#02 – Rhonda Patrick, Ph.D.: paradox of IGF-1, ketogenic diets and genetics, benefits of sauna, NAD+

1. 0:00 – 0:04

   Intro

   1. PAPeter Attia0:00

      [upbeat music]

2. 0:04 – 5:48

   Episode Preview and Guest Introduction

   1. PAPeter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. [upbeat music] The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other s- obsessions I've gathered along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Welcome to The Peter Attia Drive. In this episode, which I know is long anticipated, I spoke with Dr. Rhonda Patrick from FoundMyFitness. I suspect many of you listening to this know everything about Rhonda and have been fans of her for a really long period of time. On the off chance there's anybody listening who doesn't know who Rhonda is, I suspect by the end of this discussion you will also become a huge fan of hers and her podcast, which is exceptional. So I've known Rhonda for quite a while, and despite the fact that we both consider San Diego home, [chuckles] we've just been busy enough that we just haven't had a chance to sit down together in quite a while, so this discussion was kind of long overdue. And it was sort of funny because as soon as Rhonda walked in, we just jumped right into a really interesting discussion, and then 10 minutes in I thought, "You know, we should probably start recording 'cause this is interesting stuff," and so we did. And similarly, when the discussion finally ended, we sat around for another 20 minutes talking about a bunch of stuff that I found myself thinking, "God, I wish we were still recording this 'cause it's super interesting." So that's just basically to say I suspect Rhonda and I will speak again at, at some point soon, so don't worry if all of your questions weren't answered here. The other thing about this podcast that was a ton of fun was that in the days leading up to it, she and I had emailed each other a few times back and forth some ideas of things we would talk about, and in the end, neither of us really had any notes sitting in front of us. We just sort of sat there and shot from the hip and didn't follow a script or anything like that and didn't even get to half the things that in our emails we had suggested we would talk about. That said, all the stuff that we talked about is stuff that I think Rhonda brings a great deal of expertise to. So I don't recall the order, but I know that we certainly touched on IGF and the growth hormone, what I consider a little bit of a paradox, which is on the one hand we have some evidence to suggest that elevated levels of IGF are bad and that fasting may act in part by reducing those levels, but at the other end of the discussion you, you have some confounding and conflicting data around that. We also got into a great discussion about the PPAR enzyme, so PPAR alpha, PPAR gamma. One of the things that Rhonda does incredibly well on her podcast, and I would encourage those of you who find this episode interesting who aren't familiar with her work to go back and actually watch some of her stuff. Rhonda doesn't put out a lot of podcasts, but the reason for that is the amount of work she puts into them is enormous. So when she puts out a podcast on video, there's explanations, definitions, and stuff scrolling across the screen. So it's, uh, it's, uh, unlike me, who's incredibly lazy and can't even stand to listen to a podcast after I record it, Rhonda is methodical in her ability to make that easier for the viewer. So you'll learn a lot about this stuff if you think we're going too quickly over it by probably going back to Rhonda's site. We talk a lot about the possible genetic explanations for why some people do and don't respond particularly well to ketogenic diets. And of course, you can think of that in two ways. There's respond as far as the ability to make ketones, but then there's also sort of these patients that I describe seeing where you put them on a ketogenic diet and everything seems to go wrong, so at least biochemically wrong. So that, that's a very interesting discussion. In many ways, I think my favorite part of this discussion was the way it started, which was the first question I asked Rhonda, which was kind of a random question, I think led to some interesting back and forth between us, which was effectively what do you believe today that you didn't believe before and vice versa? And I always find that to be one of the most interesting ways to dive into a discussion with someone who's buried knee-deep into science. Because if you're really thinking about science, you have to understand, of course, that virtually all facts have a half-life, and our knowledge is constantly evolving. In many ways, that's what makes the field so difficult to stay on top of, but at the same time so interesting. And so to me, one of the marks of a very thoughtful person is someone whose beliefs are flexible and who's willing to acknowledge that something that they believed was once true or not true can be flipped. And so I think, you know, Rhonda and I share that, and I think it was actually really fun to see where her beliefs have changed over time. So with that said, I think the show notes for this particular episode are going to be very helpful, and you can find those at peterattiamd.com/podcast. And I hope you enjoy this discussion at least half as much as I did. I suspect it won't be the last. So without further delay, here's my conversation with Dr. Rhonda Patrick. [upbeat music] Rhonda, so great to have you here.

   2. RPRhonda Patrick5:15

      Happy to be here. It's great to see you again.

   3. PAPeter Attia5:18

      I can't believe we live in the same city and only see each other once a year.

   4. RPRhonda Patrick5:22

      If even. [laughs]

   5. PAPeter Attia5:23

      Well, thank you for taking the trip up here today to my office.

   6. RPRhonda Patrick5:26

      My pleasure.

   7. PAPeter Attia5:27

      And I'll join the long list of people congratulating you on your 10-month-old son.

   8. RPRhonda Patrick5:32

      Thank you. Thank you.

   9. PAPeter Attia5:33

      I almost don't know where to begin because there are so many things that, you know, we share in common as far as interests. But I want to start with a really broad question, r- which is you spend so much time thinking about many of the same problems I spend time thinking about.

3. 5:48 – 10:27

   How Patrick's Views on Caloric Restriction and Ketogenic Diets Changed

   1. PAPeter Attia5:48

      What do you believe today that you did not believe four or five years ago?

   2. RPRhonda Patrick5:54

      Probably the biggest thing that has changed in what I now believe but I didn't four or five years ago even more is that- One of the major modalities for, you know, health- increasing healthspan, which is, you know, the healthy part of, of your life, delaying the, the onset of, of age-related diseases, the major modality for doing that, that would be the best way to do it would be caloric restriction or dietary restriction. So eating, you know, 30% less food than you normally would eat. Uh, I used to really think that was the way to go for, for doing that, and I think that my beliefs have changed for that in, in that being the major modality for a, a few reasons. One reason is because I think that actually... So one of the things that, that occurs during caloric restriction is a major drop in the growth hormone IGF-1. And that's, you know, that's thought to, to regulate a lot of the, you know, improved healthspan effects, at least in, in some organisms like mice and, and in rhesus monkeys. But I do, I do believe now, uh, based off a variety of research from people like Valter Longo, that periods of growth, actually specifically periods of IGF-1 are really important. So you're not... You know, if you're constantly doing this caloric restriction, then, then you're, you're not really gonna have that period of growth because you're chronically doing that. Um, and really interesting, I don't know if you saw the recent Nature, uh, study that came out, I think it was in April of this year, on lemurs. The... So the, the study essentially showed... And these are, you know, I, I guess they're non-human primate, uh, mo- animal model, but their lifespan is, you know, median lifespan is around, what, six years or something like that, and I think their maximum is 11 or 12 years. I don't remember. But the caloric restriction did increase the median lifespan. It also increased maximum, so they, like, lived a year longer than, than typically. And there's, you know, a, a lot of delayed onset of, of, of various degenerative diseases. But there was a massive atrophy in gray brain matter in, in regions of the brain that didn't occur in control animals, which is just another sort of example of how, you know, sometimes some of these, uh, modalities that we, we think are really good for increasing healthspan sometimes have other effects. And I think that getting into the IGF-1, I think we'll probably... You and I will talk about that 'cause we, we both have a, a shared interest in that. But, but the, the periods of growth, uh, being necessary for health, I think, I think that's kind of, kind of turning point in my mind. And so now I actually think that per- perhaps even doing periodic, you know, prolonged fasts are, are, um, a better way of doing that because you can, you can get that IGF-1 boost, and you can get the, the lower, uh, IGF-1, among other things that, that occur. But, um, if- we can dive into that if you want, but I think that's, that's kind of-

   3. PAPeter Attia8:49

      Oh, oh, we'll, we'll be diving. [laughs]

   4. RPRhonda Patrick8:49

      Yeah. But, but I think that's probably one of the major things. The other would be actually an- another interest that we share would be I think I was a lot more skeptical of, of ketogenic diets about four years ago in terms of being great for long-term health and healthspan. And I think that some of my, my thoughts on that have changed a bit based off of more recent long-term studies in animals, specifically in mice, um, from work from, uh, Dr. Eric Verdin and also from out of UC Davis showing that ketogenic diets in, in rodents can increase healthspan, uh, increase median lifespan, certainly improve cognitive function. Now the caveat there is that typically with, uh, a ketogenic diet in, in rodents, it's actually can be most of the time is obesogenic, and the way that these guys worked around that was they found that had they had to limit the calorie. And what was interesting was that-

   5. PAPeter Attia9:46

      Or, or cycle them, right?

   6. RPRhonda Patrick9:48

      Well, so Dr. Eric Verdin, the way they did that was by cycling it.

   7. PAPeter Attia9:51

      Yeah.

   8. RPRhonda Patrick9:51

      But, uh, UC Davis, what they did was actually put a calorie cap. And it turns out after, uh, talking with, uh, Dr. Satchin Panda, that they ended up being on a time-restricted feeding schedule. And so the ketogenic diet was, you know, they were basically eating all their food within a, a certain, like, you know, eight or eight or so or nine-hour window, and then they were fasting for... So, you know, it's kind of one of those things where, you know, in humans, we don't, we don't really know, you know, I don't know exactly know how people... I've never actually done a ketogenic diet myself, so I don't know exactly what people are doing, if they're eating, you know, all the time or, or, or what, but-

   9. PAPeter Attia10:27

      Uh,

4. 10:27 – 17:59

   Why Ketogenic Mice Get Obese and Exogenous Ketones

   1. PAPeter Attia10:27

      so, so I'm also intrigued by that and, and in many ways almost have the mirror of your experience, which was, you know, four, five, six years ago, seven years ago, I guess, is when I really, really got into ketogenic diets. Was on a ketogenic diet for three years, save one day. And I, I wouldn't say I have any less faith in them today. I just am personally less interested and find it much harder to do. So just as far as compliance with a ketogenic diet, you know, I think my life is just more complicated today in terms of travel and things like that and kids and stuff. But the thing that surprised me with the recent... 'Cause those two publications came out in Cell, right? The ones, um, Verdin's-

   2. RPRhonda Patrick11:08

      Cell Metabolism, yeah.

   3. PAPeter Attia11:09

      Yeah, yeah. I was actually kind of surprised by a couple of things. So one was what you said, which was Eric noting that, hey, when we constitutively gave these guys this food, they just, they got obese. That's really counterintuitive when you think about how ketogenic diets increase circulating metabolic fuels, and that should downregulate appetite. And I think in humans, you know, there's a huge debate about why do people lose weight on ketogenic diets? Are they losing weight because they're eating less, or are they losing weight because they're ramping up fat oxidation disproportionate to where they were before, which drives up energy expenditure? Of course, I suspect the answer is both. In other words, if you do the latter, the former should happen. So when people say, "Why do you eat less on a ketogenic diet?" the question is really... Or the, the, the thinking would be, are you eating less because you are basically eating yourself more? Because you're obviously oxidizing all of those fatty acids to make BHB. Or is it some other reason that, you know, has to do with the neurochemistry of these things that go beyond sort of the metabolic central, uh, uh, pardon me, peripheral effects of it? So that's the first thing that surprised me with that study, which was why were those mice overeating?

   4. RPRhonda Patrick12:20

      Yeah.

   5. PAPeter Attia12:20

      Was there something else in them? Because they couldn't have had that much sucre- they usually put sucrose in mouse chow, but there couldn't have been that much sucrose or they wouldn't have been able to get into ketosis.

   6. RPRhonda Patrick12:27

      And I think even previous studies, like earlier in the literature, showed something similar where it was obesogenic. Now, there was certain, uh, genetic backgrounds that also seemed to kind of little, you know, regulate that to some degree. But what I was actually thinking, so you, you brought up some really interesting points, is that thinking of it in the context of like, let's say they're, they're eating, they're constantly eating the fat or they're not, they're not having the period of rest, I know that, for example, when you're making malonyl CoA, which is something that you do when you're oxidizing fat, malonyl CoA inhibits the carnitine palmityltransferase, the basically the transporter to transport fatty acids into the mitochondria. So if you k- constantly are making malonyl CoA because you're constantly, you know, eating the fat, then you're gonna start to have this inhibition and you're gonna start to then store the, uh, the fatty acids in adipose tissue rather than catabolizing them, right? So it seems to me that it's-

   7. PAPeter Attia13:16

      And we don't see that, by the way, with the exogenous ketones, do we? Uh, uh, this is something I'm still trying to get a handle on.

   8. RPRhonda Patrick13:21

      No, so I, I agree. I'm cer- I am, I am extremely interested in the exogenous, exogenous ketones, um, particularly because I've tried them-

   9. PAPeter Attia13:27

      I should have brought you some. Okay, you've tried them.

   10. RPRhonda Patrick13:28

       Yeah, yeah, yeah.

   11. PAPeter Attia13:28

       I was gonna bring you some. I forgot.

   12. RPRhonda Patrick13:29

       So I, I really enjoy the effects they have on, on my brain. So I've used them for like endurance exercise, and I, I also like it for that as well. Um, I, I do notice that I have a little bit of a, I seem to run longer than I usually stop at this point on the beach and like I can keep going another, you know. But, um, what I really like is, is for me, it really helps with, uh, focus and lower anxiety levels. So like I, I seem to be able to... I'm always onto the next, you know? What's... And, and so this kind of helps me like stay in the now. At least I'm... And that could be completely placebo, I don't know. But anyway, so that's, that's one thing that I like about that. But to get back to your point, I had wondered the same thing because what's the effect of exogenous ketones on normal fatty acid metabolism? And the q- the reason I'd wonder that is 'cause there was a paper that recently came out, um, where I think it was the one that was done in humans where humans, they, they were given the beta-hydroxybutyrate ester for endurance, and it enhanced endurance performance, but they found it inhibited-

   13. PAPeter Attia14:30

       Anaerobic performance.

   14. RPRhonda Patrick14:32

       Yes, and also it inhibited fatty acid, something to do with the f- lip- uh, fatty acid, uh, transport out of the adipose t- something to do with where I was like going with, um... Somewhere, something that had to do with lipid metabolism, which suggested possibly there could be an, a, a, an in- inhibition.

   15. PAPeter Attia14:49

       Now, you know, it's funny. I'm gonna see... I'm in New York next week, and Dom is gonna be in New York, Dom D'Agostino, who obviously you know well.

   16. RPRhonda Patrick14:55

       Yeah.

   17. PAPeter Attia14:55

       And we're, we're grabbing dinner, uh, one night, and I, we're gonna talk about this paper because I remember when it came out, Dom, uh, sent me an email w-

   18. RPRhonda Patrick15:05

       I can pull it up. Then I'll m- I'll know for sure if you want, or I can just send it to you.

   19. PAPeter Attia15:08

       Yeah, yeah, send it to me.

   20. RPRhonda Patrick15:08

       Okay.

   21. PAPeter Attia15:08

       Send it to me for sure. Because there was something about that study that was a little bit off. I need to kind of go back and, and, and look at it. But it does beg another question, so I want to go back 'cause well there's gonna be... This is, I know this is gonna be a theme today, which is multiple threads that are easy for us to go off on.

   22. RPRhonda Patrick15:23

       And you and I are great at going on tangents. [laughs]

   23. PAPeter Attia15:24

       Yeah, yeah, yeah. Let's go back to the mice. Let's go back to the two studies. Do you recall if in the Verdin study when they, before they started cycling the ketogenic diet, when they were just giving it to them all the time, did they have a window in which they could eat ad libitum that they overate in, or were they given 24-hour access to food?

   24. RPRhonda Patrick15:43

       24-hour. It was ad libitum.

   25. PAPeter Attia15:44

       So what they never tried then was let's give you food for 10 hours and let you eat ad libitum, 'cause that would be interesting if they would overeat in that setting.

   26. RPRhonda Patrick15:52

       Yeah. Yeah.

   27. PAPeter Attia15:52

       May- maybe not that interesting. The other experiment that I don't think has been done is remember when they did the, um, they took a variant which was high fat but high-ish carb, and so it wasn't... There was enough carb in the diet that it wasn't producing ketosis, but it was still a high-fat diet. I'd like to see that experiment repeated but with an exogenous ketone because then you could start to identify the effect of the carbohydrate specifically and tease out the effect of the fat and the BHB.

   28. RPRhonda Patrick16:22

       Right. I, I think I remember one of the big differences between the, the, the high fat, low carb, and the, the actual ketogenic diet was the, the induction of PPAR alpha-

   29. PAPeter Attia16:32

       Yes, exactly

   30. RPRhonda Patrick16:33

       ... which was, um, which makes sense because that's involved in, you know, ketogenesis itself. But to what degree that regulates, you know, any of the other important properties that were found, including the, the really, the profound effects on the brain and, you know. So I, I, I like to personally get my ketogenesis from, from my periods of fasting.
5. 17:59 – 23:02

   Attia's Ketogenic Diet Practice and Protein Limits

   1. PAPeter Attia17:59

      Yeah. It's funny. I mean, I guess it depends on how many calories you need, but at the time that, during that window when I was on a ketogenic diet, I was also still very active, certainly much more so than now, and I really required A lot of calories. I mean, I, I couldn't maintain my weight below 4,500 calories a day, and I still stuck to pretty strict absolutes on the protein and carbohydrates. I really kept my carbs... And I didn't look at net carbs. I, uh... [plane flying] Oh, by the way, for those listening and wondering what that noise is, this is something Rhonda and I are very used to. Those are F/A-18s, which... How many overhead, uh, drive-bys are we gonna get today, if you had to predict?

   2. RPRhonda Patrick18:36

      I would say-

   3. PAPeter Attia18:36

      Are we gonna get three more?

   4. RPRhonda Patrick18:38

      Yeah, I would say probably between three or four.

   5. PAPeter Attia18:40

      Okay. Yeah. It's the sound of freedom, people, so just get used to it. So I was getting probably 50 grams of carbohydrates, total carb. Or I, I should say probably about 80 grams of total carb, but you'll see the, what type of carbs it was. Really had to limit protein to about 100 to 110 grams. If I went over that, I would get kicked out. And so fat made up about 90% of my total calories. And so there's only so many ways you can get that much fat, and the most efficient way is actually salad with olive oil. I mean, I couldn't believe the amount of vegetables I had to consume to stay in ketosis. You know, I basically had to have two huge salads a day where I would make my own dressing, which was a heavy olive oil-based dressing. And I could probably only have one avocado a day, which I would always have, because other than that, I was getting too much carbohydrate. So it was, like, a lot of macadamia nuts, a lot of olive oil, olive oil-based everything, and then the hardest part for me was clearly being stingy with the protein.

   6. RPRhonda Patrick19:41

      What was in the, what was in the salads? Like, I mean, it's-

   7. PAPeter Attia19:44

      Okay, so I'd go, you know... I'm a pretty boring guy, so it's romaine, tomatoes, cucumbers, celery. Had to kinda l- like, limit the carrots a little bit. I normally love carrots, but-

   8. RPRhonda Patrick19:54

      Hmm. So you could eat tomatoes and everything on the ketogenic?

   9. PAPeter Attia19:55

      Yeah, yeah.

   10. RPRhonda Patrick19:56

       Oh.

   11. PAPeter Attia19:56

       Now again, part of it is I can get away with more 'cause I probably exercise more.

   12. RPRhonda Patrick19:59

       Right.

   13. PAPeter Attia20:00

       And I was doing this before people were sort of putting butter in their coffee and stuff like that, so that was not... I consumed a lot of dairy, though, so that's the other thing. Tons of cheese, tons of sour cream, 'cause you just needed those calories.

   14. RPRhonda Patrick20:12

       Mm.

   15. PAPeter Attia20:12

       And, uh, I actually developed, like, a spreadsheet that was customized for my caloric needs, but I, I had this formula of looking at every ingredient. Like, could you find the food that you could eat without restriction that wouldn't destroy your ratios? And so for me, at my caloric levels, like, cream cheese and sour cream were sort of the perfect thing, whereas even high-fat Greek yogurt had too much protein, so I had to consume that in moderation.

   16. RPRhonda Patrick20:38

       That's the other interesting thing, and I think I talked to Eric about this, was, you know, how much of the, the effects, you know, on, on healthspan were due to low protein intake, and how much were due to, you know, the actual being in ketosis. Yeah.

   17. PAPeter Attia20:52

       Yeah. I've talked about this with Valter a few times. We don't see eye to eye on this, because for several reasons. One, I'm not entirely convinced of the IGF paradigm anymore, so that's one thing where, you know, the question I asked you, that would be my answer. So five years ago, I would have said, "IGF is the devil. Growth hormone is the devil. You want them to be as low as possible." I'm not convinced of that today, and I can't wait to explore that with you. But the other thing is if you really want to produce the lowest level of insulin and IGF, I am not aware of a way to do that beyond a ketogenic diet that is incredibly low in protein and incredibly low in carbohydrate. When I go back and look at my blood levels, 'cause I, I check my blood about every six to eight weeks, and I've been doing this for, you know, 10 years, I mean, my lowest IGF levels were during the three years I was in ketosis.

   18. RPRhonda Patrick21:38

       Mm.

   19. PAPeter Attia21:38

       I mean, they were very low. They were, I mean, not ridiculously low, but 25th percentile for age-

   20. RPRhonda Patrick21:43

       Yeah

   21. PAPeter Attia21:43

       ... versus, say, 75th percentile today.

   22. RPRhonda Patrick21:46

       So that makes sense to me, because if you think about, you know, some of the major dietary regulators of the IGF-1 pathway are protein, uh, essential amino, amino acids specifically, and also insulin.

   23. PAPeter Attia21:57

       Insulin through IGFBP-3.

   24. RPRhonda Patrick21:58

       Exa- or IPB-1 too.

   25. PAPeter Attia22:00

       Yeah, yeah.

   26. RPRhonda Patrick22:00

       So I mean, I think that... So for example, you know, if, if, if someone's eating a, a low protein and low... You're, you're getting... I mean, you may not be a vegan, but even if you had a l- you're limiting your protein, you know, even to some degree, you're, you're certainly getting more than someone, maybe me, that's not, not doing that really, although I do kind of limit my protein. [chuckles]

   27. PAPeter Attia22:17

       But it's a misconception. You see, I think a lot of people assume ketogenic diets are high protein diets.

   28. RPRhonda Patrick22:22

       I think some people do consider that, yeah.

   29. PAPeter Attia22:23

       But if you're... There may be certain people out there who can produce ketones with high protein, but in my experience personally, and more important clinically, meaning, I don't know, over the course of my practice or my career in, in medicine, I mean, I've, I've probably at least encountered 50 or 60 patients at a very detailed level on ketogenic diets. Almost without exception, protein is the bigger thing that fouls people up.

   30. RPRhonda Patrick22:46

       Mm-hmm.
6. 23:02 – 33:05

   Genetics of PPAR, FTO and Ketogenic Diet Responders

   1. PAPeter Attia23:02

      That said, I wouldn't be surprised if there are polymorphisms that allow people more or less, and you've obviously talked a lot about the PPAR alpha. Is it PPAR alpha or PPAR gamma where you see the differences in a person's ability to generate ketones?

   2. RPRhonda Patrick23:14

      The PPAR alpha is, is predominantly found in the liver, and it's involved in, in fatty acid catabolism and the produc- production of, uh, ketone bodies. So, so that would be the, the major one. Now, there's nothing empirically I've seen in literature that's looked specifically at PPAR alpha and a ketogenic diet or fasting. But, you know, there's... Most of the literature out there looking at the effects of PPAR alpha with people that are either het or homozygous are, or have to do with the context of, like, high saturated fat-

   3. PAPeter Attia23:41

      Mm-hmm

   4. RPRhonda Patrick23:41

      ... low polyunsaturated fat diet, because polyunsaturated fat activates the PPAR, you know, family of, uh, transcription factors, which are nu- nuclear hormone receptor, um, trans- transcription factors. But the PPAR gamma is predominantly found in, like, adipose tissue. I mean, they're found in other tissues, but when I say predominantly, that's, like, the most... They're highly expressed in the adipose tissue, and it plays a role in, uh, basically taking up fatty acids into adipose tissue, whereas the, the alpha, which is in the liver, take-- plays a role in the transport, catabolism. So one would just sort of imagine... I mean, it would be nice to see that, you know, someone look at that, you know, people with these, uh, specific SNPs and, and how that-

   5. PAPeter Attia24:18

      Does Prometheus identify various SNPs of PPAR alpha?

   6. RPRhonda Patrick24:22

      Yes, but they don't really tell you anything. They, they sort of pull abstracts from PubMed and just kinda, like, dump it there so you kind of can Start with the research there. I've been developing a genetic tool and I just, we're actually developing it a lot more. I have a, a former NIH geneticist who's, uh, really phenomenal who's been working with me, uh, to h- to help me sort of develop those. Basically s- look at, look at, you know, the literature and see what some of these SNPs are, are doing, and then in conj- you know, in conjunction with looking at biomarkers, various blood biomarkers to kind of help people guide, you know, what sort of they should do, what's a bypass around it, a potential bypass, for example. So with the PPAR alpha or gamma, I think that the take home, at least from the literature, is essentially you want to have a higher ratio of poly and mono unsaturated fat to f- to saturated fat ratio in order to lower your type 2 diabetes risk.

   7. PAPeter Attia25:14

      You're saying for any, for people with the wild type or with people with certain SNPs?

   8. RPRhonda Patrick25:17

      With the s- for with the-

   9. PAPeter Attia25:18

      With the SNPs

   10. RPRhonda Patrick25:18

       ... with the SNPs.

   11. PAPeter Attia25:19

       Yeah.

   12. RPRhonda Patrick25:19

       Within PPAR alpha, yeah, because, um, and gamma as well because to some degree some, some of the ones in PPAR gamma affect the uptake of fatty acids into adipose tissue, and so, and also in muscle. And so it k- it kind of can affect, you know, you, you have a lot more free fatty acids around and that can, you know, have, have an effect on insulin sensitivity and other things as well, so.

   13. PAPeter Attia25:40

       We should talk about this offline because I have a subset of patients for which we have such rich data, and if I'm positive all of them would be interested in knowing this, and, you know, we'd certainly get their permission, but it would be interesting in taking their, you know, just their straight up 23andMe data. C- so, so here's the pattern I've seen, and I'm very curious as to what the overlap is. So there's a clearly a subset of people, I think my N is too small to quantify it, but directionally it seems like, I don't know, 10 or 20% of people, when you put them on ketogenic diets in the standard way, which usually ends up meaning you're getting f- at least 40% of your calories from saturated fat, typically 40 to 45% from mono, and the remainder from poly, everything goes to hell in a handbasket. And the obvious things that go to hell in a handbasket have been certainly written about on the blogosphere and Twitter sphere, which is usually their LDL particle number skyrockets despite the fact that their triglycerides go down. So they seem to be getting more insulin sensitive, but yet inflammation is going up, and you see that both specifically, cardiac specifically, so things like oxidized LDL and Lp-PLA2, but even non-specifically, C-reactive protein fibrinogen. But the deeper level is the why. And what you see is they're making much more cholesterol. Markers of cholesterol biosynthesis like desmosterol go way up, and some of their phytosterols go up, which is very counterintuitive. Phytosterols would generally go down on a ketogenic diet, but they're going way up, suggesting that they're absorbing much more cholesterol, like biliary cholesterol. So the first time I noticed this was 2012, and um, I think I wrote about this once on a blog, but I don't remember. Maybe I'm thinking of another example. And it was this relatively young patient who really loved being on a ketogenic diet, but when we get his blood test back, I mean, his LDL particle number was above 3,500 nanomole per liter. And I know there are a lot of guys out there who seem to think that as long as you're on a ketogenic diet, it doesn't ma- none of this stuff matters. I completely don't subscribe to that, and my view is that's irresponsible. So I said to him, I said, "Look, I don't think a ketogenic diet is right for you." And he said, "No, no, no, no, it's the best thing I've ever done. Like, I feel better, I look better, I'm performing better. We gotta figure out a way to do this." And I... And the only thing I could think of, and I talked with Tom Dayspring about this, and he said, "Let's try and experiment and rip all the saturated fat out of his diet." He was sort of like me. He was eating a lot. He, he, meaning he was a high caloric consumer, so that gets really hard. So we created a diet for him that was only about 20 to 25 grams a day of saturated fat, and he ended up getting about 65% of his fat calories from monounsaturated fat, which was pretty gross. I mean, you're drinking olive oil at that point.

   14. RPRhonda Patrick28:26

       Yeah.

   15. PAPeter Attia28:27

       But he was interested in doing the experiment. And sure enough, after, I don't know, maybe 8 to 12 weeks, same macronutrient distribution in terms of fat, protein, carbohydrate. The only shift was the type of fat. So we just substituted mono for saturated. His LDL-P was 1,300 nanomole per liter.

   16. RPRhonda Patrick28:47

       Wow.

   17. PAPeter Attia28:48

       All of the inflammation was gone, and all of the sterile biomarkers went back to normal. I've since seen that about six times, and now I'm wondering-

   18. RPRhonda Patrick28:57

       Yeah

   19. PAPeter Attia28:57

       ... if we took those patients and ran them through what you're doing-

   20. RPRhonda Patrick29:00

       Yeah, yeah. That would be really interesting

   21. PAPeter Attia29:01

       ... would they be the ones that have those SNPs?

   22. RPRhonda Patrick29:02

       And there's a variety of them that do that. So there's the PPAR alpha, PPAR gamma. There's a v- there's a couple of FTO-related SNPs also that the ratio-

   23. PAPeter Attia29:10

       Oh, really?

   24. RPRhonda Patrick29:10

       ... of saturated... And basically in the literature, these studies have all looked at the ratio of saturated to mono and polyunsaturated fat. And for whatever reason, people with those SNPs, when they have a higher saturated fat to poly or mono, and/or mono, they have higher inflammation, higher oxidized LDL, higher small dense LDL, higher, and just, you know, all these just terrible biomarkers.

   25. PAPeter Attia29:30

       Do you have a sense of the frequency based on the research you've done on this, how, how, how prevalent that is?

   26. RPRhonda Patrick29:35

       Kind of. I, I would say, you know, I'd have to look back at the data. Probably less than 20%.

   27. PAPeter Attia29:41

       So it might be in the ballpark of what I'm seeing for this different phenotype.

   28. RPRhonda Patrick29:44

       It might be, yeah. It might be. So that would be really interesting to run them through, through my tool, and, and like I said, we're, we're even expanding that a little bit. I found, I found a few more.

   29. PAPeter Attia29:52

       Are patients sending you any of their data, or are they doing it on their own and just sh-

   30. RPRhonda Patrick29:56

       They're doing it on their own. Some people have shared their data with me because they've emailed me and something interesting, and I'm like, "Oh wow, that's super interesting. Do you mind sharing that with me?" And they have, but-
7. 33:05 – 42:17

   Getting Non-Ketotic Patients into Ketosis and Patrick's Own Ketone Levels

   1. PAPeter Attia33:05

      Yeah, we're pretty... I mean, we've, we've evolved a lot in our thinking on how those patients can be helped, but it seems that the best way to get them over that hump is fasting coupled with exercise if they're capable. But it's gotta be relatively... It has to be, it's not gardening. Like, it's gotta be exercise exercise, you know? It, they, they have to really deplete glycogen. So that's the other thing I sort of wonder in some of these folks, is what's happening with, with gluconeogenesis? Because I, I, I think until you start to dip down in glycogen a little bit, it's really hard to do this. And of course, we can't do liver biopsies. So it's-

   2. RPRhonda Patrick33:39

      Wait, so fasting does get them into ketosis?

   3. PAPeter Attia33:41

      So again, we're d- dealing with such a small N that I don't, I, I want to be thoughtful about not generalizing too much. So there's one patient in particular who's the poster child for couldn't do the ketosis thing straight away, but when we put him on every month a five-day FMD, so he would do the five-day FMD, but ketogenic, not Longo's FMD, and then the 25 days of ad lib was time-restricted eating, ketogenic, then we've seen great results doing that in two people. So that would suggest that some- and again, it's not, we're not doing this as an experiment. At this point it's, like, clinical. It's like just try to get the job done sort of thing. But that would suggest that something about the fasting and/or the exercise and/or the time restriction could get them over the hump. But it's interesting because from an evolutionary perspective, you should have been selected out really quickly if you couldn't make ketones efficiently.

   4. RPRhonda Patrick34:36

      Well, it sounds to me that, uh, maybe, maybe there's a, the glycogen, you know, you're not, you're not getting, depleting the glycogen, too, if, if that's, you know.

   5. PAPeter Attia34:43

      Yeah.

   6. RPRhonda Patrick34:43

      So maybe it's not to do with the, the production of ketone bodies, but it's actually just takes a long time to deplete that glycogen. I do think there's a, a huge variation. Obviously physical activity plays a, a, a role in that as well. I can fast, I can do, you know, like when I do my time-restricted eating, ideally I like to do it within, you know, nine or 10 hours, eat all my food within nine or 10 hours, and then I, you know, I like to fast for like 15 hours. I can do that and with my physical activity levels, you know, I, I will be closer to one millimolar, uh, fast, like in the morning.

   7. PAPeter Attia35:12

      You will get to one millimolar after 15 hours of fasting?

   8. RPRhonda Patrick35:16

      I will be closer to that when I'm really physically active. Like, during the periods a couple of years ago when I was doing lots of like long, like long-distance running and stuff, I can get closer. I mean, I mean, I'm, I'm going off of like a Precision Extra, which probably is not very-

   9. PAPeter Attia35:29

      No, no, no, that's... No, no, no. Precision Extra's, it's, I mean, that's really good stuff.

   10. RPRhonda Patrick35:32

       Yeah. So I, I can get between like .7 millimolar to like .9.

   11. PAPeter Attia35:37

       But are you consuming a ketogenic diet during your feeding window?

   12. RPRhonda Patrick35:39

       So my, my, my diet typically... So I, like I said, I've never really intentionally tried to do a ketogenic diet, but my, my diet is I'm- I pretty much eat a lot of the same things and, and typically it's salmon, a salad or a sauteed vegetable with olive oil, some, uh, pasture-raised, you know, butter from pasture-raised animals, and my fruits will be like blueberries. I'll have avocado. So I'll have, sometimes I'll have a smoothie with some blueberries, avocado, and kale.

   13. PAPeter Attia36:03

       And will you have two meals in that window or three?

   14. RPRhonda Patrick36:06

       So t- it depends if I have the smoothie or not. Typically I'll have breakfast and then an early dinner, and then I'll have like a snack, either nuts or the smoothie, the kale with some blueberries and avocado. Uh, so I think it, you know, and I eat a lot of nuts, too. You know, I probably do te-

   15. PAPeter Attia36:22

       What kind of nuts?

   16. RPRhonda Patrick36:23

       Walnuts, macadamia nuts, pistachios, cashews, almonds. I, I think probably I'm-

   17. PAPeter Attia36:29

       I put cashews in the candy category. [laughs]

   18. RPRhonda Patrick36:31

       Oh, really? Yeah.

   19. PAPeter Attia36:31

       Well, no, no, I just mean like-

   20. RPRhonda Patrick36:32

       So-

   21. PAPeter Attia36:33

       ... I can't stop eating those things, so.

   22. RPRhonda Patrick36:34

       Oh, yeah. [laughs]

   23. PAPeter Attia36:35

       When I, when I talk about nuts, I'm like I eat nuts and sometimes cashews because [laughs] like I just might as well be eating M&Ms.

   24. RPRhonda Patrick36:42

       Is there, are there a lot for-

   25. PAPeter Attia36:43

       For me. Well, yeah, no, look, you know, all, all kidding aside, when I was on the ketogenic diet and I had to be very mindful of this stuff, basically I could only consume almonds and macadamia.

   26. RPRhonda Patrick36:52

       Oh.

   27. PAPeter Attia36:52

       Everything else was just a little too high in carbohydrate.

   28. RPRhonda Patrick36:54

       Mm.

   29. PAPeter Attia36:55

       The cashew is just like my own personal demons. [laughs] Like I, I don't know what it is about cashews. Like-

   30. RPRhonda Patrick37:01

       I love watermelon, like the summer, like right now.
8. 42:17 – 50:24

   The IGF-1 Paradox: Worms, Humans and Mortality Curves

   1. PAPeter Attia42:17

      So let's go back to the IGF thing.

   2. RPRhonda Patrick42:18

      Yeah.

   3. PAPeter Attia42:18

      'Cause this is sort of-

   4. RPRhonda Patrick42:19

      Let's do that

   5. PAPeter Attia42:19

      ... the thing that ... Here's the thing. I'll just jump right to my punchline and my, my question with this. There, there are two issues I now have with things I used to take to be the God's honest truth. Actually, three things. The first is I found Cynthia Kenyon's work on the daf-16 mutants in C. elegans to be the most convincing evidence of the role of IGF or attenuating IGF in longevity And I now question that, not question the work, but question the inference that that can be applied to humans given the fact that only their germ cells divide, and therefore cancer in that organism looks nothing like cancer in us. Cancer in that organism is only a cell getting larger. There is no proliferation. We have to sort of... I mean, it's obvious. It's the risk of stating the obvious, which is we're not worms, but that's a huge difference in biology.

   6. RPRhonda Patrick43:16

      Yes.

   7. PAPeter Attia43:17

      So that's the, that's the first thing. I, let me, let me let you comment on that.

   8. RPRhonda Patrick43:19

      Yes, because I've done those experiments actually.

   9. PAPeter Attia43:21

      Yeah, yeah, yeah.

   10. RPRhonda Patrick43:21

       That's probably what, straight out of college, I went to work at the Salk Institute with Andrew Dillin, who trained with Cynthia, Cynthia Kenyon. I was a chemistry major in college, and I decided I kind of wanted to try some real biology, because I had only had a little bit of biology in, in college. And so I went to work at the Salk, and, and really it was like those first experiments I did with worms where, you know, we would knock down the, the insulin IGF-1 signaling pathway, also known as the DAF-2, and the worms would live like literally 100% longer. Like they'd go-

   11. PAPeter Attia43:49

       Yeah, you'd go from two weeks to four weeks, right?

   12. RPRhonda Patrick43:51

       Yeah.

   13. PAPeter Attia43:51

       Yeah.

   14. RPRhonda Patrick43:51

       I mean, it was like... And not only that, like the worms were so youthful. Like you would look at these worms, you know, because that's all I would do day after day under the microscope is just picking and poking and looking at the worms and how they move, and you, you know, as they get older, they start to m- become less mobile, and I mean, it's just very obvious.

   15. PAPeter Attia44:07

       It's the most convincing data, right?

   16. RPRhonda Patrick44:09

       It is very convincing. And that wa- to me in my mind was kind of like when I was like, "Holy shit," like, we have a gene that's sort of homologous to this, and this is happening in those worms. Like, I want to understand that. Like, and here's the thing about that data, and this is what I think. If you get rid of another gene that's homologous to FOXO-

   17. PAPeter Attia44:26

       Mm-hmm

   18. RPRhonda Patrick44:27

       ... DAF-2, DAF-16.

   19. PAPeter Attia44:28

       DAF-2-- Oh, DAF-16 is right.

   20. RPRhonda Patrick44:29

       Then-

   21. PAPeter Attia44:29

       That's, that's homologous to FOXO. Yeah

   22. RPRhonda Patrick44:30

       ... it completely obliterates the, the lifespan extension, meaning it's the FOXO3 that seems to be really important for the life-

   23. PAPeter Attia44:38

       We have how many?

   24. RPRhonda Patrick44:39

       Yeah.

   25. PAPeter Attia44:39

       We have four FOXOs?

   26. RPRhonda Patrick44:41

       Y- uh, you mean d- different FOX genes?

   27. PAPeter Attia44:43

       Yeah.

   28. RPRhonda Patrick44:43

       Okay. Yeah. I don't know exactly how many, but the FOXO, we have three.

   29. PAPeter Attia44:47

       We have one, two, and four. Was it one, two, and-

   30. RPRhonda Patrick44:50

       Three.
9. 50:24 – 59:31

   Prolonged Fasting, Cancer Treatment and Cycling

   1. RPRhonda Patrick50:24

      But, you know, so... And the thing that was interesting to me was the effect of exercise on IGF-1, and the fact that, for one, it's been shown that the, the boost in neurogenesis after exercise in the brain via brain-derived neuro-

   2. PAPeter Attia50:38

      Mm-hmm

   3. RPRhonda Patrick50:38

      ... is requires IGF-1. Animal studies have shown that, mostly in rodents, have shown that that exercise causes IGF-1 to cross the blood-brain barrier, get into the brain. But in human studies, um, I've also seen some showing that it does lower serum levels. I think presumably it's also going into the muscle and the brain. So I think that, you know, people that are exercising, they're putting that IGF-1 to the places where it's supposed to go, muscle tissue, brain tissue as well. But in addition to that, and this is kind of what's more recent work from, uh, Dr. Valter Longo, is that we know that this... He, he does these prolonged fasts, and I think the prolonged fasting is extremely interesting for a couple of r- m- main reasons, and one is I think that it has h- tremendous potential for the treatment of autoimmune disease and, and also cancer based on, on, you know, his work. And what he has shown now i- in animal studies and some pilot clinical studies is that doing a prolonged fast and/or in some cases the fasting-mimicking diet causes this massive shrinking of organs where... Now, he doesn't know how much of it's due to cell size decreasing versus apoptosis. He does know apop- apoptosis is occurring, and he has showed that in multiple publications. Like there is a massive induction of apoptosis after a prolonged fast, uh, you know, which makes sense because it's a very strong stress. And then after, during the refeeding phase, their organs basically come back. They come back. They grow, regrow.

   4. PAPeter Attia52:06

      And presumably selectively repopulate.

   5. RPRhonda Patrick52:08

      Yeah, so he's shown that these, these stem cells get activated, so the, the... Basically, they have to be activated by the low IGF-1. But then to proliferate and differentiate into whatever tissue type we're talking about, let's say we're talking about the immune system, then IGF-1 is required for that proliferation and differentiation and repopulation of the s- of the tissue, which means you can't just keep the IGF-1 low.

   6. PAPeter Attia52:31

      Right.

   7. RPRhonda Patrick52:31

      You have to have-

   8. PAPeter Attia52:32

      The refeeding is just as important-

   9. RPRhonda Patrick52:34

      You're refeeding

   10. PAPeter Attia52:34

       ... as the deprivation

   11. RPRhonda Patrick52:34

       Exactly, and the IGF-1's key in that. And so, you know, what he's shown now is that you can take, for example, in the multiple sclerosis animal model, you can actually cause stem cells to be activated through the prolonged fast, and then during the refeeding phase, the stem cells make non-dysfunctional. So they're making normal non-autoimmune cells. And he's done like a pilot clinical study with multiple sclerosis, people with multiple sclerosis, and it's helped with symptoms. But he's also done these cancer studies, and this is kind of where there's been some, some clinical studies that he's been involved with at like a 48-hour water fast that, that's been done in, in patients undergoing standard of care treatment, and he's shown that, um, it was tolerable. Not only that, there seemed to be less myelotoxicity, less neutropenia, so basically there... And it sensitized cancer cells to death. So not only were the cancer cells dying more, but less of the normal cells were dying. And then he's gone ahead and shown this in animal models also with the fasting-mimicking diet, and it's like if you look at the data, particularly in the animal model because they can, you know, do all the tissue harvesting and stuff, I mean, it's like it's so phenomenal that I would not be surprised that in the next 10 years it will be required part of standard of care because it seems to be so incredibly robust at selectively killing cancer cells, which, you know, makes sense. I mean, oncogenes, they screw up all sorts of things. One of them is the, the stress response, and, you know, cancer cells can't respond to stress. They're primed to die. I mean, it's... I spent a long time, you know, studying cancer cell metabolism and apoptosis with, uh, Doug Green, uh, and Joseph Opperman at St. Jude Children's Research Hospital and, and that's kind of one of the primary ways that, uh, a lot of these chemotherapeutic drugs, if they can get to the tumor site, work, is that because it's a stress. Cancer cells can't handle it. You know, they die. So I kind of went off on a tangent here. So to get back to the IGF-1, I-

   12. PAPeter Attia54:18

       Let, let me say one thing going back to what you just said that is also interesting but in the same thing. So I agree that I think that it would really be great if patients had a better insight into nutrition going into chemotherapy, and the few times I go and give talks at hospitals or go and talk at like a cancer, uh, meeting, I'm amazed at how resistant the oncologists are on average, obviously there are exceptions, but on average to interfering with nutrition. Because in many ways their primary concern, tragically, is preserving weight. And so I always get a little verklempt when I walk through an oncology ward and I see patients drinking Ensure. Like I couldn't think of a worse thing you'd want to consume when you have cancer, and yet the goal is, hey, we gotta fatten these people up. So I agree with you, and I really hope that this research is accelerated because I do think patients would benefit greatly from this. And the other application that I saw of this several years ago. This is quite old now, but it blew my mind. I'm not sure if you're familiar with Jay Mitchell's work up at Harvard. He did an experiment where he took three, uh, yeah, three groups of mice. So the first group were constitutively calorically restricted for their entire life. These were probably, like, one-and-a-half-year-old mice, so they're about halfway through their life.

   13. RPRhonda Patrick55:29

       Starting... Oh.

   14. PAPeter Attia55:30

       Starting-

   15. RPRhonda Patrick55:30

       Starting adult.

   16. PAPeter Attia55:30

       Starting... Yeah, so these, these animals were constantly at 70% caloric intake. Uh, the next group was your control group, and then your third group was ad libitum diet until two days before an operation, and at which point they were calorie restricted to a near fast. And I'd have to go back and look. I can't remember if it was 24 or 48 hours of fasting. It might have been a 24-hour fast. 48 would be pretty extreme for mice. So in summary, you've got control, just straight up eating. You've got 70% or 30% CR forever, and then you've got control and then fasted for a day. All the mice were then operated on, where their femoral arteries were ligated, held for a period of time, and then they were reperfused. Uh, for people not familiar with what that means, so that means you, you open the animal up, you put clamps on the femoral arteries, which would basically stop all profusion of blood to the lower part of the body, and then after some period of time, just before you kill the animal, you release that and then you reperfuse y- the, the blood, basically the oxygen, uh, reperfuses the organism. That's considered a reperfusion injury, which is about one of the most stressful things you can do to an organism. So that, you can really rapidly kill someone by doing that, and that's something that in surgery happens quite a bit. For example, you end up having to clamp something off to repair something downstream of that. Okay, so what happened was all of the control animals died without exception. Of the other two groups, the groups that were either calorie restricted for life or transiently starved before the surgery, a significant subset did not die, and I can't remember the number. And again, I, I know we're gonna probably link to this study, so people are gonna listen to this and go, "That idiot got all those details wrong," but this is the gist of it. A non-trivial subset of them lived, and what's interesting is you could get the same benefit by an acute period of caloric restriction in proximity to an insult that you could get by a lifelong of caloric restriction. And the third piece w- that was interesting was the group that were just starved transiently actually had a faster recovery.

   17. RPRhonda Patrick57:32

       Mm-hmm.

   18. PAPeter Attia57:33

       Which again, they were fitter organisms. I remember the first time I came across that thinking, "There's got to be something to cycling." And people used to always ask me, like, "Why are you on a ketogenic diet every minute of every day? Would there be any benefit in cycling?" Now, I still don't know the answer to that question, but I'm more curious about it now based on what you just described from Valter's work, plus this type of stuff, plus just the general ethos of the way we evolved. We fasted, we fed.

   19. RPRhonda Patrick57:59

       Right.

   20. PAPeter Attia57:59

       We fasted, we fed. We fasted a long time, we gorged. Like, it just seems we've evolved-

   21. RPRhonda Patrick58:05

       Yeah

   22. PAPeter Attia58:05

       ... for cycling.

   23. RPRhonda Patrick58:06

       Right. Yeah, I agree. It, it's really... The- With Valter's work, I, I just am so excited about, about the prolonged fasting and the, the potential benefits of it. I think that actually something that you and I discussed several years ago when I had you on, interviewed you on my podcast that you brought up that I thought was really interesting had to do with, like, the failed clinical trials with binding IGF-1 in cancer. And Valter brought up something interesting, uh, in a conversation I had with him, and that is possibly that we now know IGF-1, having low and high GF1 is important. So if you're constantly having low IGF-1, and the IGF-1 is important for the immune system repopulation. You can imagine the context of cancer when you're giving-

   24. PAPeter Attia58:47

       Right

   25. RPRhonda Patrick58:47

       ... other, uh, treatments along with it. That would be important because your immune system is, is key in, in, in warding off cancer, and I thought that was a really interesting point. Uh, of course, we don't have evidence of that, but I think it, you know, it's something that would be interesting to investigate, and it makes sense. Yeah, I, I definitely am on the same page with you with I don't... I'm not, and like I s- started out with saying, I don't think that, uh, chronic caloric restriction and low IGF-1 is the essential, like, way for improving healthspan. Now, I do think that IGF-1, you want it to go to your muscle. You want it to go to your brain. So I think people should definitely be active, especially if they're eating a high protein and/or even high carbohydrate or something that's gonna produce a lot of insulin. You know, they shouldn't be eating r- refined carbs, but people do. If they're eating them, they should definitely be exercising.

10. 59:31 – 1:07:15

    Exercise as the Top Lever for Brain Health and Healthspan

    1. PAPeter Attia59:31

       That's another change in my belief system, I think, today versus, I don't know, five or six years ago. I think five or six years ago, I didn't think exercise was that important to longevity, which actually sounds ridiculous for anyone who knows me, because I was probably exercising four hours a day. But not because I believed it would make me live longer. It was just sort of soothing my addictions. But I think today I feel I am much more convinced by a lot of the data you've described, uh, certainly the central stuff. When we published this paper earlier this year with Richard Isaacs, and that you and I were talking about it before we started recording, we wanted to get a sense of, like, if you took a completely unbiased approach and look at the literature, what was the single most compelling thing you could do to generate or preserve brain health? And we came away thinking that it was actually exercise.

    2. RPRhonda Patrick1:00:19

       Yeah.

    3. PAPeter Attia1:00:19

       And I remember when the analysts were kinda going through this and showing me all the data, I was like, "Come on, guys. There's no way exercise could be the most important thing for brain health." And again, I'm saying this as a guy who loves exercise more than anybody, but it just struck me as there's no way. And again, I think part of it was I was just thinking about it through the vascular lens.

    4. RPRhonda Patrick1:00:40

       Mm-hmm.

    5. PAPeter Attia1:00:40

       And obviously, you know, I think, better than I do that when you start to think about brain health, you have to think about it through a vascular lens, a metabolic lens, growth factor lens. I mean, there are overlapping but distinct pathways that are going to influence brain health. And so I was kind of humbled by that, and now I guess in many ways, I'm a little more adamant about it with my patients. Uh, not that I wasn't, you know, adamant before, but this is like, boy, if you're, if you're not-

    6. RPRhonda Patrick1:01:07

       That's awesome

    7. PAPeter Attia1:01:08

       ... active every day-

    8. RPRhonda Patrick1:01:09

       I'm glad to hear it. Yeah

    9. PAPeter Attia1:01:09

       ... like, we gotta change that.

    10. RPRhonda Patrick1:01:11

        I actually, the The main reason I exercise is for my brain. It's certainly just not only for, you know, pr- preventing neurodegenerative disease and atrophy and all that, but just because it affects my executive function, it affects my anxiety levels, it affects my ability to make decisions. I absolutely... If I have something that's bothering me or giving me anxiety or I have to make a really important decision, going for a long run really helps me. And there's been studies showing that it, it helps with executive function, long-term planning, like aerobic exercise, um, specifically. You know, and the, and high intensity interval training, all that stuff. They all, they all do different things and they all have benefits.

    11. PAPeter Attia1:01:45

        Well, that's the thing. We couldn't, we couldn't tease this out of the literature, which again, probably is just a limitation of shitty human clinical trials. But that's the second order question, right? Which is, if you're gonna take the Tim Ferriss approach, which is what's the minimum effective dose? 'Cause there are some people like maybe you or I, who I think just generally like exercise and, and also get these other benefits, these endorphin benefits. But there are some people who are like, "Look, what do I need to do? Like, I'm gonna treat exercise like medicine." And I think in that setting, I'm still not clear. So if you were that person, would I say, "Rhonda, as long as you are lifting weights one hour, three times a week," like if, if you can only give me three hours, would that be how I'd want you to spend it? Or would I rather you be doing anaerobic/aerobic type thing? Like, I mean, that's... To me, those are where these biomarkers start to become very important because we're not gonna generate hard outcome studies with that level of control. Once you, you know, try to control that many variables and be that strict about it, you're gonna very much lose a hard outcome prospectively. But if we knew what to measure, right? And that's, you know, would we be measuring an integral of IGF, for example? So how much it rises, how much it falls, and then what that looks like over time. But I guess that's the funny thing, right? Like the more we learn, the less we know.

    12. RPRhonda Patrick1:02:58

        Yeah, absolutely. I, I think that we definitely don't know the answer to that question [chuckles] but I think there's a lot of data out there showing, for example, strength training, you know, it, it, there's benefits on the brain that's been shown, published. There's benefits on preventing muscle atrophy. There's benefits on preventing cancer incident... Like, that's all been shown for strength training, for aerobic and, you know, this high intensity interval training is also, also seems to be making its way as well. Like, like there was this study that I, that I found, VO2 max. This is, you know, the ability of your, your body to, uh, transport oxygen during, um, exercise, which also is an indicator of when you're not exercising, and obviously transporting oxygen to the brain, for example, is extremely important. VO2 max inc- declines with age like 1% per year. I forgot starting at what age, but you know, so 10% per decade. Um-

    13. PAPeter Attia1:03:44

        So that's, uh, it almost parallels the muscle mass decline.

    14. RPRhonda Patrick1:03:47

        It does. It does parallel, exactly. And there was a study showing that 24 sessions of high intensity interval training where it was like a 45-minute session, s- five-minute warm up, five-minute cool down, and then, you know, in between the max intervals, which were like pretty long, like a minute, there was, you know, the 70% of max whatever. Anyway, so 24 of those increased VO2 max by 12%. So you're literally taking an entire decade of decline and like reversing it with the 24 sessions.

    15. PAPeter Attia1:04:14

        Yeah. Th- that's, that's actually a good point. I, when I was more active as a sort of competitive, you know, in cycling, you, we would get our VO2 max tested about twice a year. Ryan Flaherty, who we were talking about before the podcast, who's o- one of my close friends and, and you've got to, to know him as well, I learned from Ryan that actually VO2 max is not the most important indicator as a runner or cyclist. It's VVO2 max or PVO2 max that matters. In other words, for a runner, VVO2 max is much more predictive of performance, which is the velocity you carry at VO2 max. And for a cyclist, it's PVO2 max, which is the power output at VO2 max. That said, every time you go to test, you want it to test well. So, you know, over time I learned how to game the system. You know, I wanna make sure my VO2 max is in the 70s, which again, to put that in perspective, like that's not at the level of professional athlete or something. Like the guys that are winning the Tour de France are in the high 80s or low 90s in terms of milligrams per ml per kilogram. But nevertheless, just altering my training for three weeks before a VO2 max test and dropping my weight, so if I shed two kilograms and did those types of intervals... I, I actually had it down to a science where there was a workout I would do. You know, in Carmel Valley you've got the 56 that goes out and it's got a bike path next to it? There's a section of that bike path that is 1.6 miles long, and it goes up at about 4%. And just doing repeat intervals of that, which takes about four minutes all out-

    16. RPRhonda Patrick1:05:41

        Wow

    17. PAPeter Attia1:05:41

        ... to go one direction, and then about six minutes to cruise back, four of those, that was it, twice a week for like three weeks, and your VO2 max exploded. Now of course, the question is, is that like, you know, cramming for the test, getting the result, but not necessarily... Like, do you have to keep doing that to get the decade-long benefit? I don't, I don't know the answer, but I, I agree that like if you can maintain muscle mass and you can maintain peak aerobic performance, it's not, it doesn't even matter at that point if you're living longer. You're clearly living better, right? Like if you, if you don't budge anything on maximum lifespan, you've dramatically improved median lifespan.

    18. RPRhonda Patrick1:06:20

        Right. And that's a, uh, you know, that's a-

    19. PAPeter Attia1:06:22

        I think for most people that's what matters.

    20. RPRhonda Patrick1:06:23

        It is. Yeah, um, for me it is. I mean, I, what's the, what's the maximum lifespan that like a human lives? 120?

    21. PAPeter Attia1:06:29

        124 or something like that.

    22. RPRhonda Patrick1:06:30

        Is it 124? Wow.

    23. PAPeter Attia1:06:31

        I thought 121 or 124 maybe.

    24. RPRhonda Patrick1:06:33

        Something like that.

    25. PAPeter Attia1:06:33

        Yeah.

    26. RPRhonda Patrick1:06:33

        Yeah. Living beyond that, I mean, that's... I think the goal is really to, at least for me, I think that's a lot more achievable, is increasing my, my median healthspan or my, my healthspan, you know? So, so basically preventing, staving off cardiovascular disease, cancer, Alzheimer's disease, those sorts of things so that I'm, so that I'm living healthier and also, you know, a little bit longer, but obviously not 125 or 6, um, years.

    27. PAPeter Attia1:06:59

        Yeah. I don't really subscribe to the theory that we're gonna meet some takeoff point where, you know, there's immortality. I'm, I'm really not convinced that that's, that that's sort of biologically possible, and I don't suspect I'll be alive at a time when it would ever [chuckles] come to fruition.

11. 1:07:15 – 1:12:35

    Inflammation, Centenarians and Immune-Targeting Trials

    1. RPRhonda Patrick1:07:15

       I don't remember the journal. It was a paper that came out of Japan, and the study looked at a variety of, uh, people of different ages, so elderly Population centenarians, which are 100, semi-supercentenarians, which are between 100 and 105, and then supercentenarians, which are 105 plus, and looked at a variety of biomarkers for health and aging. So telomere senescence, kidney function, glycated hemoglobin, lipid, the whole lipid panel, triglycerides, kidney function, hematopoiesis. Like, all that stuff was looked at. In-inflammatory biomarkers. And what was found is that aside from age, what was predictive of being able to basically stay alive was low inflammation. Like, more than hematopoiesis, more than glycated hemoglobin, blood glucose levels, lipid, all that stuff. It was basically the ability to suppress inflammation. Like, that was m- predictive of cognitive function and also basically staying alive.

    2. PAPeter Attia1:08:14

       Do you remember what they looked at? Were they looking at C-reactive protein and things like that?

    3. RPRhonda Patrick1:08:17

       They looked at-

    4. PAPeter Attia1:08:17

       Like, relatively general markers?

    5. RPRhonda Patrick1:08:19

       A whole panel.

    6. PAPeter Attia1:08:19

       Okay.

    7. RPRhonda Patrick1:08:19

       No. They, they, they could have-

    8. PAPeter Attia1:08:20

       They looked at the interleukins and stuff also?

    9. RPRhonda Patrick1:08:22

       Yeah, TNF. They looked at a, a whole panel of... And also, um, some immune cells that are indicte-indicative of inflammation. So there was a whole panel of biomarkers that were looked at for inflammation. HPV titer or something was also looked at. So the, the interesting thing about that study was that the inflammation was so key for each age group, right? Like, even more than all this other stuff like that I've thought about, like senescence and telomeres and low blood glu-glucose levels and all that stuff. And so I really ... And, and if you look at some of the rodent literature, for example, I remember this study where NF-kappa B, which is classically thought about as an inflammatory, uh, mediator, which it is, it also has an anti-inflammatory component to it. And if you get rid of the anti-inflammatory component, rodents will have this sort of low level of chronic inflammation, 'cause every time it's activated, there's not that infla- anti-inflammatory part that's kind of keeping it in check. And so there's kind of like this, like, lower chronic inflammation that's happening. And those animals live, like, 30% less, so their, so their lifespan's cut short by about 30%. So that's kind of interesting, right? That just, just getting rid of that little anti-inflammatory component of this one major regulator of immune system has a pro-profound effect on lifespan. And then of course, if you look at SNPs and stuff, of course you can always find, you know, the, well, centenarians have a higher percentage of 10 in anti-inflammatory.

    10. PAPeter Attia1:09:40

        Mm-hmm.

    11. RPRhonda Patrick1:09:40

        Anyways, you know. So the inflammation, it's an interesting finding that ke- suppressing inflammation seems to be important for at least, you know, according to that study, for making it to every part of, you know, I don't know what you would call it, every ... Basically progressing to the maximum level that, maximum lifespan level that humans can possibly live.

    12. PAPeter Attia1:10:00

        Well, there was a clinical trial published either earlier this year or last year that looked at an IL-1 antagonist. And so this was a study that took people and made no change in their lipid metabolism, lipid biomarker. Uh, you know, uh, this was ... They, they didn't do anything to the patients as far as differentiating the groups by traditional biomarkers of, um, cardiovascular disease. But one group was given a placebo, one group was given an IL-1 antagonist, and the question was could that impact cardiovascular mortality? And we've long talked about how cardiovascular disease is sort of this trifecta of lipoproteins, inflammation, and endothelial dysfunction, but this was in many ways the most elegant first test of that in humans using heart outcome. So major adverse cardiac event: stroke, MI, death. The, uh, hypothesis was found to be correct, so the patients getting the IL-1 antagonist, despite having no difference in lipids or any other biomarker, had an improved outcome with respect to cardiovascular health. About a month ago, another trial that was using low dose of methotrexate, which is an immune suppressant, was halted early, and the results will not be announced until this fall. But if you read kind of the fine print, it does not appear it was halted for a bad reason.

    13. RPRhonda Patrick1:11:19

        Wow.

    14. PAPeter Attia1:11:19

        Meaning it m-might've been halted actually for basically early efficacy, which presumably would've been in the group getting the methotrexate. So again, we won't know that until the meeting in October, I think, when this'll be presented. But if that turns out to be the case, that's pretty interesting because now you've taken something that we practically have great examples of, like the one you've given, and now potentially there's ways to think about using it. So taking a step back from all of this stuff, like, you know, of course, I think about it at the level of, like, I'm just a mechanic, right? It's like how can you manipulate these things in people? Like, cycling ... You know, using nutrition and fasting to cycle IGF. Maybe even using an, an exogenous growth hormone for all we know. May- you know, I've always been quite skeptical of growth hormones' use in, in the field of longevity, but maybe periods of oscillating rapamycin and growth hormone and fasting where you're cycling high periods of anabolic, high periods of catabolic phase, maybe there's something to it. And then cycling agents like methotrexate and all these things. So I don't know. That's my ... My hope is, like, in 10 years we've got a complete personalized toolkit for how everybody could, you know, figure out exactly what drugs or hormones or nutrients to take and cycle and how to do it. And then of course the key is you have to be able to measure stuff.

    15. RPRhonda Patrick1:12:35

        You know,

12. 1:12:35 – 1:22:23

    Sauna: Cardiovascular, Mood and Immune Effects

    1. RPRhonda Patrick1:12:35

       the, the, with the cardiovascular rate of mortality, the, the sauna is something that is interesting to me for that, for that reason, because of the profound effects that it has specifically on, uh, lowering cardiovascular-related mortality, and of course there's some clinical trials showing that, you know, there's a variety of other biomarkers and mecha- potential mechanisms by that, by which that's happening. But if you look at some of the data, um, by Dr. Jari Laukkanen out of Finland, if you look at some of the, the observational studies, you know, where there's, like, a couple thousand men that were doing ... And sauna's so ubiquitous in, in Finland.

    2. PAPeter Attia1:13:06

       Right.

    3. RPRhonda Patrick1:13:06

       But if you look at, for example, men that are using it two to three times a week versus four to seven times a week versus once a week, and you look at, for example, cardiovascular rate of mortality, two to three times a week it's lowered by, like, 27%. But when you jump to four to seven times a week it goes up to 50.

    4. PAPeter Attia1:13:22

       I think it was, like, 40. Oh, yeah, yeah, yeah.

    5. RPRhonda Patrick1:13:23

       50%. All-cause mortality goes to 40.

    6. PAPeter Attia1:13:25

       Yeah.

    7. RPRhonda Patrick1:13:25

       Uh, all-cause mortality is also lowered. Uh, dementia and Alzheimer's disease, again, like t- like 20% lowered if you're doing two to three and then jump up to-

    8. PAPeter Attia1:13:31

       Yeah, I'm so glad you brought this up because I almost forgot and I wanted to talk to you about this. This is one of those things where I think three years ago, I was completely dismissive of this stuff.

    9. RPRhonda Patrick1:13:41

       Mm-hmm.

    10. PAPeter Attia1:13:42

        Which is to say I still love going into a sauna because the one thing that I felt sauna really mattered for was sleep, and not for the growth hormone level, but because I think there's pretty good data that a great way to sleep is to create a high gradient of temperature, so the faster... The more negative the derivative of temperature, DT by DT, when you sleep, the faster you'll go to sleep and the longer you'll stay asleep. So a sauna before bed, if you could jump in the sauna, then take a cold shower, then jump into a cold bed, you're gonna sleep like a baby.

    11. RPRhonda Patrick1:14:12

        I've done it. It's absolutely true, yeah. [laughs]

    12. PAPeter Attia1:14:14

        It's remarkable.

    13. RPRhonda Patrick1:14:15

        Yeah.

    14. PAPeter Attia1:14:15

        So I always accepted that, but I looked at all of that epidemiologic stuff and I was like, the healthy user bias here is through the roof. Like, I came up with 100 reasons why I just couldn't believe it.

    15. RPRhonda Patrick1:14:27

        Mm-hmm.

    16. PAPeter Attia1:14:27

        Including saunas are painful, so if you are fit enough to sit in a sauna seven days a week versus the guy who can only sit in it one day a week, like, how do I know that that's not driving it? Now, since that time, I've become a lot more interested because now the mechanisms are starting to become more well understood. And so I- I'd love to have you talk a little bit more about this because I know you've talked about this a lot on y- on your podcast, but, uh, in many ways, your pursuit of this has become one of the more convincing arguments in, in my thinking on the actual health benefits of this, independent of the healthy, healthy user benefits of this.

    17. RPRhonda Patrick1:15:05

        You know, the healthy user benefits... So of course, and with, with, uh, Jari's work, he's, uh, tried to correct for all that physical activity. I mean, he's done everything, like looking at lipid, blood cholesterol numbers, LDL number, like just like really, you know, tried it, tried his best to kinda correct for that healthy user bias. And of course, there's a dose dependence, which always makes it more convincing. But he's then, um, since published some, some clinical trials where he's looked at, for example, the arterial compliance and of course blood pressures. And that's one of the main things that's affected is blood pressure. But also just, like, the ability of the arteries to, like, expand and contract in response to pressure, like that's improved, which is really important. So I think that, you know, obviously the sauna, the heat itself does, does affect, you know, blood flow, plasma volume, all that stuff is, is changed. So, so I think that the cardiovascular aspects... And Jari's trying to, to really kind of tease apart more mechanisms because he's a, he's an MD PhD. He's a cardiologist, uh, by training, but he's also got a PhD. Uh, so he's, he's trying, you know, really hard to, to kind of understand exactly what's going on. But I, I do think that it's really-

    18. PAPeter Attia1:16:09

        It really seems convincing.

    19. RPRhonda Patrick1:16:10

        It's really convincing. Y- With the cardiovascular-related mortality specifically, it's very robust. Personally, it's kind of interesting to think about how much of, you know, exercise also elevates your core body temperature. I mean, there's this overlap there, you know? And when I sit in a sauna, my heart rate starts to elevate like I'm doing cardiovascular el- I mean, that's, that's what happens, like I'm doing cardiovascular exercise. Start to sweat. I mean, a lot of the same adaptations that happen with exercise are happening when you're, you're sitting in a, in a hot sauna. And, and even a hot bath, like more recently another study came out showing hot bath, um, affected... had a positive effect on a variety of cardiovascular-related markers as well. Which again, if... But you have to sit in it long enough, you know, to, to experience some of those effects with the elevation of the heart rate and all that stuff. But there's also a really profound effect on the immune system. Like, part of the benefit of exercise is that it is an acute oxidative stress burst, an acute inflammatory burst. You know, there's then an, a response to that, and the net response is a positive anti-inflammatory and antioxidant response. But the inflammatory and oxidant response is required to get that. Um, and something similar is happening with, with the sauna as well. Uh, recently there was a study looking, um, by Dr. Charles Raison. He had made this, like, fancy contraption where he elevated core body temperature, and he had a sham control. So actually pe- the sham control also made people a little bit, uh, hot, and they thought they were actually getting the treatment. But it had a very strong antidepressant effect.

    20. PAPeter Attia1:17:39

        How did they do that?

    21. RPRhonda Patrick1:17:40

        He explains it on my podcast, so you can go.

    22. PAPeter Attia1:17:42

        Okay.

    23. RPRhonda Patrick1:17:42

        There's a transcript. You can just kind of-

    24. PAPeter Attia1:17:44

        That strikes me as one of the few things you can't placebo

    25. RPRhonda Patrick1:17:46

        ... he, they did some crafty thing which I'm not gonna try to explain-

    26. PAPeter Attia1:17:50

        [laughs]

    27. RPRhonda Patrick1:17:50

        ... because I will absolutely botch it. They did it, and, and they had a sham control, and in fact, about... He said about 70% of the people that had the sham control thought they had the actual treatment. So it wor- Like, there was definitely a... They were trying to control for the placebo effect. What's interesting is I even... The reason I got into the sauna was the effects that I felt on my mood, uh, when I was in graduate school. Like, I, I lived across the street from a YMCA, and so I started using the sauna, and it was, like, very black and white. Like, I was like, "Wow, this is amazing. Like, I can handle all the stress."

    28. PAPeter Attia1:18:19

        And this was a wet sauna, a dry sauna?

    29. RPRhonda Patrick1:18:21

        This was... This is a dry sauna.

    30. PAPeter Attia1:18:23

        Do we have a sense of dry sauna versus IR versus all the different...
13. 1:22:23 – 1:24:43

    Alzheimer's Heterogeneity, Ketones in the Brain, and Heat Discomfort

    1. PAPeter Attia1:22:23

       This is to me the biggest challenge with Alzheimer's disease just is, you know, we're talking about it in a pretty nuanced way. But I think unfortunately clinically it's still considered one disease. But, you know, to the best of my understanding, it's really several diseases that all have a very similar common final pathway. You know, for example, like going back some of the ketone data. You know, why, why does ketone enhance memory in some, in some models? Certainly even going back, oh God, 10 years, you see a lot of anecdote of people in early stage dementia who when given even MCT oil would see transient improvements in cognition. Now, Richard Veech did some of the most elegant work on this. Richard Veech, by the way, is the guy who along with Kieran Clarke created the ketone ester that T Delta S licenses to human. And, you know, they showed I think quite convincingly in this animal model that the BHB was basically bypassing pyruvate dehydrogenase. And so all of a sudden... You know, when you think about the energy deficit that a, that a neuron would experience if you have insulin resistance at PDH. So if, you know, glucose is going to pyruvate and pyruvate can't get in because PDH is resistant, giving BHB would just bypass it. You go straight into the Krebs cycle. You make all the ATP you want. But that might only be a subset of people that are, you know, suffering, right? There's also going to be the microvascular variant, and then there's gonna be the sort of more toxin variant. So the nice thing about sauna too, just thinking about it, is if, if ... And as again, like I'm becoming more [laughs] and more convinced of this. It's actually like a really pleasant thing that you can do to potentially live longer, uh, and certainly live better. Because many of the things we talk about, I mean, let's call a spade a spade. Fasting's not fun. I wish I could tell you that, you know, not eating is fun, but like I just love eating. So anytime I'm not eating, I'm sort of like there's a discipline that's required to do it. But I don't know, sitting in the sauna for 20 minutes before you go to bed is pretty enjoyable. Of course, the problem is-

    2. RPRhonda Patrick1:24:17

       It gets hot

    3. PAPeter Attia1:24:17

       ... it's not, it's not, it's not accessible-

    4. RPRhonda Patrick1:24:18

       No [laughs]

    5. PAPeter Attia1:24:19

       ... to everyone

    6. RPRhonda Patrick1:24:19

       ... it's not enjoyable at a certain point.

    7. PAPeter Attia1:24:20

       You don't like it. Yeah, yeah, yeah. No.

    8. RPRhonda Patrick1:24:21

       At a certain point you... It's enjoyable until you're like, "Holy shit, it's hot. I want to get out." [laughs]

    9. PAPeter Attia1:24:26

       But it's knowing that, like you get to get out, and then that, that jump into the pool or the whatever it is is, is-

    10. RPRhonda Patrick1:24:31

        Yeah

    11. PAPeter Attia1:24:32

        ... is, is pretty nice.

    12. RPRhonda Patrick1:24:33

        Yeah. And the discomfort you experience, uh, from, from like the heat stress where you're like really hot is actually I think key for the positive benefits. At least for me it was on, on my mood, where I was just like, felt

14. 1:24:43 – 1:32:48

    Cold Exposure, Stacking with Sauna, and Recovery Trade-offs

    1. RPRhonda Patrick1:24:43

       so good. Like-

    2. PAPeter Attia1:24:44

       So what about the reciprocal of that? Cold. So I used to do a lot of cold therapy, but all for DOMS, d- delayed onset muscle soreness. So that was my main in- interest was, you know, back in the olden days I would go out and buy 100 pounds of ice or 50 pounds of ice I guess, throw it in the bathtub, cold water, and I would immerse myself, and that was unbearable. But that really sped up my recovery-

    3. RPRhonda Patrick1:25:07

       Mm-hmm

    4. PAPeter Attia1:25:07

       ... um, from difficult workouts. It's a pain in the ass, so I started doing cryo. And the data, well, I, I was pretty convinced that whole body cryo, three minutes of whole body cryo at the right temperature was gonna produce a roughly comparable effect in DOMS but at a fraction of the time and 10X the cost. But I've also had people talk to me about... And a- again, I've never really looked into this, but I'm guessing you have ice cold showers for, you know, increasing norepinephrine levels, things like that, uh, mood altering. Have you, have you looked into this?

    5. RPRhonda Patrick1:25:36

       I've looked into the literature. Yeah, that's something that I d- that I did notice from, from doing cold showers, and sometimes I'll do one before like a big ... talk or something because it does help me focus and it helps with my anxiety. Kind of very similar-

    6. PAPeter Attia1:25:49

       So, so yeah, I was gonna say, so how do we square the two completely different things, right? You would, you'd sit in the sauna to help with anxiety, and then you could have the cold shower.

    7. RPRhonda Patrick1:25:57

       Well, I didn't start getting into the cold shower until probably a couple of years ago. The sauna I started doing-

    8. PAPeter Attia1:26:04

       In grad school.

    9. RPRhonda Patrick1:26:05

       Yeah, a long time, probably about 2008, so a long time ago. So, uh, they're, they're completely uncoupled in my experience. I mean-

    10. PAPeter Attia1:26:13

        So do you think the sauna is working more through GH and other-

    11. RPRhonda Patrick1:26:18

        I think the sauna has a, a very profound... First, it affects the immune system, and that, and that inflammation has a major effect on brain, and I think that, that's work from Charles Raison i- is pretty clear. It's definitely... There's definitely an antidepressant effect that seems to correlate with biomarkers of the immune system. So, so the more potent the IL-6 response, the more potent the antidepressant response. In addition to that, there's a very strong effect on beta-endorphins. Beta-endorphins are dumped, and also this other system called dynorphin-

    12. PAPeter Attia1:26:47

        Mm-hmm

    13. RPRhonda Patrick1:26:47

        ... which is, you know, the-

    14. PAPeter Attia1:26:48

        Yeah, the, the, the opposite

    15. RPRhonda Patrick1:26:50

        ... the opposite.

    16. PAPeter Attia1:26:50

        Yeah.

    17. RPRhonda Patrick1:26:50

        Yeah, and, and what's interesting is that when you activate dynorphin th- through the, the kappa-opioid pathway instead of mu-opioid, you feel uncomfortable, and it's the part where I'm, where I was talking about where you're like, "I'm hot. I wanna get out." It's the part when you're exercising where you're like, "Oh, this..." You know? It's that uncomfortable feeling. Well, that's... You're making dynorphin partly because it cools your body down, so it's kind of a response to elevating your body temperature.

    18. PAPeter Attia1:27:11

        I'm convinced, by the way, there are a subset of athletes that don't produce that at the same level.

    19. RPRhonda Patrick1:27:15

        [laughs] Yeah.

    20. PAPeter Attia1:27:16

        I mean, seriously, like, there are people, I think, who-

    21. RPRhonda Patrick1:27:19

        There are, yeah. There's-

    22. PAPeter Attia1:27:19

        'Cause, 'cause we talk about, like, why can that guy tolerate so much more pain than that guy?

    23. RPRhonda Patrick1:27:23

        Yeah.

    24. PAPeter Attia1:27:23

        And at some point, it's possible that they're actually experiencing less pain.

    25. RPRhonda Patrick1:27:27

        There, there, there definitely are variants in, in the kappa-opioid receptor pathway and, and all that, so, um, yeah.

    26. PAPeter Attia1:27:33

        I'm surprised that hasn't become a performance-enhancing drug, which is, you know, blocking that receptor-

    27. RPRhonda Patrick1:27:38

        Pain

    28. PAPeter Attia1:27:38

        ... the pain receptor in the brain, which is a, you know, a very interesting thought. But now, so, so then on the cold front-

    29. RPRhonda Patrick1:27:46

        Yes

    30. PAPeter Attia1:27:46

        ... what, what do you think's mediating that? Neurotransmitters?
15. 1:32:48 – 1:39:16

    NAD+ Precursors, PARP and Metformin

    1. PAPeter Attia1:32:48

       So there's one more topic I just want to get to i- if we can spare a bit more time, which is, which is NAD, the precursors, the whole shtick. You've spent a lot of time thinking about this. What is your current thinking on does having more NAD to NADH matter?

    2. RPRhonda Patrick1:33:04

       The, the thing about the NAD-

    3. PAPeter Attia1:33:06

       I guess I should provide context for people. Why am I asking this question, right? So there's lots of supplements out there now that are, you know, either giving NR or NAD. And the claim is that these things can enhance longevity, you could live longer, and that also you live better. You have more energy, all of these other things. And so in the mitochondria you have complex one, which converts NADH to NAD. And the idea is we, we do know that as you age, that ratio of NAD to NADH goes down. And so part of the thinking is, well... And this is outside of the sirtuin pathway, but it, this is upstream of that. But if you give more of either the precursor NAD, you're basically fixing something that is getting worse as you age.

    4. RPRhonda Patrick1:33:46

       Yeah. So that, I mean, the, the question is why does it go down? And that's, I think there's multiple reasons for that, at least that's been shown in literature. NAD is a very important cofactor for mitochondria. I mean, obviously mitochondria are making NADH and the, that hydrogen, the proton is used and electrons are used to basically generate energy through the electron transport chain, and it's also generating the mitochondrial membrane potential by kicking out the, the proton. So that, that's really important for mitochondrial function, respiratory function, energy production, which is like the key of everything, [laughs] right? But in addition to that, you have, as you mentioned, sirtuins, which are histone deacetylases, which have a whole host of functions that they're doing regulating tons and tons of different pathways. They also seem to be very important for healthspan. And then in addition to that, there's very important DNA repair enzyme PARP that literally sinks up NAD. I mean, it's like an NAD sink. I mean, it li- you know? So, you know, we're constantly having damaged our-

    5. PAPeter Attia1:34:44

       Where does it reside, that enzyme?

    6. RPRhonda Patrick1:34:46

       Where in the cell?

    7. PAPeter Attia1:34:47

       Yeah.

    8. RPRhonda Patrick1:34:48

       Um-

    9. PAPeter Attia1:34:48

       Is it nuclear? It must be, right?

    10. RPRhonda Patrick1:34:50

        Yeah.

    11. PAPeter Attia1:34:50

        And the reason I ask is how do we know that these supplements that we take orally are going to actually reach their bioavailability-

    12. RPRhonda Patrick1:34:58

        Right

    13. PAPeter Attia1:34:58

        ... in the place we want them?

    14. RPRhonda Patrick1:35:00

        Right.

    15. PAPeter Attia1:35:00

        Okay. But that said, we'll come back to that after.

    16. RPRhonda Patrick1:35:02

        Yeah. Um, I think it's in the nucleus. I mean, as far as I remember-

    17. PAPeter Attia1:35:04

        It would make sense to be there, but yeah

    18. RPRhonda Patrick1:35:06

        ... otherwise it shuttles there.

    19. PAPeter Attia1:35:07

        Yeah, yeah.

    20. RPRhonda Patrick1:35:07

        But I think it is. So it's very important for repairing, you know, DNA damage. And so that's one of the major sinks and actually inflammation, all these things are kind of upstream of PARP activation. So the more that's happening, the more PARP's being activated. So you kind of have, you have NAD going there.

    21. PAPeter Attia1:35:25

        So one argument, just to make sure I understand what you're saying, is look, if you're getting older, you're gonna have more DNA damage. That's just stochastic.

    22. RPRhonda Patrick1:35:32

        Yes.

    23. PAPeter Attia1:35:32

        And if your little guy that repairs it requires NAD as fuel-

    24. RPRhonda Patrick1:35:37

        Right

    25. PAPeter Attia1:35:37

        ... that would explain one reason potentially why NAD would decline as we age.

    26. RPRhonda Patrick1:35:41

        Yeah. It's, and it's, it's certainly a, a sink for it, yeah. And the other, so the other thing is, well, if your immune system's con- constantly, you know, activated too with the more inflammation you have, all that energy is required, so NAD is being consumed more for that as well, so that's sort of another sink. Basically, NAD levels decline with age, and it's probably because it's just getting used up more. Or the other, the alternative is, you know, is there something else going on in terms of like this whole salvage pathway? There's another pathway that you can do to regenerate A- NAD, and if that's kind of going wrong, and I think there's some increasing evidence for that as well.

    27. PAPeter Attia1:36:15

        Would that make metformin a bad idea from this standpoint? Because metformin inhibits complex one, so metformin lowers the ratio of NAD to NADH.

    28. RPRhonda Patrick1:36:23

        Does it? Has that been shown? So you're saying it should lower it.

    29. PAPeter Attia1:36:27

        It should lower it. Now of course, that's counterintuitive because we know it activates AMPK. So I, I probably have to sit down and think about this, but we do know metformin inhibits complex one, and we know that complex one turns NADH to NAD.

    30. RPRhonda Patrick1:36:41

        Right.
16. 1:39:16 – 1:49:49

    Open Questions: Fasting Frequency, Rapamycin, Senescence and Wrap-up

    1. PAPeter Attia1:39:16

       What is the most interesting question you feel you don't yet know the answer to but you feel is knowable, that you're sort of actively putting in lots of your clock cycles on thinking about?

    2. RPRhonda Patrick1:39:27

       I would really like to know if, for example, someone who is like myself, who I don't have a lot of body fat, I'm, I'm active, I eat a pretty healthy diet, you know, I don't smoke, I don't have any of those bad habits. If I were to do a prolonged fast a couple days a year, would that truly have an effect on increasing my stem cell production, potentially, you know, getting rid of any dysfunctional immune cells, dysfunctional liver cells, dysfunctional whatever, you know, muscle cells and, and repopulating them with, like, healthy new cells, like, basically this rejuvenation. Like, could I get this, like, burst of rejuvenation a couple times a year, and would that have, in turn, have an effect on delaying the onset of age-related diseases, improving my healthspan, you know, keeping my stem cells less damage? That would be very interesting to me because, to me, that's something that's very doable, uh, for myself. I mean, the experiment to, to figure that out is different because it's, you know, in humans, and so that's gonna be really hard. You have to figure out, like, if you can even look at certain biomarkers to know that. But I feel like that would be something that's so easy for someone to do that's interested in, in longevity.

    3. PAPeter Attia1:40:34

       And you think it would be sort of, um, once or twice a year doing, like, a five-day water-only, mineral-only fast?

    4. RPRhonda Patrick1:40:38

       Well, the question is how often would you-

    5. PAPeter Attia1:40:40

       Yeah, how often would you need to do it?

    6. RPRhonda Patrick1:40:41

       Yeah. And how long of a ... Like, so-

    7. PAPeter Attia1:40:43

       Yeah

    8. RPRhonda Patrick1:40:43

       ... you know, we have a lot of the studies coming out of animal data, which, I mean, these, these rodents, they lose 20% of their body weight after a 48-hour water fast.

    9. PAPeter Attia1:40:50

       Yeah, I find it hard to infer anything from rodents when it comes to fasting be- because, uh, uh, of this exact reason. It's like I ... Even the Jay Mitchell stuff I talked about earlier. I mean, I think it's an interesting proof of concept, but I don't actually know how you would apply that to humans.

    10. RPRhonda Patrick1:41:05

        Right. So the question is, it's like, okay, so if you have a 48-hour fast in a, in a rodent water fast-

    11. PAPeter Attia1:41:09

        Right. Does that mean that a human has to fast

    12. RPRhonda Patrick1:41:11

        ... like, is that an 10-day fast, or is it-

    13. PAPeter Attia1:41:12

        E- exactly.

    14. RPRhonda Patrick1:41:12

        Yeah. So I guess I'll expand my sort of answer to that question, like, maybe do a prolonged water fast, like, time a, like, genetic study.

    15. PAPeter Attia1:41:20

        Right. What's the frequency? What's the duration-

    16. RPRhonda Patrick1:41:22

        Exactly

    17. PAPeter Attia1:41:22

        ... to get the maximum benefit?

    18. RPRhonda Patrick1:41:23

        Yeah. Uh, and I'm specifically interested in this shrinking of the organs and then regrowing, like, this potential robust activation of stem cells, clearing away ... You know, we're not just talking about autophagy. We're not just talking about clearing away damaged mitochondria, pieces of DNA, protein aggre- which is all really great. You are getting that, but ... Well, in theory, in humans. In addition to that, I mean, I'm talking about clearing away the damage to the whole cell, like, just getting rid of it and replacing it with a brand-new, young, healthy cell. Like, that's what I'm interested in. You know? I would, I would love to ... You know, even just the hope that that's possible, you know, based off of some of the, the pilot studies that Valter has done in humans and, and certainly the, the animal evidence, I, like, I'm convinced I'm gonna at least try because, uh, it seem, it seems very possible. I know, I know that he is, um, trying to find the best biomarkers to look at for, you know, stem cell activation. So it's, it's not quite as straightforward. Can't just, you know, harvest a bunch of tissues and, and look at things. But I certainly have gotten some anecdotes from people that have had autoimmune-like diseases and things said, like, fasting's, like, completely reversed some of it, like, like eczema or something like that.

    19. PAPeter Attia1:42:30

        Yeah, yeah.

    20. RPRhonda Patrick1:42:30

        You know, where-

    21. PAPeter Attia1:42:30

        No, no, it's, it's, um-

    22. RPRhonda Patrick1:42:31

        Where it's, you know, where it's anecdotal, uh, but certainly when you start to have enough people saying the same thing, it's like, wow, that's interesting that you've heard that five, five or six times now. Yeah, I think that would-

    23. PAPeter Attia1:42:41

        That's a good one. I, I guess I think of a very similar question with rapamycin.

    24. RPRhonda Patrick1:42:46

        Rapamycin, yeah.

    25. PAPeter Attia1:42:47

        Yeah. What, what dose and what frequency-

    26. RPRhonda Patrick1:42:50

        Right

    27. PAPeter Attia1:42:50

        ... to produce the best longevity phenotype?

    28. RPRhonda Patrick1:42:52

        Yeah. You know the interesting thing with the rapamycin is the effect on the senescent cells.

    29. PAPeter Attia1:42:56

        Mm-hmm.

    30. RPRhonda Patrick1:42:56

        Like, like, that's so interesting to me.

Episode duration: 1:49:49