Micronutrients for Health & Longevity | Dr. Rhonda Patrick

Welcome to the Huberman Lab podcast where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Rhonda Patrick. Dr. Patrick is known to some of you as a podcaster and one of the premier educators in the landscape of mitochondria, metabolism, stress, and other aspects of brain and body health. Her podcast Found My Fitness is one of the premier podcasts in the world for disseminating knowledge about how the brain and body work and how we can use behavioral tools, microtutrients, supplements, and other protocols in order to maximize our immediate and long-term health. Dr. Patrick did her formal training in cell biology exploring the links between mitochondrial metabolism, apoptosis, which is naturally occurring cell death, which is a healthy form of cell death that occurs in our brain and body. Throughout the lifespan and cancer biology. She then went on to do postdoctoral training with Dr. Bruce Ames investigating the effects of micronutrients, meaning vitamins and minerals, and how they affect metabolism, inflammation, DNA damage, and the aging process. She has published landmark review articles and primary research, meaning original research articles in some of the premier journals in the world including science, nature cell biology, trends in cell biology, and facep. Indeed, Dr. Patrick is an expert in an extraordinarily broad range of topics that impact our health. For today's episode, we focus primarily on the major categories of micronutrients that are essential for brain and body health. I have to confess that before the discussion with Dr. Patrick, I was aware of only one of the categories of micronutrients that we discuss. You'll notice that I am wrapped with attention throughout the discussion, and I think that you'll want to have a pen and paper handy because she offers not only a very clear understanding of the biological mechanisms by which other micronutrients operate, but some very clear and actionable tools and items that we can all embark on if we are to optimize our brain and body health. We also discuss behavioral protocols. Dr. Patrick is well known for her understanding of the scientific literature on sauna and the use of heat and cold for optimizing things like metabolism, longevity, cardiovascular health, and I've delayed to say that we discussed that as well, and how behavioral protocols can interface with supplement based and nutritional protocols. I'm confident that you'll learn a tremendous amount of information from Dr. Patrick, much of which is immediately actionable. If you're not already following and listening to her excellent podcast, you'll absolutely want to do that. It's foundmyfitness.com is the website where you can get access to that podcast. It's also on Apple and Spotify and YouTube as foundmyfitness. Dr. Patrick also has a terrific newsletter that I recommend signing up for. It's foundmyfitness.com/newsletter is where you'll find it, and it includes research on fasting, microturrent sleep, depression, fitness longevity, and far more, along, of course, with actionable protocols. I'm pleased to announce that the Hubertman Lab podcast is now partnered with Momentus Supplements. Our motivation for partnering with Momentus is to provide people one location where they can go to access the highest quality supplements in the specific dosages that are best supported by the scientific research and that are discussed during various episodes of the Hubertman Lab podcast. If you go to livemomentus.com/Huberman, you will see those formulations. I should mention that we are going to add more formulations in the months to come. You will see specific suggestions about how best to take those supplements, meaning what dosages and times of day, and in fact, how to combine those supplements with specific behavioral protocols that have been discussed on the podcast and are science supported in order to drive the maximum benefit from those supplements. Many of you will probably also be pleased to learn that momentus ships not just within the United States, but also internationally. So once again, if you go to livemomentus.com/Huberman, you will find what we firmly believe to be the best quality supplements in the precise dosages and the best protocols for taking those supplements along with the ideal behavioral protocols to combine with those supplement formulations. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. And now for my discussion with Dr. Rhonda Patrick. Rhonda, welcome. There's been a long time coming. Even longer than you know, because even before we discussed you coming on this podcast as a guest, I've been watching your content for a very long time. So I want to start off by saying thank you. You were the spearhead to break through from academic science to public education. So I consider you first in and the rest of us are just in your wake. So thank you for that. That's been. Oh, that is so kind. Thank you. Thank you so much. That's absolutely true. I am so excited to be here having a conversation with you. Thank you. It's absolutely true. If anyone does their research, they will realize that the statement I just made is absolutely true. And there isn't even a close second. You know, any other public facing educators that have formal science training and do regular posting of content came in several years after you initiated it. So we're all grateful. I have so many questions, but I want to start off with a kind of a new but old theme that you're very familiar with. So temperature is a powerful stimulus as we know for biology. And you've covered a lot of material related to the utility of cold, but also the utility of heat. And as I learn more and more from your content and from the various papers, it seems that there's a bit of a conundrum in that cold can stimulate a number of things like increases in metabolism, brown fat, et cetera, et cetera. Hopefully you'll tell us more about those. But heat seems to be able to do a lot of the same things. And I wonder whether or not the discomfort of cold, deliberate cold exposure and the discomfort of heat might be anchoring to the same pathway. So would you mind sharing with us a little bit about what happens when we get into a cold environment on purpose and what happens when we get into a hot environment on purpose. And I'm hoping that this might eventually lead us to some point of conversion understanding. So if you would, I would love to let's take a step back. And I think you brought up a really important point here. And I think that point has to do with the intermittent challenging of yourself and whether that is through, you know, temperature changes like cold or heat or through other types of stressors like physical activity or perhaps even dietary compounds that are bound in plants. These are things like polyphenols or flavanols. Humans were, you know, we evolved to intermittently challenge ourselves. And before we had Instacart where you could basically just get your food delivered to you. Before the industrial revolution, you know, occurred, we were out hunting and I say we not us humans. We were out, you know, gathering, we were moving. And we had to be physically fit. You couldn't catch your prey if you were a sedentary slob, right? And you had to like, you know, pick your berries, you had to move. And so physical activity was a part of everyday life. And caloric restriction or intermittent fasting was also a part of it. This is another type of challenge. You know, we didn't always, you know, have a prey that we caught or maybe temperatures were such that, you know, there was nothing for us to gather. Right. Food scarcity was something common as well as eating plants. So getting these compounds that I mentioned. So this is these these are all types of stress intermittent challenges that activate genetic pathways in our bodies. These are often referred to in science as stress response pathways because they respond to a little bit of stress, you know, physical activity is strenuous. Fastings a little bit stressful heat cold these things are all types of little intermittent challenges. And there is a lot of crosstalk between these stressors and the genetic pathways that they activate and these genetic pathways that are activated help you deal with stress and and they do it in a way that is not only beneficial to help you deal with that little stressor exercise or heat. It's stays active and it helps you deal with the stress of normal metabolism, normal immune function happening just life aging right so this concept is referred to as hormesis right this is a little bit of stressful challenge that activates these stress response pathways in a beneficial way that is a net positive that actually, you know, it has a very profound antioxidant anti-inflammatory response or, you know, or whatever the responses it could be the production of more stem cells these are just a lot of things that are happening. For stem cells these are cells that help regenerate different cells within tissues or something like a topogy, which is a process that can clear away all the gunk inside of our cells pieces of DNA protein aggregates. So you'll find that these stress response pathways are activated by a variety of stressors. So for example, one pathway is called heat shock proteins and as their name would apply one would go, oh, they're activated by heat. They are activated very robustly by heat and we can talk about that, but, you know, you can eat a plant like broccoli sprouts, which is high in something called sulfide. for a fan. This is a compound that is sort of like a Hormetic compound or as David's clear likes to say, it's a Zeno Hormetic compound. I love that term. And it activates heat shock proteins, among other things. It also activates a very powerful detoxification pathway called NRF2, which helps you detoxify things like carcinogens that you're exposed to. Well, guess what? He activates that. So what I'm getting at is there is overlap like cold also activates heat shock proteins are like really cold. Yes, it activates. These are stress response pathways and they are activated by various types of stressors. Now, you know, you're going to more robustly activate heat shock proteins from heat versus cold, but there is overlap. So I think that sort of forms a foundation there. Yeah, that's very helpful. And you know, it brings to mind in the context of the nervous system, I was so people, you know, you only have a small kit of neurochemicals to work with. There isn't dopamine for Netflix and then dopamine for relationship and dopamine for work, et cetera. Their dopamine is a generic pathway by which motivation craving and pursuit emerge, et cetera. It just like adrenaline is a generic theme of many different behaviors. And it seems that it is the job of biological systems to be able to take a diverse range of inputs, even unknown inputs like we don't know what technology will look like in three years, but you can bet that some of those novel technologies will tap into the very systems that I'm talking about now. And there certainly will be other stressors to come about that will tap into these pathways. I have two questions related to what you just said before we talk a little bit more about cold and heat. You mentioned plants as a route to creating intermittent challenge. There's a lot of debate mostly online about whether or not plants are our friends or plants are trying to kill us. The extreme version from the carnivore types, pure carnivore diet types is that plants are trying to kill us. From the plant-based diet folks, it seems like it's more about what's healthy for the planet animals and maybe for us. But if we set aside that argument and we just raise the hypothesis that plants have compounds that are bad for us, but maybe by consuming them in small amounts, they're creating this hormisist type scenario. So then I think we conceivably solve the problem. We could say, yes, plants are bad for us, but in small amounts, they provide this hormetic response and they're good for us. Right? So in the same way that heat is too much heat is bad for us. Too much cold is bad for us can kill us can kill neurons, but appropriately dozed in an intermittent challenge type of scenarios can be good for us. Is that how I should think about plants in these compounds? Do you think of them as good for us or as bad for us? They're a very sharp blade and we want to use them politely. I actually think that it's almost impossible. I mean, you'd have to eat nothing but the same plant all day, every day in the large. I mean, the bioavailability of these these compounds in the plants, they're attached to a food matrix. You know, it's not like taking it in a supplement form as well. It's such that like it's very difficult to make it toxic. Now, there are some cases, for example, if you eat cabbage and I think there's some group in Africa somewhere that like that's all they eat is cabbage and there's a gorytrogen in cabbage. It's not so for a thing. It's another compound, but that's all they eat every day. Nothing but that and they get yeah, and they're like iodine deficient on top of that. So, you know, I do think there's there you can of course make I mean, there are types of plants that are toxic in small quantities, right? I mean, that, it hamlock exactly. So, don't play this game with him. But you're not going to get poison from eating, you know, you're you're serving a broccoli at dinner, right? So, I mean, it depends on the plant. It's I don't these generalizations are kind of they're just not useful. And I think that a lot of people online in the blogosphere, they gravitate towards them because it's easier and it's a lot more sensational. I plants meat and starches. I'm one of those rare omnivores out there now. I feel like a rare or it's rare to be an omnivore. But I think once you step out of the social media, as you said, the blogosphere, the most people, I would say 99% of people on the planet are probably omnivores. Right. And someone will probably correct me. But I doubt the number falls below 90, 98. I think if you look at data, you know, and and when we have carnivore data, like I can't wait to see it, but like right now, it's a lot of, okay, well, this is a lot of anecdotal evidence and there's, you know, there's a good there's a lot of good starts with anecdotes, but like people change a thousand things at once. And they don't realize that, but they do. And so, anecdotal data is only so good, right? It's a starting point. And so we don't really know long term what carnivore diets are going to do. You know, they may be beneficial short term. They may, you know, be beneficial for reasons of elimination of other things like who knows, right? Lots of possibilities. But I do think with respect to plants, you know, that there's, that there's so much evidence, like for example, sulfurian is one that I really like because there's just evidence that sulfurian is a very powerful activator of the NRF2 pathway. And this is a pathway that regulates a lot of genes and a lot of genes that are related to like glutathione production. Genes that are involved in detoxifying compounds that were exposed to from our food, like heterocyclic amines. In fact, there have been GWAS studies. So these are genetically, these are studies that are genome-wide associated studies for people listening that aren't familiar. People have a variety of versions of genes. And we have a gene that's able to make heterocyclic amines to basically detoxify so it's not as harmful. And people that don't have a certain version of that that's doing it well are very prone to like colon cancer and increased cancer risk. But if they eat a lot of broccoli and cruciferate vegetables that negates that risk because they're getting sulfuric fain, which activates a lot of the glutathione transfer, glutathione transferase and synthase genes. So glutathione's a major antioxidant in our brain and in our vascular system and our body basically. So there's evidence that eating things like compounds that are sulfuric fain or broccoli or broccoli sprouts, which have like a 100 up to 100 times more sulfuric fain than broccoli are activating glutathione in the brain. There's human evidence of that. I mean, that's amazing. That is amazing. In plasma. Yeah. Sorry to interrupt. I just want to make sure when so broccoli sprouts are different than broccoli. And you just told us that they have much richer in these compounds. So note to self, I should have broccoli sprouts, not just broccoli. Can we cook the broccoli and still get these nutrients? Or do we have to eat raw? I confess eating raw broccoli is really aversive to me. So the sulfuric fain is formed from a compound called glucoraphanin, which is in the broccoli. And the enzyme that converted into sulfuric fain is myrosanase and it's heat sensitive. So you do somewhat lower the sulfuric fain levels when you when you cook the broccoli. However, there was a study a few years back that showed adding one gram of mustard seed powder, ground mustard seed powder, which also contains the myrosanase enzyme. Two of your cooked broccoli increases the sulfuric fain by fourfold. So this is great because I confess I like broccoli if it's cooked to the appropriate density, not too mushy, but definitely not raw. The idea of eating raw broccoli to me just sounds horrible, but I like the way mustard seed sounds. So just a little bit of mustard seed powder added to the cooked broccoli can recover some of these compounds. Yes. So what I do is I will, you know, lightly steam my broccoli and then I add a little bit of my carigold butter. And then I add some mustard seed powder on the top of that. And it's kind of a little kick. Like it's just a little spice, you know, and if you don't taste that, it's expired. Like it should have a little kick. And because I know people will want to know how often and how much, you know, are you eating this every day or most days of the week? Well, I had shifted to supplementation with sulfuric fain. I've admitted I'm admitting right now that I've been terrible about at the past. I don't know, six months or so. The supplementation or the broccoli? Yes. Yes, the supplementation. And so there's another way to get, there's another compound and it's actually called meringa. And Dr. Jedfei, who's really the expert on sulfur fain, he's a good friend of mine. He's been on the podcast a couple of times. He, he basically thinks and, you know, has done a lot of research on meringa as well, that it's like a cousin and it activates the NRF2 pathway similarly to sulfur fain. And so I've been buying this coolie, coolie meringa powder. I don't have any affiliation with them. Coolie, coolie is a brand. Coolie, coolie is a brand that you have no affiliation. I know affiliation. But Jedfei, he like has researched it like, like that specific brand. And so it's like legitimate, it's legit, you know, it's like science back in terms of actually containing meringa and activating NRF2 and I added to my smoothies. So that's what I've been doing. What are some dose ranges? So of course we give the usual recommendations that people should talk to their physician, etc., etc. But if people are going to, what do you take? That's always the, let's take the table. David St. Clairion approach. What do you, where he'll talk about what he does as a way to deal with this? Of course, everybody's different and should, in all seriousness, should, anytime you add or delete something from your consumption, should consult some trusted healthcare professional trusted by you. What do you recall the dosages? - I do a big heaping tablespoon. - So, Moringa, coolie, coolie, Moringa. Sounds like a song. - It's with a K, I know. But, for people also listening, it's like, well, why would I do that? I mentioned the glutathione in the brain. I mentioned it in plasma. It's been shown a lower DNA damage in people and white blood cells. It's also been shown. There's been several different studies in China. In China, there's a lot of air pollution. And I mentioned that it's a very powerful activator and NRF2. And I know you're friendly with NRF2, but NRF2 is like a transcription factor. That is, it is binding to a little specific sequence in a variety of different genes. And it's like turning them on, or in some cases turning them off. It's regulating what's being activated or what's not being activated or being turned off. And some of the genes are basically these detoxifying pathways. We talked a little bit about the glutathione, but there's also ones that are involved in air-borne carcinogens like benzene. So, benzene is found in air pollution. I mean, cigarette smoke. I mean, if you're smoking cigarettes still, like please try to quit. - Hey, you're mutating your DNA. - I mean, yeah. It's just, nothing of the lung cancer. You're mutating your DNA. - And heart disease risk. Heart disease risk, but anyways, people, and this has been repeated in more than one study, that literally after 24 hours of taking, can't remember off the top of my head, what the dose of sulfur, from broccoli extract, broccoli seed extract was, or broccoli sprouts extract, not the seed. It was the sprouts. Anyways, they started excreting like 60% benzene and acroline. I mean, that's something that we get in cooked food. It's coming out in their urine. - Coming out in their urine. - Yeah. - Well, I'm not a smoker, and I have to be honest, it's rare that I hear of a supplement for the first time because I've been, you know, deep diving on supplements since I was in my teens. This is fascinating. And it brings back to this question that we have before, and I appreciate that you answered it very clearly. Plants have compounds that are good for us. They're not just stressing us. They're activating pathways that are reparative. That's what I'm taking away from everything you're telling me. - Right, and that our bodies were supposed to be getting that stress to have those pathways activated. Like it is, you know, right? I mean, this is conserved among different animals. Like this is something that is supposed to happen. And in our modern day world, we don't have to eat plants. We don't have to move anywhere or exercise. We don't have to go through periods of not eating food because we can have it at our fingertips at any second, right? So I mean, we've got this conundrum of we're never activating these stress response pathways that we're supposed to activate. We're supposed to. - I find that fascinating. And again, drawing a parallel to the nervous system. So what I'm hearing you say is that historically, we would have to go through some stress. Some confront cold or confront heat or confront effort or hunger in half to exercise, essentially, in order to obtain these compounds. And then those compounds are reparative. Yeah, I feel that resembles the dopamine pathway. I always say, you know, there's nothing wrong with dopamine. People think about dopamine hits as bad or dopamine is bad. There's absolutely nothing wrong with dopamine. The problem is dopamine, especially high levels of dopamine released without the need for effort to access that dopamine is problematic. So a line of cocaine gives you a ton of dopamine with no effort except to ingest the drug. Whereas working for four years or more to get your degree will release a lot of dopamine and a lot of cortisol along the way, as we know. And it's considered a healthy accomplishment, in most cases, a tremendous amount of, we're approaching the spring and there'll be a lot of graduations. Weddings are coming up now that the pandemic is kind of hopefully slowing. And there'll be a lot of dopamine. High levels of dopamine are great, but only after the effort of having done something in order to access it. And so that's what I'm taking away from what you're saying is that we need to go through this intermittent, the different types of intermittent challenge and we can re, we are rewarded with particular compounds that are reparative, both for the challenge, but then it make us stronger. It is, or me, since it really is, it seems a case of what doesn't kill us makes us stronger. What a, so you mentioned. - Can I add to that one thing? - Please. - Just said, because, because this has been shown with, for example, sulfuricane and animal studies, you pre-condition and give the animal sulfuricane and then you expose them to like, you know, hypoxia or some kind of exchemic stroke condition, whatever they do to induce that. And the sulfuricane, it basically protects that. Like, their pre-condition and their, their stress response pathways are primed. And so when they're then exposed to the ischemic stroke, they, their outcomes are so much better, so much better than the animals that didn't get the sulfuricane 48 hours before or whatever it was. You know, and this is like, this has been shown in multiple animal studies with sulfuricane, specifically in the brain. I know Mark Matson, Dr. Mark Matson, he's often thought of as the intermittent fasting king, but, you know, he's a neuroscientist and he did publish a work and talks about sulfuricane as well. - I'm really glad you brought that up, that example up because many of the questions I get on social media and elsewhere are about traumatic brain injury and TBI in, you know, is just one example. And people always think, oh, sports, it's football. Whenever you say TBI, people always think football. And I just want to just take a moment to editorialize, 90% or more of traumatic brain injury is construction work at home accidents. But football players are hockey players, martial artists are a tiny fraction of the people who have TBI and concussion of various kinds. It just so happens that within those communities, many of them, 75% or more, experience those. So it's salient within those communities, but concussion is prominent. People are always asking, what can I do in order to offset brain injury? I had a concussion two years ago, what can I do? And it's been a tough question because we really don't have anything for them. I mean, you tell them sleep well, eat well, exercise, but it sounds like some of these reparative pathways either should be explored in the context of brain injury or I'm guessing are being explored in the context of brain injury. - Yeah, so a couple of things there. One is that, I mean, traumatic brain injury, I mean, it's terrible, but it's also, it's so interesting because it's also like literal real-time brain aging. Like, you know, like it's, you're able to like accelerate it and understand. So I often think of when I think of traumatic brain injury, I think of so much overlap between Alzheimer's disease and dementia and these neurodegeneropathy diseases because there are a lot of similarities that there, you know, and so, so for a fein, I personally think, and I do think there's been some animal research with TBI, I mean, and so for a fein, mostly preconditioning rather than treatment. So again, it's like, well, I mean, if you're gonna, if you want a healthy lifestyle thing in your construction worker or your fill in the blank, that's, you know, gonna, I mean, anyone that drives a car, I mean, you're at risk to some degree, right? - Or bicycle. - Bicycle, yeah. - Around Stanford, we have, you know, I would say, people demonize motorcycles, people demonize a lot of things, but moving fast through space on a small object next to a 3,000 pound vehicle, I mean, we've lost, we have a number of friends who have died, we have a number of people with traumatic brain injury. I'm not against cycling or cyclist, but it is, it's a risky sport by any stretch. So in taking things like maringa or eating my broccoli sprouts, maybe cooking them a little less than I'm currently cooking them, putting on the mustard seed, is there evidence that, well, first of all, NRF2 is expressed in neurons, right? So those cells should be protected. Are there other cells of the body that could possibly gain protection from these pathways? - Well, lungs for one, but, you know, just even in plasma cells, I mean, I think it's pretty, NRF2 is pretty ubiquitously expressed, liver. So there's, I mean, there's so many animal studies that have looked at all those things. I try to kind of gravitate towards human ones 'cause it's a little, a lot more relevant. But, but I think, you know, overall, like I mentioned, you know, DNA damage lower, I think it was like 24, 24 or 34% lower in human blood cells after broccoli, broccoli sprout powder supplementation. And I made a video on this like years ago, 2016 maybe, and I think I have like the references on there to the exact amounts I can't remember. - We can look at the video, yeah. - But it was, it was kind of an old video, it was 2016. But I also had jet on the podcast, and he did talk about this. But you know, it's also been shown in randomized control trials to help treat autism and autistic symptoms. And yet again, it's doing interesting things in the brain. And I think it does have something to do with the oxidative stress and the glutathione, which would be relevant for TBI treatment. It hasn't been shown empirically that helps with treatment, but as you think someone could do that study, I think that it should be done, honestly, because it's a low hanging fruit. I mean, if there is any impact, and there is at least one preliminary study that glutathione is increased in the brain after humans are basically taking sulfurophane. So. - Which is really, for people listening, that's so important because a number of compounds that people take in supplement form don't cross the blood brain barrier, or they get metabolized in ways that what's listed on the bottle almost, becomes irrelevant for what your cells actually experience. So that's very reassuring. We will get back to heat and cold in this theme that I tried to serve as. Just find this too interesting to diverge at this point from these themes. So what other compounds or micronutrients do you place in the top tier of useful interesting? There are animal studies. Maybe there are hopefully also some human studies. We've talked about a few. I know you've talked a lot about omega-3 fatty acids. So if you had to do your top three, your superstars of nutrients for the brain and body, sounds like we've got one set. What would you put alongside them? Omega-3, the marine omega-3 fatty acids. So these are found in marine types of animals, fish, cold water fish, fatty fish. So there's three fatty acids. There's one from a plant. And that's often referred to as ALA. People call it short, afolinolate acid. And then there's a co-sapentinoic acid or EPA and doka hexanoic acid, which is DHA. Yeah. But EPA. Two of the most difficult words to pronounce right next to, and spell right next to ophthalmology, which if you can spell it, I know people who have appointments in ophthalmology departments that don't have to spell ophthalmology. A little secret. There's an extra P in there. So the ALA, I'm not going to attempt to pronounce it, because your pronunciation was perfect of both of these two compounds. And you said there are marine sources. So fish, so sardines caught this sort of thing. But what about krill? I've seen krill oil. And there was a few years back people were saying krill is a better source for omega-3s than fish oil. I took some krill oil capsules, made me itch all over. So I stopped. Do you have a shellfish allergy? No, I don't think so. I don't think so. I'm not a big fan of shellfish. But I like, you know, I'll have oysters every now and again, or shrimp or something and feel fine. Yeah, we can talk about sources. So krill is a source mostly of a type of DHA and EPA that's in phospholipid form. So it's a phosphatidal colon omega-3 fatty acid. And that's different than most of the-- well, if we're talking about fish oil supplements, that's a different story. But if you're talking about comparing fish to krill eating krill, like we're talking about the foods. Oh, I would never eat krill. Are we talking about the supplements? Yes, I apologize. So fish oil supplements. Krill supplement versus fish oil supplement. And if it fits in the conversation, talking about great sources of omega-3s in their whole form, I have a bad feeling you're going to tell me sardines. Sardines are, yeah, they're awesome. Anyway, except for the taste. And for the potential contaminants, mercury, I think, was-- no. Show is-- yeah, it was mercury. And Joe was telling me about like he used to eat sardines every day. Joe Rogan was telling me that he used to eat sardines every day. And then he had like really high mercury levels. And I was really shocked because sardines are like low in the fish group. So the higher up you get like swordfish and sharks, like really high mercury because they're eating all the other fish. But I think some brands-- and if you look at like consumer lab, consumer lab, it's like a third-party site that I'm not affiliated with. But I'll use them because they do a lot of analysis of different foods and supplements. And so you can look at like some of their sardines. And they have like they have a list of like ones that are pretty decent. But anyways, back to your question about fish oil supplements. For sure, it's krill oil supplements. So one of the major differences is the fish oil supplements. If you get a high quality one, it's in a triglyceride form. So you've got like a glycerol backbone with three fatty acids. And that's attached. And those are either DHA or the EPA. And or if you have a lower quality fish oil supplement, then you have what's called ethylester form. And typically the reason for that is it's when fish oil is purified, it's run through this column with alcohol or something. They cleave it off the glycerol backbone. And then it's just kind of easier to leave it like that than like re-stairifying it, which costs more money. So you can get it in ethylester form, which isn't as bioavailable. And in fact, if you don't take it with food, you're going to be in trouble. You're not going to absorb much of it at all. Would you see this on the packaging? Is it going to say it's in this ethyl form? Some official brands will put it on their website. Perhaps on their packaging, but most of the time you'll have to dig for it on the website and or call them. But I think for the most part, ones that are like higher end will market it like triglyceride form. And it's not that ethylester is bad. It just means take it with food. So one of the major prescription omega-3s out there is both of them, actually, LaVaza, which is a mixture of DHA and EPA, as well as Vesipa, which is a highly purified EPA. These are both prescribed by physicians to patients with hyper triglyceride,emia. So high triglycerides, among other things, I think, maybe dysregulation of lipids as well. This is amazing. So these are prescription drugs that are essentially very high potency purified omega-3s, but they're given to people for lipid issues. So this is the treatment of issues with fat metabolism by giving people fat. Just to really, I just want to push home. Again, I'm not carnivore keto or anything, I'm an omnivore, but to just push home that one thing that's so wonderful that you've done over the years that you continue to do is to move away from these very broad sweeping statements about fat is bad. I mean, here's a case where we're saying fat is not only good, it can be used to combat issues with fat metabolism. And then their fats are not just one thing. There are many things. So anyway, I just want to put a little highlighter and a point of appreciation there and make sure that people are sensitized to the fact that if you hear that fat is bad, you have to ask what kind of fat, right? And here we're talking about these omega-3s. Okay, so the triglyceride form can be taken with or without food. And there's prescription forms. What I can't get, I don't know if I can get a hold of the prescription form unless you have high triglycerides. Or I have a friend with high triglycerides. No. Well folks, don't share prescription drugs. Or you talk to your doctor and you say, I'm already taking this from, I mean, I don't know how it works. Anyways. What's the dosage that you recommend people get? So one way or another? All right. Okay, so the dosage that physicians prescribed for high triglycerides, for example, is four grams a day. Four grams of EPA? Of, yes, of the Vesipa. I think Lavaz has also prescribed it four grams a day. And you can get either those from your physician, my father and logist got one of them prescribed. He was, we were buying our own omega-3 for years and years. It's like, hey, you can actually get this in health insurance and cover it. And it's a really purified form. But you have to take it with food. That was the bottom line. I've totally gone on tangents. But like, you're asking more interesting questions. Anyways. Well, normally I ask about mechanism and then I talk about protocols. But in the, or the why? Or the why. But we'd even gotten there yet. But I think that, and we definitely will get there. But I think a number of people nowadays are just really excited about what they can do for their health. And so here we're just raising the importance of omega-3s and then we'll definitely get to the why and the underlying mechanism. I think four grams is, I mean, and in fact, like, you know, Dr. Bill Harris is just one of the pioneers on omega-3 fatty acid research. He was on our podcast last August. And he was saying the reason FDA chose that was literally just because how much they could get people to take. Like, it wasn't like an upper end like, oh, this is not anything above that is unsafe. That wasn't the case. I mean, it was, it was, it was just purely like cost and like, you know, compliance, you know. So like what they can get into it, a pill, the amount they can get and how many pills they can get people to take. I'm smiling because our good friend, Sachin Panda at the Saul Institute, who's done a lot of important work on intermittent fasting and other incredible work on circadian rhythms, et cetera. When I was talking to him in preparation for an episode on intermittent fasting, he, I said, why the eight hour feeding window? And he said, well, the graduate student who ran those studies had a partner. I think it was a girlfriend, as I recall, I hope I didn't get that backward. And the partner said, listen, you can be in lab 10 hours a day, but you can't be in lab 14 hours a day if you want this relationship to work. And so it was eight hours of feeding window plus some measurements, I mean, time to walk into the lab, park the car, et cetera. And so the eight hour feeding window that everyone holds so wholly was actually just born out of this relationship between these two graduate students, you know, had they been single, I was single all through graduate school or most of it anyway. And I lived in the lab. So if it be me, we'd all be intermittent fasting would mean eating 14 hours a day. That was a joke, not a good one, but just want to make clear I'm joking. But the point that you're making is a really good one that the four gram amount is not a threshold based on anything except the threshold of people's willingness to actually take the stop. And I think that's important for people to hear because so often we hear the eight hour feeding window, you know, four grams of EPA, you know, 150 minutes of cardio. And it's really a question of what you can reasonably do in a study. So I take four grams a day. I take two in the morning, two grams in the morning, and I take two grams in the evening. I take my EPA in the morning, and I take my DHA in the evening. You split them. I do. I don't know if I don't think it's necessary. not necessarily. I'm, I just happen to buy, I happen to get a certain fish oil supplement that separates them. And so, you know, like, Lavaza, Lavaza's a great one, and it's all like in one, and it's easier. - What if someone doesn't have a prescription? So I take over the counter, fish oil. I know I feel better, 'cause I've done the experiment of going on and off. I take that mainly for, I don't have depression, but my mood is better, my joints feel better, I just feel better. And I like to think that my platelets are slipperyer and they're, they're, you know, cruising through any little obstructions in my veins or arteries. That's the image I have in my head, but I don't have any data to support that part. - Yeah, I mean, so if you're asking for like, where do people get these? - Well, let's say I look at the bottle and it says, two grams per serving, but then I look and it's 750 milligrams of EPA, right? Or a thousand milligrams of EPA. Let's say half of it is EPA. Then do I want to hit a threshold of EPA or a threshold of, of what's listed on the bottle, right? On the front of the bottle. And because my understanding is that we need to hit a threshold level of EPA in order to derive these important benefits. - I think two grams is a good threshold. Now, the international fish oil standards, IFSO, they have a website where they do third party testing of a ton of different fish oil supplements from around the world. And they measure the concentration of the omega-3 fatty acids in the actual supplement because nothing is ever what it says on the bottle. And then they also measure contaminants. So mercury, PCBs, doxins, things that you'd find potentially in fish that are harmful to humans. And they also measure mercury and then oxidized fatty acids. So these omega-3 fatty acids are polyunsaturated fatty acids which are extremely prone to oxidation. So please keep your fish oil in the refrigerator because it's colder. Yeah, they're extremely prone. - Mine's in the cupboards and now I know. - The shelf life's increased lower oxidation. - It makes perfect sense. - Right. - So anyways, they measure that. And I typically like to look for, they give you a total oxidation number. It's called TOTOX, is what we call it for short. And I like it to be, at the least under 10, ideally under six, it's really hard to find. All the right mixtures of things, but people can go to this website and they can browse through the products. I have put together an Excel sheet which I have a YouTube little screencast that I'm yet to publish, press the publish button on. But it basically, you have to go back and check and update because these are from different lot numbers, of the products. They do have up to like 20, 27 or something. And so I've gone through and found my topics of high EPA brands and high DHA brands if I were to buy some, the ones that I would choose because of the low total oxidation and the high concentration of either EPA or DHA. Now, people can go and do this themselves. - Well, it just takes some work. - No, I'm glad you did the work. I'm going to put up a tweet every week. - Oh no. - With you tagged until this list is published online. Sorry, Ron, but I'm going to do it. I know it's very sadistic of me, but in service to the community and myself. - And I chose five brands from each. And I tried to find one in like Europe and one in Canada. So there's a great selection of. - Thank you for doing that work. - I don't want to do that work. And I trust you. So yeah, I try and get two grams per day of EPA from supplementation. I'll now put it in the refrigerator. Moot is better. Made that decision mainly based on the data that I'm aware of looking at comparison of people doing that. Anywhere from two to four grams of EPA per day compared to SSRI, serotonin, selective serotonin reuptake inhibitors and treatment of depression. And I don't want to take an SSRI if I don't have to and fortunately I don't have to. But the data by my reader are remarkable. People that take these things in sufficient doses, meaning the EPAs are able to get by with much lower dosages of SSRIs for depression relief. Or in some cases to come off their SSRIs completely or avoid going on antidepressant medication. Now of course this is not something people should cowboy at mental health issues are serious. But what other reasons, I'd love your thoughts on that on mental health part. And so maybe you could tell us what are some things that getting two to four grams of EPA per day is going to help with in our brain and the rest of our body. So do you know? So I actually published a paper back in 2015 about the role of omega three and vitamin D in depression bipolar disorder, bipolar disorder schizophrenia and pulse of behavior. But so like within that paper, like doing background research and this was a review article by the way, I was just connecting dots 'cause that was-- - No, I'm gonna grab a-- - But I confess I don't know the paper, but I love quality reviews because the references they're in are so useful. - Well, there's a huge role for inflammation, the cause of inflammation in depression. And I think we did a short animated video on this as well like here to go back when I was publishing that work where people are injected with lipopolar saccharide. I mean this is something that we're generating from our gut, mostly from our gut permeability, which happens a lot. Endotoxin, it's also called, it's endotoxin lipopolar saccharide. It's basically the outer membrane of bacterial cells when bacteria die. So like when the immune cells in our gut come into contact with the bacteria because we drink alcohol five days in a row or whatever. We release endotoxin or something stressed us out. We release endotoxin into our body and that causes inflammation. And so you can inject people with lipopolysaccharide and cause depressive symptoms. However, if you take those same cohort of people, give them EPA and I think it was somewhere around two grams and then inject them with lipopolysaccharide. We're establishing causation here, right? It totally the depressive symptoms versus the placebo. So the placebo was saline control. So there was this was a placebo control because obviously it's hugely important for depression. It emulatorated the depressive symptoms of cause by lipopolysaccharide. - Amazing and LPS lipopolysaccharide is no joke. I years ago when I was working on thermal regulation, we would inject animals with LPS to induce fever. There's the vagus nerve registers the presence of LPS signals to these particular hypithelamic areas and cranks up body temperature because basically it's a signal that the body is infected. Right? Amazing. So I will continue with my two grams per day. Maybe I'll ramp it up to four. I'm not doing the DHA separately. If there is DHA in the same supplement, is that okay? - Yes, yeah, yeah. And you know, to kind of, boy, we got a lot of things to hit back on because one of your original questions was krill oil versus fish oil. And DHA, DHA specifically is, it's, you know, in phospholipid form, it's more bioavailable. So our bodies, you know, if you're comparing exact quantity or concentration, you know, in triglyceride form versus phospholipid form, you will get more in your plasma cells or in your plasma cell, in your plasma with krill oil. However, krill oil supplements are so low dose, like I mean, good luck getting two grams of omega-3 from krill oil. And also krill oil supplements are notoriously rancid. I don't know for whatever reason. - Maybe that's what made me itchy all over. - I think there's just, like, I haven't found a good krill oil supplement. I pretty much stay away from it. I mean, if you smell it too, I mean, it just like, like, it just smells rancid. So, but the thing is, and I also published a paper on this back in 2019, or yeah, something like that. About DHA and phospholipid form getting into the brain in a, through a different mechanism than DHA in triglyceride form. And so it's going through a transporter called the MFS-D2A transporter. And I think it's very relevant for people with an apathy for allele. So I kind of-- - With an Alzheimer's susceptible. - Right, so like 25% of the population has an allyl and a gene called apoe4. And basically it's apoe, but the four is referred to as the bad kind of version of it. This is something in our bodies. It's also in our brain. And if people have one of these versions, if they got one from their mom or their dad, they have a two-fold increased risk for Alzheimer's disease if they get two, which is much more, it's less common. I think it's like 2% of the population so he has two alleles. But they have like a 10 or 11-fold increase risk of Alzheimer's disease. So there is a role for phospholipid form, DHA in the brain, but you also make phospholipid DHA inside your body. And you can do that by taking in more triglyceride form. So two grams are more, is the magic number, I think. So kind of back to like the Y for fissurel. And I personally think it is one of the most powerful anti-inflammatory things, dietary lifestyle, things that we can get, easily, relatively easily, that is gonna powerfully modulate the way you think, the way you feel and the way you age. And a variety of different types of studies kind of led me to that conclusion. a variety of observational studies. So there's been lots of work by Dr. Bill Harris and his collaborators looking at what it's called the omega-3 index. So this is actually the omega-3 level in red blood cells. So red blood cells turn over about every 120 days. So it's a long-term marker of omega-3 status. This is very different from 99.9% of any study you see or any lab that you go to to get your omega-3 levels tested. You're getting your plasma phospholipid levels tested, which is kind of like you can think of it as what did I eat a couple days before? Oh, I had fish. My omega-3 levels are great, but did you eat fish like that every week? Or was it like, you know, was like you went out to dinner? So it's not a great biomarker for long-term omega-3 status. It's kind of like the, you know, fasting blood glucose levels versus the HBA-1C, which is like a long-term marker, right, of your blood glucose levels. So the omega-3 index, he's done a variety of studies, observational studies for people listening. These are studies that are obviously flawed because they're not establishing causality. They're, you know, you're looking at people's lifestyles, but in the case of Bill Harris's work, he's measuring something. So he's measuring the omega-3 index. And he's measuring omega-3 index in people and then looking at their mortality risk, for example, or their cardiovascular disease risk. And what he has found is that most, first of all, standard American diet has omega-3 index of 5%. Japan, by contrast, has an omega-3 index of around 10 to 11%. Big, big difference there. And they also have about a five-year increase life expectancy compared to people in the US. And that's-- - Do you think that's mainly due to their fish intake, seafood intake? - So what he showed was, I think it's a big part of it. I mean, you can't always say it's the only thing, but what he showed in his data was that in-- And I think it was Framingham study where he looked at the omega-3 index and people that had a omega-3 index of 4% or lower, so close to what this standard American is, but a little bit lower. They had a five-year decreased life expectancy compared to people that had an 8% omega-3 index. And so big difference there, right? Five years life expectancy. But here's the really interesting thing, Andrew. He also looked at smokers and smokers and their omega-3 levels. And so we stratified it, right? And he found smokers that had no omega-3 were like the worst of all. I mean, it was just like worse, right? We all know smoking is bad for us and we'll take years off our life expectancy. But smokers that had the high level, like smokers that were taking their fish oil or eating fish or whatever was they were doing to get them up to 8%. They had the same life expectancy as non-smokers with the low omega-3 index. - Wow. - Right? - Wow. - And that's amazing. And it's also amazing to me that people still smoke cigarettes. But I see a lot of people evaping. And I know a lot of people consume cannabis, right? People, as there have been any studies of specifically evaping or people smoking marijuana and all cause mortality. - I haven't seen those. I haven't seen those. I'm not motivated enough to come in as research subjects. That was again a poor joke. It is hard to study people marijuana use. Unless I'm told by my colleagues that study this stuff, unless you offer people marijuana, in which case they'll do it. But again, they're actually not very good research subjects in all seriousness, because they are not very motivated or consistent and they forget their appointments. So that's incredible. And you mentioned that the data on pollution related to the plant compounds earlier. So it's almost like these things are, again, are acting in a reparative way. - The Omega-3s are, I mean, they are resolving inflammation. They're like, blunting inflammation. They're doing so many different, like, they affect so many different parts of the inflammatory pathway, which is, I think, plays a huge role in the way we age, the way our brain ages, the way we feel, our mood, just our joints, all that. And so it's amazing, but it's not, you know. - I love fish oil. I feel better when I take it. I try to eat some fatty fish a couple times a week. I do wanna just touch on food sources for a moment. First of all, are there plants that are rich in Omega-3s? And second, I have some friends who are really into meat. And I like meat a lot. My dad's Argentine, but I don't eat very much of it. I try to eat high quality meats in relatively limited amounts, but I do eat pretty often. But I've been told by these sources of a questionable authority that if an animal grazes on really good grasses, for instance, that the meat can contain a lot of Omega-3s, which in principle makes sense based on this Omega-3 index, 'cause you're telling me that a lot of it, this Omega-3 is sequestered into the red blood cells. So if I'm eating high quality grass fed meat and the grasses had Omega-3s, do my steaks have Omega-3s or no? - So there was a study published that compared conventional meat. So meat that animals are fed corn or soy or whatever it is. - Which is terrible. - Yeah. - But for animals and people, as far as I can tell, I'm sure I'll get some attacks, but that's okay. I won't read those comments. The, again, a joke, I read all the comments, but it seems to me that these animals would have to get either be taking fish oil or eat plants that are very rich in Omega-3s in order for the meat to actually contain sufficient Omega-3s. - So the meat comparing the conventional meat to the grass fed or gonna pasture raised cows or cattle, there were higher levels of alpha-linolac acid. And ALA is, it can be converted into EPA and DHA. But the conversion is very inefficient and very dependent on a variety of factors, including genetics, genetics, a huge regulator. Some people can do it much better. Others, you're getting like 5% of conversion to EPA. Estrogen is a major regulator of making that more efficient and it makes sense because pregnancy, when your estrogen just goes through the roof. I mean, these Omega-3 fatty acids play a very important role in brain development. So your, you know, women are supposed to be converting any ALA they can into the longer chain Omega-3 fatty acids, right? So Estrogen does affect that, but I would say plant sources. So if you're looking for the ALA, plant sources would be, you know, walnuts, flaxseeds, those are probably the highest. But if a person is a vegan or a vegetarian, their best bet is to actually get microalgae oil. And you can supplement with microalgae oil because microalgae do, they do make the DHA. And so that would be a better source for people that are vegetarian and vegan, rather than doing the flaxseed oil because that conversion inefficiency, you know, the enzymes that convert ALA into EPA and DHA. Again, there's, it's inefficient. - And then for people that eat fish, Sardines, you said-- - Salmon. - Salmon, and you have to eat the skin, as I understand. - You don't have to, but it's good. - It's rich with the oil. - Yeah, and the reason I say, like, I think the best would be wild, Alaskan salmon versus the farm raise, because the farm raise, again, they're feeding them, they're feeding them like green and stuff. And then they give them astazanthin. So astazanthin is a carotenoid. It's the carotenoid that's in things like krillacrystations that make their red pigment. - Yeah, it's also being used now as a supplement. And there's a prescription form to try and rescue some age-related vision loss because of the role of the vitamin A pathway in photoreceptors. - Yeah, well, you know, actually the carotenoids themselves, so like, Ludanian and Zezanthin, they're really good at sequestering single oxygen, which is some damaging, right? - Yeah, as we age, because the retinal cells, the cells of the iris, so metabolically active, they accumulate a lot of reactive oxygen species and mitochondrial repair and limiting reactive oxygen species is a major theme of trying to rescue vision. I think so. - Yeah. - That's a whole other podcast and story. There's some really interesting data now on the use of red light to try and trigger these pathways. - I've seen some-- - That's my good friend of many years and amazing scientist, Glenn Jeffries-Lavitt, University of college London. We should talk about that at some point. - I thought that study, like, 2020, was it? - Now they have a second study. - Oh, do they? - Yeah, it's looking real. I mean, you know, they're cautious. They're appropriately British and cautious about it. I always joke if those studies have been done over here, everyone would already know about it. Glenn is a very conservative guy, but they've done this stuff now in pigs, and rodent models, and now also two studies in humans. It's looking pretty interesting. So, sardines, but also anchovies. I mean, all, by the way, I hate all the food items that I'm describing. I can barely tolerate salmon. I don't like fish at all. Actually, I like live fish. - Fish well good for fish. - I like fish tanks when I was a kid. I just don't know. I find fish, unless it's in sushi form, I find it absolutely repulsive. And I don't know why. I probably have some mutation. - So raw fish is actually higher in mercury than cooked. - Okay, well, that's good. really like sushi that much anyway. You're giving me great reasons to not eat fish, but except I should eat these other fish sources or supplement more heavily. That's the message I'm eating. I eat certain, every day, my first meal almost is like a can of certain and avocado with like-- Avocado is good. Yeah, with a little bit of lemon and then some little hot sauce. Just avocado omega-3s? Avocado is very good in monoinsaturated fat. It's really high in polyinsaturated fat. Omega-3 really, I mean, it's either the DHA and EPA that's in the marine sources fish. Or it's the plant ALA source, which is like the flax seed or the walnuts. Yeah. It's rough. I mean, all these companies now are making these plant-based products that taste like meat. My wish is that they would just make a fish that tastes like a steak. Yeah. But that's-- The fish come out albino. The ones that they farm raised because they don't eat any of the-- I'm joking. I don't want a genetically modified fish that tastes like a steak. But, you know, I love the taste of steak. The point here is that if one doesn't see themselves regularly consuming these fish sources of omega-3s, it seems to me that the only way to really get them is from supplementation. And supplementation is a good way to get a high dose and to get back to your dose point. There was a couple of studies that basically, you know, I think there was some way they showed that people that are in the 4% omega-3 index range in order to get to the 8%, right? The five-year increased life expectancy for comparing the two groups was to supplement with at least two grams. It was about two grams a day. And that-- and I think it was a little bit less if it was triglyceride form, but I think two grams is a good safe number. So most Americans that are not eating a lot of fish and they're not supplementing are probably around a 4% to 5% omega-3 index. And to get to the 8%, and I think that's a good empirical way of thinking about it, right? Okay, well, I want to get to that 8%. By the way, I'm almost 16% omega-3 index. Yeah, I was going to ask about testing. So, where can somebody measure-- where and how can somebody measure their omega-3 index? Which again, just to remind people is essentially the percentage of omega-3s that you have in your blood with the caveat that the omega-3 index will be heavily biased by what you ate in the previous days. No. No, the omega-3 index. Okay. So the omega-3-- I understand. I thought you said in red blood cells, if I ate salmon two days ago, my omega-3 index is going to go up. No, that was plasma. I misunderstood. Okay. So most people are measuring-- like, if you look at a lot of studies, and honestly, Andrew, I think a lot of the reason for conflicting data is because people are measuring plasma omega-3 levels. Okay. That's a phospholipids. It's in a phospholipid, right? So your phospholipids are carrying things-- these are lipoproteins. They're carrying things like omega-3 and triglycerides and stuff and shuttling them around. So, the omega-3 index is actually in the red blood cells. And red blood cells take 120 days to turnover. So if you're going to do a baseline test, if you want to know before supplementing what your level is, you have to wait 120 days before doing the second test after supplementing to know how much you-- you went out. Because that's how long it takes for your red blood cell to turnover. So the omega-3 index-- Bill Harris has a company that he co-founded is called Omega-Quant. And they measure the omega-3 index. They have a variety of different index tests. You can do like a basic one or a little more advanced-- It's from a blood draw. It's a little blood spot thing. Yeah. And, you know, like, he uses money to funnel back into doing lipid research. So he's like out there doing all sorts of interesting studies on omega-3. It's great. But the omega-3 index is great. I think that honestly, more people and more researchers should be using it because the conflicting data, it always comes down to what we're measuring, the sensitivity of it. You know, are we even measuring anything? So you know, you're giving someone 500 milligrams of DHA and you don't see any effect. Well, did you measure what their levels were? And did you measure the omega-3 index? You know, there's all sorts of problems with randomized controlled trials. And I think that just we need to like, as scientists, we need to come together and like, make some progress. I mean, you know, let's all talk to each other. Let's figure things out. Like, this test is out there. It should be used. It should be used, not just by Bill's group, but like everyone. Yeah. Well, and I'm learning so much from you. And I agree we need more collaboration. I've always enjoyed really fruitful collaborations in my lab at Stanford and collaborating is just so much more fun. Online, there seems to be a bias more towards creating silos, as opposed to bridges. But I appreciate that you bring up the need for more collaboration and knowing which measures are best. And in this case, now, thank you for the clarification. I understand this omega-3 index is going to be best. You mentioned you, so basically, when now, when I look at you, I think you are 16 percent omega-3. And dolphins are 19 percent. I'm almost done. Is that your goal? You're trying to get there. It is. To do the interesting. Actually, they should probably do something we were trying to achieve the omega-3 ratio of the your favorite species. Now that we've covered a bit of how to get these things into one system, depending on what one eats, et cetera, and some of the better measurements, how is omega-3 and some of these other related lipids? How are they having these positive effects? In my mind, and this is incredibly elementary, but my understanding is that at some level, they're making platelets more slippery. Is that true or not? I hope I'm happy to be wrong. How is it possibly impacting my mood? Is it through the synthesis of membrane on neurons that allows neurons to release more transmitter, like serotonin and dopamine? I mean, what are some of the purported, reported, and known mechanisms? I think some of the most well-known mechanisms do have to do with the omega-3 fatty acids, being very powerful regulators of the inflammatory process in some way, shape, or form, whether that has to do with resolvins that are produced. So these from the metabolites of like DHA, for example, resolvins, player role in resolving inflammation. Like, you want your inflammatory response to be activated when it's supposed to be, but you want to resolve that inflammation and inflammatory response in a timely manner, right? And resolvins help do that. And so resolvins are one. And then there's these specialized, promediating molecules, the SPMs that also help resolve the inflammation. There's, like you mentioned, the leukotreins and prostaglandins, and these things are being affected by EPA, and they do affect platelets and platelet aggregation, and they, you know, they do affect that whole pathway as well. And so there's just, and there's, you know, I think there's just so many different ways and inputs. And so when we talk about inflammation, honestly, it's a big general term, but you're talking about, when you're talking about serotonin release, you know, at the level of neurons, you know, we know that these inflammatory molecules cross the blood brain barrier. And I just mentioned ago about injecting people with lipopolysaccharide and causing depressive symptoms. You know, it's known that omega-3, actually specifically, EPA is able to help serotonin, inflammation, inhibits the release of serotonin. And so EPA is actually able to blunt inflammatory responses along with DHA as well. DHA does that through resolvins and stuff. And this then helps more serotonin be released because you're not having so much inflammation getting into the brain and affecting serotonin release, right? That's one mechanism. And another would be, well, DHA itself has been shown. It's a very important fatty acid that makes up cell membranes, many cell membranes, including in our neurons. And as you very well know, Andrew, the structure and function of receptors, of transporters, these membrane bound proteins on the surface of ourselves, including neurons, are affected by the membrane fluidity, you know, like how rigid and how fluid the cell membrane is. And DHA plays a role in that. And so, for example, in animal studies, if you make an animal deficient in DHA, their serotonin receptors, dopamine receptors, they're affected because the structure of them is affected through the fluidity of the membrane. And so I think that's another mechanism. And I'm talking sort of general, because I'm not a neuroscientist. Nobody makes perfect sense. I mean, we know, for instance, neuroplasticity, and almost always involves the recruitment of more receptors or an improvement in some feature of receptors to neurotransmitters. And they literally move laterally in the membrane. They kind of float around like little rafts. Sometimes they are, in fact, in lipid rafts. And so it makes perfect sense that these molecules like DHA, which are part of the structural fat of the neuron, because of course the outsides of the neurons are basically fat. Not just the myelin that people have heard of, but the actual membranes that, if getting that right, you wouldn't want it as rigid as concrete, but you wouldn't want it as soft as need to come up with something here. It's like gooey stuff that kids play with. It's like that goo, anyway. There's a, yeah, it's disgusting. And it's too soft to be a membrane for a neuron. That's what that's all we know. >> Get in those machines. >> Someone put it in the comments and tell me what that disgusting gooey stuff is. You don't want your neurons to be that gooey. And yet you don't want them to be like concrete either. >> It's about. >> It's about. >> Yeah. And in mentioning DHA, I'm just going to, I realize I'm backtracking, but I want to make sure that we close all the hatches for people. We talked a lot about EPA, but our food sources of DHA that you find particularly attractive either by taste or by a potency for DHA. what are just a few that we could throw out? Because I am aware that there are supplements where you can get a nice ratio of EPA to DHA or you take them separately as you do. But if I wanna make sure that I'm getting enough DHA, what do I need to be sure I'm eating on a regular basis? - Well, the fish is packaging the DHA and EPA in the ratio. - Okay. - But I also do eat salmon row, which is very salty and it's a really high source of the phosphatile colonin DHA that we talked about. - So this is fish eggs? - It is, yeah, and actually I need-- - That I like for some reason. - Oh, do you? - Yeah, I'll eat, so I'm discovering something about myself. This was not meant to be nutritional psychotherapy, but you're doing that for me anyway. I'm discovering that, yeah, I like eating embryonic fish. I just don't like eating the actual fish. - Okay, well. - Okay, so fish eggs are okay, so caviar based-- - Caviar, yes, and that's a good source of the phospholipid form. And I was consuming that a lot because I wanted to get the phospholipid form. So it's actually really good. There's been some animal studies and piglets and rodents as well showing that consuming phospholipid DHA during fetal brain development. It like gets like 10 times more DHA in the brain. Again, it's-- - Makes sense based on fetal development. So do I need to, by beluga caviar, stuff can get pretty expensive at $200 a day? - I don't think you need to. - Okay. - I think it's a matter of preference. And if you're supplementing with your two to four grams of fish oil, I mean that you're gonna get phospholipid form anyway, because your body's gonna make it. - Okay, I've seen some containers of what I assume to be quality fish eggs that are not at the caviar level that you can find in the better grocery stores. That aren't super expensive. I wouldn't dip as low as to go eat, for instance, like fishing bait, like when we were kids, we used to go fishing, you put the fish egg on the thing. That's probably not good. Although it's good enough for the fish. - Yeah. - Okay, only half joking here folks. I'm just trying to protect you from yourselves. Don't get any crazy ideas about eating fishing bait. Okay, so that's great to know. So we have these plant-based compounds. We have the Omega-3s, so EPA-DHA. And then you mentioned there's a third category. What would you place in your third category of foods or supplement-based nutrients that our health, brain and/or body health can really benefit from? - I mean, I think the most obvious would be vitamin D, which is actually, as you know, a steroid hormone that we produce when we're in the sun, depending on the time of year, we can make it in our skin and depending on how much melanin we have in our skin or whether or not we're wearing sunscreen or how old we are. There's a sliding scale on how efficient that process is. - And as I understand, there's an inverse relationship where the darker your skin is, naturally, the more vitamin D you need to consume, is that right? - Well, the darker your skin is, the harder it is, so there was a study out of the University of Chicago, this was several years ago, where they looked at African-Americans and compared African-Americans to Caucasians with light skin, a fair skin, and how well they could make vitamin D from sun exposure and how long they had to be in the sun to make X amount, right? And it turns out that African-Americans with darker pigmentation, which protects them from the burning rays of the sun, it's a natural sunscreen, had to stay in the sun like six times as long as someone with none of that natural sunscreen. So I think the take home there is, you know, a lot of people with a darker skin, living in sub-Saharan Africa, or people living in India with darker skin, or in the Philippines, you know, these equatorial regions where there's, you tend to see darker skin because it's protection from the burning rays of the sun. - In adaptation. - They are in the sun war. - Right, yeah. - And they're getting more vitamin D, but people that may be moved to the United States to like Minnesota or in a place where, you know, UVB radiation isn't, you know, getting to the atmosphere 12 months out of the year, it's only getting their four months, for example. Or even living in our modern day society where people just don't go outside anymore. I mean, we're inside, we're at our laptops in school, we're at work, we're in our keep-it-go, whatever. So supplementation does play a major role, not only for people with, you know, darker skin that are outside all the time, but for everyone, 70% of the US population has inadequate vitamin D levels, 70 of the whole US. So this is everyone. And so I think that insufficient levels defined as less than 30 nanograms per milliliter. And that's sort of defined by the, the Andrican society looking, looking at a lot of different aggregate studies and all cosmicality, for example. There's been a lot of different meta-analyses of all cosmicality studies where vitamin D levels are really seem to be ideal between 40 to 60 nanograms per milliliter. And so in order to get to that level, if you are not outside all the time, living in Southern California, where you're always outside, without sunscreen on, I always wear sunscreen because I'm trying to protect my skin from so many wrinkles and stuff, right? But also skin cancer is, you know, somewhat of an issue as well. So basically the point is that vitamin D is a steroid hormone, meaning it actually binds to a receptor and another receptor dimerizes with it, the retinoid receptor. And that complex goes into the nucleus of a cell where your DNA is. And it recognizes little sequences of DNA called vitamin D response elements, they're called VDREs. There are specific sequences of DNA that this complex vitamin D bound with the vitamin D receptor goes inside and recognizes and turns on a whole host of genes, turns off a whole host of genes. I mean, this is important stuff. Like imagine 70% of the population having insufficient to stops to run, right? It's a steroid hormone. Which might be headed there, but probably not. No, I think that its names are very important. And I think that one of the issues is that vitamin D is called vitamin D. It's not called DHEA or variant blah, blah, blah. It doesn't sound like a hormone. I'm glad that you're mentioning skin as the major interface between the environment and vitamin D synthesis. Because a lot of people think of skin as just a protective sheath around us or something to adorn ourselves with earrings or tattoos or whatever. But skin obviously serves those roles, but the skin is an endocrine organ. It has the capacity to make things that impact hormones and to make hormones. This is beautiful study out this last year where this took place in over in Israel where they had people get outside for 20 to 30 minutes a day three times a week, exposing a culturally acceptable, yet substantial amount of their skin during that time. And saw big increases in testosterone and estrogen. And this is through a correctinocyte linked pathway involving P53. They did a bunch of-- this was done in humans, but they did some knockout studies in parallel. And what this study told me or reminded me is that skin is an endocrine organ. So the idea that sun could trigger the activation of a production of a hormone is really interesting and makes total sense. So when vitamin D gets into cells and it's binding to these VDREs, what sorts of things are they triggering? So like for testosterone, we know it's going to trigger protein synthesis, muscle growth, tendons, strength, et cetera. With estrogen, it's going to be a keeper neuron going. Your joints feeling good. I always remind people that, by the way, because guys are always seem to want to increase their testosterone and reduce their estrogen. Just remind people if you reduce your estrogen, guys, your libido will plummet to near zero. Don't crush your estrogen. It'll also make you stupid. If you're not already stupid, it will make you stupid. So estrogen is vitally important for males and females. When vitamin D gets into cells, what sorts of things is it stimulating? OK, so first of all, it's regulating more than 5% of the protein encoded human genome. And this was-- I say more than because when I was looking at this data, really in depth back in starting in 2012 to 2014, it was that. And then it's now grown. But one of the important things that you'll find interesting that I published on back in 2014 was that I'd gone through this big published database where someone had published all these genes they found VDREs in. And basically, I found that tryptophan hydroxylase 1 and tryptophan hydroxylase 2 was on there. And so then I started looking at the sequence and I was doing some insulica work. And it turns out that the VDREs and tryptophan hydroxylase 2-- so for people listening, tryptophan hydroxylase is an enzyme that converts tryptophan into serotonin. So tryptophan is what we-- an amino acid that we get from our food. You convert serotonin-- you convert tryptophan into serotonin into the gut in the gut, but you also do it in the brain. However, serotonin does not cross the blood brain barrier. So tryptophan has to get into your brain. And then you have to convert it to serotonin in your brain. Well, the enzyme that does that in your brain is called tryptophan hydroxylase 2. And it's activated by vitamin D. The one in the gut is actually tryptophan hydroxylase 1, some of my published work hypothesized that it might actually be repressed by vitamin D because it has a sequence itself. This 12 nucleotide sequence can determine-- to some degree, whether it's going to be activated or turned off. And so I was able to look at that and think, oh, maybe this and that. And so since then, there have been some groups that have confirmed more with In vivo and/or in vitro studies. I mean, I used to use his-- I mean, it was all in silicone. And all that stuff. But anyways, so serotonin, a really important one. But most people-- I mean, this is regulating our immune cell, immune system. It's regulating our blood pressure, all that water retention. I mean, bone, of course, homeostasis, 5%, more than 5%. I mean, I can't tell you so much. I mean, with-- and with 7,70% of the US population deficient, I'm beginning to think that this could be the linchpin and a number of really important issues. So supplementing vitamin D3 is what I normally hear as the-- I do. I take-- I think I end up taking 5,000 IUs. Sometimes 10 IUs of vitamin D3 per day. Just done that for a long time. And I've had my levels tested in their in range. But I have a family member. I'll just mention this. I have a family member who was not feeling well, just kind of feeling off a little load. I had some digestive issues. This went on a long period of time. Was taking on my recommendation 15,000 IUs of D3 and was still deficient in D3. Now takes-- and I'm not suggesting anyone do this. Is a special case, perhaps? But no chronic illness that we're aware of-- needs to take 30,000 IUs per day in order to bring their D3 range just into normal. Which is, to me, a striking because they eat quite well. They're a healthy weight, et cetera. But it's made a tremendous difference in terms of their mood. Now, of course, it's correlative. Now they feel better. They're doing it. Who knows? They're probably also getting outside more. But I mean, I think people need to get tested. They need to get their D3 levels tested. But where and what is a good starting range for people to think about D3 supplementation? And again, foods that can increase D3. So vitamin D3 is a good way to supplement with it. Their vitamin D2 would be a plant source. You often find it fortified in foods like milk. Usually D2. There's been a-- Does anyone still drink milk besides kids? Oh, people-- Oh, here is that you can't find cow's milk. I mean, all the lot pays that you're getting. Or milk, soy milk, it's the other one. They're fortified in those as well. OK. Oh, they are. OK. They're fortified in-- I have a hard time finding cows. And milk and oat milk and all that stuff. Yeah, they're in all that stuff. Vitamin D is naturally to some degree in fatty fish. You think about cod liver oil, right? It has vitamin D. But it's not-- you're not going to correct a deficiency with eating fish for your vitamin D. Like you're either going to correct it with sun exposure, being in the right area, having the right amount of sun and being the right age. Because as you get old, you become very inefficient at converting vitamin D-- making vitamin D3 in your skin. Well, that's probably what was going on here. Because this person is getting up in their area. There's a lot of single nucleotide polymorphisms. We talked about apoi-fore previously. But there's a variety of genes that people-- very common, actually. In fact, I've had many people that have had to do-- done that exact same thing. So measuring your vitamin D levels before and after supplementation is the only way you're going to figure that out, right? Very important. If you don't measure it, like you don't know. You can't know what you don't measure. So there's a variety of SNPs that basically make that conversion inefficient. And in fact, there've been a lot of these Mendelian randomization studies. So these are studies where scientists will look at common SNPs-- people that have these common variations of a gene that's a little more than 1% of the population. So it's not a random mutation. It's actually found in a sizeable percent of the population. And then they've looked at various outcomes. And a lot of times they'll look at genes that are also involved in some kind of lifestyle factor, so vitamin D. And SNPs that basically make the conversion of vitamin-- either vitamin D precursor into D3 or in D3 into 25 by Droxy vitamin D or into the active steroid hormone, which is 125 by Droxy vitamin D. And there's a variety of different SNPs that show people. So you're not looking at vitamin D levels at all. You're looking at just the SNPs. And you know if they have it, they have low vitamin D. So it's really a way of doing a beautifully randomized controlled trial with an observational study, because you're not biased. Vitamin D levels are also associated with health. People that have higher vitamin D are either outside more. They're more physically active. Or they're aware of their health and their supplementing. So you always have to worry about that when you're doing an observational sleep. But Mendelian randomization is beautiful for that reason where you now just randomly have these genes. And it's not like there's no health status. Like if you have the SNP, like your family member who is healthy and all that, they were healthy. And yet they couldn't get their D levels up, right? So these Mendelian randomization studies have found that people that can't convert into the precursor, the 25 by Droxy vitamin D, which is usually what's measured. It's the most stable form of vitamin D in the body. They have a higher all cause mortality if they can't do it. So people with that don't have it have a lower all cause mortality. They have a higher respiratory related mortality. They have a higher cancer related mortality. So to me, now why did I get on this rant? Oh, because you're family member. So basically, they also are more likely to get multiple sclerosis. This has all been done with Mendelian randomization. And so it really does hammer home the importance of measuring your vitamin D levels and being very proactive about that. I mean, you can get it done anywhere your doctor will do it. You ask them to do it, you know? So supplementation wise, typically, if you don't have one of those SNPs, for the most part, taking 1,000 IUs of vitamin D will raise blood levels by around five nanograms per milliliter. So let's say you're deficient, you're 20 nanograms per milliliter, and you want to get to 4G. You're going to need at least 4,000 IUs. If you are normal, don't have any of these SNPs that change your metabolism of vitamin D, right? Does it matter when you take it relative to sun exposure, time of day, with or without food? I've seen some not-so-great preliminary evidence suggesting maybe time of day is important. I don't think it real. Like, I can't seem to find anything that really suggests because like, for it to actually be converted into the hormone, I mean, it's stored-- To slow at it. These steroid hormones are slow at it. Yeah, it's not like a immediate thing, right? So maybe we'll get some new data that's otherwise, but I just don't-- It simplifies the problem anyway. So for people who are going to be stubborn and not get their D3 levels tested, or their D levels tested, and simply say, oh, I'll just take some D3. That was me, by the way, until I got tested. I threw 5,000 IUs into the mix and figured, well, it's not going to kill me. It'll bring my vitamin D levels up. I know realize that's a bit of a course way to approach it, but I feel fine, and I'm still breathing in ambulatory. So is that reasonable? 1,000 to 5,000 IUs for most people will be reasonably safe. Again, we're not making-- just assuming that people are going to just jump to it without the blood test. Of course. I think that if we look at the literature, the scientific literature, it is extremely hard to get hypercalcemia, which would be the major concern with really high levels of vitamin D3 supplementation. I mean, we're talking like hundreds of thousands of IU a day for a long time. So-- Hundreds of thousands. Yes. Yes. Now, the upper tolerable intake was set by the medicine institute to be 4,000. It was just like the safe. It was kind of like one of those things where it's safe. I personally take 5,000 IUs a day as well, and my levels really hover around 50 nanograms per mill. And I do out-- I don't put sunscreen on all the time. I do put on my face, and I wear a hat, but some of my skin is being exposed. So I do make it from the sun as well. But-- I'm glad you brought up the fact that you keep arms exposed because in these studies that I mentioned before looking at sun exposure on skin and increases in other hormones, testosterone estrogen mainly, it became clear from looking at those data that the amount of skin that you expose is important, which makes perfect sense once you hear that. But I think most people are thinking, oh, I'm out in the sun. But are you wearing shorts and a t-shirt? Or are you wearing a sweatshirt? And it's a hoodie? Or are you all covered up out in the sun? Well, that might be great for setting your circadian rhythm by way of light to through the eyes, because that's the primary mechanism for that. But it seems to me that the more of your body surface that you can safely and appropriately-- please, folks-- appropriately exposed to the sun, the more vitamin D you're going to create. So laying out on your back deck in shorts and a t-shirt with arms exposed and legs exposed is a very different stimulus than walking around in jeans and a sweatshirt. Absolutely. OK. OK. Especially if you have sunscreen on your face. I know it almost seems like trivially simple, but I'm not sure that people are used to thinking about their skin as a interface to create these hormones. Yeah. So surface area matters. And by the way, there have been studies looking at people that are deficient in vitamin D. In this case, it was African-Americans that were given a 4,000 IU a day vitamin D supplement to bring them back to sufficient levels. And this was a smaller study than I would like, but it reversed their epigenetic aging by three years. Because again, it's a hormone. It's regulating more than 5% of your protein encoding I mean, you know, there's been studies looking at vitamin D receptor knockout mice. And I use this a lot in my presentations when I'm talking about vitamin D and longevity. But if you look at these animals, the vitamin D receptor, as I mentioned earlier, vitamin D binds to the receptor and then it complexes with the retinoid receptor and they go into the nucleus of the complex and turn on and turn off genes. Well, if you get rid of that receptor, which is what you can do in animal studies, you can sort of determine what effects there will be with no vitamin D, right? How do you study no vitamin D? And so what was found was that these animals, in fact, I don't think it was a complete knockout or because I think it might be embryonic lethal, but somehow. Some hypermole. Yes. Which is basically geek speak for a gene is vastly reduced in its function, number and function. People know what I mean, but isn't eliminated completely. Right. And so, if you look at them after the age of four months, I mean, the mice look like. I mean, they're accelerated aging. They're wrinkle. They have no hair. I mean, they're lifespan shorter. You can look at this animal and not know anything about mice or work with them and be like, that animal looks like it's. Of course, mice lifespan is around like two and a half years, but like 500 years old. Right. It looks like it went to graduate school twice. Yeah. Actually, graduate school is a lot of fun. I like to think I age backwards in graduate school, which is not true. I look at the photos. I definitely aged forward. You, on the other hand, look exactly the same way you did 10 years ago. I'm not saying that to flatter you, but it's absolutely true. I mean, the data or the data, it's remarkable. So I think it's. I'm definitely going to try and get my mega-3 percentage up there. I'm not going to hinge it all on that, but clearly you're doing a lot of things, right? So if I'm taking vitamin D3, I still need to get out into the sun. Correct. Okay. I think a lot of people don't know that, or at least I have family members that have been a little bit resistant to that. I take my vitamin D, so I don't need to get outside as much. I think people are really afraid of getting out into the sun because they're worried about melanomas. And to be honest, I'm as scared of sunscreen as I am of melanoma. That some of the things in sunscreen are really spooky. Mainly the compound. And here, I'm not one of these. I drink tap water. Listen, folks. People cringe with it. I drink tap water. I have the occasional croissant or donut. I'm not. I'm 90% of the time I'm doing the right things the right way, I think. Although I'm now going to improve on them with this new knowledge. But I don't like what I see in most sunscreens because if you look at these compounds, they cross the blood brain barrier. I don't want compounds crossing the blood brain barrier. Tachyneum dioxide. Dioxides. Some of the trichlocans that are also in these cleansers. I mean, once you know a little bit about neurons, folks, you realize that the neurons you got are basically the ones you got for your entire life. There's a reason why there's a blood brain barrier, a blood ovary, and a blood testes barriers because the genetic material resides in the testes, the ovaries, and the brain those neurons don't turn over. There are a few new neurons, but not that many unless you're a mouse, frankly. So protecting those is very key. And a lot of the things in sunscreen are downright dangerous. So I think there are sunscreens that are safe, but it's very hard to figure out which sunscreens are free of these compounds. I'm amazed that they're still on the market, frankly. I've always geared towards the ones with the minerals that are reflecting it. It is somewhat difficult to penetrate things all the way through the skin into the blood stream, but I don't know maybe some of these compounds get in there easily. I have seen the evidence with some of those things. Yeah, there is. But some of them say go transdermal. And they get in. Well, I know that there's some of them react with the sun and while they do protect from the UVA and/or B, they form massive reactive oxygen species and the very thing you're trying to protect yourself from might actually cause. We don't know. It's completely speculation. There is, I think some more evidence coming out with some of those compounds. I can't remember all of them off the top of my head, but a lot of high end ones also have, you know, it's the chemical sunscreen ones, the chemical ones. We should do, I'm proposing that we do a journal club. A journal club folks is where academics get together and read papers, they get papers and they get together and they pick apart the papers. There's a strong correlation between being an early graduate student and being the most critical because once you've actually published some papers, you realize that, you know, most studies people are doing their best within the context of what they can do. It'd be great to do a journal club at some point about sunscreens because I'd love to really figure out what's in these compounds up. I mean, people are using them like crazy and I'm not one of these people who's like, oh, I won't use commercial toothpaste or anything like that. I, like I said, I drink tap water, I use commercial toothpaste, whatever. But when it comes to sunscreen, it freaks me out because some of these compounds do go transdermal and some of them cross the blood brain barrier and I'd like to keep my neurons free of that stuff. Anyway, we're speculating now. We're at. But get out in the sun and get your D3 levels up. Okay, so we've, we've talked about these plant-based compounds, the omega-3s and D3 unless there's something else that you just absolutely must throw into the mix. I'd probably will return us to the conversation that I opened up with, which is about cold and heat, which admittedly I pulled us off that path. So I want to take full responsibility for that. But before I do that, I just want to offer you the opportunity, is there, are there, is there anything that fit to supplement-based or food-based compounds that you, you know, you think are especially useful for brain and everybody? I do think magnesium is important in there as well. I mean, I think, you know, again, about 40% of the US population doesn't get enough magnesium. It's an essential mineral. We're supposed to be getting from our diet and it involved in everything. It is. It's involved, it's also involved in vitamin D metabolism. And in fact, being deficient in magnesium may make it more difficult for you to actually make vitamin D hormone, so that 125 hydroxy vitamin D. So one of those other factors, again, talking, we talked about genetics, but there's also magnesium status as well, considering 40%. That's a big number. Now, you know, magnesium is also involved in making ATP, the energetic currency of ourselves. They're, you know, basically all of our cells need ATP to do anything. And they're all, it's also involved in utilizing ATP as well as DNA repair enzymes, these are enzymes that are involved in repairing damage to our DNA. I personally think that magnesium insufficiency is a insidious type, causes an insidious type of damage daily that you can't look in the mirror and see. Like when you're deficient in vitamin C, you're like, my gums are falling apart, I have scurvy, right? But like, you can't see DNA damage, you can't see it, but it's happening. It's happening right now in my body, it's happening in your body, it's happening normal metabolism, it's happening, you know, every day. But we repair that damage. We have repair enzymes in our body called DNA repair enzymes. They require magnesium. Magnesium is a cofactor for them. What that means is, you know, a cofactor means enzymes need it to function properly. And so, without that cofactor, they're not doing it properly. And I like the way I like to think about magnesium, it's easy because people go, what food should I eat, right? Naturally, that's the next question. Well, magnesium is at the center of a chlorophyll molecule. Chlorophyll is what gives plants their green color. So, dark leafy greens are high in magnesium. That's one of the, and basically, what is the 40% insufficiency in the US tell us? People aren't eating their greens. They're not eating their greens. They're eating their packaged food, they're eating their processed food. The standard American diet isn't really high in dark leafy greens. So, dark leafy greens are how I like to get my magnesium. I think it comes along with all these other important, I mean, you get calcium in them. You get vitamin K1. You're getting a lot of other micronutrients, and you're getting other compounds that we don't know about. And ones that we know about, like silverware fame, right? As with broccoli, do I need to eat the dark leafy greens raw? In this case, I'm a little more open to it because I actually like the taste of dare I say kale. And kale's a dark leafy green, right? It's obviously-- And it's fine. And it's fine. Looting and deodorant as well. No, I'm going to try a chromat, meaning I'm not colorblind, but I just want to make sure it falls under the strict category. Yes. Because everyone's in a while, I'm like, oh, I eat my vegetables. I like avocados, and people wear my main avocados, not vegetable. I love vegetables, also. But so, kale, what are some other examples? Kale spinach, charred, like Swiss charred, rainbow charred, romaine lettuce. Is the bitterness an important component to this? For magnesium, no. But for sulfur, sulfur, for cruciferous vegetables, that would be the brassica family. But your question about cooking them-- so magnesium is-- it is bound to the food matrix, and it can be somewhat less bioavailable. So, cooking it can somewhat release the magnesium, but it goes into the water, too. So, you have to either steam it or get your water in-- You can drink it with the energy. Yeah, I personally don't worry about it. I just don't worry. Great. If you don't worry, I'm not going to-- But I also like-- I do supplement with magnesium. So, supplementation with magnesium-- we could go on and on. Let's keep this shortens week, because we're going to get back to the other stuff. But, you know, it can cause GI distress at like high doses. I personally like to take around 130 or 135 milligrams. That way it's not like a huge ballast to my gut. I think it's a better way to go. depends on the form of magnesium too. - Yes, yeah. I mean, you can take like magnesium three and eight, for example, and it doesn't affect the gut as much. - Magnesium citrate. - Citrate is what I think. - Yeah, it's a pretty potent gut stimulus. I mean, I feel like it's a little bit harder to man. - Well, I take 135 milligrams should be pretty good. And citrate actually, boy, do we wanna go here? - Sure. - I mean, it's up to you. And we don't have to. I personally, I've been supplementing with magnesium for a long time. - Yeah. - I've used three and eight and bisclycinate and mallate for different reasons. So, yes, I would love to go there if you were willing. - I would say mallate would be the best. And that has to do with the short chain ad fatty acids being good for the gut and a lot of work done by a former colleague of mine and good friend Mark Scheginaga, showing that the short chain fatty has citrate, mallate, lactate. But specifically mallate really in lactate are the major ones that get into the gut epithelial cells and are energy source for the mitochondria and the goblet cells. So anyways, whole other. - That's okay. I take mallate because I was told that it would be helpful. First of all, it doesn't make me sleepy like some of the other forms of magnesium, which act as a mild sedative for me. They do tap into the GABA orgic pathway neuro transmitter folks that in general brought sweeping generalization here can have somewhat of a sedative quality, which is why I take magnesium 3 and 8 and or biscliscinate before sleep, 30 to 60 minutes before sleep. Definitely enhances my transition time to sleep and the depth of sleep. No question. In my experience, there's some data that 3 and 8 can be cognitive, can be neuroprotective, although those are still, those studies are still ongoing. I'm getting the sense that maybe you're a little more skeptical of that. - Oh, no. I've seen the studies with the 3 and 8. I think looking at the actual data from the one clinical study, there wasn't statistical significance until all three of the pieces of data were pulled together, but that really could just be because their sample size was too small. Right. - Yeah, I'm thinking that that paired with the. - The annual stuff. - Yeah, the four-song lose work on. So in that this is getting kind of into inside ball of neuroscience, the quality of the labs matters, folks. And that's something that's not accessible to people outside of fields. And you know, go song-lew and some of the other folks at that time at MIT, I think very highly of their work. And so the animal studies are indeed just animal studies, but I was pretty impressed by what they did in those studies. Very pioneering when you think about this being done 10, 12, 15 years ago. And then yes, we need more human clinical data. But for me, I figured that given the safety profile of MAG-3 and 8, given that it helps me sleep better and sleeping better is just better for everything. Frankly, that's why I take it. And biscliscinated and 3 and 8 seem to be somewhat interchangeable. But I don't know of any reports that biscliscinated can be neuroprotective. But malate, I take it during the daytime. For me, again, this is subjective. It has a tangible effect in improving the recovery time from exercise. So I don't know that I've been sore from a workout since I started taking malate. And I used to get very sore from even trivial workouts. So I don't know what's going on there, but I keep taking it. Malate, again, the short-chain fatty acid. And when you do intense exercise, you release endotoxin from your gut. I'm just going back to the interesting work because the malate being the short-chain fatty acid and Mark Schringernauger showing this is all an animal research, by the way. But I mean, it was like feeding these animals malate. I mean, it really protected the gut. Endotoxin release and it affected metabolic syndrome and all sorts of things. But I think malate is awesome. And I always try to eat green apples. They're really high in malac acid. And tart cherries. Tart cherries are really high in it as well. It also tastes really good. But I was really interested in the magnesium 3 and 8 stuff. I take a supplement called magnesium by Moonjuice. And it's like a little powder. It's got a little bit of monk fruit, but it tastes good. So I do it a little bit before bedtime as well. Probably several more hours though, because I don't like to drink tons and tons as flu is before I go to bed. And it has magnesium 3 and 8 and a variety of other versions of magnesium in it as well. And I really like it. But I thought the magnesium 3 and 8 stuff was super interesting. I would love to see more clinical data as well. But I think once we get it, it'll probably be like, oh yeah, it's getting into the brain. And it's awesome. So why wait? Right. And along those lines, I once put out a post that said, I feel like there are a number of different categories of health information consumers online and understanding which one you're in for which topic can alleviate a lot of the strain and stress of finding the information. There's some people that are perfectly comfortable with data from a mouse study. It's like if it's done in mice, great, I'll try it. Other people say, no, it has to be done in humans, double blind placebo controlled studies, randomized clinical trials, et cetera. Then other people are just say, you know what? I don't even care about any of that. Just tell me what you do. And then other people are say, you know what? I don't even care what you do. Just tell me what to do. And then there's this other category, which are if it's in pill form or powder form, they'll take it. And so I think a lot of the battles of people picking apart, people's posts and things have to do with the fact that people don't realize that people are showing up to the table in one or some combination of those stances. We know people that will try anything and we know people that won't take anything. So the idea here is to create an array of possibilities for people. And I think the animal data are very impressive. We should have you back on to tell-- I take it with the hope of because I feel like the animal data is very promising. And so I'm like, it probably is, so why not? Well, and obviously you're doing things right. So cold and heat. Converge on some common pathways related to what you called intermittent challenge, which I love. I think if intermittent fasting, cold, heat, exercise, I mean, maybe even intermittent sleep deprivation. I keep waiting for the intermittent sleep deprivation movement. I will say I pull a few all-nighters per year, just for work demands and procrastination and deadlines. I'm the worst combination of academic, because I'm both a procrastinator and a perfectionist. So you end up pulling some all-nighters. The sleep I get the next night is pretty amazing. I must say, it's the sleep of gods. But I don't recommend anyone who's sleep deprivation for that. But I could imagine that we also evolved having some sleepless nights. So this idea of intermittent challenge is a really attractive one. And I want to make sure that we credit you with the phrase intermittent challenge. No. No. I'm not. Dr. Mark Matzen. OK. Dr. Mark Matzen gets-- Who is published? And he has-- He used those. Yes. --of that phrase. OK. Great. We'll make sure. Just like Dr. David Sinclair, I love the Xenoharmesis. He was in one of his publications just so many years ago. And I just love it. It's brilliant, brilliant term. So Mark Matzen gets-- It's hard to guys are pretty smart. I mean, it's a good school, I guess. Of course, it's a good school. We will credit the appropriate people. Thank you for that clarification. So you've talked a lot about the use of deliberate-- what I call deliberate cold exposure, only to this thing was shipped from cold that you might just be accidentally exposed to. But it's sort of obvious when we say cold exposure, there are some amazing data on cold. The other day, I saw a post from you. And you've included this in talks before. I did not know this until I learned it from you. So credit to you, that even 20 seconds of immersion in, I think, was 4 degree-- 49 degree-- 49 degree Fahrenheit. OK. I was translating this. I was saying, 49 degree Fahrenheit water. So cold water can lead to long lasting increases in epinephrine adrenaline. And I have to presume other neuromodulators and neurochemicals as well. What are some cold protocols that you find particularly interesting or attractive from the standpoint of, I don't know, pick your favorite metabolism, neuro-slash mood effects, brown fat stimulation, which, of course, we used back to metabolism. We could do an entire episode all about cold. But what I'd love to know is, what sort of activity or stimulus do you think is a reasonable and particularly potent one? To use in terms of cold. So today I did three minutes at 49 degrees Fahrenheit. I have a cold tub. So you get in up to your neck? Well, I try to keep floating up. And so I'm like, it's really hard. So I would say maybe most of my shoulder-- OK. --I mean, really, I'm floating up. I was telling my husband, I was like, there's too much water in here for me. I can't-- Or too much salt in there. Is it like the Dead Sea, where you float on top? Is there salt in there? I don't know. He takes care of all the stuff that-- you know, it's the plunge. Yeah, by the way, the podcast nor I am sponsored by Plunge, they did give me one. That thing is fantastic. Also, because it circulates the water, which makes sure that you break up the thermal air and it's even colder. It is even colder. It sucks. Anyways, so look, I'll be honest here. I wish I did more cold than I do. I do cold when I'm going to go on a podcast. I definitely do cold when I'm going to do a podcast, when I'm going to give a talk, or when I'm anxious. I need to make it more of a ritual. I love doing this on. I hate the cold. I hate it. Unless it's summertime, it's a lot easier for me to get in the cold in the summertime. But what I do love about the cold is how I feel after. And I feel less anxious. I feel good. I feel more focused, which is why I usually do it before any type of public speaking, or just when I'm just anxious. I'll just get in there. And so the 20 seconds at 49 degrees, I think it was 49 degrees Fahrenheit was really a good number because time and temperature at time or duration, I guess, would be a better word and temperature do matter. But you know, you can do 20 seconds at a colder temperature, which is I prefer, or you can do a minute or longer at a warmer temperature. I think there was another study showing 59 degrees Fahrenheit at one hour was like two three full, but who wants to do one hour? Yeah, I'm familiar with that study. I love, so this is really reveals just how absolutely nerdy I am and maybe why sometimes in relationships in my life were challenged. I love reading the methods sections of papers. So you know, people can come at me with a number of things about papers and I might miss something. Surely I miss certain things like anybody is, but the methods I sort of, I relish in reading the methods and that paper is really interesting because they had people sit in lawn chairs basically in swimming pools for an hour and it wasn't real, it was chilly, it wasn't super cold. I mean, 60s, not, it's not warm, but it's not ice cold, obviously, but an hour is ridiculous at some level, but the increases in dopamine were massive and lasted hours. So it's really, so the mood enhancing effects that you report are, they're not, you're not imagining that. Those are almost certainly a consequence of having slowly elevating, but significantly elevated dopamine that goes on for hours. That's almost a dream-like profile for dopamine because most everything else like an Adderol, a Ritalin, a cup of coffee and a workout drink or pre-workout drink or something is going to give you a big spike in adrenaline and dopamine and a big crash. And somehow it creates this really nice contoured profile. So whatever you're experiencing there is very nicely supported by the data. Well I need to get, I need to get doing it more. I've had a couple of scary experiences going from hot to cold to, can you explain? Blood pressure changes, I think where I basically went straight from a really hot Chakuzi, I was in there for like 30 minutes. I mean, I was, I was doing heat jobs. Chakuzi, okay. Yeah, 104 degrees Fahrenheit. That's toasty. And then I, for 30 minutes and then I went straight into at the time, it was our pool, it was in like, February, it was like winter time and it was 50, it was in the 50s. It was cold. And I was in there and I was like listening to Simon Garfunkel, I was like trying to stay in a long time, get on my cold and then I was trying to press Dan because he like goes in there for like, he'll stay in there for like 15 minutes. But I started to feel really like blinky, like low blood pressure or something and I got scared, so I got out and then I couldn't stand like I had vertigo or something and I was so scared, so scared. And so and I've had a couple of times too, we're just going straight from the sauna to it to the cold plunge where I'm starting to feel like, I feel a little blood pressure change or something. And it makes sense. The sauna is causing vasodilation and the cold plunge is called, cold exposure is causing vasoconstriction, it feels like a very, you know, just shocked my system. And so now I wait, like I wait like a few minutes before going in, but I do need to kind of like make it more, the cold more routine because I talk all about the science. I'm familiar with all the science and, you know, the the noraponephrine or noradrenaline, you know, it's affecting brain and mood and I'm, you know, way more about that than I do. I know how I feel and I know it's a neurotransmitter and you know, it is, it is released, at least in rats they've shown or was it mice? I think it might have been rats, but multiple studies showing in that it's released from the cold in the brain. And now in humans as well. Oh, the brain they've shown. So in that study, that's the, we could put a link to this. It's at published in 2000 European Journal of Physiology. That big dopamine increase, they also looked at epinephrine and cortisol and it's also really, yes, so this has been done in human. They did brain. Oh, I didn't know. No, no, no, no, no, no, yeah, yeah, very hard to measure a dopamine directly from the brain. And so, you know, it's unfortunately, there's, unfortunately, their skulls were intact. Fortunately for them, unfortunately for the research committee, their skulls were intact so they couldn't measure directly in the brain. But obviously, there's a correlate there. You know, it's a very real effect. I think that, but the advantage of not doing it too often is that you're not cold adapted. Now, it's very hard for anyone to get truly cold adapted. Some people start to look forward to the cold and what I think they're looking forward to is the feeling afterward, that dopamine rush. But if you get cold adapted, then it certainly blunts the sum of the effect. But I want to be cold adapted because that means I have more mitochondria in my anapost tissue and perhaps even muscle like that's been shown. So maybe there's a good opportunity to, so cold and UCP1, if you could educate us on UCP1, I find this really interesting. And I learned about it from you. So. Well, so, norup and effron actually released in the plasma does act as a hormone, phase of constrictions, one thing it does. But it also regulates a variety of molecular functions that have to do with adaption to cold. One happening to be, you know, shivering is a very inefficient way to produce heat, which is what your body is trying to do when it's exposed to cold. And your muscles are basically contracting and producing heat from that, but that's just not very efficient. So the more eloquent way to do it, or elegant, I guess, a way to do it is, you know, to basically have your mitochondria produce tons and tons of heat. So the way it does this is by activating a gene called UCP1 on coupling protein 1, nor up and effron is upstream of that activating it. So that what that does is essentially, so mitochondria are these little organelles inside of your cells that are responsible for producing energy. And actually that's in the form of adenosine triphosphate ATP, and that's what lets everything function inside your body from your neurotransmitter production to your heart beating, et cetera. However, you can uncouple your mitochondria. Basically your mitochondria, they're like a little battery, so they have, they have, well, they have a double membrane, first of all, their structure, but they have a negative charge on the inside, and they have a positive charge on the inner membrane. So in between the outer membrane and inside the inside part. Like a neuron. Like a neuron, yeah. So I guess it's like a neuron. It's like a battery, negative and positive. Well, basically you can uncouple that charge, and so that positive charge protons start leaking out of the mitochondria, and your mitochondria freak out. So this is called uncoupling. And they start to, it's maximum respiration as we call it. They try to make as much energy. They're like, I gotta get those, that proton back, that gradient, the electrochemical gradient. And so they just go insane, and they, in this case, it's uncoupled energy, so that energy they're making is actually heat, not ATP. But heat is, but you're essentially burning substrate, so who cares? You're burning, you're burning glucose, you're burning ellipids, you know, you're basically burning things and making heat. And so that's what uncoupling does, and that is a much more efficient way of producing heat than shivering. So as you become more adapted, maybe the longer duration that you've stayed in the cold or the more times you've done it, you'll no longer shiver anymore. You will start to then just do this uncoupling type of thermogenesis, as it's called. And another type of adaptation that occurs is you actually produce more mitochondria in your adipose tissue. And that actually happens also regulated by Nora Epinephrine or Nora Adrenaline through a protein called PGC1 alpha. And what that protein does is it makes more mitochondria in your adipose cell. So per adipose cell, you're getting more mitochondria. It's a beautiful way to basically make more heat when you're, it's one of those things where it's like, your body's going, okay, I'm going to be exposed to this cold next time. How can I make sure I don't die? Oh, I can have more mitochondria and I'm going to make more heat. And so you're making more mitochondria in your adipose tissue. And this is often referred to as like the browning of fat. And the reason for that is because if you look under a microscope at a lipid droplet, you know, basically a fat cell, not a lipid droplet at adipose site, you'll find that it looks darker because there's more mitochondria in there. So it's referred to as browning fat. And so I don't want to get into the whole beige fat brown. You know, there's this whole, I'm sure you've had experts on that talk all about that. Yeah, I mean, I always think of white fat, beige fat brown fat and beige is kind of intermediate. White can be converted into beige, but yeah, and beige can take on thermogenic characteristics essentially. And so, so you can activate beige fat so that it's thermogenic in the sense that it's burning glucose and or, you know, fatty acids and producing heat. So the more you expose yourself to cold, the more you can brown your fat. So to speak and therefore you can tolerate the cold for longer periods, which people do notice. And you can then have the thermogenic qualities of having more brown adipose tissue or beige, activated beige adipose tissue, which is, you know, you'll get a lot of naysayers out there saying, oh, brown fat doesn't regulate metabolism at all. The reality is there's like thousands of researchers trying to build up brown fat and thermogenic. Make it a pill because it does affect metabolism. You know, it's not the only thing. It's certainly a ferobees and trying to lose weight. You're not going to like do that just by doing cold exposure. You need to do dietary and exercise changes, you know, predominantly, but it does affect metabolism. And, you know, this is a lot of things. This has been shown in human studies. So it is an interesting, it's another possible mechanism for affecting metabolism and that's an adipose tissue. But you also make more mitochondria and muscle tissue. And this is regulated not by a Nora epinephrine, but it is still PGC1 alpha. Interestingly, not like not that anyone else really cares about me, maybe you do. I'm eating this up. So PGC1 alpha is response to Nora epinephrine and adipose tissue to make more mitochondria. But in muscle tissue, it's unclear what the regulator is. Cold exposure does it. So this was shown at least in a couple of studies I've seen where people that were exercising, I believe, or maybe made of men only that were exercising that some sort of training. And then did cold water immersion, something like 50 degrees Fahrenheit, 15 minutes. And PGC1 alpha, which is a biomarker for mitochondrial biogenesis, which is the generation of new mitochondria. By the way, that's awesome. You want more mitochondria in your muscle. It's associated with improved muscle mass, improved endurance. I mean, mitochondria are essentially, either the making energy in your cell. And we, you know, we don't make more mitochondria. And normally like you have certain inputs, high intensity interval training exercise can do it. And actually make more mitochondria. Yes. Yeah. And that's been shown in people. High intensity training or just high intensity interval training. I haven't seen weight training. I've seen it in high intensity interval training and endurance training. But that doesn't mean that it hasn't been shown. I just haven't seen it or that hasn't been looked at. So, you know, I'm always looking for reasons to finally do more hit type high intensity interval training work. I do weight training and I do low intensity cardio. There was a brilliant study by, at the time he was a postdoc Matthew Robinson. And he's now gone on to start his own lab at the University of Oregon Health Science Center and that. And he did a study where both young and older people were, they had this whole high intensity protocol, which I can't remember what it was, but their protocol for X amount of time. I'm sure it was at least a month. They then measured biomarkers of mitochondrial biogenesis in their muscle tissue and the amount of mitochondrial biogenesis in old people specifically. It happened in both young and old from hit from the high intensity interval training. It was enormous, at least 50% I think. So it was just like, whoa. And so, why would you want that? Well, you know, mitochondria, you don't make your cells are turning over. You make new cells. You replace old ones where you're mitochondria. You don't really do that for the most part. You can. Polygenesis does happen, but you have to stimulate it to happen. The way you're mitochond, what happens with your mitochondria is they essentially are bobbing around inside of your cells and then they fuse with other mitochondria exchange all their content and mitochondrial DNA and then fizz back apart. And that's how they kind of stay young-ish. But like as you age, you keep doing that with the same pool of mitochondria and you're going to get a bunch of old mitochondria mixing old stuff together, right? So why wouldn't you want to bring up new healthy young mitochondria into that pool, right? So in my mind, when I hear mitochondrial biogenesis, I'm like aging. That's the first thing I think of. So anyways, cold exposure does that. It helps other things as well. You know what, and please, thank you for offering to somehow filter the level of detail. But I assure you that listeners of this podcast are familiar with getting drinking from the fire hose of mechanism and that was really helpful. And again, this is just one example of maybe four or five other things that you've said, at least, that are going to inspire me to change my behaviors. I'm going to start doing some high intensity in real training. Dr. Andy Galpin was on this podcast recently and he told me that the subtle zone two cardio and the weight training is great, but that I really should be doing some max heart rate work per week. You know, going into max heart rate for 90 seconds and resting and repeating that maybe even mild repeats. I'm just curious, as a brief aside, before we talk about heat, what sort of cardiovascular or other types of training do you do? Do you do hit? I imagine you are doing high intensity in real training. If you could just give us a sense of the contour of your week as it relates to exercise and because you've been very gracious in sharing some of what you do for supplements and food, what about exercise? So I, it all depends on my week, of course, and what I'm going on with my son and my work schedule. But I typically, I do a lot of high intensity interval tabatas on a stationary cycle. I use peloton because I just like that instructor there, like telling me what to do and then me competing with everyone else. I'm like, you know, so it works. You were revealing something about your psychology. This is what we just learned about. So this podcast is actually just a decoy for psychological assessment of the guest, no, I'm kidding. But so now we know you're competitive. Good. So that explains a lot of how you got through graduate school and then do what you do. So you're getting on the peloton and what does it look like for someone who's not familiar with peloton? I know what they are, but I've never been on one. You are peddling against the instructor for how many seconds? So you're, there's a bunch of people that are online either doing the class with you at the same time or at all time doing it so you can, you can kind of toggle on what you want and like you can try to compete against it all the time. So it's really competitive. Oh yeah. Okay. So I'm very, very proud of what you're doing. I'm very proud of what you're doing. And then there's a part where you're standing and then you really crank the resistance up, which I really do. And then you feel it in your glutes. Like going up a hill. Yeah, exactly. And so they break it up and most of the time you'll have those two parts. And I love the efficiency of it. And I'm pushing it max. I want to get number five. Great. So three times a week. Yeah, three times a week. And then I always have my sauna on pre-heating up. Takes about an hour and a half. And then I get it to about 189 degrees Fahrenheit. I hop right in the sauna after my peloton. So the elevated heart rate continues? Is that the last you know? Yeah, I literally like down a bunch of water. And then I get in. And then I like either read a science paper, prepare for a presentation or a podcast. Or I hash over things in my mind. And it's interesting because something about getting in the sauna. I think the stress, the heat stress of it. I used to, so I started doing the sauna in 2009 in graduate school. Okay. And I. You're early adopter. I started doing it every day. I lived across the street. I lived in a studio apartment with Dan within the like small studio part. The smallest apartment you can ever imagine. And it was across the street from a YMCA. And I was in the middle of the night. I was in the middle of the night. Because I was poor and writers very poor, very poor. I mean, so, you know, I recall, I recall me. I lived in my lab. Wow. But then again, I lived in my lab as a postdoc. And as I admit, I lived in my lab with my bulldog as a faculty member. For other reasons. But I get it. I wasn't your graduate student. Your poor. Yes. And so I used to, I used to go to the sauna before going into the lab. And I would, and I would, I started noticing that I was all of a sudden able to handle stress better. Like the stress of my six month setback because of failed experiment, which is crushing. On top of the pressure from your advice, my advisor and my own pressure. Because I'm very competitive with myself. And I put a lot of pressure on myself. So I was having a hard time. I mean, I was very stressed out in graduate school. And the sauna started to really noticeably affect my anxiety. anxiety and my ability to handle stress. And I was like, what is going on here? So I started looking into the literature and you know started getting interested in the effects on the brain and in fact at the time I had a friend who was not actually experimentally but theoretically looking into the opioid system and basically so when you get in the sauna you release a lot of endorphins and endorphins are the feel good home, feel good opioids that you know make you feel good but you also release something called dynorphin and dynorphin is an endogenous opioid that binds to a receptor called the kappa opioid receptor which dynorphin is responsible for that dysfork feeling when you're in the sauna and you're hot and when you're running doing exercise and you're like you feel uncomfortable. Well I think that's dynorphin speaking absolutely I think it is. I mean that there's evidence in alcoholics that some of the symptoms of withdrawal that the experience are related to dynorphin and dynorphin is known to negatively impact the dopamine receptor system so basically it's the feel like garbage pathway. Right you feel like garbage and so you think that that would not be good but this is where my friend that comes in. He was looking at the effects of like treating morphine or heroin addiction and you know people that are using those drugs they basically the endorphins or the morphine or you know heroin they bind to a receptor in the brain called the mu opioid receptor and as they take these drugs that mu opioid receptor becomes down regulated and so you need more and more of the drug to feel as good as you do it right. Well endorphins also bind to that receptor and he was looking into some of the other other drugs that are like salvin or salvin or salvin orm or something that salvia it's called it binds to the opioid receptor it also makes you kind of feel uncomfortable anyways. He had put some studies in front of me that showed basically binding of the you know either dynorphin or you know whatever ligand to the capa opioid receptor basically sensitizes the mu opioid receptor to the feel good endorphins and also changes I think it also upregulates it or something so basically there's a lasting effect of feeling good so the endorphins that you release later from hugging someone or a joke you're laughing out or whatever you feel it for longer right and so anyways this is a with the song with respect to the song it's a big sort of hypothesis of mine I did kind of publish that part of my hypothesis in a review article but I do I do wish more people would kind of look into that that'd be amazing but what I was getting at I think was I would use I would use the sauna to memorize things this is way back in the day and I still do it and I wanted to talk to you about this because you're you're you're a neuroscientist that there's something about being in the sauna like and I think I don't know if it has to do with the like the stress response like when you when you have an emotional trigger like you remember things better right absolutely there is a clear and known explanation for mechanism for this yeah so in the sauna I mean you also release noripanepheren just like you do in the cold there's a lot of overlap you know you're really you I mean it is a stressor but I like use it to remember things like I'm going through something I want to go through a presentation or a talk or a podcast or whatever and I go in that sauna and I mean you should try it like if you haven't already I don't know if you have I have a sauna and I cold punch now and I haven't tried prepare I read books in the sauna in the evening it's it it's a time I insist on having my phone out of there mostly because I initially because I thought I'd cook the phone but also just to get some separation from the phone and screens the evening so I read books the only challenge sometimes you're dripping sweat onto the books but I'm willing to forego a few pages of a book the the the idea that being in this semi stressful environment would aid in the learning and retention of information is is really well substantiated by this beautiful work by a guy named James McGall I don't know if his lab is still active but he was at you you see your vine for a while and then I think at University of Arizona as well they have a great memory group at both places very strong in learning and memory on both places and he was the one that really defined this kind of inverted you shaped function for the relationship between adrenaline and memory basically if you're too relaxed and not stressed enough you're not going to remember any information at peak levels of stress you actually are a memory machine at least within the context of whatever it is you're trying to learn so very well see what you're describing is very well matches with that and then of course it tapers off as you really increase adrenaline to the point where people are starting to lose autonomic function where they're just they're panicking basically but obviously you're keeping it in range the other thing that I'd like to ask you about is in the sauna of course there's vasodilation and perfusion of blood to the brain is a wonderful way to enhance cognition there's even some really nice data showing that during inhales as opposed to exhales people are better at learning information believe it or not during the inhale you're taking in and absorbing and remembering more than during exhales and these are beautiful studies done in humans of course so I can imagine that vasodilation getting more perfusion of blood to the brain plus a little bit of stress or maybe a lot of stress from the epinephrine and yet it's and then of course there's going to be that I don't want to call it placebo but there's going to be the context the condition place context of it like if we if we had a good experience remembering something in the sauna once we tended the positive association effect of that location is real just like if people go to a new city and they get robbed like if you go to Cincinnati I've never been to Cincinnati but you get robbed in Cincinnati your purse gets taken your wallet gets taken you kind of hate Cincinnati as a tourist but that could happen in any number of different cities right the opposite is also true so if it's something good happens someplace I'm imagining that's a combination of those effects but I'll start it would be very hard to to do this in the cold I feel like the cold is a very potent a drink I think it takes you too far down that curve the McGaw curve I have to sing songs or something when I'm in the eye sing songs and but afterward you're very efficient at learning after I am and yeah with respect to the sauna the vasodilation does occur so there's a lot of overlap between moderate intensity aerobic exercise and heat stress and as you can imagine when you're exercising your elevating your core body temperature you're sweating and when you're actually in the sauna blood does get redistributed to the skin defceilitate sweating but much like exercise blood flow in general is improved to the brain to the muscles everywhere so you know I think generally speaking that and this you know there's studies showing that sauna use is associated with a much lower risk of dementia and Alzheimer's disease like people you know people that use it four to seven times a week have greater than 60 percent reduction in dementia and Alzheimer's disease risk compared to ones. Oh sorry I didn't mean to cut you off you said people who use it I apologize maybe you tell us again people use it four to seven times per week have they have a greater than 60 percent reduction in dementia risk and Alzheimer's disease risk compared to people that use it only one time a week people that use it two to three times a week have something like a 20 a little greater than 20 percent reduction in risk there's a dose dependent effect on dementia risk and Alzheimer's disease risk it also has a profound like there's a there's a big link between the cardiovascular system and the brain obviously blood flow a big one right you know like you need to get blood to your brain but cardiovascular mortality so mortality from cardiovascular disease if people use or actually this was men if men use this sauna four to seven times a week it's a 50 percent reduction in cardiovascular related mortality compared to one time a week again dose dependent manner two to three times a week is something like 24 percent lower death from cardiovascular disease there's also lower you know sudden cardiac death it's like a heart attack that's like 60 something greater than 60 percent lower if if men use it four to seven times a week versus once again a dose dependent thing and the thing that's so profound they're also to me when again looking at the methods when I look at the data and this is all work from Dr. Yari Lalkinin he's in the University of Eastern Finland and just one of the the the world experts on sauna use especially with respect to cardiovascular health what some of his data has also shown is that if you look at the duration the time spent in the sauna so a lot of the so I mentioned the temperature I do is about I do like 189 degrees Fahrenheit typically I go in there I'm pretty heat adapted and so the more you do the more you do the sauna or any sort of heat stress whether it's a hot tub or jacuzzi you you become adapted you're you're basically start to sweat at a lower core body temperature to cool yourself down all these sort of physiological changes start to happen earlier and and so I stay in for like 30 minutes like I mean so I say it went a long time that's a lot you have to listen to your body most of the studies that I just talked about were from the duration the time spent in the sauna when I said 50 percent reduction in cardiovascular disease related death what was shown was that men that were in the sauna for only 11 minutes even if they used it four to seven times a week that reduction was only like 8 percent set of 50 it had to be greater than 19 minutes so like 20 minutes is the sweet spot at about 174 degrees Fahrenheit and so and most most of the soreness in Finland by the way they're they're humid so they they they put hot hot hot they put water on hot rocks to create steam and so it's so usually between 10 to 20 percent humidity in the finish sauna so those those studies were I would say most the time you're going to find that their humidity is also elevated. But to me, the the dose-dependent nature of it and the duration knowing like you know to me that's a very strong data that this is more causal than some you know corollary thing because that's always the problem with observational studies including these which they corrected for a whole host of factors like cholesterol you know exercise just everything everything or the sun I mean they corrected for those and on top of that you have the dose-dependent nature of the duration the time spent in the sauna and the frequency so to me it's like something's going on here plus there's been studies intervention studies where it's like you know comparing directly head-to-head moderate intensity aerobic exercise on the stationary cycle to 20 minutes in the sauna they're physiologically the same things happen so heart rate elevates while you're doing the activity blood pressure increases while you're doing the activity but then after heart rate decreases resting heart rate decreases below baseline blood pressure is improved so it decreases below baseline this is happening the same in moderate intensity cycling versus sauna so again this sauna like this heat stress or something about it that really mimics this moderate intensity aerobic exercise which is really great for people that can't go for a run that can't even get on a bite so you know disabled people granted there are some safety concerns they're they're pretty mild but they do exist you know so people that had a recent heart attack or have some rare kind of heart disease or problem drinking alcohol never do that elderly people low prone to low blood pressure always talk to physician before doing the sauna it is it is stressful pregnant pregnant women oh yeah I definitely avoided sauna as when I was pregnant but the it is I think it's very relevant for disabled people and also people like that are sedentary I've been sedentary most of life like my mother I've been able to get her in the sauna because she's not I mean I did get on the peloton once but it's really much easier she feels like it's a spa treatment and and it's like she can listen to her music in there and like I care about her health but she's she's mostly been a sedentary person and so I find it much easier to convince her to get in the sauna than to get on peloton ideally you do both the question would be well I exercise I run I do my high intensity interval training why do I need to get in the sauna and and the reality is is and so I published all this and I review in the the experimental gerontology last year I guess early late last year and it basically cardio respiratory fitness which is a marker of it's a marker of health you know cardio respiratory fitness is improved in people that do exercise and sauna compared to exercise alone or sauna alone so for those be healthy fit people out there already exercising there's a synergistic effect by also adding a sauna into that routine and to me that's great and there's so many beneficial things happening with with the heat stress in addition to like mimicking aerobic exercise there's the heat check proteins that we talked about earlier and those it kind of brings me back to my early days of science when I was at the Salk Institute for Biolatural Studies doing research on little nematode worms that we are someone else injected amyloid beta 42 the peptide the 42 amino acid peptide that is involved in amyloid plaques found in the brain cordially with Alzheimer's disease and other you know brain disorders we injected those into the muscle tissue of worms and basically these worms become paralyzed with age because the the aggregate aggregated proteins these proteins aggregate well heat shock proteins one of the main things they do is they basically make sure the proteins inside of your cells maintain their proper three-dimensional structure and are folded right and so they don't they're not prone to aggregating and forming these plaques in your arteries and also in the brain and there's back to my my my worm studies I was doing I would I would elevate heat shock proteins in those worms and it would totally you know correct the problem where the they would no longer become paralyzed they'd move around like they're young so many animal studies have been done looking at Alzheimer's disease you know like a human like Alzheimer's disease in a rodent and heat shock proteins protecting from it you know so heat shock proteins are robustly activated in humans and this has been shown to even you know 50% higher over baseline levels after just 30 minutes at 163 degrees Fahrenheit in the sauna so and they stay activated at least in rodents for you know 48 hours at least so you know having these heat shock proteins around making sure they're they're properly taken care of our our proteins so they're not aggregating in our brains and in our in our plaques could be another potential way that sauna is protecting from Alzheimer's disease and other you know cardiovascular health as well as longevity so you know there's there's people that have snips in heat shock protein factor 70 that if they have one of them so they got one from their parents where they have more active heat shock protein 70 they live on average one year longer than people that don't have that snip and if they have two versions if they got one from their mom and one from their dad they live on average two years longer than people that don't have that snip so it's also been associated with human longevity as well as in lower organisms so you can heat shock a worm or a fly and they live 15% longer assisted worked on by Gordon Lithgow at the Buck Institute years and years ago so anyways I guess what I was getting at was the heat shock proteins are part of that stress response pathway that we talked about earlier and you know they're also activated by cold as well cold shock does activate heat shock proteins not as robust so for a free and active it activates them again it's one of the reasons I think we should get all of these things because they are more robust inputs you know their input activating mechanisms are more robust for you know different ones so there is cross talk there is you know I mean I guess I get it be more accurate to say there's overlap but but you know it's also like you want to get the most robust from all of them right I do so I mean that's why I want to do the sauna and exercise and eat myself you know my broccoli sprouts and and all that stuff all right it's super interesting a couple couple of questions came up for me one is you mentioned these snips these nucleotide repeats basically genes that some people have more of our less of than others that can predict longevity in some sense is that the Fox 03 pathway that's one that can yeah I mean Fox 03 is in fact if you go back to the warm studies I was talking about that was like one of the the first things when you see it with your own eyes you can take these worms that you basically decrease their insulin signaling pathway and their IGF one worms have what are called homologous genes so they have a lot of similarities to humans they have an insulin like receptor they have an IGF one like receptor and they make something like Fox 03 which we have and basically if you if you decrease that insulin signaling pathway their Fox 03 is always active in those worms and they they live like a hundred percent longer and and not only do they live longer I mean they are like a very young worm I mean they are like you look at this thing and you're like this looks like the worm that was just born like hours ago what's going on this things at the end of its life now as a as a side note the thing that always got me on this was by the way this was discovered by Cynthia Kenyan and this was like back in the 90s and honestly I'm not sure that anything has been as exciting in the warm world since then but I thought I mean it was a really big finding the only the only caveat there is that the worms go through this dour it's called a dour stage when this happens when you decrease their insulin signaling and stuff and they like go into this like metabolic stasis like they're not eating as much or moving and and so it's like okay well they live a hundred percent longer but like they go into this weird state you know I know people like this some in the longevity community they know who they are but they'll get the last laugh because I'll be dead well fed but dead and they'll still be going so in terms of the the many data on sauna and I also just want to acknowledge these finish groups that did this work is really pioneering right when you think 20 years ago along before social media or any of this and they're out there up there I should say measuring cortisol and growth hormone and all this stuff in in people getting in now sauna very very interesting so 20 minutes seems like the threshold at 170 degrees Fahrenheit more times per week seems to be better than fewer when you when in terms of all caus mortality cardiovascular risk according to what what I just learned for more would be a good I think minimum effect of dose four times a week and you combine it with the cold I've also seen a protocol where is a very extreme protocol I don't recommend this to people right off the bat where they had subject human subjects get into the sauna for 30 minutes get out for five 30 minutes get out for five three minutes for a total of two hours of exposure but that was what led to these massive 16 fold increases in growth hormone I actually have a so I and they had to do it very seldom so it sounds like these protocols you're describing 20 minutes done four times per week far more reasonable for most people to access but I know people are probably desperate to know what if they don't have a sauna you know sauna is kind of a unique item so I have a couple questions can people use hot baths and with the appropriate warning of course that without getting into description of the the mechanics and the underlying biology it's pretty obvious that the testes of if they get too warm, you'll kill sperm. That's the reason why the testes are housed in a structure called the scrotum that can move around. So just to be, you know, a re-arbiologist just talking about realities here. So if you're trying to conceive children or keep your sperm healthy, guys should probably stay out of warm baths. - For at least six months, that's been shown. - Six months. - So sperm, motility goes down and sperm production goes down, but that is completely like corrected if they stay out of the sauna for six months. So through six months later, it's back to normal. - Great, that's very useful information. I'm sure to a number of people out there. So there, if people don't have access to a sauna, and we get this about cold too, you always say, what about cold showers? And I always say, well, the studies have mainly been done on immersion because it's hard to keep things controlled in cold showers. It just doesn't make for a very good experiment 'cause you get a bigger person, the less of them is under the shower. And so it doesn't make for a good experiment. So it's not as good as immersion, but with heat, I could imagine that a hot bath would work almost as well. - Yeah, so there's been some studies looking at, for example, activation of heat shock proteins, also brain drive neurodiprofactor increases with heat stress. And so the hot bath at around 104 degrees Fahrenheit, which is typically what studies will use for temperature, which is actually cooler than what I, I crank my bath hot, it's so hot. - But you're very heat adapted. - I'm very heat adapted, yeah. And it's 20 minutes from the shoulders down. And that is like a very robust activation in heat shock proteins and in brain drive neurodiprofactor. And then heat shock proteins are also protecting against muscle acrophy. So that's also having to do with the protein structure and the muscle tissue as well. And this has been studies in animal data, as well as some recent human data as well. It was local hyperthermia or local heat treatment, but essentially it showed that it protected. I mean, it was like, there was a study where they were looking at muscle disuse. And it was something like the local heat treatment prevented like almost 40% of the muscle atrophy from dysu. So like, and it's funny 'cause I used to use this on when I was injured and stuff, I would go in the sauna. Because I didn't know at the time, 'cause I was a graduate student, but I knew just from experiments that like, I'm not losing as much muscle. I feel better like at the time I was reading a lot about the growth hormone and stuff back then. But and I knew about heat shock proteins and so I kind of knew, but that data wasn't around yet. And so now we have the data. And I've always felt like I wasn't losing my muscle. Like I should have been when I was doing the sauna. And I was doing it literally seven days a week. It was like hardcore. - This is also during graduate school. - Yeah, now I'm doing the sauna, like a bare minimum I do three, but I try to do four because of the, it all depends on my schedule. I also like to do long runs. I really, it's like long being like three miles, not like canhines, that's not long. But I really, for me and we were talking about this earlier, like off camera that the runs for me are for my brain. And I get this mind wandering effect where I daydream and I think about things, I work through problems, I get creative, I come up with ideas and this is all happening on the runs. And so I just, I miss my runs if I don't do them and I miss it because of the brain effects I get from it. And when I exercise, it's funny because I'm a female and you think that I'd be exercising to stay fit and in shape and care about my figure. But when I exercise, literally what I'm thinking about is my brain and I'm like, this is the best long-jegged, long-jepity drug there is. This is it right here, Ronda. Like you're always wondering, you're always wanting to know, you're wanting to do the best. Like if you don't exercise, you're missing that essential dose. And so that for me is motivation, the dopamine seeking thing I'm looking for, admittedly I do not do enough strength training. And I have to do it, I have to have to have to, I'm like, I'm just, I'm so after the endurance and the hit and I really need to add that in because muscle mass is also extremely important for aging as well, you know. So that's my fault. - Well, the brain effects are really interesting. I also run, I try and get one longer run per week and a few other runs and I do it without a phone. I don't listen to podcasts. I occasionally will listen to music, but I really try not to. I also find that my mind solves problems. I feel like it washes out the cobwebs, so to speak. Some of the most brilliant and prolific neuroscientists that I know who've had very long careers, Eric Kendall, Nobel Prize winner at Columbia, comes to mind for all his work on memory. He used to swim a mile a day and now I think swims half a mile a day, but he's in his late 90s and he's still sharp, which is incredible. And his lab has done some work showing that any load bearing exercise repeated, so endurance work unlike the Peloton or Cycling that's really load bearing all the yurt cycling really hard with the resistance, but causes the release of osteocalcin from the bones, which acts in an endocrine way, sort of like a hormone can actually travel to the hippocampus and at least in these animal studies induce the proliferation of neurons, growth of synapses, BDNF, a number of downstream things, which kind of makes sense if we were to put a just so evolutionary story on this, a body that's active can signal to the brain that the body still needs cognition. An inactive body in some ways is depriving the brain of any signal of what the body is doing. This is obviously making this up as conjecture, but we know in ocean animals that they'll swim around for some period of their life and then they'll have a completely stationary portion of their life, and basically the brain degenerates. You don't need much of a nervous system if you're not moving. So I think there's really something there and also just letting your ideas in mind drift. I love that you, and I appreciate that you shared your protocols because I think right now we're in an interesting time in public health information history where people are just kind of getting bombarded with cold is good, heat is cold, cold is good, heat is good, excuse me, I'm a spoke, there are all these micronutrients, and of course macronutrients are important too. And today you've really enriched us with the description of the underlying mechanisms and the logic behind them, but also sharing what you do is really informative because I think people need a jumping off place. And obviously they need to start someplace and getting heat adapted, et cetera, takes time, but I really appreciate that you're willing to share your protocols and that you do the things that you teach and educate people about. As a final question because I have, have, have to ask red light sauna or no red light sauna. I've been a little bit vocal about my feelings that none of the red light sauna's I've ever been in got hot enough and it was frustrating. So I feel like it's neither here nor there. However, I do acknowledge that red light and low-level light therapies are now known to do a number of interesting things because the Nobel Prize in 1908 for phototherapy, for loopess, so it's not like a new thing, the idea that red light and light could do things positive for our biology. But do you have a red light in your sauna? Do you think it's useful? And I mention this because this is the number one question I get about sauna, red light or no red light or some intermediate answer. - So I don't have an infrared sauna, but I do have a sauna that has lights, it makes red light, but I don't think it's the red light that you're talking about. - Okay. - It's not activating it at a specific wavelength, which is-- - It's usually so that the range that seems to be helpful and I confess, I use a red light panel for other things is 670 nanometer out to about 720 nanometer. So it looks like red and very dim lights, dim red and bright red and the ideas that red light can travel, the photon and energy is such that it can travel down through the de-blayers of the dermis of the skin. - I don't have a red light in my sauna. I don't know if it's essential or not. I don't think so based on all the studies I've talked about. I think that would be as, you know, the potential effect on mitochondria is interesting. I do think there's a lack of really good solid evidence in humans, but that might only be because it's just not studied enough and that's usually the case. So perhaps, you know, like there's the Juve, right? The Juve, they have those red light panels. - Juve and Cozy are the two ones I know, KOZ and Juve. They're there as far as I know. I'm probably gonna insult both companies at the same time, but I'd rather insult them both at the same time than just compliment one or insult one. Both of them seem excellent for getting the appropriate wavelengths of red light and I do not have a relationship to either of us. - Well, I personally think that the sauna in and of itself, it's about the heat stress and typically the question I get is infrared sauna or regular sauna and there are some differences as well. Infrareds on us, maybe the infrareds on us are the ones that have the red light that you're talking about. Infrareds on us only get up to around a 140 degrees Fahrenheit. So as I mentioned, the studies were about 174 degrees Fahrenheit and so you really have to stay in a longer period of time. However, there have been some studies coming out of Japan. They use infrared sauna. They have this whole protocol, it's called weigh on therapy and they get people in infrareds on us and then they wrap them in a towel and they stay warm for X amount. So the whole protocol ends up being like an hour long, but again, it's 140 degrees Fahrenheit so it's an infrared sauna and it's been shown to improve a variety of coronary heart disease and heart related like there have been some improvements. So, um, Obviously, there's evidence that infrared zonas can be beneficial for cardiovascular health. I've used infrared zonas many times that my in-laws they have an infrared zona. And I have to crank that thing up for a while until it's maxed. And then I have to sit in there for an hour at least. I do sweat a lot. And that's another thing we didn't talk about. You do sweat some heavy metals. And some heavy metals are excreted predominantly through sweat and others through urine. So for example, cadmium, there's like 125 fold increasing cadmium excretion from sweat. When you get in the zona also lead is something like 17 fold excretion is higher. Another one is aluminum. It's about four fold higher. So infrared, you do sweat a lot too. And that's because the main difference is that you're heating your body up through thermal radiation versus the ambient air. Like a standard, you know, zona is a heater and the heater is heating up the air. And that's how you're heating yourself up. So it is a little bit of a different mechanism. I prefer regular zonas. Most of the data out there is from the heat stress itself. Like your heart rate's elevating when you're in there. You're feeling hot. You're getting that cardiovascular. I mean, that's what you're feeling when you're in the hot zona. And that for me takes a really long time and the infrared zona get at the very end. But I do think there are some benefits from infrared. And they are more affordable. They're less of a fire hazard. But again, hot baths are, I think, a good alternative modality for heat stress compared to a regular zona. So great. That's a really helpful answer. I said I use the red light, but not in the zona. And thank you for reminding us of that 174 degree Fahrenheit threshold that was mainly used in all these studies. So we covered a lot of territory. But I just want to thank you again. It was extremely thorough and extremely informative. I now have my notes are always look a little bit like they were drawn out by a Macak monkey who has no knowledge of the English language. But I can decipher this to tell you that there are at least 10 additions to my current protocols that I'm going to add. And I'll have lots of questions. So I apologize in advance for that. But I'll be half of the listeners and just directly from me. Thank you so much for your time. I learned a ton. My pleasure. Thanks for having on. It was really awesome conversation. So I enjoyed it a lot. Let's do it again. Totally. Great. Thank you for joining me for my discussion with Dr. Rhonda Patrick. I hope you found it as interesting and as actionable as I did. 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There, I teach science and science-based tools, some of which overlap with the content of the Hubertman Lab podcast, but much of which is distinct from the content of the Hubertman Lab podcast. Thank you once again for joining me for my discussion with Dr. Rhonda Patrick. And as always, thank you for your interest in science. [MUSIC PLAYING]