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Tim FerrissTim Ferriss

All Things Ketones, How to Boost Cognition, Sardine Fasting, Diet Rules, & More — Dr. Dom D’Agostino

Dr. Dominic D’Agostino 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: Momentous high-quality creatine: https://livemomentous.com/tim (code TIM for up to 35% off) Helix Sleep premium mattresses: https://HelixSleep.com/Tim (27% off all mattress orders) AG1 all-in-one nutritional supplement: https://DrinkAG1.com/Tim (1-year supply of Vitamin D plus 5 free AG1 travel packs) Tim Ferriss is one of Fast Company’s “Most Innovative Business People” and an early-stage tech investor/advisor in Uber, Facebook, Twitter, Shopify, Duolingo, Alibaba, and 50+ other companies. He is also the author of five #1 New York Times and Wall Street Journal bestsellers: The 4-Hour Workweek, The 4-Hour Body, The 4-Hour Chef, Tools of Titans and Tribe of Mentors. The Observer and other media have named him “the Oprah of audio” due to the influence of his podcast, The Tim Ferriss Show, which has exceeded 900 million downloads and been selected for “Best of Apple Podcasts” three years running. Sign up for "5-Bullet Friday" (Tim's free weekly email newsletter): https://go.tim.blog/5-bullet-friday-yt/ Follow the Tim Ferriss Podcast: https://tim.blog/podcast/ Visit the Tim Ferriss Blog: https://tim.blog/ Follow Tim Ferriss on Twitter: https://twitter.com/tferriss/ Follow Tim Ferriss on Instagram: https://www.instagram.com/timferriss/ Like Tim Ferriss on Facebook: https://www.facebook.com/TimFerriss/ [00:00] Start [00:42] Why I'm interested in ketogenic strategies for neurodegenerative prevention. [02:17] Mary and Steve Newport's ketone-linked temporary cognitive improvements. [04:31] A mechanisms overview for Alzheimer's/dementia. [07:45] The immune system as longevity's "fifth horseman" — and why metabolic control is key. [08:26] How to measure ketones and GKI. [09:26] Fasting vs. ketogenic diet. [10:48] There's nothing fishy about sardine fasting. [15:05] My hiatal hernia discovery and increased cancer risk concerns. [16:46] HSCRP as a superior biomarker to LDL for cardiovascular risk. [18:39] Glucose tolerance testing revelations and CGM importance. [24:12] Upgrading the metabolic machinery through keto without getting bored. [27:43] What do do if you, like Dom and me, are among the 30% who suffer from cholesterol hyperabsorption. [31:43] Dom's day-to-day diet regimen. [37:29] How Dom optimizes his aging dogs with ketones, SARMs, and supplements. [41:50] Supplementing for sleep disruption while fasting. [45:20] Why Dom doesn't have misgivings about melatonin. [46:09] Shingles prevention through fasting protocols. [46:32] Immune system modulation: Innate vs. adaptive, vegan vs. ketogenic. [50:15] Dom at 50-something: Current meal timing and composition. [53:35] Blue zone observations: Greek and Sardinian longevity habits. [54:39] Ketogenic diet initiation tips: MCT, electrolytes, and fasted cardio. [01:01:49] Ketone metabolic therapy for cancer. [01:04:54] The metabolic psychiatry revolution. [01:08:49] The soothing effects of hyperbaric oxygen and ketosis on seizure sufferers. [01:15:10] Metformin vs. berberine. [01:18:29] The low-dose neuroprotective potential of GLP-1 drugs. [01:21:44] NAD research: MIB-626 and stabilized forms for mitochondrial health. [01:26:38] Idebenone, CoQ10, and the Deanna protocol for ALS. [01:28:55] Dom's supplement short list: CoQ10, creatine, ketones, vitamin D, melatonin. [01:31:36] KetoNutrition.org, Metabolic Health Summit, Audacious Nutrition, veteran-focused research protocols, and other parting thoughts.

Dr. Dominic D’AgostinoguestTim Ferrisshost
Sep 3, 20251h 37mWatch on YouTube ↗

EVERY SPOKEN WORD

  1. 0:00 – 0:42

    Start

    1. DD

      I know the current consensus on alcohol is that it's ... But I would, I would push back because none of that is specifically studying wine. If you go to the studies on wine, it actually shows once the first one that came up is actually decreasing cancer risk. And then I noticed that when I take wine and measure my blood, it's less viscous, so wine also decreases platelet aggregation.

    2. TF

      Sure.

    3. DD

      So the, it makes your blood less viscous, 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

  2. 0:42 – 2:17

    Why I'm interested in ketogenic strategies for neurodegenerative prevention.

    1. DD

      like that.

    2. TF

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

    3. DD

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

    4. TF

      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 [laughs] many of my friends. I have been revisiting everything ketogenic and [laughs] 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 APOE33 and my siblings and I are APOE34, which would seem to indicate we would have potentially 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. Where can or 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 or slowing of progression of symptoms or anything else?

    5. DD

      Mm-hmm.

  3. 2:17 – 4:31

    Mary and Steve Newport's ketone-linked temporary cognitive improvements.

    1. DD

      Yeah, that's a, 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-

    2. TF

      Yep

    3. DD

      ... that kind of put this on everybody's radar. I would say the early adopters of this idea were the people who understood that brain energy metabolism was pretty central to Alzheimer's-

    4. TF

      Yeah

    5. DD

      ... disease.

    6. TF

      Sometimes called type three diabetes if-

    7. DD

      Yeah

    8. TF

      ... if I'm getting that right. Mm-hmm.

    9. DD

      Oh, sure. That was coined back in 2005 or '06 I think. And, uh, 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.

    10. TF

      Mm-hmm.

    11. DD

      And Dr. Richard Veech of the NIH was also on that, and Mary was near and dear to my heart. I actually coincidentally hosted her for dinner [laughs] last night at the house and had her over here, and she's a, a close friend of mine. We co-teach together at USF. She's a guest teacher. Interestingly, I saw Steve Newport in 2008 or '09 and I, I witnessed the observation. He is a 3, 4. He has Alzheimer's. He was 3, 4 for APOE4 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, of ketones rescuing the brain in the context of Alzheimer's disease. Symptomatically, there was no doubt in my mind that it did because I witnessed him. He wasn't using the ketone ester at the time, but we quickly transitioned to that [laughs] after a meeting.

    12. TF

      Mm-hmm.

    13. DD

      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.

    14. TF

      Mm-hmm.

    15. DD

      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, which we'd give him like a 30 milliliter shot of MCT plus coconut oil [laughs] that was mixed in there, so she was really... And doing that three to four times a day with meals.

    16. TF

      Mm-hmm.

  4. 4:31 – 7:45

    A mechanisms overview for Alzheimer's/dementia.

    1. DD

      So that was my first observation and it was clear to me that there was at least a metabolic... Within the Alzheimer's spectrum [laughs] I'd just like to... Alzheimer's is kind of a fuzzy, you know, diagnosis.

    2. TF

      Sure. Very fuzzy.

    3. DD

      I'd just kind of like to call it dementia, [laughs] cognitive dementia. There's vascular dementia and there's Abeta and tau and my wife was working on tau at the Alzheimer's Center when we met. [laughs] She was working under a guy who studied tau. Then there was people at theirs who studied amyloid beta and there was like the tauists and the beta and there was kind of like 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 really, it's a constellation of things including the glucose transporter. The GLUT3 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 the production, 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 neural inflammation, 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. Epstein-Barr virus, cytomegalovirus, herpes simplex virus, HPV, you know, can contribute to things like cancer.

    4. TF

      So we're probably talking about if, I mean [laughs] 50, 60% of the population having one of these things.

    5. DD

      Steve Newport, the subject in that case report, had bouts of herpes, HSV, around-

    6. TF

      Yeah

    7. DD

      ... the eyes, and got hit pretty hard with that. But also people who have shingles, you know, that 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.

    8. TF

      Mm-hmm.

    9. DD

      It's triggering the immune system. There's a renewed interest in looking at Alzheimer's disease, looking at the root cause, and I think metabolism is central.

    10. TF

      Mm-hmm.

    11. DD

      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.

    12. TF

      Yeah.

    13. DD

      However, this kept putting on my radar, and then I was in a NIH sponsored workshop on this looking at various aspects, and the data presented by a number of different labs was very compelling-

    14. TF

      Hmm

    15. DD

      ... for this. So what does that mean?

  5. 7:45 – 8:26

    The immune system as longevity's "fifth horseman" — and why metabolic control is key.

    1. DD

      Our immune system is, you know, there's the four horsemen, right? That our friend Dr. Peter Attia talks about.

    2. TF

      Mm-hmm.

    3. DD

      I think the fifth horseman is really the immune system.

    4. TF

      Yeah.

    5. DD

      I like to add the sixth horseman as our physical form, our skeletal structure, so our bones, you know, and that, that will give over time too. But the immune system is really central-

    6. TF

      Mm-hmm

    7. DD

      ... 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.

    8. TF

      Yeah.

    9. DD

      And many longevity clinics are now looking at that.

  6. 8:26 – 9:26

    How to measure ketones and GKI.

    1. TF

      What is your preferred device for measuring ketones these days?

    2. DD

      For publications, we've used the Abbott Precision Xtra because historically we've used that.

    3. TF

      Yeah.

    4. DD

      And however, when I recommend a meter to people, I generally recommend the Keto-Mojo device because that has-

    5. TF

      Keto-Mojo

    6. DD

      ... the glucose ketone index, and so-

    7. TF

      Yeah

    8. DD

      ... the glucose ketone index is the millimolar concentration of glucose over ketones.

    9. TF

      Yep.

    10. DD

      And the strips are about nowadays still less, I was gonna say, I don't know, a few years ago they were about half the price.

    11. TF

      Yep.

    12. DD

      And we've tested the Keto-Mojo. So we have a human clinical trial where we did, [laughs] we did breath, we did urine, and we did Precision Xtra and Keto-Mojo [laughs] all together, and then subjects go into the chamber and we did metabolomics and everything else. But the Keto-Mojo consistently gives us numbers that are more in line with our biological assays that we run-

    13. TF

      Oh, okay

    14. DD

      ... in the lab, like the-

    15. TF

      Interesting

  7. 9:26 – 10:48

    Fasting vs. ketogenic diet.

    1. DD

      ... ELISAs on that.

    2. TF

      Well, let me just tell you what I'm up to.

    3. DD

      Okay.

    4. TF

      And you can tell me how ridiculous I am and off base or f- fact check as needed. Can you remind me of how to pronounce this? Dr. Thomas, is it Seyfried? Am I getting that right?

    5. DD

      Yeah. He's a good friend and colleague. Doc- Tom Seyfried, yeah.

    6. TF

      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, 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 wanna 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.

    7. DD

      Yep.

    8. TF

      Right? 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. I couldn't quite, didn't really wanna do like three to four week long fasts [laughs] a year. Just didn't wanna do it. But in terms of potentially purging pre-cancerous 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.

  8. 10:48 – 15:05

    There's nothing fishy about sardine fasting.

    1. TF

      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 schedule?

    2. DD

      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, a dietary restriction. You could do a restricted ketogenic diet, a cyclic ketogenic diet modified, a modified supplemented ketogenic diet, [laughs] I guess, which is what I do. I like to do what I call, I mean, I kinda coined it, it's like sardine fasting.

    3. TF

      [laughs]

    4. DD

      And I had a cancer patient a long time, one of the first that I sort of engaged with, actually, you might, his name was Dr. Frederick, Fred Hatfield.

    5. TF

      Hmm.

    6. DD

      So he was like kind of a famous powerlifter.

    7. TF

      Is this Dr. Squat?

    8. DD

      Yeah, yeah, Dr. Squat.

    9. TF

      Back in the day. Wow.

    10. DD

      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 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 ki- I think he steered me onto sardines in like maybe 2007 or '08 or [laughs] 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, a low carb diet, and then he would do five days, he would do a fasting mimicking diet [laughs] that Valter Longo has advanced but he has more of a plant-based approach. But Dr. Hatfield would do, Fred would do one or two cans of sardines, maybe one can of sardine per day for a week, so we called it sardine fasting, and that was-

    11. TF

      Huh

    12. DD

      ... 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.

    13. TF

      Huh.

    14. DD

      Fred ended up passing away maybe eight years later of something completely unrelated to his cancer.

    15. TF

      As a, 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.

    16. DD

      There's a lot of factors like the Gleason score, and his was not good in, in 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.

    17. TF

      Wow.

    18. DD

      And he was, like, no evidence of disease.

    19. TF

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

    20. DD

      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 when I'm doing it."

    21. TF

      Mm-hmm.

    22. DD

      Fred also surprisingly would smoke a little bit, and I got him to maybe stop that, too. So 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.

    23. TF

      Hmm.

    24. DD

      And we communicated and I just encour- "Hey, keep sending me your medical reports," and, you know, I was like maybe there is something to this. So that actually steered me into, just like the Alzheimer's, we started Alzheimer's research because of Dr. Mary Newport. I studied seizures because Mike Dancer. Just-

    25. TF

      Mm

    26. DD

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

    27. TF

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

    28. DD

      Once a month. Sorry, yeah, I meant to-

    29. TF

      Once a month? Yeah.

    30. DD

      Yeah, it's analogous to the fasting mimicking diet.

  9. 15:05 – 16:46

    My hiatal hernia discovery and increased cancer risk concerns.

    1. DD

      so.

    2. TF

      Sardine [laughs] fast. I can't wait for that to become a thing. That's gonna spread [laughs] . 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 ended up having very unexpectedly a hiatal hernia. Hiatal [laughs] I think also related to the word hiatus etymologically. But basically, I'm gonna get the definition wrong I'm sure.

    3. DD

      Yeah.

    4. TF

      But basically from your esophagus to [laughs] your stomach, typically there's 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, and 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.

    5. DD

      Yeah.

    6. TF

      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 more scarring, is there a place for doing the fasting since I don't mind doing it anyway, just to further hopefully decrease

  10. 16:46 – 18:39

    HSCRP as a superior biomarker to LDL for cardiovascular risk.

    1. TF

      the risk?" And you were saying you fast episodically? Was that the word that you used?

    2. DD

      Situationally, episodically.

    3. TF

      Situationally, situationally.

    4. DD

      Yeah [laughs] .

    5. TF

      What does that mean?

    6. DD

      If my wife is traveling and I, you know, it prevents me from being antisocial and I have a lot of work to do, and I have to-

    7. TF

      Yeah

    8. DD

      ... I have a grant deadline, oh, it's five days away, okay, I'm sardine fasting for five days until I get this grant submitted.

    9. TF

      Got it.

    10. DD

      If I'm traveling by myself, I'll do it. If I get for any reason, occasionally I'll get sort of an inflammatory flareup, and I don't know what it's... Just I'll feel a little bit off, like brain fog or my joints or something like that. It's pretty rare now 'cause my-

    11. TF

      Mm

    12. DD

      ... HSCRP is, like, non-detectable, right?

    13. TF

      Mm-hmm.

    14. DD

      Before I did ke- it was always, like, one or two to, on a higher carb diet.

    15. TF

      Yeah, so people might recognize CRP, right?

    16. DD

      Yeah.

    17. TF

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

    18. DD

      Yeah. I'd like to draw attention to that real quick because HSCRP [laughs] is a better indicator of cardiovascular disease than LDL cholesterol.

    19. TF

      Yeah.

    20. DD

      We know that now. If you, someone said that, like, 10 years ago, they would just like, "You think you're crazy." But yeah, HSCRP is what we call a cardiometabolic biomarker including-

    21. TF

      Mm

    22. DD

      ... 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 [laughs]

    23. TF

      Yeah

    24. DD

      So the things that I mentioned. I'll use it situationally if I feel like something is coming on, like I'm getting a flu. But the sardine fasting, and I advise it for cancer patients too, I want them to avoid a water-only fast in the context to prevent cancer cachexia.

    25. TF

      Muscle loss or muscle wasting.

    26. DD

      Yeah.

    27. TF

      Right.

  11. 18:39 – 24:12

    Glucose tolerance testing revelations and CGM importance.

    1. TF

      Yeah.

    2. DD

      And omega-3 fatty acids are very potent mitigators of cancer cachexia. And so you have the omega-3s and basically you have everything your body needs, especially, like, nutrition-wise-

    3. TF

      Mm-hmm

    4. DD

      ... in sardines. You might wanna add a little bit of vitamin C or magnesium or something, but, but essentially it's like you have, you have adequate nutrition and then 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, which sort of correlate with inducing and maximizing autophagy. So that was sort of-

    5. TF

      Mm-hmm

    6. DD

      ... the rationale for me to do that. And a lot of people talk about autophagy, and it's kind of a nebulous term.

    7. TF

      [laughs]

    8. DD

      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 p62 and other things that you can measure, but there's no commercially available... I think the best way to measure to suggest you're in autophagy is a glucose ketone index after-

    9. TF

      Yep

    10. DD

      ... a period of fasting.

    11. TF

      Which Keto-Mojo will do automatically.

    12. DD

      Yeah.

    13. TF

      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? Maybe it doesn't matter so much, but it seems to matter, right? Because spikes above, regular spikes above a certain kind of nanogram per deciliter seem to be indicative of all sorts of things.

    14. DD

      Yeah.

    15. TF

      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 it, is it does give you that glucose ketone index, the GKI, as a readout right there on the device.

    16. DD

      Yeah.

    17. TF

      Right? Or in the app at least that accompanies the device.

    18. DD

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

    19. TF

      That's exactly what I'm talking about. Yep.

    20. DD

      Okay. What was the difference between what was measured there?

    21. TF

      Let's say the peak at 30 minutes out after drinking this dextrose, delicious [laughs]

    22. DD

      Yeah

    23. TF

      ... not so delicious dextrose water. It's something like this. I was bumped up to probably 140 on the phlebotomist-drawn blood, and it was, like, 165 on the Keto-Mojo.

    24. DD

      Uh-huh.

    25. TF

      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, 'cause 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, 'cause Precision Xtra's kind of a pain in the ass to get ahold of, at, at least on Amazon.

    26. DD

      Hmm.

    27. TF

      So that was my experience and I was like, "Okay. Well, tricky. Tricky, tricky." [laughs] 'Cause I, you know, if, 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.

    28. DD

      What's your hemoglobin A1C?

    29. TF

      I'd have to go back and look.

    30. DD

      Okay.

  12. 24:12 – 27:43

    Upgrading the metabolic machinery through keto without getting bored.

    1. DD

      concern.

    2. TF

      Okay, cool. Yeah, I just wanted to check it out 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 kind of set of experiments, let's just say, I was strict keto for three weeks-

    3. DD

      Mm-hmm

    4. TF

      ... and then frankly just got bored to death of the diet.

    5. DD

      It's hard.

    6. TF

      So I did like-

    7. DD

      Yeah

    8. TF

      ... yeah, I did three weeks of let's just call it kind of textbook, protein also quite low, 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, 'cause I know for athletes it might be 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 2:00 PM and 10:00 PM. And then I went to a more paleo-ish diet, let's just call it, within that feeding window. And then I'd say did that for a few weeks and then started layering in exogenous ketones in my fasting state, typically 11:00 AM, 1:00 PM if I'm doing podcast recordings and things like that. And part of what I'm trying to figure out is given I'm APOE34, 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 [laughs]

    9. DD

      Yeah

    10. TF

      ... BDNF and all that good stuff, from a dietary perspective, trying to figure out like, okay, how long does keto memory last? If there is a expiration date, [laughs] 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, any thoughts on that?

    11. DD

      Well, yeah, you're, you're doing a lot of stuff there, and I would [laughs] recommend-

    12. TF

      [laughs]

    13. DD

      ... 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 could follow 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-

    14. TF

      Mm

    15. DD

      ... optimize it. But you want to follow an approach therapeutically that keeps your GKI into that one to four range. Tom Seyfried is very adamant about one to two, but the normal GKI of a, a person in the US is like 50, right? [laughs] 25 to 50.

    16. TF

      Yeah.

    17. DD

      Living in a state of having a GKI of even five would be, I think, trending towards being more metabolically flexible and 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, HSCRP, hemoglobin A1C, triglycerides, ApoB you wanna measure too.

    18. TF

      Yeah.

    19. DD

      Lp little a is good to know.

  13. 27:43 – 31:43

    What do do if you, like Dom and me, are among the 30% who suffer from cholesterol hyperabsorption.

    1. DD

      Unfortunately, 30% of 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 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.

    2. TF

      [laughs]

    3. DD

      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?

    4. TF

      Yeah.

    5. DD

      But come to find out, about 30% of the population hyperabsorb cholesterol.

    6. TF

      That's me too. I'm in the same boat.

    7. DD

      Okay.

    8. TF

      Yeah.

    9. DD

      I have an MPC1L1 receptor mutation that's a gain of function mutation, so I use ezetimibe monotherapy-

    10. TF

      Yep

    11. DD

      ... for that. So ezetimibe 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 [laughs] 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.

    12. TF

      Mm-hmm.

    13. DD

      With the lipid energy model, LDL and ApoB is sort of a carrier for fat to peripheral tissues, but we don't have to go there. But I think-

    14. TF

      Yeah. [laughs]

    15. DD

      ... the balance of the data, yeah.

    16. TF

      Dodge it for now. [laughs]

    17. DD

      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, and 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, right?

    18. TF

      What percentage did you say?

    19. DD

      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-

    20. TF

      Okay

    21. DD

      ... broccoli, asparagus, of course, you know, cauliflower, green leafy vegetables, but even fruits, like I trend towards wild blackberries, raspberries, blueberries, and buy them like in combination.

    22. TF

      Yeah

    23. DD

      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 odds and ends of-

    24. TF

      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?

    25. DD

      [laughs] Well, yeah, we have a blueberry... 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, grow blueberries and then make blueberry wines and-

    26. TF

      [laughs]

    27. DD

      ... things like that, and have huge festivals. But we get from there, but yeah, you can go to Walmart and get, you know-

    28. TF

      Oh

    29. DD

      ... the Walmart blueberries, which are like the size of grapes, and then next to that now, Costco and Sam's and, and even Walmart now have the wild blueberries, and they're about-

    30. TF

      Oh, okay, okay

  14. 31:43 – 37:29

    Dom's day-to-day diet regimen.

    1. DD

      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.

    2. TF

      [laughs]

    3. DD

      And then instead of 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.

    4. TF

      Chubb like the insurance company? C-H-U-B-B? No. How do you spell that?

    5. DD

      Uh, C-H-U-B.

    6. TF

      [laughs]

    7. DD

      Unlike a king mackerel, which are bigger, chub mackerel are a small fish.

    8. TF

      Yeah, they don't bioaccumulate as much garbage.

    9. DD

      Yeah. They're really low on the heavy metal list, which I-

    10. TF

      Mm-hmm

    11. DD

      ... 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.

    12. TF

      Oh.

    13. DD

      I take a fish and give my two dogs each a fish, and then I pour, it's got a lot of fatty water in it full of omega-3s, and I pour that on their food, and they love it.

    14. TF

      Man, where do I sign up to be reincarnated as one of your dogs? [laughs]

    15. DD

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

    16. TF

      Hold on. I can't skip over that.

    17. DD

      Yeah.

    18. TF

      Why give ketones to your dogs?

    19. DD

      Well, the brain boosting effects, the anti-inflammatory effects, the neuroprotective effects, and the anticancer effects. So these are all things-

    20. TF

      Yeah

    21. DD

      ... I worry about with my dogs. They are fixed. I do give them a SARM [laughs] surprisingly after they got injured.

    22. TF

      This is an anabolic, right? [laughs]

    23. DD

      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 we had some, I was gonna use it for a cancer cachexia study.

    24. TF

      Hmm.

    25. DD

      And it's Ostarine, I think. I, [laughs] 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 him like 90 to 100 human years, and he runs 35 miles per hour. He has like no sign-

    26. TF

      Whoa. What?

    27. DD

      ... of slowing down. Yeah. He's a Great Dane that should have passed away years ago, and he's just like a machine.

    28. TF

      You mentioned Audacious Nutrition. Just for the purposes of transparency, you do have family in the business involved with Audacious, right? [laughs] Just to confirm.

    29. DD

      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.

    30. TF

      Yeah.

  15. 37:29 – 41:50

    How Dom optimizes his aging dogs with ketones, SARMs, and supplements.

    1. DD

      so.

    2. TF

      What are your current feelings, 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, right? Have just kinda 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 answers are different. Let's, let's just say-

    3. DD

      Yeah

    4. TF

      ... it's a sardine fast, like a [laughs] man, Valter Longo [laughs] coming for you with the sardine fast. [laughs] What supplementation makes this easier or more productive just from an adaptation perspective?

    5. DD

      I will use sardines and also KetoStart, which is essentially the electro sodium, potassium, calcium, magnesium, beta-hydroxybutyrate. And that-

    6. TF

      Mm-hmm

    7. DD

      ... is, 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-

    8. TF

      Yeah

    9. DD

      ... a little bit hyper or dysphoric-

    10. TF

      Yeah

    11. DD

      ... even for some people.

    12. TF

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

    13. DD

      Yeah. That's less with a sardine fasting instead of, like, zero calories. So the sardines would then be eaten at nighttime typically. And I remember doing this repeatedly, and what I would do is take a little bit of GABA at night, and on one-

    14. TF

      Mm

    15. DD

      ... or two fasts I took just 25 milligrams of diphenhydramine.

    16. TF

      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-

    17. DD

      Yeah

    18. TF

      ... Benadryl?

    19. DD

      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 enhances, it reduces sleep latency, so I get better sleep. But I would not use it more than 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 [laughs] I think.

    20. TF

      Yeah. Yeah.

    21. DD

      I think. I mean, there's, the data's pretty clear on that. You have an older person getting 50 milligrams every night, every week is bad. So-

    22. TF

      Yeah

    23. DD

      ... 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 phenibut GABA. So which I have-

    24. TF

      Yeah

    25. DD

      ... but tend to, haven't used in a while. Phenibut, I would just wanna 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 phenibut 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, three grams of phenibut can give you euphoria, and you have, it's like a benzodiazepine kind of. But if you take 250 milligrams or 200 milligrams of phenibut, 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 do the first day of fasting.

    26. TF

      Yeah.

    27. DD

      Yeah. A little bit of GABA or phenibut, diphenhydramine, magnesium, and then I also do, I've always done melatonin, five to 10 milligrams of melatonin.

    28. TF

      That's a solid dose. [laughs]

    29. DD

      Yeah. We went on vacation and I forgot

  16. 41:50 – 45:20

    Supplementing for sleep disruption while fasting.

    1. DD

      it.

    2. TF

      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, some possibility of endocrine disruption. Can you speak to that?

    3. DD

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

    4. TF

      [laughs] Oh, man. Back in the day.

    5. DD

      Yeah. Yeah.

    6. TF

      EAS? Is that, like, way back in the day?

    7. DD

      I was a beta tester for that. Yeah, I was a beta tester.

    8. TF

      Oh, wow.

    9. DD

      And then Phosphagen came out, and then I, 1993 I think I started using creatine. I was, like, a early adopter of creatine. But yeah, to get to your question in melatonin, I've studied melatonin on the hippocampus, on brain slices. [laughs] You can slice a brain like a piece of bread and it, you know, applied melatonin, looked at reactive oxygen species and things like that. We use it for oxygen toxicity. It wasn't good for that because it did make the, the rats sleepy. Melatonin doesn't really make me sleepy. It kind of makes me more calm than anything else.

    10. TF

      Yep.

    11. DD

      So I went on a vacation where I forgot melatonin, and I slept like a baby, probably because I was up every morning. Sun is the ultimate circadian synchronizer, so-

    12. TF

      Yeah

    13. DD

      ... 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. As 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 hu-

    14. TF

      Hmm

    15. DD

      ... and I think when he talks about it, I don't think he references, like, a human study, but he does reference legit studies. Yeah, Andrew Huberman is an amazing scientist, and he puts out awesome information out there. So 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 9:00 or 10:00 in the morning, my melatonin is super physiological.

    16. TF

      Is that good or bad? [laughs]

    17. DD

      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.

    18. TF

      Huh.

    19. DD

      So use it for that. I also mega dosed 20 or 30 milligrams and then checked my LH and FSH.

    20. TF

      Milligrams?

    21. DD

      Yeah.

    22. TF

      T- okay. Yeah, yeah. 20 to 30 milligrams.

    23. DD

      10 milligram tablets are like the gorilla tablets for melatonin, right?

    24. TF

      Yeah, yeah.

    25. DD

      So I, 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. 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-

    26. TF

      Huh

    27. DD

      ... which is another topic that I can get into. But the thing is that it did not trigger an endocrine response in me, and 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 of s- some sex hormones.

    28. TF

      Okay.

    29. DD

      It is a hormone.

  17. 45:20 – 46:09

    Why Dom doesn't have misgivings about melatonin.

    1. TF

      Well, that's good to know, 'cause I actually benefit from taking melatonin, [laughs] but I, I've largely cut it out because of some of the, the murmurs, but it does help me sleep. Is this a true statement? That you do not do any fasting currently, like pure water fasting, but instead do this situational sardine fasting? 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?

    2. DD

      For me personally, it's very context dependent.

  18. 46:09 – 46:32

    Shingles prevention through fasting protocols.

    1. DD

      I was talking to someone the other day that was getting shingles. As soon as the s- first sign of tingling, which is like the precursor of getting shingles, they start fasting and it never actually surfaces.

    2. TF

      Huh.

    3. DD

      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

  19. 46:32 – 50:15

    Immune system modulation: Innate vs. adaptive, vegan vs. ketogenic.

    1. DD

      things like that.

    2. TF

      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, what's actually happening to have that suppression?

    3. DD

      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 research 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 augmenting the B cell and T cell things where it's like the adaptive immune system is like the Navy SEALs. [laughs] 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, and a two-week ketogenic diet, and this was published in Nature Medicine, augmented the adaptive immune system, and partly through the gut and partly just through changing metabolic physiology. This happens when we fast. When, if we're fasting, our gut is relaxing. I think it's restoring or preventing... When we eat something, we have things going into circulation that's keeping our immune system kind of active, right?

    4. TF

      Mm-hmm.

    5. DD

      So if we're not eating anything, our immune system becomes hypervigilant, and then in a way that it becomes hypervigilant 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 100,000 guys in an army in the immune system, and 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. Right?

    6. TF

      Mm-hmm.

    7. DD

      It just becomes more vigilant, but inflammatory cytokines, chemokines kinda 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's plays a role in inflammasome suppression.

    8. TF

      Mm-hmm.

    9. DD

      I know guys like maybe Eric Verdin and like the guys at the Buck Institute, they had kind of looking at that, and then our colleagues, Dr. Deep Dix at, at Yale 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-

    10. TF

      Mm

    11. DD

      ... in Nature Medicine in 2015. So I formulated the diet, like, for that study, and I've become 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 just one of these things that needs to be studied because it's kind of universally accepted-

    12. TF

      Mm-hmm. Yeah

    13. DD

      ... that it's kind of happening. But you also have to be in a good, healthy state. If your, 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, they have to approach it very

  20. 50:15 – 53:35

    Dom at 50-something: Current meal timing and composition.

    1. DD

      cautiously.

    2. TF

      How many meals per day do you eat now? How old are you, Dom, at this point?

    3. DD

      50s.

    4. TF

      Yeah, 50s.

    5. DD

      In my 50s, yeah.

    6. TF

      All right. Well, congrats.

    7. DD

      Thanks.

    8. TF

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

    9. DD

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

    10. TF

      And you weigh about how much at this point?

    11. DD

      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 an- another one. So I just hover right at 218 to 220.

    12. TF

      Yeah.

    13. DD

      And body fat last was 9.4.

    14. TF

      You got some muscle to feed. All right.

    15. DD

      Yes. Yeah.

    16. TF

      So, so three meals a day. What, what does it look like?

    17. DD

      This morning it was eggs and chub mackerel and yeah, and that's it. So basically just protein and fat, and the... For lunch, I typically have beef, chicken, or fish, usually fish. Lately I've been eating a David bar. Peter sent me-

    18. TF

      Mm

    19. DD

      ... some of those, and I've kinda 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.

    20. TF

      Yeah.

    21. DD

      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-

    22. TF

      Hmm

    23. DD

      ... broccoli. I could eat like three pounds of broccoli, has no gas or bloating effect for me at all.

    24. TF

      [laughs]

    25. DD

      My body loves broccoli. Our dogs do too, so I give them a little bit of that, salads. But-

    26. TF

      [laughs] All right

    27. DD

      ... usually about a pound of beef, chicken, or fish at dinner. So that's my big meal.

    28. TF

      Wow. Okay.

    29. DD

      And over the years we have done transition. Instead of eating at 7:00, we eat at like 5:00.

    30. TF

      Okay.

  21. 53:35 – 54:39

    Blue zone observations: Greek and Sardinian longevity habits.

    1. DD

      I think-

    2. TF

      Mm

    3. DD

      ... that may factor into... We just got back from Greece and they had the ouzo and everything and it just all the... We went to, then we went Sardinia. So we went to these blue zones and they just at night after their dinner the males will do a shot of alcohol, usually wine but sometimes ouzo.

    4. TF

      Mm.

    5. DD

      And, and they're all like in their 90s and like 100s, right? They're in the blue zone. So it's a universal characteristic.

    6. TF

      Well [laughs]

    7. DD

      That's my protocol. Yeah.

    8. TF

      There may be a genetic component too. I remember there was-

    9. DD

      Yeah

    10. TF

      ... 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 and he's like, "Yeah, MTHFR." He's like, "That's why. [laughs] It's none of the other stuff in the book." And he mentioned-

    11. DD

      Yeah

    12. TF

      ... a couple of other things, like who knows? But yeah, I mean I, I think if you, if-

    13. DD

      Activity. Yeah.

    14. TF

      Yeah. Yeah, you know.

    15. DD

      Living by the water, activity, and social.

    16. TF

      Yeah.

    17. DD

      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.

    18. TF

      Mm-hmm.

    19. DD

      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.

  22. 54:39 – 1:01:49

    Ketogenic diet initiation tips: MCT, electrolytes, and fasted cardio.

    1. TF

      If someone is Let's just say they wanna test out the ketogenic diet, and certainly they will note, they'll be like, "Wow, Dom does eat a lot of vegetables except for [laughs] a pound of broccoli at dinner."

    2. DD

      I can tolerate that, but I have-

    3. TF

      [laughs]

    4. DD

      ... probably, like, it comes out to 30 to 40 grams of fiber a day, which is pretty-

    5. TF

      Yeah

    6. DD

      ... pretty high, but that's broccoli, and I usually have a small apple too. Sometimes we have apples, and then, like, a cup of wild blueberries. So it comes out to-

    7. TF

      Oh, right. Okay

    8. DD

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

    9. TF

      Yeah, got it. Okay. If people wanna kickstart the ketogenic diet, any, any tips for kinda getting over the hump in the beginning? People 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 and maybe haven't given it a shot, any tips for novices?

    10. DD

      I would do fasted low intensity cardio. For me, that would just be going for a long walk, waking up in the morning, and if you're gonna 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 KetoStart 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 gotta deplete liver glycogen and ramp up beta oxidation fat enzymes, and then you have, as ketones get into circulation, over the period of a couple weeks, you're going to upregulate the ketolytic enzymes, which are basically the enzymes in the tissues that are able to, you know, utilize and leverage those ketones for, for energy over time.

    11. TF

      How long does that adaptation take, would you say?

    12. DD

      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.

    13. TF

      Yeah.

    14. DD

      I think the point is for most people is that if you start fasting or a 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 gonna spike ketones up, you're gonna 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.

    15. TF

      Okay.

    16. DD

      So MCT will stimulate your own ketone production too, so it kind of ramps it up.

    17. TF

      Now, 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?

    18. DD

      For the liquid, sometimes what I do if I'm eating tuna fish, which is packed in water, I'll pour the MCT on the tuna fish and stir it up-

    19. TF

      Okay

    20. DD

      ... 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 Steven Cunnane 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%.

    21. TF

      Huh.

    22. DD

      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, so you're ramping that up a little bit.

    23. TF

      What type of powder do you like to use?

    24. DD

      People send me things, but I actually, the powder that I have is actually, it's Keto Brainz.

    25. TF

      Mm.

    26. DD

      It's MCT powder, Alpha-GPC, theanine, and it has lion's mane mushroom in it. [laughs] So it goes under the brand name of Keto Brainz, 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-

    27. TF

      Yeah

    28. DD

      ... one or two.

    29. TF

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

    30. DD

      Oh, really? Okay.

  23. 1:01:49 – 1:04:54

    Ketone metabolic therapy for cancer.

    1. TF

      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 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 akkermansia or a few other-

    2. DD

      Yeah

    3. TF

      ... strains, lo and behold, doesn't really work.

    4. DD

      That's right.

    5. TF

      And I'm wondering if that applies to other, say, 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?

    6. DD

      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 for glioblastoma, which is a cancer-

    7. TF

      Mm-hmm

    8. DD

      ... 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 [laughs] that was gonna 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 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 the Moffitt Cancer Center, which is the largest cancer center, or one of the largest in Florida, tier one cancer center, where we've got various projects, glioblastoma, maybe a breast cancer, but also lung cancer. So we're 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 ha- 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, so just kind of enhancing that therapy. And with the checkpoint inhibitors, it tends to just enhance cancer-specific immunity that is augmented by PD-1 inhibitors. So they're specifically studying that. So I'm e- 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 [laughs] ... The Alzheimer's, the metabolic psychiatry,

  24. 1:04:54 – 1:08:49

    The metabolic psychiatry revolution.

    1. DD

      and-

    2. TF

      Yeah, let's talk about those.

    3. DD

      Okay.

    4. TF

      Let's hop to the, the Alzheimer's and metabolic psychiatry. Would love to dive into that, 'cause that's front of mind for me, and I'm not sure if I made this clear. Doing the couple weeks of strict ketosis, segueing to a sort of 16/8 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, the best oral glucose tolerance test that I've ever logged. And from a mood stability standpoint, and 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 a standpoint of sustained focus and mood, has been just kind of mind-blowing, to be honest. So yeah, I'd love to hear any and all thoughts on the Alzheimer's metabolic psychiatry front.

    5. DD

      So metabolic psychiatry, I would encourage people to listen to Chris Palmer, who-

    6. TF

      Yep

    7. DD

      ... I kinda put on your radar. I don't know if you remember. I sent you the link to a metabolic-

    8. TF

      Yeah, yeah, yeah. [laughs]

    9. DD

      So I was like-

    10. TF

      Yeah, appreciate that

    11. DD

      ... "You've gotta watch this, Tim. It's, it's going to change sort of the landscape of psychiatry."

    12. TF

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

    13. DD

      The Metabolic Health Summit.

    14. TF

      Yeah, exactly.

    15. DD

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

    16. TF

      Oh, who are well known from Roblox

    17. DD

      ... well known from Roblox, yeah, sort of billionaire philanthropists that are changing, actually, what ultimately may be the standard of care for psychiatry. And I think they kind of single-handedly are funding metabolic psychiatries 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 MetPsy, MetPsy.com. That's a collaboration with Dr. Ali Houston, he's at Oxford, and Georgia Ede, 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.

    18. TF

      How do you spell the name of the app?

    19. DD

      MetPsy is M-E-T-P-S-Y, right? M-E-T... I'm trying to think.

    20. TF

      [laughs]

    21. DD

      MetPsy.

    22. TF

      Yeah. Better, better at the psy's than the branding [laughs] I guess.

    23. DD

      Yeah. M-E-T-P-S-Y.com, MetPsy.

    24. TF

      Okay. All right.

    25. DD

      So I think they, they have their website up, so they're basically in their onboarding phase, so they should go live pretty soon. But I'd like to add that the Baszuckis, I remember that they are funding a big study at Oxford right now, and the Baszuckis will match dollar for dollar any donation and spearheading sort of that using the app and using ketogenic therapies in combination with lifestyle therapies

  25. 1:08:49 – 1:15:10

    The soothing effects of hyperbaric oxygen and ketosis on seizure sufferers.

    1. DD

      too. So metabolic psychiatry is rapidly emerging in a number. 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 this application was the racemic ketone salts and the MCT. So we were gavage-ing them.

    2. TF

      What does gavage mean?

    3. DD

      It's basically like tube feeding the animal.

    4. TF

      Mm-hmm.

    5. DD

      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, it did have an anxiolytic effect, anxiety reducing effect. And then you administer that to the animal, and what we were doing is 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, they were very chill and calm. 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. They're more extroverted if they come out, and more introverted and kind of like their fear response if they go into the cave. So we got results that we published. The title is Anxiolytic Effect of Ketone Supplementation. We published, I think, three papers and showed like the mechanisms and stuff too. So that was an early paper in, over 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.

    6. TF

      Huh.

    7. DD

      If you look at, 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 [laughs] a benzo or something. So it had that effect in the animals. And when we look at the blood work and even take out the hippocampus in 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. 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.

    8. TF

      Huh.

    9. DD

      That's like your chill or, you know, like alcohol. [laughs]

    10. TF

      Mm-hmm. It's what you take before bed.

    11. DD

      Yeah, yeah.

    12. TF

      Yeah. [laughs]

    13. DD

      In a variety of different studies, we also looked at adenosine receptor signaling. That's a little bit more complicated to describe, but 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 in 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. [laughs]

    14. TF

      Yeah, get more anxious.

    15. DD

      But there seemed to be a sweet spot, maybe one to two, I wouldn't go above three, probably 1.5 to two millimolar range that seems to be a level of ketones that safely does not produce a metabolic acidosis.

    16. TF

      Yeah.

    17. DD

      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 regulates your blood pH. But the animals that succumb to ketoacidosis and died from the ketone esters that we gave them in early studies had to do with acidification of the blood. So it was just an overwhelming... 'Cause ketones are acidic.

    18. TF

      Yeah.

    19. DD

      And when you deliver it into an ester form, there's nothing, nothing to buffer that. When you give a ketone salt, the electrolytes are kind of like a buffer for that, right?

    20. TF

      Yeah.

    21. DD

      So you have the metabolic effect, you have the changing of the brain neuropharmacology, and in bipolar you, you throw antiepileptic 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 T. gondii. I mean, it could be like [laughs] a bacteria. There are various things that could cause psychiatric disorders. Various infectious agents create that neuroinflammation. So I think 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 it. And I would throw up a big flowchart of all these mechanisms, and I think they would get frustrated and was like, "Well, what, tell us the mechanism so we can [laughs] make a drug out of this." But I think the beauty of ketogenic therapies is that it's pleiotropic, right? So 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

  26. 1:15:10 – 1:18:29

    Metformin vs. berberine.

    1. DD

      also.

    2. TF

      Do you use either of those?

    3. DD

      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 that it increases mitochondrial oxidative stress, [laughs] so it's a weak toxin to the liver. Most people didn't know that when we were studying that. And I think metformin can enhance increased 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's about 150 studies on clinicaltrials.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've felt sick. An issue with metformin is it could produce lactic acidosis. It's producing lactic acidosis because it's a weak, it is a toxin to the liver, so it's sort of de-energizing 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.

    4. TF

      You mentioned on your wrists.

    5. DD

      Yeah.

    6. TF

      Am I making that up?

    7. DD

      It tended to correlate with that, and then I got off of it. And then I experimented with it again, and it tended to be at the begin... I'm in Florida and it was 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, uh, but I don't use it.

    8. TF

      May I ask you a quick question just related to metformin for a second?

    9. DD

      Mm-hmm.

    10. TF

      I was looking back on notes on prior conversations, and I think you mentioned Dr. Dale Bredesen-

    11. DD

      Yeah

    12. TF

      ... on an episode of Stem Talk. But specifically for folks with the APOE4 genotype like yours truly-

    13. DD

      Yep

    14. TF

      ... do you think metformin may be more interesting? But let's assume in my case, let's call me metabolically healthy, maybe yes, maybe no. I remember a long time ago having a chat with Nav Chandel, I want to say, I might be getting the name slightly wrong, from Northwestern, and he was like-

    15. DD

      Yeah, Nav. Yeah

    16. TF

      ... "If you're doing a bunch of exercise and getting your diet straight," he's like, "I don't think that you're gonna see a lot of benefit." But he didn't have the APOE4 information, right, 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 APOE4 specifically.

    17. DD

      Yeah, berberine 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 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 pre-diabetic or, you know, have type 2 diabetes [laughs] that are in their 40s, 50s and 60s, and it will reduce your incidence of cancer, specific kinds of cancers like pancreatic cancer. I think the data's kind of good on that, and I think it'll shift metabolic biomarkers that we have historically good data on in the right direction.

  27. 1:18:29 – 1:21:44

    The low-dose neuroprotective potential of GLP-1 drugs.

    1. TF

      Does metformin do anything that taking a GLP-1 like tirzepatide or something doesn't do? I mean, I guess I'm just wondering if-

    2. DD

      Yeah

    3. TF

      ... there's an additive effect.

    4. DD

      Well, they're totally different drugs. But people who take metformin in 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-

    5. TF

      I see

    6. DD

      ... 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 like metabolic dysregulation or metabolic syndrome.

    7. TF

      Yeah.

    8. DD

      Right? A GLP-1 works essentially through caloric restriction and just-

    9. TF

      Yeah

    10. DD

      ... decreasing appetite through [chuckles] in part a mild gastroparesis and decreasing gastric emptying time, but also works on the brain, and I think has a wide range of beneficial effects. I think it's a game-changing drug that's gonna change the whole landscape of metabolic therapies.

    11. TF

      Seems to have a, from what I've read, and maybe I don't wanna over-interpret here, but potential neuroprotective effects, right?

    12. DD

      Yeah.

    13. TF

      So that's the main reason I would be looking at potentially low-dose GLP-1.

    14. DD

      I like the low dose. 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.

    15. TF

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

    16. DD

      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-

    17. TF

      Oh

    18. DD

      ... I got off. I don't know if it has a vasodilator 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 to mind. I don't, I, I'm a fast metabolizer of caffeine.

    19. TF

      You still consume quite a bit of coffee, yeah?

    20. DD

      I do, yeah. I fill this up. So this is Metabolic Mind.

    21. TF

      Yeah.

    22. DD

      So yeah. Actually Metabolic Mind is part of the Basuki's group, metabolic psychiatry.

    23. TF

      Ah.

    24. DD

      So they, they have a... So I do one of these per day.

    25. TF

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

    26. DD

      24, I think. About 20-

    27. TF

      24 ounces

    28. DD

      ... 24 ounces.

    29. TF

      Yeah, okay.

    30. DD

      Yeah.

  28. 1:21:44 – 1:26:38

    NAD research: MIB-626 and stabilized forms for mitochondrial health.

    1. DD

      carbs.

    2. TF

      Yeah.

    3. DD

      Yeah, GLP-1 and SGLT2 are great.

    4. TF

      Well, this is also 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-

    5. DD

      Yeah

    6. TF

      ... to comply with ongoings, and you can't have necessarily 24/7 supervision to prevent them from eating bagels.

    7. DD

      Yeah.

    8. TF

      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 with the explicit goal of mitochondrial health or maybe just the side effect of mitochondrial health?

    9. DD

      Yeah. Well, I think ketones shine there. The D-

    10. TF

      Yeah

    11. DD

      ... both the D and the L beta-hydroxybutyrate, so that's like first and foremost. And we are doing research with NAD, so NAD supplements.

    12. TF

      These injectables?

    13. DD

      Well, I can't talk about 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 and there's NR, right? Nicotinamide riboside, 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 g- so a lot of it's maybe not getting to the brain. But if people just google MIB 626, 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 of those-

    14. TF

      Mm-hmm

    15. DD

      ... preclinical animal model work in our lab.

    16. TF

      Mm-hmm.

    17. DD

      So I do think for certain applications we didn't see an effect, but at the same time they are for applications like non-alcoholic fatty liver disease, maybe Alzheimer's, maybe inflammatory disorders, improving if used for a long period of time markers of mitochondrial health, I think improve.

    18. TF

      Mm.

    19. DD

      NAD, people may know NAD is basically like a substrate for like the sirtuins, right?

    20. TF

      Mm-hmm.

    21. DD

      And various enzymes. There's like 500 different enzymes. A class of proteins that are called sirtuins rely heavily on NAD. So this is like an important thing to consider, and as we age, NAD levels fall.

    22. TF

      And the sirtuins, just for folks who are like, "Have I heard that before?" I wanna say back in the day when resveratrol was everywhere in the news-

    23. DD

      Yeah

    24. TF

      ... and Super Mouse and all you have to do is drink wine, but maybe 20 cases of wine. I mean, all of that stuff with trans-resveratrol, that that's where the sirtuins popped up.

    25. DD

      Yeah. 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 reductive stress with D beta-hydroxybutyrate?

    26. TF

      Yeah. Yep.

    27. DD

      So 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.

    28. TF

      I see.

    29. DD

      So that kind of feeds back. I don't wanna 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 31 phosphorus MRS if you have like a four or seven tesla system like Harvard has.

    30. TF

      Mm-hmm.

  29. 1:26:38 – 1:28:55

    Idebenone, CoQ10, and the Deanna protocol for ALS.

    1. TF

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

    2. DD

      I think CoQ10 is on the short list 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 CoQ10 in it.

    3. TF

      Mm.

    4. DD

      But if you're on a statin, if you're on metformin and other drugs, they, they could potentially deplete you. And then CoQ10 has a solid track record for cardiovascular health. So idebenone is kind of a drug-stabilized form of that.

    5. TF

      Mm.

    6. DD

      And then when I discussed that on your podcast, that was in the context of something called the Deanna protocol. The Deanna protocol-

    7. TF

      Mm-hmm

    8. DD

      ... is after Deanna Tidone. She has ALS. She was diagnosed well over a decade ago, was given two or three years to live. She's alive and well today. We were just emailing [laughs] yesterday. So Deanna Tidone had advanced ALS and then has been stabilized using the Deanna protocol, which included at the time idebenone, but I think it became a drug. So idebenone became-

    9. TF

      Yeah

    10. DD

      ... the standard of care for Friedreich's ataxia, and then you couldn't get it on Amazon. But I think ubiquinol or CoQ10, it would be a, a good-

    11. TF

      Mm

    12. DD

      ... 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 kidney toxicity. We had some animals die.

    13. TF

      Oh, Jesus.

    14. DD

      And we didn't know. But that was in rodent models.

    15. TF

      Play around. [laughs]

    16. DD

      And we use, again, we use like really high dose for oxygen toxicity. We've looked at everything under the sun.

    17. TF

      Yeah.

    18. DD

      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 papers came up and then we think that that's why the animals may have died. We were using a MitoQ, like various forms that are like more mitochondrial specific.

    19. TF

      Mm.

    20. DD

      We were using more potent forms of, of the CoQ10, so it may not be similar to the commercially

  30. 1:28:55 – 1:31:36

    Dom's supplement short list: CoQ10, creatine, ketones, vitamin D, melatonin.

    1. DD

      available forms.

    2. TF

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

    3. DD

      That I take? Yeah, so creatine monohydrate would be kind of the staple thing that I've used 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 the next creatine for that.

    4. TF

      Yeah.

    5. DD

      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 [laughs] of creatine.

    6. TF

      Yeah.

    7. DD

      Spread out, you know, maybe five grams three to four times a day for advanced Alzheimer's-

    8. TF

      Yeah

    9. DD

      ... if you can tolerate it. Micronized form.

    10. TF

      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. [laughs]

    11. DD

      Yep. [laughs] Vitamin D, but you have to measure that in your lab, so you want that to be, you don't want it like over 100, right? So you want vitamin D levels that are probably like 60 to 80 would be a good level of vitamin D and getting that checked. But I think you should check it first. It's weird. I live in Florida. I get tons of sun, but if I'm not supplementing vitamin D, I trend to be low 30s. It could be trend. But so when I supplement it-

    12. TF

      Right

    13. DD

      ... I basically stay in the mid 60s to 70s.

    14. TF

      Mm.

    15. DD

      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 just because I did, Rhonda Patrick connected me with the omega-3 guy and I tried the OmegaQuant, and my DHA levels and EPA levels were off the charts.

    16. TF

      [laughs]

    17. DD

      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.

    18. TF

      Mm-hmm.

    19. DD

      I'm not paid to say that or anything, but they're legit. But you could do the OmegaQuant 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.

    20. TF

      Yeah.

    21. DD

      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, you know, DHA and EPA will probably be added

  31. 1:31:36 – 1:37:30

    KetoNutrition.org, Metabolic Health Summit, Audacious Nutrition, veteran-focused research protocols, and other parting thoughts.

    1. DD

      to that.

    2. TF

      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 wanna 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 [laughs]

    3. DD

      [laughs]

    4. TF

      ... people you'd like to skewer in front of a large audience. No, I'm kidding. But anything that you would like to say or point people to? Any resources, anything that you're up to, where they can find you, anything at all?

    5. DD

      Yeah, I just wanna, you know, mention KetoNutrition, that's our informational website, KetoNutrition.org. And we've hosted a conference where many people you know, Dr. Valter Longo, Rhonda Patrick, who's been the 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, 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 so people can learn about metabolic psychiatry, people can learn about metabolic-based therapies and metabolic drugs like GLP-1 drugs and, and hormone optimization and things like that. So I'd mention that. The brand of ketones that I use that I often get asked is Audacious Nutrition KetoStart. So that evolved out of our work with cancer, neurodegeneration, and seizures. We're doing work at, you know, Byrd Alzheimer 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, be able to share some of that pre-clinical animal model work. Hyperbaric oxygen, so we have a $28 million study.

    6. TF

      That's huge.

    7. DD

      Yeah, at the University of South Florida. I am just peripherally involved in that, just know the people running that, and it's essentially evolved out of the DoD work that looked at the muddy waters of hyperbaric oxygen therapy [laughs] for that.

    8. TF

      That's a good way to put it, the muddy waters.

    9. DD

      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 University of South Florida is that it's very innovative in that it's using a sham. Instead of using hyperbaric air as the control, they're using, they basically pulse pressure in the beginning to make people think they're being pressurized and at the end-

    10. TF

      Oh

    11. DD

      ... so their ears pop a little bit, and I don't know every, uh, 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 or... 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 gonna get an unambiguous answer to this question about hyperbaric oxygen for traumatic brain injury in people with and without post-traumatic stress syndrome.

    12. TF

      Mm-hmm.

    13. DD

      My thing 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.

    14. TF

      Now, this is pretty specific to military, or what are we-

    15. DD

      Yeah

    16. TF

      ... talking about?

    17. DD

      They're all vets, and if they do find out that they get a beneficial effect from that, then after the, the experiment, they'll be able to get that for free service. So there's six, you know, quarter to half a million dollar hyperbaric chambers, so the hard shell chambers. There's six of them in this facility, and it's a very, it's the most elaborate hyperbaric oxygen therapy study that has ever been done, so and-

    18. TF

      Mm

    19. DD

      ... and it'll answer the question about the efficacy. So that's ongoing now.

    20. TF

      Yeah.

    21. DD

      And I'm excited about that. I'm also excited about potentially using that facility [laughs] 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 'cause it augments the immune system and it's actually an FDA-approved application for radiation necrosis, so if you've had radiation, then your insurance would actually cover it. But it can-

    22. TF

      Sure

    23. DD

      ... enhance certain therapies that we're working on now, so.

    24. TF

      Amazing. All right. Well, we will link to all of those things-

    25. DD

      Yeah

    26. TF

      ... in the show notes, as always, and I encourage people to check all of those out. I'm gonna check all of them out. And Dom, thanks so much for the time, as always.

    27. DD

      Great to see you, Tim.

    28. TF

      I took a ton of notes.

    29. DD

      Yeah.

    30. TF

      I have even maybe even more questions [laughs] on top of that for more text messages. Sorry in advance.

Episode duration: 1:37:41

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