2025-09-06 04:58:59
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本文是蒂姆·费里斯对多米尼克·达戈斯蒂诺博士（佛罗里达大学莫尔萨尼医学院分子药理学和生理学系终身副教授，人类与机器认知研究所访问高级研究科学家）的访谈实录摘要。达戈斯蒂诺博士的研究重点是针对神经系统疾病、癌症和人类表现优化开发和测试营养策略和基于代谢的疗法。
访谈主要内容包括：
总而言之， 这篇访谈涵盖了酮生饮食、外源性酮体、断食、补充剂、血脂管理、以及这些方法在阿尔茨海默病、癌症和精神疾病治疗中的应用等多个方面，提供了许多宝贵的见解和建议。 达戈斯蒂诺博士强调了个性化和基于证据的治疗方法的重要性。
Please enjoy this transcript of my interview with Dr. Dominic D’Agostino (@DominicDAgosti2), a tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine and a Visiting Senior Research Scientist at the Institute for Human and Machine Cognition.
He teaches medical neuroscience, physiology, nutrition, and neuropharmacology, and his research focuses on the development and testing of nutritional strategies and metabolic-based therapies for neurological disorders, cancer, and human performance optimization. His work spans both basic science and human clinical trials.
He has a strong personal interest in environmental medicine and enhancing the safety and resilience of military personnel and astronauts. In this capacity, he served as a research investigator and crew member on NASA’s Extreme Environment Mission Operations. His research has been supported by the Office of Naval Research, the Department of Defense, the National Institutes of Health, private organizations, and nonprofit foundations.
He earned his B.S. in Nutritional Science and Biological Sciences from Rutgers University in 1998, followed by a predoctoral fellowship in Neuroscience and Physiology at Rutgers and the University of Medicine and Dentistry of New Jersey. He then completed postdoctoral training in Neuroscience at Wright State University’s Boonshoft School of Medicine in 2004 and at University of South Florida Morsani College of Medicine in 2006.
Transcripts may contain a few typos. With many episodes lasting 2+ hours, it can be difficult to catch minor errors. Enjoy!
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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.
Tim Ferriss: Lots of texts. And why not? This is one of the text threads I could probably actually make public in my life without some type of mutually assured destruction with many of my friends.
I have been revisiting everything ketogenic and certainly looking at exogenous ketones for a number of reasons.
And one of which we were chatting a little bit before recording, is that I have a number of relatives who are deteriorating from neurodegenerative disease, including Alzheimer’s. And one of them is 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.
And the production of — if you look at that protein for that decreases over time, as does the catalytic activity of that enzyme over time. So we know that. And then there’s neuroinflammation, there’s a vascular component. So all these things kind of contribute to metabolic dysregulation, but also a big driver is neuroinflammation.
And I do believe, as does Dr. Mary Newport, who is the author of that paper 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. So Epstein-Barr virus, cytomegalovirus, herpes simplex virus. We do know — yeah, HPV — know can contribute to things like —
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?
Dr. Dominic D’Agostino: 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 percent higher after two weeks in a rat, for example.
I think the point for most people is that if you start fasting or ketogenic diet and to avert the keto flu, you want to hydrate, get in electrolytes and also elevate ketones as much as possible. And to do that with MCT, if you can tolerate it or ketone electrolytes. I would not be guzzling a ketone ester because you’re going to spike ketones up, you’re going to inhibit your own ketone production, especially if it’s a dose-dependent thing. But my advice would be low intensity cardio, hydrate electrolytes, and then small amounts of ketone electrolytes with MCT. So MCT will stimulate your own Ketone production too so it kind of —
Tim Ferriss: Yeah. 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?
Dr. Dominic D’Agostino: 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 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 10, 20 upwards of 30 grams and work by Stephen Cunnane actually showed that if you take MCT in the context of caffeine or coffee, you can boost your ketone production by 20 or 30 percent. 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 out —
Tim Ferriss: What type of powder do you like to use?
Dr. Dominic D’Agostino: People send me things but actually the powder that I have is actually, it’s Keto Brainz. It’s MCT powder, Alpha GPC theanine, and it has lion’s mane mushroom. 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 on the first day of fasting. Alpha GPC, if I take too much of it gives me a headache so I only do one or two.
Tim Ferriss: Yeah. I got to be careful with Alpha GPC. I also get a headache.
Dr. Dominic D’Agostino: Yeah. Oh, really? Okay.
Tim Ferriss: Yeah.
Dr. Dominic D’Agostino: So you’re the first one. I don’t know if I was creepy. But yeah, when I first got Alpha, when I first got Keto Brainz and did like six scoops and I was like, “Oh, my God. I got to have a bad headache.” But one or two scoops.
Tim Ferriss: I love that your first go was six scoops. If I just want it off the shelf, MCT oil, because I feel like there’s only so many medicinal mushrooms that I can cram into my diet also, but no offense to the mushrooms, but I actually have some interesting thought on some of them additional mushrooms. Some of them are very strongly antiviral and immunomodulatory. And so when I’ve talked to a number of very credible mycologists, so like, “Yeah. It’s probably best not to take that stuff every day. You should cycle on and off.”
Dr. Dominic D’Agostino: Yeah.
Tim Ferriss: But if I just wanted MCT, for purposes of travel, because MCT liquid can create such a goddamn mess when you’re traveling.
Dr. Dominic D’Agostino: And their pants too. Yeah.
Tim Ferriss: And in your pants too. And for people who are novices do not do creatine, caffeine and MCT oil out of the gate. You’ve got to prove to yourself that you can handle that.
Dr. Dominic D’Agostino: Unless you’re constipated.
Tim Ferriss: It depends on the airplane. Yeah. What other just MCT oil, powders might you recommend or have you used?
Dr. Dominic D’Agostino: Quest MCT powder. I think you can get that in like CVS and Walgreens now too. And Amazon, just the Nutricost. So I bought just straight up MCT. They also have a C8 powder and I’ve tested both of them wearing a continuous ketone monitor. And I saw a nice elevation over time and then I combined that MCT powder with KetoStart, and basically I was in ketosis for half the day. So just dosing twice a day with that.
Tim Ferriss: I mean, I’m going to break my own rules here, but I’ve done enough test drives. I’m about to go to, not super high altitude, but I’ll be coming from sea level to about 8,000 feet on average and we’re going to be doing a lot of intense exercise. So maybe my morning dose of coffee, which I’m sure will be some shit instant coffee, but it’s going to taste delicious when you’ve been freezing your balls off all night, maybe I’ll add some KetoStart and MCT powder to that because those would be easy to travel with I would imagine.
Dr. Dominic D’Agostino: Super easy. Yeah.
Tim Ferriss: I’m not sure how KetoStart tastes in coffee.
Dr. Dominic D’Agostino: No. No. Don’t do that. No. They have KetoSpike coffee. So Audacious Nutrition has KetoSpike cocoa, coffee and tea. So in the afternoon I don’t do caffeine after 12:00. So I will brew. I’ll just boil hot water and just put, and the KetoSpike coffee is a good Colombian coffee and it just has the BHB electrolytes in it. So I’ve been doing that.
Tim Ferriss: Yeah. All right. Cool. I’ll check it out. 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. If you get rid of Akkermansia or a few other strains.
Dr. Dominic D’Agostino: Yeah. Yeah.
Tim Ferriss: Lo and behold, doesn’t really work. 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?
Dr. Dominic D’Agostino: Yeah. I think 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 that’s largely resistant to the standard of care. So way much to talk about. It was actually like a 200 plus page paper that was going to be submitted. And we had to 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 its open access. So that has stimulated research at different places. But I’m excited about research that we’re doing with Moffitt Cancer Center, which is the largest cancer center.
We’re one of the largest in Florida, a tier one cancer center where we’ve got various projects, glioblastoma, maybe a breast cancer, but also lung cancer. So was specifically using ketone metabolic therapy to augment immune therapy, specifically the checkpoint inhibitors. And that has to do with what I described about ketone metabolic therapy, specifically beta hydroxybutyrate activating the adaptive immune system and making checkpoint inhibitors, which is a class of drug that’s, and CAR T therapy.
So now they actually have a study with CAR T therapy and checkpoint inhibitors. So ketones tend to expand the T-cells that are associated with CAR T therapy. So just kind of enhancing that therapy. And with the checkpoint inhibitors, it tends to just enhance cancer specific immunity that is augmented by PD1 inhibitors. So they’re specifically studying that.
So I’m excited about that. So that’s on the cancer front. And then we can jump, if you have no questions, I could jump to other, the Alzheimer’s, the metabolic psychiatry.
Tim Ferriss: Let’s talk, yeah, let’s talk about those. Let’s hop to the Alzheimer’s and metabolic psychiatry. Would love to dive into that because it’s in front of mind for me. And just as a, 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 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’ve got to say, psychologically from the standpoint of sustained focus and mood, has been just kind of mind-blowing, to be honest. So I’d love to hear any and all thoughts on Alzheimer’s metabolic psychiatry front.
Dr. Dominic D’Agostino: Yeah. So metabolic psychiatry, I would encourage people to listen to Chris Palmer who you, I kind of put on your radar. I don’t know if you remember. I sent you the link to the metabolic —
Tim Ferriss: Yeah. Yeah. Yeah. Appreciate that.
Dr. Dominic D’Agostino: So I was like, “You’ve got to watch this, Tim. It’s going to change sort of the landscape of psychiatry.”
Tim Ferriss: 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.
Dr. Dominic D’Agostino: The Metabolic Health Summit, which is part of Metabolic Health Institute, which is you can get educational credits through that. So yeah. We brought Chris in and it was such a compelling story and he treated Matt Baszucki. So Matt Baszucki is the son of Jan and David Baszucki, because he quickly went into durable remission.
Tim Ferriss: Who are well-known from Roblox.
Dr. Dominic D’Agostino: Well-known from Roblox. Yeah. Sort of billionaire philanthropists that are changing, actually, ultimately maybe the standard of care for psychiatry. And I think they single-handedly are funding metabolic psychiatry with Shebani 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. Ally 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.
Tim Ferriss: How do you spell the name of the app?
Dr. Dominic D’Agostino: MetPsy is M-E-T-P-S-Y, right? M-E-T-P — I’m trying to think.
Tim Ferriss: Yeah. Better at the science than the branding, I guess.
Dr. Dominic D’Agostino: Yeah. M-E-T-P-S-Y.com, MetPsy. So I think 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’re 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 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 in the MCT. We were gavaging them and she was —
Tim Ferriss: What does gavage mean?
Dr. Dominic D’Agostino: Oh, so it’s basically like tube feeding the animal. So instead of mixing the ketones in with the rat chow, they eat it. And so it’s taking a syringe and based on the weight of the animal, you pull in the amount of ketone ester or this case, it was MCT and ketone salts. We did the esters too, and it did have an anxiolytic effect, anxiety reducing effect.
And then you administer that to the animal and what we are 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.
So it was just, “Well, this is great. We can handle the animals easier and get them into the chamber without them trying to bite us.” And my wife’s a behavioral neuroscientist and she was like, “Well, we should do some behavioral studies because I think there’s something here.” So we did elevated plus maze. So in this case, the animals can go inside a closed little cave or it can come out into the open arm in the elevated plus maze, which is exploratory behavior. 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 like “Anxiolytic Effect of Ketone Supplementation.” We published I think three papers and showed the mechanisms and stuff too. So that was an early paper 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.
Like if you look at, I don’t know, Xanax or other things in elevated plus maze, it was like, yeah, 20 or 30 percent 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 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.
So the protein levels were higher, essentially showing that your brain converts more glutamate, which is anxiety evoking, like wakefulness enzyme. It’s converting more glutamate, which is excitatory to GABA, which is brain stabilizing. That’s like your chill, like alcohol.
Tim Ferriss: It’s what you take before bed. Yeah.
Dr. Dominic D’Agostino: Yeah. Yeah. So that was, and 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 FTG PET scan on someone that’s depressed, it shows glucose type of metabolism.
One thing to mention, I think an important thing to mention in the context of bipolar, you can have a hyper glycolytic effect. And Dr. Iain Campbell from Edinburgh University has published some elegant reviews and is doing some work on that front in 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.
Tim Ferriss: Yeah. Get more anxious.
Dr. Dominic D’Agostino: A sweet spot, maybe one to two. I wouldn’t go above three, probably 1.5 to 2 millimolar range. That seems to be a level of ketones that safely does not produce a metabolic acidosis. So what we do see that when you get above three, it starts to change blood pH.
So it seems to maybe overwhelm the respiratory and renal compensation and your kidneys put out by carb 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 that acidification of the blood.
So it was just an overwhelming, so ketones are acidic and when you deliver it into an ester form, there’s nothing to buffer that. When you give a ketone salt, the electrolytes are kind of like a buffer for that.
So you have the metabolic effect, you have the changing of the brain neuropharmacology, and in bipolar, you throw anti-epileptic drugs at bipolar patients, and it’s largely ineffective. So it makes sense that a ketogenic therapy would work for that.
And the neuroinflammation too. So things that trigger neuroinflammation, and that could be an infectious agent, that could be a virus, that could be T. Gandhi. I mean, it could be like a bacteria. There’s 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 in synergy to produce that. It’s not one mechanism. When we published the NLRP3, I got requests from Genentech and various pharmaceutical companies to go there and give a talk on the mechanism so they could drugify. And I would throw up a big flow chart of all these mechanisms, and I think they would get frustrated. And it was like, “Well, tell us the mechanism so we can make a drug out of this.”
But I think the beauty of ketogenic therapies is that it’s pleiotropic, right? Which means it’s many mechanisms working in synergy. You could say Metformin, GLP1 drugs are working through metabolism, and they’re kind of pleiotropic also.
Tim Ferriss: Do you use either of those?
Dr. Dominic D’Agostino: I’ve experimented with metformin, and that is a way for some patients to increase their ketone levels. So we’ve published on metformin from the context of that it increases mitochondrial oxidative stress, so it’s a weak toxin to deliver. Most people didn’t know that when we were studying that. And I think metformin can enhance, increase AMP kinase, maybe increase insulin sensitivity and has a very weak effect at reducing blood glucose if you have a normal glucose. But it does tend to increase ketones a little bit.
And I think there’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 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 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.
Tim Ferriss: You mentioned on your wrists.
Dr. Dominic D’Agostino: Yeah.
Tim Ferriss: Am I making that up? Yeah.
Dr. Dominic D’Agostino: Yeah, it tended to correlate with that. And then I got off of it. 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. 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 concerns me. So I have it, but I don’t use it.
Tim Ferriss: May I ask you a quick question just related to metformin for a second?
Dr. Dominic D’Agostino: Mm-hmm.
Tim Ferriss: Is I was looking back on notes on prior conversations, and I think you mentioned Dale Bredesen on an episode of STEM-Talk. But specifically, for folks with the APOE4 genotype, like yours truly, do you think metformin may be more interesting? But let’s assume in my case, let’s call me metabolically healthy. So maybe yes, maybe no. I remember a long time ago having a chat with Nav Chandel, I want to say, I might be getting the name slightly wrong, from Northwestern. He was like, “Ah, if you’re doing a bunch of exercise and getting your diet straight,” he’s like, :I don’t think that you’re going to see a lot of benefit.” But he didn’t have the APOE4 information on me. And then berberine I have written down for some reason. I’m just wondering if there’s anything to either of those for APOE4 specifically?
Dr. Dominic D’Agostino: 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 averse to 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 have type 2 diabetes that are in their 40s, 50s, and 60s. And it will reduce your incidence of cancer, specific kinds of cancers like pancreatic cancer. I think the data’s good on that, and I think it’ll shift metabolic biomarkers that we have historically good data on in the right direction.
Tim Ferriss: Does metformin do anything that taking a GLP-1 like tirzepatide or something doesn’t do? I’m just wondering if it’s an additive effect.
Dr. Dominic D’Agostino: Well, they’re totally different drugs. But people who take metformin and one gram to two gram dose, two grams is high. But when they do that, they tend to eat less calories. So it does create —
Tim Ferriss: I see.
Dr. Dominic D’Agostino: A little bit of, for me, GI issues. Maybe a little bit of loose stools in the beginning, and that could be factoring in there. So it does tend to improve metabolic biomarkers across the board if you’re trending towards metabolic dysregulation or metabolic syndrome. A GLP-1 works essentially through caloric restriction and just increasing appetite through 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 going to change the whole landscape of metabolic therapies. And I think —
Tim Ferriss: Yeah, seems to have a — from what I’ve read, and maybe I don’t want to over interpret here, but potential neuroprotective effects, right?
Dr. Dominic D’Agostino: Yeah.
Tim Ferriss: So that’s the main reason I would be looking at potentially low-dose GLP-1.
Dr. Dominic D’Agostino: Yeah, 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.
Tim Ferriss: Yeah. And do you take berberine or is it superfluous because of the diet, you don’t really need anything to lower glucose?
Dr. Dominic D’Agostino: Yeah, I’ve experimented with it and it did decrease my glucose in response to a meal. I did dihydroberberine, which is a more potent version of berberine. But interestingly, after about a week, I started to get a headache. And then I got off — I don’t know if it has a vasodilate or maybe it impacts liver metabolism in a way that was — who knows? Maybe decreasing my caffeine metabolism. These are things that come to mind. I am a fast metabolizer of caffeine.
Tim Ferriss: Yeah, you still consume quite a bit of coffee. Yeah?
Dr. Dominic D’Agostino: I do. I fill this up. So this is Metabolic Mind. Actually, Metabolic Mind is part of the Baszucki’s Group metabolic psychiatry. So I have —
Tim Ferriss: All right. So you’re holding up —
Dr. Dominic D’Agostino: I do one of these per day. Yeah.
Tim Ferriss: What is that? That’s like 16 to 20 ounces, something?
Dr. Dominic D’Agostino: 24. I think about 24 ounces.
Tim Ferriss: 24 ounces.
Dr. Dominic D’Agostino: Yeah.
Tim Ferriss: Yeah. Okay. It’s metal. It looks like a thermos, basically.
Dr. Dominic D’Agostino: Yeah.
Tim Ferriss: Okay, got it.
Dr. Dominic D’Agostino: Relatively strong coffee. I do that and pour one cup, and I usually finish it about now and no caffeine. Yeah, caffeine at four or 5:00 p.m. is probably going to disrupt sleep latency and sleep timing. But yeah, GLP-1, amazing class of drug. We’re covering that now at med school in our nutrition courses we’re teaching.
And then the SGLT-2 inhibitors are also a pretty interesting class of drug that I think has a lot of potential. So if someone trying to bring their glucose levels down, for example, trying to get that — these are prescription drugs. So of course, go to your doctor. But that’s a pretty good lever to pull, especially if someone’s resistant to dropping their carbs, if they’re eating some carbs.
Tim Ferriss: Well, yeah.
Dr. Dominic D’Agostino: Yeah, GLP-1 and SGLT-2 are great.
Tim Ferriss: 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 to comply with ongoing. And you can’t have, necessarily, 24/7 supervision to prevent them from eating bagels. Which maybe you can do. Just 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?
Dr. Dominic D’Agostino: Yeah. Well, I think ketones shine there. The D, both the D and the L, beta-hydroxybutyrate. So that’s first and foremost. And we are doing research with NAD.
Tim Ferriss: These injectables?
Dr. Dominic D’Agostino: 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 Alzheimer’s. So there’s NR, nicotinamide riboside, nicotinamide mononucleotide. So the problem with those is that the liver is pretty greedy and takes a lot of that. And then the muscles are — 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 preclinical animal model work in our labs. 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. So NAD, people may know NAD is basically a substrate for the sirtuins and various enzymes. There’s 500 different enzymes. So a class of proteins that are called sirtuins rely heavily on NAD. So this is an important thing to consider.
Tim Ferriss: And this sirtuin is just for folks who are like, “Have I heard that before?” I want to say back in the day when resveratrol was everywhere in the news and super mouse and all you have to do is drink wine, but maybe 20 cases of wine. All of that stuff with trans-resveratrol, that’s where the sirtuins popped up?
Dr. Dominic D’Agostino: Yeah.
Tim Ferriss: Yeah.
Dr. Dominic D’Agostino: The sirtuins are really heavily reliant on NAD. And NAD is involved in everything that we study. So five 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?
Tim Ferriss: Yeah.
Dr. Dominic D’Agostino: Reductive stress means that the NAD to NADH ratio would drop. So you get more NADH relative to NAD. That could be problematic because the availability for NAD may not be there for sirtuins and other — so a redox balance formulation.
Tim Ferriss: I see.
Dr. Dominic D’Agostino: So that feeds back. I don’t want to get too far into that, but I think it’s 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 a 31-phosphorus MRS if you have a four or 7-Tesla system like Harvard has. So this is one way to look at like phosphocreatine, ATP, pH, and also NAD to NADH ratios. So this is one way. Actually, we do have that at our Alzheimer’s center, and that’s on the list of to-dos, to look at this reductive kind of stress thing.
So NAD, I’m just throwing that out there. I think there’s a lot of criticism towards NAD now. That happens from time to time. Because moving science from cell-based systems to animal models to humans, there’s a massive learning curve there. We’re learning that with some of the ketogenic agents. We’re just at the cusp of really understanding the dosage, timing, scheduling and form of exogenous ketones that’s optimal. And it’s going to vary dependent upon the situation that you’re trying to treat. And also individually, I think people are going to have. So that opens up this whole personalized precision ketogenic metabolic therapy, or the NIH is throwing a lot of money on personalized medicine based on genetic markers, and based on biomarkers that some of them that you can measure in real time. Like continuous ketone monitoring, continuous glucose, and maybe lactate monitoring.
Tim Ferriss: That’s cool. Yeah, that’s very cool. One last supplement question because I’m looking back at past notes. And I’m probably going to mispronounce this. But idebenone, more observable version of CoQ10. Maybe that’s a fair description. Maybe it isn’t. Do you still take that or no longer?
Dr. Dominic D’Agostino: Yeah, 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 CoQ10 in it. But if you’re on a statin, if you’re on metformin and other drugs, they could potentially deplete you. And then CoQ10 has a solid track record for cardiovascular health. So idebenone is a drug stabilized form of that. And then when I discussed that on your podcast, that was in the context of something called the Deanna Protocol. The Deanna Protocol is after Deanna Tedone. 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’re just emailing me yesterday. So Deanna Tedone had advanced ALS and then has been stabilized using the Deanna Protocol, which is included at the time, idebenone. But I think it became a drug.
So idebenone became the standard of care for Friedrich’s ataxia, and then you couldn’t get it on Amazon. But I think ubiquinol, or CoQ10, it would be a good substitute for that. And I don’t use it myself. But I think that’s if you’re older in age and you have cardiovascular heart problems in your family. However, with that said, we actually ubiquinol, we did high doses in our animal models, and we saw some kidney toxicity. We had some animals die. And —
Tim Ferriss: Oh, Jesus. It’s like —
Dr. Dominic D’Agostino: But that was rodent models we used. Again, we use really high dose for oxygen toxicity. We’ve looked at everything under the sun. But it was this unexpected side effect. Then I went to the literature and showed that it’s such a powerful antioxidant in some ways, and it maybe was concentrating in the kidneys. So there was a couple of 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 more mitochondrial specific. We’re using more potent forms of the CoQ10. So it may not be similar to the commercially available forms.
Tim Ferriss: What are the other supplements on that short list? You said four or five supplements. What are the other ones?
Dr. Dominic D’Agostino: That I take. Yeah, so creatine monohydrate would be the staple thing that I’ve used since I was 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. But creatine, for Alzheimer’s disease, we didn’t talk about it. But a dosage of 10 to, even if you’re larger, 20 grams. And that’s not a misspeak there, 20 grams of creatine. Spread out maybe five grams, three to four times a day for advanced Alzheimer’s, if you can tolerate it. [inaudible 02:20:12]
Tim Ferriss: I’m taking 20 grams today just because I didn’t get very good sleep last night. I just find it to help with recovering from, let’s call it sleep deprivation. But yeah, got to watch the split dosing.
Dr. Dominic D’Agostino: Yeah. Vitamin D, but you have to measure that in your lab. So you want that to be — you don’t want it over a hundred, right? So you want vitamin D levels that are probably like 60 to 80, would be a good level of vitamin D 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, I basically stay in the mid-60s to 70s. So vitamin D and melatonin, I think is a great neuroprotective antioxidant supplement to take at nighttime. And I don’t take omega-3 supplements, but just because I did — Rhonda Patrick connected me with the omega-3 guy and I tried the OmegaQuant. My DHA levels and EPA levels were off the charts.
Out of curiosity, I got off of fish for 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 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 one of the go-to brands. I’m not paid to say that or anything, but they’re legit. But you could do the OmegaQuant test. 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. There’s so much data emerging on that, that I think probably within the next 10 years, when you get comprehensive metabolic panel, CBC, DHA, and EPA will probably be added to that.
Tim Ferriss: All right, Dom. Well, we could go for many more hours, I am sure. But let’s start to land the plane for this round. And I do want to ask, of course, if there’s anything else that you’d like to mention or point people to. Anything you’d like to recommend, formal complaints you’d like to lodge? People you’d like to secure in front of a large audience? No, I’m kidding. But anything that you’d like to say or point people to? Any resources, anything that you’re up to, where they can find you? Anything at all?
Dr. Dominic D’Agostino: Yeah, I just want to mention KetoNutrition. That’s our informational website, ketonutrition.org. And we’ve hosted a conference where many people, 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 run by three of us. My colleagues, Dr. Angela Poff and Victoria Field run that show. I 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 hormone optimization and things like that. So I would 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 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. We have some really interesting studies on Alzheimer’s and a lot of other — so hopefully in the next year be able to share some of that preclinical animal model work. Hyperbaric oxygen, so we have a 28 million study —
Tim Ferriss: That’s huge.
Dr. Dominic D’Agostino: At the University of South Florida. I am just peripherally involved in that or 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 for that. But I —
Tim Ferriss: It’s a good way to put it. The muddy waters.
Dr. Dominic D’Agostino: Yeah, I’ve 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 at 40 to 60 sessions, and 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 and 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, so their ears pop a little bit. And I don’t know every — it’s blinded. People don’t know even what they’re getting. If you question them, they don’t know if they’re getting hyperbaric oxygen. But I do think that oxygen is a powerful drug, and I am excited about that research, if you ask me. I’m excited if it proves it or disproves it. I think we’re going to get an unambiguous answer to this question about hyperbaric oxygen for a traumatic brain injury, and people with and without post-traumatic stress syndrome. So 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. If you’ve had a traumatic brain injury, your risk of oxygen toxicity seizure would increase because —
Tim Ferriss: Now, this is pretty specific to military? Or what are we talking about?
Dr. Dominic D’Agostino: Yeah, they’re all vets. And if they do find out that they get a beneficial effect from that, then after the experiment, they’ll be able to get that for free service. So there’s six — like quarter to half a million dollar hyperbaric chambers. So the hard shell chambers, there’s six of them in this facility. And it’s the most elaborate hyperbaric oxygen therapy study that has ever been done. And it’ll answer the question about the efficacy. So that’s ongoing now, and I’m excited about that. I’m also excited about potentially using that facility, because it’s next to the Moffitt Cancer Center for patients that are undergoing various cancer treatments that could be enhanced with hyperbaric oxygen therapy. Because it augments the immune system and it’s actually an FDA approved application for radiation necrosis. So if you’ve had radiation, then your insurance would actually cover it. But it can enhance certain therapies that we’re working on now. Yeah.
Tim Ferriss: Yeah. Amazing.
Dr. Dominic D’Agostino: Yeah.
Tim Ferriss: All right. Well, we will link to all of those things in the show notes as always. And I encourage people to check all of those out. I’m going to check all of them out. And Dom, thanks so much for the time, as always.
Dr. Dominic D’Agostino: Nice to see you.
Tim Ferriss: I took a ton of notes. I have maybe even more questions on top of that for more text messages. Sorry in advance. And so nice to see you again.
Dr. Dominic D’Agostino: Yeah. You too, Tim. Yeah, thank you for having me on. I appreciate it.
Tim Ferriss: Yeah. Absolutely. And folks, show notes can be found at tim.blog/podcast. Just search Dom or Dominic and a lot of them will pop up. Just look for the most recent. And until next time, be a bit kinder than is necessary. It matters, it helps, to others and to yourself. And as always, thanks for tuning in.
The post The Tim Ferriss Show Transcripts: Dr. Dominic D’Agostino — All Things Ketones, How to Protect the Brain and Boost Cognition, Sardine Fasting, Diet Rules, Revisiting Metformin and Melatonin, and More (#825) appeared first on The Blog of Author Tim Ferriss.
2025-09-03 23:10:04
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本文总结了蒂姆·费里斯秀（The Tim Ferriss Show）第825期对多米尼克·达戈斯蒂诺博士（Dr. Dominic D’Agostino）的访谈。达戈斯蒂诺博士是南佛罗里达大学莫尔萨尼医学院分子药理学和生理学系的终身副教授，也是人类与机器认知研究所的访问高级研究员。他的研究重点是针对神经系统疾病、癌症和人类表现优化开发和测试营养策略和基于代谢的疗法。
访谈涵盖了酮症、大脑保护、认知增强、沙丁鱼禁食、饮食规则、二甲双胍和褪黑素等多个方面。 达戈斯蒂诺博士讨论了以下主题：
访谈还提到了许多相关的研究、产品、机构和人物，例如：Mary Newport 医生、Richard Veech 博士、Peter Attia 博士等。 总而言之，这是一次关于酮症、代谢健康和长寿的全面而深入的讨论。
Dr. Dominic D’Agostino (@DominicDAgosti2) is a tenured associate professor in the Department of Molecular Pharmacology and Physiology at the University of South Florida Morsani College of Medicine and a Visiting Senior Research Scientist at the Institute for Human and Machine Cognition.
He teaches medical neuroscience, physiology, nutrition, and neuropharmacology, and his research focuses on the development and testing of nutritional strategies and metabolic-based therapies for neurological disorders, cancer, and human performance optimization. His work spans both basic science and human clinical trials.
He has a strong personal interest in environmental medicine and enhancing the safety and resilience of military personnel and astronauts. In this capacity, he served as a research investigator and crew member on NASA’s Extreme Environment Mission Operations. His research has been supported by the Office of Naval Research, the Department of Defense, the National Institutes of Health, private organizations, and nonprofit foundations.
He earned his B.S. in Nutritional Science and Biological Sciences from Rutgers University in 1998, followed by a predoctoral fellowship in Neuroscience and Physiology at Rutgers and the University of Medicine and Dentistry of New Jersey. He then completed postdoctoral training in Neuroscience at Wright State University’s Boonshoft School of Medicine in 2004 and at University of South Florida Morsani College of Medicine in 2006.
Please enjoy!
Listen to the episode on Apple Podcasts, Spotify, Overcast, Podcast Addict, Pocket Casts, Castbox, YouTube Music, Amazon Music, Audible, or on your favorite podcast platform. Watch the conversation on YouTube. The transcript of this episode can be found here. Transcripts of all episodes can be found here.
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KetoNutrition.org | Facebook | Twitter | University of South Florida
The transcript of this episode can be found here. Transcripts of all episodes can be found here.
“I think the beauty of ketogenic [therapy] is that it’s pleiotropic, right? Which means it’s many mechanisms working in synergy.”
— Dr. Dominic D’Agostino
“I think the best way to measure to suggest you’re in autophagy is a glucose ketone index after a period of fasting.”
— Dr. Dominic D’Agostino
“About 30 percent of the population hyperabsorbs cholesterol.”
— Dr. Dominic D’Agostino
“HSCRP is a better indicator of cardiovascular disease than LDL cholesterol. We know that now. [No one would believe it] If someone said that 10 years ago.”
— Dr. Dominic D’Agostino
“I wouldn’t go above three. Probably 1.5 to 2 millimolar range. That seems to be a level of ketones that safely does not produce a metabolic acidosis.”
— Dr. Dominic D’Agostino
“When we published the NLRP3, I got requests from Genentech and various pharmaceutical companies to go there and give a talk on the mechanism so they could drugify. And I would throw up a big flow chart of all these mechanisms, and I think they would get frustrated. And it was like, ‘Well, tell us the mechanism so we can make a drug out of this.'”
— Dr. Dominic D’Agostino
“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.”
— Dr. Dominic D’Agostino
“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 nineties and hundreds, they’re in the blue zone. So it’s a universal characteristic.”
— Dr. Dominic D’Agostino
Want to hear the last time Dom was on the show? Listen to our previous conversation in which we discussed disease prevention, longevity, cancer, ketogenic diet mastery, the detoxifying effects of ketosis on pre-cancerous cells, how to jumpstart daily ketogenic cycles, “cheat” meals, and much more.
The post Dr. Dominic D’Agostino — All Things Ketones, How to Protect the Brain and Boost Cognition, Sardine Fasting, Diet Rules, Revisiting Metformin and Melatonin, and More (#825) appeared first on The Blog of Author Tim Ferriss.
2025-08-29 14:38:33
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本文是蒂姆·费里斯对凯文·特雷西博士（Feinstein研究所所长兼首席执行官，迷走神经研究先驱，《迷走神经：迷走神经的新科学及其疗愈反射的运用》作者）的访谈记录摘要。
访谈要点：
总而言之，访谈探讨了迷走神经刺激疗法的最新进展、作用机制以及应用前景，并强调了进一步研究的重要性。 特雷西博士分享了多个引人入胜的案例，展现了该疗法在治疗炎症相关疾病方面的巨大潜力。
Please enjoy this transcript of my interview with Dr. Kevin Tracey (@KevinJTraceyMD), president and CEO of the Feinstein Institutes for Medical Research at Northwell Health, a pioneer of vagus-nerve research, and author of the recent book The Great Nerve: The New Science of the Vagus Nerve and How to Harness Its Healing Reflexes.
His contributions include identifying the therapeutic action of monoclonal anti-TNF antibodies and discovering the specific reflex control of immunity by the nervous system, called the “inflammatory reflex.” These discoveries launched the new scientific field called bioelectronic medicine, which investigates the therapeutic applications of vagus-nerve stimulation to cure disease.
Dr. Tracey, a neurosurgeon, pursued studies of inflammation after the mysterious death, from sepsis, of a toddler who was in his care. His lab has since revealed molecular mechanisms of inflammation and identified the use of vagus-nerve stimulation to treat it. An inventor on more than 120 US patents and the author of more than 450 scientific publications, he is among the most highly cited scientists in the world. He co-founded the Global Sepsis Alliance, is the author of Fatal Sequence, and is a national and international lecturer.
Transcripts may contain a few typos. With many episodes lasting 2+ hours, it can be difficult to catch minor errors. Enjoy!
Listen to the episode on Apple Podcasts, Spotify, Overcast, Podcast Addict, Pocket Casts, Castbox, YouTube Music, Amazon Music, Audible, or on your favorite podcast platform. Watch the conversation on YouTube.
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Tim Ferriss: Dr. Tracey, good sir. Nice to see you again. Thanks so much for making the time to have this conversation.
Dr. Kevin Tracey: Thanks so much for having me on. I’m really looking forward to it, Tim.
Tim Ferriss: And I am really holding in my enthusiasm, which I’m not going to do for very long because we had a brief chat maybe a week or two ago, and I was bouncing around in my chair. I was overflowing with excitement to ask so many questions. And the reasons for that excitement will, I think, become very, very clear very quickly. But let me as context for people listening, and you know some of this already, explain why I never looked at vagus nerve stimulation seriously up until very recently. And primarily it’s because there’s so much crap and so many charlatans, whether it’s deliberate or not, floating around online touting the most ridiculous approaches, devices, at best innocuous, sometimes probably putting people at risk. And at the checkout they might be selling audio chakra cleanse soundtracks and just associated nonsense that shows that they wouldn’t be able to find a logical argument if it bit them in the ass.
And I thought, you know what? I’m just going to put this in the category of things that I should ignore. And also I’d been sent, and not to throw this under the bus, but maybe we’ll get to it, a book on Polyvagal Theory. And I looked at it and I know just enough evolutionary biology to be dangerous. And I thought, I’m not convinced this actually makes a whole lot of sense. And again, I came to the conclusion I should just put this to the side, at least for now. The reason that changed is that a friend of mine who is quite technical, he is one of the top performing investors in biotech and let’s just call it medicine writ large, when it comes to public equities and other types of investments. He has patents to his name. This is a very smart guy. And he reached out to me via text, this is a good friend of mine, and asked if I’d ever looked at vagus nerve stimulation. And I was like, “No, absolutely not. Is there something interesting there?”
And he said, “I think there is.” And he’d been digging into the literature, that he’s also a former tier one operator from the military. And he had been using — and we’ll get to this because a device is not a device, is not a device. There are a lot of differences. But he had been using something purchased off the internet and had tripled his heart rate variability. And I mentioned the military piece because he has, I’m not sure if this is the right term and I’m sure I’ll misspeak a lot, so feel free to give me a polite smack when I do, but sympathetic overdrive. He would lay down to try to go to sleep, his heart would be racing, his glucose would be spiking, and not from PTSD, but from a lot of other things. And he had tried meditation, and he’s diligent. He will do what he assigns himself to do.
He had tried all these interventions to improve heart rate variability and maybe we’ll talk about that. But suffice to say, within the realm of, say, athletics and recovery and this, that, and the other thing, often higher HRV is a good thing. And all of these interventions he tried had bumped things maybe 10 percent, maybe 15 percent. And then he used a vagus nerve stimulator for a few weeks and tripled his HRV. And he’s setting personal records week after week. And I thought, okay, could be N of one and placebo, sure, but I should take a closer look. And he sent me an email with a bunch of citations and I started going, as I do, obsessively down this rabbit hole. And I listened to an interview, I want to give credit where credit is due on STEM-Talk.
And they interviewed you and I thought, okay, I should really, really reach out to Dr. Tracey. And then just coincidentally, I was walking through a bookstore, and right in front of my face was your book The Great Nerve. And I thought, okay, universe, not to get too woo-woo, but I got the message, message received, reached out, and also read the book. I recommend everybody read this book. It’s not only from a very credible source, but you are a good writer. It’s very compelling.
So let’s skip my TED Talk, thank you everyone for coming to my TED Talk, and go straight to the big news. I guess this was literally you emailed me and now it’s big. So what is the big news that literally has just been announced?
Dr. Kevin Tracey: It was just announced that the company SetPoint Medical, which will now be marketing a device to stimulate the vagus nerve to treat rheumatoid arthritis, has received FDA approval. So there’ll be a product launch underway for everything we’re about to talk about in the context of using a medical device that activates an evolutionarily conserved and ancient reflex through which the brain can suppress inflammation when it’s running out of control. We’ve discovered that signals travel from the brain through the vagus nerve. We’ll talk about what the vagus nerve is, but these signals traveling in the vagus nerve are like the brakes on your car. And when you tap those brakes to slow your car barreling down the hill, when this device activates what we call the inflammatory reflex. So you talk about this being a current event, as you and I both know, it’s the front page story in The New York Times today celebrating the successes at SetPoint Medical and kudos to them, to Murthy the CEO, to Dave Chernoff the CMO.
But it’s based, as the article explains also, on 20 years of work by my colleagues and I at the Feinstein Institute at Northwell in New York, and all of which has been essentially replicated by dozens if not hundreds of laboratories around the world. So it’s a rich story of science converging on how the vagus nerve can switch off inflammation that culminates — this morning, as you point out — in a story about patients who’ve already been treated, some of whom had rheumatoid arthritis for decades, couldn’t button their blouse, couldn’t pick up a pencil.
Tim Ferriss: If you don’t mind my interjecting.
Dr. Kevin Tracey: Yeah.
Tim Ferriss: Let’s —
Dr. Kevin Tracey: I get excited too, Tim, I apologize.
Tim Ferriss: Oh, you get excited too, please, I don’t want you muted. I don’t want muted Kevin, I want excited Kevin, and let’s feed that fire a bit. Let’s talk about, specifically, one of your patients who shows up multiple times in the book, but most memorably to me in the coda, and could you just tell her story in brief? Doesn’t have to be super brief because I want people to understand just how drastic, and this is not going to be true for everybody with every condition, but just how significant the transformation can be.
Dr. Kevin Tracey: Kelly Owens is the patient you’re referring to. I know her story very well. I know her very well now. And when I think of her story as you just introduced it, I got goosebumps again as I do every time. Kelly was a teenager when she was playing sports in high school and developed one night after a trivial injury, a major swelling in her knee that cascaded to a very serious problem that ultimately was diagnosed as Crohn’s disease, an inflammatory bowel disease complication affecting her joints. Kelly spent her teenage years and most of her twenties in and out of hospitals, in and out of wheelchairs. Her father actually gave her a cane for one of her birthdays, I’m not sure which one. Now it’s really important, I should point out, Tim, that these stories are so interesting and compelling because for much of her life Kelly always loved to write. She still loves to write, and she blogged many of these stories in the public domain for much of her life. So all this is out there for other people to read.
Kelly ultimately became a school teacher, but could not be treated. Her condition couldn’t be fixed from New York to the Mayo Clinic to Hawaii and back. And it culminated when her physician told her and her husband Sean to plan on staying home without children because of all the medications she was on, childbearing would be too risky, and to get used to her life like that. Around that time she saw me on a Huffington Post live internet interview, live stream, and she contacted me and I don’t recall that contact, but I recommended she look into SetPoint Medical, the company that I had co-founded in 2007 to do these clinical trials.
Tim Ferriss: And Kevin, can I pause you for just one second? Don’t lose your train of thought, but also I recall, and fact-check me here, chronic fatigue, having to lay down, elevate her legs, I mean really just had trouble functioning on a day-to-day basis is my recollection.
Dr. Kevin Tracey: Absolutely. People think of — they hear the word arthritis, when they hear rheumatoid arthritis, they hear arthritis. This is not the trivial sports injury you had in high school and now it’s a rainy day and your knee or your elbow is sore. This is a serious condition that affects the whole body. It can affect the kidneys, it can affect the brain, it can affect your heart. Similarly, for inflammatory bowel disease, it’s not obviously bouts of diarrhea and abdominal pain and nausea and vomiting can be disabling, but the inflammation that affects the intestines in inflammatory bowel disease or in Crohn’s disease also affects other organs, the spine, the joints in Kelly’s case, in her arms and legs. And so these are serious disabling conditions. They can cause depression, they can cause anxiety disorders, they can cause chronic fatigue. So that’s exactly right.
Tim Ferriss: All right, so she reaches out to you, you recommend she investigate SetPoint Medical, then what happens?
Dr. Kevin Tracey: My hope was that although I wasn’t optimistic because she lived in New Jersey and the clinical trials were being done in Europe, but now that I know Kelly, I understand how she was able to talk her way into a clinical trial in Amsterdam. She and her husband Sean, sold all their earthly belongings, as she said, everything that wasn’t tied down. Their friends and family through a GoFundMe kind of operation, raised the money they needed to move there for six months. She enrolled in the trial and was one of the first patients to receive an implant. I call it a generation one implant. It was like a cardiac pacemaker under the collarbone, under the clavicle with a lead or a wire that is tunneled up into the left neck where the vagus nerve travels next to the carotid artery.
A couple of weeks later, they’re in Amsterdam still, and Kelly is running a little bit late for her follow-up appointment as part of the clinical trial to get checked out by the doctors in the trial. There’s elevated trains in Amsterdam and Kelly sees a train coming and runs up the stairs to hop on the train so she won’t be late for her appointment. She turns around like where the hell’s Sean? Sean’s at the bottom of the stairs with tears streaming down his face because Kelly, it was the first time he’d seen Kelly run up the stairs in years.
Tim Ferriss: Yeah, she had trouble walking on the cobblestones in Europe —
Dr. Kevin Tracey: She had trouble walking on the cobblestones.
Tim Ferriss: — not long before.
Dr. Kevin Tracey: Her father gave her a cane for her birthday that she used for many, many years when she wasn’t in a wheelchair and now she’s running up those metal stairs in Amsterdam to catch a train. So she had a remarkable response to this therapy. So a few months go by, and I didn’t know any of this, a few months go by, I get an email. The subject line was, “Thank you for saving my life.” So it was wedged in between a lobbyist in Washington talking about research expenses and my own corporate controller talking to me about my laboratory’s research expenses. So I read Kelly’s email first and I learned her story and that she wanted to thank me in person.
And so I said, “Come on in.” But I also brought, on that first meeting, a couple of my physician colleagues, and we talked at length about Kelly. When she told me that she wanted to help us in the bioelectronic medicine universe, be a patient advocate for this idea, we spent a great deal of time with her explaining that there are risks and benefits to this. People resist change. The world is not ready for something truly new. The world’s not ready to talk about a one-inch device in your neck instead of taking pills and injections. This is going to change everything. And if you’re going to be a leading spokesperson on the patient side of this you may be — people are going to tell you you’re a placebo effect. Tim, all of those things happened.
Tim Ferriss: Oh, I’m sure.
Dr. Kevin Tracey: The CEO of a major pharmaceutical company at a social event told Kelly, this was many years ago, “If you’re real — ” I mean, how do you say this to a patient? “If you’re real, then everything I’m doing is at risk and I could be out of a job.”
Tim Ferriss: And not with a smile on his face.
Dr. Kevin Tracey: That was a real important day in my life. She hugged me, I hugged her, she cried, I cried. And then she said she had a present for me. And I said, “What’s that?” And she gave me a gift-wrapped cane. It was clearly a cane the way she wrapped it, the handle was wrapped and the cane was wrapped with a big bow on it. I opened the card, which I of course still have attached to the cane. The cane is still wrapped, the bow is still on it, and it sits in the corner of my office. And every day, if I’m having a tough day in the lab or any of my colleagues are, we come down and we look at Kelly’s cane and it reminds us why we do what we do and what we hope can happen when you do science in the hopes and dreams of discovering things that might help people someday ’cause it can happen.
Tim Ferriss: So I want to add a few things to that. What a story. And like you said, some people at the time were like, “Ah, placebo,” but placebo effect, and I’m pulling directly from you here, rarely has durability passed a certain point.
Dr. Kevin Tracey: Right.
Tim Ferriss: But when you’re looking at six months out, 12 months out, and she furthermore — not to say this is more important than anything you just described, but certainly for a lot of people listening, and for me personally, having suffered from what I would describe as chronic fatigue for decades, and we might dig into some of that — she went from basically having a blinking battery empty for her day-to-day to having too much, almost too much energy, which doesn’t say it was a problem, but just kind of running up the stairs, bouncing off the walls, and my God, what a difference. The lives that are lived by the former and the latter, the magnitude of that difference just can’t really be overstated. It’s two different experiences of life. Now I’m going to get all excited and lose my train of thought, but I’m going to scatter shot here for a second.
So just to also lay out a few things for folks. So part of what has been so exciting about this and why I want to pay a lot of attention to it, there are a few things feeding into it for me personally. So one is having some exposure to, I suppose what you might call bioelectric medicine through early, early generation TMS, but then also later accelerated TMS with better hardware, better software, better targeting for things like treatment resistant depression. People can look at Nolan Williams out of Stanford, and just some incredible data there. Focused ultrasound and conversation with Nora Volkow for potentially hitting the nucleus accumbens for addiction.
And the possibility, not just the possibility, but now a lot of compelling data, for instance, around SetPoint Medical and other forms of vagus nerve stimulation, but I know you might put some of them in quotation marks, to be an option, an alternative to biologics, let’s just say oral or intravenous or intramuscular medication that have a host of really non-trivial side effects.
And for myself, looking at past depressive episodes, looking at as I’ve tried to unwrap that for myself, which is very under control for the last, I’d say 10 years, but looking at the Lyme disease, which I’ve had twice. And by the way guys, that’s not an, oh, I just happened to be lethargic and I’m hunting for a diagnosis, going from quack to quack until I get Lyme disease. Eastern Long Island, look at the CDC map, it is as red as it gets. And thinking of, then, later neuro-inflammation, I have neurodegenerative disease in my family on both sides. So looking at all these things unfold and feeling like this is going to be a way overreach, but there seems like there might be, I don’t want to say unified theory, but there there’s some connective tissue tying this stuff together and started playing with the microbiome. Because changes in gut flora have been associated with, say, depression or animal models of depression or lack thereof.
Also looking at, say, the ketogenic diet or exogenous ketones as a way to reduce inflammation. And when you start looking at all this, and then when I read your book, the reason this ties into your book is, and we should probably define what the hell the vagus nerve is because it’s more like vagus nerves. And you’ll give a great description. I’ll just give a couple of quick samplers and then we can get back into them at any point. But GLP-1 agonists, in the news, Ozempic, Mounjaro, take your pick. But at least in animals, my understanding is if you sever the vagus nerve, those GLP-1 agonists, they cease to exert a lot of their effects that you would otherwise see.
And similarly, people may have heard these stories, which are based on research of microbiome transplants from, say, obese mice to normal/lean mice, let’s just say. And lo and behold, this amazing thing happens, which is the normal mice take on the attributes, the insulin and sensitivity, the weight gain of the obese mice. Fascinating. But if you cut the vagus nerve, that doesn’t happen. So what the hell is going on? And all of these things are interconnected in the most interesting ways. There’s so much left to learn.
But let’s begin with a definition of basic terms, vagus nerve. How should people think about the vagus nerve?
Dr. Kevin Tracey: When you look online, you’ll find billions of web impressions of vagus nerve. So I’ll just describe it anatomically and functionally first, and then we can cherry-pick where to go. We also should define, if you agree, bioelectronic medicine, because you talked about the connective tissue in the story, and then we should define inflammation.
Tim Ferriss: Let’s do it.
Dr. Kevin Tracey: So the vagus nerve, we call it the vagus nerve, and that’s what it’s called, but you have two of them. So there’s two vagus nerves, like two thumbs, one on each side. Each one arises at about the level of your ear at the base of your brain, travels down both sides of your neck with the carotid artery, and then across the chest into the abdomen. And along the way, it sends out countless branches to all the organs in the chest and abdomen that you don’t think about all day long. Now, within each of those two vagus nerves left and right, you have a hundred thousand fibers. Each fiber is a unique nerve. That’s the part that’s lost almost immediately by 99 percent of the casual readers of vagus nerve stuff.
200,000 fibers, each fiber has an origin in either the body or the brain. 80 percent of them actually originate in the body. They carry information about the organs and your body up into your brain, and then obviously the other 20 percent originate in the brain and they carry information back down to your organs. So again, we’ll try to clear up some misnomers along the way. The biggest misnomer is that you have one vagus nerve, like a solid copper wire. You don’t. You have 200,000 vagus nerves if you treated each one as a wire.
Tim Ferriss: So let me ask if this is a fair visual to paint for people. So imagine that from the base of the ear, roughly, look, this is Tim, the lay person talking. But you have these two thick cables coming down on either side, kind of tracing the carotid artery, and they’re like transatlantic cables just full of a hundred thousand fibers on either side. And they go down and then they kind of branch out like the Mississippi Delta or something like that. And innervate and touch, I don’t want to say just about everything imaginable, but there are 200,000 of these, right? And is that a fair visual to paint for people, or would you modify that?
Dr. Kevin Tracey: No, I wouldn’t modify it at all. In fact, if you go one step further, each nerve ends on either a cell in an organ or on another nerve. So if you put in and those other nerves, those secondary nerves that the vagus nerve ends on, those branch out further. Here’s how I like to visualize it. I think we chatted about this a couple of weeks ago. If I had a solution, if I had a vat of liquid that could magically dissolve all the cells in your body and I submerged you in it for five minutes and pulled you back out again, you would still look like Tim, because every cell in your body is essentially touched by or surrounded by nerves. You’re a walking nerve net. And so, one way of thinking of the vagus nerve, if your body is a walking nerve net, all your organs in your body are encased in a nerve net. Well, then the cable that pulls the nerve net out of the sea is like the vagus nerve. Because it’s connected to the brain, the brain would be like the fisherman operating.
Now, all the signals traveling in these electric networks are traveling up and down the transatlantic cable, the cable connecting the nerve net in your body to the nerve networks in your brain. And we know the identity of 200,000 individual fibers. What we don’t know, Tim, is we don’t know completely, we don’t completely understand the code of the information that’s being transmitted in each of those fibers, right? People talk about the action potentials, which are the spikes of voltage change that travel up and down a nerve fiber. Yes, we can study those. Yes, those are very important. The question is that all the information that’s being transmitted, that’s an area of active research, now that’s very interesting to me. Because on one hand, 200,000 fibers is a lot, but on the other hand, 200,000 fibers isn’t that many. And for instance, we know you can transmit, on the same fiber optic cable, lots of TV shows and lots of radio shows at the same time. So there’s a lot of interesting questions embedded there.
Tim Ferriss: And let’s just say, of those 200,000 fibers, do we know roughly how many affects HRV and cardiac function?
Dr. Kevin Tracey: It’s a much smaller number than people think. We don’t know exactly for sure. We know in mice, in some beautiful work out of Harvard Medical School by Steve Liberles and his colleagues, we know in mice that somewhere around a 100 or 150 fibers are sufficient to control breathing. Now, a mouse vagus nerve has 5,000 fibers, not a hundred thousand, but it’s still a really small fraction of the total number. And so for instance, a few dozen of those fibers control when the mouse gets a full inhaled breath, and another few dozen of those fibers control the process of holding the breath and on down, exhaling the breath. In human beings, for instance, and we’ll come back to this some more, but I estimate somewhere between a 1,000, give or take, maybe 1,500, maybe 2,000 fibers control the amount of inflammation cytokines being produced in the spleen. We can map the identity of the number of fibers going to the heart. Again, it’s a few thousand. So the open question is say we can assign the action of 10,000 fibers on each side. What —
Tim Ferriss: Yeah, the 90,000 —
Dr. Kevin Tracey: — are the other 90,000 doing? Yeah, exactly.
Tim Ferriss: I want to keep giving people Scooby Snacks here just because I’m so excited. I want to keep reiterating the potential payoff of doing this the right way. And you mentioned cytokine. I want to double click on that for a second. We don’t need to get immediately into the technical definition of that. I’m sure we will. But people may know that word from, what, COVID-19, cytokine storm, boom, can lead to fatality in some patients. And I suppose I’m curious to know, and just in short form, what happens to cytokine production when you stimulate the vagus nerve correctly?
Dr. Kevin Tracey: It gets turned off. If you stimulate the fibers we were just talking about, it turns off cytokine production quite effectively. And we discovered this by accident actually, 27 years or so ago in the laboratory. We were working on an experimental anti-inflammatory drug that we had developed, and we put it in the brains of animals with a stroke. And the idea was this anti-inflammatory drug in the brain would stop inflammation. And that did happen. And the stroke in the animals was smaller, and we were very happy. But surprisingly and unexpectedly, when we looked at inflammation in the body of those animals with the drug in the brain, they also had less inflammation. And this was a head scratcher. This made no sense whatsoever.
Tim Ferriss: And that’s a head scratcher because the effect should have been sequestered to the brain because of the blood-brain barrier, or what is the reason?
Dr. Kevin Tracey: Either the blood-brain barrier, but also because we had put such small amounts of drug into the brain, there wasn’t sufficient amounts to account for the saturating and stopping inflammation in the body. Well, we discovered years later was that the drug in the brain was actually turning on the vagus nerve. At the time we discovered the signals were in the vagus nerve, it sort of became obvious to me as a neurosurgeon working on cytokines in the lab, it became obvious that if the vagus nerve is turning off inflammation, then it should be possible to stimulate those fibers in the vagus nerve with electrodes and treat inflammation with a device instead of drugs. And so that’s what we wrote on the back of a napkin 27 years ago that led to where we are today. At the end of the day, we understand using techniques like optogenetics where you can make neurons in the mouse brain sensitive to laser light and other sophisticated molecular biology and genetic tools. I can explain to you how the brain through the vagus nerve turns off cytokines and inflammation.
Tim Ferriss: I’m sorry, Kevin, can I pause you for one second before we get there? And this is something I do not — I mean, I’m going to ask a lot of questions I don’t know the answers to, otherwise the interviews are pretty boring for me. So does this mean that you could use as an acute intervention, vagus nerve stimulation, say, hypothetically in the ER to stop anaphylaxis or to address asthma attacks or sepsis or anything like that?
Dr. Kevin Tracey: Once you understand the basic signals that flow in the vagus nerve to control one aspect of the immune system, in this case, how vagus nerve fibers can turn off cytokine production? You can ask new questions. And let me answer your question by adding a definition because I think it’s a perfect segue. So in order to understand the answer to your question, how to use vagus nerve stimulation and other conditions like asthma and other conditions, you have to back up a bit. You have to say, “Okay, what condition are we talking about?” Let’s look at how the pharmaceutical industry does this. Pharmaceutical industry starts by picking a disease, a condition. Let’s do rheumatoid arthritis first as it’ll become obvious why in a minute. We’re going to look at rheumatoid arthritis, the condition. What’s the molecular mechanism?
Well, the early research with using monoclonal antibodies against TNF show that that helps about half the patients, so that’s the mechanism. So now we can make monoclonal antibodies that hit the molecular target TNF to treat the disease. And now you sell your monoclonal antibodies and after they’re approved for safety and efficacy by the FDA, great, that’s what the pharma industry does. We proposed some years ago, 15 years ago or so now, the idea of bioelectronic medicine as an approach to develop therapies. You begin in the same way, you pick your condition. It’s rheumatoid arthritis. Then you say, rather than screen for antibodies or other molecules to stop TNF, which is the target in rheumatoid arthritis, let’s see if we can find nerves that control TNF production in the body in situ.
If we can find such nerves, then we can build devices to control the nerves, and the devices become the therapy. The bioelectronic medicine story works as long as you know the molecular mechanism, and that’s where people have to be really careful with vagus nerve stimulation. So there are many conditions today that are treated with anti-cytokine therapy, anti-TNF, anti-IL-1, anti-IL-6. Those conditions include things like rheumatoid arthritis, inflammatory bowel disease, Crohn’s disease, psoriatic arthritis, and some other conditions. Most of them are autoimmune conditions.
When you ask about asthma, and you mentioned earlier, also, depression and some other conditions, I go back to the basic starting point. What is the disease? Asthma. What is the mechanism? Tim, no one knows. That’s a full stop.
Tim Ferriss: Therein lies the rub.
Dr. Kevin Tracey: That’s a full stop for me before saying vagus nerve stimulation will or will not work. I remember one of my mentors and friends, rest his soul, Frank Austen, was one of the leading experts on asthma research for decades, and a few years before he died, I said, “Frank, I think I’m going to do some asthma research.” He said, “Okay, what are you going to do?” I said, “Well, I’ve got this mouse model.” He goes, “Kevin, the last article I wrote in asthma was entitled ‘Mice Don’t Wheeze.'”
Tim Ferriss: I like that. ‘Mice Don’t Wheeze.’ Well, you know what that makes me think of, and we’re going to digress for a second here. But look, we need the animal research and there’s a lot you can do in a metaphorical Petri dish now with synthetic biology and stuff, there’s a lot coming down the pike, but still animal models are super important. But some of the, since I’ve funded so much early research and some later stage stuff with respect to psychedelics since 2015 and psychedelic-assisted therapy, but also basic science, some of the animal models are pretty hilarious, where they’re looking at the head twitching and paw licking. In the case of Barry Jacobs giving LSD to cats way back in the day, decades ago at Princeton. And they’re using, let’s just say, the anti-depression animal models might involve swim to exhaustion.
And then you’re like, “Okay, well, I guess methamphetamine is going to be one of the best antidepressants you could possibly give someone if we’re using that as the proxy.” And so a lot of it’s imperfect. And yes, mice don’t wheeze, right? So maybe, especially if you can’t identify, like you said, it’s the mechanism, you need to be able to at least hold onto some of the variables.
So let me come to just depression for a second, and I know this is going to be all over the place. It’s like, Tim after too much caffeine and a couple of glasses of wine. Which is not where I am. I did have some pretty good ketone monoesters before our chat though. And I wanted to come back to depression because it’s a subject near and dear to my heart. It’s something that affects a lot of people. And when people experience depression, it can also feed on itself in the sense.
And I speak from experience, where you personalize it, like this is a me problem. This is a character flaw and it’s permanent. And it becomes this loop that can exacerbate the condition. But I’ve long had this suspicion, and this is part of the reason for a lot of the research involvement, is that anti-inflammation or inflammation is potentially at the core of a lot of this. Whether you look at, for instance, a very potent anti-inflammatory effects of certain psychedelics in the phenethylamine class, like 2C-B for instance. Very, very significant at very, very low doses. And when I’m looking at some of my highlights, I have a ton of Kindle highlights from your book, The Great Nerve. I’ll mention it again, pick it up guys. You’ll not be disappointed. But you can induce depression in animal models by causing inflammation.
Dr. Kevin Tracey: And people too, Tim.
Tim Ferriss: And people too. And I want to just read a little bit here. Because we’ve long had, and I think many, many doctors still ascribed to a chemical imbalance theory of say, depression or mental illness writ large, but depression. So this is directly from your book. If an SSRI has helped you or someone you know, that’s wonderful. Large randomized clinical trials of SSRIs indicate they confer some clinical benefit in some patients, which is true. I’ve seen lives changed. Now, whether it’s actually serotonin or not is a separate question, but back to your book.
But these results, in your personal experience, do not prove causality or confirm that serotonin dysfunction is causing depression. For example, SSRIs may also inhibit inflammation. And then here’s the clutch paragraph that I highlighted. Interestingly, administering SSRIs to animals and patients with inflammation after receiving cytokines in the lab. So you’re deliberately trying to provoke inflammation. Administering SSRIs can alleviate depression caused by these cytokines.
This anti-inflammatory role of SSRIs is little studied and incompletely understood, and I sincerely hope that my colleagues are inspired to investigate it further. So this raises some very, very, very interesting questions.
And since we last spoke, I have been toying around, and I use the word toy very deliberately, with some devices that I may not continue to use. But I have a variation that a friend recommended to me, very low cost that I’m going to be switching to because I don’t like the neck seizures very much. But nonetheless, I’ll say that the combination of the stimulation, plus, and I realize I’m fussing with a number of variables, intermittent fasting and exogenous ketones. So I am throwing a lot against the wall here. But the addition of the stimulation, which is just a few minutes a day, and we’ll definitely talk about your friend Ulf and his story, because that guy is not wearing a tinfoil hat, right?
Dr. Kevin Tracey: No.
Tim Ferriss: He’s credible. As credible as credible can be.
Dr. Kevin Tracey: Yes.
Tim Ferriss: The stability of my mood is remarkable. And again, I think there are people out there, just if I could throw some folks, not throw them under the bus, but just lay a criticism. There are some folks out there, well-educated but non-scientists, who worship at the altar of science with a capital S, or scientism, perhaps it is. And so they’ll criticize maybe a story like this or the story of your patient and say, “Ah, N of one placebo,” and they discard it that way. But a lot of very critical scientific investigations begin with case studies in the literature. I’m looking at that right now with respect to Alzheimer’s and exogenous ketones. There’s some very interesting stuff out there.
So this is a very long-winded way of trying to set up inflammation. Inflammation is one of those terms that gets used like it’s specific, but it’s like saying business or sports or art. It’s a big umbrella term. So what is inflammation in the context of what you have studied and observed as a clinician and as a researcher and inventor for that matter?
Dr. Kevin Tracey: Yeah, we’re going to have to do a couple of shows, Tim.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: Simply put, inflammation was defined thousands of years ago, as the redness, the pain, the swelling and the heat that you feel when you sprain your ankle or get an infected wound on your body. Everybody’s seen it, everybody’s had it, and it’s a good thing. It runs its course and it’s the product of cytokines in part, in other molecules, TNF, IL-1, IL-6, but other molecules made by white blood cells and other tissues in your body. So it’s a good thing when it stops. It’s a good thing because it helps heal the wound, helps proliferate stem cells, helps fight off infection or bacteria that might settle in the wound. And it’s a good thing if it stops. The problem is, we’ll talk about why it stops, but the problem comes when it doesn’t stop. And when it starts spinning out of control, like in Kelly Owen’s case, then it becomes like the army showing up with howitzers to break up a peaceful demonstration or a picket line.
And you have these violent outbursts of inflammatory reactions that cause the problems in rheumatoid arthritis and inflammatory bowel disease and these other conditions. So that’s what inflammation is, that’s what the textbooks say. That’s what everybody knows. That’s what everybody’s taught. That’s what everybody talks about. That’s the anti-inflammatory drugs we have today. Modify the molecules we just talked about, the TNFs, the IL-1s, the prostaglandins. That’s how the ibuprofrens and other nonsteroidals work. And we go down the list on all this. The problem is, when you look in the brain of an Alzheimer’s patient, which everyone who studies Alzheimer’s agrees has some contribution role or cause or contributing factor from inflammation in the brain, neuroinflammation, you don’t see redness, you don’t see swelling. It certainly doesn’t, it’s not painful.
And the same is true when you look in the adipocytes, the fat cells of an obese patient who has type two diabetes and has significant insulin resistance. They also, sometimes they have a few extra white blood cells in the fat, but it’s not rip-roaring inflammation that you see in an infected wound. They might have an upregulation of some of the cytokines. You might see the upregulated production of cytokines in the brains of Alzheimer’s patients. But it’s nothing like you see in an injured tissue or a rheumatoid arthritis. Some people have come up with new names, meta-inflammation, inflammaging it’s called sometimes when these kinds of changes occur.
Tim Ferriss: Inflammaging.
Dr. Kevin Tracey: Inflammaging. As tissues, age tissues from older people, from the elderly, they have higher levels of cytokines and more insulin resistance. They call it inflammaging. So we really, we do have an issue of semantics. But with that as a limitation, what’s so important about this conversation, in light of everything else we’ve been talking about is, you talked about a connective tissue in these stories and the connective tissue is in many ways inflammation. So let’s back up about what the problems facing the human race are. So 60 million people die on the planet Earth every year. And 40 million of them die from heart disease, stroke, neurodegeneration, Alzheimer’s, Parkinson’s, metabolic syndrome, diabetes, and cancer. So two thirds of the people that die every year on the planet Earth die of those conditions. And that’s according to the WHO. Those conditions all have one thing in common — they’re either caused by inflammation or made worse by inflammation.
Now, if you look back at what happened in the last 80,000 years, 75,000 years since we came down from the trees and became talking monkeys, in that time period, almost everybody until a hundred years ago, 150 years ago, almost everybody died by the time they were 30. And what happened in the last 150 years can be summarized in a very simple sentence. The human race in the last 150 years removed infection as the leading cause of death. And by doing that, we added 40, 50 years to health span, to lifespan. So the question that wakes me up at 3:00 a.m. now is, “What if we could cure inflammation?” If we cured inflammation, what would that do to the death rate from cancer, heart disease, stroke, and all the conditions that kill two-thirds of the people on the planet earth every year? Look, there’s still people that die of infection. People died of COVID. People die every day of malaria and tuberculosis. I’m not being Pollyanna about this. But if you look at the cold hard numbers, the things that reduced death and increased survival of the human species, all affected the eradication of the threat of infection. Cleaner water, ample food supply, less starvation, all these things converged on better vaccinations, antibiotics, obviously. All these things converged on improving lifespan.
I think something similar will happen maybe in the next 20 years if we can really understand how to modify inflammation. And one way I think we’ll be able to do that is by continuing to dive deeper and deeper into understanding how evolution itself put the brakes on too much inflammation. I said that inflammation is bad when it’s not restrained, when it doesn’t resolve. Well, evolution knew that hundreds of millions of years ago. So from the very beginning of the evolution of inflammation, there’s been evolutionary mechanisms that evolved to suppress inflammation, to tame it, to put the brakes on it. And what we’ve now discovered in the last 20 years is that the brain does this by sending signals through the vagus nerve. So you ask if this idea may have an application and other conditions, I’m convinced it will. It’ll have to be worked through one condition at a time, one mechanism at a time, but I think it’s a really important new idea.
Tim Ferriss: Well, I guess once the devices are out in the wild, let’s say the implant, then docs may have some latitude to also experiment with patients. I mean, TBD. But let me ask. Let me do a few things. I’m going to allow us, if we want, just to abbreviate vagal nerve stimulation to VNS if we want to just make it a little easier on ourselves. Let me ask a question that I asked in our last conversation, and I’m sure is on the mind of a lot of folks, which is, along the lines of, wait a second, inflammation seems to serve presumably some important purpose. So just like some people might label cortisol bad, if you get rid of cortisol completely, you’re going to be in a world of trouble.
So if you are, say, decreasing cytokine production and release by 70, 90 percent with vagus nerve stimulation, could that not have downstream negative effects? How would you speak to that? And I was asking that broadly speaking in our last conversation, but also with respect to weight training and physical adaptations, where certain things — and I’m getting way over my skis here, but like interleukin-6, IL-6 and blah, blah, blah, blah, blah. Temporarily at least, or seem important for catalyzing some of these tissue adaptations. So are you at risk by suppressing cytokines with vagus nerve stimulation? Do we know anything about the side effect profile?
Dr. Kevin Tracey: We know a great deal about the side effect profile, but let me just first unpack the importance of what you’re talking about. So if we know for certain, if you take biologics like anti-TNF or anti-IL-1 or anti-IL-6 that you see advertised at the nightly news every night and on all the NFL football games every weekend. These biologics, the way they’re designed to work is they suppress 100 percent of the activity of the cytokine. So if you take an anti-TNF and your monoclonal antibody in your body bumps into your TNF in your body, it’s zero. And the antibody takes away a hundred percent. It’s yes or no. And because you take away a hundred percent of TNF or IL-1, depending on what drug you’re on, those drugs carry warnings.
The most serious side effect warning the FDA can give is called the black box warning because they cause immunosuppression, which is exactly what you said. Immunosuppression means, now you no longer have enough immunological activity, or in this case inflammation activity, to fight off infections.
And so the risk is you’ll get things like sepsis or tuberculosis or other conditions, even cancer in some patients because your immune system is no longer fully armed to defend itself against these threats. You ask, does vagus nerve stimulation do that? The simple answer is no. And the reason we know this is because the FDA-approved vagus nerve stimulation to treat depression and epilepsy actually in the 1990s. So we have decades of experience implanting patients with vagus nerve stimulators.
Now, there have been peer-reviewed studies with 30 years of longitudinal follow-up in a quarter of a million patients. I estimate that millions of patients have actually been implanted with these devices. So we know that there is always a surgical risk of any surgery. The surgical risks of an incision are small, and the surgical risks of nerve damage are actually quite small. Especially with the new SetPoint device, which is only one inch large, completely encased in it. But immunosuppression-wise, we also know that vagus nerve stimulators do not have black box warnings. There’s no evidence after decades of any immunosuppression. There’s no evidence of an increased risk of infection or cancer.
Why is that? Well, it’s because, and here we go back to laboratory studies, and even now in new human studies. When you stimulate the vagus nerve fibers that inhibit inflammation, the ones that travel from the brain to the spleen, for instance, to stop cytokine production, you inhibit, as you correctly said, about 70 percent of the cytokine production. You don’t inhibit a hundred percent. So the best way I like to think of it is that, if you have an excessive or a dangerous cytokine response, you’re going to produce, call it a hundred units of TNF. And that’s going to be very bad for your tissues and for you. The normal range should be 10 or 20. The vagus nerve stimulation therapy and the SetPoint device is called actually the immunoregulation therapy because it’s only one minute a day. That drives the TNF from a hundred down to about 30 or so. So there’s plenty left to have an appropriate immune response, but it takes the TNF effects from the toxic range that cause rheumatoid arthritis and Crohn’s disease.
The monoclonal antibodies only hit one target at a time, either TNF or IL-1. The vagus nerve is actually suppressing the whole system. So it’s taking the toxic levels of IL-1 down and the toxic levels of IL-6 down. Those things together, they act synergistically, so the effects are bigger than additives. So if you take them all from the toxic range to the healthy range, you’re going to be a lot better off. And the IL-6 response in skeletal muscle response in weight training, that’s that’s still going to be down in the healthy range. And who knows, Tim? We don’t know enough about it, but it may very well be that the vagus nerve signals that you activate during exercise, like on the sheep running on the treadmill in New Zealand, we could talk about that. Those vagus nerve signals may in fact be contributing to the IL-6 metabolism and turnover that’s going on. We don’t know.
Tim Ferriss: Maybe we’ll get to this, but who knows, because we’re going to bounce around a lot. But also, another aspect of your book that is very compelling is, it includes a discussion of meditation, it includes a discussion of cold exposure, and it includes a discussion of different breathing practices, and all of which seem to have applications to vagus nerve stimulation. And maybe it’s vis-a-vis the vagus nerve, but parasympathetic activation, which might be very counterintuitive to folks. And so for instance, reading your research and reading your book and chatting with you has led me to do something more than I already do, which is, yeah, that’s great, but why? And that’s interesting, but why? Yeah, that’s interesting, but why? Because for instance, I’ve noticed for decades, and I think a lot of athletes have noticed that if you do cold plunges, and I mean pretty much every division one soccer team, for instance, or you name it, is going to do some version of this.
If you do it not necessarily immediately after training, but say you wait an hour or two, and then you do cold exposure in a bath, that it seems to enhance recovery. Now you could say, “Well, ice decreases inflammation.” But then it’s like, is that true? Could there be another explanation? And what you point out in your book, which is something that again, intuitively now makes sense to me, is in the beginning when you’re exposed to cold, and there are studies demonstrating this, whether it’s in cold chambers for hours, which sounds like more misery than I can handle. But suffice to say, initially fight or flight response, sympathetic activation, adrenaline, noradrenaline cetera. And then at some point parasympathetic rest and digest activation. And could it be that the cold is affecting the vagus nerve, which is affecting parasympathetic, that helps with recovery? I don’t know. But I’ve, for instance, always wondered why it is that after a few minutes in a 45 degree bath, I start yawning. There’s a lot of yawning. And I don’t know if that’s direct. Interestingly, that’s also a very common onset symptom after say, ingesting psychedelics like ayahuasca, is yawning.
Yawning, lots of yawning, which is why all of these things seem to touch the hem of the same fabric. So anyway, now I guess that was more of a monologue than a question.
But let me ask you something that has been also front of mind. Is it true, and I could speculate, but does it seem like within patient populations we’re dealing with more chronic inflammatory conditions? And is that because we have better diagnostics? For instance, you might say, “Oh, there’s an explosion of brain cancer.” Yeah, well, we also have much better tools and people are not dying of maybe things that are easily preventable by antibiotics, so who knows? And maybe it’s not that cellphone towers are causing an explosion of brain cancer. It’s very easily explained in other ways. But do we seem to be contending with population-level greater instances of chronic inflammatory diseases? And, question mark, can we even know that? And then if it appears to be the case, are there any plausible explanations for why that is?
Dr. Kevin Tracey: That is a billion-dollar question for which I’m not an epidemiologist, but I know there’s no easy answer to that one. There are epidemiological studies showing an increase of autoimmune diseases. There are studies suggesting some of these conditions are more common at higher latitudes, and some of them are more common at lower latitudes.
Tim Ferriss: Interesting, the latitude. Wild.
Dr. Kevin Tracey: Yep.
Tim Ferriss: I mean, correlation I guess doesn’t prove causation, but it’s interesting.
Dr. Kevin Tracey: It’s very interesting. It always comes down to two things pretty much in biology. It’s nature and nurture. It’s genes and environment. And environment is writ large. It’s the family you were brought up in, it’s your father’s income when you were six. It’s the germs, the pandemic outbreaks that were around your neighborhood when you were 10 and when you were 20, and on down the list. What you eat, what’s in the environment, in the air you breathe, how much microplastics did you consume, knowing it or not knowing it on.
So genes and environment, and sorting that out in real time is exceedingly difficult, especially when you think about the possibility that some of these things, after decades of study, turn out to be caused by previously unknown infections. One of my favorites is — stories about this, of course, is peptic ulcer disease. Everyone, when I was a kid, and in medical school, we all knew that peptic ulcer disease was type A personalities and —
Tim Ferriss: Stress.
Dr. Kevin Tracey: — stress. And it’s the patient’s fault. I mean, I love to say, and then it turns out that there’s a bacteria that causes peptic ulcer disease. And when you treat these people with —
Tim Ferriss: What is that? Not H. pylori.
Dr. Kevin Tracey: H. pylori. Yeah. And when you treat people with antibiotics to eradicate that infection, a large percentage of them get better. When I was a surgery resident, which wasn’t that long ago, I’m not that old. I mean, it was one of the commonest operations in the hospital.
Tim Ferriss: I thought you said communist for a second.
Dr. Kevin Tracey: No, no.
Tim Ferriss: I was like, “Oh, I didn’t see that coming.”
Dr. Kevin Tracey: No, no. One of the most common operations on the OR schedule was gastrectomy for peptic ulcer disease. You never see that. It doesn’t happen anymore because you take antibiotics. So my adage for this thing is, when you don’t understand a disease, think of epilepsy. You start off, you blame God. So they did exorcisms, and that doesn’t work. So if it’s not God’s fault, the next thing you do is you blame the patient. And when you realize it’s not the patient’s fault, in today’s era, oftentimes we find out it’s actually caused, there’s some infectious cause of this thing. And so autoimmune disease may have an infectious cause, it may have an environmental cause. People talk about genetic causes. You inherit some level of risk for autoimmune diseases, but very few of these conditions do you actually inherit the condition. It’s like the old story of the two guys playing golf and get hit by lightning. I’ll ask you a question, Tim. Is that environment or genes?
Tim Ferriss: Well —
Dr. Kevin Tracey: It’s environment, right?
Tim Ferriss: Good question.
Dr. Kevin Tracey: It’s environment, unless —
Tim Ferriss: Well, I’m also thinking genetic predisposition to risk taking when they’re like, “Ah, it’ll be fine.”
Dr. Kevin Tracey: Well, it’s easier than that. It’s easier than that. It’s father and son, and they play golf every afternoon in the summer in Florida. It’s like, those kinds of analyses with two people are hard to do the statistics on. When you scale it up to a population, it’s very, very, very difficult to give a simple answer to your question.
Tim Ferriss: Well, to make it even more difficult when we’re talking about H. Pylori, or pylori. I’m not sure how to pronounce it, I’ve only read it. But it seems like, tell me if I’m wading too deep into the deep end of my ignorance pool here. From your book, and this is not a counter argument from your book, but I’ll just read a paragraph that I highlighted. Which, it’s like I’d known this, but it was put very well. “Stress responses also activate your adrenal glands to release glucocorticoids, hormones that stimulate gluconeogenesis, the production of glucose in the liver.” Anyway that could explain, for instance, my friend’s sympathetic overdrive and having glucose spikes at night when he’s trying to go to sleep.
Going back to the book, “This in turn increases your blood glucose levels, elevated glucocorticoid levels as occurs in depressed patients, accelerates lipolysis.” Am I saying that correctly? “The breakdown of fats into fatty acids while suppressing digestion, muscle growth, and reproduction. Glucocorticoids also inhibit the action of insulin, meaning that your cells are less responsive to insulin. This further increases blood glucose, sometimes even to dangerous levels.”
The reason that I’m bringing this up is that if someone is type A, and if they’re subjecting themselves to situations that produce chronic stress response, could maybe all of the things I just mentioned and more make them predisposed to certain types of infections? So that they’re actually, just to complicate the picture further. Where, yes, it’s an infection, but there are certain behaviors or genetic predisposition, or who knows, even jobs that make it more likely that you would be susceptible to such an infection. I don’t know. I don’t know.
Dr. Kevin Tracey: Those kinds of studies are out there, and I think they tip both ways. Some suggest there is an increased risk and some suggest there isn’t. But I think the whole — last time I read about this, I’m not a psychologist, but the last time I probed this literature a little bit, the whole nomenclature of type A and type B personality actually broke down. What was retained is hostility. Most of the things that tracked with the classic type A personality, tracked or correlated to how much hostility. Now you’re back in the psychological domain of the top-down driving. That’s not me.
Tim Ferriss: Yeah. Which is understandable.
Dr. Kevin Tracey: But it’s interesting. I was at a scientific meeting once when that data was being discussed, and somebody stood up in the front row and said, “Well, how hostile is hostile? How hostile do I have to be to be type A versus type B?” And everybody stared at him like, “Do you hear yourself, man? Relax.”
Tim Ferriss: Let’s talk about — because people are listening. And the SetPoint device, it’s maybe slightly larger than an Omega 3 capsule, or something that’s implanted in the neck, has a number of huge benefits. But then I’m going to ask you about other tools, potentially. I’d say probably the greatest benefit is patient compliance. If you have to remember to take something or do something every day, there’s going to be a lot of breakage in terms of patient compliance. From a purely practical perspective, there are some great benefits to an implant. But could you tell the story of your friend, Ulf, and just describe who he is, and lead into his story? If you’re open to it.
Dr. Kevin Tracey: Sure. On the SetPoint device, the one the size of a fish oil pill, I think we have to talk about that in the context of people who are really sick. These are people who have spent decades, sometimes, disabled. Oftentimes, as you said, chronically fatigued or depressed, or in pain. And these are people who are injecting themselves with drugs. Many of them can’t afford any more of the drugs they have to take, the ones with these serious side effects. There’s a tendency, not by you, but there’s a tendency by some in the short form conversation of these kinds of things to say, “Well, it’s a surgery, and they should do more push-ups or try to do more things to help themselves.” Well, I’ve got to be really, really outspoken on this, because when you meet people that have these conditions, if it was as easy as doing a couple of push-ups or taking a yoga class or breathing differently, they would do it. And if it made them better, they would do it.
These are serious medical conditions. And I think for those kinds of patients, there’s always going to be a need. Because compliance is so difficult, there’s compliance with remembering, there’s compliance with going to the doctors every month. There’s compliance with going to the infusion center, there’s compliance with injecting yourself. Compliance can break down at so many different places. People with serious illnesses, you’re absolutely right. The availability, not for all, but for those that are going to be able to go down that path, to have a small immunoregulator implanted in the neck, that’s going to be very interesting to see what happens. But for people who are essentially mostly well, like you seem to be, and I seem like —
Tim Ferriss: What an effective mask I’ve created. Yeah. No, I’m generally well, yes.
Dr. Kevin Tracey: And me too, and I feel very fortunate for that. I try to do things that align with what people would call vagus nerve stimulation. Eat right, sleep right, try to get some regular exercise in, try to stay cognitively busy, try to enjoy my hobbies and my family, try to alleviate the stress from my life as much as possible. All the things that we all know we should be doing, and your GP or your primary care provider should be telling you to do every day. All those things, in one way or another that we’ve been talking about, can be said to stimulate directly or indirectly the vagus nerve. But there’s other modalities that people also talk about using electrical devices to stimulate the vagus nerve by applying these electrical devices or TENS units, transcutaneous electrical nerve stimulators, to the skin.
Before I go any further, let me be 1,000 percent clear. These are not vagus nerve stimulators. There’s only two ways to stimulate the vagus nerve directly and specifically. One is to implant an electrode on the nerve, and that’s either with the devices for epilepsy or depression. Or there’s another one now also to increase the rehabilitation outcomes from patients who have strokes. That’s a third one. Or the immunoregulator device from SetPoint. That’s the only FDA-approved way to stimulate your vagus nerve that directly specifically stimulates your vagus nerve. Full stop.
Experimentally, you can do it using focused ultrasound, and we’ve done that in the lab. My colleagues Sangeeta Chavan and Stavros Zanos, we’ve published on this in the peer-reviewed journals. It’s a special ultrasound. It’s very similar to the one that you visualize to see the baby in the womb or the gallstones, but you have a different lens on the probe, and you can focus the energy to target nerves in the body. And we’ve done this in humans to reduce the inflammatory markers in the blood of healthy volunteers by focusing the ultrasound on the splenic nerve, where the vagus nerve controls it. And we’ve done it in animal models of diabetes and obesity, and seen some very interesting effects. Everything else, the transcutaneous electrical nerve stimulation strategy to the neck, to the ear, to side of the head or the face, those are all non-invasive and non-specific, and really shouldn’t be called vagus nerve stimulators.
Tim Ferriss: Nonetheless, some interesting stuff seems to happen.
Dr. Kevin Tracey: Okay.
Tim Ferriss: Everything you said, it’s so true. So on point. I’m also tempted to go to the hockey puck for electric GLP-1 administration, but I’m going to call that a temptation and not an opportunity for the moment. And let’s talk about your friend Ulf, and what happened to him.
Dr. Kevin Tracey: I apologize for the digression, but I had to get that as you —
Tim Ferriss: No. You’ve got to do it.
Dr. Kevin Tracey: — understand on the record.
Tim Ferriss: You’ve got to do it.
Dr. Kevin Tracey: Now, what about other stuff like a TENS unit? Let’s give a little background there. Anybody interested in auricular therapy, meaning auricle as ear. A-U-R, auricular therapy. And/or auricular acupuncture. Knows that the ancient Chinese acupuncture maps date back tens of thousands of years, and that there are points on the ear that map to various organs in the body. And if you stimulate them with a small needle, a probe, or a small electric current, that you’re supposedly able to affect the metabolism or the diseases of those organs. Everybody knows that’s 10,000 —
Well it turns out, when I was writing the book, which I discovered that those ancient acupuncture maps of the ear originated in France in 1957 by a doctor named Dr. Paul Nogier, who had a patient who was being treated by a specialist, I think in Corsica. And the specialist was grounded in ancient medicine and was cauterizing a piece of this patient’s ear to treat the patient’s sciatica, the pain going down their leg.
Tim Ferriss: Burning their ear?
Dr. Kevin Tracey: Yeah, burning or cutting a piece of it off. I’m not exactly sure what they did. It wasn’t clear, but there was a little hole on the edge of this patient’s ear. And then he saw another one. And in both times the two patients claim that their sciatica got better. Dr. Nogier was a very clever guy, and curious and careful, and he took a ballpoint pen and he took the ink out of it, and he started probing all of his patient’s ears. And he aligned various conditions in the patient with the parts of the ear that he determined were most closely aligned with the symptoms and signs of the illness. And he made a map. Well, he did this for many, many years in many, many patients, and ultimately published this. And he had presented it at an acupuncture meeting that was being held somewhere in the Mediterranean, and it led to this overwhelming acclaim for him.
And the work was republished in China, which created the current textbooks of Chinese auricular acupuncture therapy based on a Frenchman’s work in the 1950s. That’s where the maps come from. They’re fun to look at. They really are. And especially in light of the story I am going to tell. If you look, you can see where the spleen is and where the bladder is and where the stomach is. They’re very clever.
We were reading, Sangeeta Chavan and I, my lab co-head and I, many years ago. 15, 20 years ago. We were reading about vagus nerve biology and physiology, and we discovered that there was a branch of the vagus nerve that goes to the cartilage of the ear. And when I say the ear, it goes to the cartilaginous part, the part outside the ear canal where you put your finger in your ear, and what looks like a seashell. It’s called the cymba concha. That’s where it gets its name, concha, like shell. Now, this branch of the vagus nerve that goes from that cartilage is very, very special. It’s the only place that the vagus nerve endings go to the surface of the skin, and they are sensory.
That means that when you stimulate the cartilage of the cymba concha, you can activate the fibers that go carrying information into the brain. And they go to the place in the brain called the nucleus tractus solitarius, which is the place where all the other sensory fibers of the vagus nerve go from your stomach and from your pancreas and from your liver. All the sensory input goes to the same place. You can think of it like the router in your house, everything goes into one spot and then it goes back out again. Well, why? Well, it turns out that fish — you like evolution, I heard you say at the beginning. Fish gills are cartilaginous and they’re innervated. And what became our human vagus nerve was one of the branches of the fish’s vagus nerve. And what became our cartilage of our ear used to be the cartilage of the fish gills. So it dragged it with it.
Tim Ferriss: Wow. Wild.
Dr. Kevin Tracey: It’s wild.
Tim Ferriss: I’ll be honest, as a non-biologist, long ago when I was shown these maps, I thought to myself, this makes absolutely no evolutionary sense. Because why would you, if in battle you get nicked by an ax and your spleen explodes? That doesn’t seem to have any adaptive purpose for natural selection. But lo and behold, fish gills. Well —
Dr. Kevin Tracey: It’s fish gills. But I didn’t say it makes sense, Tim. You said that. I didn’t say it makes sense.
Tim Ferriss: Well, no, I shouldn’t say it makes sense. It’s just like a vestigial architecture.
Dr. Kevin Tracey: It’s definitely vestigial. How much of the architecture, that’s another area that I can’t say for sure we’ve— I actually can say for sure. Nobody to my knowledge has completely mapped out Dr. Nogier’s ear maps to the human body in any convincing neuroanatomical function or neurophysiological way. But it’s still interesting.
With that information, you could think of the cartilage of the ear as a way to drive signals into the brainstem through a branch of the vagus nerve. Immediately people start calling that vagus nerve stimulation. It’s kind of true, because it’s a sensory branch of the vagus nerve. And if you put a TENS unit or your finger on the cartilage of the ear, you are technically stimulating the receptors in the skin that activate the sensory fibers that carry the signals into the NTS. But it’s not the same as — I said it before, I don’t have to say it again. It’s not the same as electrostimulant —
Tim Ferriss: Hitting the big cable.
Dr. Kevin Tracey: Right. Now, what happens? Now it gets really interesting. A long time ago, an early Russian investigator published a study where he took, essentially, an acupuncture needle and put it in the cymba concha, and put in a little electric current, and showed that he could get changes in heart rate variability, essentially. And this goes back, again, to the ’50s or ’60s. That exact study, to my knowledge, has never actually been replicated the way he did it.
This is the problem. You talked about clinical trials and proving. I agree with you, the case studies are often the most important ways to start, but you still have to do the big clinical trials, randomized controls with the appropriate control population. We’ll come back to that. Now you say, okay, what happens using other technology? Well, it turns out now, I can’t count all the publications that have been done by applying various forms of electric current into the ear and measuring.
Tim Ferriss: There’s a lot.
Dr. Kevin Tracey: You can’t count them all.
Tim Ferriss: There’s a lot.
Dr. Kevin Tracey: You can’t count them all. They come out every day now. And people have done some very sophisticated studies, usually with about 10 or 20 people per study. Usually. But you can look at and you can find brain imaging studies, FMRI. You can find pet studies. You can find far field evoked responses, which looks at the inputs and outputs into various brainstem regions and how the brain is processing the higher network signals. You can see some really interesting stuff. And what comes out of it is lots of different information. That’s the first problem. There’s no single consensus that if you put this kind of electrode in your ear at this time for this many minutes at this much current, you get this effect and this part of your brain in the morning and this part of your brain at noon, and this part of your brain — no one knows.
Put that aside for a second. And I put it in the book, I hope it was clear. What I find striking and interesting, and needing further study, is that if you compare people with electrical inputs to their ear, to people with electrical devices surgically implanted in their neck, there is some overlap in the brain centers that are activated. You see centers like the locus coeruleus, which is the top of the fight or flight chain. It’s the top of the sympathetic chain. You see regions in the basal forebrain, the cholinergic regions, which are linked up to the hippocampus and to other areas that are really important for learning and memory.
And there is clinical data that patients with implanted vagus nerve stimulators have enhanced neuroplasticity, enhanced learning, and enhanced cognition, alertness.
Tim Ferriss: In another episode of STEM-Talk, which has become one of my favorite new podcasts. There was one of the hosts, I think it’s Dr. Ken Ford, who has served on a number of defense and intelligence-related advisory boards, including advisory roles at DARPA.
Dr. Kevin Tracey: He has a great voice too, Tim.
Tim Ferriss: Oh, his voice is amazing. The Defense Advanced Research Projects Agency is incredible. A lot of the technologies we use every day now originally came out of DARPA, ARPANET, et cetera. He was in conversation, and they were discussing neuroplasticity and learning with respect to vagus nerve stimulation. And I haven’t looked into this yet, but I’ve spent time at the Defense Language Institute in Monterey, and they were talking about using vagus nerve stimulation to enhance language acquisition, and that the effects seem to be durable for months after stimulation. Which, also in your book, just a quick note. Stimulation for two weeks, having an effect on insomnia for two or three months. What could be more interesting? Now it’s just so endlessly fascinating.
Dr. Kevin Tracey: I have to respond to the DARPA.
Tim Ferriss: Yeah, please.
Dr. Kevin Tracey: I wouldn’t be talking to you right now if it wasn’t for DARPA’s support on this idea in the 1990s, when it was a freaking crazy idea that I’m going to target, with an electrode, the vagus nerve to stop sepsis and cytokine storm. And they said, “Okay, try it. What if it’s yes?”
Tim Ferriss: Yeah, people think of the “government” as just this big, monolithic, slow moving, stupid, inefficient thing. DARPA is an exception. You’ve got to check out DARPA. The brilliance and the innovation that comes out of that, and their willingness to throw a lot against the wall. And it’s science fiction, some of the stuff that comes out of DARPA.
Dr. Kevin Tracey: One of my heroes is actually a national hero. Geoff Ling. Dr. Geoff Ling, retired colonel, founded the biology technology office at DARPA. He used to instruct his team at DARPA, when the guys and gals would come in with the most crazy-ass ideas anyone could ever imagine. “You see that airplane out there? I can make it disappear. I can make it invisible.” And then everybody leaves and they go into Geoff’s office and he says to his team, “What do you think?” And they all say to Geoff, “He’s nuts. It’s crazy. You can’t make an airplane disappear.” And Geoff looked at his team and says, “What if it’s yes?” And that’s where stealth technology came from.
Tim Ferriss: Yeah. That’s so cool.
Dr. Kevin Tracey: And then you say, “Oh, I can still see the airplane.” And then Geoff slams his hand on the desk and goes, “If you can see it, it’s too late.”
Tim Ferriss: Technology to be able to see figures around corners, and that was years ago when I saw a rough description of that. In any case, they are doing lots of really interesting things. I took us off track for a second.
Dr. Kevin Tracey: One more thing. You said another thing; I’ve got to respond. The cognition part of vagus nerve stimulation is also a fascinating story that would require a full long form conversation. But in brief, patients who had epilepsy were implanted with vagus nerve stimulators. This was years ago. This goes back 20 years, or maybe 30. And a bunch of these folks did not get any significant benefit from the therapy, so the device was switched off.
Well, a very clever researcher brought them into his lab and gave them a — I’m not a psychologist, I already gave that disclaimer once. But gave them a cognitive learning test of some form, very simple. And then turned the device on and repeated it, and all their scores went up. It was very dramatic. And when they image these folks in subsequent studies, this is one of the studies that I mentioned before that pointed to the enhancement of activity in the regions of the brain that are really important for intention, learning, and memory. There’s a deep conversation there about neurocognition and vagus nerve inputs to the brain.
Tim Ferriss: I’m fidgeting around in my chair because I get so excited about finally trying to — and I’m not there, obviously. Who am I? I’m a muggle. I have to depend on pros like you. But looking at, for instance, the few things that I have come across that really seem to have very impressive effect sizes on intractable or hard to treat psychiatric conditions that resist frontline treatments with biologics for 15, 20 years. Until, for instance, just a few, some psychedelic assisted therapies, some types of brain stimulation. There are many different types, but let’s just take accelerated TMS as one example for certain conditions. And then metabolic psychiatry or ketogenic diet generally in some variation.
And a friend of mine, I’m going to pull this up. Just yesterday, and it’s not necessarily a new study, but he sent me a link because I advised that he try the ketogenic diet for certain types of overwhelm and anxiety he was experiencing. Because the downside risk is so minimal, particularly if you’re only doing it for a few weeks and your lipid profile’s under control. And he sent me this study. And the title, this is from Cell. This is not from some random person’s blog. And the title is “The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet.” The ketogenic diet was used in the early, I want to say 1900s, for epileptic children. And they’d usually use heavy cream to make it easier for compliance. But had this — maybe it even predates that — this incredible effect on eliminating or reducing the frequency of seizures. And these are kids who might have hundreds of seizures a day.
And I’m looking at this study, and here is just a little excerpt. “Mice treated with antibiotics or reared germ-free are resistant to KD-mediated seizure protection. Enrichment of, and gnotobiotic co-colonization with, KD-associated Akkermansia and Parabacteroides,” If I’m saying that correctly. “restores seizure protection.”
I literally have probiotics downstairs that are akkermansia from a company called Pendulum, which is pretty legitimate. But, what? Okay, so it’s mediated partially through the gut microbiota. And it’s like, okay, well, then you have the interplay of microbiota with potentially the vagus nerve with this two-way communication channel. And then you look at, for instance, psychedelic assisted therapies. And there’s a lot that we can get into there. But also, and this is finally — and I’m not saying — there’s a lot of nonsense and a lot of navel gazing and crystal waving folks in the psychedelic world. No offense to anyone who falls in that demo. But there were some credible folks, including, for instance, Dr. Andrew Weill, who actually has an incredible history of ethnobotany and is very, very technical. And he lost his allergy to cats after a number of experiences with, I believe it was LSD.
And these anecdotes on the underground, at least, with facilitators who have thousands, maybe tens of thousands of repetitions with patient sessions, the losing of allergies comes up pretty constantly. And then I’m asking myself, well, maybe it’s not the content. Although, I happen to believe the content of these experience matters. But maybe it’s the anti-inflammatory effects. Okay, well, what does that mean? And then, okay, well, maybe it’s having some immunomodulating effect. Okay, well, is the vagus nerve involved? Maybe. It’s not beyond possibility. And then you look at neuroinflammation and the effects of whether it’s different types of brainstem or the effects on, say, inflamed microglia by psychedelics. Like reductions in TNF and all this stuff, TNF alpha have been tracked in the scientific literature. And I just get really, really excited because I can’t parse it all, but it seems like these things all, to use an awkward phrasing, are touching the hem of the same garment in some way.
Anyway, that was a whole bunch of word salad, but I don’t want to lose the story of Ulf, because we’re talking about the maps. We’re talking about the fact that, yes, you should maybe at best put it in quotation marks, “vagus nerve stimulation.” But could you tell the story of Ulf, if I’m saying his name correctly? And maybe comically, one of only a handful of Swedes I know is also named Ulf. It makes me think that maybe it’s the John of Sweden, I don’t know. But who is Ulf, and why does he tie into this ear mapping that we’re talking about?
Dr. Kevin Tracey: Ulf Andersson is a retired professor of pediatric rheumatology at the Karolinska Institute. He practiced there for many decades. And throughout that whole time he also ran a research laboratory that was focused primarily on cytokines, on inflammation and cytokines. As you said before, this is a guy who knows his stuff.
Tim Ferriss: Karolinska Institute is also top tier. They do some of the most fundamental, kind of seminal work related to a lot of stem cell applications, and so on, has also happened at the same institute.
Dr. Kevin Tracey: It’s arguably one of the best medical research institutes in the world, it’s one of the largest in Europe. It’s a major teaching center. It’s a fantastic place. I’ve been there many, many times. Ulf and I have been close friends and collaborators for many decades. And he was diagnosed with a condition that was thought to be a cancer in his bile ducts, in his liver, that required a major surgery called a Whipple procedure, where they remove most of the pancreas, if not all of it, and they remove part of the liver, and they remove part of the bile duct system.
This was a long time ago, but at the time it was a death sentence. The cancer that they thought he had, it turned out to be benign, which was a blessing in disguise, because he had to undergo this major surgery to have this. After the surgery he developed, for the first time in his life actually, he developed intermittent bouts of depression. Serious depression. Which he attributed to excessive inflammation in his GI tract. Which was, through unknown mechanisms, coming episodically and causing this depression. Which, as he talks about in the book, and he’s written about on his own, led to the end of his marriage and was really ruining his life. Well, this was around the time that Sangeeta and I had discovered these funny acupuncture maps of the ear and saw that some people were using TENS units. And we had published a series of papers at that point, understanding how vagus nerve signals could turn off inflammation. And so we said, “What the heck?”
We put TENS unit — an over-the-counter product you can get anywhere — with the electrodes on the cymba conchae, not the tragus, not the lump that sticks out on the side, not the pinna, not the earlobe, but on the cymba conchae. And then, we drew blood on ourselves and on other volunteers, healthy volunteers, and we measured cytokine production.
It’s a little complicated how we did that. It’s not just drawing blood and doing an assay. We actually measured the ability of the white blood cells traveling around our bloodstream to make new cytokines. And when we did those experiments, we could show very conclusively, and we published it all in peer-reviewed journals that in most volunteers, about 70 percent, seven or eight out of 10 people, 16 or 17 out of 20, you could reduce the amount of inflammation that the white blood cells would make if you put this probe in the ear for five minutes.
And at that point, Ulf said, “Well, I think I have an inflammation problem.” Vagus nerve stimulation stops inflammation. If you want to call this vagus nerves, you can also call it transauricular nerve stimulation, because there’s lots of other nerves to the ear, but that’s another matter. And Ulf said, he decided he would try it.
Now, I didn’t treat my friend, Ulf. He decided he would do this. He’s a bonafide physician. He could do what he wants. And I frankly was not very encouraging. I said, “Okay, whatever.” Well, as he writes, and I know this for a fact, I see him several times a year. It turned his whole life around. He added some antibiotic therapy also to treat the bacterial overgrowth in his intestines, which comes with the surgery that he had, the Whipple. But he also uses this TENS unit in his left ear religiously twice a day like brushing your teeth, he says. And he then subjected himself to a fascinating analysis.
So you mentioned heart rate variability a while ago, and that’s really complicated. But —
Tim Ferriss: Yeah, the more I try to learn about it, the more I’m like, “Wait a second.” Quantum mechanics or something, I’m like, “Wait, I thought I kind of knew what the hell you were talking about. Now, I don’t.
Dr. Kevin Tracey: Yeah, yeah, if you understand it, then you don’t understand. “If you think you understand it,” like Richard Feynman said, “you don’t understand it,” right? I think we don’t have to get into it now, but suffice it to say if you have a — it doesn’t matter what your wearable is, if it’s a Fitbit or an iWatch or 10 other things that measure heart rate variability, I think this is a hundred percent true. It might only be 90 percent true. They’re measuring different things.
Not because — they all start with measuring the distance between individual heartbeats, which is instantaneous heart rate. They all start with that. But what they do statistically after that can vary dramatically.
I’ve done this, Sangeet and I have done this for a while. We worked on heart rate variability and we made our own devices, and it gets incredibly complicated. And we dropped it because if you miss — if you get a PVC, if you get a periventricular contraction or you get two irregular beats in a five-minute recording, you’ve got hundreds and hundreds of heartbeats. It shouldn’t do much, right? It messes everything up. It changes all the statistics.
So we can’t get into that. Now, however, Ulf was contacted by a guy in Finland who sent him a watch he had invented that recorded heart rate variability as a function of respiratory sinus arrhythmia, which is what heart rate variability is actually, quote-unquote, controlled by.
So if you want to do the experiment, if your listeners want to do this, it’s very easy. Take a couple of big breaths in, two hard sniffs in through the nose, fill your lungs completely, and you’ll feel your heart rate speed up a little bit. And then, breathe out slowly for seven or eight seconds.
That increase in heart rate during inspiration is partly due to the change in pressure in your chest cavity, your thorax. As your diaphragm drops and you increase the volume, the pressure has to decrease. And then, as you exhale slowly, you’re actually increasing the pressure in your chest, in your thorax because you compress the volume.
Those changes in pressure all activate sensory signals in the vagus nerve, which go into your brain, which accelerate or decelerate your heart. Why? Well, because when you inhale, you want to accelerate your heart and exhale, you want to decelerate your heart. That’s the optimal physiological linkage. That’s the optimal physiological mechanism to maximize the amount of oxygen in your blood.
Now, this guy in Finland invented a way from the EKG of looking at the changes in the size of the QRS wave as an indicator of the heart shifting left and right, which also happens when your diaphragm goes down and comes back up. And so he found a way to measure respirations from the EKG and link it to the instantaneous changes in heart rate.
And what his HRV indicator is, in this method, is actually a correlation between the overlap between respiratory sinus arrhythmia and the breathing cycle and heart rate variability in the cardiac cycle. And that’s how you optimize oxygen uptake and delivery. It’s really cool, right?
Tim Ferriss: Yeah, it’s cool.
Dr. Kevin Tracey: And it’s pretty sophisticated stuff.
Tim Ferriss: So he ships the watch over to Ulf? Or — not watch. Device? Yeah.
Dr. Kevin Tracey: So Ulf puts it on and he’s got a terrible correlation between his heart rate variability and his respiratory sinus arrhythmia until he does his vagus nerve stimulation, and then it got a lot better. Now, that’s a pretty good experiment. It is an N of one —
Tim Ferriss: Yeah.
Dr. Kevin Tracey: And somebody, I’d love to see somebody repeat that on 50 people. But it’s still hard to explain because he does it over and over again on many different days and many different conditions. The real kicker is during COVID, my colleagues and I at Northwell did a clinical study. We heard of results out of China, out of Wuhan actually, where patients taking famotidine, the antacid, were significantly protected against some of the lethal complications of COVID.
We actually did clinical studies of this drug. You can buy it for pennies over-the-counter at Amazon and Costco and CVS and everywhere. It’s a safe antacid. And it turns out, we did the clinical studies in Northwell, and we did, then, laboratory studies in my lab. It’s a pharmacological vagus nerve stimulator.
Tim Ferriss: Really? What was it called again?
Dr. Kevin Tracey: Famotidine is the generic name. It’s got a bunch of brand names, including one of them is Pepcid.
Tim Ferriss: No kidding.
Dr. Kevin Tracey: Yeah, you read about it, it will blow your mind, actually.
Tim Ferriss: Wow. Okay.
Dr. Kevin Tracey: So, when Ulf combined, this is the end of the story. When Ulf combined the famotidine with the TENS unit in his ear, he gets 100 percent overlap. He looks like a 21-year-old kid with this overlap between respiratory, sinus arrhythmia and heart rate variability. He’s written about it. He’s published his own personal recordings. And it’s a remarkable story.
And it’s remarkable, not because it’s a story of one, but because let’s go back to what we said before. The FDA-approved vagus nerve stimulation for the treatment of depression decades ago, and it’s used a little bit more in Europe than it is in the US. In the US, it’s not routinely covered by insurance payment. So there’s been tremendous resistance to applying this. It helps about half the patients.
Now, once again, like we said with the rheumatoid arthritis, let’s be concrete about this. Let’s not be the standoff folks who say, “Well, it only works half the time. It shouldn’t be used.” Well, in some of the people that it’s worked in, they were suicidal and now they’re not.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: What is that worth?
Tim Ferriss: Yeah.
Dr. Kevin Tracey: In some of the people it’s worked in, they’re back at work taking care of their kids, taking care of the family. I think that it shouldn’t be — we should be doing it or not doing it based on the data we know so far. There should be a screaming call that we should be diving down into. We don’t know the mechanism, Tim.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: We don’t know why Ulf got better. We don’t know why half the patients with depression got better. I think somebody should do a really simple study. We should segregate the patients into some sort of inflammatory groups, risk groups or activity groups with depression, and treat the ones with the most inflammation with the vagus nerve stimulation and see if they get better because you’ve stopped their inflammation. And the other ones have depression from another etiology, another cause, another factor. These are the important questions.
Tim Ferriss: Don’t you work at a place with a bunch of scientists? What’s required for something like that to happen? Does it just require a Scrooge McDuck to fund the study? I mean —
Dr. Kevin Tracey: I’m the president of a great organization with great scientists. And yes, I am, and there is and will be more great work coming out of our place. But one place can’t do it all alone.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: This is a call for everybody to get interested.
Tim Ferriss: It’s also potentially a call for some interesting distributed, I guess we could call them studies. They’re not going to be RCTs. But hey, something is better than nothing if it has recognition of its limitations. For instance, the people who manufacture WHOOP bands, the people who make Oura Ring, I mean, they could potentially put out a call to customers to try to do some type of distributed study.
Of course, you might be dealing, well, actually, you’re not going to be dealing with self-reporting. You’d be dealing with self-reporting perhaps in documenting, using a “Vagus nerve stimulator.” But the data is going to be available to the company vis-à-vis. Maybe it’s anonymized in some fashion, but the patients could make their actual Oura or WHOOP band or Fitbit data available to the company if it’s not already available.
So, that could be pretty interesting. I recall actually, WHOOP, I believe doing something like that with veterans who were on a standardized dosing of, I think it was microdosing of psychedelics looking at impact on HRV or potential impact on HRV. HRV fluctuations associated, let’s put it that way.
Dr. Kevin Tracey: You mentioned before depression, serotonin inflammation. Should we pick up on that for a second?
Tim Ferriss: Yeah, let’s do it.
Dr. Kevin Tracey: As you read the excerpt before, there is evidence that some patients with depression get better with SSRIs and some patients don’t. And there’s also evidence that SSRIs can even make people who have known inflammation or experimental inflammation gain some benefit.
There’s also information that SSRIs in experimental conditions, clinical studies and experimental studies in the lab, can actually reduce inflammation. What we have to agree on is we don’t know what causes depression. And if we knew what caused depression, I think our chances of fixing it in more people would be better.
Tim Ferriss: Well, also, depression is, I mean, in my mind, could be like “Inflammation,” right? There could be many different species of depression or many different causes. I don’t know.
Dr. Kevin Tracey: I think there are. I think you’re right. And I think that’s not been parsed out very well yet because the focus has been this sort of excessive focus on serotonin as the hypothesis that has to be dealt with. And there’s lots of reasons for that, that we won’t get into now. But what I do like to raise again as a call to action, if you will, and a message of hope is we know that inflammation produces depression in animals and in people. It’s to the point now, there are some inflammatory molecules that are used to treat some conditions, some forms of cancer, for instance.
And when patients are signed up and they’re going to receive these therapies, this administration of cytokines that as their therapy that are known to cause depression, they’re often given a prescription to go see the psychiatrist to go on the SSRIs before they go get their therapy.
So we know inflammation causes depression. We don’t know completely how. There’s overwhelming evidence from many labs, including my own, that the presence of inflammation in the body activates signals that travel up, you guessed it, the vagus nerve. And so you can take a mouse, for instance, and inject it with IL-1, and the mouse will run in the corner of its cage. It’ll huddle up, it will look like it doesn’t feel well, like when you have the flu. It will avoid eating. It will avoid sex. It will avoid playing with toys in the cage. It looks depressed.
If you cut the vagus nerve back to your topic before, if you cut the vagus nerve in those mice and give them IL-1, they don’t get sick. They don’t get depressed. And so it puts the question, and the mind body experts and the far east religious dogmas focus on what we said before, the brain networks and the body networks are connected. And what I said before is the vagus nerve is a principal connector.
So if you have disruption of inflammation in the body, which you’re not even, maybe nothing hurts in your body, but your brain knows the inflammation is there, we call that interoception. It’s the subconscious sense that your organs are sending information about their status to your brain. If you have inflammation in your body, does it cause depression? That’s an important question.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: Because maybe that’s why those patients who do get better and go on YouTube and type in some videos of these depressed patients whose lives were turned around with vagus nerve stimulators, it will bring a tear to your eyes, some of their stories. And if you look at those people who have benefited — and Ulf with his TENS unit in the ear.
Tim Ferriss: Quick question, has Ulf published his setup? Is that something that people can find online if they wanted to experiment with five minutes twice a day of auricular stim?
Dr. Kevin Tracey: Yes, yes, he did. He published it in a peer-reviewed journal that I believe is open access. If you Google his name, Ulf Andersson, with two Ss, Andersson.
Tim Ferriss: Good, good old Swedish last name. I will link to that in show notes. We’ll find that and put that in the show notes for everybody.
Dr. Kevin Tracey: Oh, I can send it to you for the show notes.
Tim Ferriss: Okay, perfect, perfect. We’ll do that. And I interrupted your train of thought.
Dr. Kevin Tracey: No, that was the end. I just want to call the question out to my colleagues that we should study the influence of interoception, the presence of inflammation in the body being sensed by the brain in causing depression in some patients, and can we treat that with vagus nerve stimulation? Is that why it works in the 50 percent of the — why 50 percent? Isn’t that kind of a funny number? It works.
Tim Ferriss: That is. It’s too clean, right? It’s too clean. Yeah, I got scammed recently on my credit card at a gas station, and it was $175, and I was like, “That’s too clean. That’s absolutely a scam charge.” Plus, I know gas is expensive, but it’s not $175. But in any case, yeah, when the numbers are that clean, you’re like, “Wait a second here.”
Let me ask you, this is out of personal curiosity, and I was goofing around going all over PubMed, which is sometimes a dangerous business when you’re a muggle. But it seems like there are some interesting data around acupuncture in the ears and fertility or pregnancy. And I know you don’t like to speculate, but there may be people who have looked at this closely. Is it plausible that that is mediated by a vagus nerve stimulation?
Dr. Kevin Tracey: The simple answer is, yes, I don’t like to speculate.
Tim Ferriss: But I’m just saying mechanistically, would stimulating the vagus nerve have some downstream, possible downstream effect on the ability to conceive or anything like that?
Dr. Kevin Tracey: I don’t know the studies that you’re referring to. I really don’t.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: And I don’t know if acupuncture in the ear would stimulate the vagus nerve to stop inflammation. I know that what I did with an electrical TENS unit can reduce inflammation in the bloodstream of healthy volunteers. I can answer the question in the context of, are there some conditions in the abdomen, whether in the ovaries or the uterus or the fallopian tubes where the presence of inflammation would be restrictive or would make getting pregnant more difficult?
The answer to that’s a simple, yes. I mean, now the question is, if we had ways of selectively reducing that inflammation in the context of getting pregnant, if you could specifically reduce that inflammation, would you increase the chances of getting pregnant? Well, yeah, it’s quite logical. It’s plausible. Can vagus nerve stimulation do that? To my knowledge, nobody knows.
Tim Ferriss: I was just, again curious. And you know what? The first time this kind of — I’m probably using this term incorrectly, but sort of the homunculus on the ear came up in this podcast was with Martine Rothblatt, who I think has a quote on your book. Am I making that up?
Dr. Kevin Tracey: Martine is a close friend and another —
Tim Ferriss: Also, phenom, what a wild background and such a polymath.
Dr. Kevin Tracey: Martine’s another national hero. I mean, she’s a satellite launcher. She’s a satellite communications expert. She’s an accomplished pilot including flying her own battery powered helicopter and setting land speed records and distance records, and she’s a good friend, and the CEO of United Therapeutics. Yeah, Martine’s wonderful. We talk a lot about this stuff.
Tim Ferriss: All right. So I’ll leave a shout-out if people want to get to know Martine, definitely suggest my interview with her. And I wanted to come to something that you mentioned at the end of your STEM-Talk interview. And I really don’t have context on this, but it’s of interest to me because I have for the last few years had chronic low-back pain, which is if you want to wander into the Bermuda Triangle of hand-wavy imprecision in at least pain diagnoses or orthopedics, low-back is a good place to go.
And what I have figured out, there are certain things that help and putting aside the biomechanics and strength training and so on for a moment, I know that anti-inflammation helps. There seems to be an inflammatory component. So, whether it’s through applying cold or taking oral anti-inflammatories or injectables for that matter, it suppresses symptoms. I know that, and I’m reading a number of books, Lorimer Moseley and his co-author have, actually, a very interesting book called Explain Pain, and it relates to this piece that came up maybe, which is why I wanted to talk about it. Because sometimes, like you said, the response to the equivalent of a picket line in your body is the entire Navy showing up with rockets blazing and it’s a severe overreaction.
So this relates to Professor Rolls, and I guess I’m going to try to word this in a way that makes sense. But how specific molecules inform memories/engrams in the brain and the implications of that? Could you just unpack that for me because you guys didn’t really get into it in the STEM-Talk? But I was like, “Wait, wait, wait, wait,” I want to hold onto this because it seems very interesting and it might somehow be relevant to me. It might not be. But could you just explain what I’m very clumsily trying to evoke or I guess elicit from you?
Dr. Kevin Tracey: Yes, I would love to. So let’s start with the picket line. The picket line in the low back situation. And I’ve also had on-and-off sciatica from a herniated disc in my back with pain down my leg, so I can relate to this.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: So, in those instances, you have something in one of the joints of your back or potentially a fragment of a disc that’s pushing on a nerve causing pressure on the nerve, which sets up a cycle, which would be the picket line, right? There’s some injury there. There’s some injury, injury to the nerve, or there’s some injury in the joint, and that’s the picket line. It shouldn’t be a big deal to the human body having evolved over hundreds of millions of years. But in some people, not all, if you look at MRI scans, right? Everybody else’s back looks just like yours, right?
Tim Ferriss: Yeah, they look all messed up.
Dr. Kevin Tracey: They all look the same.
Tim Ferriss: It’s just like you get wrinkles on your face, your spine starts to look pretty funky.
Dr. Kevin Tracey: Exactly.
Tim Ferriss: So, I’ve got arthropathy. I’ve got the right foraminal stenosis at blah, blah, blah, blah, blah. But —
Dr. Kevin Tracey: So does everybody else.
Tim Ferriss: Yeah, you can look at hamburger meat on an MRI of a back, and they’re asymptomatic.
Dr. Kevin Tracey: Right. So why does your back hurt and somebody’s MRI scan would be indistinguishable from it doesn’t hurt? Well, if you could maybe pinpoint the position on your MRI scan. Now, the question is different, right? Now, the question is, why is your body sending the Navy with rockets blazing to the picket line in your back, but not the guy next door?
Tim Ferriss: Yeah.
Dr. Kevin Tracey: Well, that is the question. So how can we connect that to two things? One to — because Ulf’s back pain got better. Two, by the way, he had injured his neck in a sailing — he was a world-class sailing champion. I don’t know if that made the book or not.
Tim Ferriss: I don’t think that was in there. I love this guy.
Dr. Kevin Tracey: He and his brother Jan Andersson won the European World Championships in the J class.
Tim Ferriss: Of course they did. Of course they did.
Dr. Kevin Tracey: In the 1960s. And, of course, ABBA sent them to the World Championships when they were in New Zealand or Australia or something, and they competed in the Olympics at UCLA at the L.A. Olympics.
Tim Ferriss: Wow. Wow.
Dr. Kevin Tracey: Anyways, his back got better. And so, the question is, why did his back get better? Because the signals from the ear to the brainstem went down the vagus nerve to the spleen and reduced the turnover of the inflammatory cells. Well, that’s a definite maybe. And what we know from very careful experiments in animals and some experiments in humans is that when those vagus nerve signals end up in the spleen, they switch the white blood cells.
Now, the spleen gets 20 percent of cardiac output. So all your white blood cells are racing through the spleen all day long. And when they pass through and pick up this nerve signal, they switch from a state called M1 to M2. M1 macrophages and monocytes, white blood cells, they’re the Navy shooting guns full blazing that you said. M2 are the doctors and nurses in the ambulances who race to the scene to heal.
Tim Ferriss: Mm-hmm.
Dr. Kevin Tracey: And so that’s an important area that a lot of people are chasing. And that’s in the context of therapy that we’ve been talking about. That’s probably how it works in rheumatoid arthritis actually, is the signals are switching the white blood cells as they pass through the spleen. So, when they go to the elbow or the knee or the hand, they tend to heal the cartilage of the joint.
Tim Ferriss: That’s M2 instead of M1?
Dr. Kevin Tracey: It’s M2 is better than M1. Exactly right. So, yeah, M1 to M2. So, that’s a take home point. That’s a simple way to think of how you get a nerve, the vagus nerve stimulation, which doesn’t go to your elbow and it doesn’t go to your wrist or your — but that’s why, they probably get better is because it changes the white blood cells that are going to the scene.
So what else is happening? Well, when that inflammation settles in, say, the colon, Asya Rolls, in a brilliant, I think one of the most important scientific papers in the field of what we call neuroimmunology, and maybe in the last 25 years, she discovered that what’s happening in the inflamed tissues in the colon in this case is actually forming a neural network in your brain, which you can think of as a memory. It’s called — neuroscientists call it an engram.
Tim Ferriss: So, that also be like a phantom limb. Would that be a, or is that a different thing? I don’t want to take us off track.
Dr. Kevin Tracey: No, it would be similar to a phantom limb, but it’s more concrete. And I’ll tell you why. And this is what’s so amazing about it. So, neuroscience has studied memories and engrams for many years and using a method that we call trapping technology. And so what you do is you have a genetically engineered mouse, a mouse with special genes that you can put in when it’s an embryo, and the mouse grows up with these genes.
And now, when you do something to the mouse, if you co-administer, say you give the mouse a drug, or you give the mouse inflammation, when you do that, at the same time, you give the mouse a drug that activates these special genes that turn the neurons red, for instance. But only the active neurons.
So, the neurons that get activated by the presence of, say, colitis inflammation in the bowel, they turn red and they stay red. So you can study them later, even weeks and months later. And that’s exactly what Professor Rolls did. She used another very sophisticated trick to take what’s called stereotactic injections, injecting virus particles into specific parts of the brain that she had mapped from looking at the red neurons. So she knew these are the neurons that get activated by colitis.
So she’d had the mice and she let them recover from colitis, and then she injected the virus into those neurons and reactivated. Now, just the neurons, not all the neurons in the brain, just the ones that remembered the place of the colitis, and they got colitis again.
The changes in the brain neurons. I call it a neural network. She does too. I mean, we all call it an engram or a neural network. There’s lots of neuroscientists have talked about this on lots of podcasts, but they call it the Jennifer Aniston neuron or the Santa Claus neuron. I’m a recovering neurosurgeon, right, Tim?
So you can do brain surgery under local anesthesia, and this is done a lot of times for epilepsy surgery, for instance, when you want to make sure that you don’t injure any part of the brain involved in speech. So, you can be talking to the patient during brain surgery. Now, you can put electrodes in various parts of the brain and ask the patient what’s happening. And there’s a famous story of a patient, “Well, I just saw Santa Claus,” or “I see Jennifer Aniston.”
And so it’s euphemistically, people call that, “Well, you have a Jennifer Aniston neuron.” Well, you actually don’t have a Jennifer Aniston neuron because you could put an electrode in another part of the brain and you say, “Well, Friends, the TV show,” and Jennifer Aniston’s neuron will light up in that because they’re part of a network.
Tim Ferriss: Right. It’s a constellation that is recognizable by the brain as —
Dr. Kevin Tracey: It’s a constellation. Exactly right. Well, nobody before Asya’s studies, nobody thought that a constellation in the brain would recognize inflammation in a way that would not only remember the effects of it, but could then reactivate it.
Tim Ferriss: Not to interrupt, but since every podcast I do is self-interested in some way, is there a way to delete, control Z, those constellations so that you don’t have this hair trigger response to triggering colitis or low back pain response, right? And in this book that I was mentioning, Explain Pain, they talk about how surfers in instances, sometimes when they get their leg bitten off by a great white, they report it as a thump. It wasn’t painful. Whereas you get a paper cut and it’s excruciating, and there’s so much variability.
So is there a way to deactivate a constellation or overwrite it, or I guess fix my fucking low back pain is the short answer, without taking bottles and bottles of Aleve?
Dr. Kevin Tracey: This is about the third time in this chat we’ve had that I wanted to offer you a job in my lab. You ask all the right questions. We could do the experiments if you come in.
Tim Ferriss: Well, you’re not that far away. I mean, don’t threaten me with a good time.
Dr. Kevin Tracey: The simple answer is that’s what we want to do. So you might not have to remove the whole network. You might just have to disrupt a little bit of it.
And the question is, can you disrupt it with a molecule that targets selective neurons? That’s tricky, but not impossible. You have to figure out what the neurons are, figure out what the receptors are, figure out what’s unique. Then you have to design a drug to do that. That would be one approach.
But the approach I like, and again, I’m a recovering neurosurgeon, so call me what you want, but there are millions of people walking around with deep brain electrodes, millions. And it sounds like this horrendous, terrible thing, but it’s not. The electrodes that people are putting in now, whether it’s Neuralink or somebody else, I mean, they’re smaller than a human hair. And they go in and they don’t injure blood vessels and sometimes they don’t even injure neurons. They go next to the neuron. You could imagine a time in our lifetimes, I hope, when, if we knew how to target those neurons or map them in advance, that you could put these electrodes in and inhibit them. And yeah, that is the right question. I’m dead serious.
Now Asya’s paper has been out a couple years. I said before, I think it’s one of the most important studies that I’ve read in many years, and we have, of course, pursued it. We’ve been asking questions, my colleagues and I, Sangeeta Chavan and Okito Hashimoto and Eric Chang, we’re asking a very simple question. Can we make engrams, memories, neural networks in mouse brains, of specific cytokines?
And we’re writing the manuscript as I speak, and the answer is yes. We can show that when you give a mouse TNF, which causes a sickness behavior, it looks like it has the flu, and then a bunch of other metabolic things that are specific to TNF and map an engram, we can see where the neurons in the brain are and see what they do, when we do the same experiment with IL-1, which also gives a sickness response, but has a very different sort of metabolic physiologic, you can separate them. They’re unique. TNF and IL-1 are different. The physiology is different. We see a different neural network.
So now it’s complicated because how many cytokines are there and how many physiological states? I think the brain, a human brain has what a hundred billion neurons give or take, and trillions of synapses. So it’s more complicated than we think it is, but I think it’s accessing, processing, and potentially storing all the information that we haven’t even begun to imagine yet. And that’s what this data tells me.
Tim Ferriss: What are the possible implications of identifying the constellations? I just keep thinking about stars. It doesn’t take much to screw up Orion’s belt, right? If you move one or two things around, you could disrupt that engram, so to speak. What are the implications of identifying the engram signature of TNF-α IL-1, et cetera?
Dr. Kevin Tracey: What are the implications of it?
Tim Ferriss: Yeah, well, how would that translate or might it translate to some type of clinical practice?
Dr. Kevin Tracey: Well, I think you could literally, if you knew where to put the electrodes into the brain, you could have an electrode in the brain that communicates with an app on your iPhone, and you could dial it to up regulate or down regulate your inflammatory response to a specific cytokine or condition in a specific part of your body. Yeah.
Tim Ferriss: Yeah. That’s wild.
Dr. Kevin Tracey: It is. You said it right. I mean, people used to think it was impossible to track an incoming missile from the moon, but now they know how to do that. And the best example I like, and you’re better at this than I am, but someone explained the analogy I like the most. If you look at a TV screen with all the pixels and you see a picture of the Alps, you can’t possibly pick out the black square or the altered colored square. But if you swap that one square and make it a really bright color or a really black color, you actually can see it. It’s about subtracting, right? It’s about subtracting to pick out what you don’t know.
In order to do that in humans, there’s been all this rush to do brain imaging and brain anatomy. We still have a long ways to go because to my satisfaction, as someone who thinks about systems interacting and biology, we haven’t put enough emphasis on function.
Tim Ferriss: Yeah.
Dr. Kevin Tracey: And I think even for heart rate variability, you and I can’t talk about heart rate variability ’cause we don’t know enough about the individual functions of the individual wiring diagrams.
Tim Ferriss: Yeah. And also, we can talk about science and studies and so on, maybe separately over a glass of wine or something, but sometimes the imaging tail wags the dog also for a host of reasons.
Dr. Kevin Tracey: Yes, yes.
Tim Ferriss: You get these beautiful pictures and there’s maybe some status associated with getting a bunch of money to play with the latest toys, and then you can slice and dice the data to create all these different publications. There’s an allure that I think can sometimes lead to an overemphasis on the imaging, which is not to negate some really, really incredible applications of the imaging, but I think what you said carries a lot of weight.
Let me ask, because there will be people listening who are curious about this. Cervical TENS units. So we talked about the transcutaneous auricular stimulation. There are devices, including some that are FDA-approved for, say, I believe cluster headaches and/or migraines, I can’t recall exactly, that are neck-based and could be applied to one side, could be applied to both sides, but effectively, supposedly, tracking or stimulating the vagus nerve where it would correspond to your pulse, let’s just, say carotid artery or arteries.
And there are a number of, you can find a number of publications on PubMed that talk about the data, but what might be the, if in fact they are doing something that is beyond placebo effect, what might the mechanism of action be? And you can start wherever you like. I’m just curious about the cervical devices because they’re floating around out there, and I’ve seen at least a few studies and I’m like, “Huh, okay, well, what the hell is going on here if in fact there is a signal instead of just noise?”
Dr. Kevin Tracey: I think it’s important to say that when you dive into these kinds of questions, there’s lots of factors. So the first is, can you afford to buy lots of devices and try lots of different things? That’s one approach. And second, do you like self-experimentation? That’s another approach. A third is, well, always check with your doctor first ’cause there are some things you probably shouldn’t do around the area of your neck. If you have carotid stenosis, you don’t want to put any pressure on your carotid artery. If you have cervical stenosis, you don’t want to turn your head certain ways.
Tim Ferriss: For sure.
Dr. Kevin Tracey: Check with your doctor. So those are actually important disclaimers. That’s not a joke. People should check with their doctor before they do these things, unless of course what they’re doing is FDA-approved. And some of these devices, most of them not, but some of these devices have been subjected to FDA approval.
In the context of putting electrodes on your neck, there are some FDA-approved devices that are called vagus nerve stimulators, and they are essentially TENS units. They deliver pulses of electric current, spikes of electric current, usually between 20, 30 hertz, usually on the order of milliamps. And you know it’s working because you feel a buzzing or a tingling. And when you put it on your neck, usually you know that the current is spreading around through the skin and through the nerves of your neck, because your platysma muscle, the muscles of facial expression in your neck will twitch, or your lip will twitch.
Tim Ferriss: Pull your lip down. You can make some goofy faces.
Dr. Kevin Tracey: That’s happened to you, right?
Tim Ferriss: Yes.
Dr. Kevin Tracey: Yeah. So that’s evidence that the electric current is activating lots of nerves and lots of muscles. Now, time for a slight digression. The carotid artery is encased in a sheath with the vagus nerve. So to get to the vagus nerve, you have to go through the skin, through the platysma muscle, through the layer of subcutaneous fascia, through the sternocleidomastoid muscle, which is that big thick strap muscle in your neck, thicker in some than others, but it’s there, down to the carotid sheath, maybe through another layer of fascia, through the carotid sheath, and then somehow either around or through the carotid artery.
Tim Ferriss: Right. So it seems like the TENS unit is not going to hit the vagus nerve.
Dr. Kevin Tracey: Engineers I’ve spoken to at length about this say, and I said it very politely and clearly in the beginning of the show, the only way to directly stimulate the vagus nerve is to put an electrode on the vagus nerve. That’s not this. You’re putting an electrode on the skin. Or to use focused ultrasound, which would penetrate all those tissues and could be focused to the vagus nerve in the neck. But those devices are not available for us to use at home. So your question was, could it work anyways? It’s FDA-approved to treat migraine, and the answer is —
Tim Ferriss: Well, my question was what the hell might the mechanism be if it’s not actually getting through all that stuff to hit the vagus nerve?
Dr. Kevin Tracey: I have a very good answer for you.
Tim Ferriss: All right. Collective delusion and placebo —
Dr. Kevin Tracey: No, no, no.
Tim Ferriss: Mass placebo? No?
Dr. Kevin Tracey: No, no. To defend the manufacturers and the FDA patients who put this on their neck and use it according to the FDA label and have severe migraines, a significant percentage of them do better than for patients who don’t use the device. So this is an example that we talked about before where you have a device, we don’t necessarily know how it works. It might work through some other mechanisms, but it seems to work in a statistical way in FDA-approved, randomized clinical trials.
Put that aside. How could it work? We’re talking now science here. Well, Charles Sherrington, one of the two fathers of neuroscience with Ramon Y Cajal back in the early 1900s, he wrote a famous book which I recommend to anyone, even casual readers of neuroscience should read Charles Sherrington’s book, The Integrative Action of the Nervous System. The title alone is brilliant, The Integrative Actions of the Nervous System.
He taught us this. It’s so simple, you’ll never forget it. You have to understand a simple reflex because there’s an input and then some sort of connection or process and an output. And that’s what happens when the doctor taps your knee. That’s what happens when inflammation happens in your body, and the signal goes in. Well, in the knee case, the rubber hammer stretches the tendon. The tendon sends a signal up your sensory nerves to the spinal cord. The spinal cord sends the signal back down to your quadriceps, femoris, your leg pops up, and you said, “Shit, who did that?” That’s a reflex.
In the context of inflammation, there’s inflammation in your body, the signal goes up your vagus nerve, signals come back down, stop the inflammation. That’s the inflammatory reflex.
“Got it. Okay, Charles, we got that. What’s next?” Then he said, “If you assemble a couple of reflexes, you could start to build a nervous system.” This is, again, this is your field more than mine is neural networking. You can assemble things. You can build up complex systems by just adding one more reflex, right? One more input, one more output, and then they start to connect. And then he goes, “End of the day, there’s no such thing as a simple reflex ’cause every nerve in your body is connected.”
So you put electricity on your neck. Some of it’s going to end up stimulating nerves that go into your brain or your spinal cord. Once it gets in the brain or the spinal cord, there’s the big router. The brain can decide how to send it out. In some patients, does it relax the muscles of the neck to interfere with a headache pathogenesis? Maybe. In some patients, does the brain send signals down the vagus nerve to stop inflammation contributing to migraine? Maybe. In some patients, does the brain send signals up to the resistance arteries that are controlling blood flow in and out of your brain that can give you a tension headache? Maybe. We don’t know. Nobody knows.
Tim Ferriss: I mean, it’s exciting to me that there are so many open questions. So just these like, just enough of a teaser and a taste test of something to make it really tantalizing to investigate further.
And my friend, he’s using a cervical device, the one who tripled his HRV. So who the hell knows, right? And ultimately, he and I were talking ’cause after our first chat, I was like, “Hey, man, I might have some good news, bad news.” And I was like, “Seems like your device is working for you, and I don’t want to burst the placebo effect. But also, it doesn’t seem to be a vagus nerve stimulator.” But we were joking, and I think one of us is probably me ’cause I’m a goofy ass a lot of the time, but I said, “I guess at the end of the day, ultimately you don’t really care if you’re somehow summoning Odin to come down with a magic unicorn and pierce you through your forehead with the spike like a narwhal to fix your low back pain or increase your HRV. You just want the output.”
So whatever is happening, it would be great to understand what’s happening under the hood, but it’s like you might like driving your Tesla. You don’t — how many people actually know how it works? Or the microwave or the refrigerator. Which is not to say that you want the larger scale RCTs and mechanisms of action. So I’m not trying to dismiss the importance of all of that or the power of placebo.
Dr. Kevin Tracey: Well, I don’t know if it’s placebo. You said it’s the power — It could be the power of one. And it could be that if a hundred patients were subjected to this and 75 percent of them have the effect your friend has, now that’s really interesting. Why? You know? This is where some people like to reach too far when they’re hawking their wares.
Tim Ferriss: Some of the websites selling these things are so bad, I mean, so bad. You expect them to be selling boner pills and kratom and some sketchy, shitty cryptocurrency at the same time in the checkout process, they’re so bad.
Dr. Kevin Tracey: Yeah. People say, “Oh, well, is it safe?” Well, that’s important. But then you raise people’s hopes and then you take their money and you don’t know what you’re doing. I mean, there’s real questions there. I’m not saying it’s easy. Look, the simplest, what people would say is the simplest, stupidest clinical trial of one of these devices might cost $5 million or more.
Tim Ferriss: Yes, science is expensive. Good science is expensive.
Dr. Kevin Tracey: Yes. Yes.
Tim Ferriss: Yeah. All right. So we’ve covered a lot of ground. I highly, highly, highly recommend people check out The Great Nerve if you want, not just things we’ve talked about. We could do three rounds of the podcast. I didn’t even get through a small portion of my notes. And also in your book, I want to point out, because this is important, you have an entire section dedicated to different types of tools with some really remarkable results, whether that’s breath work, cold exposure, meditation.
You know what? Maybe just as a fun way to bookend this, could you please tell the story? You’ve got some amazing stories in the book. Could you please tell the story of the Dalai Lama? You got it. I mean, people are like, “What, the Dalai Lama? How the hell. It’s a good fit into this. Yeah. All right, so please, please tell that because it’s just fun. I mean, it’s so fun. It’s also fascinating, but it’s fun.
Dr. Kevin Tracey: Back in the day, was it about 2007, give or take? I can’t remember the year. It’s in the book. Maybe 2010. I got a call from the Dalai Lama’s New York office, would I like to go to a conference? Now the call came from a gentleman named Bill Bushell, who is a scientist in his own right who was working full time in the Dalai Lama’s organization. And he had been following my work. Because of these questions on the role of the vagus nerve and meditation, the Dalai Lama, of course, famously has participated and supported many, some very sophisticated brain imaging studies and meditation studies. And the Dalai Lama is on the record of saying that he’s convinced that the major tenets of his religion are true in a quantum mechanical way, as you alluded to before, from any perspective. His tenets are like the speed of light. They don’t change.
And he said, to the point that in fact, if Western science or new world science could disprove any of his tenets, then he would change the tenets. He has a deep interest in science. He hosted a meeting here in Phoenicia, New York on the top of a mountain where they own a compound, right outside of Woodstock where the rock concert was. I drove up there. Not all the funny stories made the book, Tim, but one I have to tell is when I’m checking in, I got there late, so it was dark, and I’m in the middle of the woods. And I like the woods. I like to camp. I like to be outside.
Tim Ferriss: I’ve driven by this place. It is in the middle, I mean middle of all of the woods, yeah.
Dr. Kevin Tracey: They own the whole mountain, right? So it’s dark, it’s nighttime. And they give me keys to a cabin in the middle of the woods. And as I’m going out the door, the woman says, “Don’t mind the bears.” And I’m like, “Fine, I’m going to walk in the dark.” It was through the bears to my cabin. And I said, “Well,” I’ll make a joke. And I said, “Well, I know they were here first, right? Ha ha.” And she looks at me with steely eyes. It’s like, “Okay, welcome to Woodstock.” I’m like, “This isn’t like the concert.” So the next day —
Tim Ferriss: “Good evening, sir.”
Dr. Kevin Tracey: Exactly. The next day I’m on stage. The next day was two days of scientific talks, a whole series of times — I gave one. I remember Liz Blackburn was there, and when she was there was the time, it was during the meeting it was announced that she’d won the Lasker Prize. I think a year or two later, she won the Nobel Prize. So Liz and I were there and a bunch of other scientists. And the last day, the organizers came up to us and asked Liz and I if we would summarize the meeting for His Holiness the Dalai Lama on stage in front of all the attendees. So we said, “Sure.”
So Liz gave a talk, and then I gave a talk. I’ll never forget, I was on stage with the Dalai Lama with Bob Thurman who was sitting to his side. And that’s Uma Thurman’s dad. And he’s a professor of Tibetan studies and other studies at Columbia at the time, Columbia University. And a translator sat between us.
And I explained the vagus nerve and I said the vagus nerve. And he asked the question you did, “Where is this vagus nerve?” And I said, “It travels down your neck, across your chest, into your abdomen.” He goes, “Oh.” And then he said, through Bob, he said, “Is it in the front or the back?” I said, “Well, it’s in the front.” And then he said, “Is there one or two?” And I said, “Well, there’s two.” And then he smiled at me and that was that.
And then afterwards he left and a few monks came up to me, and In their long, flowing orange robes, as Bill Murray would say, striking, and they said to me, “His Holiness asked you those questions. Do you know why he asked you those questions?” I said, “No, I haven’t a clue.” And they said, “Well, we like to practice. One form of Tibetan meditation is we like to practice a cloud of blue energy over our heads that we channel in two waves down each side of the neck, across both sides of the chest, down into the abdomen.” And I said, “Cool.” And the monk said, “Yeah, it’s very cool.”
Tim Ferriss: Not everybody gets a Dalai Lama story. Yeah, that is a good one.
Well, people can find The Great Nerve, which includes so much more anywhere that you find your books. Dr. Kevin Tracey, T-R-A-C-E-Y. Is there anything else you’d like to say as we wind to a close, anything you’d like to add, point people to, requests, reminders, public complaints, anything you’d like to say before we land the plane?
Dr. Kevin Tracey: One thing. These things in the book and that a lot of people talk about for self-help, they’re good. I do them. Meditation is good. Exercise is good. Watching your weight is good. Getting enough sleep is good. All of these things I think are good to reduce the inflammation in your body. And they are good to probably to give your vagus nerve some exercise and improve your heart rate variability. It’s all good.
I just don’t like to say that it’s the cure for some of these serious medical conditions. And the fact that we now have a path to connect literally decades of science to now 15 years, 12 years of clinical trials on this science that gives hope to some patients with serious inflammatory conditions that stimulating their vagus nerve with this immunoregulator is what we really call it, this is an exciting time. And I really appreciate you having me on the show. And there’s more questions we could talk about next time maybe.
Tim Ferriss: Yeah, maybe round two of cognitive enhancement with vagus nerve stimulation. I mean, I could keep going, keep going for many, many hours, but I’ll call it here for now.
And everybody listening, we will provide links in the show notes to many different studies to Ulf Andersson’s protocol for the five minutes, twice a day, of course, to SetPoint to the New York Times piece as well, and to the book, The Great Nerve. And you’ll be able to find all of that at tim.blog/podcast. For the show notes, just search. My friend Kevin Rose will pop up a lot if you search Kevin, so search Tracey, T-R-A-C-E-Y, or vagus or vagus nerve, and this will pop right up. And until next time, folks, be just a bit kinder than is necessary not just to others but also to yourself. And as always, thanks for tuning in.
The post The Tim Ferriss Show Transcripts: Dr. Kevin Tracey — Stimulating the Vagus Nerve to Tame Inflammation, Alleviate Depression, Treat Autoimmune Disorders (e.g., Rheumatoid Arthritis), and Much More (#824) appeared first on The Blog of Author Tim Ferriss.
2025-08-28 01:28:58
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本期播客邀请了费恩斯坦医学研究所所长凯文·J·特雷西博士（@KevinJTraceyMD）讨论迷走神经刺激疗法。特雷西博士是迷走神经研究的先驱，也是《伟大的神经：迷走神经的新科学以及如何利用其修复反射》一书的作者。
特雷西博士的主要贡献包括：
播客内容涵盖了迷走神经刺激疗法的可信度与伪科学的区分，迷走神经的解剖结构，细胞因子和炎症，生物电子医学方法与药物方法的比较，迷走神经刺激对抑郁症和炎症的影响，以及冷暴露、冥想和呼吸练习对迷走神经的影响等方面。
讨论的疾病和疗法包括：类风湿性关节炎、克罗恩病、创伤后应激障碍、慢性疲劳综合征、抑郁症、莱姆病、神经退行性疾病、过敏性休克、哮喘、败血症、银屑病关节炎、自身免疫性疾病、COVID-19、阿尔茨海默病、帕金森病、代谢综合征、糖尿病、癌症、疟疾、肺结核、消化性溃疡病、癫痫、丛集性头痛、偏头痛、坐骨神经痛；迷走神经刺激（VNS）、音频脉轮清洁音轨、生物制剂、生酮饮食、外源性酮体、GLP-1激动剂（如Ozempic、Mounjaro）、微生物移植、经颅磁刺激（TMS）、聚焦超声、迷幻药（如LSD、2C-B、阿яхуаска）、经皮神经电刺激（TENS）装置、耳穴疗法、法莫替丁（Pepcid）、抗生素、选择性5-羟色胺再摄取抑制剂（SSRIs）、布洛芬、单克隆抗体、光遗传学等。
关键概念和理论包括：多导理论、心率变异性（HRV）、交感神经兴奋、炎症反射、生物电子医学、血脑屏障、细胞因子（如TNF、IL-1、IL-6）、细胞因子风暴、炎症衰老、神经炎症、神经可塑性、内感受、痕迹记忆、M1和M2巨噬细胞等。
播客还提到了SetPoint Medical公司获得FDA批准的用于治疗类风湿性关节炎的迷走神经刺激装置，以及其他一些研究人员和机构。 最后，播客强调了区分可信的迷走神经刺激疗法和伪科学疗法的重要性，并呼吁对炎症相关的疾病进行更多研究。
Kevin J. Tracey, MD (@KevinJTraceyMD), is president and CEO of the Feinstein Institutes for Medical Research at Northwell Health, a pioneer of vagus-nerve research, and author of the recent book The Great Nerve: The New Science of the Vagus Nerve and How to Harness Its Healing Reflexes.
His contributions include identifying the therapeutic action of monoclonal anti-TNF antibodies and discovering the specific reflex control of immunity by the nervous system, called the “inflammatory reflex.” These discoveries launched the new scientific field called bioelectronic medicine, which investigates the therapeutic applications of vagus-nerve stimulation to cure disease.
Dr. Tracey, a neurosurgeon, pursued studies of inflammation after the mysterious death, from sepsis, of a toddler who was in his care. His lab has since revealed molecular mechanisms of inflammation and identified the use of vagus-nerve stimulation to treat it. An inventor on more than 120 US patents and the author of more than 450 scientific publications, he is among the most highly cited scientists in the world. He co-founded the Global Sepsis Alliance, is the author of Fatal Sequence, and is a national and international lecturer.
Please enjoy!
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X | The Feinstein Institutes of Northwell Health | SetPoint Medical | LinkedIn
The transcript of this episode can be found here. Transcripts of all episodes can be found here.
“60 million people die on the planet Earth every year. And 40 million of them die from heart disease, stroke, neurodegeneration, Alzheimer’s, Parkinson’s, metabolic syndrome, diabetes, and cancer. So two thirds of the people that die every year on the planet Earth die of those conditions. And that’s according to the WHO. Those conditions all have one thing in common: they’re either caused by inflammation or made worse by inflammation.”
— Dr. Kevin Tracey
“It was just announced that the company SetPoint Medical, which will now be marketing a device to stimulate the vagus nerve to treat rheumatoid arthritis, has received FDA approval. So there’ll be a product launch underway for everything we’re about to talk about in the context of using a medical device that activates an evolutionarily conserved and ancient reflex through which the brain can suppress inflammation when it’s running out of control.”
— Dr. Kevin Tracey
“We’ve discovered that signals travel from the brain through the vagus nerve. … These signals traveling in the vagus nerve are like the brakes on your car. And when you tap those brakes to slow your car barreling down the hill, this device activates what we call the inflammatory reflex.”
— Dr. Kevin Tracey
“If we can find such nerves, then we can build devices to control the nerves, and the devices become the therapy. The bioelectronic medicine story works as long as you know the molecular mechanism, and that’s where people have to be really careful with vagus-nerve stimulation.”
— Dr. Kevin Tracey
“Almost everybody until a hundred years ago, 150 years ago, almost everybody died by the time they were 30. And what happened in the last 150 years can be summarized in a very simple sentence. The human race in the last 150 years removed infection as the leading cause of death. … I think something similar will happen maybe in the next 20 years if we can really understand how to modify inflammation.”
— Dr. Kevin Tracey
“My adage for this thing is, when you don’t understand a disease, think of epilepsy. You start off, you blame God. So they did exorcisms, and that doesn’t work. So if it’s not God’s fault, the next thing you do is you blame the patient. And when you realize it’s not the patient’s fault, in today’s era, oftentimes we find out it’s actually caused, there’s some infectious cause of this thing. And so autoimmune disease may have an infectious cause, it may have an environmental cause. People talk about genetic causes. You inherit some level of risk for autoimmune diseases, but in very few of these conditions do you actually inherit the condition.”
— Dr. Kevin Tracey
Want to hear another episode about the future of electroceuticals and brain stimulation? Listen to my conversation with Stanford’s Dr. Nolan Williams, in which we discussed 70%–90% remission rates for treatment-resistant depression, brain stimulation for sports performance, accelerated TMS protocols, de-risking ibogaine for TBI/PTSD, the future of “electroceuticals,” and much more.
The post What Most Has My Attention Right Now — Credible (vs. Bogus) Vagus Nerve Stimulation (#824) appeared first on The Blog of Author Tim Ferriss.
2025-08-22 03:23:48
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本文是Tim Ferriss对斯坦福大学眼科系主任兼Byers眼科研究所所长的Jeffrey Goldberg博士的访谈记录总结。Goldberg博士是视觉系统发育和退化方面的领先科学家，也是一位执业眼科医生和外科医生。
访谈主要围绕改善视力，特别是预防和治疗老花眼（presbyopia）展开，涵盖以下几个方面：
1. 超常视觉表现 (Supranormal Vision): Goldberg博士解释了专业运动员通常拥有比正常人更好的视力，并探讨了通过训练（例如使用降低帧率的眼镜）来提升视力的可能性。
2. 眼部解剖结构: 访谈中详细介绍了眼睛的解剖结构，包括角膜、瞳孔、虹膜、晶状体、玻璃体和视网膜等，以及光线进入眼睛并最终转化为大脑信号的过程。
3. 改善视力的方法: 讨论了多种改善视力的方法，包括：
4. 老花眼和近视: Goldberg博士解释了老花眼和近视的成因，并强调了佩戴眼镜的重要性，以及红光和紫光疗法在控制近视方面的作用。
5. 视觉丧失与认知能力: 访谈中指出，视觉丧失与认知能力下降之间存在关联，改善视力可能有助于延缓认知能力下降。白内障手术可以逆转部分认知能力下降和抑郁症状。
6. 神经退行性疾病和免疫系统: Goldberg博士强调了免疫系统在包括青光眼和黄斑变性等神经退行性眼病中的作用，并指出抑制特定免疫反应可能成为治疗这些疾病的新途径。
7. 线粒体健康: 访谈讨论了线粒体在细胞功能中的重要性，以及红光疗法和一些补充剂对线粒体健康的影响。
8. 临床试验: Goldberg博士鼓励人们参与临床试验，以推动眼科疾病治疗方法的研发。他推荐了clinicaltrials.gov网站以及一些眼科疾病基金会的网站作为寻找临床试验信息的资源。
总而言之，访谈内容丰富，涵盖了眼科健康领域的多个前沿研究方向，并强调了科学研究和临床试验在改善视力方面的关键作用。 Goldberg博士对未来视力恢复技术的乐观态度也令人印象深刻。
Please enjoy this transcript of my interview with Dr. Jeffrey Goldberg, chair of the Department of Ophthalmology and director of the Byers Eye Institute at Stanford University. He is a leading scientist in the development and degeneration of the visual system from eye to brain and a professor, practicing ophthalmologist, and surgeon.
Dr. Goldberg is a member of the National Academy of Medicine and has won a number of prestigious awards, including Scientist of the Year by the Hope for Vision foundation and the Cogan award from the Association for Research in Vision and Ophthalmology. Dr. Goldberg received his BS magna cum laude from Yale University and his MD and PhD from Stanford University, where he made significant discoveries about the failure of optic nerve regeneration.
Dr. Goldberg’s research is directed at vision restoration, including neuroprotection and regeneration of the retina and optic nerve, a major unmet need in glaucoma and other eye diseases. His laboratory is developing novel molecular, stem-cell, and nanotherapeutics approaches for eye repair, and he is widely recognized for translating advances in the lab into clinical trials for patients.
A number of his innovations have spun out into startups and clinical-stage companies, and he serves as medical and scientific advisor to a number of ophthalmic start-up, pharma, and device companies. His goal is to translate scientific discoveries to patient therapies.
Transcripts may contain a few typos. With many episodes lasting 2+ hours, it can be difficult to catch minor errors. Enjoy!
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Tim Ferriss: Dr. Jeffrey Goldberg. So nice to meet you. Thanks for making the time.
Dr. Jeffrey Goldberg: Absolutely. Thanks for having me on. I’m really looking forward to it.
Tim Ferriss: I have so many questions for you. And as usual, I’m scratching my own itch. This is going to be a selfish conversation for yours truly, in some respects, because the way this whole thing came about is I put up a post on social media asking for cutting edge technologies or treatments related to presbyopia. Which for those who don’t recognize the term is a very fancy way of saying age-related visual decline. If you’re a word nerd like I am, presbyterian, similar etymology. Leadership of the elders.
And I have noticed in the last year that my near work, my near vision has started to falter looking at books, looking at my iPhone, looking at supplement bottles. And this has led to somewhat of a crisis of meaning for me because I have had my identity based on, in some respects, very, very good eyesight and visual acuity for my entire life.
And Andrew Huberman, a mutual friend of ours, texted me and said, “I’ve got the guy. I know the guy.” And, “Listen to our interview.” Which I did. And for that reason, we’re going to go all over the place, but I thought we would start where I had to start, which is supranormal visual performance. And these is the notes I scribbled down from your conversation with Andrew, I recommend everyone listen to it, goggles that reduce frame rate for basketball.
And that was sort of left hanging a little bit. You guys didn’t do a deep dive on it. So I want to start right there. Because of course there’s preventing decline, there’s maybe restoring function, and then there’s going further and taking things as far as you can. And nowhere are the stakes higher and the rewards greater perhaps than in professional sports. So could you take that and run with it in any way that makes sense?
Dr. Jeffrey Goldberg: Yeah, sure, sure, sure. And yeah, presbyopia, vision of the old. So I’ll tell you just a funny side note. We all get that. I, like you, have gone my whole life without needing glasses until I hit around age 40. And when everyone hits around age 40, our lens inside the eye won’t compress and reshape to focus up close. So your distance vision might still be great, but you just can’t bring that focus in as tight. And I discovered it accidentally in myself, because I was actually in my house and I found a pair of glasses in a closet, somebody must’ve just left them there.
Tim Ferriss: I see where this is going.
Dr. Jeffrey Goldberg: And it turned out they were readers and we couldn’t figure out whose they were. We’re calling around, friends and family. Fine, nobody’s claiming. And then one day I just put them on. “Let’s see how I look in glasses.” And I look down at my phone and I’m like, “Oh, my God, wait a second. I can see a lot better with these readers on.” And then once you do it, you’re addicted because good vision is pretty addicting, right?
Tim Ferriss: Yeah, for sure.
Dr. Jeffrey Goldberg: So now I’m in them too and I’m pretending to look so young with you not wearing them right now, but here they are, just in case. Yeah.
Tim Ferriss: Yeah, very common. Yeah, very, very common.
Dr. Jeffrey Goldberg: So it raises a really cool question that you’re raising, which is as an eye doctor I spent a lot of time, and as a researcher spend a lot of time — we could come back to talking about how do we prevent the sick from losing vision on all these big eye diseases? We could come back to that. But there’s a much bigger world of people who have pretty good vision. Maybe they need glasses, but they’ve got good vision.
And how do we think about the difference, not from sick to normal, but how do we think about the difference from normal to supranormal? And we know they’re supranormal because when, for example, as you bring up, professional athletes get studied, they have better vision. They have better reflex time, they have sharper vision. We talk about 20/20 vision. That means I can see at 20 feet what a “normal” person can see at 20 feet, so I have normal vision. But you can have 20/12 vision, which means you can see at 20 feet what normal people can see at 12 feet. You’ve got better than normal. And it turns out a lot of pro athletes have that.
And then the next question becomes, and you just kind of hinted at it right there, can we train to supranormal vision? Can we induce supra — ? And almost no one studies that. But there are some really cool tools and toys that actually might have that effect. And so you brought up one of them. So we see, like our cones inside of our eyes, we’ve got rods and cones, the cones, they’ve got a refresh rate around 30 to 60 frames per second, kind of like our computer screens do.
And so if you actually subtract out a couple of frames, so if you put on some glasses that dim one out of every 30th of a second, or they dim two out of every 30th, or push it, three, and now you’re giving up visual data, and I throw a basketball at you, if you’ve got your regular vision, you’ll catch it. But if I’m only giving you 90 percent of your vision, or 80 percent or 70 percent or 60 percent of that vision, you might miss the ball. Right?
Tim Ferriss: Yeah.
Dr. Jeffrey Goldberg: But if we practiced and trained in those goggles, where you’ve got to play basketball, throwing and catch, shoot, whatever, throw a baseball back and forth at 70 percent vision, and then we put you in the game back with 100 percent vision. You’re going to be better, faster reflex time, all of that. Hand-eye coordination. So it’s actually like some of these supranormal visual tactics are actually trainable and there’s tools that athletes are using, but they’re accessible to all of us, yeah.
Tim Ferriss: All right, so I —
Dr. Jeffrey Goldberg: You can grab one of those, Tim.
Tim Ferriss: Yeah, let’s dig into this a little bit. I have a number of friends who have engineering chops and have played with sensory substitution experiments and all sorts of wild stuff. And in fact, I think there’s some folks at Stanford, David Eagleman comes to mind, who’ve developed tools along these lines. We won’t go down that route.
Let me stick with vision for a second and just note that there are, for instance, indigenous groups in various parts of the Amazon, I’ve seen them in Brazil and in Peru as well, which use eye drops of various types. Could be from a plant, could be from a toad, for improving not near work but distance work. Most of them use shotguns these days, but some still use blow guns and bow and arrows for hunting, say, monkeys.
So there seems to be something to it. Now you could say, “Ah, that’s a bunch of voodoo hoodoo nonsense.” But then you have eye drops for, as I understand it, temporarily inducing more, this isn’t going to be the right term, but flexibility in the lens. Is it pilocarpine?
Dr. Jeffrey Goldberg: It’s actually the iris. Yeah, yeah.
Tim Ferriss: The iris. There we go.
Dr. Jeffrey Goldberg: So I don’t know what they’re using in the plants, but we now have FDA approved eye drops, and what they actually do is they bring your pupil size down by having your iris constrict to a smaller circle. And it turns out that if you have refractive error, so you need glasses, the shape of the front of your eye, the shape of your lens isn’t perfect, you have a little bit of glasses or contacts, or whatever to correct that, including if it’s not focusing up to close, you can have reading glasses that change that refractive, that light coming into your eye so that you’re focusing up at close. If you come down to a pinhole, you actually kind of normalize the light so that it’s as if it’s all coming from infinity and you actually kind of correct refractive error.
One of the ways we can tell if someone needs glasses is we have you read the eye chart, and then we have you read the eye chart through a little pinhole, a little device you stick in front of that eye, and read through a pinhole. And if you can read better through the pinhole, you actually have better vision and could correct it with glasses. So now we could just give an eye drop that kind of makes your pupil closer to a pinhole and then it allows you to see without glasses, near or far. In fact, people are using it now for near vision, for that presbyopia you were talking about in the beginning.
Tim Ferriss: So for people listening, and also for me frankly, could you just give a vision 101, and in this case, let’s focus on the eye, just so people understand the basic components of the eye.
Dr. Jeffrey Goldberg: Yeah.
Tim Ferriss: And part of the reason I want to explore this is there are different levers you might be able to pull on to improve vision, some of which might be structurally related, but not all, at least to the eye. But could you just lay out the basic anatomy of the eye, the architecture?
Dr. Jeffrey Goldberg: Yeah, absolutely. So light comes in the front, goes through the clear window in the front of our eye called the cornea. You can have corneal diseases obviously that block that light from coming through clearly, but if it’s healthy, that light comes through clearly. The cornea is curved on the front, and that curvature is actually responsible for curving most of the light into the back of the eye.
Then the light goes through your pupil. So that’s the iris, which it’s brown in me, but brown, blue, hazel. So that’s our iris. And the iris can open and close like we were talking about a minute ago. Comes through the middle of that, the open middle part of that, goes through the lens. The lens does fine focusing, a little focusing from far to near, that kind of thing. And that’s what we were saying, stiffens as we age. So we can’t go far to near as well as we get older, you’re passing 40 years old, typically.
And then it goes through the gelatinous middle part of the eye. We call it the vitreous. After the lens is called the vitreous. That’s where floaters are. People who get floaters, they’re floating, it’s like little concretions of proteins and stuff floating in the vitreous. It’s a gel. As we get older, that gel turns to water, kind of shrinks up. Our eye doesn’t shrink because it fills in with salt water, but the gel shrinks up.
And then the light hits the retina. And our retinas are what we call inverted. So the light actually passes through almost all of the retina and then it hits the rods and the cones. And those are the photoreceptors. They absorb the light, like the photons of light. The rods are really, really only good for nighttime vision. They’re only good at very low light. If you go into normal daytime vision, sitting here in the room, whatever, those are getting bleached out, you’re not really using your rods too much.
And next to them, the cones. The cones are great for color vision, they’re great for bright lights. They’re what we use most of the day. That’s what you and I are using mainly right now. The rods and the cones collect all that light. They process it and transmogrify it into electrical signals. And those electrical signals are then propagated back forward through the retina. There’s some internal processing layers in the retina, so it’s not just a layer of film, you’re actually doing some computation right there in the retina.
And then they hit what are called retinal ganglion cells. And those are the cells that then send a process across the surface of the retina. It’s an axon, but it’s like a telephone wire. And that then goes back out the back of the eye into what we call the optic nerve. And that optic nerve connects the eye to the brain. So those retinal ganglion cells are collecting all the data and sending it all back through the optic nerve to the brain. And then of course all that rest of that processing is happening in the brain.
Tim Ferriss: All right, there we go. That was a great summary. Thank you very much. And I’ll tell folks, if you thought that is a lot to remember, it is a lot to remember. But the point of it is, as I, as my own N of one, am trying to consider different paths forward with presbyopia, whether it’s glasses, yes, my readers do fix the problem, they do fix the problem, but I am a little concerned of increased dependency and then increased magnification over time. I know there are arguments for and maybe some arguments against, but when I put up my social post, and I think people can identify with this, there was a lot of noise. There were some of the most harebrained, insane, certainly potentially dangerous suggestions you can imagine.
And then there were a few things that came up when I reached out to, and let me get this right, is it a vitreoretinal surgeon and researcher —
Dr. Jeffrey Goldberg: Uh-huh.
Tim Ferriss: — who I happen to know, and he sent me a number of white papers, or I shouldn’t say white papers, more so studies and meta-analyses and so on that I read up on. And I thought to myself, “Look at that. Surprise of surprises.” A few of the things that came up repeatedly in the hundreds of responses to my post actually show up in the literature and there might be something to them. And we’ll definitely come to a number of those.
But it can be very overwhelming for people to try to figure out what to do next. And the reason I wanted you to do that recap, and then I’ll stop giving my second TED talk of our conversation, is that much like if someone complains of, say, brain fog and fatigue, a rose is a rose is a rose is not a rose, in the sense that there can be many different factors and independent variables that contribute to that. So one person might have insulin insensitivity and trouble with glucose disposal. Somebody else might have Lyme disease or some infectious disease that is contributing to metabolic dysfunction. I mean, there’s so many different contributing factors that it helps to, I think, get a little thinly sliced.
So in my case, I have the stiffening of the lens. Please correct my terminology. I also have a really pretty sizable, I’d never seen it before, I did some really impressive imaging on the eye, but a huge nevus on the back of my right eye that I need to keep an eye on. So I’ll be following up on that in three or four months. But I wanted to, I suppose start with, what are other ways to improve vision?
Now there’s certain things I’m always looking for: limited downside, potential upside. So for instance, I’m taking the AREDS 2 supplement with lutein and various other ingredients in it. I would say it’s probably not going to help, but within my patient cohort of the medical practices I work with, there are a few folks who claimed after six weeks that their vision really improved and they didn’t need their readers, even though technically, mechanistically, the AREDS 2 shouldn’t have helped them. So whether it’s placebo effect or not, interesting outcome. I know the plural of anecdote is not data, but I was like, “Ah, okay, sure, I’ll take the supplement.”
What are some other cutting-edge treatments or augmentations for improving vision? And I’ll shut up in a second, but I’ve been very excited to talk to you, so I’m chomping at the bit here. Because as you mentioned, there’s this sort of eye architecture, brain interface. And among professional athletes, just because I’ve funded a lot of science in this area, low dose psychedelics also seem to improve visual acuity. So everyone from Aaron Rodgers, to very, very high level athletes that I will not dox here, report measurable performance improvements that they attribute to increased visual acuity. Well, it’s probably not changing the anatomy of the eye, so what’s going on? So I would just love you to speak to any other means of supercharging visual perception.
Dr. Jeffrey Goldberg: There are some things that we have a pretty decent sense on. AREDS 2 and some of these supplements — first of all, eating a lot of carrots, it’s probably not going to actually do it. So great, childhood, get the kids to eat their vegetables. We definitely exercised that ourselves as parents. But AREDS 2 clinically proven, if you have moderate age-related macular degeneration, to slow down your vision loss. Does that mean it doesn’t work at all if you have mild age-related macular degeneration or if you have no age-related macular degeneration? It might just be like we haven’t done a study big enough to detect those effects. And as you say, that’s probably not going to hurt, so feel free if you want. We can’t prove it’s helping, but feel free.
There are other supplements that have received some study that maybe suggest there isn’t much going on there, that again, they’re probably not going to hurt. Some patients take CoQ10, some patients take ginkgo. There is actually, maybe the hottest topic in supplement vitamin space right now internationally, is actually vitamin B3, nicotinamide, which has really been linked to a number of good potential medical uses and is receiving a lot of study. There’s actually international clinical trials, including one here in the US, actually testing whether it could restore vision in certain eye diseases like glaucoma, which is my specialty. So definitely some hints in that direction.
We already talked about some device elements, and I think between vision training, like we talked about earlier, and also visual augmentation, we’re moving into augmented reality. And so training vision and visual reflex time almost certainly makes a difference in the activities you’re training in. If you’re training in basketball, will it also help you doing some weekend surfing? I don’t know. But definitely can help move you from normal to supranormal or help enhance and improve what you’re doing.
And then there’s all sorts of stuff that, I’m going to be honest, Tim, we don’t know. Because A, it’s really new, really hot right now, like microdosing certain psychedelics, things like that, that we know act on the nervous system, including the brain. But the retina, in the back of the eye, and the optic nerve that connects the retina to the brain, those are developmentally an outgrowth from the brain. They are part of the brain, they’re part of the central nervous system, and we barely know about how to influence the wiring, the plasticity.
Are there drugs that we can give? A lot of people have talked about gabapentin and drugs in that space. Obviously microdosing in LSD is a really hot area right now for inducing plasticity. There’s actually great science showing in animal models, and a little bit now in humans, that you can actually reopen brain plasticity by dosing some of these drugs at appropriate doses. Obviously we’ve got to be careful, we don’t know what the right dose is yet.
But it’s really worth looking at because there’s clear evidence that these are relevant and likely to have some effects. We’ve just got to figure out a little bit more like how, what’s the right dose? By the way, when you’re doing it, should you be doing some behavioral training, like visual training? But these things act on the brain, and about a third of our brain inside our skull is dedicated to processing vision.
Tim Ferriss: Yeah, there’s a lot there. All right. I have been so — I’m not just over-caffeinated because I’m actually not really caffeinated, I might be over-ketoned. I have quite a bit of ketone monoester in me at the moment. But putting that aside, so I am right now, and this could make me seem like I’m in the tinfoil-hat-wearing crowd, but I had a number of companies reach out to me, not surprising after I put up my social posts. Most of them didn’t make any sense. A few of them seemed to make sense, and the people involved seemed to have technical chops and also some pretty credible research backgrounds. And I’m not going to name the company X, I’m not done with my personal testing.
But I have been testing at about eight minutes a day, I don’t know the right descriptor to use, I would say maybe visual perception training. To distinguish it from, and we can talk about this, what I suppose some ophthalmologists or optometrists might call visual education. So trying to improve the ciliary muscle strength and so on around the eyes. Much like, if people want a visual, sort of the springs around a trampoline. But in this case it’s very quick flashes of blurry or not blurry circles, and you need to identify what is more blurred. And there are many permutations. It adapts to your successes and failures over time. And it could absolutely be placebo, but after about a month now of using it, I feel like my near vision has improved. Even the woman I’m dating has commented on this. And I am still waiting. The jury is out. But this is just to say that I’d love to know what you think of visual improvement that is not dependent on surgery or drops. Is there something to the various types of visual education? Is there something there or not? And then when we go maybe upstream a bit, if that’s the right phrasing to use, to the brain, are there interesting approaches like limiting the frame rate, or removing a number of frames, that you think are at least plausibly interesting for enhancing performance?
Dr. Jeffrey Goldberg: Yeah. First of all, absolutely. And it does get back to that idea of visual training, the reducing frame rate, training on visual perception. There’s actually a fair amount of data. Actually, there’s enough data to even say there’s elements that make it better. For example, if you do visual training where you’re just showing yourself, like being shown these different objects, maybe they’re getting smaller, dimmer, blurrier, etc., your ability to train off of that is significantly better if it demands a behavioral outcome, a motor action.
So for example, you’ve got to point at the right one or choose something. And it’s not just that you’re mentally thinking that was the sharper image, it’s actually the motor output of pushing a button, or pointing at something, or doing an activity that actually reinforces the visual perception training. So that’s one great example.
Another great example is after concussion. So concussion, traumatic brain injury, of course, very common in athletes because they’re more likely to get into the head bumps and things like that, but it happens all the time in kids.
Tim Ferriss: Military. Very big problem.
Dr. Jeffrey Goldberg: Military. A very, very big issue. And the line in between mild concussion, severe concussion, traumatic brain injury, that’s all on a spectrum, a continuum. And there’s actually decent data from that group of people, that if you get a concussion, actually visual symptoms are some of the more significant symptoms. Ability to focus, ability to sleep, and vision are three of the big symptoms that people get in that concussion through TBI spectrum. And those can be debilitating, right? And kids are out of school, they’re missing high school for weeks or longer. It can be really debilitating.
Obviously, if you’re an older adult and you’re in your job situation, really tough. And it turns out though, that there are visual perception exercises that you can put patients through in those situations that, in the limited clinical studies that have been done, point to a positive effect of basically rehabbing, like neurorehabbing you back. Now, that of course is back from injured to normal, but the idea that that can also induce the same kind of plastic remodeling in our eye and brain, and particularly the eye-brain connection in patients who are starting from normal and trying to get themselves up to supranormal, try to improve performance, visual performance. We’ve set up here a whole human performance laboratory, really just to study these questions and the data rolling in make it look like, hey, there’s something here. This is definitely worth chasing. Yeah.
Tim Ferriss: What can someone search if they want to find something to read up on related to the concussion rehabilitation protocol? Because this type of visual training, because there’s a lot of nonsense floating around and charlatans out there. Any particular search terms or principle investigators or anything that people can search?
Dr. Jeffrey Goldberg: I would say, if you want to at least hit some of the science or science-adjacent web resources, you’re going to want to use a few technical terms in there, like concussion, neurorehab, neurorehabilitation, plasticity, and then some of the terms you’ve already been using, visual perception exercises. And then, look, in these situations, you’ve got to look not just at the content but of the source, right? And so, is this a dude on his blog, or is this coming from a foundation, or an institute, or one of the academic centers, or some of the choices like that?
Tim Ferriss: All right, Jeff, I would love to hop to another set of interventions, and this is in the device category. Red light in the morning for mitochondrial health, question mark? Violet light to reduce progression of nearsightedness in children. Is there an application of red light or violet light? To what extent do we have supporting data for using either of these? Do we have an idea of what best practices look like? Is it only for people with a disease state or can they be potentially used to preserve vision before vision loss?
Dr. Jeffrey Goldberg: Yeah, the disease state data is pretty good. And also the myopia control is pretty good data too.
Tim Ferriss: Just for a definition for folks, what’s myopia?
Dr. Jeffrey Goldberg: Myopia is nearsightedness and it’s an epidemic, more common in Asians or people of Asian heritage, but common in everyone. And kids can get nearsighted. If you’re a little nearsighted, it might be annoying to wear glasses. If you get more severely nearsighted, it actually can lead to all sorts of problems inside the eye, real severe vision loss, even early in life. So that’s a big one. And then what was really shocking was it turns out that a small dose of daily red light can slow down progression of myopia in young people. We’re talking about teens and younger even. So what’s even more shocking to me is that it also works with violet light. So how’s it work with light at the two ends of the visible spectrum? And definitely mitochondria are implicated.
Mitochondria are the little power houses, energy sources inside the cell. They are a big player in converting the sugar a cell takes in into energy that the cell can use for all of the cellular processes. So our bodies clearly need functioning mitochondria. In fact, one of the big features common across many neurodegenerative diseases of the eye and the brain is dysfunction of mitochondria. There’s an FDA-approved red light therapy for patients with macular degeneration, but there’s good data that it may also be supportive or protective in other eye diseases. And we’re talking in small doses. This is not overwhelmingly bright lights and we’re talking about minutes a day. You don’t have to sit in front of it for two hours a day, so minutes a day. So it’s exciting.
The data suggests that the mechanism of action is giving a little protective booster shot to our mitochondria so that they don’t get dysfunctional, whether that’s dysfunctional just from normal use throughout the day or dysfunctional because you happen to have a disease that’s getting in the way of those mitochondria. So now, we don’t know what the right dose is. We don’t know what the right brightness is. All we know is that in these initial things that have been tested, the initial brightness of how and how many minutes, three minutes a day, for example, there’s a signal there. There’s something working there. Should we have everybody buying one on the internet right now, hopping on Amazon, spending 25 bucks, spending three minutes a day? We don’t have the data to support that. Is it going to hurt? Probably not. So, Tim, it’s a problem because we’ve got so many things that are like, “Oh, that looks promising,” and we just, we need a little more science. We need a little more study.
Tim Ferriss: Yeah. Well, a friend of mine wanted me to write a blog post about — look, I’m not a doctor. I don’t play one on the internet, but the difference between getting into science versus getting out of suffering in the sense that you know and I know of just having been involved with the funding side, randomized controlled trials are expensive and they take a long time. But at the same time, if you take the advice of every wackadoodle running around on the internet, you’re going to have 600 different interventions, some of which could do a lot of damage. Or you’re going to get the wrong device.
I’ve seen this all since I’ve talked about accelerated TMS and different types of brain stimulation for potentially addressing treatment-resistant depression. And Nolan Williams at Stanford has done a lot of great research related to that. And you see these people on YouTube with DIY TMS and they’ve got the polarities reversed, and I’m just like, “Oh, my God, what are you doing to your poor brain?” But I also want to preserve my vision as long as humanly possible, and maybe you can dispel a concern that I have, and this is based on the fact that I have a lot of Alzheimer’s and Parkinson’s in my family. And I’m APOE3/4, some 2.5 times or so more likely to develop Alzheimer’s, based on what we currently think we know, than someone who is, I guess, 3/3. And it scares the hell out of me. And I’ve had conversations with audiologists who point out the correlation, I don’t know how strong the signal is, between hearing loss and onset or progression of dementia. Is there something similar for visual loss?
Dr. Jeffrey Goldberg: Absolutely. Actually, one of our faculty here has done some of the really foundational research showing that correlation between vision loss and cognitive decline, and the loss of input. Again, vision is our biggest input sense. It’s driving, a third of our brain is dedicated, as I said, to processing and using that vision, and interfaces with every other thing that we do. It also is a really critical piece around depression and mental health. Anxiety is vision, the work that Andy Huberman had done on visual fear and how that plays into the fear and anxiety pathways as well as the depression pathways. And not only does visual decline accelerate cognitive decline, possibly because, in part, because of how depression then plays in with cognitive. These things are all clearly related to each other, but also remarkably, if you have low vision, let’s say from something as simple and correctable as cataracts, a blurring of the lens that happens with age.
If we all live to a hundred, we’re all going to need cataract surgery, some people younger, some people older. But if you do cataract surgery and restore vision in an older person who appears to be suffering, is suffering with cognitive decline and/or depression, you can reverse a significant amount of that decline in either of those domains. And so it just, again, it speaks to the interplay of vision with our mental health, our cognitive health, and this is long-term, important stuff.
Tim Ferriss: And this, tell me if I’m interpreting this the wrong way, but it seems like this would lead to a strong pro argument for wearing glasses instead of suffering in silence. I don’t know, but that’s what I hear when I’m trying to read between the lines.
Dr. Jeffrey Goldberg: There’s an important myth to dispel, especially when it comes to presbyopia and wearing reading glasses. Between age 40 and around 60 or so, that lens stiffens, and stiffens, and stiffens. And the first year you only need +1.25 glasses, and then three years later you’re like, “Ah, I need +1.5, +1.50s.” A few years after that, you’re moving up to the 2.0s. Eventually you’ll peak out at around 2.5 or 3.0s, because that’s the difference, basically. That’s the refractive, the glasses difference between viewing something at infinity, which from an optics perspective is actually just three feet away or further, and viewing something at 14 inches, comfortable reading distance, right in front of us. So 2.5 to 3 power of those readers is all you’re going to need, but you’re going to progress through those numbers whether you wear the readers or not. So wear the readers!
Tim Ferriss: I got it. Is it a mistake in causality then, where people believe?
Dr. Jeffrey Goldberg: Yeah.
Tim Ferriss: Because an optometrist said this to me a couple of weeks ago, and I was like, “Well, I assume you know what the hell you’re talking about,” which is always a stupid assumption, but that you develop increased dependence, but it’s actually just tracking along with the natural stiffening of the lens, in the case of presbyopia.
Dr. Jeffrey Goldberg: It is and it’s psychological dependence. It’s just like what I went through as soon as I started wearing those readers by accident. I didn’t think I needed them. I was still reading off my phone. It was fine, but as soon as I experienced that extra crisp vision, I was like, “Well, I like that.”
Tim Ferriss: Yeah.
Dr. Jeffrey Goldberg: So I got psychologically dependent because who doesn’t want their best vision?
Tim Ferriss: Yeah, for sure. And I’m going to keep saying this, it’s going to get annoying because I’m like a sweaty-palmed fanboy, jumping all over you, but I was very excited to chat with you also because the nose, the brain, these are direct paths into the brain in a sense. And for instance, I don’t know, I don’t expect you to track all things in all fields. That’d be impossible, but Cognito Therapeutics, it’s a headset that is used and they have a lot of good data. I think they’re either phase two or phase three. They’ve raised a ton of money, and it’s a headset, and they have these visors covering the eyes, and then earpieces. And it produces, I want to say, gamma waves in the brain. There’s more to it, but using flashing lights, and this appears to — I’m getting into the deep end of my ignorance pool here, pulling from memory, but it appears to assist in the breakdown of beta-amyloid plaque, maybe tau as well. I’m not really sure.
So using flashing light to help people with conditions like Alzheimer’s. It’s mind-boggling, I guess, literally and metaphorically. And that does come from credible researchers. I wish I could cite them offhand, but it’s going to take me too much time to find the scientists involved. But that is one that appears to be — Ed Boyden and Li-Huei Tsai out of MIT.
Dr. Jeffrey Goldberg: Yeah. Yep, I know them both. Ed was a graduate student here at Stanford when I was at Stanford.
Tim Ferriss: Oh, amazing.
Dr. Jeffrey Goldberg: Yep, yep.
Tim Ferriss: Yeah, so there you go.
Dr. Jeffrey Goldberg: Yeah.
Tim Ferriss: Are we going to see more of these devices and how far away are they? Because I’m seeing decline in my near relatives. I’m currently taking care of two relatives with severe cognitive decline. It scares the hell out of me. And some of them are 3/3, by the way, and I’m 3/4, so I’m like, “Good God. Okay, if there’s anything I can do,” and I’m already doing quite a few things, but are there other devices that are on the cusp of being available that you find interesting?
Dr. Jeffrey Goldberg: Yeah, I think so, and input through the visual system and output through the visual system are both looking really interesting these days. So you’re talking about input. What can we stick in through the visual system to influence the rest of our brain, brainwave activity, plasticity, like we were talking about before, help preventing cognitive decline? We actually, there is very strong data, for example, that if you give the right amount of electrical activity of our neurons in the eye and the brain — so the neurons in the brain talk to each other through electrical activity, like little wires and too much activity is bad. Really too much activity is epilepsy, for example, Too little’s clearly bad too. If you have a stroke, then you’ve got no electrical activity in that area of your brain and it’s just not working anymore. But providing that sweet spot in the middle of electrical activity, in addition to it participating in the processing of whatever that area of the brain does. In the retina, it’s your vision, obviously.
It also stimulates pathways like plasticity and responsiveness to the survival and growth factors. And we and others have shown that very clearly in animal research over the years, that you need not just the right growth factors circulating around in the brain, but you also need the right levels of electrical activity so that the neurons are maximally responsive.
Tim Ferriss: Yeah, it’s like weightlifting. You can have all the protein in the world.
Dr. Jeffrey Goldberg: Right.
Tim Ferriss: You need the stimulus.
Dr. Jeffrey Goldberg: You’ve got to have the right amount, right? You’ve got to match that up, and so it’s really cool. We actually know in the eye the visual — you were talking about flashes of light, but it turns out different cells in our eye respond differentially to different stimuli. We have some cells that fire when the lights go on. We call those, very creatively, ON cells. We have some cells that fire when the lights go off, called OFF cells. We have some cells that are firing between blue and yellow, others that are differentiating between red and green. We have some cells that are in charge of motion detection in the eye, and all that data has got to get back to the brain. But if we stimulate, for example, the motion-direction-sensitive retinal ganglion cells in our retinas in headsets where we devise cues —
Basically imagine you’re flying through that Star Trek field of stars, like you’re going into hyperspace, right? To engage, and you’re going into — and all those stars speed up by you. Those are great stimuli for some of our direction-sensitive cells in the eye. And could those actually stimulate those cells to then perform better or not degenerate in disease? And so we’ve been studying those kinds of questions. Cognito’s engaged in that kind of work. And then how does that affect what’s going on in the brain? Very reasonable that that’s going to actually lead to specific patterns of activity, flexibility, plasticity that are going to change our brains. And the idea that some of that work can not happen only in the academic world, but that people are excited about it, and are funding the startup companies, and taking that science into that either health domain, healthspan domain or consumer domain. How do we get the normals protected against the future? There’s a lot going on there. That’s on the input side.
Tim Ferriss: Yeah. Okay. I am going to just bookmark that for a second, and I’m going to highlight a few things that I thought were of interest and I’d like you to expand on from your conversation with Andy. So glaucoma, could you have a normal reading during the day, but higher at night? And then the potential place of cannabis edibles.
And my question there was do we know what compounds are responsible? People are listening to me and they’re like, “What the hell are you talking about?” So if that’s enough of a cue, would you mind just discussing that? Because a big challenge with people who are trying to do the right thing. They’re trying to get check-ups. They’re trying to get assessed/ they’re getting their blood work done, but maybe it’s once a year and they had their blood draws, the last one was at 8:00 a.m. and the next one was at 11:00 a.m., and lo and behold, their testosterone is really different and they freak out, and this, that and the other thing. So timing matters among other things. Could you just speak to glaucoma in that respect?
Dr. Jeffrey Goldberg: Absolutely. So let me just back up one step. Glaucoma, after Alzheimer’s disease, glaucoma is the most common neurodegenerative disease. It’s the number one cause of irreversible vision loss in the world. It’s a degeneration of that optic nerve connection from the eye to the brain. So those retinal ganglion cells that are collecting the data in the retina and their axon fibers, those telephone wires running down the optic nerve, carrying that, all the vision from the eye to the brain, they degenerate in glaucoma. If you take all comers, it’s around two percent of people in an aging population that will have developed glaucoma. If you have a primary family member, a parent, a sibling, a child with glaucoma, your risk probably goes up to about 20 percent. So it runs in families, but just because your parent has it doesn’t mean a hundred percent you’ll have it.
There are two main risk factors for glaucoma. One is increasing age, and we’re all working desperately on correcting that one, but we don’t have a slam dunk treatment for that yet.
The other main risk factor for glaucoma is actually increasing eye pressure. If you have real high pressure, you’re going to get glaucoma. But a lot of people with normal looking eye pressure can also develop glaucoma. It’s just like they were more susceptible, and the eye pressure isn’t just the same number. We’ve got short-term variability and long-term variability. So long-term is, this month, it might be whatever number, next year, it might be a little higher, a little lower. You can vary through your life. But there’s also this short-term variability. It actually varies in our diurnal cycle. So everybody has a diurnal cycle where you — your circadian rhythm, and some of us, like myself, are night people, and we love to be up at night, and getting up in the morning isn’t our favorite thing, and other people are the opposite. And all this stuff relates to our diurnal cycle, our circadian rhythm.
You can try to take melatonin and affect that, but your eye pressure also varies by that. And as you say, if I take your eye pressure in the morning and then the next week I take it in the afternoon and I say, “Oh, my God, your pressure’s gone up. I’ve got to take you to surgery.” Well, wait a second. It might just be because I’m measuring at different times.
Now, you brought up the most common question that I get asked. I’ll tell you the most common question that I get asked by patients with glaucoma is, “Hey, can I take cannabis?” And by the way, it’s like legal for medical use in many states and frankly, recreational use also in many states, and certainly accessible in every state. Can I take cannabis? Cannabis, whether you smoke it, or eat it in the brownie, or take the chewy, it lowers your eye pressure, if you’re using the version which are available where you feel a little high from it, you get that good feeling. The problem is that it only really lowers the eye pressure during that time that you’re getting high. So I tell patients, it works but you’d have to be high 24/7, so maybe you should just use this eye drop instead, right?
Tim Ferriss: Do we know which compounds within cannabis are responsible for the lowering of the eye pressure?
Dr. Jeffrey Goldberg: Yeah. There’s actually data that both the THCs that do get you high and the others also that don’t can have that effect. And there’s some cool startup companies that have been working on trying to isolate and now test in human patients the, you don’t get high versions of those compounds or chemically modifying them, and by the way, turning them into an eye drop so that it’s really just treating the eye and make that really accessible. You don’t want to be on your glaucoma treatment and not able to drive, so —
Tim Ferriss: Yeah, that’d be a bummer. Trade-offs.
Dr. Jeffrey Goldberg: — it’s got to be compatible with daily life for most patients, right? Yeah, so that does work. That does work.
Tim Ferriss: Mm-hmm, so —
Dr. Jeffrey Goldberg: The second most common question I get asked is, “Well, can’t you just fix my eye, or give me stem cells?” Or that kind of thing, but number one is cannabis.
Tim Ferriss: Well, what’s your answer to the stem cells, the magic stem cells?
Dr. Jeffrey Goldberg: We’re getting there on stem cells. So if you’ve lost your retinal ganglion cell connection to the brain through the optic nerve, we are actually getting pretty good at growing retinal ganglion cells out of human stem cells, in the laboratory cell culture dish. And we’re actually starting to make real progress, in animal models to start, showing that you can transplant them in. But I still tell patients, don’t go to some clinic that’s telling you they’ll give you stem cells and pay $18,000 of your hard-earned money. It is not ready for that yet.
Tim Ferriss: Go to Tijuana and get a new pair of eyes.
Dr. Jeffrey Goldberg: Exactly. Don’t waste your money.
Tim Ferriss: Well, yeah, that’ll be the least of your problems, will be the money part. So let me circle back to the cannabis for a second. So I don’t consume much cannabis, but I have experimented with cannabis for chronic pain and specifically a number of back issues that I have and some of it’s congenital. I have a transitional segment and a bunch of orthopathy and blah, blah, blah, blah, blah. And interestingly, a lot of folks, including people who are sort of credible and familiar with the literature, recommended CBD, but I did not find it to have a pain-relieving effect that was sufficient for sleep until adding a little bit of THC, which I thought was actually pretty interesting.
And I’m wondering if this actually cycles back to our very short discussion of psychedelic compounds also because why might psychedelics, say, improve visual acuity? You can come up with a dozen sort of plausible explanations, but when you look at, say, the depression outcomes with psychedelics, people on many different parties in terms of arguing why or how they exert their effect, one that I think is under emphasized is the anti-inflammatory effects, which can be potent in some psychedelics. And you can find studies where they look at anti-inflammatory, just standard off the shelf anti-inflammatory effects on depression, which can be substantial. Do we have any data to suggest that anti-inflammatories have any effect on vision or can in any subpopulation improve vision?
Dr. Jeffrey Goldberg: Yeah, absolutely. So decades ago there was a pretty hot focus on to what degree the immune system might be playing a role, particularly in eye diseases including the common ones, macular degeneration, glaucoma, and then it was hard to pull that together in part I think because we didn’t know as much about the immune system 20, 30 years ago as we do today. And now we know a lot about what we call the innate immune system, which is not the part that learns about the flu virus and makes you immune the next time you get the flu virus. But just how our immune system interacts with our body normally and how it also might interact with our gut bacteria and then cross-react with our own body, things like that. And so it turns out now that we’ve got this much deeper appreciation from the whole immunology crowd about how the immune system and in particular the innate immune system works, we’re now revisiting in neurodegenerative diseases, including glaucoma macular degeneration, and it turns out it is just packed with evidence that the immune system and innate immunity really play a role.
Let me give you one example that is shocking. If you raise the eye pressure in a mouse, the retinal ganglion cells and the optic nerve will degenerate just like in human glaucoma, but in a really beautiful set of experiments that came from a woman, a professor at Harvard, Dongfeng Chen, she showed that if you raised the eye pressure in a mouse that was raised itself, grew up in a germ-free environment and doesn’t have all the normal mouse dirty gut bacteria and therefore its immune system is at some level fundamentally different, you can raise the eye pressure in that mouse, but the optic nerve won’t degenerate, they won’t get glaucoma damage. And then if you take the immune cells out of the first mouse and just put them back into the bloodstream of the second mouse, then the optic nerve will regenerate.
Tim Ferriss: Wow.
Dr. Jeffrey Goldberg: So the immune system is playing a huge role that was previously totally underappreciated and they’re amazing drug therapy candidates that are now moving up through the pipeline towards human testing to test, hey, if we could suppress the immune system. Not totally suppress it because by the way, we still want to be attacking bacteria and viruses but just suppress the little leg of that immune system that’s attacking our body and leading to neurodegenerative disease, that’s going to be off the charts.
Tim Ferriss: As you’re talking about the microbiome and so on, I was doing a bunch of reading for another interview I’ll be doing shortly with the scientist and one of the stories, and this is in animal models of course, but looked at how — and some people have heard through the grapevine one way or another how you could take the microbiome just for simplicity’s sake of say obese mice and transplant that to lean mice and they get fat or vice versa. And I might be getting some of the details wrong, but roughly you see some very interesting effects. However, if you sever the vagus nerve in those recipient mice, they do not exhibit those changes.
And so then some of the questions that are kind of outstanding is, well, if that indicates that you could instead of using ablation or severing something stimulation to achieve a similar effect, then what can you start to do? And then you have hockey puck size things that you put next to the liver that can via some technological wizardry affect these things. But God, I suppose that the more I look at a lot of these things also with family with Alzheimer’s and they might take something like Theracurmin, which has, on some level, inflammatory effects. I’m like, okay, well, and I don’t want to be a one trick pony with the one thing I keep beating over the head, but it’s like, okay, well, if we know that inflamed like microglia have all of these hosts, or at least they’re associated with a host of different neurodegenerative diseases and inflammations associated with depression, to what extent can we mitigate these things and we’re sort of hitting a bunch of birds with one stone.
Does that make any sense? Which is why I’m so interested in the possibility of using devices. I’m so interested in the ketogenic nutritional ketosis, but also exogenous ketones. Brain loves this stuff also, the beta hydroxybutyrate, very potent anti-inflammatory. I’m just wondering, do you think that I am just too clever by half and I’m missing the plot here?
I feel like chronic inflammation, which is kind of like saying business or the arts, right? I mean there are a million different facets to inflammation. You need inflammation for a lot of reasons, but when it is pathological and chronic, it turns into a big issue. With rapid decline in eyesight, let’s just say in glaucoma, how often is that comorbid with metabolic syndrome or something like that when the decline is faster than, say, average?
Dr. Jeffrey Goldberg: The earliest data looking at, let’s say diabetes as a marker of a lot of patients with type two diabetes, it’s associated with what we call metabolic syndrome, which is this cluster of high lipids, high blood pressure, insulin resistance. And so there was initial data suggesting that a little bit of diabetes might actually be a little protective in glaucoma.
And then some of the follow up next set of studies suggested like, no, no, no. Maybe it’s a little bit bad for your glaucoma. And so the net is it’s probably not metabolic syndrome as a whole is probably not a huge difference. But I’ll tell you the place where those two are converging is one of the hottest topics in medical science today, which is these GLP-1 receptor agonists, which are going to have a huge effect on human health by reducing metabolic syndrome, overweight, obesity, et cetera. But also are looking very promising for neuroprotective.
And I think it actually gets to that point. You’re trying to tease yourself, are you just getting ahead of it? But actually you’re touching on, I think where we’re actually coming to as an understanding is where the science is going in the field, which is this axis between the brain, which you think of, well, isn’t that mostly inside my head, but also the peripheral nerves that are going out to the whole rest of our body and the immune system and those two are talking to each other all the time and now we’ve got the microbiome and that gut axis is like a third leg of that stool because that’s clearly also interacting with both the nervous system and the immune system in very specific ways.
So we’re going to see a lot more of that really, I think, come together and understand more mechanisms. Is it going to be one day that we’re all just kind of taking that purified poop pill that we just swallow down and it changes our microbiome for the day and it protects us from Alzheimer’s or glaucoma in the future? We’re all hoping that’s going to happen. We’d love that protection one day. Should you buy the poop pill off the internet just yet? I’m not sure. Yeah, I don’t think so.
Tim Ferriss: Yeah, Sri Lankan poop pills from rural children. I’m in. Yeah, be careful with what’s out there on the internet, guys. And I’m not supporting a company, I might have to bleep this out, but called Holobiome and they’re actually creating the most comprehensive library currently of gut microbiota because it’s like what you can buy currently off the shelf. First of all, most of it’s dead. It’s inert by the time you consume it. A lot of it doesn’t actually get through your metabolism to where you want it to be. And it only represents maybe in a few dozen, I don’t know what the right term is, strains of bacteria. Whereas there’s like thousands upon thousands. So there’s so much to explore, which is also very exciting.
Dr. Jeffrey Goldberg: Let me give you one more idea of what might be that ideal world on the way to that.
Tim Ferriss: Yeah.
Dr. Jeffrey Goldberg: We share microbiomes between us. Actually we had our at Stanford Med School years ago when I was there, we had a microbiology professor and he used to kind of tease the world is covered with a thin layer of poop because no matter how well you wash your hands after going to the bathroom, there’s a couple bacteria that got on your hands or your belt buckle and then you shake hands or pat someone on the back. I don’t want to increase anyone’s anxiety, but the world is covered —
Tim Ferriss: This episode is brought to you by Purell.
Dr. Jeffrey Goldberg: There’s a thin layer of poop. “What we call clean and dirty,” he used to say, “is really just how thick that layer is.” Okay, so that joking aside, if you just shack up with someone who’s got great longevity and a great microbiome, good chance you’re going to absorb their microbiome, maybe that’ll be good for you.
Tim Ferriss: Look at that.
Dr. Jeffrey Goldberg: They’ve got to put that on the dating websites. Get your microbiome on that profile.
Tim Ferriss: Right? Craigslist, microbiome casual encounters. So this is going to be a bit of a hard left, but preservative-free strips of tears for dry eye. Why? That was one of my notes from the conversation that you had with Andrew because I’m also looking for just low-hanging fruit for people who are contending as we all do with aging eyes. Maybe you could speak to that. And then I do have to ask about the blood serum for eye drops. Maybe you can hit that too.
Dr. Jeffrey Goldberg: Sure, sure. So look, actually the most common eye disease as we get older is actually dry eye. As we get older, we make fewer tears. We also make lower quality tears. Our tears at high quality have a liquid phase, like a water, salt water phase. There’s also like an oily component to good, high-quality tears. And that oily component also kind of dissipates a little bit as we get older, gets less as we get older. So we make fewer tears and lower quality tears. And a real simple over-the-counter solution for so many people is just put in some artificial tear drops.
The thing is that those little bottles come with preservatives so that when you use it all month, by the end of the month, it’s not growing bacteria. And if you’re just using a drop or two a day, fine, that’s getting you by, fine. Just buy those bottles. They’re the cheapest. But if you’re getting to the point where it’s three, four, five, six times a day, maybe you work on the computer a lot so you blink less and your eyes get drier, you want to use more of those, then we usually recommend at that stage switch over to preservative-free artificial tears because it turns out that preservative in those bottles of drops at a drop or two a day, fine. But if you’re getting up to a lot of drops a day, the preservative is actually irritating and kind of inflammatory to the ocular surface. It actually kind of breaks down some of the cells on the surface of our eyes.
So at that point, we like to switch people to recommending the preservative-free. They’re the ones that come — like usually they come in a little strip of tiny little plastic. You break one off, it’s got its own little cap on it. It’s got this tiny little bubble of fluid that you can squeeze. It really tests if you’ve got bad fingers or bad — by the way, if we’ve got bad vision, you’re poking yourself in the eye with it. So anyway, that’s what we recommend. Switch to preservative-free. And then people who need more than that, we actually have drugs that, for example, reduce on the ocular surface to help the tear quality and quantity come bounce back a little bit.
And then we also have drugs that contain growth factors, things like nerve growth factor that are almost certainly also good for the surface. And when our eyes get dry, the surface, the reason it feels irritating is not just because it feels dry, it’s actually because the surface starts to break down a little bit. And when you go to sleep every night and your eyelids are closed and nothing can evaporate, it bounces back a little bit by morning. So it kind of regenerates or rejuvenates. The ocular surface can regenerate pretty well every day, but at some point your eyes are getting dry enough that you’re having much more chronic problems.
And that’s where sometimes we can use what are called serum tears. So our blood serum, if you take out a blood, like a tube of blood, you’re getting your blood drawn. That tube of blood has your red blood cells carrying all your oxygen, your white blood cells, which is like your immune system, and then all just the liquid with the proteins in it. That’s what we call the serum. That’s the serum. So you could take that tube, you spin the cells out —
Tim Ferriss: Let me ask a dumb question. Is that different from plasma or are we talking —
Dr. Jeffrey Goldberg: Serum and plasma. Yeah, depending how you treat some of those proteins, that’s serum and plasma. Let’s just say you’re spinning out the cells and then you can take that serum. Maybe you dilute it a little bit in some of that preservative free artificial tears. Maybe you just use it straight. Usually we dilute it a little bit and we can give patients their own serum as artificial tear drops. And that serum is filled with really good juicy growth factors that help the surface rejuvenate. And that’s the principle of, in some patients, using serum tears.
Tim Ferriss: Maybe this is just a difference in terminology, but it makes me think of a platelet-rich plasma or platelet-poor plasma. Are there experiments with different, I’m not sure, concentrations or cocktails?
Dr. Jeffrey Goldberg: Different cocktails. That’s a great way to put it. Yeah. And platelet-rich plasma, again, one of the reasons that that looks so rejuvenating for our bodies is again, it’s just like chock-a-block full of growth factors. And so I don’t know, I’m sure somebody’s testing this as another way to treat really severe dry eye, or if your dry eye is so bad, you’re actually getting kind of ulcers on the surface of your eyes. Some of the most severe cases might really benefit from like serum tears. Maybe platelet-rich plasma would work too. So that’s a hot area right now. And again, filled with growth factors.
Tim Ferriss: So we talked about the importance of timing with, say, glaucoma exams, things of that type. What are some other recommendations for perhaps avoiding common mistakes or filling gaps that are commonly unfilled? Any recommendations to folks?
Dr. Jeffrey Goldberg: Yeah, there’s a bunch of things. First of all, get an exam and if you have a family member, a blood relative with eye disease, maybe get that exam even sooner. Take glaucoma as an example. If you got an exam and you’re 40 and you don’t have a family history and your exam was normal, you don’t have to come do that full exam every year. You could come back in five or 10 years, try it again. But especially as we get older now, half the people in the world need glasses, half the people in the US need glasses. So you might be going in to your local eye care provider, optometrist, getting your glasses checked each year or two anyway, just to see if you’re still in the right prescription and they can do the full exam, check for everything else, make sure nothing else looks suspicious, leave you in great shape.
So getting that periodic eye exam, especially as we get older and more of those age related diseases like macular degeneration, glaucoma, et cetera. Obviously if you have diabetes, you’re supposed to get an eye exam every year just to make sure, because if you’ve got diabetes and it’s starting to affect the retina inside your eye, we could get ahead of that. We’ve got good treatments that can prevent you from losing vision. So we want to stay ahead on these diseases. That’s the main thing. Other things, everyone’s going to get cataracts eventually, but what can we do to slow down the development of cataracts? Well, one real easy one is reducing UV light exposure. So you’re out in the sun a lot, wear sunglasses. All sunglasses made today have UV protection. By the way, all regular glasses that don’t have darkened tinted shades, they also block the UV light from going through.
So even if you’re wearing your regular glasses outside because you need glasses, that works too. So wear sunglasses or some sort of eyewear protection. And then eyewear protection is another big one. Depending on what industry you’re in, you’re gardening, you’re in steelworks, you’ve got anything where you’ve got eye injury risk, wear a protective eyewear. It costs like a buck 50 at Home Depot to get those really attractive plastic glasses that are wraparound, but wear them when you’re in those work situations. That’s a big one too. You see a lot of athletes now wear eyewear and sometimes it’s for sun protection, but you’ll see a lot of them when it’s not that sunny day or they’re even playing inside and they might be wearing it for prescription, but also just for eye protection.
Tim Ferriss: Eye protection. Is there anyone out there, and I don’t have a dog in the fight, it’s just that this conversation around sunlight and exposure, it’s like a religious war online. Is there anyone you would consider scientifically credible who has any counter-argument with respect to UV light, why it is important to also get natural exposure or could be important to get exposure to UV light? Or does that just not exist? Is there a strongman argument for that or does it just not exist?
Dr. Jeffrey Goldberg: I don’t ever want to say something doesn’t exist because someone on the internet —
Tim Ferriss: Which is why I say scientifically credible.
Dr. Jeffrey Goldberg: But no, full-spectrum light, white light that goes from violet through red, full-spectrum light. There’s a lot of decent evidence that that’s good and important. By the way, let’s come back to the development of nearsightedness. We used to say like, oh, maybe people are getting nearsighted as kids because they’re spending too much [of their time] indoor reading. And so it’s just like too much near work is leading to nearsightedness. There’s now pretty good data actually that it’s not the near work, it’s the being inside part of reading inside. And if you just send your kid outside and let them read outside in full-spectrum lighting, they could still be doing their near work or doing their homework, whatever it is, but it’s the full-spectrum lighting that will actually slow down their development of nearsightedness.
So you can get full-spectrum white light, but skip the UV by either having full-spectrum lighting indoors or through the window and you’ve got a nice sunny window. The sun that comes through the window, the glass actually filters UV light, so that’s fine. Your car window filters UV light. So even if you’re not wearing sunglasses inside the car, you’re getting that full-spectrum sunlight. Go outside in the morning, fine, get that first sunlight if you want. But there’s no data that suggests that part of that full-spectrum light has to include UV light.
Tim Ferriss: Okay, got it.I know that this might be asking a lot, but what do you think we might be getting wrong currently in any paradigm of how we think about vision or eye health? Right? I mean, I have a lot of doctor friends, a lot of researcher friends, and I guess it’s especially common among MDs, but they’ll say, yeah, 50 percent of what we know is wrong. We just don’t know which 50 percent. Which doesn’t mean science isn’t important, guys. By the way, it is incredibly critical for not fooling ourselves. And anyway, I don’t think I need to preach that to you, but what would you not be surprised to see overturned in the next five years if you were like, you know what? We’ve always thought X and it turns out, nope, it’s different.
Dr. Jeffrey Goldberg: I’m going to pull one out of my personal favorites list here.
Tim Ferriss: Yeah, great.
Dr. Jeffrey Goldberg: And it comes back to these big ticket eye diseases like glaucoma, macular degeneration, even diabetic retinopathy and other less common versions of these degenerations, let’s say, of the retina, the optic nerve. And we have always said, I even said earlier in the podcast with you, Tim, that glaucoma is the number one cause of irreversible blindness in the world. That I think is going to be the piece that we overturn. We have always said, “Hey, we’ve got to prevent you from losing vision. We’ve got to slow down the disease because once you’ve lost whatever vision you’ve lost, I can’t get that back for you.” And I think that is about to topple.
We are about to get into vision restoration at a level that has been totally unexpected and totally unprecedented, and the science supporting these directions in these diseases is getting really, really juicy. We have discovered so many molecular pathways, approaches to cell therapy. Some of the things we even talked about earlier, like inducing plasticity in the brain. If I stick a stem cell into the adult retina and I say, “Hey, I need you to turn into a retinal cell, hook up with your partners and start doing vision.” Well, during development, the retina, those cells are all developing. They learn to wire up together, do it right.
How do we get a cell that we’re going to put into an adult person to say like, “Hey, I know all you other retina cells are already neighbors with each other, but I’m moving into the neighborhood and I want you to accept me.” But we’re figuring out how to induce that plasticity, like open up the neighborhood, let that cell get into the network, start to participate in the network and restore vision. So it is moving really quickly right now and it is starting to translate, this laboratory science is starting to really move quickly into appropriate, safe human clinical trials. And so I think that is going to be the biggest topple is going to be that we can restore vision. And I will not be surprised if our colleagues in the brain follow suit quickly. We like to tease who’s going to come first, the eye or the brain. I will not be surprised if our colleagues in the brain follow quickly and maybe we could restore cognition in people with severe cognitive disease, Alzheimer’s and these others. So I think this kind of restoring the central nervous system, including the retina and optic nerve, spinal cord injury, I think this is all, we’re going to topple that in these next few years.
Tim Ferriss: That’s very exciting. When I talk to folks I’m like, look, I know it seems like one day, they’re like bananas will kill you and the next day bananas will help you live forever. And it’s like, first of all, a lot of that is fun house mirror warping by media coverage. And secondly, there are so many breakthroughs or breakthroughs that are on the cusp of making their way into clinical practice. I can’t help but be super optimistic about so many, at least the fields that I have a decent amount of exposure to. And I’m going to ask you a few follow up questions, but first, I’ll just say for people interested, if you are interested in looking at how, for instance, and there are multiple ways to induce greater plasticity in various ways, but if you’re interested in the reopening of critical periods, which we alluded to earlier, Gul Dolen, who was at Hopkins and is now at UC Berkeley, has done some wild work and has really rocked the boat and I think a very productive way looking at how MDMA but also potentially other compounds can potentially do that.
And she’s got wild experiments with octopuses and all this stuff that people should check out. But I believe that at some point, if she’s not already doing it, she’s going to look at, for instance, using these compounds to help stroke patients recover motor function. And there are also devices like DARPA and the defense language in Monterey have used for improving language acquisition. I mean, I really feel like there’s a lot of stuff that is not only happening but converging in interesting ways. What leads you to believe that we’re so close, the next five years is close, right? So is it just the publications you’re seeing, the types of science that is being done? Is it just new and novel ways to induce plasticity? Is it because the plasticity gang is finally playing nice with the eye people who are playing nice with the other brain people? What is actually happening?
Dr. Jeffrey Goldberg: Some of those things, like I was teasing before, but the truth is, we, eye people, love to work closely with our colleagues in brain because there’s so much shared science. I do think that there’s an increasing attention to, hey, let’s answer these questions properly, let’s do proper trials, let’s really study these things properly and let’s also move things out of the laboratory and into human testing and have it not just be the fantasy and the mice, but never move it to the person. And so I think that transition, that willingness to grow in that direction, we’ve had actually, to be honest, a remarkable two to three decades now of increasing support for science at the federal level, but also startups. Biotech has had an amazing age and that biotech, when you’ve got an amazing age cooking on the pharma side like big pharma, that then trickles down. So that means startups can say like, “Hey, let’s roll the dice and test this anti-aging formula because if it hits, there’s a market for it at the end of the day. This is important. These are big impact areas.”
So I think the investment that we make in science plays out and we’re sort of coming to a head a culmination. And I think that happens to be matching in time the advances we’ve been making in neuroscience. I think we made huge advances in immunology and cancer biology a couple decades ago, even just understanding what all the cells are. And I think that the analogy is the advances we’ve made even just in the last decade of being able to map the brain, not just even down to the cell level, but the cell-to-cell connections called synapses. We’re now mapping entire brains at that level and understanding how they talk to each other and recording and creating. We’ve got a colleague here who just had an amazing suite of papers, Andreas Tolias and his colleagues creating a digital twin of the entire brain.
And then you can do experiments on the digital twin of the brain. You don’t have to actually do them on an animal or a person to start. You could start there. So the advances in neuroscience and understanding of plasticity and all of these elements I think are converging with the advances that we’ve just been willing to make over the last couple of decades in healthcare, health-related research, discovery research, translational research, clinical trial research. And I think we’re just kind of seeing those two converge right now in an amazing way.
Tim Ferriss: If you don’t mind, let’s talk about mitochondria again for a second. So mitochondria, often referred to as the powerhouses of the cell, I won’t bore people with more ketone talk, but also read a piece recently from a very credible scientist, beautifully written also, about how they’re not just the powerhouses but maybe the motherboards of the cell. And there’s actually a lot of what you could view as social interaction between mitochondria and among mitochondria. Really just the deeper you go, the more interesting it becomes. And I’m wondering outside of the red light, if there are other interventions or technologies, biologics, anything, that you think are interesting for improving mitochondrial health within the visual system, however you want to take that.
Dr. Jeffrey Goldberg: Yeah, absolutely. And in fact, mitochondria, not only are they social with each other and they actually talk to each other, they actually fuse and then separate. They get trafficked up neurons. We talked about the ones that stretch from the eye to the brain. There are neurons of course that stretch from the top of our brain all the way down to the bottom of our spinal cord. There are neurons that stretch from our spinal cord all the way down to our toe tip. These are some long cells and they’re trafficking mitochondria all up and down. So they are social creatures for sure, but it turns out they’re yet a third thing. So they’re powerhouses, they’re social creatures, but they’re also scaffolds and they’re actually the foundation upon which a lot of other cellular signaling that’s regulating what a cell is supposed to do is happening on the surface of the mitochondria.
And so you’ve got metabolism, energy, scaffolding of signaling. And so no wonder half of our neurodegenerative diseases are associated with one or another defect that we can trace back to mitochondria. So that kind of adds up at the end of the day when you look at it that way. And some of the things we’ve already talked about, I mean you brought up red light therapy, that would be one for sure, but vitamin B3, nicotinamide, it’s directly affecting some of that metabolic signaling that is interfacing with the mitochondria metabolism biology. And so actually a lot of these supplements that are about metabolism end up having some link back to mitochondria.
Tim Ferriss: Yeah, I was going to say it’s kind of hard to dodge the mitochondria.
Dr. Jeffrey Goldberg: Yeah. Yeah. And look, it’s cool. Look, I mean I just read that they’re now doing successful mitochondrial transplants, for example, into an embryo. So you can have inherited diseases where the disease is inherited because your mitochondria are bad. Mitochondria get most of their proteins and lipids and all of that that make up a mitochondria. They got most of that built from the nucleus, the regular DNA of the cell. But they have a little bit of DNA themselves that make some of the proteins inside the mitochondria. And so you can inherit that mitochondrial DNA that has mutations and have real serious diseases. It’s now been shown you can transplant mitochondria so that that baby will not have an inherited mitochondrial disease. Is it that far off to think that we could transplant mitochondria into the retina of your eye and stave off another decade of glaucoma? These things are on the table, so definitely interesting.
Tim Ferriss: Okay, so I saw some news about, I think you can’t trust the headlines, but basically babies with three parents, so to speak, out of the UK now. So you mentioned the embryo. So this is a case where you’d be taking third-party mitochondria —
Dr. Jeffrey Goldberg: You’re hitting it. That’s exactly what I was talking about. So you’ve got DNA from the mom in the egg cell. You’ve got DNA from the dad in the sperm. But you could take a third party’s mitochondria outside of their cell, inject it into that egg just like the sperm went into the egg, and now that egg with Mom and Dad’s DNA and a third person’s mitochondria, including their mitochondrial DNA, will propagate and form the whole embryo. And it’s kind of, I mean it’s an amazing headline. Does that mean there’s three parents involved?
Tim Ferriss: I mean, it’s equally fascinating when you just understand what you’re describing. And part of the reason I’ve been reading and really trying to do a deep dive, always dangerous when you are only half scientifically literate. But on my mom’s side of the family, a lot of Alzheimer’s and my mom’s had some deterioration as well, but she’s APOE 3/3. And I’m looking at it, I’m like, I wonder if there — and also just word to the wise, again, not a doctor, talk to your medical professional, but if you’re trying to evaluate your metabolic health, don’t just get fasting glucose taken because you can get lucky with fasting glucose and you might even do hemoglobin A1C, which is a running three-month average of your fasting glucose is maybe a simple way to think about it, something like that. But also get your insulin measured because that was missed by my mom’s local doc for many, many years.
And her fasting glucose, even her hemoglobin A1C was kind of within tolerable levels. Then her insulin was, it was so out of range as to just jump off the page. And so then I was looking at it, and there of course could be a million different contributing factors, but I was like, I wonder if there’s some type of issue in her mitochondria, in which case, my understanding is you do inherit the mitochondria from your mom’s side is my understanding. And I was like, okay, well if that’s the case, I’d like to — I don’t know if there’s anything to be done about it at this point, frankly, but if there is even a small possibility that you could do something about it, I’m like, well, I’d like to kind of know what I’m dealing with. So that’s the genesis of me asking about also the mitochondrial health side of things.
Dr. Jeffrey Goldberg: We don’t have a great blood test for your mitochondria. Obviously, you could get it sequenced. We don’t know how much your fidelity to mom’s mitochondria might play a role in your future cognitive health. I would add to your list though, to other standard screening tests —
Tim Ferriss: Yeah, please.
Dr. Jeffrey Goldberg: — that certainly are likely to impact your cognitive health as you age. And with that, again, the eye’s part of the brain, your visual health too, and that’s going to be your lipids, your fasting lipids, and your blood pressure. And every bit of science points to, yes, you can inherit it, your ApoE genes that can change your risk. But a very big contributor is going to be your lipids and your blood pressure because those are going to contribute to what we call microvascular disease and ultimately, brain atrophy as we get older and ultimately, cognitive function. And if you could be really ahead of the curve and be really clean with your lipids, whether that’s with diet and exercise or upgrading to some of the medicines that help with that and really clean with your blood pressure, again, diet and exercise or there are medicines we can give to help with that, staying ahead of the curve on those is almost certainly a huge contributor to your later cognitive health.
Tim Ferriss: Yeah, I’ve got those suspects under control and very well-dialed. I’m just like, are the mitochondria the boogeyman in the closet that I’m not contending with? But yeah, I’m trying to do all the stuff you would expect to also help support mitochondrial health and I don’t think this is immediately obvious, people think of exercise as body exercise. But if you want to increase the brain-derived neurotrophic factor release and Klotho release, which hopefully someday soon we will have, it’s an injectable therapy for humans, exercise, you’ve got to do it, do some weight training, do some Zone 2, do VO2 max every once in a while. It’s incredibly valuable.
Dr. Jeffrey Goldberg: And I think the important thing for listeners is that, and when I say listeners, I include myself because I intellectually know I need to do more exercise and I’ve still got to figure out how to get around to actually doing that more exercise. So I’m in the listener crowd here of what I need to say, but the important thing to remember is that the biggest gain comes from going from none to some.
Tim Ferriss: Yes.
Dr. Jeffrey Goldberg: If you go from some to twice as much, yeah, there’s an improvement there too, but not as big as the value proposition of going from none to some.
Tim Ferriss: Yeah, yeah. Just scale it down, guys, if you have to, but don’t do nothing.
Dr. Jeffrey Goldberg: Don’t do nothing because you feel like “I can’t do a million hours, so I’m throwing in the towel and I won’t do any.” Half an hour, four or five days a week, brisk walk, get that heart rate up, have it count, easy. Make it easy on yourself. If you want to then go nuts and do hardcore weight training, hit your Peloton, have your trainer, train for a marathon, okay, fine. But that biggest difference in your life was going from none to some.
Tim Ferriss: Can I give you the greatest non sequitur in the history of my podcast? It’s just because you mentioned that your number one most common question was, “Can I have cannabis?” So I’m lucky to know a bunch of very amazing docs and blah, blah, blah. I interview people, so I get to meet a lot of fascinating folks and one of these super high-end, really sophisticated docs, he was telling me the most, can you guess? I’ll give you a shot. I’ll give you a shot on the three-pointer. What do you think his — I’ll be astonished if you guessed this. Even if you believed it, you probably wouldn’t say it. But what do you think one of his most common questions is that he still refuses to answer publicly? I’ve wanted him to do it.
Dr. Jeffrey Goldberg: Oh, my God, this is a guess what you’re thinking. When we’re in training for medicine, we get asked questions like this all the time, and some of them are like, “Okay, I want you to guess what I’m thinking. Go ahead. Three trials.”
Tim Ferriss: No, no. All right, let me save you the trouble.
Dr. Jeffrey Goldberg: All right, lay it on. Lay it on. What did he say?
Tim Ferriss: This is the question he gets all the time, which is from male patients. “How can I shave my balls safely?” This is the question he gets more than any other. He’s like, “Really? I’ve done all this training, I’ve done all this. And that’s the question that I get more often than not.” Anyway, I don’t know why I felt compelled to share that. Sorry.
Dr. Jeffrey Goldberg: I’m going to trust that he’s not an eye doctor because I never get that question.
Tim Ferriss: Yeah, that’s right. He’s like, “What are you talking about?”
Dr. Jeffrey Goldberg: Tim, you interview a lot of people. What did Matt McConaughey say to that question?
Tim Ferriss: Maybe this should be one of my rapid fire questions that I finish with.
Dr. Jeffrey Goldberg: I’ll pick a path on that one. I don’t have enough experience to talk about that.
Tim Ferriss: Yeah, yeah. No, we can both pass on that one. But is there anything else that we haven’t covered that you would like to mention? Any treatment or research or researchers that you think people should take a look at? I mean, we talked a bit about mitochondria, certainly talked about the lens, we talked about glaucoma and hopefully within the next five years, as you said, being able to potentially restore function or stave it off to a much greater extent. We didn’t really get into treating nerves. I have a note about treating nerves, but I’m not sure we need to cover that. Is there anything else that you’d like to mention that we didn’t have a chance to discuss?
Dr. Jeffrey Goldberg: Look, I want people to understand that first of all, these are all amazing questions. You’ve hit a wide range and we can’t answer them without doing the science behind it. So first of all, as They Might Be Giants said, “Science is real.” So first of all, science is real. And second of all, I would just encourage people, ask your, in this case, eye care provider, “What’s going on with me? Are there clinical trials?” Volunteering to be in clinical trials, I’ll tell you, I know patients are so grateful when they get into our clinics here and they get into a clinical trial because they’re accessing a treatment before it is publicly available to see if it’s going to work. We don’t know if it’s going to work, but they’re taking a swing at that and they’re so grateful to get into these trials.
But I always say, “We are so grateful. We can’t do the trials and therefore, decide whether you should take the supplement or use this virtual reality device or go in front of red lights every day or microdose LSD or change your microbiome. We can’t figure that out if we don’t have the patients come be in the clinical trials and volunteer their time and energy, the extra trips to the office to get their eyes measured or special pictures taken or all that kind of stuff.” So I say, “I know you’re grateful to be in this trial, but I’m grateful to you too.” We are grateful to the patients. So I think we’ve all got to participate in science as a community so we can do these trials and figure out how we’re going to fix ourselves and go from disease to normal. And by the way, go from normal to supranormal. Right? We’ve got to prove it, right?
Tim Ferriss: Yeah. Where would you suggest people search for or find clinical trials around them? And I’ll just reiterate what you said. I have seen so many studies that I’ve been involved with hit a wall with subject or patient recruitment. They just hit a wall.
Dr. Jeffrey Goldberg: That’s a tough one, right?
Tim Ferriss: They really, really benefit from people who are proactive. But if someone’s listening, they’re like, “That sounds amazing. I’d love to actually see what this looks like in practice and maybe figure or help people figure out something in the process for others or myself,” where do they even look? Where would they begin?
Dr. Jeffrey Goldberg: One really good place in the US to look is a website called clinicaltrials.gov. So it’s got it right there in the name, and you go on the front page for clinicaltrials.gov and you type in your disease. So you could type in glaucoma, diabetes, whatever it is. It’ll give you a list of, here’s trials that are recruiting right now actively. And then you can click on any of those and say like, “Oh, that one’s in my city,” or “It’s not in my city, but I’m going to call or send an email to them anyway and say like, ‘Hey, could I be eligible for that?'” So that’s probably one great resource. And then the other would be, again, for diseases would be in the case of research for specific diseases, almost every disease has one or more foundations or patient support sites that bring people together.
And I think of one in our backyard, here in San Francisco called The Glaucoma Research Foundation. There’s another one in New York City called The Glaucoma Foundation, dozens more of course, but they also maintain websites that have a lot of patient-directed information, patient-facing, what to learn about your disease. You were asking before, where’s a reliable source to learn about stuff? That’s one. But they’ll also sometimes talk through what’s happening in clinical trial space or where is that happening or where some hot spots for clinical trials. So I think those are a couple good resources. Of course, nowadays, Google, just any web search engine, it’ll get you started in the right direction.
Tim Ferriss: Yeah, perfect. And if people are wondering, “Well, Tim, have you done any of this yourself?” Yeah, actually, I’ve been a subject in all sorts of different studies from undergrad all the way up to a few years ago for various things, including at Stanford, way back in the day, just a few years after college. So it’s fascinating also just to see what it looks like in real life. What does scientific study look like when it’s implemented? Well, thank you so much, Jeff. This has been a fantastic wide-ranging romp. It’s still and will continue to be intensely personal. So I will keep people listening posted. I promise not to sell you any kratom eye masks through some MLM scheme. And I will be continuing to investigate all of this. This has been super helpful. I took a ton of notes. Is there anywhere you would point people to find you online or learn more about you?
Dr. Jeffrey Goldberg: Yeah, absolutely, Tim, and you joked in the beginning that this podcast is yours and certainly allowed to be self-serving. But I’ll throw one plug in here at the end, the Stanford Ophthalmology website. We actually maintain a list of clinical trials. And again, if we want to tap this whole team here on the back, our faculty, our clinical research staff, everyone involved in it, stem to stern is fantastic. And I’d like to point out a lot of the clinical trials of trying to pull things out of the lab and test them in patients for the first time, a lot of work on vision restoration, vision protection and restoration. Clinical trials going on right here. My work and some of the work of our amazing faculty and staff here.
So you can actually go to Google Stanford Ophthalmology Clinical Trials. We have a web page on our Stanford Ophthalmology site that goes disease by disease and has contact info in how you plug right into the trials here. And we have people in our community participating, but we have people who fly in from everywhere to participate in these clinical trials. So we’re happy to see if we can fit you in too.
Tim Ferriss: Beautiful. And for people listening, I will link to that in the show notes at tim.blog/podcast. So that’ll be easy to find. If you just search Jeffrey Goldberg or Goldberg, I think you might be the only Goldberg. There might be one other. Search Jeffrey Goldberg, and it’ll pop right up and you’ll be able to find the links. Jeffrey, thanks so much. I really appreciate the time. And to everybody listening, as mentioned, show notes, tim.blog/podcast, you’ll be able to find links to everything we discussed and more. And until next time, be just a bit kinder than as necessary to others, but also to yourself. And thanks for tuning in.
The post The Tim Ferriss Show Transcripts: Dr. Jeffrey Goldberg — Creating Supranormal Vision, Cutting-Edge Science for Eye Health, Supplements, Red Light Therapy, and The Future of Eyesight Restoration (#823) appeared first on The Blog of Author Tim Ferriss.
2025-08-21 05:34:02
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这篇访谈记录了斯坦福大学眼科系主任兼Byers眼科研究所所长Jeffrey Goldberg博士的观点。Goldberg博士是视觉系统发育和退化研究领域的领先科学家，也是一位执业眼科医生和外科医生，在神经保护和视网膜及视神经再生方面取得了显著成就。
访谈主要内容包括：
访谈中提到的关键概念和术语包括： 老花眼、近视、青光眼、年龄相关性黄斑变性、白内障、干眼症、神经可塑性、超常视力、线粒体健康、代谢综合征、三亲技术等。 访谈还介绍了眼球的解剖结构，以及一些相关的机构、公司和研究人员。
总而言之，此次访谈深入探讨了眼科疾病的最新研究进展和未来治疗方向，为听众提供了关于眼部健康和视力恢复的宝贵信息。 Goldberg博士乐观地认为，许多目前被认为是不可逆的眼部疾病，在未来有望得到有效的治疗和恢复。
Dr. Jeffrey Goldberg is chair of the Department of Ophthalmology and director of the Byers Eye Institute at Stanford University. He is a leading scientist in the development and degeneration of the visual system from eye to brain and a professor, practicing ophthalmologist, and surgeon.
Dr. Goldberg is a member of the National Academy of Medicine and has won a number of prestigious awards, including Scientist of the Year by the Hope for Vision foundation and the Cogan award from the Association for Research in Vision and Ophthalmology. Dr. Goldberg received his BS magna cum laude from Yale University and his MD and PhD from Stanford University, where he made significant discoveries about the failure of optic nerve regeneration.
Dr. Goldberg’s research is directed at vision restoration, including neuroprotection and regeneration of the retina and optic nerve, a major unmet need in glaucoma and other eye diseases. His laboratory is developing novel molecular, stem-cell, and nanotherapeutics approaches for eye repair, and he is widely recognized for translating advances in the lab into clinical trials for patients.
A number of his innovations have spun out into startups and clinical-stage companies, and he serves as medical and scientific advisor to a number of ophthalmic start-up, pharma, and device companies. His goal is to translate scientific discoveries to patient therapies.
Please enjoy!
Listen to the episode on Apple Podcasts, Spotify, Overcast, Podcast Addict, Pocket Casts, Castbox, YouTube Music, Amazon Music, Audible, or on your favorite podcast platform. Watch the conversation on YouTube. The transcript of this episode can be found here. Transcripts of all episodes can be found here.
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Want to hear another podcast episode with a Stanford neuroscientist who won awards for vision research? Listen to my conversation with Dr. Andrew Huberman, in which we discussed the foundations of physical and mental performance, core supplements, sleep optimization, psychedelics, neural plasticity, and much more.
Faculty Profile | Stanford Ophthalmology | Clinical Trials
The transcript of this episode can be found here. Transcripts of all episodes can be found here.
“I have gone my whole life without needing glasses until I hit around age 40. And when everyone hits around age 40, our lens inside the eye won’t compress and reshape to focus up close.”
— Dr. Jeffrey Goldberg
“Professional athletes get studied. They have better vision. They have better reflex time. They have sharper vision. We talk about 20/20 vision. That means I can see at 20 feet what a ‘normal’ person can see at 20 feet, so I have normal vision. But you can have 20/12 vision, which means you can see at 20 feet what normal people can see at 12 feet.”
— Dr. Jeffrey Goldberg
“Glaucoma is the number one cause of irreversible blindness in the world. That, I think, is going to be the piece that we overturn. We have always said, ‘Hey, we’ve got to prevent you from losing vision. We’ve got to slow down the disease because, once you’ve lost whatever vision you’ve lost, I can’t get that back for you.’ And I think that is about to topple. We are about to get into vision restoration at a level that has been totally unexpected and totally unprecedented, and the science supporting these directions in these diseases is getting really, really juicy.”
— Dr. Jeffrey Goldberg
“Cannabis, whether you smoke it or eat it in the brownie or take the chewy, it lowers your eye pressure if you’re using the version … where you feel a little high from it, you get that good feeling. The problem is that it only really lowers the eye pressure during that time that you’re getting high. So I tell patients, ‘It works, but you’d have to be high 24/7, so maybe you should just use this eye drop instead.'”
— Dr. Jeffrey Goldberg
“A small dose of daily red light can slow down progression of myopia in young people. We’re talking about teens and younger, even. So what’s even more shocking to me is that it also works with violet light. So how’s it work with light at the two ends of the visible spectrum? And definitely mitochondria are implicated.”
— Dr. Jeffrey Goldberg
“There’s an important myth to dispel, especially when it comes to presbyopia and wearing reading glasses. Between age 40 and around 60 or so, that lens stiffens and stiffens and stiffens. That’s the refractive, the glasses difference between viewing something at infinity, which from an optics perspective is actually just three feet away or further, and viewing something at 14 inches, comfortable reading distance, right in front of us.”
— Dr. Jeffrey Goldberg
“If we all live to a hundred, we’re all going to need cataract surgery—some people younger, some people older. But if you do cataract surgery and restore vision in an older person who … is suffering with cognitive decline and/or depression, you can reverse a significant amount of that decline in either of those domains. It speaks to the interplay of vision with our mental health, our cognitive health, and this is long-term, important stuff.”
— Dr. Jeffrey Goldberg
“The important thing to remember [about exercise] is that the biggest gain comes from going from none to some.”
— Dr. Jeffrey Goldberg
The post Dr. Jeffrey Goldberg — Creating Supranormal Vision, Cutting-Edge Science for Eye Health, Supplements, Red Light Therapy, and The Future of Eyesight Restoration (#823) appeared first on The Blog of Author Tim Ferriss.
