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

00:00:00.000 Hey everyone, welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

00:00:10.140 The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking,

00:00:15.600 along with a few other obsessions I've gathered along the way. I've spent the last several years

00:00:19.860 working with some of the most successful, top-performing individuals in the world,

00:00:23.440 and this podcast is my attempt to synthesize what I've learned along the way to help you

00:00:27.840 live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more

00:00:32.100 information on today's episode and other topics at peteratiyahmd.com.

00:00:41.420 Welcome to the Peter Atiyah Drive. In this episode, which I know is long anticipated,

00:00:46.640 I spoke with Dr. Rhonda Patrick from Found My Fitness. I suspect many of you listening to this

00:00:52.960 know everything about Rhonda and have been fans of her for a really long period of time. On the

00:00:57.300 off chance there's anybody listening who doesn't know who Rhonda is, I suspect by the end of this

00:01:01.960 discussion, you will also become a huge fan of hers and her podcast, which is exceptional.

00:01:08.580 So I've known Rhonda for quite a while, and despite the fact that we both consider San Diego home,

00:01:14.680 we've just been busy enough that we just haven't had a chance to sit down together in quite a while.

00:01:18.200 So this discussion was kind of long overdue, and it was sort of funny because as soon as Rhonda

00:01:22.820 walked in, we just jumped right into a really interesting discussion. And then 10 minutes in,

00:01:27.620 I thought, you know, we should probably start recording because this is interesting stuff.

00:01:30.680 And so we did. And similarly, when the discussion finally ended, we sat around for another 20 minutes

00:01:35.860 talking about a bunch of stuff that I found myself thinking, God, I wish we were still recording this

00:01:39.780 because it's super interesting. So that's just basically to say, I suspect Rhonda and I will speak

00:01:43.240 again at some point soon. So don't worry if all of your questions weren't answered here.

00:01:47.380 The other thing about this podcast that was a ton of fun was that in the days leading up to it,

00:01:51.660 she and I had emailed each other a few times back and forth, some ideas of things we would talk about.

00:01:56.560 And in the end, neither of us really had any notes sitting in front of us. We just sort of sat there

00:02:01.020 and shot from the hip and didn't follow a script or anything like that. And didn't even get to half

00:02:06.940 the things that in our emails we had suggested we would talk about. That said, all the stuff that we

00:02:12.760 talked about is stuff that I think Rhonda brings a great deal of expertise to. So I don't recall the order,

00:02:18.200 but I know that we certainly touched on IGF and the growth hormone, what I consider a little bit

00:02:23.480 of a paradox, which is on the one hand, we have some evidence to suggest that elevated levels of

00:02:28.240 IGF are bad and that fasting may act in part by reducing those levels. But at the other end of the

00:02:34.520 discussion, you have some confounding and conflicting data around that. We also got into a great discussion

00:02:40.280 about the PPAR enzyme. So PPAR alpha, PPAR gamma. One of the things that Rhonda does incredibly well

00:02:47.160 on her podcast, and I would encourage those of you who find this episode interesting, who aren't

00:02:52.320 familiar with her work to go back and actually watch some of her stuff. Rhonda doesn't put out a lot of

00:02:57.600 podcasts, but the reason for that is the amount of work she puts into them is enormous. So when she

00:03:03.780 puts up a podcast on video, there's explanations, definitions and stuff scrolling across the screen.

00:03:09.520 So it's unlike me, who's incredibly lazy and can't even stand to listen to a podcast after I record

00:03:14.480 it. Rhonda is methodical in her ability to make that easier for the viewer. So you'll learn a lot

00:03:19.980 about this stuff. If you think we're going too quickly over it by probably going back to Rhonda's

00:03:25.160 site, we talk a lot about the possible genetic explanations for why some people do and don't

00:03:31.720 respond particularly well to ketogenic diets. And of course you can think of that in two ways.

00:03:36.500 There's respond as far as the ability to make ketones, but then there's also sort of these

00:03:41.060 patients that I describe seeing where you put them on a ketogenic diet and everything seems to go

00:03:47.080 wrong. So at least biochemically wrong. So that's a very interesting discussion. In many ways, I think

00:03:52.720 my favorite part of this discussion was the way it started, which was the first question I asked

00:03:58.120 Rhonda, which was kind of a random question, I think led to some interesting back and forth between

00:04:03.380 us, which was effectively, what do you believe today that you didn't believe before and vice

00:04:07.400 versa? And I always find that to be one of the most interesting ways to dive into a discussion

00:04:12.860 with someone who's buried knee deep into science. Because if you're really thinking about science,

00:04:18.320 you have to understand, of course, that virtually all facts have a half-life and our knowledge is

00:04:23.700 constantly evolving. In many ways, that's what makes the field so difficult to stay on top of,

00:04:28.740 but at the same time, so interesting. And so to me, one of the marks of a very thoughtful person

00:04:33.240 is someone whose beliefs are flexible and who's willing to acknowledge that something that they

00:04:38.940 believed was once true or not true can be flipped. And so I think Rhonda and I share that, and I think

00:04:45.260 it was actually really fun to see where her beliefs have changed over time. So with that said, I think the

00:04:52.960 show notes for this particular episode are going to be very helpful. And you can find those at

00:04:57.860 peteratiamd.com forward slash podcast. And I hope you enjoy this discussion at least half as much as I

00:05:04.840 did. I suspect it won't be the last. So without further delay, here's my conversation with Dr. Rhonda

00:05:10.020 Patrick. Rhonda, so great to have you here. Happy to be here. It's great to see you again. I can't believe we

00:05:18.920 live in the same city and only see each other once a year. If even. Well, thank you for taking the trip

00:05:24.640 up here today to my office. My pleasure. And I'll join the long list of people congratulating you

00:05:29.860 on your 10-month-old son. Thank you. Thank you. I almost don't know where to begin because there

00:05:35.040 are so many things that we share in common as far as interests. But I want to start with a really broad

00:05:40.980 question, which is you spend so much time thinking about many of the same problems I spend time thinking

00:05:46.540 about. What do you believe today that you did not believe four or five years ago?

00:05:54.400 Probably the biggest thing that has changed in what I now believe, but I didn't four or five years

00:06:02.020 ago even more, is that one of the major modalities for increasing health span, which is the healthy part

00:06:10.660 of your life, delaying the onset of age-related diseases. The major modality for doing that,

00:06:17.020 that would be the best way to do it, would be caloric restriction or dietary restriction.

00:06:21.100 So eating, you know, 30% less food than you normally would eat. I used to really think that was the way

00:06:26.260 to go for doing that. And I think that my beliefs have changed for that, in that being the major

00:06:31.540 modality for a few reasons. One reason is because I think that actually, so one of the things that

00:06:36.960 occurs during caloric restriction is a major drop in the growth hormone IGF-1. And that's, you know,

00:06:45.420 that's thought to regulate a lot of the, you know, improved health span effects, at least in some

00:06:52.120 organisms like mice and in rhesus monkeys. But I do believe now, based off a variety of research from

00:07:00.280 people like Valter Longo, that periods of growth, actually specifically periods of IGF-1 are really

00:07:07.980 important. So you're not, you know, if you're constantly doing this caloric restriction, then

00:07:13.540 then you're, you're not really going to have that period of growth because you're chronically doing

00:07:18.140 that. And really interesting, I don't know if you saw the recent Nature study that came out,

00:07:23.440 I think it was in April of this year, on lemurs. The, so the, the study essentially showed,

00:07:29.160 and these are, you know, I guess they're non-human primate animal model, but their lifespan is,

00:07:34.980 you know, median lifespan is around like six years or something like that. And I think their maximum

00:07:38.440 is 11 or 12 years, I don't remember. But the caloric restriction did increase the median lifespan.

00:07:45.100 It also increased maximum. So they like lived a year longer than, than typically. And there's,

00:07:50.380 you know, a lot of delayed onset of, of various degenerative diseases, but there was a massive

00:07:57.140 atrophy in gray brain matter in, in regions of the brain that didn't occur in control animals,

00:08:02.280 which is just another sort of example of how, you know, sometimes some of these modalities that we,

00:08:08.220 we think are really good for increasing health span sometimes have other effects. And I think that

00:08:13.580 getting into the IGF-1, I think we'll probably, you and I will talk about that because we both have a

00:08:18.220 shared interest in that. But, but the, the periods of growth being necessary for health, I think,

00:08:24.320 I think that's kind of, kind of turning point in my mind. And so now I actually think that perhaps

00:08:29.940 even doing periodic, you know, prolonged fasts or, or, um, a better way of doing that because you can,

00:08:36.620 you can get that IGF-1 boost and you can get the, the lower IGF-1 among other things that,

00:08:44.340 that occur. But, um, we can dive into that if you want, but I think that's, that's kind of,

00:08:49.120 yeah, but, but I think that's probably one of the major things. The other would be actually

00:08:53.840 another interest that we share would be, I think I was a lot more skeptical of,

00:08:59.420 of ketogenic diets about four years ago in terms of being great for long-term health

00:09:06.820 and health span. And I think that some of my, my thoughts on that have changed a bit based off of

00:09:13.460 more recent long-term studies in animals, specifically in mice, um, from work from Dr.

00:09:20.280 Eric Verdin and also from out of UC Davis showing that ketogenic diets in, in rodents can increase

00:09:26.260 health span, uh, increase median lifespan, certainly improve cognitive function. Now the caveat there is

00:09:32.100 that typically with a ketogenic diet in, in rodents, it's actually can be most of the time is

00:09:38.800 obesogenic. And the way that these guys worked around that was they found that had, they had

00:09:43.740 to limit the calorie. And what was interesting was that, or cycle them, right? Well, so Dr.

00:09:49.060 Eric Verdin, the way they did that was by cycling it. But, uh, UC Davis, what they did was actually

00:09:53.940 put a calorie cap and turns out after, uh, talking with Dr. Sachin Panda that they ended up being on a

00:10:00.800 time-restricted feeding schedule. And so the ketogenic diet was, you know, they were basically

00:10:05.660 eating all their food within a certain, like, you know, eight or eight or so or nine an hour window.

00:10:10.720 And then they were fasting for, so, you know, it's kind of one of those things where, you know,

00:10:15.580 in humans, we don't, we don't really know, you know, I don't know exactly know how people,

00:10:19.340 I've never actually done a ketogenic diet myself. So I don't know exactly what people are doing,

00:10:24.040 if they're eating, you know, all the time or, or, or what, but.

00:10:27.340 So, so I'm also intrigued by that. And, and in many ways almost have the mirror of your

00:10:33.120 experience, which was, you know, four or five, six years ago, seven years ago, I guess,

00:10:37.780 is when I really, really got into ketogenic diets, was on a ketogenic diet for three years,

00:10:42.920 save one day. And I, I wouldn't say I have any less faith in them today. I just am personally

00:10:48.840 less interested and find it much harder to do. So just as far as compliance with a ketogenic diet,

00:10:55.420 you know, I think my life is just more complicated today in terms of travel and things like that and

00:10:59.980 kids and stuff. But the thing that surprised me with the recent, cause those two publications came

00:11:05.620 out in cell, right? The ones, um, burdens. Yeah. I was actually kind of surprised by a couple of

00:11:12.660 things. So one was what you said, which was Eric noting that, Hey, when we constitutively gave these

00:11:18.380 guys this food, they just, they got obese. That's really counterintuitive when you think about

00:11:24.180 how ketogenic diets increase circulating metabolic fuels. And that should downregulate appetite. And

00:11:30.280 I think in humans, you know, there's a huge debate about why do people lose weight on ketogenic diets?

00:11:35.860 Are they losing weight because they're eating less? Or are they losing weight because they're ramping up

00:11:40.240 fat oxidation disproportionate to where they were before, which drives up energy expenditure?

00:11:45.120 Of course, I suspect the answer is both. In other words, if you do the latter, the former should

00:11:49.920 happen. So when people say, why do you eat less on a ketogenic diet? The question is really, or the,

00:11:56.160 the, the thinking would be, are you eating less because you are basically eating yourself more

00:12:01.040 because you're obviously oxidizing all of those fatty acids to make BHB? Or is it some other reason

00:12:07.260 that, you know, has to do with the neurochemistry of these things that go beyond sort of the metabolic

00:12:11.920 central, pardon me, peripheral effects of it. So that's the first thing that surprised me with that

00:12:16.420 study, which was why were those mice overeating? Was there something else in them? Because they

00:12:21.460 couldn't have had that much sucrose. They usually put sucrose in mouse chow, but there couldn't have

00:12:24.960 been that much sucrose or they wouldn't have been able to get into ketosis.

00:12:27.640 And I think even previous studies, like earlier in the literature showed something similar where

00:12:31.580 it was obesogenic. Now there was certain genetic backgrounds that also seemed to kind of

00:12:36.300 little, you know, regulate that to some degree. But what I was actually thinking, so you,

00:12:40.180 you brought up some really interesting points is that thinking of that in the context of like,

00:12:44.520 let's say they're, they're eating, they're constantly eating the fat where they're not,

00:12:47.880 they're not having a period of rest. I know that, for example, when you're making malonyl-CoA,

00:12:52.760 which is something that you do when you're oxidizing fat, malonyl-CoA inhibits the

00:12:57.960 conditine palmetyl transferase, the basically the transporter to transport fatty acids in the

00:13:02.300 mitochondria. So if you constantly are making malonyl-CoA because you're constantly eating the fat,

00:13:08.160 then you're going to start to have this inhibition. You're going to start to then store the

00:13:11.520 fatty acids and anipose tissue rather than catabolizing them. Right. So it seems to me

00:13:16.000 that we don't see that by the way, with the exogenous ketones, do we? This is something I'm

00:13:19.820 still trying to get a handle on. I agree. I'm certain I am, I am extremely interested in

00:13:24.200 exogenous ketones, particularly because I've tried them. Okay. You've tried them. Yeah. Yeah. I was

00:13:29.000 going to bring you some. So I really enjoy the effects they have on, on my brain. So I've used them

00:13:34.780 for like endurance exercise. And I also like it for that as well. I do notice that I have a little bit of a,

00:13:40.420 I seem to run longer than I usually stop at this point on the beach. I'm like, I can keep going

00:13:44.800 another, you know, but, um, what I really like is, is for me, it really helps with, uh, focus and

00:13:50.880 lower anxiety levels. So like, I seem to be able to, I'm always onto the next, you know, what's,

00:13:57.480 and, and so this kind of helps me like stay in the now at least I'm, and that could be completely

00:14:02.160 placebo. I don't know. But anyway, so that's, that's one thing that I like about that. But to get back

00:14:06.620 to your point, I had wondered the same thing because what's the effect of exogenous ketones

00:14:11.840 on normal fatty acid metabolism. And the, the reason I'd wonder that is because there

00:14:15.740 was a paper that recently came out, um, where I think it was the one that was done in humans

00:14:21.540 where humans, they were given the beta hydroxybutyroid ester for endurance and an enhanced endurance

00:14:27.900 performance, but they found it inhibited. Yes. And also it inhibited fatty acid, something

00:14:35.720 to do with the lip, uh, fatty acid, uh, transport out of the adipose, something to do with where I

00:14:40.960 was like going with, um, somewhere, something that had to do with lipid metabolism, which

00:14:45.620 suggested possibly there could be an, uh, an inhibition. Now, you know, it's funny. I'm going

00:14:50.720 to see, I'm in New York next week and Dom is going to be in New York. Dom D'Agostino, who obviously

00:14:54.580 you know well, and we're, we're grabbing dinner, uh, one night and I, we're going to talk about

00:14:59.800 this paper because I remember when it came out, Dom, uh, sent me an email. I can pull it up.

00:15:05.620 Then I'll, I'll know for sure if you want, or I can just send it to you. Yeah. Yeah. Send it to me.

00:15:08.540 Send it to me for sure. Because there was something about that study that was a little bit off. I need

00:15:12.520 to kind of go back and, and, and look at it, but it does beg another question. So I want to go back

00:15:17.700 because there's going to be, this is, I know this is going to be a theme today, which is multiple threads

00:15:21.560 that are easy for us to go off on. And you and I are great at going on. Yeah. Yeah. Yeah.

00:15:25.000 Yeah. Let's go back to the mice. Let's go back to the two studies. Do you recall if in the Verdon

00:15:31.260 study, when they, before they started cycling the ketogenic diet, when they were just giving it to

00:15:35.440 them all the time, did they have a window in which they could eat ad libitum that they overate in,

00:15:41.180 or were they given 24 hour access to food? 24 hour is ad libitum. So what they never tried then was

00:15:46.380 let's give you food for 10 hours and let you eat ad libitum. Cause that would be interesting if they

00:15:50.620 would overeat in that setting. Maybe not that interesting. The other experiment that I don't

00:15:54.980 think has been done is remember when they did the, um, they took a variant, which was high fat,

00:16:01.040 but high ish carb. And so it wasn't, there was enough carb in the diet that it wasn't producing

00:16:06.820 ketosis, but it was still a high fat diet. I'd like to see that experiment repeated, but with an

00:16:11.700 exogenous ketone, because then you could start to identify the effect of the carbohydrate specifically

00:16:18.580 and tease out the effect of the fat and the BHB. Right. I think I remember one of the big

00:16:24.940 differences between the, the, the high fat, low carb and the actual ketogenic diet was the,

00:16:31.000 the induction of PPAR alpha, which was, um, which makes sense because that's involved in,

00:16:36.060 you know, ketogenesis itself, but to what degree that regulates, you know, any of the other

00:16:41.840 important properties that were found, including the, the really the profound effects on the brain.

00:16:47.340 And, you know, so I, I, I like to personally get my ketogenesis from, from my periods of fasting

00:16:54.460 more so than carbohydrate restriction. Well, I do, I do refine carbohydrate restriction,

00:16:59.440 but I also, I think there's a lot of benefits and this is part of the reason why for so long I was

00:17:04.800 skeptical of a ketogenic diet is because I think there's a lot of benefits in eating a variety of

00:17:09.740 plants. I think that there's a lot of various micronutrients that are much higher density

00:17:14.260 in plants, uh, folate, magnesium, uh, vitamin K one, but also there's a lot of fermentable fibers

00:17:20.820 and, and things that are really also really good for the gut microbiome, which I also think is very

00:17:25.780 important for regulating immune function. So that's kind of been my, my, my hangup, but I think,

00:17:31.040 you know, like people like Dom seem to be doing a modified ketogenic diet where they're, you know,

00:17:36.840 definitely getting the greens, trying to get the leafy greens. Uh, so, I mean, I think that,

00:17:41.260 you know, one way to kind of get around that. Plus I think there's also a way to do a ketogenic diet

00:17:45.600 where you're eating a lot of salmon, avocado, nuts, you know, olive oil, and it's not just like

00:17:51.340 butter and keto bombs and all this like pork rinds and stuff where I'm just like, where's the nutrient

00:17:56.520 density and some of that, you know? So. Yeah, it's funny. I mean, I guess it depends on how many

00:18:01.240 calories you need, but at the time that during that window, when I was on a ketogenic diet, I was

00:18:06.120 also still very active, certainly much more so than now. And I really required a lot of calories.

00:18:12.140 I mean, I, I couldn't maintain my weight below 4,500 calories a day and I still stuck to pretty

00:18:18.860 strict absolutes on the protein and carbohydrates. I really kept my carbs and I didn't look at net

00:18:24.720 carbs. I, uh, Oh, by the way, for those listening and wondering what that noise is, this is something

00:18:29.100 Rhonda and I are very used to. Those are FA 18s, which how many overhead drive-bys are we going to get

00:18:34.620 today? If you had to predict, I would say three more. Yeah, I would say probably between three or

00:18:40.160 four. Okay. Yeah. It's the sound of freedom people. So just get used to it. So I was getting

00:18:46.120 probably 50 grams of carbohydrates, total carb. I should say probably about 80 grams of total carb,

00:18:51.680 but you'll see the, what type of carbs it was really had to limit protein to about a hundred to

00:18:57.400 110 grams. If I went over that, I would get kicked out. And so fat made up about 90% of my total

00:19:04.600 calories. And so there's only so many ways you can get that much fat. And the most efficient way is

00:19:11.840 actually salad with olive oil. I mean, I couldn't believe the amount of vegetables I had to consume

00:19:17.380 to stay in ketosis. You know, I basically had to have two huge salads a day where I would make my

00:19:22.480 own dressing, which was a heavy olive oil based dressing. And I could probably only have one avocado

00:19:27.180 a day, which I would always have because other than anything over than that, I was getting too much

00:19:29.940 carbohydrate. So it was like a lot of macadamia nuts, a lot of olive oil, olive oil based everything.

00:19:36.480 And then the hardest part for me was clearly being stingy with the protein.

00:19:41.440 What was in there? What was in the salads? Like, I mean,

00:19:43.920 okay, so I'd go, you know, I'm a pretty boring guy. So it's romaine, tomatoes, cucumbers, celery,

00:19:49.620 had to kind of like limit the carrots a little bit. I normally love carrots, but tomatoes and

00:19:54.780 everything on the ketogenic. Yeah. Yeah. Now again, part of it is I can get away with more

00:19:58.140 because I probably exercise more. And I was doing this before people were sort of putting butter in

00:20:02.980 their coffee and stuff like that. So that was not, I consumed a lot of dairy though. So it's the other

00:20:08.020 thing, tons of cheese, tons of sour cream, because you just needed those calories. And I actually

00:20:13.580 developed like a spreadsheet that was customized for my caloric needs, but I had this formula of

00:20:20.020 looking at every ingredient. Like, could you find the food that you could eat without restriction

00:20:25.920 that wouldn't destroy your ratios? And so for me at my caloric levels, like cream cheese and sour

00:20:31.500 cream were sort of the perfect thing. Whereas even high fat Greek yogurt had too much protein. So I

00:20:36.340 had to consume that in moderation. That's the other interesting thing. And I think I talked to Eric

00:20:40.400 about this was, you know, how much of the effects, you know, on, on health span or due to low protein

00:20:47.080 intake and how much were due to, you know, the actual being in ketosis. Yeah. I've talked about this

00:20:53.520 with Walter a few times. We don't see eye to eye on this because for several reasons, one, I'm not

00:20:58.340 entirely convinced of the IGF paradigm anymore. So that's one thing where, you know, the question I

00:21:03.580 asked you, that would be my answer. So five years ago, I would have said IGF is the devil. Growth

00:21:09.100 hormone is the devil. You want them to be as low as possible. I'm not convinced of that today. And I

00:21:13.260 can't wait to explore that with you. But the other thing is, if you really want to produce the lowest

00:21:18.720 level of insulin and IGF, I am not aware of a way to do that beyond a ketogenic diet that is

00:21:23.760 incredibly low in protein, incredibly low in carbohydrate. When I go back and look at my

00:21:27.980 blood levels, because I, I check my blood about every six to eight weeks, and I've been doing

00:21:32.380 this for, you know, 10 years. I mean, my lowest IGF levels were during the three years I was in

00:21:37.500 ketosis. I mean, they were very low. They were, I mean, not ridiculously low, but 25th percentile for age

00:21:43.140 versus say 75th percentile today. So that makes sense to me because if you think about,

00:21:47.960 you know, some of the major dietary regulators of the IGF-1 pathway are

00:21:52.080 protein, essentially, amino acids specifically, and also insulin.

00:21:57.460 Insulin through IGF-PP3.

00:21:58.820 Exactly. Or IPB-1 too. So, I mean, I think that, so for example, you know, if, if, if someone's eating

00:22:04.140 a low protein and low, you're, you're getting, you may not be a vegan, but even if you had,

00:22:09.100 you're limiting your protein, you know, even to some degree, you're, you're certainly getting more

00:22:12.960 than someone, maybe me, that's not, not doing that really. Although I do kind of limit my protein.

00:22:17.440 But it's a misconception. You see, I think a lot of people assume ketogenic diets are high protein

00:22:21.360 diets.

00:22:21.960 I think some people do consider that. Yeah.

00:22:23.800 But if you're, there may be certain people out there who can produce ketones with high protein,

00:22:28.060 but in my experience personally, and more important clinically, meaning, I don't know,

00:22:32.580 over the course of my practice and my career in medicine, I mean, I've, I've probably at least

00:22:37.080 encountered 50 or 60 patients at a very detailed level on ketogenic diets, almost without exception,

00:22:43.400 protein is the bigger thing that fouls people up. And so that's the thing I've always found a bit

00:22:49.020 confusing in some of those discussions is, and even Eric mentioned this on your podcast, which is,

00:22:52.600 well, you got to be careful if you're on a ketogenic diet, you don't have too much protein.

00:22:54.900 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

00:22:59.920 protein because you won't make the ketones. That said, I wouldn't be surprised if there are

00:23:04.460 polymorphisms that allow people more or less. And you've obviously talked a lot about the PPAR alpha,

00:23:08.640 is it PPAR alpha or PPAR gamma where you see the differences in a person's ability to generate

00:23:13.420 ketones? The PPAR alpha is, is predominantly found in the liver and it's involved in, in fatty acid

00:23:19.100 catabolism, the production of ketone bodies. So, so that would be the major one. Now there's nothing

00:23:24.780 empirically I've seen in literature that's looked specifically at PPAR alpha and a ketogenic diet

00:23:29.920 or fasting, but you know, there's most of the literature out there looking at the effects of

00:23:34.440 PPR alpha with people that are either had or homozygous are, or have to do with the context

00:23:39.440 of like high saturated fat, low polyunsaturated fat diet because polyunsaturated fat activates the

00:23:44.960 PPR, you know, family of transcription factors, which are nuclear hormone receptor transcription

00:23:51.320 factors. But the PPR gamma is predominantly found in like adipose tissue. I mean, they're found in other

00:23:56.260 tissues, but I say predominantly, that's like the most, they're highly expressed in that adipose tissue.

00:24:00.080 And it plays a role in basically taking up fatty acids into adipose tissue, whereas the alpha,

00:24:05.880 which is in the liver, take, plays a role in the transport catabolism. So one would just sort of

00:24:11.940 imagine, I mean, it'd be nice to see that, you know, someone look at that, you know, people with

00:24:16.220 these specific SNPs and how that. Does Prometheus identify various SNPs of PPAR alpha? Yes, but they

00:24:23.460 don't really tell you anything. They, they sort of pull abstracts from PubMed and just kind of like

00:24:29.940 dump it there. So you kind of can start with the research there. I've been developing a genetic

00:24:35.100 tool and I just, we're actually developing it a lot more. I have a former NIH geneticist who's

00:24:39.820 really phenomenal, who's been working with me on to help me sort of develop those, basically look at,

00:24:44.720 look at, you know, the literature and see what some of these SNPs are, are doing. And then in,

00:24:49.660 you know, in conjunction with looking at biomarkers, various blood biomarkers to kind of help people

00:24:54.100 guide, you know, what sort of they should do, what's a bypass around it, a potential bypass, for example.

00:24:59.660 So with the PPR alpha or gamma, I think that the take home, at least from the literature is

00:25:04.720 essentially, you want to have a higher ratio of poly and monounsaturated fat to saturated fat ratio

00:25:11.880 in order to lower your type 2 diabetes risk. You're saying for any, for people with the wild

00:25:16.300 type or with people with certain SNPs? With the SNPs within PPR alpha. Yeah, because, and gamma as well,

00:25:22.200 because to some degree, some, some of the ones in PPR gamma affect the uptake of fatty acids and adipose

00:25:28.600 tissue. And so, and also muscle. And so it kind of can affect, you know, you have a lot more free

00:25:33.720 fatty acids around and that can, you know, have, have an effect on insulin sensitivity and other

00:25:38.480 things as well. So. We should talk about this offline because I have a subset of patients for

00:25:43.660 which we have such rich data. And if I'm positive, all of them would be interested in knowing this and,

00:25:48.860 you know, we'd certainly get their permission, but it would be interesting in taking their,

00:25:52.840 you know, just their straight up 23 and me data. So, so here's the pattern I've seen. And I'm very

00:25:58.580 curious as to what the overlap is. So there's a clearly a subset of people. I think my N is too

00:26:05.880 small to quantify it, but directionally it seems like, I don't know, 10 or 20% of people when you

00:26:12.920 put them on ketogenic diets in the standard way, which usually ends up meaning you're getting at least

00:26:18.520 40% of your calories from saturated fat, typically 40 to 45% from mono and the remainder from poly,

00:26:25.680 everything goes to hell in a handbasket. And the obvious things that go to hell in a handbasket

00:26:30.120 have been certainly written about on the blogosphere and Twittersphere, which is usually their LDL

00:26:34.700 particle number skyrockets, despite the fact that their triglycerides go down. So they seem to be

00:26:40.360 getting more insulin sensitive, but yet inflammation is going up. And you see that both specifically,

00:26:47.000 cardiac specifically, so things like oxidized LDL and LPPLA2, but even non-specifically C-reactive

00:26:51.860 protein fibrinogen. But the deeper level is the why. And what you see is they're making much more

00:26:59.060 cholesterol. Markers of cholesterol biosynthesis, like desmosterol, go way up. And some of their

00:27:05.300 phytosterols go up, which is very counterintuitive. Phytosterols would generally go down on a ketogenic

00:27:10.920 diet, but they're going way up, suggesting that they're absorbing much more cholesterol, like

00:27:16.920 biliary cholesterol. So the first time I noticed this was 2012. And I think I wrote about this once

00:27:24.280 on a blog, but I don't remember. Maybe I'm thinking of another example. And it was this

00:27:28.560 relatively young patient who really loved being on a ketogenic diet. But when we get his blood test

00:27:34.200 back, I mean, his LDL particle number was above 3,500 nanomole per liter. And I know there are a lot

00:27:39.280 of guys out there who seem to think that as long as you're on a ketogenic diet, it doesn't, none of this

00:27:43.000 stuff matters. I completely don't subscribe to that. And my view is that's irresponsible. So I said to

00:27:48.740 him, I said, look, I don't think a ketogenic diet is right for you. And he said, no, no, no, no. It's

00:27:52.220 the best thing I've ever done. Like I feel better. I look better. I'm performing better. We got to figure

00:27:57.820 out a way to do this. And I, and the only thing I could think of, and I talked with Tom Dayspring about

00:28:01.480 this and he said, let's try and experiment and rip all the saturated fat out of his diet. He was sort of

00:28:07.120 like me, he was eating a lot. He, meaning he's a high caloric consumer. So that gets really hard.

00:28:12.140 So we created a diet form that was only about 20 to 25 grams a day of saturated fat. And he ended up

00:28:18.700 getting about 65% of his fat calories from monounsaturated fat, which was pretty gross. I

00:28:24.820 mean, you're drinking olive oil at that point, but he was interested in doing the experiment.

00:28:29.000 And sure enough, after, I don't know, maybe eight to 12 weeks, same macronutrient distribution in

00:28:37.260 terms of fat, protein, carbohydrate, the only shift was the type of fat. So we just substituted

00:28:42.520 mono for saturated. His LDLP was 1300 animal per liter. All of the inflammation was gone and all of

00:28:50.280 the sterile biomarkers went back to normal. I've since seen that about six times. And now I'm wondering

00:28:56.680 if we took those patients and ran them through what you're doing, would they be the ones that

00:29:01.920 have those SNPs? And there's a variety of them that do that. So there's the PPR alpha, PPR gamma,

00:29:06.020 there's a, there's a couple of FTO related SNPs also that the ratio of saturated. And basically in

00:29:11.840 the literature, these studies have all looked at the ratio of saturated to mono and polyunsaturated

00:29:16.420 fat. And for whatever reason, people with those SNPs, when they have a higher saturated fat to poly or

00:29:21.920 mono and or mono, they have higher inflammation, higher oxidized LDL, higher, a small dense LDL,

00:29:28.140 higher, you can just, you know, all these just terrible. Do you have a sense of the frequency

00:29:31.860 based on the research you've done on this? How prevalent that is? Kind of, I would say,

00:29:37.360 you know, I'd have to look back at the data probably less than 20%. So it might be in the ballpark of what

00:29:42.560 I'm seeing for this different phenotype. It might be. Yeah, it might be. So that would be really

00:29:45.920 interesting to run them through, through my tool. And, and like I said, we're, we're even expanding that a

00:29:50.120 little bit. I found, I found a few more. Are patients sending you any of their data or are

00:29:54.660 they doing it on their own and just. They're doing it on their own. Some people have shared

00:29:57.880 their data with me because they've emailed me and something interesting. And I'm like, oh, wow,

00:30:01.760 that's super interesting. Do you mind sharing that with me? And they have. So if anybody's listening

00:30:05.500 to this and they're saying, Hey, you know, I had an advanced lipid test before and after I went on a

00:30:10.520 ketogenic diet and I looked like this situation you described, can they reach out to you through your

00:30:16.500 blog and send this data to you? If they can actually just use the genetic tool and then sort

00:30:22.440 of, you know, share with you the data. If they want to share with me the data, you know, I can't

00:30:26.640 promise anything, but, but they can certainly get the why themselves by just using genetic tool right

00:30:31.580 now, which, which I have, I have free reports for, for example, the PPR genes, but then I have a whole

00:30:37.760 comprehensive report that's like $10 recommended. So if someone doesn't want to pay $10 to do the

00:30:42.340 comprehensive, they can just get the free report and get the why potential why themselves.

00:30:46.140 So I hope that anyone listening to this, cause I, again, if I'm seeing this at 10 to 20% of the

00:30:51.000 time and you're seeing it, then it'd be great to get a few hundred people who are that phenotype

00:30:55.800 and find out if the phenotype matches the genotype. Right. Yeah, it would absolutely be. And like I

00:31:00.440 said, I have, I have had people have that problem where they've tried a ketogenic diet and couldn't

00:31:04.200 figure out. And they did have one or even more than, than one of the SNPs that regulate fatty acid

00:31:09.380 metabolism. So. And then there's another phenotype that fortunately is more rare. And I also wonder,

00:31:15.360 what's going on with PPR alpha specifically, which is people who do everything by the book.

00:31:24.660 And maybe I'm a sucker and maybe I'm gullible and maybe I believe patients too much, but I don't

00:31:30.040 think I've ever had a patient lie to me. I really think like when they're not doing what they're

00:31:34.160 supposed to be doing, they tell you I'm not doing what I'm supposed to be doing. So it's not uncommon

00:31:39.360 in this rare subset of patients that is where they're doing everything by the book. I mean,

00:31:44.560 they're working their tail off to keep their carbs here, to keep their protein here, to keep their

00:31:48.940 fat here, to keep it within this distribution. And they cannot get even close to half a millimolar

00:31:55.620 of BHB in their blood. And to me, that's a really frustrating situation. It's frustrating for the

00:32:00.520 patient because they're sort of like, what the hell? I'm doing everything right. Like I'm not making

00:32:04.820 ketones. And, you know, I think Steve Finney sort of put out this notion that the threshold was about

00:32:09.400 0.5 millimolar. I don't have anything to argue that one way or the other. So I generally can,

00:32:14.680 you know, based on my own empirical experience personally, I sort of felt like one millimolar

00:32:18.900 was about the threshold. But, but again, I think that's neither here nor there. But when these people

00:32:23.560 are doing what I'm describing and they're at best 0.2, maybe 0.3 millimolar, it just made me wonder

00:32:28.880 there's something in their machinery that's not doing this. Now the question is, is it a lipolysis problem?

00:32:35.140 Is it an oxidation problem? Is it a conversion problem? I mean, that I don't know, but it would

00:32:39.980 also be interesting to understand where could the weak links be in their ketosis machinery?

00:32:45.140 Right. And there's probably, you know, there's a variety of SNPs in the, in these genes and,

00:32:49.320 you know, there, there may be certain SNPs that aren't, haven't even really been tested or

00:32:53.180 who knows, but it sounds, it sounds like, you know, to me that there, there's, there's certainly

00:32:57.440 something going on with, with the process of ketogenesis in some of the patients and their act,

00:33:02.980 their activity levels or are they're active?

00:33:04.820 Yeah, we're pretty, I mean, we've, we've evolved a lot in our thinking on how

00:33:09.460 those patients can be helped, but it seems that the best way to get them over that hump

00:33:13.800 is fasting coupled with exercise if they're capable, but it's gotta be relatively, it has

00:33:19.620 to be, it's not gardening. Like it's gotta be exercise, exercise, you know, they have to

00:33:23.980 really deplete glycogen. So that's the other thing I sort of wonder in some of these folks

00:33:28.600 is what's happening with, with gluconeogenesis, because I, I, I think until you start to dip

00:33:34.020 down in glycogen a little bit, it's really hard to do this. And of course we can't do

00:33:37.820 liver biopsies.

00:33:38.860 Wait, so fasting does get them into ketosis.

00:33:41.680 And so again, we're dealing with such a small N that I don't, I want to be thoughtful about

00:33:46.460 not generalizing too much. So there's one patient in particular who's the poster child

00:33:50.780 for couldn't do the ketosis thing straight away. But when we put him on every month, a

00:33:58.560 five day FMD. So he would do the five day FMD, but ketogenic, not Longo's FMD. And then

00:34:05.420 the 25 days of ad lib was time restricted eating ketogenic. Then we've seen great results

00:34:12.580 doing that in two people. So that would suggest that something again, it's not, we're not doing

00:34:18.200 this as an experiment at this point. It's like clinical. It's like, just try to get the job

00:34:21.260 done sort of thing. But that would suggest that something about the fasting and or the exercise

00:34:25.500 and or the time restriction could get them over the hump. But it's interesting because

00:34:29.760 from an evolutionary perspective, you should have been selected out really quickly if you

00:34:34.600 couldn't make ketones efficiently.

00:34:36.280 Well, it sounds to me that maybe, maybe there's the glycogen, you know, you're not, you're not

00:34:40.560 getting depleting the glycogen too, if that's, you know, so maybe it's not to do with the production

00:34:45.560 of ketone bodies, but it's actually just takes a long time to deplete that glycogen. I do think

00:34:49.620 there's a huge variation. Obviously physical activity plays a role in that as well. I can fast,

00:34:54.780 I can do, you know, like when I do my time restricted eating, ideally, I like to do it

00:34:58.440 within, you know, nine or 10 hours, eat all my food within nine or 10 hours. And then I, you know,

00:35:02.960 I like to fast for like 15 hours. I can do that. And with my physical activity levels, you know,

00:35:08.560 I will be closer to one millimolar fast. Like you will get to one millimolar after 15 hours of fasting.

00:35:16.280 I will be closer to that when I'm really physically active, like during the periods a couple of years

00:35:20.520 ago when I was doing lots of like long, like long distance running and stuff, I can get closer.

00:35:25.160 I mean, I mean, I'm, I'm going off of like a precision extra, which probably is not very.

00:35:29.520 No, no, no. Precision extras. It's, I mean, that's really good stuff.

00:35:32.620 Yeah. So I can get between like 0.7 millimolar to like 0.9.

00:35:37.380 But are you consuming a ketogenic diet during your feeding window?

00:35:39.640 So my, my, my diet typically, so I, like I said, I've never really intentionally tried to do a

00:35:44.460 ketogenic diet, but my, my diet is, I'm, I pretty much eat a lot of the same things. And typically

00:35:49.220 it's salmon, a salad or a sauteed vegetable with olive oil, some pasture raised, you know,

00:35:55.580 butter from pasture raised animals. And my fruits will be like blueberries. I'll have avocado. So I'll

00:36:00.720 have, sometimes I'll have a smoothie with some blueberries, avocado, and kale.

00:36:03.740 And will you have two meals in that window or three?

00:36:06.340 It depends if I have the smoothie or not. Typically I'll have breakfast and then an

00:36:10.160 early dinner and then I'll have like a snack, either nuts or the smoothie, the kale with

00:36:15.000 some blueberries and avocado. So I think it, you know, I need a lot of nuts too. You know,

00:36:21.100 I probably do.

00:36:21.980 What kind of nuts?

00:36:23.540 Walnuts, macadamia nuts, pistachios, cashews, almonds. I think probably.

00:36:29.100 I put cashews in the candy category.

00:36:31.360 Oh really?

00:36:31.880 Well, no, no. I just mean like, I can't stop eating those things.

00:36:34.080 So when I, when I talk about nuts, I'm like, I eat nuts and sometimes cashews because like,

00:36:39.640 I just might as well be eating M&Ms for me. Well, yeah, no, look, all kidding aside,

00:36:45.940 when I was on the ketogenic diet and I had to be very mindful of this stuff,

00:36:49.620 basically I could only consume almonds and macadamia. Everything else was just a little

00:36:53.560 too high in carbohydrate. The cashews just like my own personal demons. I don't know what it is about

00:36:59.700 cashews. Like I love watermelon. Like the summer, like right now. Oh, like my son loves watermelon.

00:37:04.740 You could eat a whole one.

00:37:05.740 Oh yeah. Like put a little salt on it. Like my father-in-law's from the South and taught me that.

00:37:09.860 So in the, in the summertime, I like to, I like to eat some watermelon. I like to eat peaches,

00:37:14.700 you know, so I'll, I'll definitely indulge in, in more fruits cause that's when they're around.

00:37:19.580 But you know, so I do, I think my diet tends to be.

00:37:22.320 So I wouldn't be surprised if before you entered your, like, so let's say you finish your feeding

00:37:26.300 window just before you went to bed, it wouldn't surprise me if you're already at 0.2 or 0.3

00:37:31.140 millimolar, right?

00:37:31.900 Probably. Yeah.

00:37:32.780 Yeah.

00:37:33.400 I never actually measured that right.

00:37:35.140 So check that and that'll give me a sense because if you, if you're going.

00:37:38.740 Well, I'm not doing as strict cause I'm still nursing. So I'm, because it's just so hard to

00:37:42.800 like time-wise get everything I'm, I'm eating probably more like within the 11 to 12 hour.

00:37:46.980 Okay. Okay. Well, when you, when you get back to the 15, I'd be curious because if you're actually

00:37:50.780 able to go from zero or 0.1 millimolar to 0.7 to one millimolar in a 15 hour fast, that's

00:37:57.740 impressive.

00:37:58.480 So, so when I took the exogenous ketones and I've done this multiple times.

00:38:02.760 Did you do the ester?

00:38:04.000 I did the ester by HVMN. I did their instructions, which is eat it with a high carbohydrate diet.

00:38:10.440 So I had a little bowl of some whole oats with some blueberries in it. And then I took the BHB

00:38:16.480 ester. I literally went from like 0.1 millimolar ketones in one hour to six millimolar.

00:38:23.020 Wow.

00:38:23.640 Six in one hour.

00:38:24.760 That's really high.

00:38:25.940 So.

00:38:26.640 That's impressive.

00:38:28.040 Okay.

00:38:30.320 I'm trying to think. I definitely don't get that high. And that's just with one bottle?

00:38:34.480 With one bottle.

00:38:35.400 And then how, how long did it last? Do you recall?

00:38:37.900 Let's, it depends on whether or not I did exercise, like intense exercise. And so if I did

00:38:42.200 the intense exercise, like an hour later, I was down to like two or three or something.

00:38:47.380 And have you ever taken it and just done work, for example, where basically the brain is doing

00:38:51.500 more of the exercise than.

00:38:52.760 Yeah. I, that's mostly what I do it now, but I don't, I'm not measuring it because I'm usually

00:38:56.880 like doing a podcast or going traveling and doing, you know, something, but that's, that's

00:39:01.520 typically what I use it for is that. So I'm not really doing the, using it for a exercise.

00:39:05.920 Yeah. They've really come a long way in taste.

00:39:08.400 Really? They still taste awful.

00:39:09.860 Yeah. You know, it's funny. I remember Kevin Rose, who's a good mutual friend of ours.

00:39:14.640 When he tried them first, he texted me and he's like, dude, these things aren't that bad. Like

00:39:19.360 you made it sound like these things were horrible. And I was like, when I had it, it, I thought I was

00:39:24.920 drinking kerosene or jet fuel. I thought I was going to die, go blind first, then die. He goes,

00:39:30.480 no, no, no, this stuff's good. He goes, actually, I wouldn't call it a sipping ketone, but it's

00:39:34.780 actually, I always thought the guys at human and the T delta S folks have, I think they've done a good

00:39:38.840 job kind of making them less ridiculous.

00:39:41.620 They must really have tasted bad when you tried it. Cause I personally think it's closer to the

00:39:46.460 kerosene side than the, it was so bad Rhonda that there was like a good three month period where my

00:39:52.360 favorite thing to do, like more than anything in the world was if anyone came over to my house for

00:39:57.140 dinner, they had to try one finger dip worth of, of, of, of stuff. And of course the first time I drank

00:40:03.620 it, I just took 50 ml and chugged it neat without mixing it or anything like that. And yeah, oh, I, I, I, I feel

00:40:09.600 day just getting people to try this stuff. The salts are obviously much more palatable.

00:40:14.060 Um, less, less studied, but I didn't really, I wasn't, uh, I certainly didn't feel like I had

00:40:19.760 the same effects as the, the ester. And also if I took a really high dose of it, I felt like I had

00:40:25.520 some GI distress.

00:40:26.840 Absolutely. I, and I have also noticed that for some people that is for me, that's the case. So I

00:40:32.820 cannot take the BHB ester on an empty stomach. The only way I can tolerate that at high doses is

00:40:38.880 either to put it with powdered MCT or actually just take it with a meal, which in many ways defeats the

00:40:44.240 purpose. Cause I kind of like it as a way to avoid meals.

00:40:47.600 Does, did it lower your blood glucose? Cause I mean, like it, like so significantly it was like,

00:40:53.760 like astounding.

00:40:54.540 Yeah. Yeah. No, it's pretty, it's pretty impressive.

00:40:56.860 Yeah.

00:40:57.360 Yeah. Well, and I, and I know that Jeff Wu, uh, the CEO at human is very interested in that. And, uh,

00:41:02.820 I republished a post I wrote five years ago on exogenous ketones, like a couple of weeks ago.

00:41:07.100 And a lot of scientists have reached out and said, Hey, we're really interested in studying this.

00:41:11.200 Like, what can you tell us about this? And anything. So I think people are starting to

00:41:13.780 realize that's an interesting way to lower glucose really significantly.

00:41:18.160 More than 20%.

00:41:19.060 I dropped 30 points.

00:41:21.300 Wow. Yeah. That's again, you're like carbohydrate after a high carbohydrate. Like I said, I had oatmeal,

00:41:26.740 uh, with some blueberries. It was nuts. Of course my, my blood sugar, because at the time too,

00:41:33.140 I mean, I've just been nursing at night. And so I'm waking up multiple times that has,

00:41:37.820 is terrible on your, for your, uh, blood glucose levels and such. But, um, so they were a little

00:41:43.100 higher than usual, but yeah, I dropped me 30 points.

00:41:45.360 Well, yeah, that that's more than we typically see.

00:41:47.220 Is it?

00:41:47.700 Yeah. Okay.

00:41:48.260 On the topic of blood glucose, have you ever experimented with Acrobose?

00:41:51.600 No, I've experimented with it in, with cells and culture, but not like personally.

00:41:56.120 The stuff's pretty interesting. It works quite well. Um, yeah, I'll, I'll certainly,

00:42:00.700 if I'm going to indulge in some high carb action, I'm going to take a hundred milligrams of Acrobose

00:42:05.420 beforehand and just flatline my glucose. Wow. You know, I, in many ways I find it actually

00:42:10.480 more potent than metformin at glucose reduction. I mean, I think metformin has many other effects

00:42:14.740 that we'll probably get into as well. So let's go back to the IGF thing, because this is sort

00:42:19.260 of the thing that here's the thing. I'll just jump right to my punchline and my, my question with

00:42:23.900 this. There are two issues I now have with things I used to take to be the God's honest truth.

00:42:29.220 Actually three things. The first is I found Cynthia Kenyon's work on the DAF 16 mutants

00:42:36.420 in C. elegans to be the most convincing evidence of the role of IGF or attenuating IGF in longevity.

00:42:45.500 And I now question that, not question the work, but question the inference that that can be applied

00:42:51.760 to humans, given the fact that only their germ cells divide and therefore cancer in that organism

00:43:01.040 looks nothing like cancer in us. Cancer in that organism is only a cell getting larger. There is

00:43:07.180 no proliferation. We have to sort of, I mean, it's obvious. It's the risk of stating the obvious,

00:43:12.380 which is we're not worms, but that's a huge difference in biology. So that's the, that's the

00:43:17.620 first thing. Let me, let me let you comment on that. Yes, because I've done those experiments.

00:43:21.340 That's probably what straight out of college. And I went to work at the Salk Institute with

00:43:25.260 Andrew Dillon, who trained with Cynthia, Cynthia Kenyon. I was a chemistry major in college and I

00:43:30.680 decided I kind of wanted to try some real biology because I'd only had a little bit of allergy

00:43:34.060 in college. And so I went to work at the Salk and, and really it was like those first experiments I did

00:43:39.700 with worms where, you know, we would knock down the, the insulin IGF-1 signaling pathway,

00:43:44.860 also known as the DAP2. And the worms would live like literally a hundred percent longer.

00:43:49.540 Like they'd go from two weeks to four weeks, right? Yeah. I mean, it was like, and not only that,

00:43:53.660 like the worms were so youthful. Like you would look at these worms, you know, cause it's all I would

00:43:58.760 do day after day under a microscope is just picking and poking and looking at the worms and how they move.

00:44:02.700 And you, you know, as they get older, they start to become less mobile. And I mean, it's just very

00:44:07.540 obvious. It's the most convincing data, right? It is very convincing. And that was to me in my

00:44:11.040 mind was kind of like when I was like, holy shit, like we have a gene that's sort of homologous to

00:44:16.140 this and this is happening in those worms. Like I want to understand that. Like, and here's the

00:44:20.680 thing about that data. And this is what I think. If you get rid of another gene that's homologous to

00:44:25.900 FOXO, DAF16. Oh, DAF16 is right. That's homologous to FOXO. It completely obliterates the lifespan

00:44:32.280 extension, meaning it's the FOXO3 that seems to be really important.

00:44:37.540 Four. We have how many? We have four FOXOs?

00:44:41.320 You mean different FOX genes? Okay. Yeah. I don't know exactly how many, but the FOXO,

00:44:46.680 we have three. We have one, two, and four. Was it one, two, and three? I thought there was like

00:44:51.420 a one, two, four, five, but, but their analog is 16. I remember that, right? Their DAF16 is basically

00:44:56.460 our FOXO. FOXO. Yeah. So, okay. Well, anyways, yeah, I'm not sure I'm, I'm getting confused with

00:45:00.840 the number. You know this better than I do, but okay. Yeah. But what is interesting is that the,

00:45:04.180 the lifespan extension was completely like ameliorated. So like,

00:45:06.940 did their health span curves, cause the experiment you're describing and no one can see what I'm

00:45:10.640 doing, but you know what I'm talking about. Like the, the natural was a two week lifespan where

00:45:15.920 for the first week they're youthful and then they have a declining health span curve. So at the time

00:45:20.820 of their death, they're totally decrepit in the experiment you're describing. If I'm thinking of

00:45:25.640 the same one, you doubled the lifespan and their longevity curve became a square function. It just

00:45:31.280 went out. Kind of. Yeah, exactly. Yeah. That's exactly what happened. But you get rid of the

00:45:34.920 DAF16 and they're like wild type. Oh, they're like wild type. Yes. I think so. And that largely

00:45:39.860 has to do with, you know, so that the IGF1 insulin signaling pathway, both inhibit FOXO3. So if you get

00:45:46.200 rid of that inhibition constitutively, the FOXO3 is just constantly active on those worms. I mean,

00:45:50.540 it's just like super, you know, making superoxide dismutase. They're making more stem cells. They're

00:45:54.880 making just, everything's active, you know, more autophagy, more stress, like all these stress

00:45:59.020 resistance pathways. I mean, FOXO3 is a transcription factor. It regulates a whole host of genes, many of

00:46:04.600 which have to do with DNA repair, autophagy, stem cell function, production of antioxidants and

00:46:10.480 anti-inflammatory pathways. So it's a lot of really good stuff that you want active all the time.

00:46:15.160 So there's that component to the longevity pathway. And actually, if you look at the animal data from

00:46:20.340 rodents where they're caloric restricted, if you get rid of the FOXO3, the median lifespan extension

00:46:26.980 is gone. So the lifespan extension depends on FOXO3. The cancer stuff was still, like, it didn't

00:46:32.960 matter. So the cancer reduction didn't depend on FOXO3, only the lifespan extension. So I think there

00:46:38.620 may be an uncoupling between humans and IGF-1. One of the major problems with IGF-1 is actually,

00:46:43.980 I think, cancer. And if you look at, you know, animal studies, if you look at human studies,

00:46:48.960 like humans that have polymorphisms that make them have more IGF-1, they have much higher cancer

00:46:53.560 incidence, vice versa. So if you look at people that have polymorphisms, either.

00:46:57.900 Is that the case? I mean, we look at the opposites, right? We look at the ones that have low GH

00:47:02.500 and by proxy, low IGF and have less cancer.

00:47:06.220 So you're talking about Lahren syndrome. Yeah. So Lahren syndrome, yeah, yes, they do. But I think

00:47:10.860 there's also another one in IGF. There's HETS and IGF-1 receptor.

00:47:14.960 So this is, you're not talking about acromegaly or people that are making too much GH.

00:47:18.460 They also are more susceptible to cancer as well. Yes, I am talking about them as well,

00:47:25.180 actually. The people with acromegaly are more susceptible to cancer. Maybe that's what I was

00:47:30.100 referring to with that have higher circulating levels of IGF-1. So you're saying you can't

00:47:34.980 uncouple the growth hormone from IGF-1? Yeah, that's been one of the things I've

00:47:38.240 struggled with is it's hard to uncouple the GH, the effect of GH on the liver.

00:47:42.240 In humans.

00:47:42.540 Yes, yeah, exactly. But animal studies, that has been uncoupled. Like if you do any sort of

00:47:47.980 tumor transplant animals and then make them have high GF-1 through a variety of modalities,

00:47:52.500 the cancer will grow rapidly. So how do we explain the human epidemiology, which, and I'm like,

00:47:58.560 there are a few people that are more critical of epidemiology than me. I'm not a particular fan of

00:48:02.980 it. But I find it to be quite interesting in the negative, meaning the contrapositives within

00:48:08.820 epidemiology can be quite interesting. So this is the next thing that kind of got me going,

00:48:13.520 wait a minute. And that was, there's a U-shaped mortality curve that is skewed to the right for IGF

00:48:20.260 and all-cause mortality, cancer mortality, cardiovascular mortality, and neurodegenerative

00:48:26.220 mortality. But when you uncouple them by disease, you see a very interesting pattern. So all-cause

00:48:32.880 mortality, as IGF goes up, it actually starts to go down. It nadars at the 70th percentile and then

00:48:40.140 it starts to rise. But it doesn't get as high as it started. I know for people listening, this is

00:48:46.400 confusing. So we'll include the figures of all these from the papers. But the point is, it's not

00:48:51.700 that as IGF goes up, mortality goes up. It's the opposite for 70% of the ledger, only at the very end.

00:48:59.480 In other words, only high levels of IGF, very high levels of IGF seem problematic. And as I know you've

00:49:05.020 talked about, I've heard you talk about this on your podcast, you have to then disaggregate that by

00:49:09.080 age. The older you get, the better IGF seems to be, presumably because of the preservation of lean

00:49:15.300 tissue. It turns out that most of the uptick in the mortality above the 70th percentile is driven by

00:49:23.620 cancer. But actually cardiovascular disease and neurodegenerative disease seem to get, they flatline by

00:49:29.040 the end. So meaning there was no benefit to being at the 100th percentile or the 99th percentile versus

00:49:34.080 the 80th versus the 70th, but you weren't getting penalized for it. Which suggested to me that low

00:49:39.980 IGF might not be the ticket. Maybe it's some combination of cycling high and low IGF, but living

00:49:46.460 at around the median to slightly above that, the 60th, 70th percentile. And again, that's probably more a

00:49:52.800 function of my misunderstanding of the literature five years ago. But I really came away thinking,

00:49:57.780 IGF, we've got to keep that as low as possible. It's funny, you and I kind of have...

00:50:01.960 We've evolved in the... Yeah.

00:50:03.680 Very similar, because I now also think that, you know, so IGF-1 does play a very important role,

00:50:07.960 obviously in development, but also in the repair of muscle, in the growth of muscle,

00:50:12.000 preserving muscle mass. Also, it gets transported across the blood-brain barrier, plays an important

00:50:17.160 role in neurogenesis and allowing existing neurons to survive, which kind of brings me back to that

00:50:22.380 gray matter thing with the lemurs. But, you know, so... And the thing that was interesting to me

00:50:27.900 was the effect of exercise on IGF-1. And the fact that, for one, it's been shown that the boost in

00:50:35.080 neurogenesis after exercise in the brain via brain-derived nerve requires IGF-1. Animal studies

00:50:40.960 have shown that, mostly in rodents, have shown that exercise causes IGF-1 across the blood-brain barrier

00:50:46.320 getting to the brain. But in human studies, I've also seen some showing that it does lower

00:50:52.140 serum levels. I think, presumably, it's also going into the muscle and the brain. So I think

00:50:56.140 that, you know, people that are exercising, they're putting that IGF-1 to the places where it's supposed

00:51:00.940 to go, muscle tissue, brain tissue as well. But in addition to that, and this is kind of what's

00:51:06.100 more recent work from Dr. Walter Longo, is that we know that he does these prolonged fasts. And I think

00:51:12.580 the prolonged fasting is extremely interesting for a couple of main reasons. And one is, I think,

00:51:19.660 that it has tremendous potential for the treatment of autoimmune disease and also cancer based on,

00:51:27.180 you know, his work. And what he has shown now in animal studies and some pilot clinical studies is

00:51:33.160 that doing a prolonged fast and or, in some cases, the fasting-mimicking diet causes this massive

00:51:40.240 shrinking of organs where, you know, he doesn't know how much of it's due to cell size decreasing

00:51:47.320 versus apoptosis. He does know apoptosis is occurring, and he has showed that in multiple

00:51:52.140 publications. Like, there is a massive induction of apoptosis after a prolonged fast, you know,

00:51:57.220 which makes sense because it's a very strong stress. And then after, during the refeeding phase,

00:52:02.160 the organs basically come back. They come back. They grow, regrow.

00:52:05.960 And presumably selectively repopulate.

00:52:08.060 Yeah. So he's shown that these stem cells get activated. So basically, they have to be activated

00:52:13.820 by the low IGF-1. But then to proliferate and differentiate into whatever tissue type we're

00:52:19.520 talking about, let's say we're talking about the immune system, then IGF-1 is required for that

00:52:25.420 proliferation and differentiation and repopulation of the tissue, which means you can't just keep the

00:52:31.180 IGF-1 low. You have to have-

00:52:32.060 Right. The refeeding is just as important as the deprivation.

00:52:34.680 And the IGF-1 is key in that. And so, you know, what he's shown now is that you can take,

00:52:38.560 for example, in the multiple sclerosis animal model, you can actually cause stem cells to be

00:52:43.400 activated through the prolonged fast. And then during the refeeding phase, the stem cells make

00:52:47.900 non-dysfunctional. So they're making normal, non-autoimmune cells. And he's done like a pilot

00:52:53.680 clinical study with multiple sclerosis, people with multiple sclerosis, and it's helped with symptoms.

00:52:58.080 But he's also done these cancer studies. And this is kind of where there's been some clinical

00:53:02.400 studies that he's been involved with, like a 48-hour water fast that's been done in patients

00:53:07.080 undergoing standard of care treatment. And he's shown that it was tolerable. Not only that,

00:53:12.860 there seemed to be less myelotoxicity, less neutropenia. So basically there, and it sensitized

00:53:17.620 cancer cells to death. So not only were the cancer cells dying more, but less of the normal cells were

00:53:22.380 dying. And then he's gone ahead and shown this in animal models, also with the fasting mimicking diet.

00:53:26.860 And it's like, if you look at the data, particularly in the animal model, because they can, you know,

00:53:31.280 do all the tissue harvesting and stuff. I mean, it's like, it's so phenomenal that I would not be

00:53:36.380 surprised that in the next 10 years, it will be required part of standard of care, because it seems

00:53:40.880 to be so incredibly robust at selectively killing cancer cells, which, you know, makes sense. I mean,

00:53:46.520 oncogenes, they screw up all sorts of things. One of them is the stress response. And, you know,

00:53:51.760 cancer cells can't respond to stress. They're primed to die. I mean, it's, I spent a long time,

00:53:56.000 you know, studying cancer cell metabolism, apoptosis with Doug Green and Joseph Opperman

00:54:01.400 at St. Jude Children's Research Hospital. And that's kind of one of the primary ways that

00:54:05.440 a lot of these chemotherapeutic drugs, if they can get to the tumor site work, is that because

00:54:10.860 it's a stress, cancer cells can't handle it. You know, they die. So I kind of went off on a tangent

00:54:15.560 here. So to get back to the IGF-1.

00:54:18.340 Let me say one thing going back to what you just said that is also interesting, but in the same thing.

00:54:22.220 So I agree that I think that it would really be great if patients had a better insight into

00:54:26.500 nutrition going into chemotherapy. And the few times I go and give talks at hospitals or go and

00:54:32.280 talk at like a cancer meeting, I'm amazed at how resistant the oncologists are. On average,

00:54:38.640 obviously there were exceptions, but on average to interfering with nutrition, because in many ways,

00:54:43.440 their primary concern tragically is preserving weight. And so I always get a little verklempt when

00:54:50.280 I walk through an oncology ward and I see patients drinking insure. Like I couldn't think of a worse

00:54:54.840 thing you'd want to consume when you have cancer. And yet the goal is, hey, we got to fatten these

00:54:59.560 people up. So I agree with you. And I really hope that this research is accelerated because I do think

00:55:05.520 patients would benefit greatly from this. And the other application that I saw of this several years

00:55:10.780 ago, this is quite old now, but it blew my mind. I'm not sure if you're familiar with Jay Mitchell's

00:55:15.220 workup at Harvard. He did an experiment where he took three, yeah, three groups of mice. So the

00:55:21.080 first group were constitutively calorically restricted for their entire life. These were

00:55:25.560 probably like one and a half year old mice. So they're about halfway through their life.

00:55:29.140 Starting, starting, starting. Yeah. So these, these animals were constantly at 70% caloric intake.

00:55:36.280 The next group was your control group. And then your third group was ad libitum diet until two days

00:55:42.420 before an operation. And at which point they were calorie restricted to a near fast. And I'd have

00:55:49.040 to go back and look. I can't remember if it was 24 or 48 hours of fasting. It might've been a 24 hour

00:55:52.980 fast. 48 would be pretty extreme for mice. So in summary, you've got control. There's straight up

00:55:58.120 eating. You've got 70% or 30% CR forever. And then you've got control and then fasted for a day.

00:56:05.840 All the mice were then operated on where their femoral arteries were ligated, held for a period

00:56:12.560 of time. And then they were reperfused for people not familiar with what that means. So that means

00:56:16.500 you, you open the animal up, you put clamps on the femoral arteries, which would basically stop all

00:56:21.860 perfusion of blood to the lower part of the body. And then after some period of time, just before you

00:56:26.880 kill the animal, you release that. And then you reperfuse the blood, basically the oxygen

00:56:31.800 reperfuses the organism. That's considered a reperfusion injury, which is about one of the

00:56:37.160 most stressful things you can do to an organism. So that you can really rapidly kill someone by

00:56:42.160 doing that. And that's something that in surgery happens quite a bit. For example, you end up having

00:56:46.560 to clamp something off to repair something downstream of that. Okay. So what happened was all of the control

00:56:52.600 animals died without exception. Of the other two groups, the groups that were either calorie restricted

00:57:00.000 for life or transiently starved before the surgery, a significant subset did not die. And I can't

00:57:05.920 remember the number. And again, I know we're going to probably link to this study. So people are going

00:57:09.520 to listen to this and go, that idiot got all those details wrong. But this is the gist of it.

00:57:12.980 A non-trivial subset of them lived. And what's interesting is you could get the same benefit by an

00:57:19.700 acute period of caloric restriction in proximity to an insult that you could get by a lifelong of caloric

00:57:25.460 restriction. And the third piece that was interesting was the group that were just starved

00:57:30.340 transiently actually had a faster recovery, which again, they were fitter organisms. I remember the

00:57:35.620 first time I came across that thinking there's got to be something to cycling. And people used to always

00:57:39.800 ask me like, why are you on a ketogenic diet every minute of every day? Would there be any benefit in

00:57:44.180 cycling? Now, I still don't know the answer to that question, but I'm more curious about it now based on

00:57:49.940 what you just described from Valter's work, plus this type of stuff, plus just the general ethos of

00:57:56.200 the way we evolved. We fasted, we fed, we fasted, we fed, we fasted a long time, we gorged. It just

00:58:03.840 seems we've evolved for cycling. Right. Yeah, I agree. It's really, with Valter's work, I just am so

00:58:10.360 excited about the prolonged fasting and the potential benefits of it. I think that actually is something

00:58:15.580 that you and I discussed several years ago when I had interviewed you on my podcast that you brought

00:58:20.680 up that I thought was really interesting, had to do with like the failed clinical trials with binding

00:58:26.220 IGF-1 and cancer. And Valter brought up something interesting in a conversation I had with him,

00:58:31.720 and that is possibly that we now know IGF-1 having low and high IGF-1 is important. So if you're

00:58:39.880 constantly having low IGF-1 and the IGF-1 is important for the immune system or population,

00:58:44.760 you can imagine the context of cancer when you're giving other treatments along with it,

00:58:48.900 that would be important because your immune system is key in warding off cancer. And I thought that was

00:58:54.760 a really interesting point. Of course, we don't have evidence of that, but I think it's something

00:58:59.640 that would be interesting to investigate and it makes sense. Yeah, I definitely am on the same page

00:59:04.840 with you. I'm not, like I started out with saying, I don't think that chronic calorie restriction

00:59:10.000 and low IGF-1 is the essential like way for improving health span. I do think that IGF-1,

00:59:16.420 you want it to go to your muscle, you want it to go to your brain. So I think people should definitely

00:59:20.180 be active, especially if they're eating a high protein and or even high carbohydrate or something

00:59:25.600 that's going to produce a lot of insulin. You know, they shouldn't be eating refined carbs,

00:59:28.620 but people do. If they're eating them, they should definitely be exercising.

00:59:31.860 That's another change in my belief system. I think today versus, I don't know, five or six years ago,

00:59:37.300 five or six years ago, I didn't think exercise was that important to longevity, which actually

00:59:41.960 sounds ridiculous for anyone who knows me because I was probably exercising four hours a day, but not

00:59:47.240 because I believed it would make me live longer. It was just sort of soothing my addictions.

00:59:52.280 But I think today I feel, I am much more convinced by a lot of the data you've described,

00:59:58.180 certainly the central stuff. When we published this paper earlier this year with Richard Isaacson,

01:00:03.500 that you and I were talking about it before we started recording,

01:00:05.780 we wanted to get a sense of like, if you took a completely unbiased approach and look at the

01:00:10.220 literature, what was the single most compelling thing you could do to generate or preserve brain

01:00:14.560 health? And we came away thinking that it was actually exercise. And I remember when the analysts

01:00:21.040 were kind of going through this and showing me all the data, I was like, come on guys, there's no

01:00:25.020 way exercise could be the most important thing for brain health. And again, I'm saying this as a guy who

01:00:31.180 loves exercise more than anybody, but it just struck me as there's no way. And again, I think part of it

01:00:36.800 was, I was just thinking about it through the vascular lens. And obviously, you know, I think

01:00:42.660 better than I do that when you start to think about brain health, you have to think about it through

01:00:46.220 a vascular lens, a metabolic lens, growth factor lens. I mean, there were overlapping,

01:00:51.600 but distinct pathways that are going to influence brain health. And so I was kind of humbled by that.

01:00:56.520 And now, I guess in many ways, I'm a little more adamant about it with my patients. Not that I

01:01:03.460 wasn't, you know, adamant before, but this is like, boy, if you're, if you're not active every day,

01:01:09.160 like we got to change that. I actually, the, the main reason I exercise is for my brain. It's

01:01:14.540 certainly just not only for, you know, preventing neurogenetic disease and atrophy and all that, but

01:01:19.500 just because it affects my executive function and affects my anxiety levels. It affects my ability to

01:01:24.120 make decisions. I absolutely, if I have something that's bothering me or giving me anxiety or have

01:01:29.480 to make a really important decision, going for a long run really helps me. And there's been studies

01:01:35.240 showing that it helps with executive function, long-term planning, like aerobic exercise,

01:01:40.220 specifically, you know, and then in high intensity interval training, all that stuff, they all,

01:01:44.680 they all do different things.

01:01:45.580 Well, that's the thing. We couldn't, we couldn't tease this out of the literature, which again,

01:01:49.140 probably is just a limitation of shitty human clinical trials, but that's the second order

01:01:53.920 question, right? Which is if you're going to take the Tim Ferriss approach, which is what's the minimum

01:01:57.960 effective dose? Cause there are some people like maybe you or I, who I think just generally like

01:02:03.000 exercise and also get these other benefits, these endorphin benefits. But there are some people who

01:02:07.900 are like, look, what do I need to do? Like I'm going to treat exercise like medicine. And I think in that

01:02:12.660 setting, I'm still not clear. So if you were that person, would I say, Rhonda, as long as you are

01:02:18.400 lifting weights one hour, three times a week? Like if, if you can only give me three hours,

01:02:23.400 would that be how I'd want you to spend it? Or would I rather you be doing anaerobic aerobic type

01:02:28.140 thing? Like, I mean, that's to me, those are where these biomarkers start to become very important

01:02:33.420 because we're not going to generate hard outcome studies with that level of control. Once you, you

01:02:37.780 know, try to control that many variables and be that strict about it, you're going to very much lose

01:02:42.360 a hard outcome prospectively. But if we knew what to measure, right. And that's, you know, would we be

01:02:48.020 measuring an integral of IGF, for example? So how much it rises, how much it falls, and then what

01:02:53.700 that looks like over time. But I guess that's the funny thing, right? Like the more we learn,

01:02:57.880 the less we know. Yeah, absolutely. I think that we definitely don't know the answer to that question.

01:03:02.960 But I think there's a lot of data out there showing, for example, strength training,

01:03:06.960 you know, there's benefits on the brain that's been shown, published. There's benefits on preventing

01:03:10.760 muscle atrophy. There's benefits on preventing cancer incident. Like that's all been shown for

01:03:15.680 strength training, for aerobic. And, you know, this high intensity interval training is also,

01:03:19.800 also seems to be making its way as well. Like, like there was a study that I, that I found

01:03:24.760 VO2 max. This is, you know, the ability of your, your body to transport oxygen during exercise,

01:03:30.540 which also is an indicator of when you're not exercising. And obviously transporting oxygen to

01:03:35.160 the brain, for example, is extremely important. VO2 max declines with age, like 1% per year.

01:03:41.080 I forgot starting at what age, but, you know, so 10% per decade.

01:03:44.820 So that's, it almost parallels the muscle mass declines.

01:03:47.140 It does. It does parallel. Exactly. And there was a study showing that 24 sessions of high

01:03:51.200 intensity interval training, where it was like a 45 minute session, five minute warmup,

01:03:56.620 five minute cool down. And then, you know, in between the max intervals, which were like

01:04:00.480 pretty long, like a minute, there was, you know, the 70% of max water. Anyway, so 24 of those

01:04:06.400 increased VO2 max by 12%. So you're literally taking an entire decade of decline and like

01:04:12.240 reversing it with the 24 sessions. Yeah, that's, that's actually a good point. I, when I was more

01:04:16.740 active as a sort of competitive, you know, in cycling, you, we would get our VO2 max tested about

01:04:21.160 twice a year. Ryan Flaherty, who we were talking about before the podcast, who's one of my close

01:04:25.440 friends and you've got to know him as well. I learned from Ryan that actually VO2 max is not the

01:04:30.440 most important indicator as a runner or cyclist. It's VVO2 max or PVO2 max that matters. In other words,

01:04:36.100 for a runner, VVO2 max is much more predictive of performance, which is the velocity you carry

01:04:41.940 at VO2 max. And for a cyclist, it's PVO2 max, which is the power output at VO2 max. That said,

01:04:48.940 every time you go to test, you want it to test well. So, you know, over time I learned how to game

01:04:54.420 the system. You know, I want to make sure my VO2 max is in the seventies, which again, to put that in

01:04:58.600 perspective, like that's not at the level of professional athlete or something like the guys that are

01:05:02.440 winning the Tour de France are in the high eighties or low nineties in terms of milligrams per mil per

01:05:07.260 kilogram. But nevertheless, just altering my training for three weeks before a VO2 max test

01:05:14.440 and dropping my weight. So if I shed two kilograms and did those types of intervals, I actually had

01:05:20.500 it down to a science where there was a workout I would do, you know, in Carmel Valley, you've got

01:05:24.820 the 56 that goes out and it's got a bike path next to it. There's a section of that bike path

01:05:29.940 that is 1.6 miles long and it goes up at about 4%. And just doing repeat intervals of that,

01:05:38.980 which takes about four minutes all out to go one direction. And then about six minutes to cruise back

01:05:43.920 four of those, that was it twice a week for like three weeks and your VO2 max exploded.

01:05:51.240 Now, of course the question is, is that like, you know, cramming for the test, getting the result,

01:05:56.880 but not necessarily like, do you have to keep doing that to get the decade long benefit? I don't know

01:06:01.340 the answer, but I agree that like, if you can maintain muscle mass and you can maintain peak

01:06:07.800 aerobic performance, it's not, it doesn't even matter at that point. If you're living longer,

01:06:12.920 you're clearly living better, right? Like if you, if you don't budge anything on maximum lifespan,

01:06:18.120 you've dramatically improved median lifespan. Right. And that's a, you know,

01:06:21.960 I think for most people, that's what matters. It is. Yeah. For me, it is. I mean, I, what's the,

01:06:25.800 what's the maximum lifespan that like a human's lived? 120? 124 or something like that. Is it 124?

01:06:31.960 121 or 124 maybe. Something like that. Yeah. Living beyond that. I mean, that's,

01:06:36.080 I think the goal is really to, at least for me, I think that's a lot more achievable is increasing my,

01:06:41.360 my median health span or my, my health span, you know? So, so basically preventing,

01:06:45.860 staving off cardiovascular disease, cancer, Alzheimer's disease, those sorts of things so

01:06:50.600 that I'm, so that I'm living healthier and also, you know, a little bit longer, but obviously not

01:06:56.280 125 or six years. Yeah. I don't really subscribe to the theory that we're going to meet some takeoff

01:07:04.220 point where, you know, there's immortality. I'm really not convinced that that's, that that's sort

01:07:09.420 of biologically possible. And I don't suspect I'll be alive at a time when it would ever come to

01:07:15.160 fruition. I don't remember the journal. It was a paper that came out of Japan and the study looked

01:07:20.720 at a variety of people of different ages. So elderly population, centenarians, which are a hundred

01:07:28.200 semi-super centenarians, which are between a hundred and a hundred and five and then super centenarians,

01:07:33.380 which are a hundred and five plus, and looked at a variety of biomarkers for health and aging. So

01:07:39.680 telomere, senescence, kidney function, glycated hemoglobin, lipid, the whole lipid panel,

01:07:45.620 triglycerides, kidney function, hematopoiesis, like all that stuff was looked at inflammatory

01:07:49.840 biomarkers. And what was found is that aside from age, what was predictive of being able to basically

01:07:57.000 stay alive was low inflammation, like more than hematopoiesis, more than glycated hemoglobin,

01:08:03.860 blood glucose levels, lipid, all that stuff. It was basically the ability to suppress inflammation.

01:08:09.520 Like that was predictive of cognitive function and also basically staying alive.

01:08:14.180 Do you remember what they looked at? Were they looking at C-reactive protein and things like

01:08:17.380 that, but relatively general markers?

01:08:19.040 They looked at a whole panel. No, they included-

01:08:20.800 They looked at the interleukins and stuff also?

01:08:22.260 Yeah, TNF. They looked at a whole panel of, and also some immune cells that are indicative of

01:08:27.400 inflammation. So there was a whole panel of biomarkers that were looked at for inflammation.

01:08:31.260 HPV titer or something was also looked at. So the interesting thing about that study

01:08:36.480 was that the inflammation was so key for each age group, right? Like even more than all this other

01:08:42.700 stuff like that I've thought about, like senescence and telomeres and low blood glucose levels and all

01:08:47.700 that stuff. And so I really, and if you look at some of the rodent literature, for example,

01:08:52.480 I remember the study where NF-kappa B, which is classically thought about as an inflammatory

01:08:57.200 mediator, which it is, it also has an anti-inflammatory component to it. And if you

01:09:02.280 get rid of the anti-inflammatory component, rodents will have this sort of low level of chronic

01:09:07.580 inflammation because every time it's activated, there's not that anti-inflammatory part that's

01:09:12.360 kind of keeping it in check. And so there's kind of like this like lower chronic inflammation that's

01:09:16.780 happening. And those animals live like 30% less. So their lifespan's cut short by about 30%.

01:09:22.920 So that's kind of interesting, right? That just, just getting rid of that little anti-inflammatory

01:09:26.780 component of this one major regulator of immune system has a profound effect on lifespan. And

01:09:32.860 then of course, if you look at SNPs and stuff, of course, you can always find, you know, well,

01:09:36.680 centenarians have a higher percentage of 10 and anti-inflammatory anyways, you know, so the

01:09:41.580 inflammation, it's an interesting finding that suppressing inflammation seems to be important for at

01:09:47.440 least, you know, according to that study for making it to every part of, you know, I don't know

01:09:52.580 what you would call it every, basically progressing to the maximum level, that maximum lifespan level

01:09:57.680 that humans can possibly live.

01:09:59.960 Well, there was a clinical trial published either earlier this year or last year that

01:10:04.380 looked at an IL-1 antagonist. And so this was a study that took people and made no change in their

01:10:11.800 lipid metabolism, lipid biomarker. You know, this was, they, they didn't do anything to the patients

01:10:17.580 as far as differentiating the groups by traditional biomarkers of cardiovascular disease. But one

01:10:23.460 group was given a placebo, one group was given an IL-1 antagonist. And the question was, could that

01:10:27.900 impact cardiovascular mortality? And we've long talked about how cardiovascular disease is sort of

01:10:33.500 this trifecta of lipoproteins, inflammation, and endothelial dysfunction. But this was in many ways,

01:10:40.520 the most elegant first test of that in humans using hard outcomes. So major adverse cardiac event,

01:10:45.940 stroke, MI, death. The hypothesis was found to be correct. So the patients getting the IL-1

01:10:51.580 antagonist, despite having no difference in lipids or any other biomarker had an improved outcome with

01:10:59.460 respect to cardiovascular health. About a month ago, another trial that was using low dose of

01:11:05.780 methotrexate, which is an immune suppressant, was halted early. And the results will not be

01:11:11.580 announced until this fall. But if you read kind of the fine print, it does not appear it was halted for

01:11:17.680 a bad reason. Meaning it might've been halted actually for basically early efficacy, which

01:11:25.100 presumably would have been in the group getting the methotrexate. So again, we won't know that until

01:11:28.900 the meeting in October, I think when this will be presented. But if that turns out to be the case,

01:11:33.840 that's pretty interesting because now you've taken something that we practically have great examples

01:11:39.620 of, like the one you've given, and now potentially there's ways to think about using it. So taking a

01:11:44.540 step back from all of this stuff, like, you know, of course I think about it at the level of like,

01:11:48.320 I'm just a mechanic, right? It's like, how can you manipulate these things in people? Like

01:11:52.380 cycling, you know, using nutrition and fasting to cycle IGF, maybe even using an exogenous growth

01:11:58.480 hormone for all we know. Maybe, you know, I've always been quite skeptical of growth hormones use

01:12:02.460 in the field of longevity, but maybe periods of oscillating rapamycin and growth hormone and

01:12:08.160 fasting where you're cycling high periods of anabolic, high periods of catabolic phase,

01:12:13.220 maybe there's something to it. And then cycling agents like methotrexate and all these things. So

01:12:17.780 I don't know, that's my, my hope is like in 10 years, we've got a complete personalized toolkit for

01:12:25.040 how everybody could, you know, figure out exactly what drugs or hormones or nutrients to take and cycle

01:12:31.800 and how to do it. And then of course, the key is you have to be able to measure stuff.

01:12:35.060 You know, the, the, with the cardiovascular rated mortality, the, the sauna is something that is

01:12:39.740 interesting to me for that, for that reason, because of the profound effects that it has

01:12:43.640 specifically on lowering cardiovascular related mortality. And of course, there's some clinical

01:12:49.340 trials showing that, you know, there's a variety of other biomarkers and potential mechanisms by that,

01:12:54.620 which that's happening. But if you look at some of the data by Dr. Yari Laukonen out of Finland,

01:12:59.260 if you look at some of the observational studies, you know, where there's like a couple thousand

01:13:03.200 men that were doing, the sauna is so ubiquitous in Finland. But if you look at, for example,

01:13:07.820 men that are using it two to three times a week versus four to seven times a week versus once a

01:13:12.740 week. And you look at, for example, cardiovascular related mortality, two to three times a week,

01:13:16.880 it's lowered by like 27%. But when you jump to 47 times a week, it goes up to 50, 50%. All cause mortality

01:13:23.880 goes to 40. All cause mortality is also lowered. Dementia and Alzheimer's disease, again,

01:13:28.820 like 20% lowered if you're doing two to three.

01:13:31.300 Yeah. I'm so glad you brought this up because I almost forgot. And I wanted to talk to you about

01:13:34.580 this. This is one of those things where I think three years ago, I was completely dismissive of

01:13:40.940 this stuff, which is to say, I still love going into a sauna because the one thing that I felt sauna

01:13:46.080 really mattered for was sleep and not for the growth hormone level, but because I think there's

01:13:52.040 pretty good data that a great way to sleep is to create a high gradient of temperature. So the faster,

01:13:57.760 the more negative, the derivative of temperature, DT by DT, when you sleep, the faster you'll go to

01:14:03.940 sleep and the longer you'll stay asleep. So a sauna before bed, if you could jump in the sauna,

01:14:08.920 then take a cold shower, then jump into a cold bed, you're going to sleep like a baby.

01:14:12.760 I've done it. It's absolutely true.

01:14:14.140 It's remarkable.

01:14:15.160 Yeah.

01:14:15.320 So I always accepted that, but I looked at all of that epidemiologic stuff and I was like,

01:14:21.200 the healthy user bias here is through the roof. Like I came up with a hundred reasons why I just

01:14:26.640 couldn't believe it, including saunas are painful. So if you are fit enough to sit in a sauna seven

01:14:31.720 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

01:14:36.300 driving it? Now, since that time, I've become a lot more interested because now the mechanisms are

01:14:43.080 starting to become more well understood. And so I'd love to have you talk a little bit more about

01:14:49.020 this because I know you've talked about this a lot on your podcast, but in many ways, your

01:14:54.580 pursuit of this has become one of the more convincing arguments in my thinking on the actual

01:15:01.540 health benefits of this, independent of the healthy user benefits of this.

01:15:05.000 You know, the healthy user benefits, so of course, with Yari's work, he's tried to correct for all that

01:15:11.360 physical activity. I mean, he's done everything like looking at lipid, blood cholesterol numbers,

01:15:15.740 LDL number, like just like really, you know, try to try his best to kind of correct for that healthy

01:15:20.520 user bias. And of course there's a dose dependence, which always makes it more convincing, but he's

01:15:25.540 then since published some, some clinical trials where he's looked at, for example, the arterial

01:15:30.980 compliance and of course blood pressures. And that's one of the main things that's affected is blood

01:15:36.140 pressure, but also just like the ability of the arteries to like expand and contract in response

01:15:41.280 to pressure, like that's improved, which is really important. So I think that, you know, obviously the

01:15:46.580 sauna, the heat itself does, does affect, you know, blood flow, plasma volume, all that stuff is,

01:15:51.120 is changed. So, so I think that the cardiovascular aspects and Yari's trying to, to really kind of tease

01:15:57.080 apart more mechanisms because he's a, he's an MD PhD. He's a cardiologist by training, but he's also got

01:16:02.620 a PhD. So he's, he's trying, you know, really hard to, to kind of understand exactly what's going on.

01:16:08.100 But I do think that it's really, it's really convincing with the cardiovascular related

01:16:13.440 mortality specifically. It's very robust. Personally, it's kind of interesting to think

01:16:17.780 about how much of, you know, exercise also elevates your core body temperature. I mean,

01:16:21.420 there's this overlap there, you know, and when I sit in a sauna, my heart rate starts to elevate,

01:16:26.020 like I'm doing cardiovascular. And that's, that's what happens. Like I'm doing cardiovascular

01:16:29.440 exercise, start to sweat. I mean, a lot of the same adaptations that happen with exercise are

01:16:35.520 happening when you're, you're sitting in a, in a hot sauna and even a hot bath, like more recently,

01:16:39.880 another study came out showing hot bath affected, had a positive effect on a variety of cardiovascular

01:16:45.200 related markers as well, which again, but you have to sit in it long enough, you know, to, to experience

01:16:50.240 some of those effects with the elevation of the heart rate and all that stuff. But there's also

01:16:54.960 really profound effect on the immune system. Like part of the benefit of exercise is that it is an

01:17:00.560 acute oxidative stress burst, an acute inflammatory burst, you know, there's then a response to that.

01:17:08.000 And the net response is a positive anti-inflammatory and antioxidant response, but the inflammatory and

01:17:14.000 oxidant response is required to get that. And something similar is happening with, with the sauna as

01:17:19.280 well. Uh, recently there's a study looking, um, by Dr. Charles Rezon. He had made this like fancy

01:17:25.600 contraption where he elevated core body temperature and he had a sham control. So actually people,

01:17:30.400 the sham control also made people a little bit, uh, hot and they thought they were actually getting

01:17:35.520 the treatment, but it had a very strong antidepressant. How do they do that? He explains

01:17:40.880 it on my podcast. So you can go, there's a transcript. You can just kind of strikes me as

01:17:44.800 one of the few things you can't placebo. He, they did some crafty thing, which I not going to try to

01:17:50.320 explain. I will absolutely botch it. They did it. And, and they had a sham control. And in fact,

01:17:55.360 about, he said about 70% of the people that had the sham control thought they had the actual

01:17:59.280 treatment. So it were like, there was definitely a, they were trying to control for the placebo effect.

01:18:04.080 What's interesting is I even, the reason I got into the sauna was the effects that I felt on my mood,

01:18:09.120 uh, when I was in graduate school, like I lived across the street from YMCA. And so I started using

01:18:13.600 the sauna and it was like very black and white. Like I was like, wow, this is amazing. Like I

01:18:19.280 can handle all this. And this was a wet sauna, dry sauna. This was, this is a dry sauna. Do we have

01:18:23.200 a sense of dry sauna versus IR versus all the different? Yeah. So, I mean the infrared saunas

01:18:28.560 are like, they only get to like about 140 degrees Fahrenheit. I mean, it's not very hot. If you look

01:18:34.480 at Yari's work, like their saunas that they're using in Finland, they do, they have a lot of what they

01:18:40.080 call low or something, which is like, they throw the water on and makes the humid, which makes it

01:18:44.960 really hot. Uh, I've been to Finland and try that, try the, their saunas before, but basically the

01:18:49.680 temperature gets to around 170, between 175 and 79 degrees Fahrenheit. And most of the men in these

01:18:56.240 studies are doing about 20 minutes to get the maximum benefits. 11 minutes had some benefits

01:19:00.640 sitting in 11 minutes, but there was a stronger effect. They stayed to 20 minutes. So if you're in

01:19:05.120 an infrared sauna that only gets to 140 degrees Fahrenheit, you probably would have to stay in

01:19:09.680 a much longer to get the same benefit. I see. So the IR doesn't, doesn't get deeper penetration,

01:19:16.480 thereby alleviating the need to stay in at a higher temperature. It doesn't, I mean,

01:19:20.080 sometimes people talk about this. There's a lot of marketing involved in a lot of that stuff.

01:19:23.120 If you strip that out though. If you strip that out, um, the, the infrared saunas do affect

01:19:27.680 the sweating mechanisms, like something to do with the penetration there. You do sweat,

01:19:32.960 which is great because you actually do excrete things like BPA and phthalates and mercury and

01:19:36.880 heavy metals and things like that from sweat. So that, that is, that's what a lot of those mark,

01:19:41.200 those straight up dry sauna to 170 degrees, spend three or four nights a week in that.

01:19:46.640 My favorite. Yeah. That's personally, I, I would much prefer sitting in a, in a regular dry sauna or

01:19:52.560 even a sauna that you can throw water on, but just not an infrared sauna. Um, yeah. So that,

01:19:58.240 so that would be, you know, the, obviously there, the, the fire hazard risk is more when you're

01:20:02.880 having a sauna like that versus just an infrared and, uh, the infrared ones are, I think, cheaper

01:20:07.280 as well. So it's, it's certainly more convenient to, to have an infrared sauna, but personally I,

01:20:12.720 I prefer, for the other, like the barrel saunas are really nice. There's also an effect on the immune

01:20:18.320 system. I was mentioning Charles Reisson, he met, he measured IL-6, which is also, it's part of the

01:20:23.600 Janus cytokine because it's, it does like, it's, it's got like multiple pleiotropic effects

01:20:28.560 and it's, it's, it's acutely released upon exercise as well. And it has, it's very important

01:20:32.880 for, you know, an anti-inflammatory response, releasing myokines and all these things in

01:20:37.520 muscles. So it has, it's important for insulin sensitivity. Uh, a lot of the insulin sensitivity

01:20:41.920 effects, um, exercise has. So, so the sauna does the same thing that the exercise does where there's

01:20:46.640 just a rapid IL-6 release, at least according to Charles Reisson's data. And he said that actually

01:20:52.320 correlates with the antidepressant response. You know, I've never looked at, I wear a

01:20:54.880 continuous glucose monitor a lot, but I've never really paid much attention to it in the sauna.

01:20:58.720 And I don't have a sauna, but I'm going to be this weekend at a friend's place who has a barrel

01:21:02.640 sauna. And so I'll make sure that I document what my glucose level is doing. Um, cause you would

01:21:09.520 think transiently it would go up. Right. Right. But I know that at least there's an one animal study

01:21:14.400 where, um, the heat stress quote unquote animal sauna, it, it actually increases glucose transporters and

01:21:20.320 a type two diabetic model that actually improved insulin sensitivity and lowered blood glucose

01:21:25.040 because the glucose was now being taken up into muscle butter. So I wonder, you know, how much of

01:21:29.920 the, again, it's like you're, you're affecting the IL-6 is, is, is really important for that. And IL-6 is

01:21:35.280 released upon heat stress without, without the exercise. So uncoupling, you know, how much of the

01:21:40.320 benefits from exercise, there's certainly some overlap. And I think that there's also, there are

01:21:45.040 separate benefits that exercise has as well, independent of, of the heat stress component

01:21:50.480 of it. But I certainly think there is a lot of overlap between those two things. And so the sauna

01:21:54.720 becomes very interesting. And there's the whole heat shock protein part where, you know, the heat

01:21:58.560 stress is one of the major ways to, to increase heat shock proteins, which do play an important

01:22:02.640 role in neurodegenerative, preventing neurodegenerative diseases. And I do think it's also really hard to

01:22:08.640 uncouple the, the effects on the vascular system, which is important, right, as well, because it's

01:22:14.320 having such a profound effect on the vascular system, the heat stress. It's hard to uncouple,

01:22:18.400 well, how much of the staving off of dementia and Alzheimer's has to do with that versus heat shock

01:22:22.720 proteins, you know? This is, to me, the biggest challenge with Alzheimer's disease just is, you know,

01:22:27.120 we're talking about it in a pretty nuanced way. But I think, unfortunately, clinically, it's still

01:22:31.600 considered one disease. But, you know, to the best of my understanding, it's really several diseases that

01:22:37.040 all have a very similar common final pathway. You know, for example, like going back some of the

01:22:41.760 ketone data, you know, why, why does ketone enhance memory in some, in some models? Certainly,

01:22:47.280 even going back, oh God, 10 years, you see a lot of anecdote of people in early stage dementia,

01:22:53.680 who, when given even MCT oil, would see transient improvements in cognition. Now, Richard Veach did some

01:23:01.260 of the most elegant work on this. Richard Veach, by the way, is the guy who, along with Kieran Clark,

01:23:05.440 created the ketone ester that T delta S licenses to human. And, you know, they showed, I think,

01:23:11.000 quite convincingly in this animal model that the BHB was basically bypassing pyruvate dehydrogenase.

01:23:17.760 And so, all of a sudden, you know, when you think about the energy deficit that a neuron would

01:23:22.300 experience if you have insulin resistance at PDH. So, if, you know, glucose is going to pyruvate and

01:23:27.620 pyruvate can't get in because PDH is resistant, giving BHB would just bypass it. You go straight into

01:23:34.860 the Krebs cycle, you make all the ATP you want. But that might only be a subset of people that are,

01:23:40.380 you know, suffering, right? There's also going to be the microvascular variant, and then there's

01:23:44.400 going to be the sort of more toxin variant. So, the nice thing about sauna, too, just thinking

01:23:48.520 about it, is if, as again, like I'm becoming more and more convinced of this, it's actually like a

01:23:53.600 really pleasant thing that you can do to potentially live longer and certainly live better. Because many

01:23:58.940 of the things we talk about, I mean, let's call a spade a spade. Fasting is not fun. I wish I could

01:24:03.580 tell you that, you know, not eating is fun, but like I just love eating. So, anytime I'm not eating,

01:24:08.240 I'm sort of like, there's a discipline that's required to do it. But I don't know,

01:24:12.280 sitting in the sauna for 20 minutes before you go to bed is pretty enjoyable. Of course,

01:24:16.560 the problem is it's not accessible to everyone. No, it's not enjoyable at a certain point.

01:24:20.240 You don't like, yeah, yeah, yeah. At a certain point, it's enjoyable until you're like,

01:24:24.040 holy shit, it's hot. I want to get out. But it's knowing that like you get to get out

01:24:28.300 and then that jump into the pool or the whatever it is, is pretty nice.

01:24:33.300 The discomfort you experience from like the heat stress where you're like really hot is actually,

01:24:38.140 I think, key for the positive benefits. At least for me, it was on my mood where I was just like,

01:24:43.640 felt so good.

01:24:44.440 So, what about the reciprocal of that cold? So, I used to do a lot of cold therapy,

01:24:49.040 but all for DOMS, delayed onset muscle soreness. So, that was my main interest was, you know,

01:24:54.020 back in the old days, I would go out and buy 100 pounds of ice or 50 pounds of ice, I guess,

01:24:58.900 throw it in the bathtub, cold water, and I would immerse myself. And that was unbearable. But that

01:25:04.540 really sped up my recovery from difficult workouts. It's a pain in the ass. So, I started doing cryo

01:25:11.440 and the data, I was pretty convinced that whole body cryo, three minutes of whole body cryo at the

01:25:16.980 right temperature was going to produce a roughly comparable effect in DOMS, but had a fraction of

01:25:22.080 the time and 10x the cost. But I've also had people talk to me about, and again, I've never really

01:25:27.200 looked into this, but I'm guessing you have ice cold showers for, you know, increasing

01:25:32.020 norepinephrine levels, things like that, mood altering. Have you looked into this?

01:25:36.740 I've looked into the literature. Yeah, that's something that I did notice from doing cold

01:25:40.940 showers. And sometimes I'll do them before like a big talk or something, because it does help me

01:25:46.740 focus and it helps with my anxiety. Kind of very similar.

01:25:49.560 So, yeah, I was going to say, so how do we square the two completely different things, right? You would,

01:25:53.420 you'd sit in the sauna to help with anxiety and then you could have the cold shower.

01:25:57.680 Well, I didn't start getting into the cold shower until probably a couple of years ago. The sauna I

01:26:03.180 started doing.

01:26:04.360 In grad school.

01:26:05.060 Yeah, a long time, probably about 2008. So, a long time ago. So, they're completely

01:26:10.960 uncoupled in my experience.

01:26:13.420 So, do you think the sauna is working more through GH and other?

01:26:18.640 I think the sauna has a very profound, first it affects the immune system and that inflammation

01:26:23.420 has a major effect on brain. And I think that that's worked from Charles Raison is pretty

01:26:28.140 clear. It's definitely, there's definitely an antidepressant effect that seems to correlate

01:26:32.380 with biomarkers of the immune system. So, so the more potent the IL-6 response, the more

01:26:37.740 potent the antidepressant response. In addition to that, there's a very strong effect on beta

01:26:42.640 endorphins. Beta endorphins are dumped. And also this other system called dynorphin, which

01:26:47.880 is, you know, the opposite.

01:26:49.960 Yeah. And what's interesting is that when you activate dynorphin through the kappa opioid

01:26:55.760 pathway instead of mu opioid, you feel uncomfortable. And it's the part where I was talking about

01:27:00.440 where you're like, I'm hot. I want to get out. It's the part when you're exercising where you're

01:27:03.280 like, oh, this, you know, it's that uncomfortable feeling. Well, that's, you're making dynorphin

01:27:07.560 partly because it cools your body down. So, it's kind of a response to elevating your body temperature.

01:27:11.320 I'm convinced, by the way, there are a subset of athletes that don't produce that at the same

01:27:15.080 level. I mean, seriously, like there are people, I think, who...

01:27:19.160 There are, yeah.

01:27:19.800 Because we talk about like, why can that guy tolerate so much more pain than that guy?

01:27:23.080 Yeah.

01:27:23.560 And at some point, it's possible that they're actually experiencing less pain.

01:27:27.560 There definitely are variants in the kappa opioid receptor pathway and all that.

01:27:32.120 So, yeah.

01:27:33.000 I'm surprised that hasn't become a performance enhancing drug, which is, you know, blocking

01:27:37.240 that receptor, the pain receptor in the brain, which is a, you know, a very interesting thought.

01:27:42.840 But now, so then on the cold front, what do you think is mediating that? Neurotransmitters?

01:27:47.880 So, basically on the cold front, the norepinephrine, that's been shown. So,

01:27:52.280 animal studies have shown where norepinephrine's released in the locus corallius reason of the

01:27:57.080 brain after cold exposure and a variety of cold water exposure cryotherapy. If you're doing a cold

01:28:03.560 water 50 degree, you know, if it's like 50 degrees Fahrenheit, you got to stay in a little

01:28:07.000 longer than like a couple of minutes in a really cold cryotherapy chamber.

01:28:10.680 But in humans, plasma norepinephrine's been looked at, which does seem to sort of correlate

01:28:15.720 with the release in the brain.

01:28:16.840 It's so hard, though, to look at the plasma to understand that stuff.

01:28:20.040 I know. I know. It is. It is. So, I do think that some of the mood is affected by the norepinephrine

01:28:26.200 as well.

01:28:26.680 Have you experimented with the stacking, which is go do the sauna for 20 minutes, then go do the

01:28:31.880 ice shower for whatever, 10 minutes, and do you get an additive effect in terms of...

01:28:35.640 I feel really good. Yeah, I feel really good. And that's when I did notice that my sleep was really

01:28:40.440 profoundly affected. What's interesting is there's some studies showing that heat stress,

01:28:44.360 at least in piglets, does affect... Actually, it seems to elongate the REM sleep stage,

01:28:49.640 which I don't know how, you know, what all that means. But so, there's certainly an effect of heat

01:28:55.160 on sleep. And then, of course, cold is, you know, lowering your body. Body temperature is

01:28:59.720 important for sleep onset. But I don't know. There's something about the combination of the

01:29:03.480 two. Absolutely. Like, I sleep amazing after doing the combination of both. I think cold is

01:29:10.520 really interesting for the effects on mitochondrial biogenesis. I mean, exercise is probably one of

01:29:14.520 the best ways to increase mitochondrial biogenesis. But cold exposure has been shown in human studies,

01:29:19.480 both in adipose tissue and in muscle tissue, to boost biomarkers of mitochondrial biogenesis.

01:29:27.320 Well, it depends on what tissue we're looking at. So, like, you know, PGC1-alpha would probably be

01:29:32.360 one of the best, I would say, for muscle tissue. In adipose tissue, perhaps the same. I would say PGC1-alpha

01:29:41.320 is probably one of the best. It's another downstream one. I can't... For some reason,

01:29:44.680 I'm drawing a blank. Yeah. So, that's interesting to me, the effect on mitochondrial biogenesis. But

01:29:50.760 personally, I like the exercise, you know, for my mitochondrial biogenesis. I'm not like doing cold

01:29:57.400 exposure all the time. It's not like something that I do often. Like I said, I'll do it once in

01:30:01.800 a while before a big event I have to talk at or something, just because it does seem to help me

01:30:05.560 with my mood and my focus. Have you ever swum in water that's so cold that you actually feel like

01:30:11.560 you're on fire? Yeah, I have been. Yeah. Uh-huh. That to me is amazing. I assume it's due to the

01:30:17.240 vasoconstriction. I don't know. But it's... The coldest water I ever swam in was in the Colorado

01:30:23.560 River. And it was 42 degrees, which is... I mean, that's unusually cold. And the only reason I think

01:30:29.640 I was able to swim in it was it was May. And so, the sun was... It was about 90 degrees Fahrenheit

01:30:35.240 was the air temperature. So, you could... Like, I wouldn't be able to swim in 42 degree water

01:30:39.640 on a cloudy day, for example, or a cold day. But I couldn't believe the sensation of feeling like I

01:30:45.960 had jumped into boiling oil. It was incredible, which is very different from my normal exposure to

01:30:51.960 cold. I used to swim a lot in the ocean. And, you know, if you do a three-hour swim at 50 degrees

01:30:57.280 Fahrenheit or 52, 53, you get a little bit of that effect. But, you know, more or less, you can still...

01:31:03.400 You still know you're in cold water. But this particular time, I remember... And I probably spent

01:31:07.580 15 to 20 minutes in this 42 degree temp. The entire time, I felt like I was burning.

01:31:14.820 Wow. And again, I had no idea why. I guess it's... My assumption was that's such profound

01:31:20.040 vasoconstriction in the periphery that... You know, the one thing that I wanted to mention

01:31:23.820 when you brought this up for recovery is because there is some evidence that, for whatever reason,

01:31:29.360 strength training, when you do cold exposure, like, immediately after strength training,

01:31:34.820 if you do it within, let's say, before, like, sometimes within an hour before...

01:31:40.360 Before.

01:31:40.920 Sorry, after strength training. It seems to blunt some of the hypertrophy effects.

01:31:45.900 Yes. Yes. And actually, it's interesting you say that. That's the exact reason I would never take,

01:31:51.420 like, ibuprofen or any anti-inflammatory agent. I would limit it even that day. I wouldn't take

01:31:57.140 any of those agents because you're impairing that rebuild.

01:32:01.320 Yeah. Yeah. So that's also interesting that the timing of it seems to be... You know, again,

01:32:05.920 there's... It's been shown that about an hour after exercise is when the anti-inflammatory

01:32:11.360 response starts to peak. And so it's like, if you can... You basically... If you're within that

01:32:16.720 hour window when the inflammation is happening to create that anti-inflammatory response,

01:32:20.860 you don't want to dampen that. At least that's... It seems to be what I think and literature seems

01:32:27.160 to suggest. And there's, of course, mechanisms where it's like specific macrophages and muscle tissue

01:32:32.180 are really important for activating all these things that, you know, eventually result in satellite

01:32:36.660 cell proliferation, you know, and of course, IGF-1's in there somewhere. So again, you know,

01:32:41.180 the immune system activation is important for a lot of the benefits of exercise, including

01:32:46.800 muscle hypertrophy. So... So there's one more topic I just want to get to, if we can spare a bit more

01:32:52.400 time, which is NAD. The precursor is the whole shtick. You've spent a lot of time thinking about

01:32:57.800 this. What is your current thinking on... Does having more NAD to NADH matter? The thing about the NAD...

01:33:06.020 I guess I should provide context for people. Why am I asking this question, right? So there's lots of

01:33:09.720 supplements out there now that are, you know, either giving NR or NAD. And the claim is that

01:33:16.200 these things can enhance longevity. You could live longer and that also you live better. You have

01:33:21.580 more energy, all of these other things. And so in the mitochondria, you have complex one,

01:33:26.660 which converts NADH to NAD. And the idea is we do know that as you age, that ratio of NAD to NADH goes

01:33:33.740 down. And so part of the thinking is, well, and this is outside of the sirtuin pathway, but this

01:33:38.760 is upstream of that. But if you give more of either the precursor NAD, you're basically fixing

01:33:43.900 something that is getting worse as you age. Yeah. So that, I mean, the question is, why does it go

01:33:49.980 down? And that's, I think there's multiple reasons for that. At least that's been shown in literature.

01:33:54.000 NAD is a very important cofactor for mitochondria. I mean, obviously mitochondria are making NADH and

01:34:00.960 that hydrogen, the proton is used and electrons are used to basically generate energy through the

01:34:05.780 electron transport chain. And it's also generating the mitochondrial membrane potential by kicking out

01:34:10.500 the proton. So that's really important for mitochondrial function, respiratory function,

01:34:14.980 energy production, which is like the key of everything, right? But in addition to that,

01:34:18.980 you have, as you mentioned, sirtuins, which are histone deacetylases, which have a whole host of

01:34:24.020 functions that they're doing, regulating tons and tons of different pathways. They're also seem to be

01:34:29.180 very important for health span. And then in addition to that, there's very important DNA

01:34:33.580 repair enzyme PARP that literally syncs up NAD. I mean, it's like an NAD sync. I mean, it, you know,

01:34:40.900 so, you know, we're constantly having damage. Where does it reside, that enzyme?

01:34:46.520 Where in the cell? Yeah. Is it nuclear? It must be, right? Yeah. And the reason I ask is,

01:34:51.940 how do we know that these supplements that we take orally are going to actually reach their

01:34:57.280 bioavailability in the place we want them? Right. Okay. But that said, we'll come back to

01:35:01.820 that after. I think it's in the nucleus. I mean, as far as I remember, otherwise it shuttles there,

01:35:07.620 but I think it is. So it's very important for repairing, you know, DNA damage. And so that's

01:35:13.620 one of the major syncs and actually inflammation, all these things are kind of upstream of PARP

01:35:18.540 activation. So the more that's happening, the more PARPs being activated. So you kind of have,

01:35:23.420 you have NAD going there. So one argument, just to make sure I understand what you're saying is,

01:35:27.580 look, if you're getting older, you're going to have more DNA damage. That's just stochastic.

01:35:32.420 And if your little guy that repairs it requires NAD as fuel, that would explain one reason,

01:35:39.200 potentially why NAD would decline as we age. Yeah. And it's certainly a sync for it. Yeah.

01:35:44.440 And the other, so the other thing is, well, if your immune system's constantly, you know,

01:35:48.140 activated too, if the more inflammation you have, all that energy is required. So NAD is being

01:35:53.400 consumed more for that as well. So that's sort of another sync. Basically NAD levels decline with

01:35:58.540 age and it's probably because it's just getting used up more or the other, the alternative is,

01:36:03.900 you know, is there something else going on in terms of like this whole salvage pathway? There's

01:36:07.700 another pathway that you can do to regenerate NAD and if that's kind of going wrong. And I think

01:36:12.720 there's some increasing evidence for that as well. Would that make metformin a bad idea from this

01:36:17.400 standpoint? Because metformin inhibits complex one. So metformin lowers the ratio of NAD to NADH.

01:36:23.060 Does it? Has that been shown? So you're saying it should lower it?

01:36:26.940 It should lower it. Now, of course, that's counterintuitive because we know it activates

01:36:31.100 AMPK. So I probably have to sit down and think about this, but we do know metformin inhibits

01:36:35.980 complex one and we know that complex one turns NADH to NAD, which makes me wonder, does,

01:36:43.260 is it possible that metformin would impair DNA repair through that mechanism by reducing substrate?

01:36:49.620 I have no idea.

01:36:51.940 Well, I'm going to write that down. That's something we're going to have to look into.

01:36:54.920 Because I wasn't aware of the NAD. I didn't understand that link, but yeah.

01:36:59.320 Yeah. I think that's a major one. I literally think that's a major sink for it. I think that

01:37:03.360 the PARP is, I think it's just like going there.

01:37:06.040 Yeah. So the animal evidence, you mentioned some of the supplements, you know, precursors

01:37:09.620 that can form NAD. I think that the animal evidence suggests that it can, at least in rodents,

01:37:15.580 improve healthspan, particularly in models with like, that are heavily dependent on mitochondria,

01:37:21.540 like muscle myopathy models or something like that. I think, I think that was one. And also

01:37:26.300 the brain. So I think those are the two, the two organs I've seen like major positive effects

01:37:30.860 with, with NAD supplementation. And then there's some, of course, pilot clinical studies showing

01:37:36.180 that yes, you can take, for example, nicotinamide riboside and it does seem to increase NAD levels

01:37:42.040 in plasma in a dose dependent manner. Now, again, you raised the question, is it getting

01:37:46.360 in the cell? Is it getting in the, now we do know in animal studies, I think that has been shown

01:37:51.660 because it's affecting the mitochondria, like I said, those animal models of myopathy and stuff

01:37:56.780 and mitochondrial function was improved and all that stuff. So, so in animal models, it obviously

01:38:01.300 is affecting mitochondrial function. So it must be getting to the right place.

01:38:04.840 I don't know why I have found myself kind of skeptical of this.

01:38:07.340 I think it's good to start with skepticism. I mean, I think that NAD levels are, you can,

01:38:12.860 you can increase them with fasting. So when you fast, you know, as you mentioned, you convert

01:38:16.960 NAD into NADH in the presence of, of energy. Cause, cause that's basically what, when you

01:38:22.580 have a substrate like glucose or a fatty acid, that's when you produce NADH or FADH2. So in

01:38:29.280 the absence of those substrates, then you start to make your NAD starts to build up. So back

01:38:33.440 to your metformin question, you said, I know who to ask. I definitely know. I'm going to

01:38:38.840 ask Nav Chandel. He will know the answer to this question.

01:38:41.800 I follow a lot of his work when I was in grad, him, Ralph D. Bardini's, I did, cause I was

01:38:46.420 doing a lot of cancer metabolism, cancer metabolism, mitochondrial function and stuff. So I followed

01:38:51.300 a lot of his work.

01:38:51.840 Do you have Nav's book, Navigating Metabolism?

01:38:54.860 No, I don't. No, I just used to read his papers back when I was a graduate school.

01:38:59.140 Yeah. So Nav and David Sabatini were in town a couple of weeks ago and I was leaving town

01:39:04.480 the day they were coming into town. So we hung out for three hours near the airport and I was

01:39:09.260 just reminded of how much fun it is to talk about mitochondria.

01:39:13.000 Yeah, for sure.

01:39:16.040 What is the most interesting question you feel you don't yet know the answer to,

01:39:20.040 but you feel is knowable that you're sort of actively putting in lots of your clock cycles

01:39:26.160 on thinking about? I would really like to know if, for example, someone who is like myself,

01:39:32.640 who I don't have a lot of body fat, I'm active, I eat a pretty healthy diet, you know, I don't smoke,

01:39:38.580 I don't have any of those bad habits. If I were to do a prolonged fast a couple of days a year,

01:39:43.580 would that truly have an effect on increasing my stem cell production, potentially, you know,

01:39:49.500 getting rid of any dysfunctional immune cells, dysfunctional liver cells, dysfunctional,

01:39:54.260 whatever, you know, muscle cells and repopulating them with like healthy new cells, like basically

01:39:58.720 this rejuvenation, like, could I get this like burst of rejuvenation a couple times a year? And

01:40:03.880 would that have, in turn, have an effect on delaying the onset of age-related diseases,

01:40:09.600 improving my health span, you know, keeping my stem cells less damaged? That would be very

01:40:14.920 interesting to me because to me, that's something that's very doable for myself. I mean, the experiment

01:40:20.000 to figure that out is different because it's, you know, in humans. And so that's going to be

01:40:23.740 really hard. You have to figure out like if you can even look at certain biomarkers to know that.

01:40:28.460 But I feel like that would be something that's so easy for someone to do. It's interested in

01:40:33.100 longevity. And you think it would be sort of once or twice a year doing like a five-day water only

01:40:38.160 mineral? Well, the question is how often. Yeah, how often would you need to do it? And how long of

01:40:42.260 it? Like, so, you know, we have a lot of the studies coming out of animal data, which I mean,

01:40:46.760 these rodents, they lose 20% of their body weight after a 48-hour water fast. Yeah, I find it hard to

01:40:52.320 infer anything from rodents when it comes to fasting because of this exact reason. It's like

01:40:57.860 I, even the Jay Mitchell stuff I talked about earlier. I mean, I think it's an interesting

01:41:01.260 proof of concept, but I don't actually know how you would apply that to humans. Right. So the

01:41:05.980 question is, it's like, okay, so if you have a 48-hour fast in a rodent, does that mean that a

01:41:10.460 human has to fast? Exactly. Yeah. So I guess I'll expand my sort of answer that question, like maybe

01:41:16.740 do a prolonged water fast, like a time. Right. What's the frequency? What's the duration to get

01:41:22.420 the maximum benefit? Yeah. And I'm specifically interested in this shrinking of the organs and

01:41:27.160 then regrowing like this potential robust activation of stem cells, clearing away, you know, we're not

01:41:32.980 just talking about autophagy. We're not just talking about clearing away damaged mitochondria, pieces of

01:41:37.380 DNA, protein, which is all really great. You are getting that, but well, in theory, in humans, in addition

01:41:43.420 to that, I mean, I'm talking about clearing away the damage to the whole cell, like just getting

01:41:46.960 rid of it and replacing it with a brand new, young, healthy cell. Like that's what I'm interested

01:41:52.220 in. You know, I would, I would love to, you know, even just the hope that that's possible, you know,

01:41:57.340 based off of some of the pilot studies that Vulture has done in humans and certainly the,

01:42:01.680 the animal evidence, like I'm convinced I'm going to at least try because it seemed, it seems very

01:42:06.660 possible. I know, I know that he is trying to find the best biomarkers to look at for,

01:42:12.700 you know, stem cell activation. It's not quite as straightforward. Can't just, you know,

01:42:17.800 harvest a bunch of tissues and look at things. But I certainly have gotten some anecdotes from

01:42:22.400 people that have had autoimmune like diseases and things said like fasting is like completely

01:42:26.860 reversed some of it, like, like eczema or something like that, you know, where it's, you know, where

01:42:31.860 it's anecdotal. But certainly when you start to have enough people saying the same thing, it's like,

01:42:36.780 wow, that's interesting that you've heard that five, five or six times now. Yeah. I think that

01:42:41.360 would, that's a good one. I guess I think of a very similar question with rapamycin.

01:42:46.960 Rapamycin. Yeah. What, what dose and what frequency to produce the best longevity phenotype?

01:42:52.640 You know, the interesting thing with the rapamycin is the effect on the senescent cells.

01:42:56.940 Like, like that's so interesting to me. I didn't know really about that until I listened to your

01:43:01.740 podcast with Judith. Yeah. She's amazing. She's really, she's really, she's really great and very

01:43:07.640 knowledgeable in the whole senescent field. Yeah. I had no, I had no idea either. The life

01:43:12.480 expanding effect is, is that males only or was that both males? No, male and female. Is it? And

01:43:17.180 it's across, I mean, it's, it's everything from yeast to worms, to flies, to mammals. I mean,

01:43:21.960 it's the only drug that's uniformly extended life across a billion years of evolution. I mean,

01:43:26.960 and there's really interesting work. I mean, I think Matt Caberlin. You're talking maximum lifespan or

01:43:30.960 are we talking median? Actually in the mice, it was, I have to go back and look. I have to go back

01:43:36.740 and look. It's most of the time it's median, but yeah. Yeah. And what was interesting in the mice

01:43:40.260 is they started late in life. They started at 600 days, which is, you know, that's about 60 years

01:43:45.820 old. Yeah. That's, that's like starting as with a 60 year old. Wow. That was really late in life for

01:43:50.400 the, for the mice. Yeah. Yeah. It was. Wow. Which made it that much more impressive. That is,

01:43:54.020 that is very interesting. So Caberlin's work, do you know Matt up at the University of Washington?

01:43:58.760 No. He, um, is giving rapamycin to dogs, but these are pets, right? So these are not laboratory

01:44:05.520 animals, which is what makes it really interesting is you've got animals that live in our environment

01:44:10.360 that are, and, and, and dogs sort of have a very predictable demise, right? They're either going to

01:44:15.080 be, you know, die in an accident, be euthanized, have cardiomyopathy or die of cancer. That's basically

01:44:20.140 how dogs die. And the cardiomyopathy that they get is not an atherosclerotic cardiomyopathy.

01:44:27.160 They get a cardiomyopathy where the muscles are actually just getting weaker and weaker and their

01:44:30.820 ejection fraction is going down. And in studies as short as 12 weeks, they're seeing a 10% increase

01:44:38.620 in ejection fraction of these dogs. And so the question is how much of that is working through

01:44:44.840 senescence, just selectively knocking out senescent cells and letting myocytes regenerate.

01:44:50.880 Yeah. The study out of the myoclinic where they, they did some drug that selectively targeted

01:44:55.620 senescent cells and it led to a 20% increase in median lifespan. Sort of an interesting proof

01:45:01.660 of principle how just, well, that was an, I think an accelerated aging model. So they had

01:45:05.780 accumulated more senescent cells. Obviously they had to do something like that, but, um,

01:45:10.340 But it all comes back to this idea of specificity and selection. You know, everything we've talked

01:45:14.420 about, if you really stop to think about it comes down to how could you target this tissue

01:45:19.140 and leave that tissue alone? Or how could you target this cell and leave that cell alone?

01:45:23.100 And, uh, in many ways I think that's kind of got to be the next frontier here is, you know,

01:45:30.220 even if you think about something as crude as chemotherapy, it is not hard to kill a cancer

01:45:34.660 cell with a chemical that's trivial. It's hard to kill a cancer cell and not a normal cell.

01:45:39.780 And that's why chemotherapy obviously targets rapidly dividing cells and it's still very crude.

01:45:43.960 But the stuff we're talking about is like taking that to the next level, which is how could you

01:45:48.840 get this enzyme to work more efficiently, but in this subset of cell, you know, just in the muscle,

01:45:54.220 but not in the fat or not in the liver. And that's again, where the fasting is just so impressive to

01:45:58.620 me. The fact that, you know, all the normal cells is you're enhancing all these stress response

01:46:02.660 pathways. So the chemo drug becomes that most more less, almost less, you know, efficacious. Like it's

01:46:08.460 almost like a lower dose because it's like got these robust anti-apoptotic and anti-stress response

01:46:14.440 genes that are dealing with that sort of stress. And so it's like, it can take the toxic in soul

01:46:18.380 because of that upregulation that fasting is doing and the cancer cells just can't. So I'm,

01:46:23.820 I'm so glad that that work's being done. I hope that there is more funding that goes in that area.

01:46:28.880 I think that it is a really important area of research. Again, like I said, for the,

01:46:33.040 you know, this is, and this is all from, from Walter's work and some of, some of his colleagues.

01:46:36.680 So I'm just kind of like the fangirl, you know, but I'm certainly, I'm happy someone's doing that

01:46:41.040 research and I would love to see that be used as a standard of care someday for sure.

01:46:45.300 So Rhonda, many of the people listening to this will know everything about where to find you,

01:46:48.740 but for the, let's assume there's someone here who this is their first time meeting you,

01:46:52.460 where can they learn more about you and how can they interact with you?

01:46:55.700 I have a podcast. It's called found my fitness. You can find it on iTunes and on my,

01:47:00.260 my website foundmyfitness.com all the episode pages there with links to the video,

01:47:05.260 which, and your videos are remarkable because you put so much work into actually like a podcast

01:47:12.060 like this. Unfortunately, we're too lazy. Like I'm not going to actually do much except create

01:47:16.720 show notes, but on yours, it's like, it's like a Khan Academy, right? It's like everything is being

01:47:21.400 explained in the video as well. Like in text. Yeah. It's explaining the figures, definitions and all

01:47:27.200 that are there in the video. And also on, I think we're, we're having now definitions and stuff on the

01:47:31.380 website. So people can, the, the goal is to definitely showcase, you know, a lot of the,

01:47:36.140 the researchers and scientists that I interview and also to educate people as well. So found my

01:47:40.740 fitness, I'm on iTunes and my website and social media. You can find me on.

01:47:44.680 And what do you like most? Is Twitter the easiest place for people to get to you?

01:47:47.740 Twitter, Facebook, Instagram, I'm on all of them, but yeah.

01:47:50.280 And what's your handle?

01:47:51.320 Found my fitness.

01:47:52.040 That's all found my fitness.

01:47:52.660 Found my fitness. Yeah.

01:47:53.640 So you were ahead of me on this. Like you, you immediately recognize the value of exercise.

01:47:57.360 I'm, I'm a late comer to this. I mostly from, from personal experience, I realized I was like,

01:48:03.400 this is like, this is great for my brain. And, uh, from there I just kind of dove into it and was

01:48:07.680 convinced. Yeah, for sure. Rhonda, I can't thank you enough. This has been awesome. I don't suspect

01:48:12.180 it's the last time we'll talk about this stuff. So, uh, until next time. Awesome.

01:48:18.400 You can find all of this information and more at peteratiamd.com forward slash podcast.

01:48:23.500 There you'll find the show notes, readings, and links related to this episode.

01:48:27.860 You can also find my blog and the nerd safari at peteratiamd.com. What's a nerd safari you ask?

01:48:33.900 Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to

01:48:38.140 sign up for my subjectively non-lame once a week email, where I'll update you on what I've been up to,

01:48:42.940 the most interesting papers I've read, and all things related to longevity, science, performance,

01:48:48.080 sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook,

01:48:52.060 all with the ID, peteratiamd.com. But usually Twitter is the best way to reach me to share

01:48:57.060 your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational

01:49:02.120 purposes only and does not constitute the practice of medicine, nursing, or other professional

01:49:06.680 healthcare services, including the giving of medical advice. And note, no doctor-patient

01:49:11.900 relationship is formed. The use of this information and the materials linked to the podcast is at the

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01:49:26.980 medical advice for any medical condition they have, and should seek the assistance of their

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01:49:36.740 conflicts of interest very seriously. For all of my disclosures, the companies I invest in and

01:49:41.580 or advise, please visit peteratiamd.com forward slash about.

The Peter Attia Drive - July 02, 2018

#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

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