The Peter Attia Drive - #02 - Rhonda Patrick, Ph.D.: the performance and longevity paradox of IGF-1, ketogenic diets and genetics, the health benefits of sauna, NAD+, and more

Episode Date: July 2, 2018

Rhonda and I go on a Nerd Safari into the jungle of health, nutrition, fitness, performance, and longevity. We visit IGF-1 and whether there’s a tradeoff of having high or low levels. We discuss the PPARs (receptor proteins) and genetic polymorphisms. Does Rhonda think there’s any benefit in a NAD+ booster for health and longevity? Can saunas lower the risk of heart disease, dementia, and all-cause mortality?  Rhonda is a wealth of knowledge on so many topics and was the perfect companion to dig into so many fun topics in this episode. She puts a ton of thought into her research and it really shows in this conversation.   We discuss: What Rhonda believes differently today than she did a few years ago [5:40]; The paradox of GH/IGF-1 in performance and longevity [21:00]; The role of PPAR in fat metabolism and ketogenic diets [23:00]; The possible genetic explanations for why some patients don’t respond well to a ketogenic diet [31:00]; The health benefits of heat and cold exposure [1:12:30]; NAD+ [1:32:45]; And more. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram

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 live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other

topics at peteratia-md.com. Welcome to the p Atia Drive. In this episode, which I know is long anticipated, I spoke with Dr. Rhonda Patrick from Found My Fitness. I suspect many of you listening to this know everything about Rhonda and have been fans of her for a really long period of time on the off-chanceters anybody listening who doesn't know who Rhonda is. I suspect by the end of this discussion, you will also become a huge fan of hers and her podcast, which is exceptional.

So I've known Ronda for quite a while, and despite the fact that we both consider San Diego home, and we've just been busy enough that we just haven't had a chance to sit down together in quite a while. So this discussion was kind of long overdue, and it was sort of funny because as soon as Ronda walked in, we just jumped right into a really interesting discussion. And then 10 minutes in, I thought, you know, we should probably start recording because this is interesting stuff.

And so we did. And similarly, when the discussion finally ended, we sat around for another 20 minutes talking about a bunch of stuff that I found myself thinking, God, I wish we were still recording this because it's super interesting. So that's just basically to say, I suspect Rhonda and I will speak again at some point soon. So don't worry if all of your questions weren't answered here. The thing about this podcast that was a ton of fun was that in the days leading up to it, she and I hit emailed each other a few times back and forth some ideas of things we would talk about. And in the end, neither of us

really had any notes sitting in front of us. We just sort of sat there and shot from the hip and didn't follow a script or anything like that and didn't even get to half the things that in our emails we had suggested we would talk about. That said, all the stuff that we talked about is stuff that I think Rhonda brings a great deal of expertise to. So I don't recall the order, but I know that we certainly touched on IGF

and the growth hormone, what I consider a little bit of a paradox, which is on the one hand, we 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 Rhonda does incredibly well on her podcast, and I would encourage

those of you who find this episode interesting, who aren't familiar with her work to go back and actually watch some of her stuff. Rhonda doesn't put out a lot of podcasts, but the reason for that is the amount of work she puts into them is enormous. So when she puts up a podcast on video, there's explanations, definitions and stuff scrolling across the screen. So it's an unlike me who's incredibly lazy and can't even stand to listen to a podcast after I record it. Rhonda is methodical in her ability to make that easier for the viewer. So you'll learn a lot about

this stuff. If you think we're going too quickly over it, by probably going back to run this 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 monocidogenic diet and everything seems to go wrong, so at least biochemically wrong. So that's a very interesting discussion.

In many ways, I think my favorite part of this discussion was the way it started, which was the first question I asked Rhonda, which was kind of a random question, I think led to some interesting back and forth between us, which was effectively, what do you believe today that you didn't believe before and vice versa? And I always find that to be one of the most interesting ways to dive into a discussion with someone who's buried knee deep into science. Because if you're really thinking about science, you have to understand, of course, that virtually all facts have a half-life.

And our knowledge is constantly evolving. In many ways, that's what makes the field so difficult to stay on top of, but at the same time, so interesting. And so, to me, one of the marks of a very thoughtful person is someone whose beliefs are flexible and who's willing to acknowledge that something that they believed was once true or not true can be flipped. And so, I think, you know, Rhonda and I share that, and I think it was actually really fun to see where her beliefs have changed over time.

So with that said, I think the show notes for this particular episode are going to be very helpful and you can find those at peteratiamd.com forward slash podcast. And I hope you enjoy this discussion, at least half as much as I did. I suspect it won't be the last. So without further delay, here's my conversation with Dr. 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. And 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, 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, and that being the major modality for a few reasons. One reason is because I think that actually, so one of the things that occurs during

caloric restriction is a major drop in the growth hormone IGF1. And that's, you know, that's thought to regulate a lot of the, you know, improved health span effects, at least in some organisms like mice and in racist monkeys. But I do, 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 you're not, you know, if you're constantly doing this caloric restriction, then you're not really gonna 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 in April of this year on lemurs. So the study essentially showed, and these are, you know, I guess they're not human primate animal model, but their lifespan is, you know, 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 health span sometimes have other effects. And I think that getting into the IGF1,

I think we'll probably, you know, and I will talk about that because we both have a shared interest in that. But the periods of growth and being necessary for health, I think that's kind of turning point in my mind. And so now I actually think that perhaps even doing periodic, prolonged fast or a better way of doing that because you can get that IGF-1 boost

and you can get the lower IGF-1 among other things that occur. But we can dive into that if you want. But I think that's good. What will be diving? Yeah. 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 Verden 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 a 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 Verdin, 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 being on a time-stricken 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, 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 all the time or what, but.

So I'm also intrigued by that. And in many ways, almost have the mirror of your experience, which was 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, say, 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, 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, uh, birdies. Cell and cobble 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 circulating metabolic fuels, and that should down-regulate appetite. And I think in humans, there's a huge debate about why do people lose weight on ketogenic diets? Are they losing weight

because they're eating less, or are they losing weight because they're ramping up fat oxidation, disproportionate to where they were before, which drives up energy expenditure? Of course, I suspect the answer is both. In other words, if you do the latter, the former should happen. So when people say, why do 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 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, so they wouldn't have been able to get into ketosis. And I think even previous studies, like earlier in the literature, I showed something similar where it was obesity genetic. Now, there was certain genetic backgrounds,

it also seemed to kind of little, 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 the fat or they're not having the period of rest, I know that, for example, when you're making malinil CoA,

which is something that you do when you're oxidizing fat, malinil CoA inhibits the conatine palmityl transfer is basically the transporter to transport fatty acids in mitochondria. So if you constantly are making malinil CoA because you're constantly eating the fat, then you're going to start to have this inhibition and you're going to start to then store the fatty acids in anapostitia rather than catabolizing them.

So it seems to me that 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. I'm sure I brought you some. Oh, OK. You'd try them. I was going to bring you so much.

So I really enjoy the effects they have on my brain. So I've used them for 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. 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 level so like I seem to be able to I'm always on to the next you know what's and and so this kind of helps me like stay in the now at least I'm and that could be completely basically but I don't know but anyway so that so 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 enhanced endurance performance, but they found inhibited, 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 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 this for sure. Yeah, send this 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 I know this is going to be a theme today, which is multiple threads that are easy for us to go off. 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 is ad libidum. So what they never tried then was, let's give you food for 10 hours and let you eat at limited 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, but high-ish carb. And so there was enough carb in the diet that it wasn't producing ketosis,

but it was still a high-fat diet. I'd like to see that experiment repeated, but with an exogenous ketone. Because then you could start to identify the effect of the carbohydrate specifically, and tease out the effect of the fat and the BHB. 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, which makes sense because that's involved in ketogenesis itself. But 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. And this is part of the reason why for so, 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, you know, like 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 mean, I think that, you know, one way to kind of 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, you know, olive oil, and it's not just like butter and keto bombs and all this like pork rinds and stuff where I'm just like, where's the nutrient density and some of that, you know, so.

Yeah, it's funny. I mean, I guess it depends on how many calories you need, but at the time that during that window when I was on a ketogenic diet, I was also still very active, certainly much more so than now. And I really required a lot of calories. I mean, I 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 Ron and I are very used to. Those are F A 18s, which, how many overhead drive buys are we gonna get today if you had to predict? 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 mean, I should say probably about 80 grams of total carb, but you'll see the what type of carbs it was. Really had to limit protein to about 100 to 110 grams. If I went over that, I would get kicked out. And so fat made up about 90% of my total calories. And so there's only so many ways you can get that much fat. And the most efficient way is actually salad with olive oil. I mean, I couldn't believe the amount of vegetables I had to consume to stay in ketosis. You know, I basically had to have two huge salads a day where I would

make my own dressing, which was a heavy olive oil based dressing. And I could probably only have one avocado a day, which I would always have, because other than anything 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 salads? Like, I mean, yeah. Okay, so I'd 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, but. So you get tomatoes and everything on the kitchen.

Yeah. Yeah. Now again, part of it is I can get away with more because I probably exercise 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 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 in 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 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 some of the major dietary regulators of the IGF-1 pathway are protein essentially amino acids specifically and also insulin. Insulin through IGF-BP3. Or IPB1. So I mean, I think that, so for example,

if someone's eating a low protein and low, 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 certainly getting more than someone maybe me that's not 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 gotta 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 alpha. Is it P-PAR 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 PPR-alpha and a ketogenic diet or fasting. But, you know, there's most of the literature out there looking at the effects of PPR-alpha with people that are either hetero homozygous or have to do with the context of like high saturated fat, low polyunsaturated fat diet because polyunsaturated fat activates the PPR, you know, family of transcription factors, which are nuclear hormone receptor transcription factors. But the PPR gamma is predominantly found in like adipose tissue. I mean, they're

found in other tissues, but I say predominantly that's like the most, they're highly expressed in that adipose tissue. And it plays a role in basically taking up fatty acids into adipose tissue, whereas the alpha, which is in the liver, plays a role in basically taking up fatty acids and catapults 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 would be nice to see that, someone look at that, you know,

people with these specific snips and how they... Does Prometheus identify various snips of P-Para alpha? Yes, but they don't really tell you anything. They sort of pull abstracts from PubMed and just kind of like, gomp 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 the literature and see what some of these nips are doing. And then in conjunction with looking at biomarkers, very blood biomarkers, to kind of help people guide what they should do, what's a bypass around a potential bypass, for example. So with the PPR 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 and saturated fat ratio in order to lower your type of diabetes risk. You're saying for people with a wild type or with people with certain snips?

With the steps. Yeah. With the steps. Yeah. And gamma as well, because to some degree some of the ones in PPR gamma affect the uptake of fatty acids and adipose tissue. And so, and also muscle. And so it kind of kind of, you know, you have a lot more free fatty acids around and that can, you know, have, have an effect on insulin sensitivity and other things as well.

So 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 we'd certainly get their permission. But it would be interesting in taking their, 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-fibreinogen, but the deeper level is the Y, and what you see is they're making much more cholesterol. Markers of cholesterol biosynthesis, like Desmosisolol, go way up, and some of their phytosterels go up, which is very counterintuitive. Phytosterols would generally go down on a ketogenic diet, but they're going way up, suggesting

that they're absorbing much more cholesterol, like biliary cholesterol. So the first time I noticed this was 2012, and I think I wrote about this once on a blog, but I don't remember. Maybe I'm thinking of another example. And it was this relatively young patient who really loved being on a ketogenic diet. But when we get his blood test back, I mean, his LDL particle number was above 3,500 nanomole per liter. And I know there are a lot of guys out there who seem to think that as long as you're on

a ketogenic diet, it doesn't, none of this stuff matters. I completely don't subscribe to that. And my view is that's irresponsible. So I said to them, 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 Dasepring about this, and he said, let's try and experiment and rip all the saturated fat out of his diet. He was sort of like me.

He was eating a lot. He, evening his 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 monoinsaturated 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 eight to 12 weeks, same macronutrient distribution, in terms of fat protein carbohydrate, the only shift was the type of fat. So we just substituted mono for saturated. His 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, 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 thatpark 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 my tool. And like I said, we're even expanding that a little bit. 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've emailed me and something interesting and I'm like, oh wow, that's super interesting. Do you mind sharing that with me? And they have. 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 want to share with me the data, I can't promise anything, but they can certainly get

the Y 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 like $10 recommended. So if someone doesn't want to pay $10 to do the comprehensive, they can just get the free report and get the Y why potential why themselves. So I hope that anyone listening to this because I 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 I have had people have that problem where they've tried a cusinectite and couldn't figure out and they did have one or even more than one of the SNPs that regulate fatty-assum metabolism.

And then there's another phenotype that fortunately is more rare. And I also wonder what's going on with P-PAR 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. It's 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, you know, 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, you know, 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 polisous 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, you know, there's a variety of snips in these genes. And, you know, there may be certain snips that aren't having even really been tested or who knows. It sounds like, you know, to me that there's certainly something going on with the process of ketogenesis and some of the patients. And their activity levels are they're active? ketogenesis in some of the patients and their activity levels or are they 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 got to be relatively, it has to be, it's not gardening, like it's got to

be exercise, exercise, you know, they have to really deplete glycogen. 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. Of course, we can't do liver biopsies. So, it's... So, fasting does get the meticutosis. So again, we're dealing with such a small N that I don't, I want to be thoughtful

about not generalizing too much. So there's one patient in particular who's the poster child for couldn't do the ketosis things 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 ago's FMD. And then the 25 days of ad lib was time restricted eating ketogenic. Then we've seen great results doing that in two people. So that would suggest that some, and again, 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 end or the exercise end 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, you know, so maybe it's not to do with the production of ketone bites, but it's actually just takes a long time to deeting the glycogen too. If that's, you know, so maybe it's not to do with the production of ketenbiase, 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, you know, like 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, you know, I like to fast for like 15 hours. I can do that. And with my physical activity levels, you know, I will be closer to one millimeter fast. Like, you will get to one millimeter after 15 hours of fasting. I will be closer to that when I'm really physically active, like during the periods, a couple of years ago, and I was doing lots of like long distance running and stuff, I can get closer. I mean, I mean, I'm going off of like long distance running and stuff. I can get closer. I mean, I'm going off of like a precision extra, which probably is not very...

No, no, no, no precision extras. It's, I mean, that's really good stuff. Yeah, so I can get between like 0.7 millimolar to like 0.9. But are you consuming a ketogenic diet during your feeding when you... So my diet typically, so like I said, I've never really intentionally tried to do a ketogenic diet, but my diet is, I pretty 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 butter from

pasturized animals. And my fruit 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 a snack either nuts or the smoothie, the kale with some blueberries and avocado. So I think I need a lot of nuts too. 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. Oh, yeah. 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.

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 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 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 because that's when they're around. But, you know, so I do, I think my diet tends to be. So 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 the right. So check that, and that'll give me a sense because if you're going- Well, I'm not doing as strict because 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 point one millimolar to point seven to one millimolar in a 15 hour fast, that's impressive. So, so when I took the exogenous ketones and I've done this, did you do the ester? I did the ester ketones, and I've done this. Did you do the ester? I did the ester by HBMN. I did their instructions, which is either with a high carbohydrate diet. So I had a bowl of bowl of some whole oats with some blueberries in it.

Then I took the BHB ester. I literally went from like 0.1 millimeter ketone in one hour to six millimeter. Wow. Six, and one hour. That's really high. So. That's impressive.

Okay. 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 because I'm usually like doing a podcast or going traveling and doing, you know, something, but that's 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 carousine or jet fuel. I thought I was going to die. Go blind first then die. He goes, no, no, this stuff's good. He goes, actually, I wouldn't call it a sipping ketone, but it's actually pretty, I was something guys at human in the T-Dalte 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 try it because I personally think it's closer to the kerosene side than the...

It was so bad, wrong of it. There was like a good three-month 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 of stuff. 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, 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 ester on an 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 because I kind of like it as a way to avoid meals. Does it lower your blood glucose? Because I mean, it's so significantly, it was like astounding. Yeah, yeah, no, it's pretty impressive. That needs to be studied. Yeah. 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 anything? So I think people are starting to realize that's an interesting way to lower glucose. Really significantly. More than 20%. I dropped 30 points.

Wow. Yeah, that's great. Like after a carbohydrate, after a high carbohydrate, like a sheep who is a... Like 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. 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. This stuff's pretty interesting. It works quite well. Yeah. I'll certainly, if I'm going to indulge in some high-carb action, I'm going to 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. Because 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 Olegans 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. It's the risk of stating the obvious which is we're not worms, but that's a huge difference in biology So that's the that's the first thing. Let me let me let you comment on that

Yes, because I've done those experiments So that's probably what straight out of college And I went to work the salt 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. 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 one signaling pathway also known as the dev 2 and Their worms would live like literally a hundred percent longer like they 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 microscope It was 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 honest. It's the most convincing data. 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, oh, death 16 is right, that's homologous to Foxo. It completely obliterates the lifespan extension.

Meaning it's the Foxo 3 that seems to be really important for the whole. We have how many? We have four Foxos? You mean different Fox genes? Yeah. Okay, 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 DAF 16 is basically our Foxo. Yes, Foxo, yeah. So, okay, well anyways, yeah, I'm not sure I'm getting confused with the other. You know this better than I do, but okay, 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. Like 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. But yeah, exactly. Yeah, that's exactly what happened. But you get rid of the Daphsixteen and they're like wild type.

Oh, they're like wild type, okay. Yes, I think so. And that largely has to do with, so that the IGF-1 insulin signaling pathway, both inhibit FOX-03. So if you get rid of that inhibitionF-1 insulin signaling pathway, both inhibit foxyl-3. So if you get rid of that inhibition, constitutively, foxyl-3 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 stress, like all these stress resistance pathways. I mean, foxyl-3 is a transcription factor, it regulates whole host of genes, many of which have to do with DNA repair, etophaegi, stem cell function, production of antioxidants, and anti-inflammatory path. So it's a lot of really good stuff. You won't 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 didn't matter. So the cancer reduction didn't depend on FOXO3, only the lifespan extension. So I think there may be an uncobbling 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, vice versa. So if you look at people that have polymorphisms, either in... 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? Yes, laryn syndrome, yes, they do. But I think there's also another one in IGF. There's heads and IGF one receptor.

So this is you're not talking about acromegaly 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, with that have higher circling levels of IGF1. So you're saying you can't uncopple the growth hormone from IGF1. Yeah, that's been one of the things I've struggled with, is it's hard to uncopple the GH, the effect of GH on the liver. Humans. Yes, exactly. But animal 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? Which, and I'm like, 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 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 un couple 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 a- We've evolved in the- Yeah, 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 effective exercise on IGF 1. And the fact that for one, it's been shown that the boost in neurogenesis after exercise in the brain via brain drive is requires IGF 1. Animal studies have shown that mostly in rodents have shown that that exercise causes IGF1 across the blood brain barrier getting to 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 people that are exercising, they're putting that IGF1 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. Faldtolongo, is that we know that he does these prolonged fasts, and I think the prolonged fasting is extremely interesting for a couple of main reasons. And one is, I think that it has tremendous potential for the treatment of autoimmune disease and also cancer, based on his work. 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 this massive shrinking of organs where he doesn't know how much of it's due to cell size decreasing versus apoptosis. He does know apoptosis is occurring and he has shown that in multiple publications. Like there is a massive induction of apoptosis after a prolonged fast, 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 come back.

They grow, regrow. And presumably selectively repopulate. Yes. So he's shown that these stem cells get activated. So they have to be activated by the low IGF1. 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 IGF1 is required for that proliferation and differentiation and repopulation of the tissue,

which means you can't just keep the IGF1 low. The refeeding is just as important as the deprivation. And the IGF1's key in that. And so what he's shown now is that you can take, for example, in the multiple sclerosis, animal model, you can actually cause stem cells to be activated through the prolonged fast, and then during the refeeding phase, the stem cells make non-dysfunctional. So they're

making normal non-automium 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 clinical studies that he's been involved with, like a 48 hour water fast 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 neutropenias, 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 makes sense. I mean, oncogenes, they screw up all sorts of things. One of them is the stress response, and cancer cells can't respond,

they're primed to die. I spent a long time studying cancer cell metabolism, apoptosis with a dug green, and just for a moment at St. U. Cholens Research Hospital, and that's kind of one of the primary ways that a lot of one of the primary ways that a lot of these chemotherapy drugs if they can get to the tumor site work,

is that because it's a stress, cancer cells can't handle it, 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 reclempt when I walk through an oncology ward and I see patients drinking in shore. Like I couldn't think of a worse thing you'd want to consume

when you have cancer, and yet the goal is, hey, we gotta fatten these people up. So I agree with you, and I really hope that this research is accelerated because I do think patients would benefit greatly from this and the other Application that I saw of this several years ago. This is quite old now, but it blew my mind I'm not sure if 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% color I can 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. It 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, that means you open the animal up,

you put clamps on the femoral arteries, which would basically stop all perfusion 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 an insult that you could get by a lifelong

of caloric restriction. And the third piece that 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 Volter'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, with Walter's work, I'm so excited about the pro long fasting

and the potential benefits of it. I think that actually 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 how to do with like the failed clinical trials with binding IGF1 and cancer. And Walter brought up something interesting in a conversation I had with him and that is possibly that we now know IGF1 having low and high IGF1 is important. So if you're constantly having low IGF1 and the IGF1 is important for the immune system or population, you can imagine the context of cancer when you're giving

other treatments along with it that would be important because your immune system is key 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 it's something that would be interesting to investigate and it makes sense. Yeah I definitely am on the same page with you with I'm not like I started out with saying, I don't think that chronic caloric restriction and low IGF1 is the essential way for improving health span.

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 a 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 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 Robic 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 Ferris 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 gonna 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'd rather you be doing, an aerobic aerobic type thing? 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 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 seems to be making its way as well. Like, there was a study that I found, VO2 max, this is 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 so 10% per decade. So that's almost parallels the muscle mass decline. It does starting at what age, but you know, so 10 percent per decade. So that's almost parallel is the muscle mass decline?

Yes, 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, five-minute warm-up, five-minute cool-down, and then, you know, in between the max intervals, which were like pretty long, like a minute, there was, you know, the 70 percent of max water. Anyway, so 24 of those increased VO2 max by 12%. So you're literally taking an entire decade of decline and like reversing it with the 24%. So that's actually a good 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 Flarity, 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. And for a cyclist, it's PVO2 max, which is the power output at VO2 max. That said, every time you go to test, you want it to test well. So over time, I learned how to game the system. I want to make sure my VO2 max is in the 70s, which, again, to put that in perspective, 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 mil 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 necessarily like, do 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, I- what's the- what's the maximum lifespan that like a human's like 120? 124 or something like that? Is it 124? 121 or 124? I feel 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- my median health span, my health span, you know, so- so basically preventing- staving off cardiovascular disease, cancer, Alzheimer's disease, those sorts of things,

so that I'm living healthier, and also a little bit longer, but obviously not 125 or six years. Yeah, I don't really subscribe to the theory that we're gonna meet some takeoff point where there's immortality. I'm really not convinced that that's sort of subscribe to the theory that we're gonna 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 I'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? They looked at the inner lukins and stuff also. Yeah, TNF. 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 inflammation was so key for each age group, right? Like even more than all this other stuff, like that I've thought about like senescence and telomeres and 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 NFKAPB, 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 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 this 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? You're just getting rid of that little anti-inflammatory component of this one major regulator of immune system has an 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, since an area has a higher percentage of 10 in anti-inflammatory anyways, you know. 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 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. You know, 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. The question was, could that impact cardiovascular mortality? And we've long talked about how cardiovascular disease is sort of this trifecta of lipoprotein's 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 patients getting the IL-1 antagonist, despite having no difference in lipids or any other biomarker, had an improved outcome with respect to cardiovascular health. About a month ago, another trial that was using low dose of methotrexate, which is an immune suppressant,

was halted early, and the results will not be announced until this fall, but if you read kind of the fine print, it does not appear it was halted for a bad reason. 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 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, there's some clinical trials showing that there's a variety of other biomarkers and potential mechanisms by which that's happening. But if you look at some of the data by Dr. Yari Lalkin and out of Finland, if you look at some of the observational studies where there's a couple thousand men that were doing in Sanasso ubiquitous and 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 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% all cosmotality goes to 40, all cosmotalities also lowered dementia and Alzheimer's disease again, like 20% lowered if you're doing two to three and then just jump out. 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 Sana 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-markable.

Yeah. 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 saunas are painful. So if you are fit enough to sit in a sauna seven days a week versus the guy who can only sit in it one day a week, like, how do I know that that's not driving it? Now since that time, I've become a lot more interested because now the mechanisms are starting to become more well understood. And so I'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. You know of the healthy user benefits of this. You know, the healthy user benefits, so of course, with Yari's work, he's tried to correct for all that physical activity that he's done everything, like looking at lipid blood cholesterol numbers,

LDL number, like just like really, you know, tried it, tried his best to 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 pressures. That's one of the main things that's effected as 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 obviously the sun, the heat itself does affect blood flow, plasma volume, all that stuff is changed. So I think that the cardiovascular aspects, and Yari's trying to really tease apart more mechanisms because he's an MDPHD, he's a cardiologist by training, but he's also got a PhD. So he's trying really hard to kind of understand

exactly what's going on, but I do think that it's really convincing. It's really convincing. With a cardiovascular, really related mortality, specifically, it's very robust. Personally, it's kind of interesting to think about how much of exercise also elevates your core body temperature. I mean, there's this overlap there.

And when I sit in a sauna, my heart rate starts to elevate, like I'm doing cardiovascular, and 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 sitting in a hot sauna.

And even a hot bath, like more recently, another study came out, trying to hot bath, a positive effect on a variety of cardiovascular related markers as well, which again, but you have to sit in it long enough 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 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. 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. In fact, he said about 70% of the people that had the sham control thought they had the actual treatment. So it worked. There was definitely a, they were 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 the street from a YMCA and so I started using this sauna and it was like very black and white like I was like, wow, this is amazing, like I can handle all the rest. And this was a Wetsana 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 saunas are 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 they're saunas that they're using in Finland, they do, they have a lot of what they call low-loo or something,

which is like they throw the water on and 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 this. There's a lot of marketing involved in 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 phallates and mercury and heavy metals and things like that from swath. So that is, that's what a lot of those some of them are needed. But straight up dry sauna to 170 degrees, spend three or four nights a week in that. My favorite. Yeah. That's personally, I would much prefer sitting in a regular dry sauna or even a sauna that you can throw

on. You can throw out on a sheet of paper. You can throw out on a sheet of paper. Just not infrared sauna. Yeah, so that would be, you know, 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, I think, cheaper as well. So it's certainly more convenient to have an infrared sauna.

But personally, I prefer the other, like the barrel sonnas 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's part of the Janice cytokine because it does like, it's got like multiple pleiotropic effects and it's acutely released upon exercise as well. It has, it's very important for, you know, an anti-inflammatory response, releasing myocines, and all these things and muscles. 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 Rayson's data. And he said that actually correlates with things. You know, 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 gonna be this weekend at a friends 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 better.

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 this on becomes very interesting. And there's the whole heat shock protein part where, you know, heat stress is one of the major ways to increase heat shock proteins, which do play an important role in neurodegenerative preventing neurodegenerative diseases.

And I do think it's also really hard to uncouple the effects on the vascular system, which is important as well, because it's having such a profound effect on the vascular system, the heat stress. It's hard to uncouple how much of the staving off of dementia and Alzheimer's test study with that versus heat shock proteins in our own. 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 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 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 suffering, right? There's also going to be the microvascular variant and then there's gonna be the sort of more toxic variant. So the nice thing about sauna too, just thinking about it is 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, a 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. No, it's not accessible to everyone.

It's not like, yeah, yeah, yeah, yeah. It's a certain point. It's enjoyable until you're like, holy shit, it's hot, I wanna get out. But it like holy shit'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 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 increasing norip and efferin 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 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 similar. So yeah, I was gonna say, how did 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 of years ago. The sauna I started doing in grad school. Yeah, 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 the more potent the isle six response, the more potent the antidepressant response. In addition to that, there's a very strong effect on beta adorphins, beta adorphins are dumped.

And also this other system called dynorfen, which is, you know, the opposite. Yeah. And what's interesting is that when you activate dynorphin through the capopioid pathway instead of new opioid, you feel uncomfortable. And it's the part where I'm, we're talking about 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 dinoirfin partly because it cools your body down. So it's kind of a response to elevating your body temperature. I'm 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. Yeah, because we talk about like, why can that guy tolerate so much more pain than that guy? Yeah. And at some point, it's possible that they're actually experiencing less pain. They're definitely our variants in the capitol-good receptor pathway and all that. I'm surprised that hasn't become a performance enhancing drug, which is blocking that receptor,

the pain receptor in the brain, which is a very interesting thought. But now, so then on the cold front, what do you think's mediating that neurotransmitters? So basically on the cold front, the norapeneferin, it's that's been shown. So animal studies have shown, or norapeneferins 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 degrees, you know, if it's like 50 degrees Fahrenheit, you gotta stay in a little longer than like a couple of minutes in a really cold cryotherapy chamber. But in humans, plasma, norepinephrine has been looked at, which does seem to sort of co-coulate with the release in the industry.

It's so hard, though, to look at the plasma to understand that. I know, I know, it is. It is. So I do think that some of the mood is affected by the norepinephrine 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 terms of? I feel really good, yeah, I feel really good.

And that's when I did notice that my sleep was really profoundly affected. What's interesting is there's some studies showing that heat stress, at least in piglets, does affect actually, it seems to elongate the REM sleep stage, which I don't know how, what all that means, but so there's certainly an effect of heat on sleep, and then of course, cold is lowering your body temperature is important for sleep onset, but I don't know.

There's something about the combination of the two. Absolutely, I sleep amazing after doing 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 boost biomers of a mitochondrial biogenesis. Well, it depends on what tissue we're looking at. So, like, you know, PGC1 alpha would probably be one of the best, I would say, for muscle tissue. In anapost 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's interesting to me that the effect on mitochondrial biogenesis, but personally, I like the exercise, for my mitochondrial biogenesis. I'm not doing cold exposure all the time. It's not like something 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 because it does seem to help me with my mood and my thoughts. 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

due 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. 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. 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 if you do a three hour swim at 50 degrees Fahrenheit or 52, 53, you get a little bit of that effect. But more or less, you can 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, 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, you know, again, there's, 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 is happening to create that anti-inflammatory response, you don't want to dampen that. At least, that's, 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, you know, eventually result in satellite cell proliferation, you know, and of course, IGF ones in there somewhere. So again, you know, 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 want to 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 just 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? 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. You could live longer, and that also you live better. You have more energy, all of these other things. And so in the mitochondria, you have complex one, which converts NADH to NAD.

And the idea is we 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 CER2 and pathway, but this is upstream of that. But if you give more of either the precursor or 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 the literature. NAD is a very 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 Tuin's, 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 sinks up NAD. I mean, it's like an NAD sink. I mean, you know, so, you know, 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? Right. Okay, but that said, we'll come back to that after. I think it's in the nucleus.

I mean, it's very important to be there, but yeah. Otherwise, it shuttles there, but I said, we'll come back to that after. I think it's in the nucleus. It makes sense to be there, but yeah. Otherwise, it shuttles there, but I think it is. It's very important for repairing DNA damage. That's one of the major sinks and actually inflammation. All these things are upstream of part activation. The more that's happening, the more parts being activated. You have NAD going there. 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.

Yes. 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 NADs being consumed more for that as well. So that's sort of another sink.

Basically, NAD levels decline with age. And it's probably because it's just getting used up more. Or the other, the alternative is, you 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 gonna write that down. That's something I'm gonna have to look into.

There we go. Because I wasn't aware of the, and I didn't understand that link, but yeah. 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.

And I think that the animal evidence suggests that it can, at least in rodents, improve health span, particularly in models with like 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 that is showing that, yes, you can take, for example, nicotinamide 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, you raise the pressure. 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, there was animal models of myopathy and stuff and mitochondrial function was improved and all that stuff.

So in animal out 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, you know, 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 acid that's when you produce NADH or FADH2. So in the absence of those substrates then you start to emit your NAD starts to build up. So back to your metformin question. You said...

I know who to ask. I definitely know. I'm gonna ask Nav Chendell. He will know the answer to this question. I thought a lot of his work when I was in grad, him D. Bardini's I did it because I was doing a lot of cancer metabolism metabolism mitochondrial Function and stuff. So I followed a lot of you have nabs book navigating metabolism. No, I don't no I just used to read his paperage back when I was a graduate school Yeah, so nav and david sabotein were in town a couple of ago, and I was leaving town the day they were coming in the 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 knowable, 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, basically this rejuvenation. Could I get this burst of rejuvenation a couple times a year, and would that have in turn have an effect on delaying the onset of age-related diseases,

improving my 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 is 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 out is different because it's in humans. And so that's going to be really hard. You have to figure out if you can even look at certain biomarkers to know that. But I feel like that would be something that's so easy for someone to do.

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 in the back? Well, the question is how often would you need to do that? And how long? So 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 fast. Yeah, I find it hard to infer anything from rodents when it comes to fasting because of this exact reason. It's 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 road

and order, does that mean that a human has advanced? Exactly. Yeah. So I guess I'll expand my sort of answer that question, like maybe do a prolonged water fast, like time, like, what's the frequency? What's the duration to get the maximum benefits? Yeah. And I'm specifically interested in this shrinking of the organs and then regrowing, like this potential robust activation of stem cells clearing away. You know, we're not just talking about a topid, you're not just talking about clearing away

damage to mitochondria, pieces of DNA, protein agri, 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 harvest a bunch of tissues and look at things. But I certainly have gotten some anecdotes from people that have had autoimmune like diseases and things said that fasting is like completely reversed some of it like like like XM or something like that. 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, what what does and what frequency to produce the best longevity phenotype? You know the interesting thing with the rapamycin is the effect on the senescent cells 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, she's amazing. She's really, she's really, she's really great. Very knowledgeable in the whole Sinesan field. Yeah, I had no idea either.

The life's expanding effect is that males only or was that both males? No, male and female. Is it? And it's across, I mean, 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, 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 Cabral and stuff. 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, okay. And what was interesting in the mice is they started late in life. They started at 600 days, which is... Which I'm here. It's about 60 years old you know, that's about 60 years old. Yeah, that's like starting is with a 60 year old. That was really late in life for the mice. Yeah, it was. I made it that much more impressive. That is very interesting. So Cabrelin's work, do you know Matt, up at the University of Washington, he is giving

rap and mice 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 gonna be, you know, dying in accident, be euthanized, have cardiomyopathy or diaphanc, or 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 synescence, just selectively knocking out synescent cells and letting myocytes regenerate. Yeah, the study out of the myoclinc where they did some drug that

selectively targeted synescent cells in it, 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 synescent 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- But it all comes back to this idea of specificity and selection. You know, 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 front here. Here is, you know, 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. And that's why chemotherapy obviously targets rapidly dividing cells and it's still very

crude. But the stuff we're talking about is like taking that to the next level, which is, how could you get this enzyme to work more efficiently, but in this subset of cell, you know, just in the muscle, but not in the fat or not in the liver and the muscle? Yeah. And that's again, where the fasting is just so impressive to me. The fact that, you know, all the normal cells, it's you're enhancing all these stress response pathways.

So the chemo drug becomes that most more, less, almost less, you know, efficacious. Like it's like almost like a lower dose because it's like got these robust anti-apoptotic and anti-stress response genes that are dealing with that sort of stress. And so it's like, it can take the toxicant soul because of that up regulation that fasting is doing.

And the cancer cells just can't. So I'm so glad that 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, for the, you know, this is, and this is all from, from Valtors work and some of some of his colleagues. So 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 found myfitness.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, we're too lazy. Like I'm not gonna 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, yeah, it's explaining the figures, definitions and all 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 are there in 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 a lot of the researchers and scientists that I interview and also educate people as well. So, found my fitness 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?

Found my fitness. That's all found my fitness, okay? Found my fitness, yeah. So you were ahead of me on this. Like you immediately recognized the value of exercise. I'm a late-comer to this. I mostly, from personal experience, I realized 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. 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 peteratamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at peteratia-md.com. 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 Peter Atia MD, 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

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