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Tim Ferriss: Dom, nice to see you again. It’s been a few years. Thanks for making the time.

Dr. Dominic D’Agostino: Yeah, it’s great to see you, Tim. Yeah, we’ve stayed in contact here and there with texting, but yeah.

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. What data do we have, and if there’s a little bit of speculation of all them, 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.

Dr. Dominic D’Agostino: Yeah, that’s a rapidly emerging area of research, and I think you’re aware, we talked previously of the case reports that are out there that got 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 disease. 

Tim Ferriss: Sometimes called type 3 diabetes, if I’m getting that right.

Dr. Dominic D’Agostino: Yeah. That was coined back in 2005 or ‘6, I think, and that was brought to my attention actually by Dr. Mary Newport and her husband, Steve Newport, was the subject actually in the case report for the use of the beta-hydroxybutyrate monoester for that. 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 last night at the house and had her over here. And she’s a close friend of mine. We co-teach together at USF. She’s a guest teacher.

Interestingly, I saw Steve Newport in 2008 or ’09, and I witnessed the observation. He’s 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. And I observed — I was still pretty — I was questioning this idea of ketones rescuing the brain in the context of Alzheimer’s disease.

Symptomatically, there was no doubt in my mind that it did, because I witnessed him. He wasn’t using the ketone ester at the time, but we quickly transitioned to that after meeting, but he was taking coconut oil and MCT oil. And he would bring these little shot glasses. Mary taught my class. We went out to dinner. He did the shot glasses. 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 a 30 milliliter shot of MCT plus coconut oil that was mixed in there. So she was really — and doing that three to four times a day with meals.

So that was my first observation. And it was clear to me that there was at least a metabolic — within the Alzheimer’s spectrum, I just like to — Alzheimer’s is kind of a fuzzy diagnosis and — 

Tim Ferriss: Sure. Very fuzzy.

Dr. Dominic D’Agostino: Yeah. And I just like to call it dementia, cognitive dementia. There’s vascular dementia and there’s Aβ and tau. And my wife was working on tau at the Alzheimer’s center when we met. She was working under a guy who studied tau. Then there was people there who studied amyloid beta, and there was the tauists and the beta. And there was an argument as to what was more profound.

But a universal feature of Alzheimer’s is amyloid plaque accumulation. But also now we know that glucose hypometabolism is central to that. And as we age, our ability to use glucose as an energy source decreases over time due to they thought maybe vascular reasons. But come to find out, it’s really, it’s a constellation of things, including the glucose transporter, the GLUT3 is on neurons. Pyruvate dehydrogenase complex, which is really the governor or the rate limiter of glucose metabolism in neurons. That’s PDH, pyruvate dehydrogenase complex.

Tim Ferriss: So we’re probably talking about — 

Dr. Dominic D’Agostino: — cancer.

Tim Ferriss: — if, I mean, 50, 60 percent of the population having one of these things.

Dr. Dominic D’Agostino: Sure, yeah. Well, Steve Newport, the subject in that case report, had bouts of herpes, HSV, around the eyes and got hit pretty hard with that. But also people who have shingles that I think they’re at risk too. We know Epstein-Barr virus, you’re four or five times more risk for things like MS. It’s triggering the immune system.

So I think there’s a renewed interest in looking at Alzheimer’s disease, looking at the root cause. And I think metabolism is central, but the metabolic hit that may be contributing to dysregulated metabolism and neuroinflammation could be an infection. And I think there’s accumulating evidence for that. I was skeptical 10 years ago, probably, when we talked. However, this kept putting on my radar. And then I was in an NIH sponsored workshop on this looking at various aspects, and the data presented by a number of different labs was very compelling for this.

So what does that mean? Our immune system is — there’s the four horsemen that our friend Dr. Peter Attia talks about. I think the fifth horseman is really the immune system. I like to add a sixth horsemen as our physical form, our skeletal structure, so our bones, and that will give over time too. But the immune system is really central to longevity. And the metabolic control of epigenetic regulation and metabolic control of immune system function is of very high interest. I know the Buck Institute has refocused on that, and many longevity clinics are now looking at that. 

Tim Ferriss: What is your preferred device for measuring ketones these days?

Dr. Dominic D’Agostino: For publications, we’ve used the Abbott Precision Xtra because historically we’ve used that. However, when I recommend a meter to people, I generally recommend the Keto-Mojo device because that — 

Tim Ferriss: Keto-Mojo.

Dr. Dominic D’Agostino: — has the glucose ketone index. And so the glucose ketone index is the millimolar concentration of over ketones, and the strips are about, nowadays, still less — I was going to say, I don’t know, a few years ago, they were about half the price. And we’ve tested the Keto-Mojo. We have a human clinical trial where we did breath, we did urine, and we did Precision Xtra and Keto-Mojo all together. 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 in the lab.

Tim Ferriss: Okay, interesting.

Dr. Dominic D’Agostino: Like the [inaudible] on that.

Tim Ferriss: Yeah, yeah. Let me just tell you what I’m up to and you can tell me how ridiculous I am in off base or fact-check as needed. Can you remind me of how to pronounce this Dr. Thomas? Is it Seyfried? Am I getting that right?

Dr. Dominic D’Agostino: Yeah. He’s a good friend and colleague. Dr. Tom Seyfried.

Tim Ferriss: Tom Seyfried. All right. So in terms of fasting, we’ve talked quite a bit about fasting. It still is very interesting to me. And I’m wondering just in brief, if you could, without getting too much in the weeds, but I’m wondering what the ketogenic diet does that exogenous ketones do not achieve? And then I’m wondering what fasting does that the ketogenic diet does not do.

But the way I want to get to that is to ask you, because for a long time I was doing a one week, we could call it a water-only fast, but let’s call it a calorie-free fast, 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 didn’t really want to do three to four week-long fasts a year, just didn’t want to do it. But in terms of potentially purging precancerous cells and so on, I was like, you know what? I like the aesthetic practice — seems like a bit of autophagy and cellular cleanup is a good thing. Why don’t I do that?

Do you do any fasting anymore or is that something that you have omitted from the current version of Dom’s schedule?

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

Tim Ferriss: This is Dr. Squat?

Dr. Dominic D’Agostino: Yeah, yeah, Dr. Squat. 

Tim Ferriss: Back in the day. Wow.

Dr. Dominic D’Agostino: Yeah, we were good friends. He was a mentor to me in many ways. But he had advanced metastatic prostate cancer, and it went to the bones where they did 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 I think he steered me onto sardines in maybe 2007 or oh eight or something like that. So that was my love for sardines was probably from him.

But he would do low-carb. He called it ketogenic, but I think it was just more of a low-carb diet. And then he would do five days, he would do a fasting mimicking diet that 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 just as I was getting into this. And essentially what happened is that he went into rapid remission and the doctors didn’t really know. Fred ended up passing away maybe eight years later of something completely unrelated to his cancer.

Tim Ferriss: As a non-oncologist, I have to pause and just say, I mean, it seems like prostate, for a lot of people, they hear that, they think “Death sentence.” Metastasized prostate cancer, they think, “No way, you’re done.” Am I exaggerating? I mean, how frequent is it that people have complete remission of something like that? Maybe I’m exaggerating things.

Dr. Dominic D’Agostino: Yeah, there’s a lot of factors like the Gleason score and his was not good in a number of factors. So he was given, I think he told me three months to live, but he went years and years — 

Tim Ferriss: Wow.

Dr. Dominic D’Agostino: — after that. And he was like, no evidence of disease. 

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

Dr. Dominic D’Agostino: Yeah, 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.” 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 and we communicated and I just encouraged, “Hey, keep sending me your medical reports.”

And I was like, “Maybe there is something to this.” So that actually steered me into just like the Alzheimer’s, we did started Alzheimer’s research because of Dr. Mary Newport. I studied seizures because of Mike Dancer. Just Google Mike Dancer, epilepsy, and you’ll find some remarkable stories. I 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 Fred, but that was prostate cancer. But then I started engaging with other patients and then connected with Thomas Seyfried soon after that.

Tim Ferriss: How frequently was Fred doing the week-long sardine fasts, if you had to guess?

Dr. Dominic D’Agostino: Once a month. Sorry. Yeah, I meant to — 

Tim Ferriss: Once a month.

Dr. Dominic D’Agostino: Yeah, it’s analogous to the fasting mimicking diet. I think Valter Longo can do that. He advises patients based on, situationally, their situation. But I encourage Fred to do it every month. And his feedback to me was that he would do it once every month to two months. He enjoyed doing it, so it was something that he kind of looked forward to doing.

Tim Ferriss: Sardine fast. I can’t wait for that to become a thing. That’s going to spread. I don’t want to gloss over what you personally do. So for you, for instance, I found out recently — and everybody get your checkups. 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, I think also related to the word hiatus etymologically. I’m going to get the definition wrong, I’m sure. But basically from your esophagus to 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 maybe not this bluntly, but that puts me at some increased risk of throat cancer or esophageal cancer, some type of cancer.

And I was like, “Shit, that’s not typically what kills people in my family. Usually it’s the cardiac stuff.” And I feel like I have that. My lipid profile is very well under control, 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 the risk.” 

And you were saying you fast episodically, was that the word that you used?

Dr. Dominic D’Agostino: Yeah. Situationally, episodically.

Tim Ferriss: Situationally. Situationally. What does that mean?

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

Tim Ferriss: So people might recognize CRP, right? I mean, C reactive protein is a marker of inflammation. I mean, if you get your annual blood test or whatever, chances are it’s on there somewhere.

Dr. Dominic D’Agostino: Yeah, I’d like to draw attention to that real quick because HSCRP is a better indicator of cardiovascular disease than LDL cholesterol. We know that now. If someone said that 10 years ago, they’re just like, “We think you’re crazy.”

But yeah, HSCRP is what we call a cardio metabolic biomarker, including 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 cancer and all the other, I call it six horsemen. No. The things that I mentioned. But yeah, so occasionally I will use it situationally just if I feel my body, if I feel like something is coming on, I’m getting a flu. But the sardine fasting is, and I advise it for cancer patients too. I want them to avoid a water-only fast in the context to prevent cancer cachexia.

Tim Ferriss: Muscle loss or muscle wasting.

Dr. Dominic D’Agostino: Yeah. 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 nutrition-wise in sardines. You might want to add a little bit of vitamin C or magnesium or something. But essentially it’s like you have adequate nutrition and then you 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, that the constellation of things that if you measure that would correlate with inducing and maximizing autophagy. So that was the rationale for me to do that. A lot of people talk about autophagy and it’s kind of a nebulous term. We measure it. We look at the autophagosome. So we’re a lab that actually does look at things like that. 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 a period of fasting.

Tim Ferriss: Which Keto-Mojo will do automatically. It’ll do the calculation for you. I did have a quick question. 

When I compared my Keto-Mojo to an 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 because regular spikes above a certain nanogram per deciliter seem to be indicative of all sorts of things. Have you run into any issues with the device or any caveats related to specifically the glucometer side? What I do like that’s nice about it is it does give you that glucose ketone index, the GKI as a readout right there on the device or in the app at least that accompanies the device.

Dr. Dominic D’Agostino: Are you talking about measuring glucose at the exact same time point that a phlebotomist pulled blood. 

Tim Ferriss: That’s exactly what I’m talking about. Yep.

Dr. Dominic D’Agostino: Okay. What was the difference between what was measured there?

Tim Ferriss: Let’s say the peak at 30 minutes out after drinking this 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. The return was much faster and much better on the phlebotomist drawn blood than it was on the Keto-Mojo device, which not to throw them under the bus. It could be operator error or just a single bad device. I have friends who have used it very successfully on the ketogenic diet, which is why I ended up buying it because Precision Xtra is kind of a pain in the ass to get a hold of, at least on Amazon. So that was my experience and I was like, “Okay. Well, tricky, tricky, tricky,” because 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.

Dr. Dominic D’Agostino: What’s your hemoglobin A1C?

Tim Ferriss: I’d have to go back and look. It’s trending down, but I would have to go back and look.

Dr. Dominic D’Agostino: If you wear a CGM, you’re under maybe 100 with the CGM. So the meters tend to trend a little bit high, about 10 percent high. I think they were 10 to 20. Keto-Mojo was 10 percent higher than our assays, and the Precision Xtra was 20 percent higher than the assays that we do when we pulled blood from the animal. So if that helps, I think you want to at all. You want to look at your insulin levels, your hemoglobin A1C, hs-CRP.

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

Dr. Dominic D’Agostino: Or put a CGM on them. That’s what motivated me to be, I guess, one of the first advisors for Levels. I’ve worked with them on a research front. I think you’ve interviewed Sam, right?

Tim Ferriss: Yeah.

Dr. Dominic D’Agostino: But Levels, I mean, that’s — 

Tim Ferriss: Yeah, Sam Corcos.

Dr. Dominic D’Agostino: Yeah, Sam. I mean, that’s like the ultimate kind of metabolic optimization platform. I mean, there’s others emerging too, but simply wearing — I mean, now they have the Stelo device that came out, so CGM’s are over-the-counter now, but the analytics from that and also the biomarkers that if you’re part of that program that you can measure, which include many things that we could talk about, but that would capture your relatives if your relatives put a CGM on. That’s really important, but what you observed is pretty normal and not to probably be of concern, like your — 

Tim Ferriss: Yeah. 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 ketones on a continual basis, are there longer term adaptations? Part of the reason I’m asking is that in the most recent set of experiments, let’s just say, I was strict keto for three weeks, and then frankly just got bored to death of the diet.

Dr. Dominic D’Agostino: It’s hard.

Tim Ferriss: Yeah, I did three weeks of let’s just call it kind of textbook — protein also quite low, like 10 to 15 percent 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. We could talk about that because 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 p.m. and 10:00 p.m. Then I went to a more paleo-ish diet, let’s just call it, within that feeding window. Then I did that for a few weeks and then started layering in exogenous ketones in my fasting state, typically 11:00 a.m., 1:00 p.m. if I’m doing podcast recordings and things like that.

Part of what I’m trying to figure out is given I’m APOE3/4, scared to death of Alzheimer’s, and maybe there’s nothing to be done about it, but if there is something to be done in addition to exercise rights and kicking out the Klotho and BDNF and all that good stuff, from a dietary perspective, trying to figure out, okay, how long does keto memory last if there is an expiration date? If you were in my shoes, how you would think about not just the exogenous ketones, but fasting and ketogenic diet? Do you have any thoughts on that?

Dr. Dominic D’Agostino: Well, yeah, you’re doing a lot of stuff there, and I would recommend following a protocol that you could do day in and day out that should ideally almost be effortless and mesh with your schedule, which may be variable if you have podcasts and things like that. I’m of the opinion that you could follow a baseline diet, which is a low-carb Mediterranean-like diet. Mediterranean is kind of a fuzzy term, I hate it, but low-carb Mediterranean style diet that essentially keeps biomarkers in check and then situationally going the ketosis now and then to just 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 person in the US is like 50, or 25 to 50.

So just 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. 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 different agents on that, but insulin HSCRP, hemoglobin A1C, triglycerides, ApoB you want to measure too, Lp(a) it’s good to know. 

Unfortunately, 30 percent of people — this is probably important when navigating what protocol to use. I have a mutation. I did GB HealthWatch, which looked at my genetics for dyslipidemia. So GB HealthWatch, 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.” He’s a very smart, aggressive or proactive kind of guy and suggested this test. He’s like, “I think you’re a hyperabsorber.” I was like, “Isn’t one percent of the population hyperabsorber?” But come to find out about 30 percent of the population hyperabsorb cholesterol.

Tim Ferriss: That’s me too. I’m in the same boat.

Dr. Dominic D’Agostino: Okay. I have an NPC1L1 receptor mutation that’s a gain-of-function mutation. I use an ezetimibe monotherapy for that. Ezetimibe was sold as Zetia, and I can get by with half of a tablet, which is five milligrams, and half my ApoB. It put my ApoB — it cut it in half, and also half my LDL. So I can follow a ketogenic diet. 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 LDL in the context of optimal metabolic biomarkers that it’s not to be concerned about, but that data is emerging and there’s groups of people that I believe are credible and then working on that front, looking at the lipid energy model. With the lipid energy model, LDL and ApoB is a carrier for fat to peripheral tissues, but we don’t have to go there.

Tim Ferriss: Dodge it for now.

Dr. Dominic D’Agostino: Yeah. If your LDL pops up, then a pescatarian Mediterranean-like diet that’s low-carb that’s 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 percent of what carbohydrate you consume should be fiber, and then that’ll essentially make it non-glycemic, right?

Tim Ferriss: What percentage did you say?

Dr. Dominic D’Agostino: 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 percent of that carbohydrate is fiber, so for example, broccoli, asparagus, of course, cauliflower, green, leafy vegetables, but even fruits, I trend towards wild blackberries, raspberries, blueberries, and buy them in combination. Then wild blueberries are about half the size and they have more fiber, less sugar, so I have a cup of that per day. My carbs come from mostly broccoli, wild berries, dark chocolate, and maybe a few other odds and ends.

Tim Ferriss: Where do you get wild berries? Is that something you buy or do you have to go out and steal from your neighbor’s patch?

Dr. Dominic D’Agostino: Well, yeah, we have a blueberry — surprisingly, blueberries grow great in Florida — but we have a blueberry farm right by us. It’s a winery, so they grow blueberries and then make blueberry wines and things like that and have huge festivals, but we get from there. But yeah, you can go to Walmart and get the Walmart blueberries, which are the size of grapes. Then next to that, now Costco and Sam’s and even Walmart now have the wild blueberries.

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

Dr. Dominic D’Agostino: I took out heavy cream, but put sour cream back in, but maybe about half of the sour cream, but also just switched out the eggs. I think the eggs were getting to me because eggs have a lot of cholesterol, and I was eating a dozen a day. 

When I prepare my food in the morning, my dogs get my food. So I’ll make 10 eggs, but I’ll have three yolks, and then I divide the other yolks between my two dogs. 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.

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

Dr. Dominic D’Agostino: Yeah, C-H-U-B. Unlike a king mackerel, which are bigger, chub mackerel are small fish.

Tim Ferriss: Yeah, don’t bioaccumulate as much garbage or — 

Dr. Dominic D’Agostino: Yeah. So they’re really low on the heavy metal list, which I tend to check because I eat so much of it. One can is almost a pound, and there’s three fish in each. I take a fish and give my two dogs each a fish. 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.

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

Dr. Dominic D’Agostino: Yeah, this morning they got — my wife has an Audacious canine supplement, so we give them a — that’s got spirulina, ketones and a few other things. We give them that, creatine monohydrate.

Tim Ferriss: Hold on, I can’t skip over that. Why give ketones to your dogs?

Dr. Dominic D’Agostino: Yeah. Well, the brain-boosting effects, the anti-inflammatory effects, the neuroprotective effects, and the anti-cancer effects, so these are all things I worry about with my dog. They are fixed. I do give them a SARM, surprisingly, after they got injured.

Tim Ferriss: This is an anabolic, right?

Dr. Dominic D’Agostino: I do, yeah. I transitioned. They got attacked by a big pit bull and they kind of immobilized for a while. I was going to use it for a cancer cachexia study, and it’s ostarine, I think. So I started giving it to them and it seems like they are leaner, stronger. We have a Great Dane that’s 12 years old. That makes him 90 to 100 human years, and he runs 35 miles per hour. He has no sign of slowing down.

Tim Ferriss: What?

Dr. Dominic D’Agostino: Yeah, he’s a Great Dane that should have passed away years ago and he’s just like a machine. 

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

Dr. Dominic D’Agostino: Yeah, I can’t have any company. I don’t sell anything personally, but my wife decided to create a product that used the ketones that we actually used in research. So it evolved out of that was various salts, and the idea was that if that product was created, then we can use it for research. And that was the initial part.

Tim Ferriss: Cool.

Dr. Dominic D’Agostino: I was using it anyway. I was like, “Well, why don’t you just make a product out of this? I can’t do it.” But it actually was an I-Corps NSF program through the university that got that started.

Tim Ferriss: Question, do you give rapamycin to your dogs or to yourself. Do you currently take or give your dogs rapamycin?

Dr. Dominic D’Agostino: I’ve gone back and forth. I follow Matt Kaeberlein’s work pretty closely and go back and forth. I’ve decided not to just because of the immune suppression. I know I got about a handful of people that use it, and I would say half of them get sores in the mouth. That can’t be a good thing.

Tim Ferriss: That’s super, super common, the mouth sores.

Dr. Dominic D’Agostino: Yeah. The data’s too early for that. I think the same thing can be achieved in a greater — a bigger lever would be sardine fasting for one thing and just beta-hydroxybutyrate and well-formulated low-carb supplemented ketogenic diet, by definition, a diet that elevates ketones and exercise, so exercise and a whole host of other lifestyle things. I’m not ready to pull the rapamycin trigger on my — anything I do with my dogs, excluding the SARM, I haven’t used that, but seeing the effects and looking at their blood work, it looks perfect. So there are no side effects with that and it seems to be helping with their advanced age.

Tim Ferriss: Can you take just a paragraph, explain what this SARM refers to for people?

Dr. Dominic D’Agostino: Yeah, there’s a specific androgen receptor modulator that hits the androgen receptor but doesn’t have the androgenic-like qualities.

Tim Ferriss: It’s not going to give you a third Adam’s apple, but it’ll help with muscle growth.

Dr. Dominic D’Agostino: It helps to stimulate skeletal muscle protein synthesis, and then the context of this drug also bone metabolism. Both of our male dogs are fixed too. We have discussions with various vets that are of the opinion — they’re more progressive that your dog should be on like TRT or testosterone if they’re fixed, because that will increase the quality of their life, especially as they age. Our dog look — I can’t detect any loss of skeletal muscle mass even when I look at pictures — 

Tim Ferriss: For clarity, your dogs are all male?

Dr. Dominic D’Agostino: Yeah, we have two male dogs and both of them are considered advanced age, and the black Lab is showing it a little bit. He has hardware in his two back legs. We had two knees put in with him, but he was a little bit heavier and now we’ve dropped his weight with what I feed him now, which is essentially fish, meat, eggs, ketones, and we give him a mushroom supplement. That’s a mushroom kind of lion’s mane and a reishi, maybe cordyceps and a few other things, and then I give them creatine monohydrate. Yeah, they’re pretty optimized as dogs. I think the big thing is that we live on a farm and they get a lot of activity too. They get two non-negotiable walks every day. I do that for me too. That’s part of my creative downtime is to do a non-negotiable walk morning and night. So they get a lot of that and they chase our animals around too.

Tim Ferriss: What are your current feelings on — let’s just say on the sardine fast, when you’re doing a week-long sardine fast, and maybe you’re so adapted at this point that you don’t experience this, but certainly when I’ve done water fasts, and even if I’m following a lower calorie ketogenic diet, I can have a really tough time sleeping, at least for a handful of days, right? I have just 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 just say it’s a sardine fast like, man, Valter Longo coming for you with a sardine fast. What supplementation makes this easier or more productive just from an adaptation perspective?

Dr. Dominic D’Agostino: Yeah, I will use sardines and also KetoStart, which is essentially the electric sodium, potassium, calcium, magnesium, beta-hydroxybutyrate and that will be used two to three times per day. At nighttime, when you go with a caloric deficit, your sympathetic nervous system is activated a little bit, especially with the water-only fast, so you get a little bit hyper or dysphoric even for some people.

Tim Ferriss: Yeah, I feel like you just ran up three flights of stairs when you’re trying to go to sleep. Yeah, it’s unpleasant.

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

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

Dr. Dominic D’Agostino: Yeah, diphenhydramine is — yeah, it’s a histamine. It’s 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 memory recall if taken acutely, but 25 milligrams, there’s no effect of that. 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. Yeah, I do think diphenhydramine and these over-the-counter sleep aids used every night by various people that are emailing me, I mean, it’s creating dementia, I think. I mean, the data’s pretty clear on that. You have an older person getting 50 milligrams every night, every week is bad.

So melatonin, magnesium, a small dose, I guess for my size, it would be a half dose of diphenhydramine, and then GABA. So you could take GABA in the form of GABA that you can get over the counter, or there’s also phenibut GABA, which I have but tend to haven’t used in a while. 

Phenibut I would just want to put out there can be a really nasty drug for people. It could be addictive. You build a tolerance real fast, and coming off of 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 two, three grams of phenibut can give you euphoria.

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 to do that. But if you’re going to fast, 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, a little bit of GABA or phenibut, diphenhydramine, magnesium. I’ve always done melatonin, five to 10 milligrams of melatonin.

Tim Ferriss: Oh, that’s a solid dose.

Dr. Dominic D’Agostino: Yeah, we went on vacation and I forgot it.

Tim Ferriss: Do you still use melatonin continually? Because I remember there was some conversation floating around the ether and never looked too closely into it because I don’t use melatonin all the time about some possibility of endocrine disruption, or can you speak to that?

Dr. Dominic D’Agostino: Yeah, I’ve been using melatonin probably when I started using creatine in 1993, the old phosphagen when I was in high school.

Tim Ferriss: Back in the day.

Dr. Dominic D’Agostino: Yeah. Yeah.

Tim Ferriss: Yeah. EAS is that way back in the day?

Dr. Dominic D’Agostino: I was a beta tester for that. Yeah, I was a beta tester when phosphagen came out. Then 1993, I think I started using creatine. I was an early adopter of creatine. But to get to your question in melatonin, I studied melatonin on the hippocampus on brain slices. You can slice the brain like a piece of bread and applied melatonin, looked at reactive oxygen species and things like that. We used it for oxygen toxicity. It wasn’t good for that because it did make the rats sleepy. Melatonin doesn’t really make me sleepy, it makes me more calm than anything else. I went on a vacation where I forgot melatonin and I slept like a baby probably because I was up every morning. The sun is the ultimate circadian synchronizer. 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 it. I love Huberman. So I was following him and he was talking about melatonin. So I went to the primary literature and I was like, “Man, he’s right. It is an endocrine disruptor and suppressor.” But then I dug into the literature more and it was not the case for humans. So there was no evidence in human. I think when he talks about it, I don’t think he references a human study, but he does reference legit studies. Yeah, Andrew Huberman is an amazing scientist and he puts out awesome information out there, but it did get me concerned about it. So I got off of melatonin, and then I confirmed that my body does make normal amounts of melatonin, so I measured that. I also confirmed that five milligrams of melatonin, if I go and measure the next day, my melatonin is off the charts, meaning that I take five milligrams at night, the next day in the morning at nine o’clock or 10 o’clock in the morning, my melatonin is super physiological.

Tim Ferriss: Is that good or bad?

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

Tim Ferriss: Milligrams?

Dr. Dominic D’Agostino: Yeah.

Tim Ferriss: Okay. Yeah. 20 to 30 milligrams.

Dr. Dominic D’Agostino: 10 milligram tablets are like the gorilla tablets for melatonin. So 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 aura ring was 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 high end of normal, which is another topic that I can get into. But the thing is that it did not trigger an endocrine response in me. I do not think there’s any data in humans, although specific animals are very sensitive to melatonin, and if you give it to them, it can cause endocrine suppression, some sex hormones. So it is a hormone. Yeah.

Tim Ferriss: Yeah. Okay. All right. Well, that’s good to know because I actually benefit from taking melatonin, but I largely cut it out because of some of the murmurs, but it does help me sleep. Is this a true statement that you do not do any fasting currently or recurrent pure water fasting, but instead do this situational sardine fasting? I mean, is that sort of 99 percent 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?

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

Tim Ferriss: Yeah, I was going to ask, I don’t know anything about shingles, so what’s happening there? Do endogenous ketones, and therefore, could you just take a bunch of shots of exogenous ketones, or what’s actually happening to have that suppression?

Dr. Dominic D’Agostino: I think we’re augmenting metabolic control of immune regulation in the context. You have the innate immune system, which is always kind of running around. 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 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 of — 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. 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? 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 and because the immune system is like an army, you have a hundred thousand 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. It becomes more vigilant, but inflammatory cytokines, chemokines kind of go down.

So I think that’s part of it in that it’s stimulating, I think cancer-specific immunity but also just generally suppressing inflammation. And that’s happening for a number of different reasons. In part due to elevating beta-hydroxybutyrate, which is an endogenous metabolite that plays a role in inflammasome suppression.

So I know guys, maybe Eric Verdin and like the guys at the Buck Institute, they had kind of looking at that. And then our colleagues, Dr. Deep Dixit 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 in Nature Medicine, 2015.

So I formulated the diet for that study and I’m 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. It’s kind of happening, but you also have to be in a good, healthy state.

If your nutritional status is low, it depends on your baseline characteristics, your therapeutic response to fasting, and I think that’s really important, especially for people who have cancer, maybe getting chemotherapy where they have compromised nutritional state in some ways, then you have to approach it very cautiously.

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

Dr. Dominic D’Agostino: 50s. Yeah. I just turned — 

Tim Ferriss: Yeah. 50s.

Dr. Dominic D’Agostino: In my 50s. Yeah.

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

Dr. Dominic D’Agostino: Yeah. It’s situational, but always probably three meals per day that I do and I did — 

Tim Ferriss: And you weigh about how much at this point?

Dr. Dominic D’Agostino: I just did a DEXA this weekend, actually. I did a DEXA two weeks ago and I did another one after I got off creatine and then did another one. So I just hover right at 218 to 220 and body fat last was 9.4 so — 

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

Dr. Dominic D’Agostino: This morning it was eggs and chub mackerel and that’s it. So basically just protein and fat. And for lunch, I typically have beef, chicken, or fish, usually fish. Lately I’ve been eating a David bar. So Peter sent me some of those and I have kind of 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. So I’ve been doing that.

And then for dinner, we went out for Mexican the other night and last night hosted Mary Newport and usually have beef, chicken, or fish with a vegetable, like always broccoli. I’m a huge fan of broccoli. It worked. I could eat three pounds of broccoli has no gas or bloating effect for me at all. So somehow my body is just broccoli. My body loves broccoli, so our dogs do too. So I give them a little bit of that, salads, but usually about a pound of beef, chicken, or fish at dinner. So that’s my big meal.

Tim Ferriss: Wow.

Dr. Dominic D’Agostino: And over the years we have transitioned. Instead of eating at 7:00, we eat at 5:00 — 5:00 or 5:30, so we eat earlier. And then I do physical activity after that. So if it’s squats or deadlifts, I have to do it before I eat. But for pressing movements and activity, I do after that. And I do farm work for an hour or two in the evening after that.

And I typically have, every other night, wine. So I’ll have a bit of wine, lower alcohol, non-sugar Dry Farm wines, which has less than one gram of sugar. I would never drink wine without doing some kind of activity after. If wine at nine o’clock and then try to go to bed, I would never do that because I see that on my aura. But if I do a glass of wine in some form of physical activity, we always do an evening walk. I think I sleep better, I think.

I don’t do two glasses, but I just do one glass. I know the current consensus on alcohol is that it’s — but I would push back because none of that is specifically studying wine. If you go to the studies on wine, 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. So it makes your blood less viscous. And that is well known. I observed it and was like, “Something’s going on here.” And then I went to PubMed and it’s actually well known. I didn’t know it at the time that it decreases platelet aggregation, so less potential for clotting, for stroke and things like that.

So I think that may factor into — we just got back from Greece and they had the ouzo and everything, then we went to 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 and they’re all in their 90s and hundreds, they’re in the blue zone. So it’s a universal characteristic. That’s my protocol.

Tim Ferriss: Well, there may be a genetic component too. I remember there was this book that was like, Why French Women Don’t Get Fat or something and way back in the day, I remember before his passing, I was talking to Charles Poliquin, he’s like, “Yeah, MTHFR.” He is like, “That’s why. It’s none of the other stuff in the book.” And he mentioned a couple of other things, like, who knows? I think — 

Dr. Dominic D’Agostino: Yeah. Living by the water, activity, and social. So the social interaction is probably the biggest lever. I mean, I just see them, they’re all out and about walking around and yeah, that’s probably the biggest lever. And getting sun. So they’re outside in the sun, everybody, it’s multifactorial, but it doesn’t seem to be hurting them, let’s put it that way.

Tim Ferriss: If someone is, let’s just say they want to test out the ketogenic diet, and certainly they will note, they’ll be like, “Wow. Dom doesn’t eat a lot of vegetables except for a pound of broccoli at dinner — “

Dr. Dominic D’Agostino: I can tolerate that but I have, probably it comes out to 30 to 40 grams of fiber a day, which is pretty high, but that’s broccoli. And I usually have a small apple too. Sometimes we have apples and then a cup of wild blueberries. So it comes out to about 30 grams. That’s maybe a higher, sometimes 10 or 20 but I try to shoot for about 30 grams of fiber.

Tim Ferriss: Yeah. Got it. Okay. If people want to kickstart the ketogenic diet, any tips for getting over the hump in the beginning? It can sometimes have a bit of a hard time before they kind of click over. I’m not sure. For me, it’s like once I’m above 1.2 millimolar I feel totally fine. That’s just me on a Precision Xtra. But for people who are looking to give it a shot and maybe haven’t given it a shot, any tips for novices?

Dr. Dominic D’Agostino: Yeah. 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 going to start your ketosis experiment or whatever you’re doing that morning, getting out in the sun, staying well hydrated, you could take MCT and also ketone electrolytes like 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 got to deplete liver glycogen and ramp up beta oxidation fat enzymes.

And then 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 and the tissues that are able to utilize and leverage those ketones for energy over time.

Tim Ferriss: How long does that adaptation take, would you say?