The Tim Ferriss Show Transcripts: Rhonda Patrick, Ph.D. — Protocols for Fasting, Lowering Dementia Risk, Reversing Heart Aging, Using Sauna for Longevity (Hotter is Not Better), and a Few Supplements That Might Actually Matter (#819)

Please enjoy this transcript of my interview with Rhonda Patrick, Ph.D. (@foundmyfitness), a biomedical scientist and the founder of FoundMyFitness, a platform dedicated to delivering rigorous, evidence-based insights on improving healthspan and mitigating age-related diseases. Through her podcast, website, and YouTube channel, reaching millions globally, she translates complex science into actionable strategies for metabolic health, brain aging, and overall improved healthspan.

Dr. Patrick's research explores genetic determinants of nutritional response, metabolic health, micronutrient deficiencies, sleep biology, and hormetic stressors, such as exercise, heat, cold exposure, fasting, and phytochemicals. She is an associate scientist and board member at the Fatty Acid Research Institute, where her work focuses on the role of omega-3 fatty acids in metabolic health and brain aging. Her peer-reviewed publications have appeared in top-tier journals, including Nature Cell Biology, The FASEB Journal, and Experimental Gerontology.

By uniting scientific integrity with protocol-driven precision, Dr. Patrick equips individuals and organizations alike with practical, scientifically sound strategies for optimizing health and longevity.

Transcripts may contain a few typos. With many episodes lasting 2+ hours, it can be difficult to catch minor errors. Enjoy!

Listen to the episode on Apple Podcasts, Spotify, Overcast, Podcast Addict, Pocket Casts, Castbox, YouTube Music, Amazon Music, Audible, or on your favorite podcast platform. You can watch my interview with Rhonda on YouTube.

DUE TO SOME HEADACHES IN THE PAST, PLEASE NOTE LEGAL CONDITIONS:

Tim Ferriss owns the copyright in and to all content in and transcripts of The Tim Ferriss Show podcast, with all rights reserved, as well as his right of publicity.

WHAT YOU'RE WELCOME TO DO: You are welcome to share the below transcript (up to 500 words but not more) in media articles (e.g., The New York Times, LA Times, The Guardian), on your personal website, in a non-commercial article or blog post (e.g., Medium), and/or on a personal social media account for non-commercial purposes, provided that you include attribution to “The Tim Ferriss Show” and link back to the tim.blog/podcast URL. For the sake of clarity, media outlets with advertising models are permitted to use excerpts from the transcript per the above.

WHAT IS NOT ALLOWED: No one is authorized to copy any portion of the podcast content or use Tim Ferriss' name, image or likeness for any commercial purpose or use, including without limitation inclusion in any books, e-books, book summaries or synopses, or on a commercial website or social media site (e.g., Facebook, Twitter, Instagram, etc.) that offers or promotes your or another's products or services. For the sake of clarity, media outlets are permitted to use photos of Tim Ferriss from the media room on tim.blog or (obviously) license photos of Tim Ferriss from Getty Images, etc.

---

Tim Ferriss: Rhonda, it is very nice to see you again. Thanks for — 

Dr. Rhonda Patrick: Likewise.

Tim Ferriss: — making the time.

Dr. Rhonda Patrick: Yeah, I'm excited to be here.

Tim Ferriss: Yeah. I was going back through the archives, doing my homework as I always do, looking at our past conversations. And it was such a trip down memory lane because our first podcast together was podcast number 12 of The Tim Ferriss Show, which was in June of 2014. And then preceding that by a few months, April 2014 was when you had a guest post on my blog called “Are Saunas the Next Big Performance Enhancing Drug?” So well done. That's become quite the topic.

Dr. Rhonda Patrick: I know. I like to take a little bit of that claim to making saunas popular.

Tim Ferriss: The godmother, the fairy godmother of heat shock proteins, the context of saunas. And we are going to run out of time before we run out of topics or questions, as always. And what's so fun about having a conversation with someone like you who is not only very scientifically credible and literate, but who's actively involved with the science, tracking the science, and have published, is that there's always more stuff to talk about. Things change. There are new developments, there are new discoveries, there are revisions, which makes me very excited to hop into the conversation. And for people listening, we're going to cover a lot of things that are very, very actionable and practical. And I just wanted to give people an idea of some of what's coming. We may not cover it all, but if you'll bear with me, Rhonda, I'm just going to read some of these because it's great. How to increase VO2 max and why you should. Looking at VO2 max as a predictor of longevity with high intensity interval training. What type of exercise reduces heart aging by 20 years? Brain aging in the same context or reversing brain aging. The benefits of exercise snacks on glucose regulation and mitochondrial function. We're going to get a lot because this is something that is a perennial topic for me, but I've been really doing a deep dive on all things fasting related, intermittent fasting, metabolic benefits. IF versus extended fasting versus ketogenic diet, et cetera, et cetera.

Daily protein requirements and optimal timing for protein intake. The role of vitamin D and brain health and protection against klotho decline. How a low Omega-3 index is as bad as smoking and what to do about it. Benefits of creatine for brain and muscle health and best practices. Microplastic exposure: the biggest offenders, and so on. It just goes on and on. We could cover so much ground. And the way this conversation came to be, to give people a peek behind the curtain, is we were texting about all sorts of things, including aging parents and what we're trying and what we're thinking about what has worked, what hasn't worked seemingly.

I thought we would just start there if you're open to sharing because I really gained from our exchanges, enjoyed our exchanges. And for instance, talking about creatine as one example. There are potential applications to preserving or at least halting the decline or slowing the decline of cognitive deterioration. And why don't we just begin with the personal, because I think that's the most universal. All of my friends of my vintage or younger — no one is getting younger, so they're all contending with aging parents and what to do with them, how to help them. Can you speak to just some of the circumstances with your parents and what you have used as interventions that have seemed to have an effect?

Dr. Rhonda Patrick: I'm one of those people that my parents, neither of them are really physically active. My dad for many years was physically active in the sense that he played a team sport. He was a baseball player and he did it for many, many years all the way into his early 60s and then he just couldn't do it anymore. So my mother never really got into any sports and she wasn't the kind of person that would go out to the gym or go for runs or anything like that. And so physical activity really wasn't part of the equation and neither is really a healthy diet.

But as I started to do a lot of research into these sort of what I think are interventions that are low-hanging fruits, things that are easy for people to do that can have a pretty big outcome in terms of the effect, the size effect is greater than what you have to put in.

So examples of that would obviously be something like a supplement that you could take. That's the easiest thing you can do is kind of swallow a pill and hope that it has a great effect. And this is where both of my parents are taking a multivitamin. And you might go, “Well, multivitamin? Really what's that going to do?” And I'll tell you, we've come full circle. 10 years ago, there was a huge splash that was made in the media. A big article came out and it was called enough is enough. Multivitamins are not only useless, they may be harmful.

It was a study that had looked at a variety of different studies. It's called a meta-analysis that basically said, “Well, all these vitamins that you're taking are useless.” And in some cases they can be harmful because they can allow cancer to grow faster. I debunked that 10 years ago. But over the course of those 10 years, and as you mentioned in the intro here, science is always changing and revisions are made. We learn new things. And in that 10-year frame, three different randomized controlled trials have come out. And randomized controlled trials are really key because you are comparing this intervention, which in this case was a multivitamin to a placebo because people taking anything are obviously going to want a positive effect. And many people do anticipate that and they can actually change their biology. Placebo is a real thing. 

So three trials came out looking at the effect of multivitamins on cognition. And I'm talking the multivitamin that was used was the standard, run-of-the-mill. It was Centrum Silver. I mean it was the same — 

Tim Ferriss: Centrum. I knew it was going to be Centrum, yeah.

Dr. Rhonda Patrick: It was the vitamin that you would go, “That's the one vitamin that's not going to have any effect.” It's like that, but actually it turns out it's got over 40 essential nutrients in it and it's also got some other non-vitamins. So things that are like polyphenols, like lutein and zeaxanthin. These are actually really important for eye health, but also the brain. And these three randomized controlled trials were two years long. What they showed was that taking a multivitamin for two years had pretty enormous effects on cognitive aging. These were in older adults. These were adults who were 65 years of age or older. That's where my parents are.

And after two years of taking the multivitamin, they had improved cognition on a battery of different tests that equated to reducing global cognitive aging by about two years. And on top of that, they reduced their episodic aging by five years. Almost five years. It was 4.8 years. Episodic memory is the kind of memory that's involved in remembering events, things that happen in your life. And so that's a big effect. Five years of reduced episodic brain aging, episodic memory, brain aging.

And so I think that anyone that's concerned about their parents, one of the easiest things that you can do in terms of improving cognition — now I should mention these were older adults, yes, but they weren't older adults with neurodegenerative disease. So these were older adults that were — otherwise, didn't have any sort of neurodegenerative disease. That's also important because once you get to a pathological state, you have to do more things to help improve cognition than just a multivitamin.

I have my mom and my dad on a multivitamin. That's the easiest thing. Vitamin D is also another no-brainer. I mean 70 percent of the US population has insufficient levels of vitamin D. Older adults are even higher than that. So almost the majority of all older adults are vitamin D deficient. I mean, most people aren't going outside and even if they are going outside, they're either wearing sunscreen or just the fact that they're older affects their skin's ability to make vitamin D3 from the sun, from UVB radiation from the sun. And so they're much less efficient at it.

In fact, a 70-year-old makes about four times less vitamin D than their former 20-year-old self. So vitamin D supplement is a low-hanging fruit. It is super easy to bring some up to that level.

Tim Ferriss: Can I ask you a question about vitamin D, because I know you love vitamin D? So here's my question about vitamin D, and it actually relates to, I believe this is a publication you had in 2019, so we'll see if things have changed or not, but APOE4 for an Omega-3 brain delivery. So my family, a lot of benefits to having my genetics. Also, a whole bunch of bugs in the code, including quite a bit of APOE4, I'm APOE34. And should that change how I consume vitamin D or consume fish oil or Omega-3s to having that type of status?

Dr. Rhonda Patrick: I would say vitamin D, there hasn't really been any effect that I'm aware of in terms of having an APOE4 allele as you mentioned. And for people listening or watching, APOE4 allele, if you have one of those, it can double your risk of Alzheimer's disease. If you have two of them, you can go up to a tenfold increased risk for Alzheimer's disease. When it comes to fish oil, particularly fish oil, there does seem to be — and this is where my publication came from, but also there's a lot of evidence that has shown people with APOE4 alleles, they don't tend to have as much DHA getting into their brains as people without the alleles.

And on top of that, in trials, people with mild cognitive decline, for example, if they supplemented with fish oil and they had APOE4, they didn't have the cognitive benefits that the people that were not APOE4 had. And so there was this big question in the field as to why that is. And it's still not entirely known. Although I will say what my take on that is, and in fact I've talked to some of the experts in the field as well, is that you have to have a higher dose of fish oil, for one, and it's better if it's in phospholipid form. If you're eating fish, it is in phospholipid form, it's in triglyceride form as well. 

Tim Ferriss: So just for clarity, if you're taking capsules, it may not be the case, but if I'm eating my can of sardines in the morning, then phospholipid form?

Dr. Rhonda Patrick: You're getting more phospholipid form, exactly. Now, if you are taking your supplement oils, you can actually make phospholipid form, but you have to get to that two gram dose range. That's when your body is also converting into phospholipid form. And then the other way around that is actually consuming a phospholipid form of Omega-3.

And so that's something that can be done if you're supplementing with either krill oil, which I'm not a huge fan of because it's super — it's not very concentrated, so you'd have to really take a lot of it. Or you could eat something like salmon roe, which is a really high phospholipid concentration of Omega-3 fatty acids. You might go, “Why phospholipid form?” Well, it turns out the way your brain, you actually get Omega-3 into the brain, there's two ways. The first way doesn't require phospholipid form. It's just this Omega-3 is in a free fatty acid form and it diffuses across the membrane and gets into the brain that way.

The second way actually is through a transport mechanism, and that is phospholipid form. And that's why it seems as though people with APOE4, their free fatty acid form isn't going into the brain as well because they have breakdown of the blood-brain barrier early, early on. APOE4 tends to lead to early breakdown of the blood-brain barrier. And when your blood-brain barrier breaks down, it's hard for things to kind of just passively diffuse as well.

I know that is counterintuitive, but without getting into all the crazy molecular and biochemistry involved, just take my word on that for the two different forms of Omega-3, or you can read that publication as well.

Tim Ferriss: So let's step back for a second and just get into the parental specifics and then we can zoom out and talk about mechanisms and all sorts of stuff. But if you just had to give a couple of bullets on the things that you feel confident in having your mom and dad continue doing or taking, let's start with the supplements because like you said, it's sort of a low-hanging fruit in a sense from a behavioral change perspective. What do you have them doing?

Dr. Rhonda Patrick: I think you listened to a podcast I did with Dr. Mark Mattson several years ago. I had mentioned that my dad was diagnosed with Parkinson's disease in 2017. And that's an important context to consider what sort of supplements I'm giving my dad. And also the fact that you have to think about compliance. What were your parents? Do you have a parent that'll take a lot — 

Tim Ferriss: I actually do.

Dr. Rhonda Patrick: — of vitamins or a few vitamins? Right?

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: So with my dad knowing his disease was Parkinson's disease, multivitamin was in there because that's already so important just to cover a lot of bases. You're getting a lot of different vitamins and minerals. And then it was Omega-3, and in fact it was a high DHA and he's getting about two grams a day. And there's a lot of evidence that Omega-3 can help with dopaminergic transmission, can help with a lot of brain function, and particularly as it relates to Parkinson's disease as well as Alzheimer's disease.

So that was the second supplement that he's taking. And then the last one that I could really get him to take was ubiquinol, which is a reduced form of CoQ10. Now, coenzyme Q10 is actually something that we have inside of our cells and it's involved in mitochondrial health. So having a depleted CoQ10 can lead to mitochondrial toxicity. And so taking CoQ10, there's actually been some early studies with even Parkinson's disease patients showing that supplementing with CoQ10 can be beneficial. And he's actually taken those supplements for many, many years now and very, I would say surprisingly, but also I'm thankful that his Parkinson's disease has progressed very, very slowly.

So it's been nine years, almost 10 years, and he's really essentially had this Parkinson's disease limited to one tremor in his hand. So that's great. And that's all I can say is — 

Tim Ferriss: That's great news.

Dr. Rhonda Patrick: Yeah, it's great news. And you never really know at the end of the day what is the reason for that. But he's convinced, I'm convinced, his doctor is convinced that he should keep doing what he's doing and that it seems to be beneficial. My dad is one of those guys that doesn't like to take a lot of pills. If he would take more, I would give him more. 

Tim Ferriss: If he were willing to take more, what would you give him?

Dr. Rhonda Patrick: I would also give him sulforaphane. Definitely tried, but he doesn't want to take more pills. So sulforaphane is, it's a compound that is formed when you eat cruciferous vegetables like broccoli, cauliflower, for example. And it's formed from something inside of it called glucoraphanin. When you break the plant tissue, when you bite it or chop it up or whatever, it forms sulforaphane.

Sulforaphane is not necessarily in the plant itself, it just gets formed when you break the plant tissue. That's a technical thing. So I'm just going to talk about sulforaphane and call it sulforaphane as if it's part of the plant, but it's not, just so you know. Sulforaphane is, like I said, it's something that's formed in these cruciferous vegetables, broccoli sprouts, the young, young sprout of broccoli actually is the best source of it. It has a hundred times more of that active precursor glucoraphanin than mature broccoli. So that's the best dietary source of it.

Tim Ferriss: Are you growing your own broccoli sprouts or are you doing off the shelf now?

Dr. Rhonda Patrick: I'm off the shelf now. I used to. It's work. It's not that much work, but it is work. But you also, you have to be very fastidious about not having it contaminated, and that's where the real work comes in. But I like it because there are people that can't afford the supplement, and this gives them another way to basically get it for cheap. So the reason I really like sulforaphane and why I want both my parents on it and my mom, it has been taking it, we can talk about that in a minute, is because it is the most potent dietary activator of this system that we have called NRF2, which is this major system. It's basically a transcription factor that activates a lot of different genes inside of our body, and it activates genes that are involved in stress.

Basically, it activates a lot of what are called stress response genes. And these are the things that are activated when you're doing stress, stressful things like exercise or if you are fasting. So you really want this pathway to be active. 

Tim Ferriss: It gives a little bit of stress, right? It's like chronic overdose of stress, bad, but little doses of stress has this, I guess, what would you call it, hormetic effect. Right?

Dr. Rhonda Patrick: Exactly.

Tim Ferriss: Am I getting that right?

Dr. Rhonda Patrick: You got it. Yeah, you nailed it. Yeah. So essentially we're talking about what's sometimes called eustress or good stress. It's these small doses of stress where your body is responding to that stress by activating all these beneficial pathways that deal with stress, whether we're talking about antioxidant pathways, anti-inflammatory pathways, pathways involved in clearing out damaged stuff from your cells like autophagy. Just all sorts of beneficial stuff.

And those pathways are activated for a longer period of time than the acute stress that you're giving it. So in this case, the sulforaphane is a little bit of an acute stress like polyphenols in general are. So the amount of time that you're ingesting that polyphenol is very small and digesting it. And then the reality is that it's activating these stress response pathways that last on the orders of 24 to 48 hours, sometimes longer. So you're having this beneficial effect that's overall beneficial from that little bit of stress.

And so sulforaphane activates NRF2, and one of the main pathways that it's activating is increasing glutathione production. And it's been shown in a couple of different human studies that it increases glutathione in both plasma but also in the brain. Glutathione is the major antioxidant that we have in our body, and it's very important in the brain. Super important for not only preventing brain aging, but also for dealing with dysfunction in the case of acute injury like traumatic brain injury or in the case of Alzheimer's disease or Parkinson's disease, which are other types of injury on the brain.

Glutathione plays a big role there. And so I obviously would want my dad to be taking sulforaphane, and there's a supplement out there that I use that has been used in many 12 or so different studies. And so it's been shown to be beneficial across the board. And that is something that I do give my mom. Now, the reason I gave it to my mom, well, I was kind of hoping my mom interestingly has two other types of brain dysfunction problems, but they're not neurodegenerative in the sense of Alzheimer's disease and Parkinson's disease are there. It's kind of like something going wrong in the brain and it affects her motor control. So she has tremors. She has essential tremor, and she has orthostatic tremor.

I have secretly wanted the increase in glutathione to affect those tremors. But when I gave the sulforaphane to my mom, because I knew the placebo effect, I did tell her that we were using it to detoxify these chemicals that are associated with plastic like BPA because that is also something that I'm using sulforaphane for because that NRF2 pathway does activate what are called phase two detoxification enzymes, and it's been shown to detoxify. Even if you're living in a city like New York or L.A. where there's a lot of air pollution, it's been shown to detoxify benzene. Within 24 hours, people start excreting 60 percent more benzene from their body. Now, benzene needs something that is found in air pollution. It's also in cigarettes.

Tim Ferriss: Yes. So don't drink your own urine if you're taking sulforaphane is what you're saying.

Dr. Rhonda Patrick: Definitely don't do that. But also if you're living in a polluted place — I tell all my friends in L.A., I am like, you have to be taking sulforaphane. It's just like a non-negotiable, right? So I told her to take the sulforaphane because I wanted her to detoxify BPA because she does eat a lot of processed foods and stuff, which are found in plastic. Anyway, so she started taking it and she came back to me and told me that it was helping her tremors and that she wanted more. 

Tim Ferriss: How long did that take?

Dr. Rhonda Patrick: Not long. It was actually, I think within a week or so, maybe two.

Tim Ferriss: Wow.

Dr. Rhonda Patrick: It was very quick.

Tim Ferriss: That's wild.

Dr. Rhonda Patrick: It was very quick. And she is religious about it. I mean she comes — I buy it for her and I give her these bottles and she takes two a day. She takes a certain brand called Avmacol. I don't have any affiliation with them. They're a brand that, again, 12 different published studies using their supplement.

Tim Ferriss: A-V-M-A-C-O-L.

Dr. Rhonda Patrick: That's right.

Tim Ferriss: Avmacol.

Dr. Rhonda Patrick: She takes two of their advanced formula. So she's taking that. She's taking the multivitamin, the vitamin D, and she's also taking the Omega-3. She's doing great. What's funny is that I was able to then get her into CrossFit. And I don't know if it's because her tremors, I think her tremors have lessened a bit, and so she's been more active and wanting to be more active. She's out dancing more. My mom likes to dance. I mentioned how I really wanted to get her into a seniors CrossFit class, and she sees me do it.

I have a coach come to my house and we do CrossFit training at my house. My mom has seen me doing it and she's been interested in it. I told her that there's a great seniors class and I would be willing to pay for it and get her in it. It would be huge. She's been doing it now for a couple of months, maybe like three or four months. She goes three times a week and she loves it. She loves it. She's made friends there.

Sometimes the coaches take videos and she sends them to me. She sends them to her friends. She's so proud. She's doing kettlebell swings. She's doing wall squats. I mean, it's amazing. 

Tim Ferriss: Go, Mom. That's amazing.

Dr. Rhonda Patrick: It's a very different type of atmosphere than your usual CrossFit class would be, right? You're aware that these are seniors, and so they're not doing barbell, squatting like heavy weights and stuff. They start out with wall squats and then they're squatting with just a really light bar and it's really great.

Tim Ferriss: So let me hop in for a second here and I want to know if there's anything else to add to that. But we've talked about this, you and I. Or texted a hell of a lot about it that I have Alzheimer's in my family. I now have multiple relatives who are moderate to advanced with respect to Alzheimer's. Saw my grandmother disintegrate. Terrifying to watch and terrifying to imagine yourself experiencing the same thing.

And also at least one of them is APOE33. And I'm APOE34, so I'm like, “Well, wait a second. If that is where they are right now, and I'm at hypothetically 2.5x greater risk of developing Alzheimer's disease, AD, I should really double down on paying attention to as much as possible for myself, certainly for them as well.” But the earlier the intervention, the better the outcomes generally. So I've been looking at all sorts of things. And just to reiterate a few things you said. So on the Omega-3 side of things, just like with sulforaphane, not all brands are created equal, right? There's a lot of garbage floating around out there.

Neither of us have any affiliation with this company, but I know our mutual friend, Kevin Rose, had this particular brand tested that, I guess it's O.N.E. Pure Encapsulations. Is that what you have your parents are taking or did you use a different brand?

Dr. Rhonda Patrick: So with my dad, he is now taking the Zymogen brand, which is also very good. And the reason for that is because it's higher DHA, which is what I wanted.

Tim Ferriss: Fascinating.

Dr. Rhonda Patrick: My mom is taking the O.N.E.

Tim Ferriss: Yeah, got it.

Dr. Rhonda Patrick: Yeah.

Tim Ferriss: Cool.

Dr. Rhonda Patrick: Yeah, both those brands, by the way, are great. They've both been third-party tested and have very high quality fish oil, and I don't have affiliation with either of them.

Tim Ferriss: So I've got my parents on those. I'm taking those. You mentioned lutein and zeaxanthin, which is good for quite a few things. Now, for those people who may be interested, and this probably won't help me with my particular presbyopia. So age-related visual decline, particularly with near work, reading a book, let's say, but AREDS2, people could check out studies that have been done on AREDS2. And two of the principle ingredients are lutein and zeaxanthin. So there's that.

Now, also have been very, very curious about how to activate some of the pathways that you mentioned. Sulforaphane would be a good option for that. Also, looking at, and we don't have to spend a ton of time on this, but exogenous ketones because ideally, sure, I would have my parents maybe do intermittent fasting or some extended fasts. I don't think that's going to happen for a million different reasons, but perhaps exogenous ketones and have looked at that.

This is a work in progress I've been doing, and I know you have too. Lots of self-experimentation, but there are some case studies in the literature, one of which you sent to me that are pretty interesting, looking at administration. In other words, giving an older patient with Alzheimer's disease, oral exogenous ketones. They tend to taste like jet fuel. They're not tasty. But the effects of, at least in these case studies are pretty remarkable.

Now, granted with the monoester they use in some of these, the off-the-shelf cost per day would be like $150 or something like that. Maybe even more. So there's sort of a cost question. But I'm just going to throw a couple of more things out there that are on my mind. So you mentioned the exercise piece. This has been so important for me. So I've hired a trainer and I realize my parents are kind of sneaky and sometimes a little, I don't want to say passive-aggressive, but they'll say they're going to do something to please me and then they won't do it.

So getting the trainer to actually pick them up at their house is something that I decided to do because there are a lot of reasons. Exercise is amazing, one of which is the natural release of klotho and people can look this up. I'm hoping that you'll be able to inject this in the next handful of years. We'll see in humans. But K-L-O-T-H-O. Also worth checking out. 

Tim Ferriss: Anything else that you would add to that or any commentary you want to sprinkle in? Am I missing any criticals?

Dr. Rhonda Patrick: There's definitely commentary.

Tim Ferriss: Multivitamin, yeah.

Dr. Rhonda Patrick: There's commentary, but we can get into that if you want to go dive into the why the ketone esters are beneficial and why the exercise is beneficial. We can go into that because I love talking about it.

Tim Ferriss: Yeah. This is going to be a conversation just between you and me. That's how I treat all of these things. And I'm very self-interested because I think the personal is the most universal. Maybe that's just an excuse to make this all about what I want. But we have been texting also because I told you I've been thinking about doing a 14-day fast, and actually I ratcheted that back from doing a 30-day fast.

I've done 10 days before, water only. I've done lots of seven days. And part of the reason is I think I would be better equipped now to do longer fasts because of the intermittent fasting I've been doing. And this ties into the conversation around the parents because what I have noticed is, for instance, doing 16:8 fasting, which was, and I'm so sorry, the scientist you mentioned before, whose podcast interview I listened to on your podcast, what was his name again?

Dr. Rhonda Patrick: Dr. Mark Mattson.

Tim Ferriss: Yeah, Mark Mattson. Amazing, amazing scientist. Fantastic conversation. A lot of seminal work related to intermittent fasting. So 16:8, what does that actually mean? I did this today, I've done this most days now, which is basically eating between, for me it's like 2 p.m. and 10 p.m. There are arguments that it should be shifted earlier, like noon to 8 p.m. or something like that. But socially, just practically, again, coming back to compliance, like the good system you do being better than the perfect system you don't, generally it's like two till, let's say 9 p.m. is when I eat and then I fast the rest of the time. And for the first five to seven days, pretty grumpy, kind of pissy, I'm not going to lie. Sent some emails that I probably shouldn't have. But then once I adapted, I did a recent set of labs and they're my best set of labs that I've seen.

I can't solely attribute it to the intermittent fasting, but the best set of labs I've had in ages on things that were very hard to move prior, also did an oral glucose tolerance test and my sort of insulin sensitivity and glucose management, the best it's been in ages. So I was like, okay, that's really interesting. The last time I did a seven-day fast, it was kind of brutal. I hadn't done one in a few years and I don't think my metabolic machinery was ready for the task, very unpleasant. But I have some chronic inflammation or at least chronic pain in my low back. And after doing that seven day fast, I had four weeks of zero symptoms and that's the first time in three years that that's been the case. So I was like, okay, that's pretty interesting.

So I've ended up harassing you with all sorts of questions such as, well, what if I had a little bit of heavy cream in my coffee in the morning, so it's kind of dirty fasting, but if I did that, what am I accepting as a compromise or a penalty if anything? Because then I think of, say, Longo's work and others looking at fast-mimicking diets where I'm like, well, wait a second, these people are doing, let's just say five days of fast-mimicking dieting per month for three months straight. And they seem to have all these benefits that maybe of lower magnitude, but mirror water fasting on some level, but they're consuming a few hundred calories, let's just say for simplicity per day of those five days of “fasting.” If you look at the actual meal composition, it ends up being very low calorie keto, basically very low calorie keto with very low protein, like 10 percent or less avoiding animal products.

That's the basic way that I've been thinking of it. And so I was like, well, should I do something like Wilhelmi in Germany who have, again, “fasted thousands of people,” but they do give them bone broth, a little bit of juice, it's akin to the fast-mimicking diet, but they will do that with people for 30, 60, 90 days or am I better off doing shorter water fasts or maybe even a 14-day water fast? And a lot of the questions came down to, I know this is mouthful, but as you know, I've been thinking about this nonstop. I was up until 2 a.m. this morning reading really, really old stuff out of the Soviet Union on psychiatric clinics fasting patients for schizophrenia.

And so that tells you metabolic psychiatry also goes back a long, long, long time, not to mention ketogenic diet for epilepsy. So there are a lot of similarities, but if I want the benefits, as many benefits as possible with the least pain possible, which includes not losing a ton of muscle tissue, which is not always the same thing as lean body mass, what should I do? Right? That's kind of the open question. And that is a huge, huge mouthful. Thank you for coming to my TED talk.

But where is your current thinking when it relates to all of this stuff? And I said earlier at the very beginning that it ties into my parents. Why is that? Because when we looked at some of my relatives and I got my docs to come in and do a real proper full workup, looking at all sorts of things that normally wouldn't be tested, absolutely some metabolic syndrome in the sense that they're highly, highly insulin insensitive, like insulin off the charts. And it's like, okay, well this has been going on for years to get to this point and Alzheimer's is sometimes called type 3 diabetes. And it's like, okay, well if I can't help them, at least I want to try to help myself and other people who might be listening at an early enough stage. So how do you think about all this stuff?

Dr. Rhonda Patrick: Well, there's a lot to talk about here, and I think we've got to kind of — 

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: Let's — 

Tim Ferriss: Let's chew on one bit at a time.

Dr. Rhonda Patrick: Right. Let's chew one bit at a time and zoom out for a minute and talk about this intermittent fasting concept and why do people want to do intermittent fasting? What are the benefits that they're looking for? Now, you mentioned some metabolic benefits that you had noticed after doing your intermittent fasting.

So there's lots of different types of intermittent fasting. You've mentioned the 16:8. So essentially you're talking about not eating food for a period of time, and that period of time can either be 16 hours, it can be 24 hours, it can be longer, in which case it would not be an intermittent fast. It would be more prolonged fast, which you also talked about. But with respect to the intermittent fasting, there are a few things that happen and there are a few reasons why people like to do intermittent fasting. First and foremost, I think most people like doing intermittent fasting is because they want to actually lose weight and the weight that they want to lose is not necessarily their lean body mass. They actually want to lose their fat mass, so they want to lose fat, and that's a big reason why people do intermittent fasting.

Well, it turns out that intermittent fasting is more of a tool for weight loss. And what I mean by that is that there have been multiple studies now that have looked at different types of intermittent fasting in sort of a community dwelling aspect where people are just kind of free to eat the way they're going to eat, but they're supposed to be practicing intermittent fasting. And what it's been discovered is that naturally, people end up eating about 200 fewer calories per day when they're doing some form of intermittent fasting. So if they're eating all their food within an eight or 10 hour period, for example, usually they'll eat their food within a 10-hour period and then they'll fast for 14 hours. If they do that, they end up actually eating 200 fewer calories. And so they end up performing what's called caloric restriction, which we know can lead to weight loss.

And so a lot of the weight loss actually comes from reducing calorie intake, but that doesn't necessarily mean that everything that's beneficial from intermittent fasting comes down to calories because it doesn't. But the weight loss definitely seems to come down to the calories because if you keep calories the same and then have people do intermittent fasting or not intermittent fasting, they won't lose the weight, but they will have a whole host of metabolic benefits. You mentioned glucose regulation improvements. I mean fasting glucose, postprandial glucose, HbA1c, which is a long-term marker of glucose regulation, their lipids are more favorable, and then they have improvements in blood pressure, for example, that's another big one that people get with more of a longer type of intermittent fasting. So they're fasting more like 18 hours and eating their food within a six-hour window. Now that's another benefit.

Now you go even further, and I know this is something you are very interested in, so beyond metabolic benefits and people want to get then, they want to get into what's called ketosis. So they want to be making ketones, these things that we're talking about earlier with respect to taking an exogenous ketone ester, well, you make something naturally when you start to actually burn fat as energy, you start to make something called beta hydroxybutyrate, but it takes about 12 hours or so. It depends on the person. It depends on how heavy of a carb diet they eat or how physically active they are. It can be a range. So if someone's doing a more ketogenic type of diet, they can actually deplete their liver glycogen quicker than 12 hours. It might even cut it down to like eight if they're physically active on top of that, you might go down to even six or something.

So there's a big range here, but for a standard person on a normal diet, they're going to take around 12 hours before they start to deplete their liver glycogen and then start to immobilize fatty acids from their adipose tissue and use that as energy. And when you start to do that, then you start to get into ketosis, your body starts to then make beta-hydroxybutyrate the major circling ketone. Why do people want that in their system? Because it's not just a very energetically favorable source of energy. What I mean by that is it takes less energy to use beta-hydroxybutyrate to make energy than it does to use glucose, for example. It takes more energy to actually use glucose, so it's more energetically favorable, right?

Tim Ferriss: It's a clean fuel. Yeah. Also, BHB, the beta-hydroxybutyrate, as I understand it, I mean highly anti-inflammatory effects as well, right?

Dr. Rhonda Patrick: Exactly. That was the next point I was going to make is that it's called a signaling molecule. So it's actually a way so your body knows that it's in this stress mode, okay, there's no food. It's food scarcity time. And this is something that it's evolutionarily tapped into our system, into our DNA where times of food scarcity, when we're not eating, our body switches into ketosis, beta-hydroxybutyrates produce, and it signals to these other genes to basically make more of something beneficial. So it's been shown to reduce inflammation. It depresses something called the inflammasome, which causes inflammation. It's an HDAC inhibitor, so it's a histone deacetylase inhibitor. So it's globally affecting gene expression and in such a way that it reduces genes that are involved in making oxidative stress, it actually activates brain-derived neurotrophic factor. That's the beneficial neurotrophic compound that's made in the brain that exercise also activates as well.

So it's doing all these beneficial things. And the other thing that it's doing is it's getting into the brain. It's being used as a very great source of energy. And so you have this sort of bypass where the glucose can then be shunted to be used to make glutathione, that very important antioxidant I talked about earlier that sulforaphane activates.

Well, it turns out when you give your body ketones or your body's making ketones, your brain actually consumes a lot of that. There've been tracer studies that have looked at that. And what happens is because neurons are now using the beta-hydroxybutyrate as energy, glucose is no longer needed. And so that glucose that is there is then used to make NADPH, which is a precursor to make glutathione, and so it's called glucose sparing. You get this glucose sparing effect. And so that's another reason why people are interested in intermittent fasting. 

And then another main reason, and there's many others, I'm not going to touch on everything, but the other main reason is it activates repair processes. And what I mean by repair processes is to be in repair mode, you have to be in more of a catabolic state. And we were talking about this earlier, people get so freaked out by the word catabolism.

Tim Ferriss: Last night when I was walking around New York City, we were talking about this catabolism —

Dr. Rhonda Patrick: And I think even over the last few years, intermittent fasting has kind of gotten a bad rap because people now equate it with, “Oh, loss of muscle mass. I'm going to be catabolic.” Well, in order to be in a repair mode, you actually do need to be in a catabolic mode. And these repair systems are so important for cleaning up all the garbage that's inside of our cells. And that can be things like protein aggregates. These are things that lead to aggregation like alpha-synuclein, which is involved in Parkinson's, amyloid beta aggregates, which is involved in Alzheimer's disease. It's not the cause. It's like the cause and the symptom. It's like both. It's involved in Alzheimer's disease and then aggregates in our cardiovascular system that play a role in cardiovascular disease, but it also cleans out even damaged little what are called organelles.

And so mitochondria or an organelle, and these, our organelles get damaged. So you want to be able to repair that damage. And this process of autophagy is the process that does that. And there's lots of different types of autophagy. So if it's a mitochondria repairing damage to itself, it's mitophagy but for all this stuff to be active, you have to be in that more catabolic state, which can be induced by not eating, can also be induced by heavy endurance exercise as well.

Okay. So talking about those sort of outcomes that people are interested in, those different endpoints that people are interested in achieving, I think something that you are specifically interested in is the metabolic effects of intermittent fasting as well as the repair processes like the autophagy.

Tim Ferriss: Yeah, for sure. And that's why I was asking because I don't really, look, I'm as vain as the next person. I like looking less fat if I can, but it's not my main driver, right? It's mental acuity and hopefully staving off on some level things like neurodegenerative disease and even cancer possibly, which has been part of the reason I've done a lot of these extended water fasts, which is I realize there are a couple of hops here in terms of speculation, but it seems plausible that you might zap punch a couple of pre-cancerous cells in the nuts by doing that.

Dr. Rhonda Patrick: Definitely. Not only does autophagy play a role in preventing Parkinson's disease, but also Alzheimer's disease as well. Again, this has been shown in many animal studies. We know that autophagy plays a role in clearing away the amyloid beta plaques that are involved in Alzheimer's disease. And yes, there are some people that have amyloid beta plaques that don't get Alzheimer's disease. They may be the more resilient non-APOE4 type of person, but we do know that many, many people do get Alzheimer's disease with amyloid plaques. And in fact, people that have, again, the SNPs in what's called the amyloid precursor protein APP, that leads to amyloid beta plaque buildup, they get early onset Alzheimer's disease. So autophagy plays an important role in clearing away those plaques. And I will say what we don't have a lot of evidence on is what's the minimal effect of fasting dose to activate autophagy?

Tim Ferriss: Yeah, I know. God, I wish we had this

Dr. Rhonda Patrick: Right. We don't. I think what we do know in humans from some of these old studies is that you do see some signal of autophagy activation after 24, 48 hours in humans. Now, does that mean that that is the only amount of time that it takes to activate autophagy? No. So most humans are probably doing anywhere between a 12 to 16 hour nightly fast. There's a period of time when we're not eating, and that is when we're sleeping a little bit before bed autophagy still happens in people, we just aren't measuring it because we don't have sensitive tools yet. And so it's not that I don't think a 16-hour fast doesn't activate. I believe it does in human. I believe there's some autophagy going on. It's probably not that much. But if you go into that 48 hour fast, then you're really starting to get more robust activation of autophagy.

Tim Ferriss: Can I throw something else in here just for fun?

Dr. Rhonda Patrick: Yes.

Tim Ferriss: So you mentioned sleep, and I've been looking, trying to look at Alzheimer's from every possible angle and found literature looking at disruption of sleep architecture in patients with Alzheimer's disease and the possible application of Xyrem, I believe it is, which is another, it's a brand name in a bifurcated schedule for GHB gamma hydroxybutyrate, which you have to be very careful with. It's a party drug. People die of it because it suppresses respiration. The person who bought my apartment in San Francisco died of a GHB overdose, but it actually is a tremendously interesting compound for increasing, I think it's deep wave sleep specifically, which does what? It helps the cleanup crew to do its work and to actually take out the garbage cellularly. And so if I could wave a magic wand, I would have my relatives on something like Xyrem, might actually be a different type of sleep medication like the NORA class. NORA, might be DORA.

I would also look at, and this is something obviously not suitable for most elderly people, but potentially lower dose psilocybin or psilocin. And there is some actually very interesting, I don't want to call them speculative, hypothetical applications of that to Alzheimer's disease, which you can find on PubMed. And from a mechanistic perspective, they're super, super interesting. So I just want to double click on the sleep because that is such a critical component, whether you're fasting or not, to try to ensure that your sleep architecture is not hyperdisrupted, which can be the case with lots of different types of sleep medications that you might take. And if you have really bad insomnia, it's like, okay, you can do all of these other things, but boy, oh boy, it would make a lot of sense to try to fix sleep whenever possible.

Dr. Rhonda Patrick: Great. Yeah, so true. The low-wave sleep does activate the glymphatic system, which is cleaning out the amyloid beta aggregates as well. And the last thing I kind of want to mention is you were talking about the intermittent fasting and more prolonged fasting and the muscle mass loss or lean body mass, which people equate with muscle mass, which it's not, there's a lot of things going on. So the thing is, when people are doing intermittent fasting, I mentioned they eat fewer calories, which means they're eating less meals, they're eating fewer meals, they're not eating as many meals. And so what ends up happening is people lower their protein intake, and that's an important signal for maintaining muscle mass and certainly growing muscle mass as well. So it increases muscle protein synthesis, which is important. If people are engaged in resistance training and doing intermittent fasting, they're not losing muscle mass.

And in fact, they can even gain muscle mass a little bit, not much, but they can gain it too. So I think the key here is that if you're doing an intermittent type of fast, like 16:8 where you're fasting for 16 hours, that's really not a long, long fast. There's not a lot of concern with losing muscle mass if you're resistance training. Now a more prolonged type of fast, you're talking about 14 days, that's a long fast. And definitely, you're going to be losing some muscle mass no matter what. Now, how much you lose depends on how, I guess if you can resistance train lightly while you're fasting, that would be huge because you would be then activating muscle protein synthesis through another signal, which is not protein, it's mechanical force.

So that, I think, would be really important for preventing the loss of a lot of muscle mass. But what is interesting is that you do lose lean body mass, a lot of it, when you are doing a prolonged fast like that and looking at the old literature and some of the literature that's been done, a lot of water up to 10 pounds of water rate, which is crazy, you lose that and your organs shrink. And this is something that's been also shown in animal studies and also by Dr. Valter Longo many years ago, and he's shown in animal studies, prolonged type of fasting actually causes organs to shrink because a lot of the damaged cells, not only is autophagy getting activated and you're cleaning out damage within a cell, but cells that are so damaged that autophagy can't even fix them, they actually undergo death, cell death.

And so you end up getting a lot of cells that die. And then what happens is during the re-feeding phase, and this is key, the re-feeding phase is the growth phase, and this is when you regrow organs, it's when your muscle mass comes back, you can go back, get your muscle mass gains back. And so having that refeeding phase is really important. And getting the right nutrients, like protein for example, is key for that refeeding phase. But you also lose fat during that fast and you're losing visceral fat. And you had brought this up last night when we were talking and I did some reading on it because it was like, oh, I made perfect sense because your organs are shrinking, you're losing a lot of cells in your organs. You're also losing some of the visceral fat that surrounds the organs, right?

Tim Ferriss: And that can get misclassified. Yeah.

Dr. Rhonda Patrick: Exactly. It gets misclassified as lean body mass. And so you look at this lean body mass and all you think about is muscle. Well, it turns out, muscle's a small part of that. There's a lot of other stuff that's going into that lean body mass. It's a pretty big undertaking, a 14-day fast. But I'll say this, and this kind of goes into what you mentioned about the fasting mimicking diet and perhaps even adding cream. We can talk about that as well. I do think, I mean the fasting mimicking diet, you're not going to get the same amount of autophagy that you would get if you did a five-day fast, water fast, because it's just impossible.

You're getting some protein, you're getting some amino acids that's activating mTOR, that shuts down autophagy. You're getting energy, ATP, there's a ratio called the ATP to AMP ratio, which you want it to be low to activate something called AMP kinase for autophagy to happen. And so when you're eating heavy cream or eating whatever, fill in the blank, any type of calories, you are changing that ratio. And so that AMP kinase is not getting activated as robustly. Now, the amount of inactivation of those pathways, which then will inactivate autophagy, depends on how much you're feeding, how many calories that you're eating, how much of that is amino acids.

Tim Ferriss: And specifically leucine, right? In the case of Longo, really trying to minimize leucine as in an activator of mTOR and so on.

Dr. Rhonda Patrick: Yes, exactly. Yeah. So I think for the cream, if you're trying to do 16:8, if someone is trying to do 16:8 on a daily basis, and it's a non-negotiable for having an earlier feeding window because social, just everything compliance wise isn't going to work and you have to do it later, which means you have to wake up and still be fasting in the morning, then you either have to love black coffee, learn to love it, or try maybe MCT powder, MCT oil, because then you're not getting the amino acids in there to activate the mTOR, but you can do a small, maybe a tablespoon of it, and so you'll maybe just get a little bit of depression of autophagy, but not much. That would be my recommendation.

Tim Ferriss: And I also want to clarify for folks listening just to really make it specific. When I have had, I just like saying dirty fasting, I didn't realize it was an expression, I just think it feels fun like a dirty martini. So dirty fasting is kind of cheating in this way. But when I do that, which is not all the time, I usually have black coffee or tea or something like that, but it is heavy cream, which is almost entirely fat. It is not creamer that you would just pull off the shelf. It is not half-and-half. It is heavy cream, which just from a macronutrient perspective is very, very, very different. And you can really overdo it on the calories also, it's just liquid fat effectively. But the MCT powder is a good idea.

I tell you what, if you're open to it, let's shift gears a little bit. I will just say, I wish somebody, nobody's going to do this, but would somehow get the ethics board, IRB, etc, to approve long-term human studies, again, in fasting, that would be great because you used to be allowed to do it. There are case studies of people who literally fast for 300 plus days, I mean fat, what is it? 9,000 calories per pound. You can do a lot with that fat. So we'll see if I do 14 days. If I can do 14 days, then I might just go to 30. But then the refeeding gets really tricky.

Dr. Rhonda Patrick: I think people are concerned with gallstones. So when you don't eat for a long period of time, then you're not stimulating the gallbladder and the gallstone risk increases, which is what I think is the big concern with the long, long fasts. But I mean, if you're doing something like that once a year, I don't know if it's that big of a deal.

Tim Ferriss: Yeah, I mean that's why I was doing a seven-day fast once a year for a long time, and then I took a break for a few years and I did a seven-day water fast and it was so incredibly unpleasant. And I had orthostatic hypotension where I stand up and I felt like I was going to fall over and vision started to get funny and I was like, you know what? Maybe this isn't for me, but I think it's because my machinery just wasn't developed for that. Having seen really stark differences in my mental acuity and sustained focus with the intermittent fasting, I'm like, okay, I feel like doing intermittent fasting, which part of my reason behaviorally for my interest in that also is that getting people to change their diet is fucking hard, meaning their diet composition, the food they eat. So if you can just say, Hey, look, keep eating whatever you want, same thing, but you have to fit it within this window.

It's an interesting option B that might work for people who otherwise aren't going to follow a paleo diet or whatever. But if you do the IF, and then what I've done is like, all right, do the IF, maybe if you have some grains or in my case legumes and stuff, okay, fine. And then shift to a mostly ketogenic diet for a period of time, then I feel like you're pretty well teed up for a longer water only fast. Maybe you supplement with electrolytes. This gets into all sorts of controversial territory.

But if you're okay with it, let's talk about training for a minute because, and I'll force a really awkward segue maybe, which is one thing I noticed is that my ability to do Zone 2 training, let's just for simplicity's sake, say that for people that you're on a bike, stationary, is just easier to keep consistent and you're cycling for 60 minutes at a wattage and a speed that leads you to the point where you could have a conversation with someone on the phone in short, full sentences, but you don't really want to, right? That's like the talk test. Intermittent fasting plus ketosis really helps my Zone 2. And then this leads into the question of just training in general. So I have to click on this, what type of exercise reduces heart aging by 20 years? Do you want to start there or do you want to start with VO2 max?

Dr. Rhonda Patrick: We can start with VO2 max maybe because — 

Tim Ferriss: Okay, let's do it.

Dr. Rhonda Patrick: — they kind of lead in to each other.

Tim Ferriss: Great.

Dr. Rhonda Patrick: And so people might be going, what is VO2 max? It's essentially a cardio respiratory fitness. It's measured by VO, it's measured or calculated by VO2 max, which is essentially the maximum amount of oxygen you can take up during maximal exercise. And what's so fascinating about that is it's a really important predictor of longevity. So there have now been enough studies that have come out looking at cardiorespiratory fitness in the sense of VO2 max and how people with a higher cardiorespiratory fitness have a five-year increased life expectancy compared to people with a low cardiorespiratory fitness. In fact, if you have a low cardiorespiratory fitness and you go anywhere above that from low to low normal, it's associated with a two-year increased life expectancy. And people with a low cardiorespiratory fitness actually have a higher all cause mortality that's comparable or worse than people with known diseases like type 2 diabetes or cardiovascular disease or smokers, for example.

So in other words, being sedentary is a disease and we need to think about it as a disease and we should be trying to train to improve our VO2 max. And that is something that should be in our minds. And I say this because just having this conversation that you and I are having right now, it takes about 11 milliliters of oxygen per minute, per kilogram body weight just to have this conversation. Now, just sit still and just breathe. It takes about three milliliters of oxygen per minute, per kilogram body weight. And that's important because as we're aging, we're sort of heading towards this cliff of VO2 max. Our VO2 max goes down as we age just naturally. Even if you're training and doing everything, it goes down.

And once you get to that cliff, everything becomes a maximal effort like talking, you're out of breath. Carrying groceries to your car from the store, you're just out of breath. Everything is a maximal effort, and you don't want to be there.

So you want to start from a higher-up point so that when you're going down, that cliff is much further away. And that's where the training comes in because you want to find a training program that's going to improve that cardiorespiratory fitness, right?

And that's where you talked about Zone 2 training and that's the kind of what I would call moderate intensity exercise. So you're able to sort of the talk test, I like the talk test because heart rate is so dependent on a person's fitness level. But let's just say on average, generally people, they're not at like 75 or 80 percent max heart rate. They're kind of below that on average.

Now some people may actually be above that, but the talk test is great because you can have a conversation, you're breathy. You don't want to have a conversation, but you can or so.

We know that people that are doing that moderate intensity type of training, if they do the standard guidelines of physical activity, which are about two and a half hours a week of moderate intensity physical activity, people that do that for two months, 40 percent of those people still can't improve their VO2 max.

Tim Ferriss: Just different gears.

Dr. Rhonda Patrick: Well, unless they actually add in high intensity interval training.

And that's where I kind of get into this. I think people should be doing vigorous intensity exercise. That's the type of exercise where you're unable to talk, so you can't have a conversation because you're going harder. Your heart rate is about 80, 85 percent. It's above 80 percent max heart rate.

That type of exercise has been shown to improve VO2 max, especially if you're doing sort of what's called high intensity interval training, as you know, you've talked about this a lot as well. But you're doing sort of these intervals of going more vigorous intensity exercise, and then you have recovery periods where your heart rate goes down. So there's been a variety of different protocols out there that have been shown to improve the VO2 max if you do them.

Generally speaking, what's happening is you're putting a stronger stress on your cardiovascular system, so on your muscular system, even on your brain. So the adaptations are greater, and one of those adaptations is increasing your stroke volume, so being able to like basically transport oxygen to tissues faster. And that's an adaptation that happens when you're going at a harder, when you're training at a harder intensity.

Tim Ferriss: What do you do personally? What's your HIIT look like?

Dr. Rhonda Patrick: So my training is three days week I do some sort of CrossFit training that involves high intensity interval training with it as well. And the high intensity interval training will either be on a rowing machine, or it'll be on a stationary bike or AssaultBike, or it'll be like a skier, like those skiers or jumping rope.

And I also do longer intervals, so I'll do the Norwegian 4×4. So that's where I do, on a stationary bike, or I do it on a rowing machine actually as well. I do four minutes of as hard as I can go and maintain for that entire four minutes. So this is obviously not an all-out 30-second sprint. I'm just working hard, as hard as I can, and maintain that for four minutes.

And then you recover for three minutes, and then you do it four times. I'm thinking of a variation I do sometimes with my husband. I recover for four minutes because we're switching on the rower. So I sometimes do a little bit longer recovery.

But that Norwegian 4×4 where you're doing as hard as you can for four minutes and maintain that intensity for the four minutes and then you recover for three minutes, you do that four times, that's been shown to be one of the best ways to improve VO2 max.

But you can also do one minute on, one minute off, which I've also done. So you do that 10 times. It's more like a 20-minute workout. That's also been shown to improve VO2 max.

But also even doing something like 20 seconds on, 10 seconds off like a Tabata, again has been shown.

And I do all of these, by the way, and I do variations of them depending on the week. Most of my exercise is high intensity interval training, CrossFit training, which incorporates, it's more dynamic. So it's including like strength training stuff, but it's like more high intensity.

And then I do a couple of runs. I do like two 30-minute runs a week, sometimes three. And that's more of my Zone 2 stuff.

Tim Ferriss: Yeah, it's a nice roster.

So I'll share, just for people who might be curious, some of my goals and program at the moment, right?

So I'm about to turn 48 and feel good overall, but have realized that I really hate endurance training, generally speaking. So I've neglected that and specifically have neglected the stuff that makes me think I want to puke into a bucket, i.e. VO2 max training. The Zone 2 is like listen to a podcast, maybe I have like a slightly breathy conversation. Like it's pretty chill. Watch something on Netflix. It's pretty straightforward.

VO2 max, specifically chatting with Peter Attia, I'm doing the Zone 2, which I do either on a stationary bike or on the treadmill, typically with a rucksack at a lower incline. I found that when I had the speed too high, incline too high, I ended up getting lower back pain just from a like really long stride with my lordosis and stuff.

And then for the VO2 max, doing the 4×4 that you described. And I think I'm getting this translation right, but the way it was described to me was like, all right, for each of those four minutes you have these four-minute work intervals, and then you have three or four minutes of rest, and then you repeat four times.

It's like first minute you're like, “Wow, this is a lot of work.” Second minute you're like, “Wow, this really sucks.” Third minute you're like, “I don't know if I'm going to make it. I don't think I'm going to make it.” And then minute four is like, “I feel like I'm going to die and I'm being chased by wolves.” So it's like when we say like maximal effort, at least as it's been, and those are not Peter's words, but another person that I like a lot.

It's a lot of work. Like it's pretty pukey, but I'm going to be doing that, given the longevity associations that you mentioned.

Now, I would love just to get your two cents, and this relates to vitamin D2 a little bit for me where I'm like in these studies looking at VO2 max as a predictor or correlate of longevity, are there other possible confounders, confounding variables that might actually be the real McCoy?

In other words, because you could say, and I know you know all this, but just for people listening, it's like, okay, well, I'll make this up. Like women who do Pilates in Manhattan have four years of additional lifespan. Okay, great. So you could conclude then we should all do Pilates to improve lifespan. It's like, well, wait a second, Pilates is expensive, and maybe they're also following a better diet and so on and so on and so on.

So are there any confounders that might apply, possible confounders to these VO2 max studies? I'm assuming they're observational, more than experimental, or sort of intervention-based. So what are your thoughts there?

Dr. Rhonda Patrick: Yeah, I mean there's absolutely a possibility for some sort of confounding factors in any sort of observational study, including the ones I'm discussing. Because, yes, they're going in and measuring their cardio respiratory fitness, which is better than a lot of observational studies that you're going off a questionnaire, right? So that's already sort of one, at least a one up over other observational data.

But at the end of the day, you may have someone that has undiagnosed cancer or some kind of undiagnosed disease because diseases are, I mean, they're not, they're supposed to be disease free or if they have a disease, it's known and so everything's corrected for. But there's always the possibility that some people have some disease and that's why they can't exercise very well because they're diseased, and it's the disease that's causing them to have a higher mortality rate than the lower cardiorespiratory fitness is.

Studies always try to account for diet and all that stuff, but at the end of the day, you can never really establish causation, right? So that is why we turn to randomized controlled trials. And I will say this is where the heart aging comes in and also this type of training.

Tim Ferriss: Can I do one more thing real quick? Before we get to the heart aging, real quick.

So when I've done VO2 max training, my legs grow, my legs grow like weeds, like they adapt and get big. So along with the age-related decrease in VO2 max, there's also sarcopenia and age-related loss of muscle mass.

So I'm like, I wonder if these people who also have higher VO2 max tend to have a higher percentage of lean body mass or muscle tissue be more heavily muscled than the people without, I don't know. I mean, that's just — I'm just kind of poking at it out of curiosity. 

Okay, so the heart aging.

Dr. Rhonda Patrick: This goes into why randomized controlled trials are important because you can establish more causation from an intervention. And this study was done by Ben Levine out of UT Southwest and Dallas. And really, to me, it's a seminal, groundbreaking study that isn't talked about enough.

By the way, he's just a phenomenal cardiovascular exercise physiologist. I mean, he trained with, like, the biggest giants out there.

And what he did was he took, him and his lab took 50-year-olds that were sedentary. So they're middle-aged, 50 years old, sedentary, but otherwise healthy. So you didn't have any other diseases besides being sedentary, which I think is a disease, but they didn't have any other diseases like cardiovascular disease or type 2 diabetes or hypertension, right? So they were otherwise healthy, just not active. And he wanted to see if he could put these guys on a pretty long two-year training protocol, how would that affect the aging of their heart?

So as we age, our hearts typically shrink in size, and they get stiffer. And that affects not only our cardiorespiratory fitness and our ability to exercise, and I mentioned our cardiorespiratory fitness goes down with age, but it affects our cardiovascular disease risk as well.

So the reason our hearts get stiffer, by the way, does come down to a lot of glucose. So the more glucose stimulation, more glucose is around in your vascular system, it through a chemical reaction forms advanced glycation end products. So this glycation essentially stiffens the collagen that surrounds your myocardium and your pericardium, and so you get like this stiffer heart that can't respond to stress well.

So you want your heart to be very plastic and malleable and flexible, right? You don't want it to be stiff.

Tim Ferriss: Doesn't sound good, yep.

Dr. Rhonda Patrick: So just like you don't want your blood vessels to be stiff, right.

So what he wanted to do was see if he could change the structure and the trajectory of these aging hearts. So he put them on a two-year training program, which involved the Norwegian 4×4, by the way. And when you start someone out that's not physically active and you want them to do the Norwegian 4×4 when you have them doing their interval, their four-minute interval, and this speaks to you as well, or anyone, you don't have to necessarily go as hard as you can the whole four minutes. But you just have to be working hard that interval.

Tim Ferriss: Yeah, you do have to last four minutes, right? So — 

Dr. Rhonda Patrick: You have to last four minutes. So some people even start off, they're just briskly walking because that's hard for them, right?

Tim Ferriss: Yeah. Yeah, totally.

Dr. Rhonda Patrick: So it's all tailored to the individual. So some people get really intimidated where they're like, “Oh, there's no way I could ever do that.”

Well, actually these people did do it, and they started out doing the Norwegian 4×4, but they also did a variety of other exercises, including moderate intensity and some more vigorous intensity exercise, as well as some resistance training. And the control group was just this like yoga flexible training sort of stuff that people were doing.

By the end of the two years, these people were working out about five hours a week, and at some point they were doing two Norwegian 4x4s a week, and then they went down to just doing one a week. But over the course of two years, they were getting a lot of exercise, about five hours a week.

And essentially at the end of those two years, the structure of their heart, so the stiffness of it and the shrinking of it was reversed. So their hearts grew and they became more flexible. And it was reversed in such a way that it was 20 years less aging. So their hearts looked more like 30-year-olds than 50-year-olds, which is pretty incredible.

Tim Ferriss: That is amazing. And I think it's also like, well, you think 50, it's too late to start exercising.

Well, it's not too late. I mean you can be in your 90s and get benefits. So I think that's another really important sort of take-home with that story is that you can reverse your aging of your heart by 20 years if you really put in the effort.

Five hours a week is about what I do, five or six hours a week. It's a lot of work. I didn't always do that, but I've decided as I started to get into my mid-40s, I'm going to spend less time podcasting and more time exercising because this is my health.

Tim Ferriss: Yeah, foundational for everything else, that's the base of the pyramid.

Dr. Rhonda Patrick: Right.

Tim Ferriss: All right. So let's park that particular piece of training for a moment. Do you want to piggyback on that and talk about reversing brain aging with exercise? Is it a different type of exercise, or do you get two birds with one stone?

Dr. Rhonda Patrick: You do get two birds with one stone. And that's why I do like the vigorous intensity exercise because when you're kind of shifting into working out harder, when you're getting that vigorous intensity exercise, you are shifting somewhat to anaerobic metabolism.

So you're working so hard that you can't get oxygen to your muscles fast enough to use mitochondria for the mitochondria to then make energy. So your body goes, I need energy quick right now, there's not enough oxygen here, and so you start to use glucose outside of the mitochondria as energy, and that's called glycolysis.

And you're not just only doing glycolysis, by the way. I mean even if you're doing an all-out sprint, you're still somewhat using your mitochondria. It's not like a black-or-white thing, right? There's sort of gray here. But the reality is, is that when you're not going intense, you are not, mostly you're not doing anaerobic exercise.

So what happens is when you're doing that, sort of getting in that anaerobic state, what I mean is like you're not using oxygen to make energy. You're just using glucose. You actually make something called lactate as a byproduct, and lactate is what's essential for the brain health.

So there have now been a variety of studies. This was pioneered by Dr. George Brooks at UC Berkeley decades ago. So many studies have now shown this now. It's no longer a hypothesis, but it used to be called the lactate shuttle hypothesis where, when you start to do this vigorous intensity exercise and you get your lactate levels higher than baseline, baseline, you're usually about 0.9 millimolar or so lactate.

You start to go above that and well beyond, you're getting 7, 10 millimolar or 15 millimolar, right? The lactate gets into your bloodstream and it's used by other tissue. So it goes back into the muscle. It's used for energy, gets into the brain, it gets into the heart, liver quickly. It happens within 20 minutes. You can do a HIIT workout, see your lactate go up to 15 millimolar, measure it 20 minutes later, and it's back to baseline. I mean, it's quick. It gets consumed.

One of the major organs that consumes it is the brain. This has been shown in human studies. Not only is lactate very much like beta hydroxybutyrate, our favorite ketone that we've been talking about, because it's an energetically favorable source of energy. Lactate is used by neurons to make energy, just like beta hydroxybutyrate is very similar. It's energetically favorable. All that stuff is happening, same stuff. So you're using the lactate, glucose is being spared, you're making glutathione.

Lactate is also a signaling molecule. So in the brain, it's activating brain-derived neurotrophic factor, which is important for growing new neurons in the brain, which has been shown in human studies. So there've been human studies that have done exercise for even just one year and shown that you can increase the growth of the hippocampus by like one to two percent after that year of training versus losing one to two percent of the hippocampus. That usually happens as you get in older age.

So the lactate is again a product of that vigorous intensity exercise. It's increasing norepinephrine in the brain, serotonin. It's a signaling molecule. It's basically your body's, your muscle's way of communicating with the brain, “Hey, I'm really working hard. This is a stressful time. Let's respond to that stress,” right? So your brain is also working hard during exercise and particularly vigorous intensity exercise. It's stressful in the brain. Anybody that's done it knows it.

Resistance training also increases lactate and resistance training is very stressful on the brain. And so it's like this response to that stress. Your brain is now being communicated from the muscles by lactate, which is the communicator and saying, “Hey, make all this good stuff so that we can not die,” right? That's essentially the adaptations that are happening.

So that's why I like to also incorporate vigorous intensity exercise into my program because I am also prone to neurodegenerative disease. I have Parkinson's disease on my dad's side, I have Alzheimer's disease on my mom's side, so I'm very, very tuned in to neurodegenerative disease and wanting to prevent it and do what I can. And I do think that vigorous intensity exercise is part of that equation because I want to get that lactate, which is so beneficial for brain health.

Tim Ferriss: So let me ask you about two other things related to brain health since this is on the mind, ha-ha. For the first is related to saunas and the second one is vitamin D.

So with saunas, I was looking back, and I think this is probably summarized by some LLM, so I want to be very careful with citing numbers. But I'm looking at a summary, I believe, of the findings of a large Finnish study published in JAMA Internal Medicine 2015 that followed 2,000 middle-aged men for 20 years. That's wild. And it looks like, please correct me from memory, you can correct any of this, but all-cause mortality, 24 percent lower risk with two to three times per week. This is sauna use and four to seven times per week was associated with 40 percent lower risk.

And I'll just cut to the one that's of greatest interest to me right now. It says in a follow-up paper, using the sauna four to seven times per week was associated with a 66 percent lower risk of dementia and 65 percent lower risk of Alzheimer's. Now at face value, if those numbers are roughly accurate, those numbers seem incredible, right?

And I guess what I'm wondering is how should we think about those results? Because if out of 100 people, two people were getting dementia and now it's one person, it's less interesting than other ways of interpreting the data. How should we think about this, and how do you personally use if you do sauna or hot tub or heat stress at this point?

Dr. Rhonda Patrick: Yeah. So those numbers are accurate, By the way. They're spot on, and there is a dose-dependence there, which kind of strengthens the data. So people that are using the sauna more frequently are having a more robust effect. You mentioned 24 percent lower all-cause mortality, and then 40 percent if they're doing two to three times a week versus four to seven times a week, they're having a 40 percent lower all-cause mortality. And the dementia risk is also extremely interesting to me.

And this goes back, Tim, to some of the earliest experiments that I did as a sort of budding young biologist at the Salk Institute where I was working with these little nematode C. elegans worms and injecting human amyloid beta-42 into these worms, and essentially injecting it into their muscle so that they become basically the amyloid beta-42 aggregates and forms these aggregates as these worms age.

And it happens very rapidly because their life expectancy is only 15 days. So within a day or so, they start to become paralyzed where they can't move their lower half of their muscles, their muscular cells are, and they can only move their nose to feed in this little Petri dish with E. coli bacteria, which is what they eat.

So I would do these experiments and then I would overact, basically when you do a genetic manipulation and you can make them overexpress heat shock proteins, which are something that are robustly activated upon heat stress as the name implies. And sauna has been shown to activate heat shock proteins. If you're in the 163 degree Fahrenheit sauna for around 30 minutes, you can activate your heat shock proteins by 50 percent more than baseline.

So when I would add heat shock proteins that would be activated in these worms, it would prevent this from happening. These protein aggregates don't happen. And that's because one of the things that heat shock proteins do is they help repair damaged proteins that are misfolded and prevent them from aggregating. So you want to have more active heat shock proteins if you're wanting to prevent Alzheimer's disease.

Now, there's a lot of animal studies that have shown this as well. For example, you can take a mouse and sort of give it Alzheimer's disease in this similar way. And if they have a lot of active heat shock protein genes, then they're not getting the Alzheimer's disease. It delays it, right?

So when I remember reading this study, and it was like one of the things I was thinking about was, of course, the heat shock proteins are activated upon the sauna use that you would probably see a lower incidence of Alzheimer's disease and even dementia.

There's other things as well. Cardiovascular health is really improved with the sauna. So sauna sort of mimics moderate intensity exercise. So if you're having improved cardiovascular health, that means more blood flow to the brain. Lots of things are happening, right?

The one thing I do want to mention, Tim, and this study was, I think it came out in 2020-ish, I don't remember the exact year, but it was not out of Finland. I believe it was a Polish study. And that study looked at sauna use and dementia risk, and there was very interesting results there.

So they sort of looked at people that are using saunas, but they also sort of categorized them based on the amount of heat, so how hot their saunas got.

So in the Finnish studies and out of Finland, majority of the people are using the sauna at around equivalent of 174 degrees Fahrenheit. That's about what the average temperature of pretty much any of those studies that you cited. That's about the average temperature that they're using in, and they're in there for about 20 minutes.

Now, this other study looked at a wide range of different temperatures, that temperature versus like the really, really high extreme end so people that were doing like 200 degrees Fahrenheit or more.

And this is something that you can see nowadays, like there's this sort of go all in, go hard or go home, right? So people think that they need to go in a 200 degree sauna. And if they go in a 200 degree sauna, it's going to be better than going in a 175 degree Fahrenheit sauna, right? Apparently, not the case.

So in that study, again, you saw a protective effect of people that use the sauna, and I think it was also dose-dependent, but I can't recall, there was a protective effect, but only if they used saunas that were less than 190 degrees Fahrenheit. People that started going into the 190 degrees to 200 degrees Fahrenheit range actually had an increased risk.

Tim Ferriss: Oh, no.

Dr. Rhonda Patrick: So that was something that I don't know that anyone talks about, but I've done really, really hot saunas before. I personally don't like it. I get headaches, actually. So your head is in there and you have to think about that. Your head is getting heated up. So I don't know that it's necessarily good to go in a 212 degree Fahrenheit sauna for your head.

Now I don't want to say that with certainty because there could be all kinds of confounding factors, but it's something to keep in mind.

And why do you have to go above 190? Well, 190 is hot as hell. That's good enough. Like you don't have to go above that.

Tim Ferriss: Yeah, my default setting, my sauna is 194, so it's just kind of like — well, I guess I set it some time ago, so it's just been set at 194, so that's kind of my default. So maybe I want to dial it back. Yeah.

Dr. Rhonda Patrick: I think 190 is great. Yeah, 190 is great.

So you asked about me and how I use the sauna. Now I should also mention that hot tubs are good as well. And in fact, the study just came out a few weeks ago showing that hot tubs have comparable effects on blood pressure regulation, all these parameters that are looked at with sauna use as well.

And a lot of people ask that question. “Oh, what about a hot tub or a hot bath?” And I think not everyone has access to a sauna, not everyone has access to a hot tub, but a lot of people have access to a hot bath.

And I think if you can get a sort of pool thermometer and keep the temperature of your bath 104 degrees Fahrenheit, which is what all the studies use, you have to keep adding hot water. That's fine.

Tim Ferriss: It's pretty hot.

Dr. Rhonda Patrick: But you want to stay in there.

Tim Ferriss: Yeah, it's hot.

Dr. Rhonda Patrick: Yeah, it's pretty hot. You stay in there for about 20 minutes and you're going to have comparable effects.

Tim Ferriss: Yeah, you'll be sweating like you're in a sauna. Don't worry about it. Yeah, 104.

Dr. Rhonda Patrick: Exactly. 104 is hot. And I actually do both. I do a hot tub and I do sauna.

I like to do hot tub at night. It does seem to help with my sleep. But sometimes I'll do the sauna in the day and I'll do it after a workout, and it sort of extends my workout. I particularly like doing them after a workout like in the winter when it's cold and if I work out outside. So that's kind of how I use the sauna.

I used to do hot, I was doing hot tubs for a while like every night. I don't do that in the summer because it's just hot and so I don't like — I actually shift more to doing cold exposure more in the summer, which is kind of funny. Pretty much the only time I do it is in the summer. Such a wuss. I like doing the heat a lot in the winter.

Tim Ferriss: I would be very curious to see if they measured sperm like motility and morphology for all the males who are doing this. And they're like, “Good news. You have this incredibly lowered risk of Alzheimer's. Bad news. You're effectively sterile from all the heat on your swimmers.”

Dr. Rhonda Patrick: Good point. Yeah, there's been studies that have shown you do lower motility, for sure. The motility rate's lowered and that those changes are reversed after six weeks of abstaining. So it is reversible.

But also don't use it as a contraception method, either, because I know some people that have tried that. It doesn't work. You can still get pregnant.

Tim Ferriss: That's not so smart. Do you still use, if needed, curcumin or Theracurmin or any of these products? I think Meriva or Meriva was one that you mentioned as a formulation in place of NSAIDs, like ibuprofen or naproxen? Or is that something that you may have changed your mind on?

Dr. Rhonda Patrick: I actually just did it like a couple days ago when I had a headache, and I didn't know why. That's the thing that I go to still, and I mean, there's some cases where it won't work, where it's just like, I don't know, this is like a really bad headache. I don't usually get headaches, but if I don't sleep well or something, something going on or my cycle, I will get a headache and I use it.

I use four of the Meriva, which is a phytosomal curcumin, which increases the bioavailability of the curcumin. I use the Thorne brand just because I like the, I think the brand is reliable, no affiliation with them, but it works for me. It really does. So it's, I think, 500 milligrams of curcumin per capsule, I believe. And so I do four, so I'm getting two grams.

Tim Ferriss: Yeah, cool.

Dr. Rhonda Patrick: But I do still use it.

Tim Ferriss: Yeah, just don't take it right after your workout, right?

Dr. Rhonda Patrick: Yeah, It doesn't have the same effect.

Tim Ferriss: Yeah, it doesn't have the same kind of COX-2 inhibition as the other does, right?

Dr. Rhonda Patrick: It doesn't. Uh-huh. And in fact, I think it helps with DOMs, delayed onset muscle soreness.

Tim Ferriss: Oh, I'm sure, yeah.

Dr. Rhonda Patrick: And so sometimes, I do use it actually after a really, like, hard squat workout.

Tim Ferriss: All right. I'm glad I asked.

So speaking of not getting enough sleep, let's hop to creatine because, God, I don't know where I read this, but that higher doses of creatine, maybe like 25 grams, 20, 25 grams could combat sleep loss or some of the effects of sleep loss.

What should we know about creatine? Creatine has been around for a long time. There are dozens of questionable sports performance, athletic performance products come out every year. Most of them are all marketing, no substance.

Creatine has been used by athletes for a very long time, but for at least the last five years, I have been taking it typically five grams a day, more for the cognitive or potential cognitive benefits.

But what else should we know about creatine? Because what you put in your newsletter not too long ago was forwarded to me, and then you told me via text. I was like, okay, we should probably talk about this. So how should we think about creatine and best practices for different applications?

Dr. Rhonda Patrick: Well, it's funny. As you mentioned, it's one of those supplements that have been, it was like in the gym bro world forever, and still people associate it with that. But yet it's been one of the supplements that's actually stuck, right? It's worked. And there's been countless studies showing its effectiveness, particularly with respect to increasing exercise volume.

So in other words, what creatine is, is it's essentially, it's stored in our muscles as something called phosphocreatine. When you take creatine exogenously, it's stored in our muscles as phosphocreatine and then used for energy. So it's a way to make energy quicker, right? So the more of it you have stored, the quicker you can sort of make that energy.

So what it's been shown to do is really help with increasing exercise volume. In other words, you can do one to two more reps per set or sets. I mean, you could do an extra set, or whatever it is you're doing. And that leads to obviously if you're increasing your workload, you're going to have increased muscle mass and muscle strength because you're increasing your workload. It doesn't work like protein in the sense that you can increase muscle mass because it's anabolic. You need to put the work in.

So creatine by itself isn't going to make your muscles grow, but it is going to make you work harder. It's going to be easier for you to work harder, and so you end up increasing your exercise volume, which then has adaptations on your muscle. And that's why a lot of people like it because for one, they want their muscles to grow bigger and stronger, and two, some people like to use it during competitions or something because they want to be able to increase that exercise volume as well. It's also really good for that explosive-power type of exercise, again, because getting that quick mobilization of producing energy.

And I'm just glossing over decades of research and a lot of specifics here, because I want to get to the brain. But it turns out creatine is something that our liver makes a little bit, I think maybe one to two grams a day. It's also something that's found in dietary sources, particularly animal products. So it's high in meat, poultry, fish, dairy, not so much in vegetables. So vegans and vegetarians actually end up — they can have lower creatine if they're not supplementing with it because they're not eating animal products. Well, it turns out that it seems as though if you're supplementing and eating a high meat diet, you're getting a good amount of creatine. Five grams seems to be about the point at which your muscles get saturated at least over the course of a month or so. So if you've been using creatine for a month or two, your muscle stores are saturated, and five grams a day is kind of what's consumed by the muscle on a daily basis to kind of maintain that.

So I would argue that you might want to go above that to get the brain benefits, and here's why. Because your muscle is very, very greedy when it comes to creatine. So that five grams that you're taking — I used to take five grams a day until about last April or March or something like that. So the five grams a day is what's been shown in countless studies, and that's probably why you take it. I took it because it was countless studies showing five grams a day was the dose. That was the dose that you needed to get the muscle benefits.

All these brain benefits now coming out seem to be at higher doses, and you mentioned one that was 25 grams, I mean 20 to 25 grams, which is kind of a crazy study where they did about 21 hours of sleep deprivation, essentially. They were barely sleeping at all. And giving them the 25 grams of creatine, 20 to 25 grams, depending on their weight, seemed to not only negate the negative effects of sleep deprivation on their cognition, but it also improved their cognition beyond what their baseline normal cognition is when they were sleeping.

And that's what was really intriguing to me as well as some of the other studies where older adults are given 20 grams of creatine and it improved their cognition. We now have the first pilot study in Alzheimer's disease where, again, 20 grams were given to a very small number of people with Alzheimer's disease. It also improved cognition. It turns out that when you start to go above the five grams and you get into more the 10 grams range, then some of that creatine is getting into the brain versus being all consumed by the muscle. I personally use creatine now. I do 10 grams a day, every day. And what I have noticed, and this could be totally placebo, but I'll tell you when I don't do my 10 grams a day, what I have noticed is that the afternoon sleepiness kind of slump I get is completely gone if I take my 10 grams a day. 10 grams. I don't get afternoon sleepiness. I miss it. I get it.

So it's not like a stored-up kind of thing. It's like, no, if I miss it that day, it's noticeable. If I travel and I don't have it, it's noticeable. So I'm hooked on the 10 grams a day. If it's placebo, I don't care. It works. On top of that, what I've also been doing ever since that study came out with 21 hours of sleep deprivation, I take about 20 grams of creatine when I'm traveling and I have to give a talk or I'm doing a podcast, particularly because oftentimes I'm traveling either to Central Time or to Eastern Time. And I'm giving a talk early in the morning, which is 6:00 a.m. my time. I got to be on my game. So I take the 20 grams and I kid you not, it's like you get this brain boost, but without the caffeine. It's hard to explain.

Tim Ferriss: Without creepy crawly ants on your skin, jittery caffeine overdose.

Dr. Rhonda Patrick: Right. Without that jittery thing. And even that, sometimes the caffeine isn't enough if you're really jet-lagged, especially if you're going across time zones.

Tim Ferriss: Well, also for me, it's like I'm a caffeine fast metabolizer. If I have a cup of coffee, I'm on fire for 25 minutes and then I'm sleepy. I think some of that is actually a glucose response, but that's a whole separate thing. I've been using glucometer when I was doing all my ketogenic experiments and so on. I'm like, wow, if I have too much coffee, there is a huge, which is not that surprising, spike in glucose and then a very predictable subsequent drop off. So it doesn't end up being net net that helpful for me unless I'm doing a 20-minute sprint on something, which is probably never.

So the creatine is super interesting to me. Let me ask some very specific, maybe mundane questions, but I think they're practical, which is, when these subjects were taking 20 or 25 grams, was that in one sitting? Was that in multiple divided doses? When you take it, is it in powder form? Is it little sachets that you can take with you on travel days? Is it encapsulated? What does it actually look like?

Dr. Rhonda Patrick: Yeah. With respect to all the studies, I don't remember if they were in one sitting. A lot of studies are. If they do like a 20 gram, it will be in one sitting. What I do is different. I do five-gram doses. So creatine monohydrate is the form I take. It's the absolute tried and true — 

Tim Ferriss: The gold standard. Yeah, it's been around — 

Dr. Rhonda Patrick: It's the gold standard.

Tim Ferriss: It's been around forever.

Dr. Rhonda Patrick: Yeah. There's a lot of other marketing out there that talks about other types of creatine, but that's really the gold standard. And I had Dr. Darren Candow on my podcast. He's a creatine researcher at the University of Regina in Canada, and we talked all about this and he really convinced me, creatine monohydrate is the way to go. I asked him about every type of creatine under the sun. But the way I take it is in five-gram doses. And so I do five grams first thing in the morning, and then I'll do my workout and then I do another five grams about 11:00 a.m. And that's my 10 grams that I get.

Tim Ferriss: Got it.

Dr. Rhonda Patrick: When I'm traveling, I do have these sachets that, again, Thorne makes. By the way, no affiliation. I mean, there's probably a million other — I like Thorne because their creatine is NSF-certified, and so it's free of contaminants. I really like that. So again, find your own favorite brand, but I like this brand. And they have sachets, which are five-gram sachets. And so I will have my 10 grams for the day, or again, if I'm traveling for work-related purposes, I will take 15 to 20 grams depending on how much I need. In that case, I will do two 10-gram doses. For me, I can tolerate that. I don't have any GI problems with it. Some people do.

Tim Ferriss: Yeah. I was going to bring that up.

Dr. Rhonda Patrick: Yeah. Some people do. I think doing the five-gram doses is pretty easy on the gut. Most people don't have a big problem with the five grams.

Tim Ferriss: Yeah, five is fine.

Dr. Rhonda Patrick: It's when they go above that.

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: Right.

Tim Ferriss: Yeah. So I'll say a few things. So the NSF-certified is a pretty simple cheat code just to use as a filtering mechanism for a lot of supplements. And it is shocking how inconsistent supplement contents are. I mean, I've looked at lab reviews of 20 off-the-shelf melatonin products, and it ranges from zero melatonin up to 20x the label amount. It's just bananas. So I use Momentous creatine, but it's passing the same hurdle.

And I'll say good news, you can reduce the likelihood of cognitive deficit from sleep deprivation. Bad news is you could increase the likelihood of disaster pants if you have 20 grams at one sitting. And I will say, maybe from personal experience, maybe I'm just talking about somebody else, but if you really want to increase the likelihood of disaster pants, then you can do a bunch of caffeine, like a double espresso or black coffee with MCT powder, and then have your creatine around the same time. That would be asking, you're going to want to pack some Pampers in your travel kit if you do that. So yeah, just be aware of the GI stuff.

But I'm excited to up my intake, because the science that you cited in the study or studies in your newsletter seemed really compelling. And it's also one of those supplements where it's like, okay, look, I assume this is on the grass list. They generally recognized it's safe, seems very well-tolerated, over decades and decades of research, assuming you don't have some who knows, right? Really outstanding kidney dysfunction or something, maybe. So why not, in a sense? It's also relatively inexpensive compared to a lot of things.

Let me ask you, just because this has been on my mind. With the sulforaphane — I mangled the pronunciation a bit. Sulforaphane. Do you take that better on an empty stomach? Better with food? This has become an issue when I'm doing the intermittent fasting sometimes, especially if there's something like the AREDS 2, which I'm taking for the eye health, which is supposed to be twice a day. And I'm like, oh, it's part of the reason why I've been doing the, quote, unquote, “dirty fasting,” with a little bit of fat in the form of that heavy cream in coffee, was to try to take supplements earlier in the day that are benefited from some type of fat in terms of absorption. Sulforaphane. Does it matter?

Dr. Rhonda Patrick: I think if you can take it fasted, that's great. Some people find it kind of as hard on their stomach and so they like to take it with food, and that's really the only reason to take it with food is because they get upset stomach. It's like GI problem. So that would be, again, the only really real reason that you would have to really take it with food.

Tim Ferriss: I wanted to loop back around just so people aren't like, “Ferriss, you forgot about vitamin D.” I wanted to talk about vitamin D. So the vitamin D, I've taken vitamin D forever, tend to take 5,000 IU a day. I particularly in the summer get I would say at least an hour in the sun without skin protection. And I built up to that. I'm not an idiot about it. And yet, I am barely — in my labs, I'm always barely squeaking by on vitamin D.

And for almost all of my adult friends who get labs — and this is also race agnostic, right? Everybody is deficient or just on the border of being deficient, even if they seem to be taking a lot of supplemental vitamin D and getting a lot of sunshine. And I have to ask myself, what the hell is going on here? In what set of circumstances is it possible that everyone would be so deficient if they seem to be getting a bunch of sunlight, they're taking a bunch of supplemental vitamin D? Can you shed any light on this?

Dr. Rhonda Patrick: I can.

Tim Ferriss: Or is there a problem with this measurement in the first place? Which is why I was talking about proxies and confounders and stuff earlier with respect to some of the other studies. Yeah, so please and please educate me.

Dr. Rhonda Patrick: Yes. Okay. So the way vitamin D is measured, so vitamin D actually gets converted into a steroid hormone, and this steroid hormone, essentially, it's going inside the nucleus of our cells where all of our DNA is and it's activating 5 percent of the protein encoding human genome. Many of these genes, it activates Klotho. By the way, you mentioned Klotho. Vitamin D is important for activating Klotho.

Tim Ferriss: Yeah. Nice.

Dr. Rhonda Patrick: Yeah. So very hugely important for dementia risk, which we can talk about. But to answer your question, so your vitamin D levels are measured by a proxy and it's called 25-hydroxy vitamin D, which is the precursor to the steroid hormone. So essentially, vitamin D3, which is made in your skin, or if you supplement with it, exogenously gets into your bloodstream. And that vitamin D3 then goes to the liver and it's converted into 25-hydroxy vitamin D. That's the major circulating form of vitamin D.

After 25-hydroxy vitamin D is made in the liver, it then goes to the kidneys and it's made into the actual act of steroid hormone, which is called 1,25-hydroxy vitamin. Well, it turns out the enzymes that are doing the conversion of vitamin D3 into that stable form that everyone gets when they're getting a vitamin D blood test, that's what they're looking at, requires magnesium to work. And there have been studies showing that with low magnesium, it doesn't happen readily at all.

Tim Ferriss: Interesting. Interesting.

Dr. Rhonda Patrick: And so 50 percent of the US population has insufficient levels of magnesium. So you're talking about a coin toss here, right? One out of two. One out of two. You have 50/50 chance a person's not going to be getting enough magnesium. That's been shown to actually play a role in circulating levels of vitamin D. There have been NHANES studies and stuff showing that people that have low magnesium intake also have low circulating forms of 25-hydroxy vitamin D. So that's one thing.

Another thing comes down to genetics. There's actually a lot of people that have SNPs, very common ones that probably came from more southern areas, that don't make as much vitamin D3 from the sun exposure because probably they're getting so much sun, right?

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: So essentially, there's the genetic component as well. And I've seen a lot of people's different SNP makeups, and I know quite a few people that actually have to take a super high level of vitamin D3 to actually get enough vitamin D. And then the other thing is that you mentioned earlier the variation between supplements. There have been studies on vitamin D supplements, and it's the same problem with melatonin. There's some vitamin D supplements with a fraction of what is stated in terms of concentration of vitamin D3 on the nutrition facts, and then some of them have 10 times as much vitamin D.

So there's just this huge variation where you're like, it says it has 5,000 IUs but it only has 500. So there's a lot of different factors that could be contributing to that as well. And then there's also in terms of people getting sun exposure, you said you don't wear sunscreen, some people do. People that have darker skin pigmentation have melanin. That's a natural sunscreen. There have been studies showing that, for example, out of the University of Chicago, there was a study that was published a few years back showing African-Americans have to stay in the sun six to 10 times as long as a Caucasian to make the same amount of vitamin D3 from the same amount of sun exposure. Because they have a natural sunscreen, melanin, which is that darker skin pigmentation. It's a natural sunscreen. It's also why their skin always looks great as they're aging. You're like, “Oh, you're 75? Your skin looks like you're 30.”

Tim Ferriss: Yeah. I remember, I won't mention him by name, but meeting this African-American fellow. And I thought he was 25, and he was 53 and had five big — and the way we got to that is I was like, “Oh, are you married?” And he's like, “Yeah, I have five kids.” And I was like, “Wait, what? You have five kids? You don't look Mormon.” Like, “Wait, what's going on here?” And lo and behold.

So let me dig into some of this real quick. So recommended brands for vitamin D and how much should someone like me potentially be taking as a starting point, because I'm also wary of taking too much vitamin D. I don't want to overdose on vitamin D. It seems like there are some risks associated with that. Maybe I'm overstating them, but how do you think about that? And then in terms of this rate limiting factor that you mentioned, magnesium, what type of magnesium? How much? How should I think about both of these?

Dr. Rhonda Patrick: Okay. So first of all, we need to talk about vitamin D levels and what the optimal levels are, and that's really important for someone to figure out how much they should supplement with. I tend to think anywhere between 40, 60 to 80, 40 to 80 nanograms per mil, you're in an optimal range. I like 40 to 60. I think that's my sweet spot, and that's because there's lots of studies out there showing all-cause mortalities lower within that range. Fifty nanograms per mil would be great. I mean, that's a great place to be. If you're below 30, if you're about just 30, you might want to try to get up to 40. 

Tim Ferriss: Let's just say for argument's sake that I'm at 30. I think I'm probably closer to 40, but let's say it's 30.

Dr. Rhonda Patrick: Okay. For someone that's at 30 nanograms per mil is supplementing with 5,000 IUs a day and getting an hour of sun in the summer without sunscreen, that you probably should be closer to 50 nanograms per mil, I would say, if you're taking that — 

Tim Ferriss: Yeah. I'll check my last labs. I just had them pulled two weeks ago, so I'll double check.

Dr. Rhonda Patrick: Right. So for someone in that case, you might go up to 7,000 IUs and check and see where you're at a month later. And if you then are in the 40 to 50 range, then that's your optimal dose to take. And this is an important conversation to have, Tim, because it really is, there's an individual component here and people just want to, at the end of the day, they want to — how much do I take? How much do I take?

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: Well, you have to get a vitamin D blood test. This is one of those — 

Tim Ferriss: For sure.

Dr. Rhonda Patrick: This is one of those that you have to really measure because, as you mentioned, there's huge variation there in terms of absorption. And then the magnesium issue, there's the RDA for magnesium. So for men, it's about 400 milligrams a day. For women, it's about 300 milligrams a day of magnesium intake from diet or supplemental sources. If you're taking a supplement, and also if you're athletic and sweating a lot and using the sauna, those requirements can go up between 10 percent to 20 percent, depending on how physically active you are. If you're like the endurance athlete, you're on the 20 percent higher range. If you're more just like the average, like I'm a committed exerciser, then you might have to go up 10 percent above that.

So typically, the best forms of magnesium to take are the forms of magnesium that are the organic forms. So that would mean it's bound to salt, like magnesium citrate or magnesium malate or magnesium taurate. Those are more bioavailable than magnesium oxide, for example. There's also magnesium glycinate, which is also a very bioavailable form. It's the form that I take as well. And dose range, you can take 300 milligrams a day and probably not have any GI distress. And so that gets you most of the way there. And then you get the rest from your diet. You're eating some leafy greens. You're eating maybe some almonds or something, which are really high in magnesium. If you're not getting any greens at all, then you're going to have to go up a little bit more to the 400-450 milligram range, especially if you're athletic. But that if you're taking something like electrolytes, you're getting some magnesium there so you can figure out how much magnesium is in your electrolyte and that can be counted towards it as well.

There's also magnesium threonate, which is the magnesium form that is allegedly able to cross the blood-brain barrier better than other forms of magnesium that I mentioned. And I say allegedly because it's animal studies that have shown that. There have been a couple of human studies that were, unfortunately, there's a conflict of interest. They were done by the makers of the magnesium threonate supplement. So that's always important to keep in mind. But they have shown that magnesium threonate could improve some cognitive scores if you kind of pulled all the cognitive scores together. And so I think that there's no reason why if you're interested in cognition and stuff, trying the magnesium threonate.

A lot of people like it as well. So that's another form of magnesium, although I do think you should probably take some magnesium glycinate along with that because you don't want all the magnesium going into your brain. You want some of it going into your liver and activating the enzymes that are converting vitamin D3 into 25-hydroxy vitamin D. So that is something to keep in mind if that form of magnesium indeed is going into the brain more, you want to make sure you're getting some of the other forms to cover the other bases of other organs as well.

Tim Ferriss: What brand of vitamin D supplementation and magnesium glycinate do you use? Is that also Thorne, or are they other suppliers?

Dr. Rhonda Patrick: I use Pure Encapsulations for the vitamin D. I have some friends, mutual friends of ours, that like the VESIsorb Vitamin D3. So people that are not able to increase their vitamin D as well, VESIsorb really increases the bioavailability of a lot of things, including ubiquinol, the CoQ10 I mentioned. I should have mentioned that I buy my dad. That's the form I get for him because it increases the bioavailability. Also, some fish oil, it's been shown to increase the bioavailability. So VESIsorb Vitamin D3 can be found at Pure Encapsulations. I don't have an affiliation with them, either. They also have a lot of clean third party tested products as well. And then I use their magnesium glycinate. For the magnesium threonate, I use Xymogen. I like the Xymogen magnesium threonate.

Tim Ferriss: Great. All right, thank you. I'll get on the magnesium, and I'll also check my last labs. I mean, I am very bespoke about this stuff, and to your point, you got to check your levels, guys. You can't just be shooting in the dark here. It's not a good idea.

Dr. Rhonda Patrick: Right.

Tim Ferriss: All right. Where should we zig and zag to next? Do you want to talk about microplastics and mitigation strategies? 

Dr. Rhonda Patrick: It's really a big mess. And the microplastics are now, it's not just, okay, well, I'm not going to drink out of bottled water, plastic bottled water. If you can get any kind of water filter, any kind of water filter is great. Reverse osmosis is the best because it filters out the smallest, smallest nanoplastics, which are the kind that are actually crossing the blood brain barrier and getting into the brain. In the brain, they're associated with Alzheimer's disease and all kinds of things, but we now know they're in chewing gum. So anything with the word “gum base” is made of a plastic polymer. So if you chew gum, it has to be plastic-free gum. And it's not the same. I'll tell you that. But it's in gum. It's tea bags. Tea bags. If you make tea with tea bags, all sorts of tea bags, they're releasing just thousands of microplastic into your beverage.

They're in essentially everything. And the problem is that it's very hard to avoid. The best things that you can do to avoid them is reduce exposure, which would be the water filter, try to avoid drinking out of any type of water that's in a plastic bottle. But it turns out a new study just came out showing it's also been found in glass bottles. I know. It's like, are you kidding me? Come on.

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: Apparently, the paint that's on the lid of the glass bottle is shedding little particles into the beverage, and those are microplastics because the paint has got plastic in it. And so essentially my take home from this is still, you want to probably use — if you're traveling and you have to choose between a plastic water bottle with water in it and a glass one to buy, I would still buy the glass one because the particle size is higher. It's larger in the glass bottles, and that doesn't get absorbed in the gut very well at all. If any, you actually excrete it through feces.

And so I think the next study that's going to be done will be to show this essentially. I'm sort of speculating here, but because the size matters, the size of plastics and the plastic bottles are super small, and that's really absorbed well by the gut epithelia and taken up into the bloodstream and gets to the other organs. Also, the plastic chemicals like BPA are in plastic. They're not in the glass. So I still think that opting for glass is the best option. Even though that study came out, “Oh, glass has more plastic than plastic bottles.” It's like one of those sensational headlines. The devil's in the details, right? There's always a nuance there. And in this case, the size does — 

Tim Ferriss: The size matters. In this case, size matters.

Dr. Rhonda Patrick: Size matters in this case, for sure. But when it comes to people want to know, is there anything I can do to sort of detox these microplastics? That's the big concern that people have. Well, if I can't reduce, if it's impossible to reduce my exposure because they're just absolutely everywhere, then can I sort of get rid of them? And unfortunately, there's not a lot of evidence right now out there that you can perhaps some of this electrophoresis sort of thing where you kind of filter your blood. But who's doing that? Maybe you'll do it, but that's not something that the public's generally going to do. And I don't even know that I'm going to do it.

Tim Ferriss: It's also, even if they were going to do it or willing to do it, it's not readily accessible or cost-effective for people to use.

Dr. Rhonda Patrick: Exactly. Exactly. Yeah. So again, your best strategy here is minimizing your exposure to them. And the way to do that for one would be obviously a water filter, top of the list, because the water that's coming through your tap, through your sink, does have microplastics in it, and that's a major, major source of microplastic exposure for many, many people. So if you can get any type of water filter again. You can even get countertop reverse osmosis water filters. Those are great for filtering out the majority of microplastics. Big, big, big — 

Tim Ferriss: I wonder if the Big Berkey countertop filtration system is effective at filtering out microplastics? I don't know.

Dr. Rhonda Patrick: It is. It's effective at filtering out microplastics. It's not clear about the nano-nano, like the super, super small size ones. It might. It might not. I don't know, but it does, definitely the micro size ones, it does filter out microplastics. So the thing with reverse osmosis is it's really filtering out all, even the nanoplastics as well. Of course, you have to consider re-adding certain minerals and trace elements that are found in water back to your water. And some reverse osmosis companies do that. You can have them put on a filter that'll just add it back in after it filters out all the microplastics. But you can also just buy mineral drops and put those in your water, or you can take a mineral supplement that has some of these minerals that are taken out as well.

The other thing I do want to mention is that the plastic-associated chemicals are another concern, and that would be like the BPA, BPS. These chemicals are endocrine disruptors. They disrupt hormones. They're also associated with Alzheimer's disease or associated with cancer, all sorts of things. And those can actually — I think, actually. This is a big speculation on my part, just based on animal studies. I think sulforaphane plays a role in detoxing BPA from our system, and that's because of the whole situation where it activates the very same enzymes that do excrete BPA through urine. It does that, and it's been shown in animal studies, animal studies that are given sulforaphane, and then given a high dose of BPA, it completely blunts the toxicity of the BPA, which is pretty interesting as well.

So the other thing to keep in mind is heat, and I'll say this. All the to-go cups that you're out there buying when you go to your favorite coffee shop, fill in the blank for the most part, with the exception of the Blue Bottle Coffee, phenomenal, they're great, all these paper cups are lined with plastic. And when you add a hot beverage into the plastic lining, it releases all these microplastics into your beverage, and it releases the chemicals like BPA into them, like 50-fold. Blue Bottle Coffee, by the way, they apparently line their cups with sugarcane, polylactic acid, and so they don't have any plastic.

I remember the other day I went into a Blue Bottle coffee shop and I was like, I really wanted to get a hot tea, and I was like, “Do you guys line your cups with plastic?” And she's like, “No, we line them with sugarcane.” I was like, “Yes.” So that's something to keep in mind. You see a lot of people drinking these to-go cups everywhere, and you're pouring a hot beverage into it. It's a really, really major source of microplastic exposure because you're accelerating the breakdown of the plastic. Heat accelerates the breakdown of the plastic, and essentially, you're doing that in real time, like in an instant, right?

Tim Ferriss: And ditto for the — 

Dr. Rhonda Patrick: Bring your own cup. Yeah.

Tim Ferriss: — teabags, right? So.

Dr. Rhonda Patrick: And the teabags, so you have to do loose leaf tea, which is what — now I'm always, it's got to be loose leaf. I'll bring my own little — I'll sometimes open the teabag out and I bring my own little tea steeper thing with me that you can — 

Tim Ferriss: Like the little half globes that connect together.

Dr. Rhonda Patrick: Yeah, exactly. Mine are the ones that you kind of squeeze on it and opens up and then closes the clamps back together. But yeah, so I use that because the teabags, again, you're getting the heat on top of the plastic, polymers that are making up the teabag and accelerating the breakdown of plastic. So you're drinking plastic beverage.

And there's all these health consequences now associated with microplastics. You mentioned the brain. It's been found 20 times — to accumulate 20 times more in the brain than in other organs. And people with Alzheimer's disease have up to 20 times more microplastics in their brain than people that didn't have Alzheimer's disease. And then the same goes for cardiovascular disease. There's been a study that was published in the New England Journal of Medicine about a year ago, showing that people that had microplastics in their whatever aortic part that they were doing surgery on, those individuals ended up dying of a heart attack within the next three years versus ones that didn't have any microplastics.

Anyways, all sorts of interesting stuff. We don't know enough about it. But I think enough said, we do know that they're not good and we want to try to avoid them as much as we can, and that they are pervasive. They're everywhere. It's ubiquitous.

Tim Ferriss: Yeah. Yeah. And there's some simple things people can do. I mean, this is not necessarily in the same category, but it's like, look, the effects at least seem to be, I don't know if they're well established, maybe there are animal studies on this, but certainly there's a lot of seemingly compelling evidence pointing to the effects of, say, phthalates as endocrine disruptors on male fertility. And it's like, look, if you have shampoo or soap with a really strong fragrance, just stay away from it. I mean, they're very simple guidelines for some of these things that I think can be very helpful.

Yeah, the microplastic stuff is kind of terrifying. I did not realize the gum. I knew about the teabags, the water filtration. Did not realize the gum. I don't chew a lot of gum, but one of my relatives who has Alzheimer's has chewed four packs of gum a day for 10 years. And I was like, “Oh, shit. I wonder if that's a contributor.”

Dr. Rhonda Patrick: Wow, that's crazy. I started chewing gum when I learned about the research showing that xylitol could inhibit some of the S-mutagens bacteria that are involved in cavity formation.

Tim Ferriss: Then a few years later, you're like, “Goddamn it.”

Dr. Rhonda Patrick: Well, I was able to reverse cavities multiple times, and my doctor was like, “Keep doing it.” I'm like, “Yes, the xylitol.” And then I found out, it was like this year, I found this out, Tim. This year the study came out with the gum, and I was devastated. I mean, I've chewed so much gum, so much gum, and I've let my child chew it, and it's like, all I could think about was how great it was for the teeth, and now it's like, oh my God, this has been a source of microplastics that I had no idea. I did thankfully find an alternative xylitol source of gum that is microplastic-free, but yeah — 

Tim Ferriss: It's like chewing on bark? Is it like chewing on —

Dr. Rhonda Patrick: It's pretty much bark.

Tim Ferriss: — tasteless bark?

Dr. Rhonda Patrick: It's actually made from bark.

Tim Ferriss: That's awesome.

Dr. Rhonda Patrick: No, it's made from trees, like some kind of sap or something from the bark.

Tim Ferriss: Resin or something, yeah.

Dr. Rhonda Patrick: Yeah.

Tim Ferriss: Sounds delicious. You can't just do xylitol mints? You have to chew it? I guess you have to get it up —

Dr. Rhonda Patrick: You can do xylitol mints. Yeah.

Tim Ferriss: Okay.

Dr. Rhonda Patrick: You can do xylitol mints. I have those as well.

Tim Ferriss: Well, just to, on the same thread of you don't always get it completely right, I was looking at some of the research docs that I have in front of me, and there's one section that I highlighted, which was each three-hour increase in nighttime fasting was linked to 20 percent lower odds of elevated hemoglobin A1C, this long-term marker of blood glucose. And then one of your bullets was the effects of alcohol in the brain and cancer risk, and so I was reading this document over dinner. I sent this to you, and my time zones are all screwed up, because I just got back from Polynesia, and so I'm eating at 10:00 p.m., first of all, and then I had a glass of wine, so I put the glass of wine on top of my research document with all of this text visible, and I sent it to you and I was like, am I doing it right? You're not going to always get it right. But let's talk about — do you want to talk about the booze for a second?

Dr. Rhonda Patrick: I mean, so alcohol, yeah, and especially since we were talking about APOE4.

Tim Ferriss: Just to depress people after the microplastics?

Dr. Rhonda Patrick: I know. It's like, “You can't have any enjoyment at all if you want to live a long, healthy life.” No, you need to find a good balance, obviously. So alcohol is — it's a toxin. It's also a lot of fun. I mean, it's fun to drink and have a glass of wine. Sometimes it helps — it feels like you're lowering your stress, lowering some inhibitions. It's fun to do with a group of friends and stuff.

It's not so great for the brain though, and certainly, if you're concerned about Alzheimer's disease and dementia risk, and I will say that there's been a lot of mixed research out there looking at alcohol consumption and dementia and Alzheimer's disease, where some of it says, well, if you're doing moderate alcohol consumption, you can actually have a protective effect against dementia and Alzheimer's disease, where it's like this idea that alcohol, like a glass of wine a day is actually beneficial for you. So you should be doing that.

Tim Ferriss: I wonder if it's actually the social interactions facilitated by alcohol versus the moderate alcohol itself, I wonder.

Dr. Rhonda Patrick: Well, there's a lot of things going on here. Certainly social interactions, that's a confounding factor. Also, when people then looked for their APOE genotype, it was found that it was actually in the non-APOE4 carriers that you would find that benefit, not in the APOE4 carriers. And then on top of that, there's been all this research that, over the years, has looked at moderate alcohol consumption, and depending on the study, that number changes, which is such a big bummer. It's like, well, what does that even mean? In some cases, it can be seven drinks a day in some cases.

Tim Ferriss: Seven drinks a day?

Dr. Rhonda Patrick: Sorry, a week.

Tim Ferriss: Okay.

Dr. Rhonda Patrick: Oh, my gosh. No. In some cases it's seven drinks a week for a woman, but for a man, it's like 14 drinks a week.

Tim Ferriss: I wonder who authored that study.

Dr. Rhonda Patrick: Yeah, exactly. It's a big difference. But on average, moderate alcohol consumption is more like seven drinks a week. Seven drinks a day would definitely be heavy alcohol consumption. That would be more like substance abuse, substance use or use disorder. Let's cut the substance abuse part out. Alcohol use — 

Tim Ferriss: Why can't you say abuse anymore? Why do these things have to keep changing? It's so ridiculous.

Dr. Rhonda Patrick: And it's hard for me because I'm always tripping on my words.

Tim Ferriss: Use disorder sounds better than abuse? I mean, what are the reasons behind this? Do you know?

Dr. Rhonda Patrick: I guess it's politically correct.

Tim Ferriss: Because I'm finding all this psychedelic stuff, and it was abuse for a long time, and then all of a sudden, nope. Verboten. Can't say that. Who knows? Anyway.

Dr. Rhonda Patrick: It's funny. I still have read so much of the literature that I still say abuse, because that's what I'm familiar reading. But anyways, back to this, what I was saying, which is seven weeks — sorry. All right, we're going to cut this out, Tim. Seven drinks a week.

Tim Ferriss: How many drinks have you had before this podcast, Rhonda?

Dr. Rhonda Patrick: Well, I did have some ketone ester, where there's a little bit of alcohol that is involved with that.

Tim Ferriss: Yeah, that's true. Yeah. Watch out for the — 

Dr. Rhonda Patrick: There's been — 

Tim Ferriss: — 1,3-Butanediol. Anyway.

Dr. Rhonda Patrick: Right. There's something called the sick quitter hypothesis, which is essentially a lot of these studies we're comparing people that are drinking this moderate alcohol consumption with non-consumers, people that abstain from drinking. And it turns out that many, many, many, many studies did not account for the sick-quitter aspect, which is essentially — 

Tim Ferriss: What is sick quitter? Is that English?

Dr. Rhonda Patrick: — someone gets sick. Yes.

Tim Ferriss: Oh, sick quitter. I got it. Okay.

Dr. Rhonda Patrick: Sick quitter.

Tim Ferriss: Okay.

Dr. Rhonda Patrick: Quitter, yes. So essentially, what it means is they get sick, and so they quit drinking alcohol. And then when they're filling out their questionnaire, however many years later, whatever, they are asked, “How many drinks do you have a week?” And they say “Zero” because they quit, but they don't — the question wasn't asked, “Were you a former drinker?”

Tim Ferriss: The prior drinking habit.

Dr. Rhonda Patrick: Yes, very important. And now, more studies are, when they're doing the questionnaires, are asking that question. But many, many, many years and many, many studies did not ask that question. And so it's very possible when you're looking at these cohorts of people that are comparing moderate alcohol consumption to no alcohol consumption, they're saying, “Oh, look, there's a benefit. You have less cardiovascular disease risk. You have less dementia risk if you drink versus not drink. We don't really know if that's because these people were former drinkers and did so much damage already that that's why they're getting dementia more.

Tim Ferriss: In the non-drinker group.

Dr. Rhonda Patrick: In the supposed non-drinker group.

Tim Ferriss: Quote-unquote non drinker group.

Dr. Rhonda Patrick: Exactly.

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: Right, which could have been a former drinker. But I think at the end of the day, when you look at alcohol and cancer, it's just unambiguous. Alcohol is now classified as — I think it's a — is it a group-1 carcinogen? Where it's known to play a role in causing cancer. There's no gray area here, and there's many, many different cancers that it's associated with. So alcohol does get metabolized into acetaldehyde — that is something that can be a mutagen. It is a mutagen. It can cause cancer.

And so there's a lot of different cancers that's associated with breast cancer, colon cancer, for example. Breast cancer is a big one because women's lifetime risk of breast cancer is already high. I mean, a woman has a lifetime risk of one in eight of getting breast cancer. So if you have a room with eight people, one of those women, if you're at a dinner party, and eight women are there, then one of those women will come down and be diagnosed with breast cancer in her lifetime.

So when you add alcohol consumption on top of that, if you're talking about moderate alcohol consumption, that risk can go to one in six, which is very significant for lifetime risk. So I do think that alcohol, I mean obviously some people enjoy it, and I don't know that there's any amount that's actually safe, but if you're really looking for a number, it seems like one or two drinks a week seems to be the safe spot.

I mean, the safest would be zero, right? Zero drinks. But if you're really not wanting to have the damage, the light drinking, which is the one to two drinks a week, that's where you're probably the best off. Talking about a weekend, you have a weekend and you're doing a glass of wine, maybe Friday or Saturday night. I think that's the safest if you're looking for some alcohol consumption. If you're going above that, just be aware there is definitely a risk of increasing dementia, increasing cancer risk.

However, there are other lifestyle factors that also play a role here, like being obese and exercise. In fact, some of the alcohol and dementia studies that have shown an increase in dementia incidence with alcohol consumption were negated by people that were highly physically active. So I do think there's other things to consider. You can't just silo everything, right? I mean, you've got to look at the whole lifestyle.

Tim Ferriss: So air squats before gelato and my tequila shots?

Dr. Rhonda Patrick: Right.

Tim Ferriss: Well, let me ask you, what is the purported mechanism, maybe it's known, by which alcohol increases the likelihood that you'll experience some of these maladies like cancer, dementia, et cetera? Is acetaldehyde acting as a mutagen and therefore just smashing your DNA, so you have these mutations that then proliferate and turn into some type of dangerous cancer? Is there more to the story of mechanism of action?

Dr. Rhonda Patrick: Yeah. I mean, acetaldehyde is one aspect of it. It's an important one. But the alcohol itself is causing inflammation. I mean, it's causing gut permeability, essentially. It's very hard on the gut. And so what ends up happening is you release inflammatory factors into your bloodstream, like the polysaccharide gets released into the bloodstream. Inflammation gets activated. Inflammation is a major cause of cancer and also brain aging. So the brain aging aspect is definitely linked to the oxidative stress component and the inflammation component. Damage is happening to neurons, and I think one of the reasons why people with APOE4 are a little more sensitive to alcohol is because the repair processes in individuals with APOE4 isn't as robust.

Tim Ferriss: It's compromised already.

Dr. Rhonda Patrick: It's compromised already, right. And so they're not able to repair that damage that's being generated from the alcohol, whereas people without the APOE4 somewhat can repair it a little bit better. And then you add the breakdown of the blood-brain barrier on top of that, and then you're just getting more inflammation into the brain. And neuroinflammation is a major cause in Alzheimer's disease. I mean, it's really a known factor now. And you're disrupting mitochondria, you're disrupting — just everything you know about to be important for health is sort of affected by alcohol, through a variety of mechanisms.

Tim Ferriss: Do you ever drink?

Dr. Rhonda Patrick: I don't drink very much. I used to drink more. Sometimes I go several months without having anything.

Tim Ferriss: I do. So I'm not putting you on the stand here.

Dr. Rhonda Patrick: Yeah, no.

Tim Ferriss: I don't drink all the time, but I'm just giving you a little leeway.

Dr. Rhonda Patrick: Yeah. I used to drink at least a couple times a week where I would do the weekend thing, but I don't drink much anymore. Once in a while I'll have a glass of Prosecco for a celebration. I do enjoy it, but I definitely try to limit it to certainly once a week. But like I said, these days I'll go a couple of months without having anything, and then I'll have a social situation where I like to do it. And the great thing about that is I'm so sensitive to the alcohol that I'm such a lightweight, and it's great because I get one glass of Prosecco and I'm like, “This is amazing.”

Tim Ferriss: So I'll say, what fringe benefit, and this could be — 

Dr. Rhonda Patrick: Oh.

Tim Ferriss: Go ahead.

Dr. Rhonda Patrick: Can I mention one other thing, Tim?

Tim Ferriss: Jump in. Yeah, yeah.

Dr. Rhonda Patrick: So I forgot to mention with respect to the dementia risk and alcohol, you asked about mechanisms, the sleep aspect, right?

Tim Ferriss: Oh, for sure. That's a huge one.

Dr. Rhonda Patrick: Yes, it's a huge one because alcohol does disrupt sleep.

Tim Ferriss: That's massive, yeah.

Dr. Rhonda Patrick: Massive. I know people that use it because it helps them fall asleep easier, so it's definitely something that decreases that sleep latency. People can fall asleep easier, but it completely disrupts. So they have more awakenings in the middle in the night, and it disrupts REM sleep. So there's every reason to definitely not drink and certainly don't drink close to bedtime. You want to kind of be able to get rid of the alcohol before you go to sleep. Going back to your picture, you were doing everything wrong, but — 

Tim Ferriss: Oh, that was, yeah. Am I doing it right? Yeah, that was very much deliberate. 

Rhonda, one thing, and I'm so curious if maybe you've heard reports of this, I could ask my audience and figure it out. Wasn't placebo effect because I didn't expect it, but it seems like when in ketosis past 1.5 millimolars, even above 1.2 for me, and I use a precision extra device to track that. I've tried a number of other devices that are remarkably erratic. In any case, I am much more sensitive to alcohol, much, much, much more sensitive to alcohol, which is great, because then I'm a cheap date. I could have my one glass of mezcal or whatever, and I'm good. And I don't drink super often. I might take three or four weeks off, but then it'll be like this week I'm in New York City, this is a city of drinking. A lot of people have decided to do ketamine instead, which I think is a Faustian bargain, shitty trade for a number of reasons.

And then I'll stop. I've a party with my oldest friends this weekend. I'm sure there's going to be drinking, and then I'll stop for two weeks, and take a month off or two months off or something like that. It's kind of how I operate these days. But the ketosis seems to sensitize me, which I thought was pretty interesting. I hadn't noticed that before when I was in ketosis, probably because I wasn't drinking during those periods.

But on the ketamine substitute, right? “Oh, this is what I'm using now as a healthier alternative.” I think the “Is this risky?” question is often, “Is this risky or is this bad for me?” can be answered in absolute terms, but it can also be answered in relative terms. So zero alcohol might be better than two drinks. Seems pretty unequivocally that's the case. But if you then ask in relative terms as compared to what, if you're swapping in another behavior or smoking after your dinner, or — I mean, smoking's a whole different kettle of fish that we could unpack some other time. Nicotine's pretty interesting, but lung cancer less interesting. There is the, as compared to what, when people fight another coping mechanism.

So I just wanted to throw that out there as just another question that I think is worth people asking. If they're going to abandon something, that's great if you can just delete it without replacing it with something. But if there is a substitute, if there is an alternative or something that you may end up adding to your behavior or your consumption, just to be aware of that, because you have to measure A versus B, not just a versus lack of A. So just wanted to throw that out there. I've seen so many people unravel from ketamine and that I feel a moral responsibility to mention it because it can be so, so incredibly addictive. Fast-acting, short duration, and even though it is very successfully used to treat, say, treatment-resistant depression when it's administered in a clinic at reasonably higher doses for, let's just say, six infusions over two weeks, something like that. John Krystal at Yale's done a lot of great research, and his teams and co-authors — used recreationally, it actually increases your predisposition to depression.

Dr. Rhonda Patrick: I think psilocybin is a better candidate when it comes to something like that, because it's really not addicting. And I don't know if you saw this, Tim, but this really — it's, of course, people may not be aware, but it's been shown to treat depression as well, and in more than one study.

Tim Ferriss: Oh, for sure. Oh yeah, yeah. Yeah. The two major applications are major depressive disorder and alcohol use disorder, as it stands right now.

Dr. Rhonda Patrick: Right. This study just came out, like, gosh, this last two weeks or something showing — is the animal study that psilocybin increased life expectancy by almost 20 percent in mice.

Tim Ferriss: Yeah, I saw that. And I think that was out of Emory? Am I making that up?

Dr. Rhonda Patrick: Yeah, I think it was.

Tim Ferriss: And I remember looking at it because I was like, wait a fucking second. I think they were giving something like five milligrams of psilocybin to these rats or mice. And I'm going to mess up the numbers a little bit, but I was like, wait a second, because I've funded a lot of the science, and for humans who are walking around at one, let's just call it whatever, 125 to 200 pounds, it's 25 to 30 milligrams. So on a mix-per-kicks basis, are those rats getting the equivalent of 300 dried grams of mushrooms on a monthly basis?

Dr. Rhonda Patrick: No.

Tim Ferriss: I was like, let me look at that. Let me look at that a little more closely. And the metabolism is very different, but it's still non-trivial. I do think those little furry friends are probably tripping balls, even though I — I do think the life-extension stuff is interesting, and I would say just anecdotally, looking at people who have consumed in South America, ayahuasca for decades, they are — can't prove cause and effect, but almost always sharper than the rest of the people in their age cohort, almost always, which is interesting. I mean it raises more questions than it provides answers.

But the life extension stuff is interesting. And I've been funding some science that Chuck Nichols is doing, looking at the anti-inflammatory applications of different psychedelic compounds, and they are profound, really profound. And what makes it most interesting is that it can be achieved depending on the compound, and he's tested dozens of them with very, very trace quantities, in sub-perceptual quantities. You do not need any hallucination, any sort of reality distortion to achieve the anti-inflammatory effects.

Dr. Rhonda Patrick: So like a microdosing.

Tim Ferriss: Yeah.

Dr. Rhonda Patrick: A microdosing of it.

Tim Ferriss: Even less than what someone would consider a microdose, like a nanodose.

Dr. Rhonda Patrick: Wow.

Tim Ferriss: It's remarkable. And part of my reason for looking at the fasting, the ketogenic diet, also looking at cold exposure, and most recently, this is a whole separate topic, obviously for another time. I'll be having a scientist on this podcast soon, super credible, very, very well-cited, to talk about vagus nerve stimulation. But when you look at how fasting, I was talking about this old Soviet work looking at schizophrenia, okay, interesting, ketosis for epilepsy and also all sorts of psychiatric conditions, but also things like potentially rheumatoid arthritis or any number of Crohn's disease, let's say in the case of vagus nerve stimulation.

My theory also with psychedelics is that in a lot of cases, the anti-depressive effects, anti-depressant effects, the anxiolytic effects, this would be true for exogenous ketones as well, maybe largely, I don't think it's a trivial piece of the puzzle, mediated by anti-inflammatory effects addressing chronic inflammation, including neuroinflammation.

Dr. Rhonda Patrick: Totally.

Tim Ferriss: And so as you said, if you're chronically suffering from neuroinflammation does not bode well for later life with Alzheimer's and Parkinson's and things like this, so I'm trying to throw everything sort of the kitchen sink at this to see what these subjective and then measurable objective effects are. So it's like, okay, if I did intermittent fasting and I'm doing then cold exposure during — which, by the way, past a certain point seems to shift from sympathetic to parasympathetic activation, particularly with certain breathing patterns. Like, okay, if I did that during the intermittent fast, I'm taking the sulforaphane, doing all that stuff, and then the exercise we talked about and once a quarter doing a three to seven — let's call it probably every quarter. I used to do a three-day fast. I don't think I'd do a seven-day every quarter. That's probably once a year.

But just looking at like, okay, and then the curcumin. It's like, all right. If we threw four or five at this problem and didn't get too crazy, go “Murica!” Like more is better, we did the minimal effective dose, but recognized there might be a synergistic effect, like what happens, and what can we measure? So I'd like to do, and I'm in the position where I could spend a lot of money just to see, okay, if we take out my white blood cells and then look at their ability to produce cytokines after certain interventions, like, oh, okay, cool, let's spend the money. Let's see what happens after you do this stuff for a couple of weeks. Very, very, very, very interested in all of this. 

Let's do this, Rhonda. Where can people find you, find what you're up to, get into all things Rhonda Patrick?

Dr. Rhonda Patrick: I have a podcast. You can find it on Spotify, Apple Podcasts, YouTube. It's called FoundMyFitness. You can also just search Rhonda Patrick.

Tim Ferriss: One of the OGs. You've been doing it for a while now.

Dr. Rhonda Patrick: Doing it for a while, yeah. And I've got a website, foundmyfitness.com. You can find all my stuff there. You can follow me on Twitter, or sorry, X.

Tim Ferriss: I still say Twitter.

Dr. Rhonda Patrick: I still do it. I still do it. You can call me on X or Instagram, FoundMyFitness, all one word, or look, just search my name, Dr. Rhonda Patrick.

Tim Ferriss: And you have a newsletter.

Dr. Rhonda Patrick: I have a newsletter. I have a newsletter, yeah. I send out a weekly email that covers some fascinating new either science, health, fitness, nutrition-related study, and usually it's applicable. Sometimes it's something that's misunderstood in the media, and I break it down every week. I sent you the creatine one. We covered a Vitamin D, dementia one as well. I mean a lot of different fascinating studies. So you can again find that on my website, foundmyfitness.com. You can sign up for the newsletter there.

Tim Ferriss: Awesome. Yeah, I took so many notes, as always. I always take a lot of notes when we have our conversations, not necessarily on the podcast, but also in our text exchanges. Very actionable. I so appreciate what you do in the world. You've called a lot of things early. Looking at our timelines has been wild, to look back and I'm like, “Wow, April, 2014, talking about the stuff that now all the fitness influencers are ranting and raving about today in 2025.” It's like, yeah, you've called a lot of things early, and I appreciate your ability to simplify without mangling. Simplify without disfiguring the science. I really respect that. It's not easy to do. It is such a service to people who care about being scientifically literate, but they also care about and benefit from someone who can take what could be impenetrable and translate it without mistranslating it into something that they can test with limited downside and plausible or supported upside. I just think it's such a tremendous service. So I appreciate you, Rhonda. I really do.

Dr. Rhonda Patrick: I appreciate you too, Tim. Thank you for all you do, and your podcasts have been great. I've listened to them over the years. You're one of the few podcasts that I've listened to, so you've got great, insightful, thoughtful questions and I've read your books, so I appreciate all you do. So the feeling's mutual, and I'm glad we get to still have conversations over 10 years later.

Tim Ferriss: I know, I know. I love it. Yeah. The long game. It's fun to play the long game. So nice to see you, Rhonda. Everyone, we will put links to everything Rhonda Patrick in the show notes. Check her out. You'll not be disappointed. And as always, until next time, be just a bit kinder than is necessary to others, but also to yourself, and thank you for tuning in.

All right, so that's a wrap. Thank you, Rhonda. Really appreciate it.

Dr. Rhonda Patrick: Same. Thank you.