Dr. Rhonda Patrick: Micronutrients for Health & Longevity

Andrew Huberman:

Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life.

Andrew Huberman:

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, micronutrients, supplements, and other protocols in order to maximize our immediate and long-term health.

Andrew Huberman:

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 FASEB. Indeed, Dr. Patrick is an expert in an extraordinarily broad range of topics that impact our health.

Andrew Huberman:

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, and so you'll notice that I am rapt 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.

Andrew Huberman:

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'm delighted to say that we discuss 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.

Andrew Huberman:

And 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 "Found My Fitness." 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, micronutrients, sleep, depression, fitness, longevity, and far more, along of course with actionable protocols.

Andrew Huberman:

I'm pleased to announce that the Huberman Lab podcast is now partnered with Momentous Supplements. Our motivation for partnering with Momentous 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 Huberman Lab podcast. If you go to livemomentous.com/huberman, you will see those formulations. I should mention that we are going to add more formulations in the months to come. And you'll 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 derive the maximum benefit from those supplements. And many of you will probably also be pleased to learn that Momentous ships not just within the United States, but also internationally.

Andrew Huberman:

So once again, if you go to livemomentous.com/huberman, you'll 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.

Andrew Huberman:

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.

Andrew Huberman:

Rhonda, welcome. This has 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.

Rhonda Patrick:

Oh, that is so kind. Thank you. Thank you so much.

Andrew Huberman:

Well, it's absolutely true.

Rhonda Patrick:

I am so excited to be here having a conversation with you, so thank you.

Andrew Huberman:

Well, it's absolutely true. If anyone does their research, they'll realize that the statement I just made is absolutely true and there isn't even a close second. 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.

Andrew Huberman:

I have so many questions, but I want to start off with 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.

Andrew Huberman:

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 convergent understanding. So, if you would?

Rhonda Patrick:

I would love to. Let's take a step back, 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 temperature changes, like cold or heat, or through other types of stressors, like physical activity or perhaps even dietary compounds that are found in plants, these are things like polyphenols or flavanols. Humans, 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 occurred, we were out hunting. And I say we, not us, but humans. We were out gathering, were moving, and we had to be physically fit. You couldn't catch your prey if you were a sedentary slob, right? You were moving and you had to pick your berries, you had to move.

Rhonda Patrick:

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. We didn't always have a prey that we caught, or maybe temperatures were such that there was nothing for us to gather. So food scarcity was something common, as well as eating plants, so getting these compounds that I mentioned. So 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. Physical activity is strenuous, fasting is a little bit stressful, heat, cold, these things are all types of little intermittent challenges.

Rhonda Patrick:

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 they do it in a way that is not only beneficial to help you deal with that little stressor, exercise or heat, it stays active and it helps you deal with the stress of normal metabolism, normal immune function happening, just life, aging.

Rhonda Patrick:

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 has a very profound antioxidant, anti-inflammatory response, or whatever the response is. It could be the production of more stem cells, these are cells that help regenerate different cells within tissues. Or something like autophagy, which is a process that can clear away all the gunk inside of our cells, pieces of DNA, protein aggregates.

Rhonda Patrick:

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." Well correct, they are activated, very robustly, by heat and we can talk about that. But you can eat a plant like broccoli sprouts, which is high in something called sulforaphane. This is a compound that is sort of like a hormetic compound, or as David Sinclair likes to say, it's a xenohormetic compound. I love that. 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? Heat activates that.

Rhonda Patrick:

So what I'm getting at is there is overlap, like cold also activates heat shock proteins. You're like, "Really, cold?" Yes, these are stress response pathways and they are activated by various types of stressors. Now, you're going to more robustly activate heat shock proteins from heat versus cold, but there is some overlap. So, I think that sort of forms the foundation there.

Andrew Huberman:

Yeah, that's very helpful. And it brings to mind, in the context of the nervous system, I always tell people, 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. Dopamine is a generic pathway by which motivation, craving and pursuit emerge, et cetera, 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.

Andrew Huberman:

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 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.

Andrew Huberman:

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 hormesis-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." So in the same way that too much heat is bad for us, too much cold is bad for us, can kill us, can kill neurons, but appropriately dosed in an intermittent challenge type of scenario, can be good for us. Is that how I should think about plants and 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 potently.

Rhonda Patrick:

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 large ... I mean the bioavailability of these compounds in the plants, they're attached to a food matrix; it's not like taking it in a supplement form as well. It's such that it's very difficult to make it toxic. Now there are some cases; for example, there's some group in Africa somewhere that that's all they eat is cabbage, and there's a goitrogen in cabbage. It's not sulforaphane, it's another compound. But that's all they eat every day, nothing but that.

Andrew Huberman:

They get goiter, the thick neck.

Rhonda Patrick:

Yeah. And they're iodine deficient on top of that. So, I mean there are types of plants that are toxic in small quantities, right? I mean-

Andrew Huberman:

Hemlock.

Rhonda Patrick:

Hemlock, exactly.

Andrew Huberman:

Will kill you. Folks, don't play this game with hemlock.

Rhonda Patrick:

But you're not going to get poisoned from eating your serving of broccoli at dinner. So, I mean, it depends on the plant. These generalizations, they're just not useful. And I think that a lot of people online in the blogosphere, they gravitate towards them because it's just easier and it's a lot more sensational.

Andrew Huberman:

I eat plants, meat and starches. I'm one of those rare omnivores out there now.

Rhonda Patrick:

I do too.

Andrew Huberman:

I feel like it's rare to be an omnivore. But I think once you step out of the social media, as you said, the blogosphere, most people, I would say 99% of people on the planet, are probably omnivores. And someone will probably correct me, but I doubt the number falls below 98.

Rhonda Patrick:

I think if you look at data ... And when we have carnivore data, I can't wait to see it. But right now it's a lot of, "Okay, well this is a lot of anecdotal evidence." And there's ... a lot of good starts with anecdotes. But people change a thousand things at once and they don't realize that, but they do. And so anecdotal data is only so good, it's a starting point. And so we don't really know long-term what carnivore diets are going to do. They may be beneficial short-term; they may be beneficial for reasons of elimination of other things, who knows? Lots of possibilities.

Rhonda Patrick:

But I do think, with respect to plants, that there's so much evidence. For example, sulforaphane is one that I really like because there's just evidence that sulforaphane is a very powerful activator of the Nrf2 pathway. And this is the pathway that regulates a lot of genes, and a lot of genes that are related to glutathione production. Genes that are involved in detoxifying compounds that we're exposed to from our food, like heterocyclic amines.

Rhonda Patrick:

In fact, there have been GWA studies. So 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 it 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 colon cancer and increased cancer risk. But if they eat a lot of broccoli and cruciferous vegetables, it negates that risk because they're getting sulforaphane, which activates a lot of the glutathione transferase and synthase genes.

Rhonda Patrick:

So glutathione is a major antioxidant in our brain and in our vascular system, in our body basically. So there's evidence that eating things like compounds that are like sulforaphane or broccoli or broccoli spouts, which have up to a hundred times more sulforaphane than broccoli, are activating glutathione in the brain. There's human evidence of that. I mean, that's amazing.

Andrew Huberman:

That is amazing. Can I just-?

Rhonda Patrick:

And plasma ... Yeah.

Andrew Huberman:

Sorry to interrupt. I just want to make sure, so broccoli sprouts are different than broccoli, and you just told us that they're 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.

Rhonda Patrick:

So the sulforaphane is formed from a compound called glucoraphanin, which is in the broccoli. And the enzyme that converts it into sulforaphane is myrosinase, and it's heat sensitive. So you do somewhat lower the sulforaphane levels 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 myrosinase enzyme, to your cooked broccoli increases the sulforaphane by fourfold.

Andrew Huberman:

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.

Rhonda Patrick:

Yes. So what I do is I will lightly steam my broccoli and then I add a little bit of my Kerrygold butter, and then I add some mustard seed powder on the top of that. And it's got a little kick, it's just a little spice. And if you don't taste that, it's expired. It should have a little kick.

Andrew Huberman:

And because I know people will want to know, how often and how much? Are you eating this every day or most days of the week?

Rhonda Patrick:

Well I had shifted to supplementation with sulforaphane. I'm admitting right now that I've been terrible about it the past, I don't know, six months or so.

Andrew Huberman:

The supplementation or the broccoli?

Rhonda Patrick:

Yes, the supplementation. And so, there's another way to get ... There's another compound, and it's actually called moringa. And Dr. Jed Fahey, who's really the expert on sulforaphane, he's a good friend of mine, he's been on the podcast a couple of times. He basically thinks, and has done a lot of research on moringa as well, that it's like a cousin and it activates the Nrf2 pathway similarly to sulforaphane. And so I've been buying this Kuli Kuli moringa powder. I don't have any affiliation with them.

Andrew Huberman:

Kuli Kuli is a brand.

Rhonda Patrick:

Kuli Kuli is the brand.

Andrew Huberman:

That you have no affiliation to.

Rhonda Patrick:

I have no affiliation. But Jed Fahey has researched it, like that specific brand. And so, it's legit. It's science-backed in terms of actually containing moringa and activating Nrf2. And I add it to my smoothies, so that's what I've been doing.

Andrew Huberman:

What are some dose ranges? So of course we give the usual recommendations that people should talk to their physician, et cetera, et cetera. But if people are going to, what do you take? Let's take-

Rhonda Patrick:

A big heaping tablespoon-

Andrew Huberman:

... the David Sinclairian approach, where he'll talk about what he does as a way to deal with this. And of course everybody's different and, in all seriousness, anytime you add or delete something from your consumption, should consult some trusted healthcare professional, trusted by you. What do you recall the dosage is?

Rhonda Patrick:

I do a big, heaping tablespoon.

Andrew Huberman:

So, Kuli Kuli moringa. It sounds like a song.

Rhonda Patrick:

It's with a K. I know, it does. But for people also listening who are like, "Well why would I do that?" I mentioned the glutathione in the brain, I mentioned it in plasma, it's been shown to 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 of Nrf2. And I know you're familiar with Nrf2, but Nrf2 is like your transcription factor. It is binding to a little specific sequence in a variety of different genes and it's 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 airborne carcinogens like benzene. So benzene is found in air pollution, cigarette smoke. If you're smoking cigarettes still, please try to quit.

Andrew Huberman:

Yeah, you're mutating your DNA. To say nothing of the lung cancer, you're mutating your DNA.

Rhonda Patrick:

And heart disease risk, heart disease risk. But anyways, this has been repeated in more than one study, that literally after 24 hours of taking ... I can't remember off the top of my head what the dose of sulforaphane from broccoli sprouts extract was. Not the seed, it was the sprouts. Anyways, they started excreting like 60% benzene and acrolein. I mean, that's something that we get in cooked food.

Andrew Huberman:

It's coming out in their urine?

Rhonda Patrick:

Coming out in their urine. Yeah.

Andrew Huberman:

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 deep diving on supplements since I was in my teens. This is fascinating and it brings it back to this question that we had before, and I appreciate that you've 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.

Rhonda Patrick:

And that our bodies were supposed to be getting that stress to have those pathways activated. I mean, this is conserved among different animals. 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. 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.

Andrew Huberman:

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, confront cold or confront heat or confront effort or hunger, have to exercise, essentially, in order to obtain these compounds. And then, those compounds are reparative.

Andrew Huberman:

Yeah, I feel that resembles the dopamine pathway. I always say there's nothing wrong with dopamine. People think about dopamine hits as bad or dopamine as 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.

Andrew Huberman:

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 different types of intermittent challenge and we are rewarded with particular compounds that are reparative, both for the challenge but then make us stronger. Hormesis really is, it seems, a case of what doesn't kill us makes us stronger. So, you mentioned-

Rhonda Patrick:

Can I add to that one thing you just said?

Andrew Huberman:

Please.

Rhonda Patrick:

Because this has been shown with, for example, sulforaphane in animal studies. You precondition, give the animal sulforaphane and then you expose them to hypoxia or some kind of ischemic stroke condition, whatever they do to induce that, and the sulforaphane, it basically protects that. Like, their precondition and their stress response pathways are primed. And so when they're then exposed to the ischemic stroke, their outcomes are so much better, so much better, than the animals that didn't get the sulforaphane 48 hours before, whatever it was. And this has been shown in multiple animal studies with sulforaphane, specifically in the brain. I know Dr. Mark Mattson; he's often thought of as the intermittent fasting king, but he's a neuroscientist and he did publish some work and talks about sulforaphane as well.

Andrew Huberman:

I'm really glad you brought that example up, because many of the questions I get on social media and elsewhere are about traumatic brain injury, and TBI 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 take a moment to editorialize, 90% or more of traumatic brain injury is construction work, at-home accidents ... Football players, 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.

Rhonda Patrick:

Yeah. So a couple of things there. One is that, I mean, traumatic brain injury, it's terrible, but it's so interesting because it's also literal real-time brain aging. You're able to accelerate it and understand. So when I think of traumatic brain injury, I think of so much overlap between Alzheimer's disease and dementia and these neurodegenerative diseases because there are a lot of similarities there. And I do think there's been some animal research with TBI and sulforaphane, mostly preconditioning rather than treatment. So again, it's like, well if you want a healthy lifestyle thing and you're a construction worker or you're, fill in the blank, that's going to ... I mean anyone that drives a car, you're at risk to some degree, right?

Andrew Huberman:

Or bicycle.

Rhonda Patrick:

Bicycle, yeah.

Andrew Huberman:

Around Stanford, 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 have a number of friends that have died. We know a number of people with traumatic brain injury. I'm not against cycling or cyclists, but it's a risky sport by any stretch. So in taking things like moringa 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, so those cells should be protected. Are there other cells of the body that could possibly gain protection from these pathways?

Rhonda Patrick:

Well, lungs for one, but just even in plasma cells. I mean, Nrf2 is pretty ubiquitously expressed. Liver. There's so many animal studies that have looked at all those things. I try to gravitate towards human ones because it's a lot more relevant. But I think overall, like I mentioned, DNA damage lower, 24 or 34% lower in human blood cells after broccoli sprout powder supplementation.

Andrew Huberman:

Wow.

Rhonda Patrick:

And I made a video on this years ago, 2016 maybe, and I think I have the references on there to exact amounts. I can't remember.

Andrew Huberman:

We can link to the video.

Rhonda Patrick:

It's kind of an old video, it was 2016. But I also had Jed on the podcast and he did talk about this. But it's also been shown in randomized controlled 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 that helps with treatment, but I do 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's any impact, and there is at least one preliminary study that glutathione is increased in the brain after humans are basically taking sulforaphane.

Andrew Huberman:

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.

Andrew Huberman:

We will get back to heat and cold and this theme that I tried to serve us, but I 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 kind of top three, your superstars of nutrients for the brain and body. Sounds like we've got one set, what would you put in alongside them?

Rhonda Patrick:

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 for alpha-linolenic acid. And then there's eicosapentaenoic acid, or EPA, and docosahexaenoic acid, which is DHA. Yeah.

Andrew Huberman:

I'm amazed you can pronounce two of the most difficult words to pronounce and spell right next to ophthalmology, which if you can spell it ... I know people who have appointments in ophthalmology departments that don't know how to spell ophthalmology. Little secret, there's an extra P in there.

Andrew Huberman:

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 are in marine sources. So fish, so sardines, cod, 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 is fish oil. I took some krill oil capsules, made me itch all over, so I stopped.

Rhonda Patrick:

Do you have a shellfish allergy?

Andrew Huberman:

No, I don't think so. I don't think so. I'm not a big fan of shellfish, but I'll have oysters every now and again, or shrimp or something and feel fine.

Rhonda Patrick:

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 phosphatidylcholine 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 eating krill, like we're talking about the foods-

Andrew Huberman:

Oh, I would never eat krill.

Rhonda Patrick:

Okay. Are we talking about the supplements?

Andrew Huberman:

Yes, I apologize.

Rhonda Patrick:

Okay. So, fish oil supplements.

Andrew Huberman:

Yeah, 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.

Rhonda Patrick:

Sardines are, yeah, they're awesome. Anyways, except for the-

Andrew Huberman:

Except for the taste.

Rhonda Patrick:

And for the potential contaminants. Mercury, I think, was one. No. Yeah, it was Mercury. And Joe was telling me that he used to eat ...

Rhonda Patrick:

Joe was telling me about, he used to eat ... Joe Rogan was telling me that he used to eat sardines every day. Then he had really high mercury levels, and I was really shocked because sardines are low in the fish groups. The higher up you get, like swordfish and sharks, really high mercury because they're eating all the other fish. Right? But I think some brands, and if you look at ConsumerLab, ConsumerLab, 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. You can look at some of their sardines and they have a list of ones that are pretty decent.

Rhonda Patrick:

But anyways, back to your question about fish oil supplements versus krill oil supplements. So, one of the major differences is that fish oil supplements, if you get a high-quality one, it's in a triglyceride form. You've got a glycerol backbone with three fatty acids and that's attached. Those are either DHA or the EPA. Or if you have a lower-quality fish oil supplement, then you have what's called ethyl ester form. Typically, the reason for that, 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 easier to leave it like that than re-esterifying it, which costs more money. So, you can get it in ethyl ester 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.

Andrew Huberman:

Would you see this on the packaging? Is it going to say it's in this ethyl form?

Rhonda Patrick:

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 higher end will market it like triglyceride form. It's not that ethyl ester is bad. It just means take it with food. So, one of the major prescription omega-3s out there is, both of them actually, Lovaza, which is a mixture of DHA and EPA, as well as Vascepa, which is a highly purified EPA, these are both prescribed by physicians to patients with hypertriglyceridemia. So, high triglycerides, among other things, I think, maybe dysregulation of lipids as well, but-

Andrew Huberman:

This is amazing for people. 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.

Rhonda Patrick:

Yes.

Andrew Huberman:

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. Here's a case where we're saying fat is not only good. It can be used to combat issues with fat metabolism. Then, fats are not just one thing. They're many things.

Andrew Huberman:

Anyway, I just want 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. And here we're talking about these omega-3s. Okay. The triglyceride form can be taken with or without food, and there's prescription forms. I don't know if I can get a hold of the prescription form unless-

Rhonda Patrick:

You have high triglycerides.

Andrew Huberman:

Or I have a friend with high triglycerides. No. It's illegal, folks. Don't share prescription drugs.

Rhonda Patrick:

Or you talk to your doctor and you say, I'm already taking this from ... I don't know how it works. Anyways.

Andrew Huberman:

What's the dosage that you recommend people get, one way or another?

Rhonda Patrick:

All right. Okay. The dosage that physicians prescribed for high triglycerides, for example, is four grams a day.

Andrew Huberman:

Four grams of EPA?

Rhonda Patrick:

Yes, of the Vascepa. I think Lovaza is also prescribed at four grams a day. You can get either of those from your physician. My father-in-law just got one of them prescribing it to use. We were buying our own omega-3 for years and years. It's like, hey, you can actually get this and health insurance can cover it. And it's really purified form, but you have to take it with food. That was the bottom line. I've totally gone on tangents, but you're asking more interesting questions, anyway.

Andrew Huberman:

But normally I ask about mechanism and then I talk about protocols. But in the-

Rhonda Patrick:

Or the why.

Andrew Huberman:

Or the why.

Rhonda Patrick:

We haven't gotten there yet.

Andrew Huberman:

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. So, here we're just raising the importance of omega-3s, and then we'll definitely get to the why and the underlying mechanism.

Rhonda Patrick:

Yeah, I think four grams is ... in fact, Bill Harris, Dr. Bill Harris, he's just one of the pioneers on omega fatty acid research. He was on our podcast last August. He was saying the reason FDA chose that was literally just because how much they could get people to take. It wasn't an upper end, like, this is ... anything above that is unsafe. That wasn't the case. I mean it was just purely cost and compliance. So, what they can get into a pill, the amount they can get, and how many pills they can get people to take.

Andrew Huberman:

I'm smiling because our good friend Satchin Panda at the Salk 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, 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, 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."

Andrew Huberman:

It was eight hours of feeding window plus some measurements, and time to walk into the lab, park the car, et cetera. So, the eight-hour feeding window that everyone holds so holy was actually just born out of this relationship between these two graduate students. 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 had been me, we'd all be intermittent fasting would mean eating 14 hours a day. That was a joke. Not a good one. But I just want to make clear I'm joking.

Andrew Huberman:

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 stuff. I think that's important for people to hear because so often we hear the eight-hour feeding window, four grams of EPA, 150 minutes of cardio. And it's really a question of what you can reasonably do in a study.

Rhonda Patrick:

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.

Andrew Huberman:

You split them?

Rhonda Patrick:

I do. I don't know if ... I don't think it's necessary. Not necessarily. I just happen to buy, I happen to get a certain fish oil supplement that separates them. Lovaza, Lovaza is a great one and it's all-in-one and it's easier.

Andrew Huberman:

What if someone doesn't have a prescription? So, I take over-the-counter fish oil. I know I feel better because I've done the experiment going on and off. I take them 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 slipperier and they're 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.

Rhonda Patrick:

Yeah. If you're asking for where do people get these fish oil supplements?

Andrew Huberman:

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 1,000 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 what's listed on the bottle, on the front of the bottle? Because my understanding is that we need to hit a threshold level of EPA in order to derive these important benefits.

Rhonda Patrick:

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. Then they also measure contaminants, so mercury, PCBs, dioxins, things that you'd find potentially in fish that were harmful to humans. 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. They're extremely prone-

Andrew Huberman:

Okay. Mine is in the cupboard. So, now I know.

Rhonda Patrick:

The shelf life is increased with lower oxidation.

Andrew Huberman:

No. It makes perfect sense.

Rhonda Patrick:

Right. Anyways, they measure that and I typically like to look for ... They give you a total oxidation number. It's called T-O-T-O-X. 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 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 2027 or something. So, I've gone through and found my top picks 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. It just takes some work.

Andrew Huberman:

No. I'm glad that you did the work. I'm going to put up a tweet every week with you tagged until this list is published online. Sorry, Rhonda, but I'm going to do it. I know it's very sadistic of me, but in service to the community and myself.

Rhonda Patrick:

And I chose five brands from each, and I try to choose. I tried to find one in Europe and one in Canada. So, there's a great selection of U.S. and other-

Andrew Huberman:

Great. No. Thank you doing that work. I don't want to do that work, and I trust you. I try and get two grams per day of EPA from supplementation. I'll now put it in the refrigerator. Mood is better. I 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 SSRIs, 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.

Andrew Huberman:

But the data, by my read, 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. Mental health issues are serious, but what other reasons, I'd love your thoughts on that, on the mental health part. Maybe you could tell us what are some things that getting two to four grams of EPA per day is going to help within our brain and the rest of our body.

Rhonda Patrick:

I actually published a paper back in 2015 about the role of omega-3 and vitamin D in depression, bipolar disorder, schizophrenia and impulsive behavior. Within that paper, doing background research, and this was a review article, by the way, I was just connecting dots because-

Andrew Huberman:

No. I'm going to grab that. I confess I don't know the paper, but I love quality reviews because the references therein are so useful.

Rhonda Patrick:

Well, there's a huge role for inflammation, the cause of inflammation and depression. And I think we did a short animated video on this, as well, years ago back when I was publishing that work, where people are injected with lipopolysaccharide. 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 lipopolysaccharide. It's basically the outer membrane of bacterial cells when bacteria die. So, when the immune cells in our gut come into contact with the bacteria, because we drank alcohol five days in a row or whatever, we release endotoxin, or something stressed us out.

Rhonda Patrick:

We release endotoxin into our body and that causes inflammation. 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, totally, the depressive symptoms versus the placebo. So, the placebo was saline control. This was a placebo control because obviously it's hugely important for depression. It ameliorated the depressive symptoms that was caused by lipopolysaccharide.

Andrew Huberman:

Amazing. And LPS, lipopolysaccharide is no joke. Years ago when I was working on thermoregulation, we would inject animals with LPS to induce fever. The vagus nerve registers the presence of LPS signals to these particular hypothalamic areas and cranks up body temperature, because basically it's a signal that the body is infected. Right? Amazing. I will continue with my two grams per day. Maybe I'll ramp it up to four. I'm not doing the DHA separately. There is DHA in the same supplement. Is that okay?

Rhonda Patrick:

Yes. 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-

Andrew Huberman:

Yes, go in the few.

Rhonda Patrick:

DHA, specifically, it's in phospholipid form. It's more bioavailable. Our bodies, if you're comparing exact quantity or concentration in triglyceride form versus phospholipid form, you will get more in your plasma cells or in your plasma with krill oil. However, krill oil supplements are so low dose, good luck getting two grams of omega-3 from krill oil. Also, oil supplements are notoriously rancid. I don't know, for whatever reason-

Andrew Huberman:

Maybe that's what made me itchy all over.

Rhonda Patrick:

I haven't found a good krill oil supplement. I pretty much stay away from it. If you smell it too, it just smells rancid. But the thing is, and I also published a paper on this back in 2019 or something like that, about DHA and phospholipid form getting into the brain through a different mechanism than DHA in triglyceride form. So, it's going through a transporter called the Mfsd2a transporter. And I think it's very relevant for people with an APOE4 allele. So, I kind of-

Andrew Huberman:

People with an Alzheimer's susceptibility.

Rhonda Patrick:

Right. Twenty-five percent of the population has an allele and a gene called APOE4. Basically, APOE4 is referred to as the bad version of it. This is something in our bodies. It's also in our brain. If people have one of these versions, if they got one from their mom or their dad, they have a twofold increased risk for Alzheimer's disease. If they get two, which is less common, I think it's 2% of the population or something has two alleles, but they have a ten or elevenfold increased risk of Alzheimer's disease. So, there is a role for phospholipid form DHA in their brain, but you also make phospholipid DHA inside your body. And you can do that by taking in more triglyceride forms. So, two grams is the magic number, I think.

Rhonda Patrick:

Back to the why for fish oil. 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 going to powerfully modulate the way you think, the way you feel, and the way you age. A variety of different types of studies 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, it's called the omega-3 index. This is actually the omega-3 level in red blood cells. So, red blood cells turn over about every 120 days. It's a long-term marker of omega-3 status.

Rhonda Patrick:

This is very different from 99.9% of any study you see or any lab that you go 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? I had fish. My omega-3 levels are great!" But did you eat fish like that every week, or was it 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 fasting blood glucose levels versus the HbA1C, which is like a long-term marker of your blood glucose levels.

Rhonda Patrick:

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. You're looking at people's lifestyles. But in the case of Bill Harris's work, he's measuring something. He is measuring omega-3 index and he's measuring the omega-3 index in people and then looking at their mortality risk, for example, or their cardiovascular disease risk. 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 difference there. They also have about a five-year increased life expectancy compared to people in the U.S. And that's-

Andrew Huberman:

Do you think that's mainly due to their fish intake, seafood intake?

Rhonda Patrick:

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, and I think it was Framingham study, where he looked at the omega-3 index in people that had a omega-3 index of 4% or lower, so close to what the 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. So, big difference there, right? Five years life expectancy.

Rhonda Patrick:

But here's the really interesting thing, Andrew. He also looked at smokers, and smokers and their omega-3 levels, and so he stratified it. Right? And he found smokers that had no omega-3 were the worst of all. It was just worst. We all know smoking is bad for us and will 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 it was they were doing to get them up to 8%, they had the same life expectancy as nonsmokers with the low omega-3 index.

Andrew Huberman:

Wow.

Rhonda Patrick:

Right?

Andrew Huberman:

Wow. That's amazing. It's also amazing to me that people still smoke cigarettes, but I see a lot of people vaping, and I know a lot of people consume cannabis. Has there been any studies specifically of vaping or people smoking marijuana and all-cause mortality?

Rhonda Patrick:

I haven't seen those. I haven't seen those.

Andrew Huberman:

They're 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. You mentioned that the data on pollution related to the plant compounds earlier. So, it's almost like these things again, are acting in a reparative way. Food-

Rhonda Patrick:

The omega-3s, they are resolving inflammation. They're blunting inflammation. They're doing so many different ... They affect so many different parts of the inflammatory pathway, which is ... I think it 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. So, it's amazing. It's not-

Andrew Huberman:

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 want to 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 is Argentine, but I don't eat very much of it. I try and eat high-quality meats in relatively limited amounts, but I do eat pretty often. But I've been told by these sources of 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, because you're telling me that a lot of this omega-3 is sequestered into the red blood cells. If I'm eating high-quality grass-fed meat and the grasses had omega-3s, do my steaks have omega-3s or no?

Rhonda Patrick:

There was a study published that compared conventional meat, so meat that animals are fed corn or soy or whatever it is-

Andrew Huberman:

Which is terrible, 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. Again, a joke. I read all the comments, but it seems to me that these animals have to 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.

Rhonda Patrick:

The meat, comparing the conventional meat to the grass-fed or pasture-raised cows or cattle, there were higher levels of alpha-linoleic acid. And ALA, 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 5% of conversion to EPA. Estrogen is a major regulator of making that more efficient. It makes sense because pregnancy, when your estrogen just goes through the roof, these omega-3 fatty acids play a very important role in brain development. So, women are supposed to be converting any ALA they can into the longer chain omega-3 fatty acids. Right?

Rhonda Patrick:

Estrogen does affect that. But I would say plant sources, if you're looking for the ALA, plant sources would be 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, they do make the DHA. That would be a better source for people that are vegetarian and vegan, rather than doing the flaxseed oil, because that conversion inefficiency, the enzymes that convert ALA into EPA and DHA, again, it's inefficient.

Andrew Huberman:

Then for people that eat fish, sardines, you said-

Rhonda Patrick:

Salmon.

Andrew Huberman:

... salmon, and you have to eat the skin, as I understand.

Rhonda Patrick:

You don't have to, but it's good.

Andrew Huberman:

It's rich with omegas.

Rhonda Patrick:

With the oil, yeah. The reason I say, I think the best would be wild Alaskan salmon versus the farm raised because the farm raised, again, they're feeding them corn. They're feeding them like grain and stuff.

Andrew Huberman:

Really?

Rhonda Patrick:

Then they give them astaxanthins. Astaxanthin is a carotenoid. It's the carotenoid that's in things like krill or crustaceans that make their red pigment.

Andrew Huberman:

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 and photoreceptors.

Rhonda Patrick:

Yeah. Well actually, the carotenoids themselves, so luteins, zeaxanthin, they're really good at sequestering singlet oxygen, which is damaging, right?

Andrew Huberman:

Right. Yeah. As we age, because the retinal cells, the cells of the eye are 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 that's a whole other podcast in story. There's some really interesting data now on the use of red light to try and trigger these pathways.

Rhonda Patrick:

I've seen some.

Andrew Huberman:

Glen, that's my good friend of many years and amazing scientist, Glen Jeffery's lab at University of College London. We should talk about that at some point, if not today.

Rhonda Patrick:

I saw that study, like 2020, was it?

Andrew Huberman:

Now they have a second study.

Rhonda Patrick:

Do they? They've gone ... okay.

Andrew Huberman:

Yeah, it's looking real.

Rhonda Patrick:

That's exciting.

Andrew Huberman:

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. Glen 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. 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.

Rhonda Patrick:

Fish oil is good for you.

Andrew Huberman:

I have fish tanks when I was a kid. No. Fish, unless it's in sushi form, I find it absolutely repulsive. And I don't know why. I probably have some mutation that-

Rhonda Patrick:

Raw fish is actually higher in mercury than cooked.

Andrew Huberman:

Okay. Well, that's good. Now I don't 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 getting.

Rhonda Patrick:

I eat sardines every day. My first meal, almost, is a can of sardines and an avocado with-

Andrew Huberman:

Avocado is good.

Rhonda Patrick:

I love it. With a little bit of lemon and then some little hot sauce.

Andrew Huberman:

Does Avocado have omega-3s?

Rhonda Patrick:

Avocado is very good in monounsaturated fat. It's not really high in polyunsaturated fat. Omega-3, really, it's either the DHA and EPA that's in the marine sources, fish, or it's the plant ALA source, which is the flaxseed or the walnuts.

Andrew Huberman:

It's rough. 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, but that's-

Rhonda Patrick:

The fish come out albino, the ones that they farm raise, because they don't eat any of the-

Andrew Huberman:

I'm joking. I don't want a genetically modified fish that tastes like a steak. Although, 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.

Rhonda Patrick:

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 ... 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%, the five-year increased life expectancy if we're comparing the two groups, was to supplement with at least two grams. It was about two grams a day. 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% ... 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 am almost 16% omega-3 index.

Andrew Huberman:

I was going to ask about testing. 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.

Rhonda Patrick:

Not the omega-3 index. Okay. So, the omega 3-

Andrew Huberman:

Sorry. I misunderstood. I thought you said in red blood cells. If I ate salmon two days ago, my omega-3 index is going to go up.

Rhonda Patrick:

No. That was plasma.

Andrew Huberman:

I misunderstood.

Rhonda Patrick:

That's okay. Most people are measuring ... 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. The phospholipids, it's in a phospholipid. Right? So, your phospholipids are carrying thing, these are lipoproteins, like they're carrying things like omega-3 and triglycerides and stuff and shuttling them around. The omega-3 index is actually in the red blood cells, and red blood cells take 120 days to turn over. 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 went up, because that's how long it takes for your red blood cell to turn over. The omega-3 index, Bill Harris has a company that he cofounded, is called OmegaQuant. And they measure the omega-3 index. They have a variety of different index tests. You can do a basic one or a little more advanced.

Andrew Huberman:

This is from a blood draw.

Rhonda Patrick:

It's a little blood spot thing, yeah. He uses money to funnel back into doing lipid research. He's out there doing all sorts of interesting studies on omega-3s. 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. Are we even measuring anything? 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? There's all sorts of problems with randomized controlled trials. I think that as scientists, we need to come together and make some progress. Let's all talk to each other. Let's figure things out. This test is out there. It should be used. It should be used not just by Bill's group, but everyone.

Andrew Huberman:

Well, 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. Basically now when I look at you, I think you are 16% omega-3.

Rhonda Patrick:

And dolphins are 19%. I'm almost-

Andrew Huberman:

Is that your goal? You're trying to get there?

Rhonda Patrick:

It is.

Andrew Huberman:

Interesting. Actually, they should probably do something where you're trying to achieve the omega-3 ratio of 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'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? What are some of the purported, reported, and known mechanisms?

Rhonda Patrick:

I think some of the most well-known-

Andrew Huberman:

Mechanisms.

Rhonda Patrick:

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, from the metabolites of like DHA, for example, resolvins play a role in resolving inflammation. You want your inflammatory response to be activated when it's supposed to be, but you want to resolve that inflammation in the inflammatory response in a timely manner. And resolvins help do that.

Rhonda Patrick:

So, resolvins are one. And then there's these specialized pro-mediating molecules, the SPMs, that also help resolve the inflammation. There's, like you mentioned, the leukotrienes and prostaglandins, and these things are being affected by EPA, and they do affect platelets and platelet aggregation, and they do affect that whole pathway as well.

Rhonda Patrick:

So, I think there's just so many different ways and inputs. When we talk about inflammation, honestly it's a big general term, but you're talking about, when you're talking about serotonin release at the level of neurons, 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.

Rhonda Patrick:

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.

Rhonda Patrick:

And then 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 our cells, including neurons, are affected by the membrane fluidity, 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 'cause I'm not a neuroscientist.

Andrew Huberman:

No, but it makes perfect sense. I mean, we know, for instance, neuroplasticity 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 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 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. What's that gooey stuff that kids play with? It's like that goo.

Rhonda Patrick:

Oh, yeah. Um.

Andrew Huberman:

Anyway, there's a, it's disgusting and it's too soft to be a membrane for a neuron. That's what we know.

Rhonda Patrick:

You get it in those machines, like claw machines.

Andrew Huberman:

Someone put 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.

Rhonda Patrick:

It's a balance.

Andrew Huberman:

It's a balance. 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 are food sources of DHA that you find particularly attractive either by taste or by 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 want to make sure that I'm getting enough DHA, what do I need to be sure I'm eating on a regular basis?

Rhonda Patrick:

Well the fish is packaging the DHA and EPA in ratio.

Andrew Huberman:

Right, Okay.

Rhonda Patrick:

But I also do eat salmon roe, which is very salty, and it's a really high source of the phosphatidylcholine DHA that we talked about-

Andrew Huberman:

This is fish eggs.

Rhonda Patrick:

It is.

Andrew Huberman:

Yeah.

Rhonda Patrick:

And actually-

Andrew Huberman:

That I like for some reason.

Rhonda Patrick:

Oh do you?

Andrew Huberman:

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 I like eating embryonic fish. I just don't like eating the actual fish.

Rhonda Patrick:

Okay, well ...

Andrew Huberman:

Okay, so fish eggs are okay, so caviar basically.

Rhonda Patrick:

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. It's actually really good ... There's been some animal studies in piglets, and rodents as well, showing that consuming phospholipid DHA during fetal brain development gets 10 times more DHA in the brain. Again, it's-

Andrew Huberman:

Makes sense based on fetal development. So do I need to buy beluga caviar? Stuff can get pretty expensive at $200 a tin?

Rhonda Patrick:

I don't think you need to.

Andrew Huberman:

Okay.

Rhonda Patrick:

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 going to get phospholipid form anyway, because your body's going to make it.

Andrew Huberman:

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'd put the fish egg on the thing. That's probably not good.

Rhonda Patrick:

No.

Andrew Huberman:

Although it's good enough for the fish apparently.

Rhonda Patrick:

Yeah.

Andrew Huberman:

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.

Andrew Huberman:

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?

Rhonda Patrick:

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, it's a very, there's a sliding scale on how efficient that process is.

Andrew Huberman:

And it's, 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?

Rhonda Patrick:

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, 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.

Rhonda Patrick:

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 six times as long as someone with none of that natural sunscreen.

Rhonda Patrick:

I think the take home there is 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, these equatorial regions where there's, you tend to see darker skin because it's protection from the burning rays of the sun.

Andrew Huberman:

It's an adaptation. Yeah.

Rhonda Patrick:

They are in the sun more.

Andrew Huberman:

Right. Yeah.

Rhonda Patrick:

And they're getting more vitamin D. But people that maybe moved to the United States to Minnesota or in a place where UVB radiation isn't getting to the atmosphere 12 months out of the year, it's only getting there 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 cubicle, whatever.

Rhonda Patrick:

So, supplementation does play a major role, not only for people with darker skin that aren't outside all the time, but for everyone. Seventy percent of the U.S. population has inadequate vitamin D levels. Seventy, of the whole U.S.

Andrew Huberman:

Amazing.

Rhonda Patrick:

So this is everyone. And so I think that insufficient level is defined as less than 30 nanograms per milliliter. And that's sort of defined by the endocrine society, looking at a lot of different aggregate studies and all-cause mortality, for example. There's been a lot of different meta-analysis of all-cause mortality studies where vitamin D levels are really, seem to be ideal between 40 to 60 nanograms per milliliter. In order to get to that level, if you are not outside all the time, live 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. But also skin cancer is somewhat of an issue as well.

Rhonda Patrick:

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. 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. They are specific sequences of DNA that this complex 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. Imagine 70% of the population having insufficient testosterone. Right? It's a steroid hormone.

Andrew Huberman:

Which we might be headed there, but probably not. No, I think that it's ... 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.

Andrew Huberman:

I also, I'm glad that you're mentioning skin as the major kind of 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.

Andrew Huberman:

There's this beautiful study out this last year where, this took place over in Israel, where they had people get outside for 20 or 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 keratinocyte-linked pathway involving p53.

Andrew Huberman:

They did a bunch ... 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.

Andrew Huberman:

So when vitamin D gets into cells and it's binding to these VDREs, what sorts of things are they triggering? So for testosterone, we know it's going to trigger protein synthesis, muscle growth, tendon strength, et cetera. With estrogen it's going to be keep your neurons 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's vitally important for males and females. When vitamin D gets into cells, what sorts of things is it stimulating?

Rhonda Patrick:

Okay, so first of all it's regulating more than 5% of the protein encoded human genome. More than, 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. Basically I found that tryptophan hydroxylase 1 and tryptophan hydroxylase 2 was on there.

Rhonda Patrick:

Then I started looking at the sequence, and I was doing some in silico work. And it turns out that the VDREs in tryptophan hydroxylase 2 ... So for people listening, tryptophan hydroxylase is an enzyme that converts tryptophan into serotonin.

Rhonda Patrick:

Tryptophan is an amino acid that we get from our food. You convert serotonin, you convert tryptophan into serotonin 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.

Rhonda Patrick:

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. The 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 kind of look at that and think, oh, maybe this and that.

Rhonda Patrick:

Since then there have been some groups that have confirmed more with in vivo and or in vitro studies. Mine was all in silico 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, that's water retention. I mean bone, of course, homeostasis 5% more than 5%. I mean I can't tell you, like, so much.

Andrew Huberman:

And with 70% of the U.S. population deficient, I'm beginning to think that this could be the linchpin on a number of really important issues. Supplementing vitamin D3 is what I normally hear is the ... And that's, I do. 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 and they're in range.

Andrew Huberman:

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 low, 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, it's 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.

Andrew Huberman:

Which is, to me, it's striking because they eat quite well, they're a healthy weight, et cetera. And 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?

Rhonda Patrick:

So vitamin D3 is a good way to supplement with it. There, vitamin D2 would be a plant source. You often find it fortified in foods like milk, it's usually D2. There's been a few.

Andrew Huberman:

Does anyone still drink milk besides kids?

Rhonda Patrick:

People, I mean-

Andrew Huberman:

Out here it's like you can't find cow's milk.

Rhonda Patrick:

Oat milk.

Andrew Huberman:

You get oat milk, oat milk, soy milk.

Rhonda Patrick:

I mean all the lattes that you're getting. Yeah.

Andrew Huberman:

What's the other one?

Rhonda Patrick:

Yeah. They're fortified in those as well.

Andrew Huberman:

Okay. Oh they are, okay.

Rhonda Patrick:

They are, yeah. They're fortified in almond milk.

Andrew Huberman:

I have a hard time finding cow's milk. Okay.

Rhonda Patrick:

And oat milk and all that stuff. Yeah, they're in all that stuff.

Andrew Huberman:

Okay.

Rhonda Patrick:

Vitamin D is naturally to some degree in fatty fish. You know, you think about cod liver oil, right? It's like it has vitamin D, but it's not, you're not going to correct a deficiency with eating fish for your vitamin D. 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 doing that, converting vitamin D, making vitamin D3 in your skin.

Andrew Huberman:

Well that's probably what was going on here. Cause this person is getting up in their age.

Rhonda Patrick:

There's a lot of single nucleotide polymorphisms ... We talked about APOE4 previously, but there's a variety of genes that people have. Very common actually. In fact, I've had many people that have done that exact same thing.

Rhonda Patrick:

Measuring your vitamin D levels before and after supplementation is the only way you're going to figure that out. Very important. If you don't measure it, you don't know, you can't know what you don't measure.

Rhonda Patrick:

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. These are studies where people, 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 sizable 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 factors.

Rhonda Patrick:

So, vitamin D and SNPs that basically make the conversion of vitamin, either vitamin D precursor into D3, or in D3 into 25 hydroxyvitamin D or into the active steroid hormone, which is 125 hydroxyvitamin 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 if they have it, they have low vitamin D. Okay? So it's really a way of doing a beautifully randomized controlled trial with an observational study because you're not biased.

Rhonda Patrick:

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 they're supplementing. So you always have to worry about that when you're doing an observational study. But when dealing in randomization, its beautiful for that reason where you now just, random, people randomly have these genes and it's not like there's no health status. If you have the SNP like your friend, your family member was healthy and all that, they were healthy and yet they couldn't get their D levels up. Right?

Rhonda Patrick:

So these Mendelian randomization studies have found that people that can't convert into the precursor, the 25 hydroxyvitamin 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 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.

Rhonda Patrick:

So, to me ... Now why did I get on this rant? Oh, because your family member. So basically they also are more likely to get multiple sclerosis. This has all been done with Mendelian randomization.

Rhonda Patrick:

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, if you ask him to do it.

Rhonda Patrick:

Supplementation wise, typically if you don't have one of those SNPs, for the most part, taking 1000 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 40, you're going to need at least 4,000 IUs if you're normal, don't have any of these SNPs that change your metabolism of vitamin D. Right?

Andrew Huberman:

Does it matter when you take it relative to sun exposure, time of day, with or without food?

Rhonda Patrick:

I've seen some not-so-great preliminary evidence suggesting maybe time of day is important. I don't think it real ... I can't seem to find anything that really suggests ... Because for it to actually be converted into the hormone, I mean it's stored in fat. It's like-

Andrew Huberman:

It's slow acting. The steroid hormones are slow acting.

Rhonda Patrick:

Yeah, it's not like an immediate thing. Right. So, maybe we'll get some new data that's otherwise, but I just don't ... Yeah.

Andrew Huberman:

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. And I realize that's a bit of a coarse way to approach it, but I feel fine and I'm still breathing and 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.

Rhonda Patrick:

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 hundreds of thousands of IU a day for a long time. So-

Andrew Huberman:

Hundreds of thousands.

Rhonda Patrick:

Yes. Yes.

Andrew Huberman:

Yeah. Okay.

Rhonda Patrick:

Now the upper tolerable intake was set by the medicine institute to be 4,000. It was just the safe, it was kind of 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 mil. 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-

Andrew Huberman:

I'm glad you brought up the fact that you keep arms exposed if you, 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?

Andrew Huberman:

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 seems to me that the more of your body surface that you can safely and appropriately, please folks, appropriately expose to the sun, the more vitamin D you're going to create. Right?

Andrew Huberman:

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.

Rhonda Patrick:

Absolutely.

Andrew Huberman:

Right. Okay.

Rhonda Patrick:

Yeah.

Andrew Huberman:

Okay. 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 an interface to create these hormones. So surface area matters.

Rhonda Patrick:

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. 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 human genome.

Rhonda Patrick:

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 as a complex and you 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 determine what effects there will be with no vitamin D. Right? How do you study no vitamin D? What was found was that these animals, and in fact I don't think it was a complete knockout or 'cause I think it might be embryonic lethal, but-

Andrew Huberman:

Some hypomorphic ...

Rhonda Patrick:

Yes.

Andrew Huberman:

Which is basically geek speak for a gene is vastly reduced in its number and function. Number. People know what I mean, but isn't eliminated completely.

Rhonda Patrick:

Yeah, right. Well these animals, 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 wrinkled, they have no hair. I mean their life lifespan's shorter. I mean 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 life spans are only like two and a half years, but like 500 years old.

Andrew Huberman:

Looks like it went to graduate school twice.

Rhonda Patrick:

Yeah.

Andrew Huberman:

Actually graduate school's 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, it's remarkable.

Andrew Huberman:

I think it's, I'm definitely going to try and get my omega-3 percentage up there. I'm not going to hinge it all on that. But clearly you're doing a lot of things right.

Andrew Huberman:

If I'm taking vitamin D3, I still need to get out into the sun. Correct?

Rhonda Patrick:

Absolutely.

Andrew Huberman:

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. It's like, "I take my vitamin D so I don't need to get outside as much."

Andrew Huberman:

I think people are really afraid of getting out into the sun because they're worried about melanomas. And I'm as, to be honest, I'm as scared of sunscreen as I am of melanoma. Like that, some of the things in sunscreen are really spooky, mainly the compound. And, here, I'm not one of these conspiracy ... I drink tap water, listen folks. People cringe with ... I drink tap water, I have the occasional croissant or donut. I'm not, you know, I'm 90%, 80% 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.

Rhonda Patrick:

Titanium dioxide?

Andrew Huberman:

Dioxide, some of the triclosans that are also in these cleansers. I mean it's once you know a little bit about neurons folks, you realize that the neurons you got are basically the ones you've got for your entire life. There's a reason why there's a blood-brain barrier, a blood ovary and a blood testes barrier, is 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. And 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.

Rhonda Patrick:

I've always geared towards the ones with the minerals that are reflecting. It is somewhat difficult to penetrate things all the way through the skin into the, get into the bloodstream. I don't, but I don't know, maybe some of these compounds get in there easily. I have seen the evidence with some of those things.

Andrew Huberman:

They go, there is some evidence they go transdermal and they, you know, they get in.

Rhonda Patrick:

They get in? Okay, well I know that they're, 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 carcinogen. I mean it's the very thing you're trying to protect yourself from might actually cause.

Andrew Huberman:

Right.

Rhonda Patrick:

We don't know. I mean it's completely speculation. But there is, I think, some more and more evidence coming out with some of those compounds. And I can't remember all of them off the top of my head. But a lot of high-end ones also have, it's the chemical sunscreen ones.

Andrew Huberman:

Right.

Rhonda Patrick:

The chemical ones.

Andrew Huberman:

Right. We should do, I'm proposing that we do a journal club. A journal club folks, is where academics get together and read 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 most studies people are doing their best within the context of what they can do. But 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. I mean people are using them like crazy.

Andrew Huberman:

I'm not one of these people who's like, "Oh. I won't use commercial toothpaste," or anything like that. 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.

Andrew Huberman:

Anyway, we're speculating now.

Rhonda Patrick:

Wear a hat.

Andrew Huberman:

Wear a hat. But get out in the sun and get your D3 levels up.

Andrew Huberman:

Okay, so 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 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 take full responsibility for that. But before I do that, I just want to offer you the opportunity, is there anything that ... to supplement-based or food-based compounds that you think are especially useful for brain and or body health?

Rhonda Patrick:

I do think magnesium is important in there as well. I mean, I think again, about 40% of the U.S. population doesn't get enough magnesium. It's an essential mineral we're supposed to be getting from our diet. And-

Andrew Huberman:

It's involved in everything.

Rhonda Patrick:

It is. 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 hydroxyvitamin 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.

Rhonda Patrick:

Now, magnesium's also involved in making ATP, the energetic currency of our cells. Basically all of our cells need ATP to do anything. And 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 an 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?

Rhonda Patrick:

But 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 is happening every day. But we repair that damage. We have repair enzymes in our body called DNA repair enzymes. They require magnesium.

Rhonda Patrick:

Magnesium is a cofactor for them. What that means is a cofactor means enzymes need it to function properly. And so without that cofactor, they're not doing it properly.

Rhonda Patrick:

The way I like to think about magnesium, it's easy to, 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. It's one of the ... And people, basically, what is the 40% insufficiency in the U.S. 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. 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 sulforaphane. Right?

Andrew Huberman:

As with broccoli, do I need to eat the dark leafy greens raw? And 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, I'm not-

Rhonda Patrick:

Yes. It's high in lutein and zeaxanthin, as well.

Andrew Huberman:

No, I'm going to try chromat ... meaning I'm not colorblind, but I just want to make sure it falls under the strict category. Yes. Cause every once in a while I'm like, "Oh, I eat my vegetables. I like avocados." And people remind me avocado's not a vegetable.

Rhonda Patrick:

Right.

Andrew Huberman:

I love vegetables also, but so kale, what are some other examples? And-

Rhonda Patrick:

Kale, spinach, chard, like Swiss chard, Rainbow chard, Romaine lettuce.

Andrew Huberman:

Is the bitterness an important component to this?

Rhonda Patrick:

For magnesium, no. But for sulforaphane, for cruciferous vegetables. That would be the brassica family.

Rhonda Patrick:

... vegetables. That would be the Brassica family. But your question about cooking them, so magnesium, 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.

Andrew Huberman:

You drink the ... No drink.

Rhonda Patrick:

Yeah. I personally don't worry about it. I just don't worry. I think-

Andrew Huberman:

Okay, great. Well, if you don't worry, I'm not going to worry.

Rhonda Patrick:

But I too supplement with magnesium ... I do take a round of ... So supplementation with magnesium, I mean, we could go on and on. Let's keep this short and sweet because we're going to get back to the other stuff. But it can cause GI distress at high doses. I personally like to take around 130 or 135 milligrams. That way, it's not like a huge bolus to my gut.

Andrew Huberman:

But I think it depends on the form of magnesium too. Right?

Rhonda Patrick:

Yes. Yeah. I mean, you can take magnesium threonate, for example, and it isn't as effect ... It doesn't affect the gut as much.

Andrew Huberman:

Magnesium citrate-

Rhonda Patrick:

Citrate is what I take.

Andrew Huberman:

Is the pretty-

Rhonda Patrick:

I take-

Andrew Huberman:

... is pretty potent gut stimulus. I mean, I feel like it's a little bit harder to take that.

Rhonda Patrick:

Well, I take a hundred ... 135 milligrams should be pretty good. And citrate actually ... Oh boy. Do we want to go here?

Andrew Huberman:

Sure. I mean, it's up to you and we don't have to ... Personally, I've been supplementing with magnesium for a long time. I use threonate and bisglycinate and malate for different reasons. So yes, I would love to go there if you're willing.

Rhonda Patrick:

I would say malate would be the best. And that has to do with the short chain fatty acids being good for the gut, and a lot of work done by a former colleague of mine and good friend, Mark Shigenaga, showing that the short chain citrate, malate, lactate, but specifically malate, really, and lactate are the major ones that get into the gut epithelial cells and are an energy source for the mitochondria and the goblet cells. So anyways, whole other topic.

Andrew Huberman:

That's okay. Yeah, I take malate 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 GABAergic pathway, neurotransmitter folks, that, in general, broad sweeping generalization here, can have somewhat of a sedative quality, which is why I take magnesium threonate and/or bisglycinate before sleep, 30 to 60 minutes before sleep.

Andrew Huberman:

Definitely enhances my transition time to sleep and the depth of sleep, no question in my experience. There's some data that threonate can be neuroprotective. Although those studies are still ongoing. I'm getting the sense that maybe you're a little more skeptical of that than I am.

Rhonda Patrick:

Yeah. No, I've seen the studies with the threonate. 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.

Andrew Huberman:

Right.

Rhonda Patrick:

Right?

Andrew Huberman:

Yeah. I'm thinking that paired with the ... There's some work-

Rhonda Patrick:

The animal steps. Yeah.

Andrew Huberman:

Hua-song Liu's work on ... So this is getting into inside ball of neuroscience, that the quality of the labs matters, folks. And that's something that's not accessible to people outside of fields. And Hua-song Liu and some of the other folks at that time at MIT did ... I think very highly of their work.

Andrew Huberman:

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 figure that given the safety profile of mag threonate, given that it helps me sleep better and sleeping better is just better for everything, frankly, that's why I take it.

Andrew Huberman:

And bisglycinate and threonate seem to be somewhat interchangeable. But I don't know of any reports that bisglycinate can be neuroprotective. But malate, I take during the daytime. For me, and 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.

Rhonda Patrick:

Malate, again, the short chain fatty acid and, I mean, when you do heavy ... 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 Shigenaga showing, this is all in animal research, by the way.

Rhonda Patrick:

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's awesome and I always try to eat green apples. They're really high in malic acid.

Andrew Huberman:

Oh, good to know.

Rhonda Patrick:

And tart cherries. Tart cherries are really high in it as well. So-

Andrew Huberman:

Yeah. They also tastes really good.

Rhonda Patrick:

But I was really interested in the magnesium threonate stuff. I take a supplement called Magnesi-Om by Moon Juice 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 of fluids before I go to bed.

Rhonda Patrick:

And it has magnesium threonate and a variety of other versions of magnesium in it as well, and I really like it. But I thought the magnesium threonate 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?

Andrew Huberman:

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," that there's some people that are perfectly comfortable with data from a mouse study.

Andrew Huberman:

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 saying, "You know what? I don't even care what you do. Just tell me what to do."

Andrew Huberman:

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.

Andrew Huberman:

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 talk-

Rhonda Patrick:

I take it with the hope of, because I feel like the animal data is very promising.

Andrew Huberman:

There you go.

Rhonda Patrick:

And so I'm like, "It probably is. So why not?"

Andrew Huberman:

And obviously, you're doing things. 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 ... And I keep waiting for the intermittent sleep deprivation movement.

Andrew Huberman:

I will say I pull a few all-nighters per year just for work demands and procrastination and deadlines. And 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 use sleep deprivation for that.

Andrew Huberman:

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?

Rhonda Patrick:

No. Credit Dr. Mark Mattson.

Andrew Huberman:

Okay. Dr. Mark Mattson.

Rhonda Patrick:

Who has published and he has used that-

Andrew Huberman:

Used those words, oh, that phrase.

Rhonda Patrick:

Yes.

Andrew Huberman:

Okay, great. We'll make sure.

Rhonda Patrick:

Just like Dr. David Sinclair. I love the xenohormesis. It was in one of his publications just so many years ago and I just love it. It's brilliant, a brilliant term. So Mark Mattson gets the credit for that.

Andrew Huberman:

Those Harvard 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 what I call deliberate cold exposure only to distinguish it from cold that you might just be accidentally exposed to.

Andrew Huberman:

But it's sort of obvious when we say cold exposure. There's 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, it was four degree, four-

Rhonda Patrick:

Forty-nine degree Fahrenheit.

Andrew Huberman:

Forty-nine degree Fahrenheit. I was translating to Celsius, but 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.

Andrew Huberman:

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/mood effects, brown fat stimulation, which, of course, weaves back to metabolism?

Andrew Huberman:

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?

Rhonda Patrick:

So today, I did three minutes at 49 degrees Fahrenheit. I have a cold tub.

Andrew Huberman:

So you get in up to your neck?

Rhonda Patrick:

Well, I try. I keep floating up and so it's like really hard. So I would say maybe most of my shoulder. 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-"

Andrew Huberman:

Or too much salt in there. Is it like the Dead Sea where you float on top?

Rhonda Patrick:

Is there salt in there? I don't know. He takes care of all the stuff that ... It's the Plunge.

Andrew Huberman:

But yeah, they make ... Then, 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.

Rhonda Patrick:

It does.

Andrew Huberman:

Which makes sure that you break up the thermal layer and it's even colder.

Rhonda Patrick:

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.

Rhonda Patrick:

I love doing the sauna. I mean, 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.

Rhonda Patrick:

And so the 20 seconds at 49 degrees, I think it was 49 degrees Fahrenheit, was really a good number because time and temperature do ... Time or duration, I guess would be a better word, and temperature do matter. But 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. It was like two, three, four. But who wants to do one hour-

Andrew Huberman:

Yeah. I'm familiar with that study.

Rhonda Patrick:

... at 69-

Andrew Huberman:

I love ... So this really reveals just how absolutely nerdy I am and maybe why some times and relationships in my life were challenged. I love reading the methods sections of papers. So people can come at me with a number of things about papers and I might miss something. Surely, I miss certain things like anybody does.

Andrew Huberman:

But the methods, I relish in reading the methods. And that paper's really interesting because they had people sit in lawn chairs basically in swimming pools, so for an hour. And it wasn't real ... It was chilly, it wasn't super cold. I mean, 60 is not ... It's not warm, but it's not ice cold, obviously. But an hour is ridiculous at some level.

Andrew Huberman:

But the increases in dopamine were massive and lasted hours. So the mood-enhancing effects that you report, you're not imagining that. Those are almost certainly the consequence of having slowly elevating but significantly elevated dopamine that goes on for hours.

Andrew Huberman:

That's almost a dreamlike profile for dopamine because most everything else, like an Adderall, a Ritalin, a cup of coffee and a workout drink, or preworkout 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.

Rhonda Patrick:

Well, I need to get doing it more. I've had a couple of scary experiences going from hot to cold where-

Andrew Huberman:

Can you explain? Yeah.

Rhonda Patrick:

... blood pressure changes, I think, where I basically went straight from a really hot Jacuzzi. I was in there for 30 minutes. I mean, I was doing heat ...

Andrew Huberman:

Jacuzzi. Okay.

Rhonda Patrick:

Yeah, 104 degrees Fahrenheit.

Andrew Huberman:

That's toasty.

Rhonda Patrick:

And then ... For 30 minutes. And then I went straight into, at the time it was our pool, it was in February, it was like wintertime and it was 50. It was in the 50s. It was cold. And I was in there and I was listening to Simon & Garfunkel.

Rhonda Patrick:

I was trying to stay in a long time, get on my cold and I was trying to impress Dan because he goes in there for ... He'll stay in there for 15 minutes.

Andrew Huberman:

Wow.

Rhonda Patrick:

But I started to feel really blinky, low blood pressure or something and I got scared, so I got out. And then I couldn't stand. I had vertigo or something and I was so scared, was so scared. And I've had a couple of times too where just going straight from the sauna to it, to the cold plunge where I'm starting to feel ... I'm like, "Ooh, I feel a little blood pressure change or something."

Rhonda Patrick:

And it makes sense. The sauna is causing vasodilation and the cold plunge or cold exposure is causing vasoconstriction. So it's a very just shock to my system. And so now, I wait. I wait a few minutes before going in, but I do need to make the cold more routine. Because I talk all about the science, I'm familiar with all the science.

Rhonda Patrick:

And the norepinephrine, or noradrenaline, it's affecting brain and mood and you know way more about that than I do. I know how I feel and I know it's a neurotransmitter, and 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 that it's released from the cold in the brain.

Andrew Huberman:

And now in humans as well.

Rhonda Patrick:

Oh, in the brain, they found-

Andrew Huberman:

So in that study, that's the ... We can put a link to this. It's published in 2000, European Journal of Physiology, that big dopamine increase. They also looked at epinephrine and cortisol and saw some really ... Yeah, so this has been done in humans.

Rhonda Patrick:

They did brain. Oh, I didn't know.

Andrew Huberman:

Oh, no, no, not yet.

Rhonda Patrick:

The plasma.

Andrew Huberman:

No.

Rhonda Patrick:

Yeah, yes, plasma.

Andrew Huberman:

Yeah, very hard to measure dopamine directly from the brain unless you're doing microdialysis. No, 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. It's a very real effect.

Andrew Huberman:

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 some of the effect.

Rhonda Patrick:

But I want to be cold-adapted because that means I have more mitochondria in my adipose tissue and perhaps even muscle. That's been shown.

Andrew Huberman:

So maybe there's a good opportunity to ... So cold and UCP-1, if you could educate us on UCP-1, I find this really interesting, and I learned about it from you. So-

Rhonda Patrick:

Yeah. So norepinephrine actually released in the plasma, it does act as a hormone. Vasoconstriction is 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 ... Shivering is a very inefficient way to produce heat, which is what your body's trying to do when it's exposed to cold.

Rhonda Patrick:

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, way to do it is to basically have your mitochondria produce tons and tons of heat. So the way it does this is by activating a gene called UCP-1, uncoupling protein 1, norepinephrine is upstream of that, activating it.

Rhonda Patrick:

So what that does is essentially ... So mitochondria are these little organelles inside of your cells that are responsible for producing energy. Usually, that's in the form of adenosine triphosphate, ATP, and that's what lets everything function inside of your body, from your neurotransmitter production to your heart beating, et cetera

Rhonda Patrick:

However, you can uncouple your mitochondria. Basically, your mitochondria, they're like a little battery. So they have ... Well, they have a double membrane, first of all, they're structured. 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 the inside part.

Andrew Huberman:

Like a neuron.

Rhonda Patrick:

Like a neuron. Yeah.

Andrew Huberman:

Yeah, cool.

Rhonda Patrick:

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 the mitochondria and your mitochondria freak out. So this is called uncoupling it. And they start to ... It's maximum respiration, as we call it.

Rhonda Patrick:

They try to make as much energy. They're like, "I got to get that proton back, that gradient, the electrochemical gradient." And so they just go insane. And in this case, it's uncoupled energy. So the energy they're making is actually heat, not ATP, but heat is ... But you're essentially burning substrate, so who cares?

Rhonda Patrick:

You're burning glucose, you're burning your lipids, 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. And 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.

Rhonda Patrick:

And another type of adaptation that occurs is you actually produce more mitochondria in your adipose tissue. And that actually happens, also regulated by norepinephrine or noradrenaline, through a protein called PGC-1 alpha. And what that protein does is it makes more mitochondria in your adipose cell. So per adipose cell, you're getting more mitochondria.

Rhonda Patrick:

It's a beautiful way to basically make more heat when you're ... It's one of those things where it's, like it's 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 the browning of fat.

Rhonda Patrick:

And the reason for that is because if you look under a microscope at a lipid drop, basically a fat cell ... not a lipid drop, an adipocyte, 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. There's this whole ... I'm sure you've had experts on that talk all about that.

Andrew Huberman:

No, not yet. I mean, I always think of white fat, beige fat, brown fat, and beige just kind of intermediate. White can be converted into beige but-

Rhonda Patrick:

Right, and beige can take on thermogenic characteristics essentially. And so you can activate beige fat so that it's thermogenic in the sense that it's burning glucose and/or fatty acids and producing heat. So the more you expose yourself to cold, the more you can brown your fat, so to speak.

Rhonda Patrick:

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'll get a lot of naysayers out there saying, "Oh, brown fat doesn't regulate metabolism at all."

Rhonda Patrick:

And the reality is there's thousands of researchers trying to pill up brown fat and thermogenic ... They're trying to make it a pill because it does affect metabolism. It's not the only thing. Certainly if you're obese and trying to lose weight, you're not going to do that just by doing cold exposure. You need to do dietary and exercise changes predominantly, but it does affect metabolism.

Rhonda Patrick:

And this has been shown in human studies, so it is an interesting another ... 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 via norepinephrine, but it is still PGC-1 alpha. Interestingly, not that anyone else really cares but me, and maybe you do, Andrew.

Andrew Huberman:

I'm eating this up.

Rhonda Patrick:

So PGC-1 alpha is response to norepinephrine in 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 may have been men only that were exercising, did some separate training and then did cold water immersion, something like 50 degrees Fahrenheit, 15 minutes.

Rhonda Patrick:

And PGC-1 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 ... they're making energy in your cell. And we don't make more mitochondria normally. You have certain inputs. Extra high-intensity interval training exercise can do it.

Andrew Huberman:

Can actually make more mitochondria.

Rhonda Patrick:

Yes. And that's been shown in people. And I mean-

Andrew Huberman:

Weight training or just high-intensity interval training.

Rhonda Patrick:

I haven't seen weight training. I've seen it in high-intensity interval training, endurance training. But that doesn't mean that it hasn't been shown. I just haven't seen it or that it hasn't been looked at. So-

Andrew Huberman:

Good to 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. But-

Rhonda Patrick:

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.

Andrew Huberman:

Great place.

Rhonda Patrick:

And he did this 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.

Rhonda Patrick:

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, was ... I mean, it was enormous, at least 50%, I think.

Andrew Huberman:

Fantastic.

Rhonda Patrick:

So I mean, it was just like, "Whoa." And so why would you want that? Well, mitochondria ... You don't make your cell ... Your cells are turning over, you make new cells, you replace old ones. Well, your mitochondria, you don't really do that for the most part. You can. Mitochondrial biogenesis does happen, but you have to stimulate it to happen.

Rhonda Patrick:

And the way your mitochondria ... 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, mitochondrial DNA and then fizz back apart. And that's how they kind of stay youngish. But as you age, you keep doing that with the same pool of mitochondria, then you're going to get a bunch of old mitochondria mixing old stuff together.

Rhonda Patrick:

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.

Andrew Huberman:

Amazing.

Rhonda Patrick:

Other things as well.

Andrew Huberman:

No. 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 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.

Andrew Huberman:

I'm going to start doing some high-intensity interval training. Dr. Andy Galpin was on this podcast recently, and he told me that the subtle Zone 2 cardio and the weight training's great, but that I really should be doing some max heart rate work per week, going into max heart rate for 90 seconds and resting and repeating that, maybe even mild repeats.

Andrew Huberman:

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 interval 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?

Rhonda Patrick:

So it all depends on my week, of course, and what I've got going on with my son and my work schedule. But typically, I do a lot of high-intensity interval Tabatas on a stationary cycle. I use Peloton because I just like that instructor there telling me what to do and then me competing with everyone else. I'm like, "Ha!" You know. So it works for me.

Andrew Huberman:

You're revealing something about your psychology. This is good. We just learned about ... So this podcast is actually just a decoy for psychological assessment of the guest. No, I'm kidding. So now we know you're competitive. Good.

Rhonda Patrick:

Yeah.

Andrew Huberman:

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?

Rhonda Patrick:

So there's a bunch of people that are online either doing the class with you at the same time or have all time doing it, so you can just toggle on what you want and you can try to compete against the all-time number.

Andrew Huberman:

Oh, so it's really competitive.

Rhonda Patrick:

Oh, yeah.

Andrew Huberman:

Okay.

Rhonda Patrick:

And the instructor is just there to whip you, make you-

Andrew Huberman:

Wow.

Rhonda Patrick:

The brilliance with Peloton is ... I used to do Rush, what's called Rush cycle, and I used to go in ... It's basically you go in and group cycle and have an instructor there and you do all this high-intensity interval training stuff.

Rhonda Patrick:

And I loved it because there was a competitive aspect to it that had me working harder than I would work if it was just me in the room without an instructor or anyone there. And it was just like I'm at a gym, any gym and I'm just on a stationary cycle listening to a podcast, doing something, which is fine if that's your groove.

Rhonda Patrick:

But there is something about that group setting that holds you accountable too. And the Peloton made it somehow virtual. It was amazing. And I remember being back at Rush cycle, this is before pandemic, and people talking about Peloton in my class and I'm like, "Oh, that's ridiculous. Why would I do that? That's never going to work. I need to be here."

Rhonda Patrick:

And then the pandemic hit and I was all over the Peloton and it works for me really well. So I tend to do that at least three times a week. Sometimes I do it more. I'll do four, and I do a 10-minute, just 10 because it's efficient and I push my ass. I push myself really hard.

Andrew Huberman:

That's the Tabata.

Rhonda Patrick:

It's the 20 seconds on, 10 seconds off and it's 10 minutes.

Andrew Huberman:

And on means you're peddling like your life depending on it.

Rhonda Patrick:

You're maxing it, and-

Andrew Huberman:

And there's a lot of resistance in the pedals.

Rhonda Patrick:

Yeah, so you basically ... There's a part where you're ... I always do resistance. I'm like the power, I do the power for ... There's a part where you're sitting, cycling and you're trying to go really fast, but I always crank the resistance up. I always go above what they give me.

Rhonda Patrick:

And then there's a part where you're standing and then you really crank the resistance up, which I really do. And you feel it in your glutes and-

Andrew Huberman:

Like going up a hill.

Rhonda Patrick:

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. You get it done and people sometimes hear me go, "10 minutes? Oh, really? You think you work ..." I'm look like, "You do max, you do Tabata for 10 minutes and it's intense."

Andrew Huberman:

Most people can't sprint for the gate of an airplane they're about to miss carrying a backpack. So if I think about that, and then I ... I've just described myself sprinting through the airport and going, "All right, Andy Galpin, I got my 90 seconds max heart rate in for you, carrying this thing." But 20 seconds on, 10 seconds off, repeating that over and over for 10 minutes. So by the time you're done, you're cooked.

Rhonda Patrick:

And then because I'm competitive during the recovery that they give you at the minute, at the end, I'm pushing at max, so the number's higher.

Andrew Huberman:

Great. So three times a week?

Rhonda Patrick:

It's a trick. Yeah, three times a week. And then I always have my sauna on preheating up, takes about an hour and a half and I get it to about 189 degrees Fahrenheit. I hop right in the sauna after my Peloton.

Andrew Huberman:

So the elevated heart rate continues? Is that the rationale?

Rhonda Patrick:

Yeah. I mean, I literally down a bunch of water and then I get in and then I either read a science paper or 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 and I-

Andrew Huberman:

You're an early adopter.

Rhonda Patrick:

I started doing it every day. I lived across the street. I lived in a studio apartment with Dan. We lived in this small studio apartment, like smallest apartment you can ever imagine. And it was across the street from a YMCA because I was poor in graduate school, very poor, very poor. So I [inaudible 02:09:03] and-

Andrew Huberman:

I recall being ... I lived in my lab.

Rhonda Patrick:

Wow. Really?

Andrew Huberman:

But then again, I lived in my lab as a postdoc and as a ... I admit I lived in my lab with my bulldog as a faculty member for other reasons. But I get it. When you're a graduate student, you're poor basically.

Rhonda Patrick:

Yes. And so I used to go to the sauna before going into the lab. And I started noticing that I was, all of a sudden, able to handle stress better. The stress of my six-month setback because of failed experiment, which is crushing, on top of the pressure from 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.

Rhonda Patrick:

I mean, I was very stressed out in graduate school, and this sauna started to really noticeably affect my anxiety and my ability to handle stress. And I was like, "What is going on here?" So I started looking into the literature and 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.

Rhonda Patrick:

And basically ... So when you get in the sauna, you release a lot of endorphins. Endorphins are the feel-good opioids that 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 dysphoric feeling when you're in the sauna and you're hot, and when you're running, doing exercise and you feel uncomfortable. Well, I think that's dynorphin. I'm speaking, absolute ... I think I-

Andrew Huberman:

No, I think it is.

Rhonda Patrick:

I think it is.

Andrew Huberman:

I mean, there's evidence in alcoholics that some of the symptoms of withdrawal that they 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.

Rhonda Patrick:

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 treating morphine or heroin addiction. And people that are using those drugs, they basically ... The endorphins or the morphine or heroin, they bind to a receptor in the brain called the Mu opioid receptor.

Rhonda Patrick:

And as they take these drugs, that Mu opioid receptor becomes downregulated, and so you need more and more of the drug to feel as good as you did. Right? Well, endorphins also bind to that receptor. And he was looking into some of the other drugs that are like Salvinorin or something, Salvia, it's called. It binds to the kappa opioid receptor. It also makes you feel uncomfortable. Anyways, he had put some studies in front of me that showed basically binding of the-

Rhonda Patrick:

... That showed basically binding of either dynorphin or whatever ligand to the kappa 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 at or whatever, you feel it for longer, right? With respect to the sauna, 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 wish more people would kind of look into that. It'd be amazing.

Rhonda Patrick:

But what I was getting at, I think, was, 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 a neuroscientist, that there's something about being in the sauna, I don't know if it has to do with the stress response. When you have an emotional trigger, you remember things better, right?

Andrew Huberman:

Absolutely. There is a clear and known explanation mechanism for this. Yeah.

Rhonda Patrick:

So in the sauna, I mean you also release norepinephrine, just like you do in the cold. There's a lot of overlap. It is a stressor. But I use it to remember things, like I'm going through something, I want go through a presentation or a talk, or a podcast or whatever, and I go in that sauna. I mean, you should try it if you haven't already. I don't know if you have.

Andrew Huberman:

I have a sauna and a cold plunge now, and I haven't tried ... I read books in the sauna in the evening. It's a time I insist on having my phone out of there. Initially because I thought I'd cook the phone, but also just to get some separation from the phone and screens in the evening, so I read books. The only challenge sometimes is you're dripping sweat onto the books, but I'm willing to forego a few pages of a book.

Andrew Huberman:

The idea that being in this semistressful environment would aid in the learning and retention of information is really well substantiated by this beautiful work by a guy named James McGaw. I don't know if his lab's still active, but he was at UC Irvine 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, both places.

Andrew Huberman:

And he was the one that really defined this kind of inverted U-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 what you're describing very well matches with that.

Andrew Huberman:

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 panicking basically. But obviously you're keeping it in range. The other thing that I would 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.

Andrew Huberman:

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 then of course, there's going to be the, I don't want to call it placebo, but there's going to be the context, the conditioned place context of it. If we had a good experience remembering something in the sauna once, we tend to ...

Andrew Huberman:

The positive association effect of that location is real. Just like if people go to a new city and they get robbed. 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. The opposite is also true, if something good happens someplace. So I'm imagining that it's a combination of those effects, but it would be very hard to do this in the cold. I feel like the cold is a very potent ... I think it takes you too far down that curve, the McGaw curve.

Rhonda Patrick:

I have to sing songs or something when I'm in there.

Andrew Huberman:

Distract yourself.

Rhonda Patrick:

Oh, yeah, I sing songs.

Andrew Huberman:

But afterward, you're very efficient at learning.

Rhonda Patrick:

After, I am.

Andrew Huberman:

Yeah.

Rhonda Patrick:

And 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, you're elevating your core body temperature, you're sweating. And when you're actually in the sauna, blood does get redistributed to the skin to facilitate sweating. But much like exercise, blood flow in general is improved to the brain, to the muscles, everywhere. So I think generally speaking, and there's studies showing that sauna use is associated with a much lower risk of dementia and Alzheimer's disease. People that use it four to seven times a week have greater than 60% reduction in dementia and Alzheimer's disease risk compared to once.

Andrew Huberman:

Oh sorry, I didn't mean to cut you off. You said people who use it ... I apologize, but maybe you tell us again. People who use it four to seven times per week have ...

Rhonda Patrick:

They have a greater than 60% 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 little greater than 20% reduction to risk. There's a dose dependent effect on dementia risk and Alzheimer's disease risk. There's a big link between the cardiovascular system and the brain. Obviously, blood flow a big one, 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 a sauna four to seven times a week, it's a 50% 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% lower death from cardiovascular disease.

Rhonda Patrick:

There's also lower sudden cardiac death, like a heart attack. That's greater than 60% lower if men use it four to seven times a week, versus once. Again, a dose-dependent thing. And the thing that's so profound there also to me, when again looking at the methods, when I look at the data. And this is all work from Dr. Jari Laukkanen, he's in the University of Eastern Finland, and just one of the world experts on sauna use, especially with respect to cardiovascular health.

Rhonda Patrick:

What some of his data has also shown is that if you look at the duration, the time spent in the sauna. I mentioned the temperature I do is about ... I do 189 degrees Fahrenheit. Typically, I go in there, I'm pretty heat-adapted. And so the more you do the sauna or any sort of heat stress, whether it's a hot tub or jacuzzi, you become adapted. You 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 so I stay in for 30 minutes. I stay in a long time. That's a lot. You have to listen to your body.

Rhonda Patrick:

Most of the studies that I just talked about were from the time spent in the sauna, when I said 50% 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 8% instead of 50. It had to be greater than 19 minutes, so 20 minutes is the sweet spot, at about 174 degrees Fahrenheit.

Rhonda Patrick:

And most of the saunas in Finland, by the way, they're humid. So they put water on hot rocks to create steam. And so usually between 10 to 20% humidity in the Finnish sauna. So those studies were, I would say, most of the time you're going to find that their humidity is also elevated. But to me, the dose-dependent nature of it and the duration, to me, that's a very strong data that this is more causal than some corollary thing. Because that's always the problem with observational studies, including these, which they corrected for a whole host of factors like cholesterol, exercise, just everything, everything under the sun, they corrected for those.

Rhonda Patrick:

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 comparing directly head-to-head moderate or intensity aerobic exercise on a stationary cycle to 20 minutes in a sauna.

Rhonda Patrick:

There, 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, the sauna, this heat stress, there's 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 bike.

Rhonda Patrick:

So disabled people, granted there are some safety concerns, they're pretty mild, but they do exist. 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 are prone to low blood pressure, always talk to a physician before doing the sauna. It is stressful.

Andrew Huberman:

Pregnant.

Rhonda Patrick:

Pregnant women. Oh yeah, I definitely avoided saunas when I was pregnant. But I think it's very relevant for disabled people, and also people that are sedentary, have been sedentary most of their life. Like my mother, I've been able to get her in the sauna. I did get her on the Peloton once, but it's really much easier. She feels like it's a spa treatment, and she can listen to her music in there. I care about her health, but 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.

Rhonda Patrick:

Ideally, you do both. But 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 so I published all this in a review in Experimental Gerontology, last year I guess, late last year. And basically, cardiorespiratory fitness, which is a marker of health. Cardiorespiratory fitness is improved in people that do exercise and sauna, compared to exercise alone or sauna alone.

Rhonda Patrick:

So for those 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. There's so many beneficial things happening with the heat stress. In addition to mimicking aerobic exercise, there's the heat shock 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 Biological Studies doing research on little nematode worms that we or someone else injected amyloid beta 42, the peptide, the 42-amino acid peptide that is involved in amyloid plaques found in the brain correlated with Alzheimer's disease and other brain disorders.

Rhonda Patrick:

We injected those into the muscle tissue of worms. And basically, these worms become paralyzed with age because 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're not prone to aggregating and forming these plaques in your arteries, and also in the brain.

Rhonda Patrick:

Back to my worm studies I was doing, I would elevate heat shock proteins in these worms, and it would totally correct the problem, where they would no longer become paralyzed. They'd move around, they were young. Many animal studies have been done looking at Alzheimer's disease, a human-like Alzheimer's disease in a rodent, and heat shock proteins protecting from it. So heat shock proteins are robustly activated in humans. This has been shown to even 50% higher over baseline levels after just 30 minutes at 163 degrees Fahrenheit in the sauna. And they stay activated, at least in rodents, for 48 hours at least.

Rhonda Patrick:

So having these heat shock proteins around, making sure they're properly taking care of our proteins so they're not aggregating in our brains and in our plaques, could be another potential way that sauna is protecting from Alzheimer's disease, and other cardiovascular health, as well as longevity. So there's people that have SNPs 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 SNP. And if they have two versions, 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 SNP. So it's also-

Andrew Huberman:

Wow.

Rhonda Patrick:

... been associated with human longevity as well as in lower organisms. So you can heat shock a worm or a fly, and they'd live 15% longer. This is the work done by Gordon Lithgow at the Buck Institute, years and years ago. 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 they're also activated by cold as well. Cold shock does activate heat shock proteins. Not as robust, sulforaphane activates them.

Rhonda Patrick:

Again, it's one of the reasons I think we should get all of these things, because their input-activating mechanisms are more robust for different ones. So there is crosstalk. It'd be more accurate to say there's overlap, but it's also like, you want to get the most robust from all of them, right? I do. I mean that's why I want to do the sauna and exercise, and eat my broccoli sprouts and all that stuff.

Andrew Huberman:

It's super interesting. A couple of questions came up for me. One is, you mentioned these SNPs, these nucleotide repeats, basically genes that some people have more of or less of than others that can predict longevity in some sense. Is that the FOXO3 pathway?

Rhonda Patrick:

That's one that can. Yeah, I mean FOXO3 is ... In fact, if you go back to the worm studies that I was talking about, that was one of 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-1. 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-1 receptor, and they make something like FOXO3, which we have.

Rhonda Patrick:

And basically if you decrease that insulin signaling pathway, the FOXO3 is always active in those worms. And they live like a hundred percent longer. And not only do they live longer, I mean, they are like a very young worm. You look at this thing and you're like, this looks like the worm that was just born hours ago. What's going on? This thing's at the end of its life.

Rhonda Patrick:

Now, as a side note, the thing that always got me on this was ... By the way, this was discovered by Cynthia Kenyon, and this was back in the '90s. And honestly, I'm not sure that anything has been as exciting in the worm world since then. But I thought it was a really big finding. The only caveat there is that the worms go through this dauer, it's called the dauer stage, when this happens, when you decrease their insulin signaling and stuff. And they go into this metabolic stasis, they're not eating as much or moving. And so it's like, okay, well they live a hundred percent longer, but they go into this weird state.

Andrew Huberman:

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 many data on sauna, and I also just want to acknowledge these Finnish groups that did this work, it's really pioneering, right? When you think, 20 years ago, long before social media or any of this, and they're up there measuring cortisol and growth hormone, and all this stuff in people getting in and out of 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, in terms of all-cause mortality cardiovascular risk, according to what I just learned from you.

Rhonda Patrick:

Four would be a good, I think, minimum effective dose.

Andrew Huberman:

Four times a week. And you combine it with the cold. I've also seen a protocol where ... it's a very extreme protocol, I don't recommend this to people right off the bat. Where they had human subjects get into the sauna for 30 minutes, get out for five, 30 minutes, get out for five, 30 minutes, for a total of two hours of exposure. But that was what led to these massive 16-fold increases in growth hormone, 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.

Andrew Huberman:

But I know people are probably desperate to know what if they don't have a sauna? A sauna is kind of a unique item. So I have a couple of questions. Can people use hot baths, with the appropriate warning, of course, that, without getting into description of the mechanics and the underlying biology, it's pretty obvious that the testes, if they get too warm, you'll kill a sperm. That's the reason why the testes are housed in a structure called the scrotum that can move around. We are biologists 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 hot baths-

Rhonda Patrick:

For at least six months. That's been shown.

Andrew Huberman:

Six months.

Rhonda Patrick:

Sperm motility goes down and sperm production goes down. But that is completely corrected if they stay out of the sauna for six months. So after six months later, it's back to normal.

Andrew Huberman:

Great, that's very useful information, I'm sure, to a number of people out there. If people don't have access to a sauna, and we get this about cold too, people 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, because you get a bigger person, 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. Is that right?

Rhonda Patrick:

Yeah, so there's been some studies looking at, for example, activation of heat shock proteins, also brain-derived neurotrophic factor increases with heat stress. And so the hot bath at around 140 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.

Andrew Huberman:

But you're very heat-adapted.

Rhonda Patrick:

I'm very heat-adapted, yeah. And it's 20 minutes from the shoulders down. And that is a very robust activation of heat shock proteins, and in brain-derived neurotrophic factor. And then heat shock proteins are also protecting against muscle atrophy. 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 ...

Rhonda Patrick:

There was a study where they were looking at muscle disuse, and it was something like the local heat treatment prevented almost 40% of the muscle atrophy from disuse. And it's funny because I used to use the sauna when I was injured and stuff, I would go in the sauna because I didn't know, at the time, because I was a graduate student, but I knew just from experiments that I'm not losing as much muscle. I feel better. At the time, I was reading all about the growth hormone and stuff back then, and I knew about heat shock proteins, 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.

Andrew Huberman:

This is also during graduate school?

Rhonda Patrick:

Yeah. Now I'm doing the sauna, bare minimum I do three, but I try to do four because of ... It all depends on my schedule. I also like to do long runs. It's like long being three miles, not like Cam Hanes’s long. But really for me, and we were talking about this earlier off camera, that the runs for me are for my brain. 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. I miss my runs if I don't do them, and I miss it because of the brain effects I get from it.

Rhonda Patrick:

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 longevity drug there is. This is it right here, Rhonda. You're always wondering, you're always wanting to know, you're wanting to do the best. If you don't exercise, you're missing that essential dose.

Rhonda Patrick:

And so that for me is the motivation. The doping seeking thing I'm looking for. Admittedly, I do not do enough strength training, and I have to do it. I have to. I have to. I have to. 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. So that's my fault.

Andrew Huberman:

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 Kandel, Nobel Prize winner at Columbia, comes to mind for all his work on memory, 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.

Andrew Huberman:

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, although you're cycling really hard with the resistance. Causes the release of osteocalcin from the bones, which acts in an endocrine way, sort of like a hormone. It 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.

Andrew Huberman:

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 about what the body is doing. Obviously, I'm making this up as conjecture, but we know in ocean and various 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 and mind drift.

Andrew Huberman:

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 good." 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.

Andrew Huberman:

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.

Andrew Huberman:

As a final question, because I 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 saunas 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. It was a Nobel Prize in 1908 for phototherapy for lupus, so it's not 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?

Rhonda Patrick:

I don't have an infrared sauna, but I 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.

Andrew Huberman:

Okay.

Rhonda Patrick:

It's not activating it at a specific wavelength, which is-

Andrew Huberman:

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 light, dim red and bright red. And the idea is that red light can travel ... the photon and energy is such that it can travel down through the deep layers of the dermis of the skin.

Rhonda Patrick:

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 ... 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 there's the Joovv, right? The Joovv, they have those red light panels and stuff.

Andrew Huberman:

Joovv and KOZE are the two ones I know. K-O-Z-E and Joovv, as far as I know. I'm probably going to 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 those.

Rhonda Patrick:

Yeah, well, I personally think 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. Maybe the infrared saunas are the ones that have the red light that you're talking about. Infrared saunas only get up to around 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.

Rhonda Patrick:

However, there have been some studies coming out of Japan, they use infrared sauna, they have this whole protocol, it's called Waon therapy, and they get people in infrared saunas and they wrap them in a towel, and they stay warm for X amount. So the whole protocol ends up being 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 conditions, there've been some improvements. So obviously there's evidence that infrared saunas can be beneficial for cardiovascular health.

Rhonda Patrick:

I've used infrared saunas many times at my in-laws, they have an infrared sauna. 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 increase in cadmium excretion from sweat when you get in the sauna. Also, lead is something like 17-fold, excretion is higher. Another one is aluminum, it's about fourfold higher.

Rhonda Patrick:

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 sauna is a heater, and the heater's 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 saunas. 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 ...

Rhonda Patrick:

I mean, that's what you're feeling when you're in a hot sauna. And that for me, takes a really long time in the infrared sauna. I get it 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 sauna.

Andrew Huberman:

Great. That's a really helpful answer. Like I said, I use the red light but not in the sauna. 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. My notes always look a little bit like they were drawn out by a macaque 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 on behalf of the listeners, and just directly from me, thank you so much for your time. I learned a ton.

Rhonda Patrick:

My pleasure. Thanks for having me on. It was really awesome conversation, so I enjoyed it a lot.

Andrew Huberman:

Let's do it again.

Rhonda Patrick:

Totally.

Andrew Huberman:

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. Once again, if you'd like to learn more about Dr. Patrick's work, sign up for her newsletter. And to listen to her excellent podcast, go to foundmyfitness.com. You'll find links to the newsletter as well as the podcast there. Or you can go direct to the podcast by going to FoundMyFitness on YouTube, FoundMyFitness on Apple, or FoundMyFitness on Spotify. And once again, the newsletter is foundmyfitness.com/newsletter.

Andrew Huberman:

If you're enjoying and or learning from the Huberman Lab podcast, please subscribe to our YouTube channel. That's a terrific zero-cost way to support us. In addition, please subscribe to the podcast on both Spotify and Apple. And on Apple, you have the opportunity to leave us up to a five-star review.

Andrew Huberman:

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Andrew Huberman:

Many of you will also be pleased to learn that Momentous supplements, of course, ships within the United States, but also internationally. If you're not already following us on Instagram and Twitter, please do so. It's hubermanlab on both Instagram and Twitter. There, I teach science and science-based tools, some of which overlap with the content of the Huberman Lab podcast, but much of which is distinct from the content of the Huberman 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.

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