it.

• 1:50:10Tim Ferriss?

  Absolutely. And folks, show notes can be found at tim.blog/podcast. Just search Dom or Dominic and a lot of them will pop up. Just look for the most recent. And until next time, be a bit kinder than is necessary. It matters. It helps to others and to yourself. And as always, thanks for tuning in. Hey guys, this is Tim again. Just one more thing before you take off, and that is Five Bullet Friday. Would you enjoy getting a short email from me every Friday that provides a little fun before the weekend? Between one and a half and two million people subscribe to my free newsletter, my super short newsletter called Five Bullet Friday. Easy to sign up,

• 1:50:50Tim Ferriss?

  easy to cancel. It is basically a half page that I send out every Friday to share the coolest things I've found or discovered or have started exploring over that week. It's kind of like my diary of cool things. It often includes articles I'm reading, books I'm reading, albums perhaps, gadgets, gizmos, all sorts of tech tricks and so on that get sent to me by my friends, including a lot of podcast guests. And these strange esoteric things end up in my field and then I test them and then I share them with you. So if that sounds fun, again, it's very short, a little tiny bite of goodness before you head off for the weekend, something to think about. If you'd like to try it out, just go

• 1:51:30Tim Ferriss?

  to tim.blog/friday, type that into your browser, tim.blog/friday, drop in your email and you'll get the very next one. Thanks for listening. Creatine isn't just for muscle, it turns out. It's essential daily fuel for your brain, your body, and long-term performance. For me, I have Alzheimer's and dementia risk in my family. The cognitive benefits are the reason I take creatine every single day. And it also seems there's some evidence to support if you don't get enough sleep, that you can use creatine to compensate, to recover from that. I also use it for that purpose. And today's episode sponsor, Momentous, is the gold standard in creatine. There's a lot of BS floating around, a lot of questionable creatine.

• 1:52:12Tim Ferriss?

  But I choose them. Why? Because they source Creapure creatine, the purest, most effective creatine monohydrate available, single sourced from Germany and not cut with fillers or junk, which is hard to avoid otherwise. Their new lemon travel packs make consistency easy, naturally flavored, perfectly portioned, single serve packets that you can take with you on the road or at any time to mix with water and you're set. Every batch is NSF certified for sport. This is something I look for on a lot of products I use, which means it's independently tested for safety, label accuracy and banned substances. So if you've been curious about creatine, this is your moment to get back on track or try it for the first time with a formula you'll actually enjoy that will make you feel great

• 1:52:57Tim Ferriss?

  thanks to superior quality and quality assurance. So just go to livemomentous.com. That's L I V E M O M E N T like live moment. O U S livemomentous.com/tim for 35% off your first subscription or simply use code TIM at checkout. livemomentous.com As many of you know, for the last few years, I've been sleeping on a Midnight Luxe mattress from today's sponsor, Helix Sleep. I also have one in the guest bedroom downstairs and feedback from friends has always been fantastic. Kind of over the top, to be honest. I mean, they frequently say it's the best night of sleep they've had in ages. What kind of mattress is it? What do you do? What's the magic juju? It's something they comment on without any prompting from me whatsoever.

• 1:53:42Tim Ferriss?

  I also recently had a chance to test the Helix Sunset Elite in a new guest bedroom, which I sometimes sleep in, and I picked it for its very soft but supportive feel to help with some lower back pain that I've had. The Sunset Elite delivers exceptional comfort while putting the right support in the right spots. It is made with five tailored foam layers, including a base layer with full perimeter zoned lumbar support right where I need it and middle layers with premium foam and micro coils that create a soft, contouring feel, which also means if I feel like I want to sleep on my side, I can do that without worrying about other aches and pains that I create. And with a luxurious pillow top for pressure relief, I look forward to nestling into that bed every night that I use it. The best part, of course, is that it helps me wake up feeling fully rested with

• 1:54:26Tim Ferriss?

  a back that feels supple instead of stiff. That is the name of the game for me these days. Helix offers a 100-night sleep trial, fast free shipping, and a 15-year warranty. So check it all out. And now you can get 27% off anything on their website, so site-wide. So just go to helixsleep.com/tim. One more time, helixsleep.com/tim. With Helix, better sleep starts now.