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Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other 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 with a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peteratiamd.com. Welcome to the Peter Atia Drive. In this episode, which I know is long anticipated, I spoke with Dr. Ronda Patrick from Found My Fitness. I suspect many of you listening to this, know everything about Ronda 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 Ronda is. I suspect by the end of this discussion, you will also become a huge fan of hers and her podcast, which is exceptional. I've known Ronda for quite a while, and despite the fact that we both consider San Diego home, we've just been busy enough that we just haven't had a chance to sit down together in quite a while. This discussion was long overdue, and it was sort of funny because as soon as Ronda walked in, we just jumped right into a really interesting discussion, and then 10 minutes in, I thought, "We should probably start recording because this is interesting stuff." We did. 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 because it's super interesting." That's just basically to say, "I suspect Ronda and I will speak again 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. 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 Ronda brings a great deal of expertise to. 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 have some confounding and conflicting data around that. We also got into a great discussion about the P-PAR enzyme, so P-PAR-alpha, P-PAR-gamma. One of the things that Ronda 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. Ronda doesn't put out a lot of podcasts, but the reason for that is the amount of work she puts into them is enormous. When she puts up a podcast on video, there's explanations, definitions, and stuff scrolling across the screen. It's unlike me who's incredibly lazy and can't even stand to listen to a podcast after I record it. Ronda 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 Ronda'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 about 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 the monochytogenic diet and everything seems to go wrong, so at least biochemically wrong. 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 Ronda, 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? 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. 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. 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. I think Ronda and I share that, and I think it was actually really fun to see where her beliefs have changed over time. With that said, I think the show notes for this particular episode are going to be very helpful, and you can find those at peteratiamd.com/podcast. I hope you enjoy this discussion at least half as much as I did. I suspect it won't be the last. Without further delay, here's my conversation with Dr. Ronda Patrick. Ronda, so great to have you here. Happy to be here. It's great to see you again. I can't believe we live in the same city and only see each other once a year. If you're even. Well, thank you for taking the trip up here today to my office. My pleasure. I'll join the long list of people congratulating you on your 10-month-old son. Thank you. Thank you. I almost don't know where to begin because there are so many things that we share in common as far as interests, but I want to start with a really broad question, which is you spend so much time thinking about many of the same problems I spend time thinking about. What do you believe today that you did not believe four or five years ago? 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 increasing health span, which is the healthy part of your life, delaying the onset of age-related diseases. The major modality for doing that would be the best way to do it would be caloric restriction or dietary restriction, so eating 30% less food than you normally would eat. I used to really think that was the way to go for doing that, and I think that my beliefs have changed for that in that being the major modality for 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 IGF1. And that's thought to regulate a lot of the improved health span effects, at least in some organisms like mice and in racist monkeys. But I do believe now based off a variety of research from people like Walter Longo, that periods of growth, actually specifically periods of IGF1 are really important. So if you're constantly doing this caloric restriction, then you're not really going to have that period of growth because you're chronically doing that. And really interesting, I don't know if you saw the recent nature study that came out. I think it was an April of this year on lemurs. The study essentially showed, I guess they're not human primate animal model, but their lifespan is, median lifespan is around 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 lived a year longer than typically. And there's a lot of delayed onset of various degenerative diseases. But there was a mass of atrophy in gray brain matter, in regions of the brain that didn't occur in control animals, which is just another example of how sometimes some of these modalities that we think are really good for increasing calisthenics sometimes have other effects. And I think that getting into the IGF1, I think we'll probably, and I will talk about that because we both have a shared interest in that. But the periods of growth being necessary for health, I think that's turning point in my mind. And so now I actually think that perhaps even doing periodic, you know, prolonged fast or a better way of doing that, because you can get that IGF1 boost and you can get the lower IGF1 among other things that occur. But we can dive into that if you want. But I think that's probably one of the major things. Yeah, there would be actually another interest that we share would be, I think it was a lot more skeptical of ketogenic diets about four years ago, in terms of being great for long-term health and health span. And I think that some of my thoughts on that have changed a bit based off of more recent long-term studies in animals, specifically in mice, from work from Dr. Eric Verdon, and also from out of UC Davis, showing that ketogenic diets in rodents can increase health span, increase median lifespan, certainly improve cognitive function. Now the caveat there is that typically with ketogenic diet in rodents, it's actually can be, most of the time, is obesity genic. And the way that these guys worked around that was they found that they had to limit the calorie. And what was interesting was that-- Or cycle them, right? Well, so Dr. Eric Verdon, the way they did that was by cycling it. But UC Davis, what they did was actually put a calorie cap and turns out after talking with Dr. Sachenpanda that they ended up But being on a time restricted feeding schedule, and so the ketogenic diet was, you know, they were basically eating all their food within 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 really know, you know, I don't know exactly 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 what. So, I'm also intrigued by that, 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 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, because those two publications came out in cell, right? The ones, um, versions of-- Cell in the table is mine. 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 bigot obese. That's really counterintuitive when you think about how ketogenic diets increase circulate that in 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? Were 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 we less on a ketogenic diet, the question is really-- or 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-- 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? Was there something else in them because they couldn't have had that much sucrose-- 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. And I think even previous studies, like earlier in the literature, showed something similar where it was obesity genetic. Now, there was certain genetic backgrounds. It also seemed to kind of, you know, regulate that to some degree. But what I was actually thinking-- so you brought up some really interesting points-- is that thinking of that in the context of, like, let's say 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 conatine palmityl transferase, the-- basically the transporter to transport fatty acids in the mitochondria. So if you constantly are making malonyl coA because you're constantly eating the fat, then you're going to start to have this inhibition. You're going to start to then store the fatty acids in antipostitia rather than catabolizing them, right? So it seems to me that-- And we don't see that, by the way, with the exogenous ketones, do we? This is something I'm still trying to get a handle on. I agree. I'm extremely interested in exogenous ketones, particularly because I've tried them. Oh, OK, you've tried them. Yeah, yeah, yeah. I was going to bring you something. So I really enjoy the effects they have on my brain. So I've used them for, like, endurance, exercise, and I also like it for that as well. I do notice that I have a little bit of a seem to run longer than I usually stop at this point on the beach, and I'm like, I can keep going another, you know? But what I really like is for me, it really helps with focus and lower anxiety levels. So I seem to be able to-- I'm always on to the next, you know? And so this kind of helps me, like, stay in the now. At least I-- and that could be completely placebo, I don't know. But, anyway, 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 reason I had wondered that is because there was a paper that recently came out where I think it was the one that was done in humans where humans-- they were given the beta-hydroxybutyrate ester for endurance and in enhanced endurance performance. But they found inhibited-- >> Antelope, triphone. >> Yes. And also it inhibited fatty acid, something to do with the fatty acid transport out of the adipose-- something to do with where I was, like, going with some of what-- some of that had to do with lipid metabolism, which suggested possibly there could be an inhibition. >> Now, you know, it's funny. I'm going to see-- I'm in New York next week, and Dom is going to be in New York. Dom DeGasino, who obviously you know well. And we're grabbing dinner one night. And we're going to talk about this paper because I remember when it came out, Dom sent me an email with-- >> Can you pull it up? >> Then I'll know for sure if you want. Or I can just send it to you. >> Yeah, send it to me. >> Okay. >> Yeah, 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 look at it. But it does beg another question. So I want to go back because there's going to be-- I know this is going to be a theme today, which is multiple threads that are easy for us to go off on. >> If you and I are great at going on dates. >> Yeah, yeah, yeah. Let's go back to the mice. Let's go back to the two studies. Do you recall, if in the verdant 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 libidum that they over ate in or were they given 24-hour access to food? >> 24-hour. >> So what they never tried then was, let's give you food for 10 hours and let you eat ad libidum. Because that would be interesting if they would over eat in that setting. Maybe not that interesting. The other experiment that I don't think has been done is-- remember when they did the-- 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 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. >> Right. I think I remember one of the big differences between the high-fat, low carb and the actual ketogenic diet was the induction of PPR alpha. >> Yes, exactly. >> Which makes sense because that's involved in ketogenesis itself. >> To what degree that regulates any of the other important properties that were found, including the really the profound effects on the brain. So I like to personally get my ketogenesis from my periods of fasting. >> More so than carbohydrate restriction? >> Well, I do refine carbohydrate restriction. But I also think there's a lot of benefits. This is part of the reason why for so long I was skeptical of a ketogenic diet is because I think there's a lot of benefits in eating a variety of plants. I think that there's a lot of various micronutrients that are much higher density in plants, folate, magnesium, vitamin K1. But also there's a lot of fermentable fibers and things that are really also really good for the gut microbiome, which I also think is very important for regulating immune function. So that's kind of been my hang up. But I think people like Dom seem to be doing a modified ketogenic diet where they're definitely getting the greens, trying to get the leafy greens. So I think that one way to get around that plus, I think there's also a way to do a ketogenic diet where you're eating a lot of salmon, avocado, nuts, olive oil. It's not just butter and keto bombs and all this pork rinds and stuff. I'm just like, where's the nutrient density and some of that? >> Yeah, it's funny. I guess it depends on how many calories you need. But 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 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, oh, by the way, for those listening and wondering what that noise is, this is something that Ron and I are very used to. Those are F-A-18s, which how many overhead drive buys are we going to get today if you had to predict? >> I would say-- >> How many get three more? >> Yeah, I would say probably between three or four. >> 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. I should say probably about 80 grams of total carb, but you'll see what type of carbs it was. We 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 percent 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 over that I was getting too much carbohydrate. So it's 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. >> What was in the salad? It's like-- >> Okay, so I go, you know, I'm a pretty boring guy. So it's romaine, tomatoes, cucumbers, celery, had to kind of like limit the carrots a little bit. I normally love carrots. >> So you get tomatoes and everything on the ketogenic? >> Yeah, yeah. Now again, part of it is I can get away with more because I've probably exercised more. 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 it's the other thing, tons of cheese, tons of sour cream, because you just needed those calories. And I actually developed like a spreadsheet that was customized for my caloric needs, but 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. That's the other interesting thing. And I think I talked to Eric about this was, you know, how much of the effects, you know, on, on health span or due to low protein intake and how much were due to, you know, the actual being in ketosis. Yeah. I've talked about this with Walter 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, because 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. I mean, they were very low. They were, I mean, not ridiculously low, but 25th percentile for age versus say 75th percentile today. So that makes sense to me because if you think about, you know, some of the major dietary regulators of the IGF one pathway are protein essential amino acids specifically and also insulin. Insulin through IGF, BP three. Exactly. Or IPB one. So I mean, I think that, so for example, you know, if, if someone's eating a low protein and low, you're, you're getting, you may not be a vegan, but even if you had a, 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 doing that really. Although I do kind of limit my protein. But it's a misconception. You see, I think a lot of people assume ketogenic diets are high protein diets. I think some people do consider that, yeah. 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 importantly, clinically, meaning, I don't know, over the course of my practice, my career in medicine, I mean, I've probably at least encountered 50 or 60 patients at a very detailed level on ketogenic diets. Almost for that exception, protein is the bigger thing that fows people up. And so that's the thing I've always found a bit confusing in some of those discussions is, and even Eric mentioned this on your podcast, which as well, you got to be careful if you're on a ketogenic diet. You don't have too much protein. And I was like, those don't go hand in hand. You're not on a ketogenic diet if you're eating a lot of protein because you won't make the ketones. 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 P-PAR, is it P-PAR? Our alpha or P-PAR gamma, where you see the differences in a person's ability to generate ketones. The P-PAR alpha is predominantly found in the liver, and it's involved in fatty acid catabolism, the production of ketone bodies. So that would be the major one. Now, there's nothing empirically. I've seen a literature that's looked specifically at P-PAR alpha and a ketogenic diet or fasting. But, you know, there's most of the literature out there looking at the effects of P-PAR alpha with people that are at their home asagus or have to do with the context of high saturated fat, low polyunsaturated fat diet because polyunsaturated fat activates the P-PAR family of transcription factors, which are nuclear hormone receptor transcription factors. But the P-PAR gamma is predominantly found in adipose tissue. I mean, they're found in other tissues, but I see predominantly that's the most, they're highly expressed in that adipose tissue. And it plays a role in basically taking up fatty acids and adipose tissue, whereas the alpha, which is in the liver, plays a role in the transport, catabolism. So one would just sort of imagine, I mean, it'd be nice to see that, you know, someone look at that, you know, people with these specific snips and how they. Does Prometheus identify various snips of P-PAR alpha? Yes, but they don't really tell you anything. They sort of pull abstracts from PubMed and just kind of like, gump it there. So you kind of can start with research there. I've been developing a genetic tool and I just were actually developing it a lot more of a former NIH geneticist who's a really phenomenal who's been working with me to tell me sort of develop those. Basically, look at. Look at, you know, the literature and see what some of these snips are doing and then in conjunction with looking at biomarkers, very blood biomarkers to kind of help people guide, you know, what sort of they should do, what's a bypass around a potential bypass, for example. So with the P-P-P-R 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, in fact, to saturated fat ratio in order to lower your teptidibides risk. You're saying for people with a wild type or with people with certain snips? With the snips. With the snips within P-P-R alpha. Yeah, because and gamma as well, because to some degrees, some of the ones in P-P-R gamma affect the uptake of fatty acids and adipose tissue, and so and also in muscle. And so it kind of kind of affect, you know, you have a lot more free fatty acids around and that can, you know, have an effect on insulin sensitivity and other things as well. So 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 23 and me data. So here's the pattern I've seen and I'm very curious as to what the overlap is. So there's 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 at least 40% of your calories from saturated fat, typically 40 to 45% from mono and the remainder from poly, everything goes to hell on a hand basket. And the obvious things that go to hell on a hand basket have been certainly written about on the blogosphere and Twitter sphere, which is usually their LDL particle number sky rockets, 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 LPPLA2, but even non-specifically, C-reactive protein fiber engine. But the deeper level is the Y and what you see is they're making much more cholesterol. Markers of cholesterol biosynthesis like Desmosisralol go way up and some of their phytosterels go up, which is very counterintuitive. Phytosterels 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 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, 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 got to figure out a way to do this. And the only thing I could think of when I talked with Tom Daye's bring 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, evening, he's a high caloric consumer. So that gets really hard. So we created a diet form 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 mono unsaturated fat, which was pretty gross. I mean, you're drinking olive oil at that point, but he was interested in doing the experiment. And sure enough, after I don't know, maybe 8 to 12 weeks, same macro nutrient distribution, in terms of fat protein carbohydrate, the only shift was the type of fat. So we just substituted mono for saturated. His LDLP was 1300 animal per liter. All of the information 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 if we took those patients and ran them through what you're doing. Yeah, yeah. That would be the ones that have those snips. And there's a variety of them that do that. So there's the PPR alpha, PPR gamma. There's a couple of FTO related snips also that the ratio of saturated. And basically in the literature, these studies have all looked at the ratio of saturated to mono and poly unsaturated fat. And for whatever reason, people with those snips, when they have a higher saturated fat to poly your mono and or mono, they have higher inflammation, higher oxidized LDL, higher O small, then cell LDL, higher, you know, all these just terrible. Do you have a sense of the frequency based on the research you've done on this? How prevalent that is? Kind of. I would say, you know, I'd have to look back at the data probably less than 20%. So it might be in the ballpark of what I'm seeing for this different phenotype. It might be, yeah, it might be. So that would be really interesting to run them through through my tool. And like I said, we're we're even expanding that a little bit. I found I found a few more. Are patients sending you any of their data? Or are they doing it on their own and just they're doing it on their own? Some people have shared their data with me because they emailed me in and something interesting, and I'm like, oh wow, that's super interesting. Do you mind sharing that with me? And they have. - So if anybody's listening to this, and they're saying, hey, I had an advanced lipid test before and after I went on a ketogenic diet, and I looked like this situation you described, can they reach out to you through your blog and send this data to you? - They can actually just use the genetic tool, and then sort of-- - Share with you the data. - If they wanna share with me the data, I can't promise anything, but they can certainly get the why themselves by just using genetic tool right now, which I have free reports for, for example, the PPR genes, but then I have a whole comprehensive report that's a $10 recommended, so if someone doesn't wanna pay $10 to do comprehensive, they can just get the free report and get the why, potential why themselves. - All right, so I hope that anyone listening to this, 'cause again, if I'm seeing this at 10 to 20% of the time and you're seeing it, then it'd be great to get a few hundred people who are that phenotype, and find out if the phenotype matches the genotype. - Right, yeah, it would absolutely be, and like I said, I have had people have that problem where they've tried a caesonic diet and couldn't figure out and they did have one or even more than one of the SNPs that regulate fatty-assum metabolism, so. - And then there's another phenotype that fortunately is more rare, and I also wonder what's going on with PPR Alpha specifically, which is people who do everything by the book, and maybe I'm a sucker and maybe I'm gullible and maybe I believe patients too much, but I don't think I've ever had a patient lie to me. I really think like when they're not doing what they're supposed to be doing, they tell you, I'm not doing what I'm supposed to be doing, so it's not uncommon in this rare subset of patients that is where they're doing everything by the book. I mean, they're working their tail off to keep their carbs here, to keep their protein here, to keep their fat here, to keep it within this distribution, and they cannot get even close to half a millimolar of BHB in their blood. And to me, that's a really frustrating situation, frustrating for the patient because they're sort of like, what the hell I'm doing, everything right, like I'm not making ketones, and I think Steve Finney sort of put out this notion that the threshold was about 0.5 millimolar. I don't have anything to argue that one way or the other, so I generally can, based on my own empirical experience, personally, I sort of felt like one millimolar was about the threshold, but again, I think that's neither here nor there. But when these people are doing what I'm describing, and they're at best 0.2, maybe 0.3 millimolar, it just made me wonder, there's something in their machinery that's not doing this. Now, the question is, is it a like-police's problem? Is it an oxidation problem? Is it a conversion problem? I mean, that I don't know, but it would also be interesting to understand where could the weaklings be in their ketosis machinery? - Right, and there's probably, there's a variety of SNPs in these genes, and there may be certain SNPs that aren't having even really been tested or who knows. It sounds like, to me, that there's certainly something going on with the process of ketogenesis in some of the patients, and their activity levels are either active? - Yeah, we're pretty, I mean, we've evolved a lot and are 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, 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 gluconeogenesis, because 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. - Wait, so fasting does get them into ketosis? - And so again, we're dealing with such a small N that I don't, I wanna 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 long goes 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 something, again, 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. - Well, it sounds to me that maybe there's the glycogen, you're not getting depleting the glycogen too, if that's, so maybe it's not to do with the production of ketone bias, but it's actually just takes a long time to deplete that glycogen. I do think there's a huge variation, obviously physical activity plays a role in that as well. I can fast, I can do, when I do my time restricted eating, ideally I like to do it within nine or 10 hours, eat all my food within 10 or 10 hours, and then I like to fast for 15 hours. I can do that, and with my physical activity levels, I will be closer to one millimeter fast. - You will get to one millimeter after 15 hours of fasting? - I will be closer to that when I'm really physically active, during the periods a couple of years ago, when I was doing lots of long distance running and stuff, I can get closer, I mean, I'm going off of a precision extra, which probably is not very. - No, no, no, no precision extra is, that's really good stuff. - Yeah, so I can get between 0.7 millimeter to 0.9. - But are you consuming a ketogenic diet during your feeding? - So my diet typically, like I said, I've never really intentionally tried to do a ketogenic diet, but my diet is, I pretty much eat a lot of the same things, and typically it's salmon, a salad, or a sauteed vegetable with olive oil, some pasture, I mean, a butter from pasture as 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. - And will you have two meals in that window? - So it depends if I have the smoothie or not, typically I'll have breakfast and then early dinner, and then I'll have like a snack either nuts or the smoothie, the kale with some blueberries and avocado. So I think it, you know, I need a lot of nuts too. You know, I probably do. - What kind of nuts? - Walnuts, macadamia nuts, pistachios, cashews, almonds, I think probably-- - I put cashews in the candy category. - Oh really? - No, no, I just mean like I can't stop eating those things. So when I talk about nuts, I'm like, I eat nuts, and sometimes cashews, because like I just, might as well be eating M&Ms. - Is there other love for me? - Well, yeah, no, look, 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. Everything else was just a little too high in carbohydrate. The cashews just like my own personal demons. I don't know what it is about cashews. Like-- - I love watermelon, like the summer, like right now. Oh, like my son loves watermelon. - You could eat a whole one. - Oh yeah, like put a little salt on it, like my father-in-law's from the south and taught me that. So in the summertime, I like to eat some watermelon. I like to eat peaches, you know, so I'll definitely indulge in more fruits 'cause that's when they're around. But, you know, so I do, I think my diet tends to be-- - I wouldn't be surprised if before you entered your, like so let's say you finish your feeding window, just before you went to bed, it wouldn't surprise me if you're already at 0.2 or 0.3 millimolar, right? - Probably, yeah. I never actually did measure that right. - So check that. And that'll give me a sense, because if you-- - Well, I'm not doing as strict, 'cause I'm still nursing, so I'm just so hard to, like time-wise get everything, I'm eating probably more like within the 11 to 12 hour. - Okay, well, when you get back to the 15, I'd be curious, because if you're actually able to go from zero or 0.1 millimolar to 0.7 to one millimolar in a 15 hour fast, that's impressive. - So when I took the exogenous ketones, and I've done this-- - Did you do the ester? - I did the ester by HVMN. I did their instructions, which is either with a high carbohydrate diet. So I had a bowl of some whole oats with some blueberries in it. And then I took the BHP ester. I literally went from like 0.1 millimolar ketone in one hour to six millimolar. - Wow. - Six, and one hour. - That's really high. - So-- - That's impressive. - Okay. (laughing) - I'm trying to think, I definitely don't get that high. And that's just with one bottle. - With one bottle. - And then how long did it last, do you recall? - It depends on whether or not I did exercise, like intense exercise. And so if I did the intense exercise, like an hour later I was down to like two or three or something. - And have you ever taken it and just done work? For example, where basically the brain is doing more of the exercise than-- - Yeah, that's mostly what I do it now, but I'm not measuring it 'cause I'm usually like doing a podcast or traveling and doing something. But that's typical what I use for, is that. So I'm not really doing the using it for exercise. - Yeah, they've really come a long way and taste. - Really? They still taste awful. - Yeah, you know, it's funny. I remember Kevin Rose, who's a good mutual friend of ours when he tried them first. He texted me and he's like, dude, these things aren't that bad. Like you made it sound like these things were horrible. And I was like, when I had it, I thought I was drinking caracene or jet fuel. I thought I was gonna die. Go blind first then die. He goes, no, no, no, this stuff's good. He goes, actually, I wouldn't call it a sipping ketone, but it's actually, I was something guys at Human and the T-Dalthe S-Fox have. I think they've done a good job kind of making them less ridiculous. - They must really have tasted bad when you tried it 'cause I personally think it's closer to the caracene side than the-- - It was so bad, Rhonda, that there was like a good three months period where my favorite thing to do. Like more than anything in the world was if anyone came over to my house for dinner, they had to try one finger dip worth it. - Wow. - Of stuff. And of course, the first time I drank it, I just took 50 ml and chugged it neat without mixing it or anything like that. And yeah, I feel they're just getting people to try this stuff. The salts are obviously much more palatable. - Yeah, I tried this last study, but more. - I didn't really, I wasn't, I certainly didn't feel like I had the same effects as the Esther. And also, if I took a really high dose of it, I felt like I had some GI distress. - Absolutely. And I have also noticed that for some people, that is, for me, that's the case. So I cannot take the BHB estrogen and empty stomach. The only way I can tolerate that at high doses is either to put it with powdered MCT or actually just take it with a meal, which in many ways defeats the purpose 'cause I kind of like it as a way to avoid meals. - Did it lower your blood glucose? 'Cause I mean, like so significantly, it was like astounding. - Yeah, yeah, no, it's pretty, it's pretty impressive. - That means we studied, yeah. - Well, and I know that Jeff, the CEO at Human is very interested in that. And I republished a post I wrote five years ago on exogenous ketones like a couple of weeks ago. And a lot of scientists have reached out and said, "Hey, we're really interested in studying this. "Like, what can you tell us about this?" And so I think people are starting to realize that's an interesting way to lower glucose. - Really significantly, a very powerful. - I dropped 30 points. - Wow, yeah, that's perfect. - Again, you're a super-sperm. - Like after a carbohydrate, after a high carbohydrate, like I said, I had oatmeal with some blueberries, it was nuts. Of course, my blood sugar, because at the time too, I mean, I've just been nursing at night and so I'm waking up multiple times that has terrible on your, for your blood glucose levels and such, but so they were a little higher than usual. But yeah, I dropped me 30 points. - Well, yeah, that's more than we typically see. - Is it? - Yeah. - Okay. - On the topic of blood glucose, have you ever experimented with acrobose? - No, I've experimented with it in, with cells and culture, but not like personally. - The stuff's pretty interesting. It works quite well. Yeah, I'll certainly, if I'm gonna indulge in some high-carb action, I'm gonna take 100 milligrams of acrobose beforehand and just flatline my glucose. - Wow. - You know, in many ways, I find that actually more potent than metformin at glucose reduction. I mean, I think metformin has many other effects that we'll probably get into as well. So let's go back to the IGF thing. - Yeah, that's good. - 'Cause this is sort of the thing that, here's the thing, I'll just jump right to my punchline and my question with this. There are two issues I now have with things I used to take to be the gods on a truth. Actually, three things. The first is, I found Cynthia Kenyon's work on the DAF 16 mutants in sea elegance to be the most convincing evidence of the role of IGF or attenuating IGF and 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. The risk of stating the obvious, which is we're not worms, but that's a huge difference in biology. So that's the first thing. Let me let you comment on that. Yes, because I've done those experiments. I feel that's probably what straight out of college, and I went to work at the Salk Institute with Andrew Dillon who trained with Cynthia Kenyon. I was a chemistry major in college and I decided I wanted to try some real biology. Because they only had a little bit of biology in college. And so I went to work at the Salk and really it was like, those first experiments I did with worms where you know, we would knock down the insulin IGF-1 signaling pathway, also known as the DAF2. And their worms would live like literally 100% longer. They'd go from two weeks to four weeks, right? Yeah, 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 it'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 know, as they get older, they start to become less mobile. And I mean, it's just very obvious. It's the most convincing day, right? It is very convincing. And that was 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, Daph-16. Oh, Daph-16 is right. That's the homologous to Foxo. It completely obliterates the lifespan extension. Meaning it's the Foxo-3 that seems to be really important for the-- We have how many? We have four Foxos. You mean different Fox genes? OK, yeah. I don't know exactly how many, but the Foxo-- We have three. We have one, two, and four. Was it one, two, and-- Three. I thought there was like a one, two, four, five. But their analog is 16. I remember that, right? Their Daph-16 is basically our Foxo. Yes, Foxo. Yeah. So, OK. Well, anyways, yeah. I'm not sure I'm getting confused with-- You know this better than I do. But OK, yeah. But what is interesting is that the lifespan extension was completely like, ameliorated. So like-- And did their health span curves? Because the experiment you're describing and no one can see what I'm doing. But you know what I'm talking about. The natural was a two-week lifespan. Where for the first week they're youthful. And then they have a declining health span curve. So at the time of their death, they're totally decrepit. In the experiment, you're describing, if I'm thinking of the same one, you doubled the lifespan. And their longevity curve became a square function. It just went out kind of. Kind of, yeah. Yeah, exactly. Yeah, that's exactly what happened. But you get rid of the Daph-16, and they're like wild type. Oh, they're like wild type, OK? Yes. I think so. And that largely has to do with-- so that the IGF-1 insulin signaling pathway both inhibit FOXO3. So if you get rid of that inhibition, constitutively, FOXO3 is just constantly active in those warm. I mean, it's just like super-- you know, making superoxide dismutase, they're making more stem cells. They're making just everything's active, you know, more autophagy, more-- like all these stress resistance pathways. I mean, FOXO3 is a transcription factor. It regulates a whole host of genes, many of which have to do with DNA repair, autophagy, stem cell function, production of anti-oxidants and anti-inflammatory pathways. So it's a lot of really good stuff. You want to act up all the time. So there's that component to the longevity pathway. And actually, if you look at the animal data from rodents where the caloric restricted, if you get rid of the FOXO3, the median lifespan extension is gone. So the lifespan extension depends on FOXO3. The cancer stuff was still-- it didn't matter. So the cancer reduction didn't depend on FOXO3, only the lifespan extension. So I think there may be an uncoupling between humans and IGF1, one of the major problems with IGF1 is actually cancer. And if you look at animal studies, if you look at human studies, like humans that have polymorphisms that make them have more IGF1, they have much higher cancer incidence by subversive. So if you look at people that have polymorphisms either-- Is that the case? I mean, we look at the opposites, right? We look at the ones that have low GH and by proxy, low IGF and have less cancer. So you're talking about laryn syndrome. Yeah, so laryn syndrome, yes, they do. But I think there's also another one in IGF. There's heads in IGF1 receptor. So this is-- you're not talking about acromegally or people that are making too much GH. They also are more susceptible to cancer as well. Yes, I am talking about them as well, actually. The people with acromegally are more susceptible to cancer. Maybe I am-- that's what I was referring to-- that have higher circling levels of IGF1. So you're saying you can't uncouple the growth hormone from-- Yeah, that's been one of the things I've struggled with is it's hard to uncouple the GH, the effect of GH on the liver. In humans. Yes, exactly. In other animals studies that has been uncoupled. Like if you do any sort of tumor transplant animals and then make them have high GF1 through a variety of modalities, the cancer will grow rapidly. So how do we explain the human epidemiology? And I'm-- there are a few people that are more critical of epidemiology than me. I'm not a particular fan of it. But I find it to be quite interesting in the negative, meaning the contrapositives within epidemiology can be quite interesting. So this is the next thing that got me going, wait a minute. And that was there's a U-shaped mortality curve that is skewed to the right for IGF and all-cause mortality, cancer mortality, cardiovascular mortality, and neurodegenerative mortality. But when you uncouple them by disease, you see a very interesting pattern. So all-cause mortality as IGF goes up, it actually starts to go down. It natures at the 70th percentile, and then it starts to rise. But it doesn't get as high as it started. I know for people listening, this is confusing. So we'll include the figures of all these from the papers. But the point is it's not that as IGF goes up, mortality goes up. It's the opposite for 70% of the ledger, only at the very end. In other words, only high levels of IGF, very high levels of IGF seem problematic. And as I know you've talked about, I've heard you talk about this on your podcast, you have to then disaggregate that by age. The older you get, the better IGF seems to be, presumably because of the preservation of lean tissue. It turns out that most of the uptick in the mortality above the 70th percentile is driven by cancer. But actually cardiovascular disease and neurodegenerative disease seem to get they flatline by the end. So meaning there was no benefit to being at the 100th percentile or the 99th percentile versus the 80th versus the 70th, but you weren't getting penalized for it. Which suggested to me that low IGF might not be the ticket. Maybe it's some combination of cycling high and low IGF, but living it around the median to slightly above that, the 60th and 70th percentile. And again, that's probably more a function of my misunderstanding of the literature five years ago, but I really came away thinking, IGF, we got to keep that as low as possible. It's funny you and I kind of have we've evolved in the end very similar because I now also think that you know So IGF one does play a very important role obviously in development But also in the repair of muscle in the growth of muscle preserving muscle mass Also, it gets transported across the blood brain barrier plays an important role in neurogenesis and allowing Existing neurons to survive which kind of brings me back to that gray matter thing with the lemurs But you know so and the thing that was interesting to me was the effect of exercise on IGF one and the fact that for one it's been shown that the the boost in neurogenesis after exercise in the brain via brain Drive is requires IGF one animal studies have shown that mostly in rodents have shown that that exercise causes IGF One across the blood brain barrier get into the brain, but in human studies 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 one 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 Dr. Falt to Longo is that we know that he does He does these prolonged fast and I think the prolonged fasting is Extremely interesting for a couple of main reasons and one is I think that it has Remindess potential for the treatment of autoimmune disease and also cancer based on on you know his work and what he has shown now In animal studies and some pilot clinical studies is that doing a prolonged fast and or in some cases the fasting mimicking diet Causes as a massive shrinking of organs where You know he doesn't know how much of its due to cell size decreasing versus apoptosis He does know apoptosis is occurring and he has showed that in multiple publications like there is a massive induction of apoptosis after a prolonged fast And you know which makes sense because it's a very strong stress and then after during the refeeding phase The organs basically come back they come back they grow regrow and presumably selectively repopulate Yes, so he's shown that these stem cells get activated So the basically they have to be activated by the low IGF one 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 one is required For that proliferation and differentiation and repopulation of this of the tissue Which means you can't just keep the IGF one low The refeeding is just as important as the deprivation and the IGF one's key in that and so you know what he's shown now is that you can take for example 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 Like a 48 hour water fast that that's been done in patients undergoing standard of care treatment And he's shown that it was tolerable not only that there seemed to be less mylo toxicity 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 just read their prime to die. I mean it's I spent a long time you know studying Cancer cell metabolism a pup doses with a dug green And just for a moment at St.T.U. children's research hospital and and that's kind of one of the primary ways that 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 one 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 Meeting I'm amazed at how resistant the oncologists are on average obviously there were 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 Voclamped when I walk through an oncology ward and I see patients drinking insure 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 got to 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 I'm here with Jay Mitchell's work up at Harvard He did an experiment where he took three Yeah, three groups of mice so the first group were Constitiously colorically restricted for their entire life These were probably like one and a half year old mice so they're about halfway through their life Starting starting. Yeah, so these these animals were constantly at 70% colorican take The next group was your control group and then your third group was add a little bit of 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 might have been a 24 hour fast 48 would be pretty extreme for mice So in summary you've got control this 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 reprefused For people not familiar with what that means so that means 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 reprefuse The blood basically the oxygen Reprefuses the organism that's considered a reprefusion 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 a 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 know we're going to probably link to this study So people are going to 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 with it was interesting was The group that were just starved transiently actually had a faster recovery 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 Volta's work Plus this type of stuff plus just the general ethos of the way we evolved We've fasted we fed we fasted we fed we fasted a long time we gorged like it just seems we've evolved for cycling right Yeah, I agree It's really that with Volta's work I just I'm so excited about about the pro longfassing and the the potential benefits of it I think that actually is something that you and I discussed several years ago and I had you 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 iGF1 and cancer and Volta brought up something interesting in a conversation I had with him and that is Possibly that we now know iGF1 Having low and high Jeff one is important So if you're constantly having low iGF1 and the iGF1 is important for the immune system where population You can imagine the context of cancer when you're giving other treatments along with that that would be Important because your immune system is key in in in working off cancer and I thought that was a really interesting point Of course, we don't have evidence of that but I think you know, it's something that would be interesting to investigate and it makes sense Yeah, I definitely am on the same page with you if I don't I'm not and like I started out with saying I don't think that a chronic color restriction and low iGF1 is the Essential like way for improving health span. Now. I do think that iGF1 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 Hi carbohydrate or something that's going to produce a lot of insulin You know, they shouldn't be eating refined carbs, but people do they're eating them. They should definitely be exercising 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 certainly the central stuff When we published this paper earlier this year with Richard Isaacson, 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. And I remember when the analysts were kind of 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 is 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. 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 were 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. Not that I wasn't, you know, adamant before, but this is like, boy, if you're not active every day, we got to change that. I actually, the main reason I exercise is for my brain. It's certainly just not only for, you know, preventing neurogenetic disease and atrophy and all that, but just because it affects my executive function and 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 helps with executive function, long-term planning, like a aerobic exercise, specifically, you know, and the high intensity interval training, all that stuff. They all do different things. 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 going to take the Tim Ferriss approach, which is, what's the minimum effective dose? Because there are some people like maybe you or I, who I think just generally like exercise, 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 going to treat exercise like medicine. And I think in that setting, I'm still not clear. So if you were that person, what I say, Rhonda, as long as you are lifting weights, one hour, three times a week, like 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 an aerobic aerobic type thing? Like, I mean, that's, to me, those are where these biomarkers start to become very important. Because we're not going to 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 going to 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. Yeah, absolutely. I think that we definitely don't know the answer to that question. But I think there's a lot of data out there showing, for example, strength training, you know, there's benefits on the brain that's been shown, published. This 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, there was a study that I found, VO2 max, this is, you know, the ability of your body to transport oxygen during exercise, which also is a indicator of when you're not exercising. And obviously, transporting oxygen to the brain, for example, is extremely important. VO2 max declines with age, like 1% per year. I forgot starting at what age, but, you know, so 10% per decade. So that's almost parallel as the muscle mass decline? 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, 5-minute warm-up, 5-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 water. Anyway, so 24 of those increased VO2 max by 12%. You're literally taking an entire decade of decline and, like, reversing it with the 24 sessions. Yeah, that's actually a point. When I was more active as a sort of competitive, you know, encycling, we would get our VO2 max tested about twice a year. Ryan Flarety, who we were talking about before, the podcast, who's one of my close friends, and you've got 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 to test well. So, you know, over time, I learned how to game the system. You know, I want to 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 or in the high 80s or low 90s in terms of milligrams per mill, 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 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 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 necessary? Like, you have to keep doing that to get the decade-long benefit. I don't know the answer, but I agree that, like, if you can maintain muscle mass and you can maintain peak aerobic performance, it doesn't even matter at that point if you're living longer. You're clearly living better. Right? Like, if you don't budge anything on maximum lifespan, you've dramatically improved median lifespan. Right. And that's a, you know, that's- I think for most people, that's what matters. It is. Yeah, for me, it is. I mean, what's the- what's the maximum lifespan that like a human's live 120? 124 or something like that? Is it 124? 121 or 124 maybe? Like that, 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 median health span, my health span, you know, so basically preventing- staving off cardiovascular disease, cancer, all-time-rich 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 six years. Yeah, I don't really subscribe to the theory that we're going to meet some takeoff point where, you know, there's immortality. I'm really not convinced that that's that that's sort of biologically possible. And I don't suspect they'll be alive at a time when it would ever come to fruition. I don't remember the journal. It was a paper that came out of Japan, and the study looked at a variety of people of different ages, so elderly population, centenarians, which are 100, semi-super centenarians, which are between 100 and 105, and then super centenarians, 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, hematopoesis, like all that stuff was looked at 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 hematopoesis, more than glycated hemoglobin, blood glucose levels, lipid, all that stuff. It was basically the ability to suppress inflammation. Like that was predictive of cognitive function and also basically staying alive. Do you remember what they looked at? Were they looking at sea reactive protein and things like that by relatively general markers? No, no. They looked at the inner lukins and stuff also. Yeah, T&F. They looked at a whole panel of, and also some immune cells that are 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 interesting thing about that study was that that inflammation was so key for each age group. Even more than all this other stuff, like that I've thought about like senescence and telomeres and low blood glucose levels and all that stuff. And so I really, and if you look at some of the rodent literature, for example, I remember the study where NFKAPBE, which is classically thought about as an inflammatory 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 because every time it's activated, there's not that 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 lifespan's cut short by about 30%. So that's kind of interesting, right? That just getting rid of that little anti-inflammatory component of just one major regulator of immune system has a 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-sensitarians have a higher percentage of 10 and anti-inflammatory in any way. So the inflammation, it's an interesting finding that 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. 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. This was, they didn't do anything to the patients as far as differentiating the groups by traditional biomarkers of cardiovascular disease. But one group was given a placebo, one group was given an IL-1 antagonist. One 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 hard outcomes. So major adverse cardiac event, stroke, MI death. The hypothesis was found to be correct. So the patient's 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. Meaning it might have been halted actually for basically early efficacy, which presumably would have been in the group getting the methotrexate. So again, we won't know that until the meeting in October, I think when this will 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 exogenous growth hormone for all we know. Maybe, you know, I've always been quite skeptical of growth hormones use 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 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. You know, with the cardiovascular rate and mortality, the sauna is something that is interesting to me for that reason because of the profound effects that it has specifically on lowering cardiovascular-related mortality. And of course, just some clinical trial showing that there's a variety of other biomarkers and potential mechanisms by that, but which that's happening. But if you look at some of the data by Dr. Yari Laokan and out of Finland, if you look at some of the observational studies, you know, where there's like a couple thousand men that were doing, it's sauna, so ubiquitous in Finland. 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 and mortality, two to three times a week, it's lowered by like 27%. But when you jump to 47 times a week, it goes up to 50%. It was like 40, 50%. All cause mortality goes to 40. All cause mortality is also lowered. Dimension and Alzheimer's disease. Again, like 20% lowered if you're doing two to three. And I'm so glad you brought this up because I almost forgot and I wanted to talk about this. This is one of those things where I think three years ago, I was completely dismissive of this stuff, 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 going to sleep like a baby. I've done it. It's absolutely true. It's rum-marcable. 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, including sauna's 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'd love to have you talk a little bit more about this because I know you've talked about this a lot on your podcast. But in many ways, your pursuit of this has become one of the more convincing arguments in my thinking on the actual health benefits of this independent of the healthy user benefits of this. Healthy user benefits, of course, and with Yari's work, he's 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 to try his best to kind of correct for that healthy user bias. And of course, there's a dose dependence, which always makes it more convincing. But he's then since published some clinical trials where he's looked at, for example, the arterial compliance and of course blood pressure. That's one of the main things that's affect his 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 sun at the heat itself does affect, you know, blood flow, plasma volume, all that stuff is changed. So I think that the cardiovascular aspects and Yari's trying to really kind of tease apart more mechanisms because he is a, he's an MDPHT. He's a cardiologist by training, but he's also got a PhD. So he's, he's trying, you know, really hard to kind of understand exactly what's going on. But I do think that it really seems convincing. It's really convincing. The, with the cardiovascular, really 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 the sauna, my heart rate starts to elevate, like I'm doing cardiovascular, and 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 even a hot bath, like more recently, another study came out, trying to hot bath, 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 experience some of those effects with the elevation of the heart rate and all that stuff. But there's also 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 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, and something similar is happening with, with the sauna as well. Recently, there was a study looking by Dr. Charles Rayzon. He had made this like fancy contraption where he elevated core body temperature and he had a sham control. So actually, the sham control also made people a little bit hot, and they thought they were actually getting the treatment. But it had a very strong antidepressant effect. How do they do that? He explains it on my podcast, and you can go to the screen script. Okay. That strikes me as one of the few things you can't placebo. They did some crafty thing, which I'm not going to try to explain. I will absolutely botch it. They did it, and they had a sham control. And in fact, about 70% of the people that had the sham control thought they had the actual treatment. So it were. Like, they were definitely trying to control for the placebo effect. What's interesting is the reason I got into this sauna was the effects that I felt on my mood when I was in graduate school. Like I lived across history from my home, CA, and so I started using this sauna. It was like very black and white like I was like, wow, this is amazing. I can handle all this. This was a wet sauna dry sauna. This was this is a dry sauna. Do we have a sense of dry sauna versus IR versus all the different. Yeah. So I mean, the infrared sun is or like they only get to like about 140 degrees Fahrenheit. I mean, it's not very hot. If you look at Yari's work, like their sonas that they're using in Finland, they do they have a lot of what they call low-lu or something, which is like they throw the water on makes the humid, which makes it really hot. I've been to Finland and tried their sonas before. But basically the temperature gets to around 170 between 175 and 79 degrees Fahrenheit. And most of the men in these studies are doing about 20 minutes to get the maximum benefits. 11 minutes had some benefits sitting in 11 minutes, but there was a stronger effect. They stayed to 20 minutes. So if you're in an infrared sauna that only gets to 140 degrees Fahrenheit, you probably would have to stay in a much longer to get the same benefit. So the IR doesn't get deeper penetration there by alleviating the need to stay in at a higher temperature. I mean, sometimes people talk about that. There's a lot of marketing involved and a lot of that stuff. If you strip that out though. If you strip that out, the infrared sunas do affect the sweating mechanisms, like something to do with the penetration there. You do sweat, which is great because you actually do excrete things like BPA and thalates and mercury and heavy metals and things like that from sweat. So that is, that's what a lot of those some of them are. Straight up dry sauna to 170 degrees, spend three or four nights a week in that. My favorite. Yeah. Personally, I would much prefer sitting in a regular dry sauna or even a sauna that you can throw water on. You can throw water on it. But just not infrared sauna. Yeah. So that would be, you know, the other thing. Obviously, the fire has at risk is more when you're having a sauna like that, versus just an infrared. And the infrared ones are cheaper as well. So it's certainly more convenient to have an infrared sauna. But personally, I prefer the other, like the barrel saunas are really nice. There's also an effect on the immune system, who's mentioning Charles Risson, he measured IL-6, which is also part of the Janus cytokine because it's got multiple pleiotropic effects and it's acutely released upon exercise as well. It's very important for an anti-inflammatory response, releasing myocines and all these things in muscle. So it has, it's important for insulin sensitivity. A lot of the insulin sensitivity effects exercise has. So the sauna does the same thing that the exercise does, where there's just a rapid IL-6 release, at least according to Charles Risson's data. And he said that actually correlates with things. I've never looked at, I wear a continuous glucose monitor a lot, but I've never really paid much attention to it in the sauna. And I don't have a sauna, but I'm going to be this weekend at a friend's place who has a barrel sauna. And so I'll make sure that I document what my glucose level is doing, because you would think transiently it would go up. Right. Right. But I know that, at least there's in one animal study where the heat stress, quote unquote animal sauna, it actually increases glucose transporters and a type 2 diabetic model that actually improved insulin sensitivity and lowered blood glucose, because the glucose was now being taken up into muscle butter. So I wonder how much of the, again, it's like you're affecting the IL-6 is really important for that. IL-6 is released upon heat stress without the exercise. So on coupling, how much of the benefits from exercise, there's certainly some overlap. And I think that there's also their separate benefits that exercise has as well, independent of the heat stress component of it. But I certainly think there is a lot of overlap between those two things. And so the sauna becomes very interesting. And there's the whole heat shock protein part where, you know, the heat stress is one of the major ways to increase heat shock proteins, which do play an important role in neurodegenerative diseases. And I do think it's also really hard to uncouple the effects on the vascular system, which is important, right, as well, because it's having such a profound effect on the vascular system, the heat stress. It's hard to uncouple. Well, how much of the staving off of dementia and Alzheimer's test study with that versus heat shock protein is inherent? 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 does ketone enhance memory 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 Veach did some of the most elegant work on this. Richard Veach, by the way, is the guy who, along with Kirin Clark, 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, you think about the energy deficit 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 crebs 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 going to be the sort of more toxin variant. So the nice thing about sauna too, just thinking about it is it, as I get, like I'm becoming more and more convinced of this. It's actually like a really pleasant thing that you can do to potentially live longer and certainly live better because many of the things we talk about, I mean, let's call a spade is spade. Fasting is 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 it's not, it's not accessible to everyone. You don't like, yeah, yeah, yeah. Is there a point? It's enjoyable until you like, holy shit, it's hot. I want to get out. But it's knowing that like you get to get out and then that jump into the pool or the whatever it is is, is pretty nice. Yeah. And the discomfort you experience 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 my mood where I was just like, felt so good. So what about the reciprocal of that cold? So I used to do a lot of cold therapy, but all for doms, delayed onset muscle soreness. So that was my main interest was, you know, back in the old days I would go out and buy under 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 from difficult workouts. It's a pain in the ass, so I started doing cryo. And the data, I was pretty convinced that whole body cryo, three minutes of whole body cryo at the right temperature was going to produce a roughly comparable effect in doms, but had a fraction of the time and 10x the cost. But I've also had people talk to me about, and again, I've never really looked into this, but I'm guessing you have ice cold showers for, you know, increasing norip and effron levels, things like that, mood altering. Have you looked into this? I've looked into literature. Yeah, that's something that I did notice from from doing cold showers and sometimes I'll do them before like a big talk or something, because it does help me focus and it helps with my anxiety kind of very something. So yeah, I was going to say, 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. Well, I didn't start getting into the cold shower until probably a couple of years ago. The sauna I started doing in grad school. Yeah, a long time, probably about 2008. So a long time ago. So they're completely uncoupled in my experience. So do you think the sauna is working more through GH and other? I think the sauna has a very profound first, it affects the immune system and that inflammation has a major effect on brain. And I think that that's work from Charles Raison 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 aisle six response, the more potent the antidepressant response. In addition to that, there's a very strong effect on beta adorfins, beta adorfins are dumped. And also this other system called dynorphin, which is, you know, the opposite. Yeah, and what's interesting is that when you activate dynorphin through the, the capopioid pathway instead of new opioid, you feel uncomfortable and it's the part where I'm, we're talking about what your relation, I'm hot, I want to 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 elevate. From convinced by the way, there are a subset of athletes that don't produce that at the same level. I mean, seriously, like there are people, I think who, there are. Because we talk about like, why can that guy tolerate so much more pain than that guy? And at some point, it's possible that they're actually experiencing less pain. They're, they're definitely our variants in, in the capopioid receptor pathway and all that. So, I'm surprised that hasn't become a performance enhancing drug, which is, you know, blocking that receptor, the pain receptor in the brain, which is a, you know, a very interesting thought. But now, so, so then on the cold front, what do you think's mediating that neurotransmitters? So, so basically on the cold front, the norapinephrine, you're, you're, it's, that's been shown. So animal studies have shown, or norapinephrons released in the locust corollius reason of the brain after cold exposure and a variety of cold water exposure, cryotherapy. If you're doing a cold water, 50 degree, you know, if it's like 50 degrees Fahrenheit, you got to stay in a little longer than like a couple of minutes in a, in a really cold cryotherapy chamber. But in humans, plasma, norapinephrons been looked at, which does seem to sort of co-coulate with the release in the brain. It's so hard, though, to look at the plasma to understand that. I know, I know it is, it is. So, I do, I do think that the, the, some of the mood is affected by the norapinephrine as well. Have you experimented with the stacking, which is go do the sauna for 20 minutes, then go do the ice shower for whatever 10 minutes, and you get an additive effect in too. I feel really good. Yeah, I feel really good. And, and that's when I did notice that my sleep was really profoundly affected. What's interesting is there's some studies showing that, that heat stress, at least in piglets, does affect, actually, it seems to elongate the REM sleep stage, which I don't know how, you know, what, what all that means. But, so there's, there's certainly an effect of heat on sleep. And then, of course, cold is, you know, lowering your body, body temperature is important for sleep onset. But I don't know. I can, combination of the two, absolutely like, I sleep amazing after doing the, the combination of both. I think cold is really interesting for the effects on mitochondrial biogenesis. I mean, exercise is probably one of the best ways to increase mitochondrial biogenesis. But cold exposure has been shown, human studies, both in adipose tissue and in muscle tissue, to, to boost biomarkers of a mitochondrial biogenesis. What is the best biomarker? Well, it depends on what tissue we're looking at. So, like, you know, PGC1 alpha would be, would probably be one of the best, I would say, for muscle tissue. In, in adipose tissue, perhaps the same. I would say PGC1 alpha is probably one of the best. It's another downstream one. I can't, for some reason, I'm drawing a blank. Yeah. So that, that's interesting to me that, the, the effect on mitochondrial biogenesis. But personally, I like the exercise, you know, for my, my, my mitochondrial biogenesis. I'm not like doing cold exposure all the time. It's not like something that that I do often, like I said, I'll do it once in a while before a big event, I have to talk at it or something, just 'cause it does seem to help me with my mood and my feelings. - If you ever swam in water that's so cold that you actually feel like you're on fire? - Yeah, I have been, yeah. - That's me as an amazing, I assume it's through to the vasoconstriction. - I don't know. - But it's the coldest water I ever swam in was in the Colorado River and it was 42 degrees, which is, I mean, that's unusually cold. And the only reason I think I was able to swim in it was, it was May and so the sun was, it was about 90 degrees Fahrenheit was the air temperature. So you could, like I wouldn't be able to swim in 42 degree water on a cloudy day, for example, or a cold day, but I couldn't believe the sensation of feeling like I had jumped into boiling oil. It was incredible, which is very different from my normal exposure to cold. I used to swim a lot in the ocean. And, you know, if you do a three hour swim at 50 degrees Fahrenheit or 52, 53, you get a little bit of that effect, but, you know, more or less you can still, you still know you're in cold water. But this particular time I remember, and I probably spent 15 to 20 minutes in this 42 degree temp, the entire time I felt like I was burning. - Wow. - And again, I know no idea why, I guess it's, my assumption was that such profound vasoconstriction in the periphery that. - You know, the one thing that I wanted to mention when you brought this up for recoveries, because there is some evidence that for whatever reason, strength training, when you do cold exposure, like immediately after strength training, if you do it within, let's say before, like sometimes within an hour before. - Before, okay, okay. - After strength training, it seems to blunt some of the hypertrophy effects. - Yes, yes. And actually, it seems to me you say that that's the exact reason I would never take like ibuprofen or any anti-inflammatory agent. I would limit it even that day. I wouldn't take any of those agents, because you're impairing that rebuild. - Yeah, so that's also interesting that the timing of it seems to be, again, it's been shown that about an hour after exercise is when the anti-inflammatory response starts to peak, and so it's like if you can, basically, if you're within that hour window, when the inflammation's happening to create that anti-inflammatory response, you don't wanna dampen that. At least, it seems to be what I think, and literature seems to suggest. And there's, of course, mechanisms where it's like specific macrophages and muscle tissue are really important for activating all these things that eventually result in satellite cell proliferation, and, of course, IGF1s in there somewhere. So, again, the immune system activation is important for a lot of the benefits of exercise, including muscle hypertrophy. - So there's one more topic I just wanna get to if we can spare a bit more time, which is NAD. The precursor is the whole stick. You've spent a lot of time thinking about this. What is your current thinking on, is having more NAD to NADH matter? - The thing about the NAD-- - 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 either giving NR or NAD, and the claim is that these things can enhance longevity. They 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 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 Certo and pathway, but 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. - Yeah, so 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 really important co-factor for mitochondria. I mean, obviously, mitochondria are making NADH, and 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 proton. So that's really important for mitochondrial function, respiratory function, energy production, which is like the key of everything, right? But in addition to that, you have, as you mentioned, Sir Twins, which are histone deacetylases, which have a whole host of functions that they're doing, regulating tons and tons of different pathways. They're also seemed to be very important for health span. And then in addition to that, there's very important DNA repair enzyme part that literally syncs up NAD. I mean, it's like an NAD sync. I mean, you know, so we're constantly having damage. Where does it reside that enzyme? Where in the cell? Yeah, is it nuclear? It must be, right? Yeah. And the reason I ask is, how do we know that these supplements that we take orally are going to actually reach their bioavailability in the place we want them? Okay, but that said, we'll come back to that after. I think it's in the nucleus. I mean, it's part of the membrane. It makes sense to be there, but yeah. Otherwise, it shuttles there, but I think it is. So it's very important for repairing DNA damage. And so that's one of the major syncs and actually inflammation. All these things are kind of upstream of part activation. So the more that's happening, the more parts being activated. So you kind of have, you have NAD going there. So one argument just to make sure I understand what you're saying is, look, if you're getting older, you're going to have more DNA damage. That's just stochastic. And if your little guy that repairs it, requires NAD as fuel, that would explain one reason potentially why NAD would decline as we age. Yeah. And it's certainly a sink for it. Yeah. And the other-- so the other thing is, well, if your immune system's constantly activated too, if you're 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 alternative is, is there something else going on in terms of this whole salvage pathway? There's another pathway that you can do to regenerate NAD. And if that's kind of going wrong. And I think there's some increasing evidence for that as well. Would that make Metformin a bad idea from this standpoint? Because Metformin inhibits complex one. So Metformin lowers the ratio of NAD to NAD. Does it? Has that been shown? So you're saying it should lower it? It should lower it. Now, of course, that's counterintuitive, because we know it activates AMPK. So 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, which makes me wonder, is it possible that Metformin would impair DNA repair through that mechanism by reducing substrate? I have no idea. Well, I'm going to write that down. That's something I'm going to have to look into. Because I wasn't aware of the NAD. I didn't understand that link. Yeah. I think that's a major one. I literally think that's a major sink for it. I think that the part is, I think, it's just like going there. Yeah. So the animal evidence, you mentioned some of this supplements, precursors I can form NAD. I think that the animal evidence suggests that it can, at least in rodents, improve health span, particularly in models that are heavily dependent on mitochondria, like muscle, myopathy models, or something like that. I think that was one. And also the brain. So I think those are the two organs I've seen, like, major positive effects with NAD supplementation. And then there's some, of course, pilot clinical study is showing that, yes, you can take, for example, Nikotonamide riboside, and it does seem to increase NAD levels in plasma and a dose dependent manner. Now again, you raise the question. We have no idea if it's getting in the middle of the room. Is it getting in the cell? Is it getting in the-- Now, we do know in animal studies, I think that has been shown because it's affecting the mitochond-- like I said, those animal models of myopathy and stuff, and mitochondrial function was improved and all that stuff. So in animal models, it obviously is affecting mitochondrial function. So it must be getting to the right place. I don't know why I have found myself kind of skeptical of this. I think it's good to start with skepticism. I mean, I think that NAD levels are-- you can increase them with fasting. So when you fast, as you mentioned, you convert NAD into NADH in the presence of energy, because that's basically when you have a substrate, like glucose or fatty acid, that's when you produce NADH, or FADH2. So in the absence of those substrates, then your NAD starts to build up. So back to your metformin question, you said. I know who to ask. I definitely know. I'm going to ask Nav Chendell. He will know the answer to this question. I thought a lot of his work when I was in grad-- him, Ralph D. Bardini's-- I did it because I was doing a lot of cancer metabolism, mitochondrial function and stuff. So I followed a lot of the work on this. Do you have Nav's book, Navigating Metabolism? No, I don't. No, I just used to read his paper which back when I was a graduate school. Yeah, so Nav and David Sabatini were in town a couple of weeks ago. And I was leaving town the day they were coming into town. So we hung out for three hours near the airport. And I was just reminded of how much fun it is to talk about mitochondria. Yeah. For sure. What is the most interesting question you feel you don't yet know the answer to, but you feel is no a bull, that you're sort of actively putting in lots of your clock cycles on thinking about. 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 active, I eat a pretty healthy diet. 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 getting rid of any dysfunctional immune cells, dysfunctional liver cells, dysfunctional, whatever, muscle cells and repopulating them with 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 and proving my health span, you know, keeping my stem cells less damaged? That would be very interesting to me because to me, that's something that's very doable for myself. I mean, the experiment to figure that out was different because it's, you know, in humans. And so that's going to be really hard. You have to figure out like if you can even look at certain biomarkers to know that. And I feel like that would be something that's so easy for someone to do. It's interested in longevity. And you think it would be sort of once or twice a year doing like a five-day water-only, mineral-only effect? Well, the question is how often would you need to do that? Yeah. And how long of it? Like, so, you know, we have a lot of the studies coming out of animal data, which, I mean, these rodents, they lose 20% of their body weight after a 48-hour water-fat. Yeah, I find it hard to infer anything from rodents when it comes to fasting because of this exact reason. Like, even the J. 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. Right. So the question is it's like, okay, so if you have a 48-hour fast in a rodent order-fat, like does that mean that a human has a fast? Exactly. Yeah. So I guess I'll expand my sort of answer to that question, like maybe do a prolonged water-fast like a time in the next- Right. What's the frequency? What's the duration together maximum benefits? Yeah. So I'm really, really interested in this shrinking of the organs and then re-growing, like, this potential robust activation of stem cells clearing away. You know, we're not just talking about a top issue, we're not just talking about clearing away damage to mitochondria, pieces of DNA, protein agro, 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 love to, you know, even just the hope that that's possible, you know, based off of some of the pilot studies that Walter has done in humans and certainly the animal evidence. Like, I'm convinced I'm going to at least try because it seems very possible. I know that he is trying to find the best biomarkers to look at for stem cell activation. It's not quite as straightforward. I can't just, you know, harvest a bunch of tissues and look at things. I certainly have gotten some anecdotes from people that have had autoimmune like diseases and things said, like, fasting is like completely reversed some of it, like, like, like, like, like, some, or something. Yeah, I know. It's, like, it's, you know, where it's anecdotal, 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 or six times now. Yeah, I think that would, that's a good one. I guess I think of a very similar question with rapamycin. Rapamycin, yeah. So what, what dose and what frequency to produce the best longevity phenotype? You know the interesting thing with the rapamycin is the effect on the senes and cells. Like, like, that's so interesting to me. I didn't know really about that until I listened to your podcast with Judas. Yeah. She's amazing. She's really, she's really, she's really great and very knowledgeable in the whole senes and field. Yeah, I had no, I had no idea either. The life's expanding effect is, is that males only or was that both males? No, male and female. And it's across, I mean, it's, it's everything from yeast to worms to flies to mammals. I mean, it's the only drug that's uniformly extended life across a billion years of evolution. I mean, and there's really interesting work. I mean, I think Matt Kiberlin's though, you're talking maximum lifespan, are we talking median? Actually, and the mice, it was, I have to go back and look, I have to go back and look. Probably median, it's most of the time it's median. But yeah, yeah. And what was interesting in the mice is they started late in life. They started at 600 days, which is, you know, that's about 60 years old. Yeah, that's, that's like starting is with a 60 year old. That was really late in life for the mice. Yeah, yeah, it was. Which made it that much more impressive. That is, that is very interesting. So Kiberlin's work, do you know Matt, up at the University of Washington, he is giving rapamice into dogs. But these are pets, right? So these are not laboratory animals, which is what makes it really interesting is you've got animals that live in our environment that are, and dogs sort of have a very predictable demise, right? They're either going to be, you know, dying in accident, be euthanized, have cardiomyopathy or die of cancer. That's basically how dogs die. And the cardiomyopathy that they get is not an atherosclerotic cardiomyopathy. They get a cardiomyopathy where the muscles are actually just getting weaker and weaker. And their ejection fraction is going down. And in studies as short as 12 weeks, they're seeing a 10% increase in ejection fraction of these dogs. And so the question is, how much of that is working through senescence? Just selectively knocking out senescent cells and letting myocytes regenerate. Yeah, the study out of the myoclinic where they did some drug, they selectively targeted senescent cells in it, lit to 20% increase in median lifespan. Sort of an interesting proof of principle, how just, well, that was in, I think, an accelerated aging model. So they had accumulated more senescent cells. Obviously, they had to do something like that. But it all comes back to this idea of specificity and selection. Everything we've talked about, if you really stop to think about it, comes down to how could you target this tissue and leave that tissue alone? Or how could you target this cell and leave that cell alone? And in many ways, I think that's kind of got to be the next frontier. Here is, even if you think about something as crude as chemotherapy, it is not hard to kill a cancer cell with a chemical. That's trivial. It's hard to kill a cancer cell and not a normal cell. That's why chemotherapy, obviously, targets rapidly dividing cells. It's still very crude. But the stuff we're talking about is taking that to the next level, which is how could you get this enzyme to work more efficiently, but in this subset of cell, just in the muscle, but not in the fat or not in the liver and the muscle? That's, again, where the fasting is just so impressive to me. The fact that all the normal cells, you're enhancing all these stress response pathways. So the chemo drug becomes that almost less efficacious. It's almost like a lower dose because it's got these robust anti-apoptotic and anti-stress response genes that are dealing with that sort of stress. So it can take the toxicant soul because of that upregulation that fasting is doing. The cancer cells just can't. I'm so glad that works being done. I hope that there is more funding that goes in that area. I think that it is a really important area of research, again, like I said, and this is all from Valtors work and some of some of his colleagues. I'm just kind of like the fan girl, you know? But I'm certainly, I'm happy someone's doing that research and I would love to see that be used as a standard of care someday, for sure. So Rhonda, many of the people listening to this will know everything about where to find you, but for the, let's assume there's someone here who this is their first time meeting you. Where can they learn more about you and how can they interact with you? I have a podcast. It's called "Found My Fitness." You can find it on iTunes and on my website, foundmyfitness.com, all the episode pages there with links to the video, which I see. And your videos are remarkable because you put so much work into actually, like a podcast like this, unfortunately, were too lazy. Like I'm not going to actually do much, except create show notes. But on yours, it's like, it's like a Khan Academy, right? It's like everything is being explained in the video as well. Like, yeah, I think that's amazing. Yeah, it's explaining the figures, definitions and all that. And the video and also, I think we're having now definitions and stuff on the website, so people can, the goal is to definitely showcase, you know, a lot of the researchers and scientists that I interview and also educate people as well. So foundmyfitness, I'm on iTunes and my website and social media, you can find me on. And what do you like most? Just Twitter, the easiest place for people to get to you. Twitter, Facebook, Instagram, I'm on all of them, but yeah. And what's your handle? Foundmyfitness. That's all foundmyfitness, okay? Foundmyfitness, yeah. So you were ahead of me on this. Like, you immediately recognize the value of exercise. I'm a late comorant of this. I mostly from personal experience, I realize I was like, this is great for my brain. And from there, I just kind of dove into it, it was convinced, yeah. For sure. Rhonda, I can't thank you enough. This has been awesome. I don't suspect it's the last time we'll talk about this stuff. So until next time. Awesome. You can find all of this information and more at [email protected]/podcast. Here you'll find the show notes, readings, and links related to this episode. You can also find my blog and the nerd safari@[email protected]. What's a nerd safari you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, etc. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID, [email protected], but usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor/patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously for all of my disclosures. The companies I invest in and/or advise please visit [email protected]/about. [BLANK_AUDIO]