Rethinking Protein Needs for Muscle and Longevity, and the Benefits of Creatine & Sauna Use

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Attia.

>> Rhonda, so great to see you. And I didn't realize until a few minutes ago that the last time we spoke it was virtual. >> Yeah, good to see you. We go back a long way. >> You're still in the same our same former neighborhood in San Diego. >> I know. And I'm thinking that, you know, you found the same feeling here in Austin. >> Yeah, we did. Um, all right. Well, there's a lot we want to chat about today, and I'm a little hesitant to say this, but I do feel like, reluctantly, we need to have one more discussion about a particular macronutrient that seems to get a lot of attention lately.

And I don't necessarily want to talk about this because I think it's especially interesting, or even because there's some new study that we need to shed light on, but it does seem to remain somewhat surrounded in some controversy. Which I will refrain from publicly speculating on why said controversy exists, although privately I'm very happy to speculate on all the reasons for it.

So with that said, let's talk about protein.

>> Let's do it. I do think it's an important topic. You know, you and I have probably talked to all the world's experts on protein. And you know, we were chatting a moment ago about this recommended daily allowance for protein, the so-called RDA.

And really what it should be called is the minimal daily allowance. In fact, I would say recommended almost sounds like optimal in a way—I think people confuse that with the optimal amount of protein, right? So it's kind of tricky.

>> Um, and I think that's an important place to start because of that reason, where this amount, which is 0.8 grams per kilogram body weight per day, is the RDA for protein, right? And I know that you've probably had countless experts on talking about this; I've had experts on talking about this, Stu Phillips being one.

There are so many different publications that people can start off by reading, one of them being Stu Phillips' perspective on Protein requirements and optimal intakes in aging: Are we ready to recommend more than the recommended daily allowance? And there are several of these out there. Okay, this is just one.

And essentially, if you have the time and the willingness to go into the scientific literature and actually read something for yourself—or listen to The Drive or listen to my podcast and the actual experts talking about it—what you will hear, or what you will learn, is that a lot of the studies that were done to determine this RDA were flawed. They were called nitrogen balance studies, and for many reasons, they're flawed.

I don't want to get into all the technical reasons, but for one, you know, what they are doing is measuring the amount of nitrogen that is excreted in urine after you are metabolizing protein, right? And some of the flaws that are the most important here are that:

• Different types of foods that have protein in them have different nitrogen-to-protein ratios.
• They're collecting urine, in which case the issue is that it's incomplete collection—meanin, when you pee in one of those cups, you don't get all the urine.
• We lose nitrogen through other means that is not just urine.

>> Yes, exactly. We lose the nitrogen through other means, and so essentially the signal-to-noise ratio is pretty low. And ultimately, what countless experts have now agreed upon is that the protein for the RDA has been underestimated because of those reasons.

And there have been new studies that have been done. These have been more stable isotope studies. The major isotope that's used is L-[1-$^{13}$C]phenylalanine, in which case these studies take a small cohort of people, give them a known amount of protein with that isotope tracer, and then that tracer is oxidized when it's metabolized, and that's measured through breath—the oxidation of phenylalanine, right?

And so now you're getting a quantification that's much more accurate in terms of your protein steady state and turnover, right? And so the whole point here is that you're trying to figure out the minimal amount of protein you need to take in every day to make sure that you're not in a negative protein balance.

Why is that important? Well, that's important because we don't store amino acids, right?

We don't store amino acids like we store fatty acids as triglycerides, or we store glucose as glycogen, right? The major source of our amino acid storage tank, so to speak, is our muscle, skeletal muscle tissue.

And you don't want to be pulling from that skeletal muscle tissue to get amino acids every day. Why do we need amino acids every day? Because everything in our body requires proteins. Proteins are doing all the work in our body, and proteins are made up of amino acids. And so we have to be giving ourselves a daily intake of amino acids to make sure we're able to do all those functions, right?

I just want to state that again because I do think there's a very important and fundamental point here that is glossed over when we talk about it, because we take it for granted. If we studied biochemistry—and anybody who's studied biochemistry will know this—we can store fat in unlimited quantities, right? So if you deprive a person of fat calories for a period of time, they have a long reservoir that they can dig into (not indefinitely, but they can).

We can store carbohydrates. Now, we can't store them quite as much because we only have so much glycogen we can store in the muscle and in the liver. But when we break down fat, we keep making the substrate to actually make glucose. So, we get into a nice little rhythm.

But to your point, the only place that an amino acid sits in residence in our body is in the muscle. Therefore, if we even get near the edge where we are not getting sufficient intake of amino acids, we don't have a buffer. We don't have a rainy day fund that we can dip into; we immediately start to catabolize or break down muscle.

Now, I don't think we have to make the case that that's a bad idea. But for the sake of completeness, we should state there is not really a single scenario I can think of that is clinically relevant where it would be desirable to give up muscle mass.

You know, maybe if you're Mr. Olympia, you can sacrifice muscle mass. But for you and me, and I think everybody listening to us, giving up muscle mass because we are falling short on our protein intake would be a strategic error and an unforced error.

>> Exactly. I mean, for short-term and long-term health. So I mean I think that's pretty clear, and that's where this RDA not being enough is a very important point.

Because if we look at the actual—so let me go back to these isotope tracer studies. Those multiple studies, okay—multiple studies, as you know, have shown that the minimum...

>> And we'll link to these in the show notes, by the way, just so that people can go and actually look at the papers as opposed to reading about it on social media. >> Sounds good. Um, multiple of these papers have shown that, you know, really going up to more like 1.2 grams per...

kilogram body weight per day is what is needed to prevent people, us adults, from being in this negative protein balance. >> That's quite a bit more than the 0.8 grams, right? It's 50% more. So like most of the studies done, isotope tracer studies, are between 30 to 50% more. So that's really important because, um, if we look at the actual protein intakes of adults, you know, these are nutritional surveys that are done. Of course, they're all flawed. We can talk about—I mean, we all know the flaws of questionnaires—but let's just talk about what we think people are actually taking in. Adults are mostly taking in—all adults are taking in about 0.9 grams per kilogram body weight per day of protein. So pretty close to what that RDA is, not what it should be, right? Older adults, um, if we look at the gender, male versus female, males are taking in about 0.9 grams per kilogram body weight, females are taking in 0.8. So they're really just hitting that what we call RDA, which now we have established is not enough. The RDA is not enough to basically be in a net protein balance. So, that's really important. And that's essentially telling us that most adults are walking around without being in a good, you know, steady-state protein balance, right? So they're— >> So here's an interesting question, Rhonda. We know the rates at which muscle mass, skeletal mass, are declining by decade in an aging population. Is there any way we can estimate—I'm guessing the answer is no, but on the off chance you would know—can we estimate what percent of that decay is simply being driven by insufficient amino acid consumption versus other factors, right? Other factors would be anabolic resistance associated with aging. Other factors would be anabolic resistance associated with sedentary behavior. Other factors would be lack of sufficient resistance training. There are many factors that explain clearly the fact that as a person goes from 50 to 60 to 70, on average they're losing muscle mass. But it would be interesting to consider how much of that is explained by the fact that they are also barely skirting the minimum amount of nitrogen that they need, and in many cases falling below it. >> Right. So to answer your question, I don't know that there's a direct way to do that, but I do know that there are studies that have shown that when older adults—older adults that are really more susceptible to the things that you were saying, like anabolic resistance, where your muscle tissue is not as sensitive to amino acids, mostly because of physical inactivity which increases with age— when older adults take in 1.2 grams per kilogram body weight per day of protein, it nearly eliminates some of the age-related muscle loss that happens. So I think that is some evidence to sort of support what you were saying, in that if you just increase your protein intake >> to the minimum, yeah, by 50% to this minimum of what the RDA should be: 1.2 grams per kilogram body weight per day. I think that's pretty much what all the experts agree on, that it's time to change that RDA to that number, right? The minimal amount that you need per day. If older adults just do that, they're actually preventing a lot of the age-related loss in muscle that occurs. And we also know that older women, if they take in that amount of 1.2 grams per kilogram body weight per day, they're 30% less likely to have frailty in old age, which is also very important, right? So, I think that's pretty good evidence that it's clear that just increasing your protein intake by 50% is really important for aging, right, for our muscle health, and also for getting us out of that net negative state that we're in. So, I mean— >> So step one is we should move the floor

from 0.8 to 1.2. >> Yes. I think the floor being the minimal amount of protein that we need to take in per day. This is not optimal—we're going to get into optimal, right? This is just like the new RDA, right? And as you mentioned, you kind of hit on this anabolic resistance, and I think that's also a really, really important point because it compounds with the fact that we're already not getting enough protein to be in a positive state of protein balance. And then you compound that with anabolic resistance, right? Now, anabolic resistance is when your muscle tissue becomes less sensitive to amino acids, and so muscle protein synthesis isn't occurring as much as it does when you're younger. I think it's pretty much a consensus now that a lot of anabolic resistance is not necessarily the aging process per se, so much as— >> Inactivity. >> Inactivity. >> Yeah. And the experiment that Luke van Loon shared when he was on the podcast I think was a very elegant way to demonstrate this, which is they took young subjects— I don't remember if they were in their 20s, but around there, maybe in their 30s—very young subjects, and they put a cast on one leg, no cast on the other, and they left them in this state for a period of time. Again, the details have now completely escaped me, but the point hasn't escaped me, which is after whatever period of time the individuals were casted on one leg and not on the other—let's just say it was 2 weeks, 4 weeks, something to that effect—they removed the cast. Of course, while the person was casted, the casted leg did nothing. The other leg continued to go through exercises; they were doing just single-leg leg extensions, leg curls, things like that. They then ran a stable isotope experiment in these individuals and looked at muscle protein synthesis rates. And lo and behold, the leg that was uncasted was perfectly normal; the other one showed significant anabolic resistance. So to me, that's the clearest demonstration

that inactivity is the main culprit. There's probably an all-things-equal, age-related component as well, but I suspect that inactivity is playing a larger role than aging per se. >> I totally agree. Um yeah, I think there was also another study that was done in older adults. First of all, if we look at—maybe we should talk about— >> Can we explain what anabolic resistance is? I think it's worth people understanding why this idea matters. >> Yeah. Anabolic resistance. When we eat protein, we're breaking down amino acids, and the primary amino acid that is anabolic is leucine, right? So these amino acids like leucine get into the muscle tissue, and that is a signal to increase muscle protein synthesis, right? So you're making more protein in your muscle, and that in turn increases muscle hypertrophy, right? The other major signal to do that is mechanical force, right— that would be resistance training, the working of the muscles. As we get older, our muscles do become less sensitive to those amino acids, with the leucine transporter being one of the major factors, though I think there are others as well. And so what happens is that for the same protein dose—and this study has been done—if you compare younger adults and older adults 65 years of age and older, and you give them the same

exact protein dose. The older adults have—or let me say it the other way: the younger adults have twice as much muscle protein synthesis. And for the older adults to get the same amount of muscle protein synthesis, they had to double their amount of protein to get the same amount of muscle protein synthesis as the younger adults. That's a lot! They had to double that amount of protein, okay?

And that's because, again, your muscle tissue is simply not as sensitive to the amino acids. To get more of them in, you have to increase your intake of protein. Now, to your point about physical activity being the major driver here, I think that's 100% true. I agree completely, and there's so much evidence out there to prove that—Luke Van Loon's study being one, but also, older adults that do engage in resistance training have the same anabolic response to the same amount of protein as younger adults. So, in other words,

>> The activity makes up for it.

>> It does! You don't have to—as you're aging—if you're a 65- or 70-year-old male listening to this episode and you're engaging in resistance training, you're likely not experiencing much anabolic resistance. Maybe a little, but not much. And so you don't necessarily have to experience it if you are physically active and training.

And that's really the bottom line here. That's the most important thing. If there's a public health message in this episode, it really is that you should be training.

>> Yeah. And think about the impact that physical training has on insulin resistance as well. Completely different mechanism of action, probably tying in more to fatty acid accumulation within muscles and all sorts of other things that lead to it. But again, the most effective remedy is physical activity. And again, this has been demonstrated so conclusively that actually nobody really talks about it anymore; it's just taken for granted.

>> No, it's a good point. But you know, the anabolic resistance—if we're talking about the general population, and again, going back to those surveys looking at how physically active people are, because those numbers are out there, right? We know that generally speaking, adults—including young and old—about 32% of them engage in resistance training.

>> How much?

>> 32%, both young and old. If you just look at older adults, it's 22% of the population.

So essentially, most older adults—most people—are not engaging in resistance training. They're not doing it, right? And physical activity kind of mirrors those numbers a bit. But I think the bottom line here is that for most people, putting in the effort is harder. Putting in the effort is just harder, so it's easier for them to simply put something in their mouth. That's why pills are so popular, right? People always gravitate towards the easier thing to do, which is like, "I'm going to eat something, I'm going to put something in my mouth," versus putting in the effort. It's unfortunate, but it's a reality.

And so, going back to this RDA being too low, it's just so important. People are out there thinking they're getting enough protein—older adults, younger adults. It's really more critical with older adults; you have a little bit of wiggle room when you're younger, right? But on top of that, first of all, it's not enough protein, and then this anabolic resistance is setting in, and most people are not being active. They're not engaging in resistance training.

So there are all these compounding factors that are really just digging into their muscle. It's taking it away—this insidious sort of taking away each year, each year—and then the next thing you know, you're frail, you have sarcopenia, you know.

>> Yeah. My patients are obviously indoctrinated into this, but I'm a bit surprised that there aren't more people who talk about this. You do a lot, but the medical system doesn't seem to talk enough about frailty and sarcopenia.

And I worry that even when I wrote Outlive, I didn't do enough of a job emphasizing it. I mean, I certainly talked about it, but when I talked about the Four Horsemen, I talked about cardiovascular and cerebrovascular disease, cancer, neurodegenerative and dementing diseases, and metabolic disease— because of course those are the main assaults on your lifespan.

Relative to those, assault on lifespan. It is, as you know, the risk of falls is enormous, and mortality is very high once you're north of 75. But relative to those four, I had to pick four horsemen, I didn't want to go with five. But when

frailty is not as big an you think about quality of life, which most people care about at least as much, if not slightly more than length of life, I think frailty just kind of wins the day.

Along with cognitive health and minimizing cognitive decline, frailty is the thing that seems to determine the quality of your final decade on this earth. And here we have lots of great tools, both in terms of training and nutrition, that can offset that. And yet it is surprising that despite the fact that most people have witnessed it—that's the part that's amazing to me. It's not like the people suffering from frailty and sarcopenia are out of sight, because they're our parents and our grandparents. We've watched it. We've been to the movie over and over and over again; we see how it goes.

And yet somehow we either don't think it's going to happen to us, or it still seems abstract because it's so many years off. What's your take on this overall challenge?

>> Well, for one, I think that I completely agree with the frailty risk being as important if not more. Witnessing it with family members, it's... what I think it is, is that it's this incremental thing, right? Where something happens— maybe there's a fall, maybe there's a planned surgery like a hip replacement or a knee replacement—and your parents or grandparents are inactive for many weeks and they lose a lot of muscle mass, right?

Now, this happens when you're young, it's much easier to gain back that muscle mass. It's not the same with an older adult. It's just not the same. Even if you're engaging in resistance training after, you're not going to get the same amount of muscle mass back as you've lost. And these sorts of events happen in periods of time, right? Where there's a planned surgery, then a fall, maybe another surgery, maybe COVID or the flu, or whatever it is—they keep hitting, right?

And you reach this sort of what's called the disability threshold, where all of a sudden your parents just can't walk much at all anymore. And it's like, "When did this happen?" Well, the evidence was mounting over the last five years when those points of inactivity were occurring. And so I think...

people kind of just don't follow the timeline, you know, where it's like they see what's leading up to it and before this sort of catabolic crisis occurs where then they reach this point now where they've just lost so much muscle mass from these several events that have occurred where they're just not mobile and then of course anabolic resistance is kicking in even more and more and more and everything is just compounding. And I don't think they've like they've like observed the timeline and said, "Oh, A plus B plus C is getting me to this point, right?" And so I think that's kind of what happens. Whereas with Alzheimer's disease, I don't know. It's just like this disease everyone knows about and it's like, yeah, this one thing causes the problem. Do you know what I mean?

Yeah. I—I think and again, um, you know, Luke Van Loon made a really good point when we spoke, which was when we draw the curve for how people lose strength and how people lose muscle mass, we draw it in a curved smooth line, which gives us the incorrect impression that this is a gradual and, um, imperceptible changing physiologic process. But he goes, that's because it's averaging everything. If you zoom in and look at it at the individual level, it looks like this: exactly as you described, discrete periods of loss from which there is no recovery because at the later points in life, it becomes very difficult to make those recoveries. All of this of course points back to where we're going today, which is when you are young, and young is 40, 50, even 60, you have to build up as much physiologic headroom as possible. You have to prepare for the rainy day because the rainy day is coming. It's not a question of if. It's simply a question of when and exactly in what fashion it will be delivered. But you must prepare for this. You must steel yourself for what is coming. And you must build up as much muscle mass and strength and cardiovascular fitness as you can muster because the longer you can ride it out, the better you're going to be.

The cliff is coming for sure. I mean, it's like your retirement fund, right? You have to—you have to put money in because one day you will retire, and if you don't put any money in that fund, you're gonna be—you're gonna be screwed. And so with the muscle mass, um, you're right, you have to bank as much as you can while you're young. And we haven't even talked about optimal. We've just talked about like, like...

Not going backwards, right? We've talked about not going backwards, which is what most people are doing, right? Because this RDA is too low for one. I think that's the—the big—the big problem. Um, but—but optimal is a whole other story, right? And that's again where it is hard to wrap your head around why there's controversy around this. Although coming from the field of aging, I do have somewhat of a—I think there's been a little bit of a nuanced, um, you know, there's a nuanced approach to looking at how protein affects the way we age. And I think some of that data has biased researchers and, you know, people to think that protein is bad. I think some of it's coming from that evidence which we're talking about. >> Yep. Yep.

But, um, but again, aside from that, it's really hard to understand why someone would be so opposed to increasing protein intake when there's really just no evidence that it's harmful, at least in healthy adults.

Yeah. I mean, I'd—I'd like to talk about harm down the line as we get further up the chain because we're—we've now just—I like the way we're talking about this, where we're going from sort of the 0.8 up to 1.2, and now let's talk about going from 1.2 to 1.6, and 1.6 to 2. But as you continue this, um, journey and you, let's say, look at the data—of which there are some studies looking at 3 grams per kilogram per day, um, which I think anybody who looks at the data would argue you're not really getting a benefit at 3 grams per day that you aren't getting at 2 grams per day. You're not like the—the curve is saturating, you know, you're hitting an asymptote of muscle protein synthesis at that point. So there may be other reasons a person would choose to consume that much protein: satiety and things of that nature. But from a purely anabolic reason under normal conditions—so let's leave bodybuilding out of it—um, you sort of hit the saturation curve, but can't seem to find the evidence that it's causing any harm, right? So this is experimental evidence, even epidemiologic evidence, just no evidence. So that said, let's not get ahead of ourselves. Let's go back to—we've established a new floor. Really, there is nobody that should be consuming less than 1.2 grams of protein per kilogram per day. What happens as we start to increase that from 1.2 to 1.6?

Great question. And this is again where I turn to the experts like Stu Phillips. In fact, he did a really great meta-analysis looking at about 49 different studies in adults that were undergoing this. These are controlled trials: resistance training alone or resistance training plus supplemental protein. And the supplemental protein went up to 1.6—well, actually went up above that. But, um, what was really found in that study was that even going from, like, 1.2 grams per kilogram body weight per day, obviously, to 1.6 grams per kilogram body weight, people gained about 27% more lean body mass and 10% more muscle strength compared to just training alone—same training, just adding the protein, right? >> Um, that's pretty big. >> I—I was going to say, that is bigger than I would expect, especially on the strength side. >> Ex—on the strength side, they were gaining, so the protein itself— >> But if you think about it, in a way we're talking about supply and demand, right? So now we're talking about more optimal, a little more optimal. We're talking about people that are training. That's number one. You need to be training. If we're talking about optimal protein intake, you need to be training. Um, and then, you know, what's happening when you're training is you're breaking down muscle. You need protein to support the repair of that muscle and the rebuilding of it. And so that makes sense in a way. >> Yeah. >> Um, but yeah, I was surprised by the strength as well. And so really once you get—once you went above 1.6 grams, you would—there was still increases in muscle protein. >> The curve is slowing down. >> It's—it was—I like the analogy that Stu Phillips uses. He says like if you have like a wet washcloth and you squeeze it to get all the water out, you know, like most of that water is coming out at 1.6 grams per kilogram body weight. But you can keep squeezing a little and you're still getting some water out. It's just—it's just sort of marginal. It's like most people don't care about that difference. Some people do. Now, let's say you're someone that's obsessed with banking muscle mass. You're going to care about that. Let's say you're a, you know, a high-level athlete, definitely going to have to go above 1.6, right? That's when you get into the more 2.2 grams per kilogram body weight. So, people that are doing a high level of training, whether that's endurance or strength training, resistance training, right? Because endurance athletes, I mean, they're—you are battling, um, being catabolic. So, um, so that would be, I think—I think

The evidence for the more optimal intake, you're talking about 1.6 grams per kilogram of body weight, and then you can get marginal benefits above that, right up to like 2, 2.2, 2 grams per kilogram of body weight. But again, that's for people who are really training.

>> Yeah. To me, there's an analogy here with ApoB and cardiovascular disease. Right? So, if you look at the three bodies of evidence—if you look at all of the epidemiologic data, if you look at all of the clinical trial data, and if you look at all of the Mendelian randomization data—and you plot every single one of them on a graph (and there's a beautiful graph which we'll include in the show notes that does this).

So on the x-axis, and it's done in LDLC, but again, LDLC, ApoB, easy, easy to sort of view them together. So you have on the x-axis LDLC going down, right? So from 160, 140, 120, 100, 80, 60—descending LDLC. And on the y-axis, you have mortality, cardiovascular mortality. So not surprisingly, all of these point down; as LDLC goes lower, cardiovascular mortality goes lower.

What's interesting, though, is you can see that there are different points on the curve at which it starts to matter more, and at some point it flattens out. You don't get as much benefit from reduction. And so we could use the same argument of, well, what is optimal? Because we're doing the reverse here—lower is better, as opposed to going up on protein. But Peter Libby has done an analysis that has demonstrated that you will continue to see a meaningful reduction in cardiovascular disease as ApoB heads towards 30 milligrams per deciliter.

30 milligrams per deciliter is really low by most people's standards. For context, 60 milligrams per deciliter is about the fifth percentile at the population level. 30 milligrams per deciliter is about what a child is. So, you know, we're born with relatively low levels of Apo, and as we age, they just keep going up and up and up, which of course is one of the things that's driving cardiovascular disease—this rise in Apo.

So the question then becomes: How low do you need to go? Should everybody be walking around at 30 milligrams per deciliter? Is that the solution to eliminating ASCVD? And the answer is probably not, right? It probably depends on your previous exposure, though, right? So if I have a patient who's already had two stents placed and has a significant burden of disease, you bet your bottom line they're at 30 milligrams per deciliter of Apo, even if we have to put three drugs on them to make sure that's the case, because their burden of disease and their lifetime exposure to Apo has been so high.

But if I have an individual who's 40 years old, who has perfectly pristine coronary arteries and is walking around with an Apo of 60 milligrams per deciliter, I don't think you need to do a thing. I think they're just fine. And again, it's the inability for people to understand that level of nuance, and understanding when it's worth the second squeeze versus when just the sloppy squeeze is good enough, is very frustrating for a person like me who craves nuance.

>> Right. Agreed. I love that analogy, and I think it's perfect, because again, I do think most people that are training probably are getting a great amount of benefit from 1.6 grams per kilogram body weight. But that doesn't mean you can't go above that and still get a little more benefit, right? And certainly when you start to get into that energy deficit phase as well—like, so we were talking about elite endurance athletes, that's one way to be in an energy deficit, but there's also people that are actively trying to lose fat and gain muscle. If you want to lose fat and gain muscle at the same time, you're going to have to take in a lot of protein.

>> Yeah. And that's another very important point. Another point I want to make is you're still dealing with an asymmetric target. And so we tell our patients to be closer to 2. Now, I know that's just going to get a whole bunch of people on the anti-protein train just losing their mind. I can just see the phosphorylation going off right now as they're watching this clip: "How is this guy so irresponsible to tell his patients to eat 2 grams of protein per kilogram of body weight? Didn't he just hear what Rhonda said? 1.6 is good enough for most people."

Well, my patients unfortunately don't live in labs. Unfortunately, Rhonda, my patients live in this place. It's called the real world. And in the real world, you can't always hit your targets. Some days you do, some days you don't. Some days you're traveling, some days you're not. Some days you can figure it out, some days you can't.

So if I'm telling somebody to hit 1.6, and one day they're at 1.2, another day they're at 1.7, another day they're at 1.5, another day they're at 1.9, on average they might hit 1.6. But how many days were they below versus how many days were they above? Let's just say it's an equal split. But we've just established the shape of this curve is like this. So that means every day you're below, the downside is much greater than the upside of being above. In other words, all the days you're above are not making up for all the days you're below.

So what I'd really like to do is shift the range so that your low day is 1.6 and your high day is maybe 2.2. And then guess what? You don't have days where you are ever, ever amino acid restricted.

And this is the difference between people who take care of people in the real world and bozos who write on Substack who don't know the first thing about clinical medicine when it comes to managing athletes and people who have to fend for themselves every day with every meal. And this is why I'm so tired of talking about this, but I feel we need to talk about it. And so if you're sitting there listening to this and you're confused and you're asking, "Oh my god, should I be eating two grams per day?" Yeah, more or less. And that way if you fall short at 1.6, you can be confident that you're okay. But if you're aiming at 1.6 and you have a bad day—and you will, when you hit 1.2—you might be taking a step backwards and you won't make up for it the next day.

>> I can just tell you from personal experience, it's actually smarter to aim higher, because I'm constantly not meeting the one— I am not! This is the thing. People look at me like I'm a protein-eating machine, which first of all, I'm not. But secondly, I have a hard time hitting my goals, too. I'm busy. I miss meals. Sometimes we just have a low-protein meal. Like, for whatever reason, my kids want to have pasta for dinner, and we literally have pasta and sauce. It's like, there's no freaking protein in this anyway.

So, it's very difficult if you don't have a chef preparing your every meal—and I never have a chef preparing any of my meals unless I'm out at a restaurant—to hit these targets every day. And also, I was thinking about this because we mentioned the 1.2 being the sort of minimum buy-in, but 1.6 grams per kilogram body weight isn't necessarily just for people training a little bit; it's also older adults that are not training, because we talked about anabolic resistance meaning I need twice as much protein as well. And so what you're talking about here is going up to 2 so that you can really have an average at least of 1.6, right? You're getting that...

average. But again, well, and it's just I never want to fall below that. That's really the point is I know because again, I'm training every single day right now. Am I training like a madman? No. But seven days a week, I'm either doing some form of cardio or something in the gym. So it's just I know that I'm going to take steps backwards if I'm below 1.6. So, I'm going to overshoot so that my down day is 1.6, right?

And if my up day is 2.5 once in a while, who cares? Because that gets to the next point. Show me the data. Show me the data that eating 2.5 grams of protein per kilogram per day is even remotely harmful. I'm still waiting for it. I'm still waiting for the data. David Allison wrote a piece on LinkedIn recently where it was basically a call to anyone. Just show me the data that meets these criteria: human clinical trial of this duration—and it's like nothing but crickets.

Yeah. I mean, I haven't seen any human data either for sure. I mean, the most negative data I saw recently was a study that looked at total parenteral nutrition in ICU patients where the question was, hey, should we be ramming high amounts of protein in these people? And the most negative thing you could say is it had no benefit.

And that's interesting. Yeah. Right. So maybe we shouldn't be ramming high protein total parenteral nutrition into the central veins of critically ill ICU patients. Um, but it didn't harm them. And if anybody's going to be harmed, I would think it's the people that are in renal failure.

Right. Yeah. Exactly. Um, I haven't seen that data either. We haven't spoken specifically about pregnancy or adolescence. What do we know about protein requirements? Cuz there are clearly women listening to us right now who are pregnant or who will be pregnant. Um, and I don't think there are any adolescents listening to us, but I bet there are parents of adolescents. Um, so what kind of guidance would we want to give these people?

I mean, it just goes up with pregnancy and also adolescence. I mean, so... Are there formal recommendations? I don't remember the exact numbers, but again, it's all about going a little bit above the RDA, and we've already established that's not enough, right? So I mean, honestly, I think if people are listening to this episode, just knowing that 0.8 grams per kilogram body weight per day is just not enough at all.

So if we accomplish nothing else, that's the single most important take-home message here. I really think it is because everyone looks at those guidelines, you know. Yeah. It's really funny. The other day I was eating something and I forget how much protein it had in it, but it had like percent of daily requirement, but it was obviously based on a very low number because I remember my son was looking at it with me and he goes, "Is that really—like, I forget what the number was—is that really like 40% of your daily protein requirement?" And it was a relatively... and I said no, but I just didn't have the energy to explain the RDA to him, so I was like, no, this is just wrong, you can ignore this.

Growing is also an important time for protein, right? Because these amino acids and the essential amino acids are activating IGF-1 growth hormone and that's really important for growth. I know there were studies done in like infants and toddlers that were given egg versus milk versus some kind of vegan protein. And it was clear that the egg was the winner here. Giving protein with more essential amino acids was important for growing taller. And that's always something that I, as a mom, think about, right? I'm always trying to get protein in my son. Plus, the kids are more active. You know, kids are more physically active. They're doing sports and things like that, right? Adolescents.

So it's really important to get the protein requirements right. I haven't dug into all the nuance of that data. It's just kind of the way I look at it is, you know, it's gotta be like a 1.2. Even though that's an adult metric, it's more like a 1.2 grams per kilogram for an adolescent who's pretty close in body size to an adult. Generally speaking, they start growing pretty tall.

Yeah. I mean, I would think for kids it should be at least 1.2 to 1.6. I just look at the activity level of my kids; they make me look sedentary, right? Okay, anything else we want to say on the topic of protein to help with some of the confusion that is out there? I think we should talk a little bit about some of the misconstrued understanding of mechanisms of action around mTor, cancer, and stuff like that.

I would say the other thing would be calorie restriction, people doing intermittent fasting, people doing anything if they want to do body recomposition—the gaining of muscle and losing fat. I think that is a very specific population of people where the high protein intake is critical, right? Because if you're in a caloric deficit, you really are battling your body pulling from your muscle reserve. If you're resistance training, that helps somewhat, but you're certainly not going to gain muscle. And we just talked about wanting to bank as much muscle as possible while we're younger while we can, right? Because we need that reserve because we're going to start pulling from it eventually.

And so I think that's where you start to get really high numbers: 2.2, even higher. I mean, you can find studies out there, like 3 grams per kilogram of body weight. Going above 1.6 in this scenario seems to be key as well, when you're getting up to that 2.2 grams per kilogram body weight per day, because it does give you a little bit more edge over gaining muscle (muscle protein synthesis) in combination with resistance training. As well as, like you mentioned, it's satiating. It's a little bit thermogenic. I don't know that that's the big mechanism here, but I think the big mechanism here is just that you're really wanting to prevent this catabolism, right?

So, I think that's just another important point because there are a lot of people that do intermittent fasting, time-restricted eating, you know, they're trying to do body recomp, gain muscle, lose fat. I think a lot of people are interested in that. There was one period of my life when, over the course of a year, I made a very dedicated goal to lose body weight and gain muscle. So, I wanted to see, could this be done? And it did require quite a bit of intermittent fasting— or time-restricted eating, I suppose, to be more accurate. But the amount of attention I had to pay to protein intake was pretty incredible. And what I did seemed counterintuitive because I wasn't intermittent fasting because I believed that a fasted state was producing some benefit, right? So you know, there are some people who think that if I don't eat breakfast, I'm kicking off some autophagy or something. No, no, it wasn't. It was purely caloric.

restriction ploy. So my fasting window did not prevent consuming liquid protein.

In other words, if I wasn't eating breakfast or lunch—which I wasn't, I was only having a meal a day, which was dinner—I would still consume protein shakes outside of those windows. Otherwise, I could never hit the protein target. So, I was in a caloric deficit, but an amino acid excess. And again, you can actually do that with liquid protein pretty easily, because basically all you're getting is, you know, you're getting relatively few calories because you're just consuming whey protein.

>> Did you have any, like, GI problems consuming so many shakes? >> No, not really. I get... >> No, but I did a lot of experimentation, right? So, ultimately, I settled on a brand. I'm blanking on the name of it now. I have no affiliation with these guys, and I'm blanking on their name. Ascent, maybe? Does that ring a bell? >> Yeah. >> I really like them. Again, I'll give them a shout out because, one, it was the only protein I found I could mix directly in water and not have it be lumpy. I didn't even need a blender. This sounds silly, but the hassle of me having to wash a blender twice a day was sometimes an impediment to not making a shake. So, just to be able to put the scoop—or two scoops, I would usually put into a glass with water—and mix it with a fork and actually drink it, and have it be totally fine and not, you know, lumpy... I don't know how they do this, but it was amazing. It actually tasted fine. I don't like sweet drinks that much, but it was not too sweet. And absolutely no GI issues at all. Whereas sometimes the pure egg proteins, I just... I didn't like the feeling on my gut. So for whatever reason that worked for me.

But to your point, it is another level of challenge if you're trying to recomp in that way, right? Or people on GLP-1 receptor agonists, right? I mean, like... >> And I don't know how difficult it is to eat a meal versus take a protein shake, because I know you don't have a real... you're satiated pretty much all the time, you don't have a real appetite, but also digestion is slowed. So, if you're consuming more protein, I don't know how that all affects... >> We've seen it in our patients. So, again, I would say... I get asked this all the time. I would say 15 to 20% of our patients are on tirzepatide.

And unlike five years ago when we started using semaglutide in patients and were just watching muscle fall off these people—and frankly, my point of view five years ago was, "I don't know about these drugs. I think there's some benefit in some people, but I think there's a lot of downside"—I today think that virtually anybody can use these drugs safely. And by safely, I don't just mean in the obvious sense of the word; I mean, safely for long-term muscle health as well, right? But it requires a ton of deliberate attention. So I'm glad you brought it up. This is exactly the group of people who you want to be using easy-to-digest protein sources.

If you're on tirzepatide, you don't really want a steak. You know, you don't really want to have a big chicken breast. You might not want to even have an omelette. But if we have to make sure you're hitting that 1.6 [g/kg], you might be doing a bunch of liquid shakes. >> Right. >> Yeah, we can sit here and poo-poo processed food and say, "How disgusting is it that people have to resort to eating shakes?" Okay, fine. But if the alternative is they're not getting enough protein and they're on a drug that is making them anorexic—I mean, we know the downside of that. >> Well, the answer's clear, right? You don't want to be losing muscle mass for sure. My point is, you know, we do DEXA before and after. We're not seeing the type of muscle loss we saw with our V1 approach to this, right? >> What kind of dose are they on? Like a higher dose? >> Well, I mean, tirzepatide starts at 2.5. Some people are getting enough benefit there. I mean, the other thing our approach has been is that slow and steady wins the race, right? So, we've seen anecdotally some data—I've heard from others, and we've seen it as well—that yo-yoing on and off these drugs is probably a bad idea. So, I always tell a patient, "Look, I'd probably rather you were on 2.5 milligrams until there was a new drug that we felt was even better, than you're on 10 milligrams, you lose a ton of weight, you come off, you gain, you go back on, you lose." It's like, this idea of being on a seesaw is probably a bad idea.

I think the data suggests you're getting most of the value by about 10 milligrams. So once you go to 12.5 and 15, which are the two highest doses, you're still getting a benefit, but it's like most drugs: you're getting most of the benefit at the lowest dose. So 5 to 7.5 milligrams of tirzepatide is probably where you're getting the majority of the dose. And again, I'd much rather a patient be sort of slow and steady on it, as opposed to trying to go for maximum and rapid weight loss.

>> What do you think about some of that data on like heart issues or bone loss? Do you think... does that concern you at all? >> Sure, I think it all does. I mean, I think all of this stuff has to be paid attention to. And the question again comes back to how much of that is occurring due to training, right? How much of that is happening due to the loss of amino acid intake and the loss of training... >> Or the neuropsychiatric effects? I mean, like, that's another one. What I'm interested in is, you know, we have these GLP-1 receptors on so many different tissues. So systemically, how is it beneficial? Is it not beneficial? I don't know that we really know. We have data where there are obviously positive effects—you see reduced Alzheimer's disease incidence with people taking these GLP-1 receptor agonists—but how much of that is due to weight loss, right? >> Yeah, we've looked into this a lot because I do remain... it's funny, we did a podcast on this somewhat recently where I went through this particular question, which is: will GLP-1 receptor agonists ultimately prove to be geroprotective? And I came up with a very obscure way to define that, which is: independent of weight loss.

Right? Because obviously at the macro level they're going to be geroprotective, because if you apply them to people with type 2 diabetes and significant obesity and you correct the metabolic dysfunction, you're going to live longer. So by that regard, it's a geroprotective agent. But the real question is: if you take a person who is of normal weight, who does not have type 2 diabetes, but maybe has a higher risk for Alzheimer's disease, and you microdose them—so you're giving them 2.5 milligrams per day, which by the way we are doing in some patients for an obscure metabolic condition without obesity, right? We have patients who have diabetes, but are already at very low body weight. We have two patients actually in our practice in...

this in this regard. And after lots of detailed back-and-forth machination with Ralph DeFronzo, who's a previous guest on the podcast, you know, we sort of realized that at least one component of the drug regimen for these patients was going to be a GLP-1 receptor agonist. Now, it seemed very counterintuitive to give tirzepatide to people who have a BMI of 23. But we've been able to do it without them losing weight. So again, very careful strategies around nutrition and the effect on their diabetes is profound.

>> So they're looking more metabolically healthy.

>> Oh my god, totally. I mean, these are really interesting cases that, you know, maybe at some point obviously in a de-identified way, it would be interesting to talk about where you have OGTTs that are unrecognizable. Like you simply cannot believe the degree of metabolic dysfunction in a person who otherwise looks the way they look. And in one case in particular, it was so confusing that even after all the genetic testing we did, we simply couldn't figure out an answer for this. We couldn't understand where the beta cell fatigue was coming from, absent a formal diagnosis of type 1 diabetes. And within 3 months of being on 2.5 milligrams of tirzepatide, this individual's OGTT had almost normalized, and I suspect by about 6 months it will.

>> That's fascinating. And we've managed to do this without any weight loss. So this to me is the interesting question, right? Which is when you look at some of the Alzheimer's biomarkers, which are improving significantly, it begs the question: should this be part of the playbook for an individual who's at high risk, especially given that we now I think really understand how to make sure people don't lose weight and don't lose lean mass, and therefore I suspect don't lose bone density and all these other things that matter?

>> Or like you said, you know, if you're doing this micro-dose, maybe you're not going to be as satiated, like you'll still have somewhat of an appetite because you're on such a low dose. Maybe you're going to have a little bit of an—

>> We've also seen some other weird things anecdotally. Patients have told us that when they inject in the abdomen—so when you inject in the subcutaneous fat of the abdomen—the anorexic effects are greater than if you inject in the leg or butt. And we looked into this, and there was some mechanistic data to suggest that maybe you're getting more vagal tone when you inject in the abdomen. Again, I just don't know if any of these things are correct; they would need to be studied. But again, that would be a very important piece of data, right? If there's a location you can inject this where you minimize the anorexic effect of the drug—again, for some people that would be a feature, not a bug, whereas for others that would be a bug as opposed to a feature. So you have to understand how to use the tool.

And this just reminded me of something that we should have pointed out, talking about protein requirements in grams per kilogram of body weight. I do think it's important, because we were just talking about obese people.

>> This is—I'm glad you brought this up.

>> And where it's like, most people aren't going to do a DEXA scan to see what their lean body mass is. But ultimately, I think—and I've talked to a variety of experts like Brad Schoenfeld and Stuart Phillips—they agree that really, if you're someone who's overweight or obese, you shouldn't be calculating it based on your actual weight, because your protein requirement will be way too high. It's more like your target weight, right? Or that would be—I mean, if you empirically could measure your lean body mass, that would be better. But yeah, I just wanted to point that out.

>> Yep, and I'm glad you did. So that's right; for most people, probably not much of an issue. But if you're at 300 lbs right now and your ideal body weight is 220—and again, you don't need a DEXA to figure that out, a DEXA can help, but most people who are 300 lbs remember, "Gosh, at the end of high school I was 220, that was my good weight," or maybe, "At the end of high school I was 200 lbs, which I'll probably never get back into those jeans again, but by the end of my freshman year of college I was 220, that was kind of a good weight for me." And then it's just kind of gone downhill from there, you know, I had this orthopedic injury—there's the story of how you got to be 300 lbs. But most people can figure out, "220 is probably my goal weight and that's what I should be targeting."

>> Yeah. But yeah, so should we get back into like where—

>> So you made a great point, right? Which is: how do we reconcile the following? So caloric restriction as an intervention, as a geroprotective intervention, is the oldest one in the book. I'm not really aware of a non-genetic intervention that from a long-standing perspective has produced a more consistent outcome in terms of laboratory animals where you restrict them of calories and they're going to live longer. So again, to my knowledge, there are only two interventions that have extended life across all four model organisms from yeast, worms, flies, and mammals/rodents, and that is caloric restriction and rapamycin. And they have something in common, which is they both result in the downregulation of mTOR.

>> Right. So we also know that an amino acid you just mentioned a moment ago called leucine is the single most important of all the amino acids at turning up mTOR. So how can we reconcile the idea that protein seems to be good for you, but mTOR going down seems to be good for you at least in another way? Well, for one, this is—

>> I'm being very facetious because I know the answer to this question, and it's like, oh gosh, where do we start? Because let's ignore the worm and the fly and all that, because who cares? I mean, even with rodents it's like we're getting to be a stretch, right? But obviously, you know what else turns on mTOR? Exercise.

>> Yeah.

>> Physical activity, mechanical force turns it on in our muscle. And we know exercise is one of the best things that we can do for our health. I think here, for simplicity, the best way to think about this is that you want mTOR active in your skeletal muscle. You want it active in your skeletal muscle; you don't necessarily always want it active systemically. But if you are exercising, if you're moving around and you're taking your protein, it's going to your muscle. We know that for a fact. I just talked about anabolic resistance and how exercise can counter that. Well, it's increasing the leucine transporter, the expression of the leucine transporter. It's causing leucine and other branched-chain amino acids to go up into skeletal muscle. Multiple human studies have shown this. These are tracer studies, beautiful data, no argument: exercise causes—

leucine and other branched-chain amino acids to be taken up into skeletal muscle where you want it to be, so that it activates mTOR and increases muscle protein synthesis.

When it comes to deactivating mTOR—whether that's through protein restriction or rapamycin—I mean, that would be like an hours-long podcast talking about all the nuanced data there, because there are all sorts of differences with, you know, sex differences in rodents, everything you're aware of with this data.

My biggest thing here with protein restriction... let's talk about one. I spent six years in grad school working with mice. I did a lot of animal studies. Okay, these mice are in a small cage. They are not physically active. They're not running around. I mean, they move a little bit, but they're ultimately... >> They're not under threat. >> They're not under threat. They're being fed. They're ad libitum. They're just being fed, you know, as much protein as they want, but perfectly thermoregulated. >> Totally. No, they're not being exposed to influenza or COVID or whatever viruses—anything that's going to take them out for a period of a couple of weeks. They're in a sterile environment. And so, I mean, they're happy. They're happy, and that's it, right?

People are not mice, right? We, like we talked about earlier, as we get older, we're being exposed to infectious diseases, things that are going to make us immobile for a period of weeks, and that is devastating to us, especially when you add them up and they happen this year, and then the next year it happens again, and then you're just losing that muscle mass, right?

And then you reach that disability threshold you talked about—Luke Van Loon talking about those curves. It's very clear. I mean, you can see the data where there's a disability threshold. You get enough of these like catabolic crisis events, right, where you're just immobile for a certain period of time because you've had a surgery or you've had the flu or whatever kept you inactive. That doesn't happen to these mice, right?

So, protein is much more important to humans because we, of course, need that muscle mass and we need to bank it early. We've established that. And I think that's a really important difference here—that, you know, we can't just look at the data in mice and go, "Oh, you can restrict them from protein and they live longer and they're fine."

Well, they're not going through these catabolic crises. They're not going through these points of not moving for a period of time and losing all this muscle mass, and then that happening repeatedly until they reach this disability threshold. It's very different. So I think that's first and foremost important to point out.

The second thing is that if we're talking about protein intake, I think that you and I agree the optimal scenario here isn't a sedentary person just sitting there eating as much protein as they want. No, they need to be moving, physically active. Like, that's the whole point. You're supporting your physical activity by increasing your protein intake.

And so in that scenario, again, the amino acids that are activating mTOR are going to skeletal muscle. Like, that's been shown—leucine is going into skeletal muscle. So who cares if you're taking in more... >> Yeah. In fact, I think that's such an important point, Rhonda, that I would even go one step further, which is: if you told me, "Come up with the optimal nutrition strategy for the individual who is active," and then come up with the optimal nutrition strategy for a person who is going to be sedentary, they would be very different.

I'm going to try to talk that sedentary person into not being sedentary. But if, at the end of the day, I can't—if that individual says, "I just don't want to do anything, I just want to sit in front of my computer"—um, you know what? It probably makes sense to be a little bit caloric restricted, right? Because at least I want to make sure... I can't solve your metabolic challenge through activity, but what if I could at least solve it through nutrition restriction?

And again, I think it's the inability of people to understand that those are very different states, right? You cannot treat those two people the same way.

>> Right, and there was even a study by Valter Longo of all people, like years ago, that came out—a large cohort study looking at dietary protein intake from vegetable versus meat sources, right? And we all know that meat sources have higher levels of essential amino acids like leucine. And all-cause mortality was looked at, and you know, the same statement that you've heard millions of times from other studies about, okay, if you know, vegans have a lower all-cause mortality than meat eaters.

Well, it turns out when you actually start to analyze the data and correct for a lot of confounding factors, meat-eaters that were physically active, were not obese or overweight, didn't smoke, didn't drink excessive alcohol—so, in other words, they didn't have all these unhealthy lifestyle factors—they had the same mortality rate as the vegans.

So, I think that also is a good point here where it's like, okay, if you're going to be a sedentary person that's smoking and has unhealthy lifestyle factors, maybe you don't need to be so obsessed. You definitely want to make sure you're at least getting the minimal amount of protein because you don't want to be in a deficit, but you don't want to necessarily just be constantly activating mTOR if you're just going to sit around and smoke and be overweight and not do anything with that protein, right?

>> Yeah. And the other thing I think is missing from this discussion—and this is where I think inflammation serves as a great analogy. Right? So I think most people on the surface understand that a constant on state of the inflammatory system would be bad. But of course, if you had no inflammatory response, that would also be bad.

So the ideal state is: inflammation when you need it, otherwise off. Inflammation when you need it, otherwise off. And I think that's probably the right way to think about this, right? Which is, we want mTOR on when it has a job to do, and we want it relatively silent when we don't.

And I think if rapamycin is geroprotective—and when I say "if," I mean in humans; I think it's unambiguously protective across most species, but we still don't know if the species of interest is going to benefit from this drug, and we may never, by the way—it's probably working by tamping down the chronic inflammatory component of what we see with mTOR activation, which by the way might actually involve inflammation as well as one of the many things.

So there's also this challenge of trying to get folks to understand the difference between chronic and acute things. Again, cortisol, right? Great example. Cortisol is a vital hormone; the appropriate rhythm of cortisol is essential for life. If you took that away, you would actually be dead—that's called Addison's disease. But cortisol constantly being on would also be a problem, right? That would be Cushing's disease. So, both extremes are bad.

it's do you do you know when you need it and what it's supposed to do, and I think the same is true with mTOR.

>> I'd also like to see data comparing, like, even even if it's animal data, um, comparing like giving giving rapamycin or inhibiting, you know, somewhat inhibiting mTOR versus like physical activity—like, making them run on a treadmill, like being physically active. Because if you look at like a lot of the protective effects of rapa, I'm like, this is what exercise does, and exercise does it better. So...

>> I'm just not convinced that someone who's already bought into, like, how important exercise is—both cardiovascular and weight training—

>> Well, Eric Verdin made a very interesting podcast, a very interesting comment on my podcast a while ago. And so Eric is in the camp that he does not believe RAPA will be geroprotective in humans, and he talked about the longevity quotient. So for listeners, the longevity quotient is a plot, a very famous plot that on the x-axis puts body size and on the y-axis puts lifespan. And you just plot all the organisms on this thing. And as a general rule, it rises up and to the right: the larger an animal is, the longer it lives, and it's a pretty straight line. In fact, we should find a good example of it and link to it in the show notes. But there are always animals that punch above and below their weight. So there are animals that fall off that line either too high—these are animals that live much longer than you would expect based on their body size— and there are animals that punch well below their body weight; they live much shorter than they should based on their body weight.

Well, it turns out two interesting examples are mice and humans. Mice live on average two years—I forget the exact number— they should be living close to four or five years, I think, based on the longevity quotient line. So they are punching well below their weight. And humans, we live 80 years; we should probably be 40 according to the data. By the way, we did live 40 years until modern medicine came along! So maybe we were totally on the curve correctly until medicine 2.0 came around at the turn of the last century and basically over five generations doubled our lifespan.

Um, Eric argues—and I think this is a very interesting argument—that rapamycin disproportionately works well in animals that are below the longevity quotient. So that's why it works so reproducibly in mice, right? But he argues it might not have any effect in humans because we've already captured so much of our genetic potential in terms of lifespan now that the idea that RAPA would give us an extra 15% of life, he feels is just kind of hard to imagine. And again, a theoretical argument, it's super interesting, but I'd never heard it in relation to the longevity quotient before, and I thought it was very much worth pondering.

>> Yeah. Well, that's interesting. I've also seen data with rapamycin given to people that were undergoing resistance training, and it like blunted, obviously, some of the muscle protein synthesis, as would be expected. I don't remember the dose of mTOR, but it wasn't like... I'm sorry, it wasn't super, super high. >> But to me, that was like enough to be like, well, I mean...

>> Yeah, and then the question, of course, is could is there a way around that, right? Is there a way where you could intermittently dose it? You just take it once, you time it so that it's not in proximity to a bout of resistance training by a couple of days or something like that. But yeah, there's a lot there. There's a great expression I heard recently which is: Mice usually lie, monkeys sometimes lie, it's humans we care about. I thought it was just fantastic, right?

>> Well, to get back to the mTOR story, I think that's like that recent study— I don't know, it was in the last couple of years it came out. It was the animal study where they gave mice... 25 grams of protein? And you know, mTOR was activated in macrophages, and it was like this this whole story was pieced together about... >> 25 grams of protein? >> Sorry, maybe it was the equivalent dose, the human equivalent dose— >> Like, wow, that's the way they're eating their body weight and... >> A human equivalent dose was 25 grams, yeah. But it essentially was arguing that atherosclerosis was being caused by protein. And I'm like, are you kidding me? Like, well, for one, we know atherosclerosis, like the bigger story there, right? Is not protein. But again, it comes down to this whole activating mTOR in like systemic circulation versus the leucine going to the muscle because you're physically active. And keep in mind, like those transporters, like the leucine transporters, they're pretty sensitive for quite a while. I mean, you're talking about at least 24 hours, right? Maybe even longer. But definitely—

>> I always I think that I think the mice atherosclerosis studies are very dangerous. It's it's we have to be very careful. They have a very different lipoprotein system than we do; they evolved in a totally different manner than we did. The amount of protein they require is totally different from us. So I'm always I'm always really wary when I see these studies that are using the mouse model of atherosclerosis. I think I understand why we do it, because it's much easier and cheaper than looking at primates, and obviously, you know, we can't do these studies in humans. But you can find a lot of things in mice when it comes to atherosclerosis that don't seem to matter whatsoever in human biology. I would chalk this up to one of those examples.

>> So then there you have it. I mean, that's like a lot of the controversy around protein being bad for you and activating mTOR coming from that study. And then there's countless studies on cancer increasing with IGF-1 and mTOR. And again, same deal, where you know, IGF-1... exercise is causing IGF-1 to go into the brain, to go into muscle. So—

>> People also don't appreciate how short the half-life of IGF-1 is. Like, it's a staggeringly short half-life molecule. >> Oh, really? >> Oh, yeah. Yeah, it's insanely short half-life. >> What's the half-life? >> Um, when administered systemically, it's on the order of minutes. >> Okay. >> Yeah. And by the way, administering IGF systemically is a lousy way to get it to the muscle, right? Like, you want to think of it almost as a paracrine thing, right? Where it has to be delivered into the muscle. So—

>> Yeah, look, all roads for me still point back to this idea that—and I know you would agree with me, so it's not going to be that controversial— exercise is the most important drug. I just don't... I'm just not aware of a drug, in quotes, that is better than exercise. And I know there's this enormous effort to figure out a way to put exercise into a pill; I just can't imagine it'll ever happen. There might be there might be several pills that come out of it, right? We might figure out a way to make klotho, we might figure out a way to make BDNF, we might figure out a way to deliver IGF directly to muscles— like, there might be a whole bunch of little things. >> Say 500 molecules. >> Yeah, this is the—remember, I don't know if you remember...

this. I'm dating myself, but god I don't know if you remember Iris. >> Yeah. >> Yeah. Like, I mean, there's no shortage of these things, right? And and it's there's so many things going on for sure that is beneficial with exercise. Um, and just kind of bring it back to the protein, you know, I think that they go hand in hand, like we're talking about being optimal, increasing our health span, increasing our lifespan, having a good quality of life. Then you're talking about having a higher protein intake to support your physical activity, period.

And athletes, they're some of the longest-lived individuals on the planet. And we talked about this in our last podcast. I mean, Olympic athletes live on average 5 years longer than the general population. Same goes with a lot of these athletes playing these indoor team sports. And there are several studies out there looking at elite athletes, including people in the NBA, um, Major League Baseball, all you know, a lot of these big, um, professional sports leagues, they're taking in at least, you know, two grams per kilogram of protein per day. So clearly, protein isn't killing them. In fact, they're living longer than the general population.

So again, it comes down to that supporting like exercise. Exercise is the king, right? Exercise is like the most important thing, but you need protein to support that physical activity, and so I don't understand why anyone's arguing about that. Like, what's the argument? >> Yeah, I'm I'm despite all the — despite all the flack I'm taking, um, I'm going to just defend this one and continue. And and by the way, if new data emerge, I'm always happy to change my mind. I've changed my mind about so many things. It is absurd the number of things I've changed my mind on. I've changed my mind on GLP-1s. I've changed my mind on saunas. I mean, I can count the list of things I've changed my mind on over the past 10 years. And if there are data that will make me change my mind, I will stand up here with a straight face and I will eat crow and I will tell you that I've changed my mind. But I'm going to stand by my recommendation: 2 grams per kilogram per day.

And my rationale again, I explained it earlier in the podcast, but just to restate it, if you aim for two on the day you fall short, you'll still be at 1.6. If you aim for 1.6, on the day you fall short, you'll be 1.2. And that 1.2 won't be made up for on the next day because the downside is asymmetric compared to the upside. So that's that's that's our recommendation clinically and that's how we work with real people in the real world, not on our Substack pages, to try to help them live a longer life. >> Yeah. Is there anything else with the protein? I mean, >> No. Let's never talk about this again. Pending new data that fundamentally changed the way we think about it.

All right, I want to pivot to another topic which you may be single-handedly more responsible for the buzz on this topic than anybody else I can think of, and that is creatine.

So um should we start with — well, first of all, just tell me what got you interested in this topic, right? So so this is when like you're you know you're not the typical demographic, no no offense intended by that, but like when I was in high school, right, and I'm probably 15 years older than you, like we as young boys in high school in the '80s were mainlining creatine like it was our day job. But here's the thing, I don't remember why? Right? Like I it must have been from your friends were doing it. >> Well, no, but it must have come from bodybuilding magazines. Like I don't know what the I don't know where we got the information, cuz like I was thinking about this the other day 'cause I knew we were going to talk about this and I was like okay there was no internet. Like like what was our source of truth? It was Muscle & Fitness. So there must have been something in Muscle & Fitness that told us this. And then you know what I realized we did? We would hang out at supplement stores. Like we'd literally go in and the supplement stores always had some big bro in baggy pants that tapered down to his feet and he was barely wearing a shirt and he was yolked and he was explaining to us and we were like at the altar of this guy and he was telling us there's creatine monohydrate and then there's like

creatine phosphate, and at the time everyone said creatine phosphate is better and you have to load 30 grams a day for 2 weeks, then you go into your maintenance phase at 5 grams a day, and then you repeat the cycle every 8 weeks or whatever it was, and we were like buying this stuff by the truckload. And this is like almost, I don't know what, 40 years ago, right? Or you know, 30, 30 — yeah, easily 35-40 years ago.

Okay, fast forward, I don't know, a few years ago we're paying attention to creatine again. >> Well, you just made a really important point, and I'll talk about my journey in a minute, and that is it's one of the most well-studied sports-related supplements ever, right? I mean, there's just decades and decades of research out there on creatine. A lot of it has to do with muscle. We'll talk about, you know, the brain, which is sort of my interest, but I mean, it's it's one of the tried and true. I mean, it's safe. I don't know that there's any other sports supplement out there that's as safe as creatine. I don't think there is. So, um, that's an important point, right?

My journey with it began with my obsession with increasing my resistance training after >> Like your performance, or your hypertrophy, or your recovery? What specifically? >> Everything that we talked about in the first, like, half of this episode, where I realized that I was so focused on endurance training for long-term health, for brain health, that I sort of neglected my muscle mass and thinking about how important muscle mass was for long-term health. You've been — you've chronicled this pretty well on your social media. You've got videos of you deadlifting, like you're you're really embracing this. >> Awesome. >> So this is um so you know after having a couple of experts on, and just when I have an expert on I read the literature voraciously, like I just dive in and I I want to be in it, right? Um, and it's part of the fun. I love it, right? Like this is like I get to learn all this new material that I'm interested in. And so I finally realized that I wasn't doing enough training, resistance training.

And so I um got a trainer — I have a personal trainer now. I'm doing resistance-type training. I do like a CrossFit-type training for at least 3 hours a week. I'm doing now. It started out I was doing like 30 minutes a week. So I've gone from 30 minutes to like three hours a week. Big difference, right? And that's when I became really interested in creatine where I was like, "Okay, I know this one supplement is obviously like shown to benefit people that are working out." I didn't know why everything until I got into the literature, but that's kind of what got my interest into creatine.

So, um, I started supplementing with — well, let's talk about creatine, right? So creatine, most people know, creatine is stored in our skeletal muscle as creatine phosphate. And it's essentially used to rapidly recycle ATP (adenosine triphosphate). This is the major energy currency in our cells. And um, so creatine phosphate is able to help

rapidly recycle that so you can make energy quicker. It's very relevant for a lot of scenarios, including high-intensity interval training, resistance training, and even endurance training, because it decreases recovery time by recycling that ATP.

So it's really relevant for a lot of scenarios. And we do make creatine endogenously — that's another thing where it's like, okay, this is a molecule that we make in our body, so it's not a dangerous thing that I'm really scared of. We make about 1 to 2 grams in our liver every day, and then we can take in more depending on how much meat we eat. Meat is the major dietary source of creatine, right?

So vegetarians 100% rely only on their 1 to 2 grams a day, and they're probably the population that benefits the most from supplementing with creatine. There are just countless studies out there showing this, because they are essentially not getting anything from their diet— I mean, whatever is in plants is negligible.

>> Does the type of meat matter? Like, fish versus beef versus chicken? I would imagine there are differences.

>> Yes, there are. Beef would be the highest. Yeah. And it's probably why people on a carnivore diet just get so jacked, right? They're getting the creatine, they're getting the protein, and they're working out, and it's this combination—they're just getting so much.

>> Do you have a sense of how many grams of creatine you'd get in a 12-ounce steak?

>> People can figure that out with Google. I just know generally speaking that on average people are getting an additional 1 to 2 grams in their diet. So you've got your endogenous production plus—

>> Okay, yes. And then you can supplement on top of that, right?

And this is where I would say for many, many decades the literature was all about the effects on exercise performance, because the muscle is a big consumer of energy, especially if you're working it. And I'm totally just summarizing this—I'm not going into every single detail—but generally speaking, 5 grams a day of creatine is enough to saturate your muscle tissue. It takes about a month, maybe 3 weeks, to fully saturate it if you're doing 5 grams a day, which is where the loading phase comes in—

>> The bros that were telling me to take 30 when I was 13.

>> That's kind of—

>> That might have been overkill. >> Well, it stems from the fact that in these studies, because participants weren't taking 5 grams a day for 3 weeks during these short, week-long studies, researchers wanted to quickly saturate their muscles, which is why they used a loading phase. Most people don't have to do that. Unless you're doing some competition and you need it right then and there, generally speaking, it's just not necessary, and you really just increase the risk of GI distress.

My thinking today is just take 5 grams every day and you should be all right. Well, that was my thinking up until a few months ago. For the last year and a half, I've been taking about 5 grams a day. The evidence shows that creatine essentially improves your exercise performance by allowing you to do one to two more reps. Your training volume goes up because you're recycling that energy quicker and able to do more work.

That is why you then get gains in muscle mass and strength. It's not like creatine itself acts like protein; it's not increasing muscle protein synthesis if you're just a couch potato.

>> Yep, you have to do the work.

>> You have to do the work, right? And the reason you increase muscle mass and strength is because you're able to do more work. For me and my CrossFit, it really is useful because there's a lot of explosive leg training and HIIT. So for me, it was pretty obvious that it was having an effect—though of course, there's probably a mixture of placebo in there as well, I'll definitely admit that.

But then I started getting interested in some of these brain studies. As you know, I'm very interested in brain health, neurodegenerative disease risk, and anything that can improve cognitive function in a safe way—like a safe nootropic. That's where I really started to get interested, and this built up over years. Even though I hadn't been supplementing with it yet, I had been keeping an eye on the literature, and finally, when I started using it, I was pushed all the way over. I'm like, okay, I'm all in and I want to dive into this.

>> And so you felt like you went all in because you actually felt a difference, or you thought, well, I'm already taking it for muscle purposes, let me really go deeper on the cognitive science?

>> Yes, I was already thinking that this is clearly improving—first of all, the literature was clear with the muscle. There's so much literature you just can't deny it, no matter what one-off study comes out.

>> It is a little odd. There aren't that many things where the consistency of the studies is always in the same direction. Really, you're basically looking at the magnitude or the effect size, but you're always on the same side of the tornado plot.

>> Exactly. And when we're talking about 40 years of research, that's a lot of data.

Now, regarding the brain: for one, your brain does make a little bit of creatine as well—somewhere between 1 to 3 grams a day, I believe. But the data on the effects of supplemental creatine on the brain doesn't date back as far. So you do have to take the data with somewhat of a grain of salt, because there are a lot of small studies, and you can't hang your hat on it and say this is the be-all and end-all. However, as more data comes out, I'm pretty certain that it's—

>> Let's talk about some of the measurements, because I think one of the advantages of studying the effects of creatine on physical performance is that we have really good objective measurements that you can demonstrate in a short period of time. You could do a 12-week study and objectively, unambiguously determine if there was hypertrophy and an increase in performance, right?

How do we do that on the cognitive side? What are the data you've been looking at that have given you an increasing level of confidence?

>> Okay. Well, first let's talk about dose, because that's important, and that's initially where researchers were looking into—

effects of creatine on the brain, the five grams a day didn't seem to be doing anything in terms of like getting creatine into the brain. And so the question...

>> So creatine is crossing the blood-brain barrier, that's established? >> It is. However, the muscles are greedy as hell. >> Ah, those lovely greedy muscles. >> Yeah, the greedy muscles. And so they're, when you're taking in up to about 5 grams of creatine, they're consuming it. They're taking their share. >> Especially if you're training. >> If you're training, yeah, exactly. But even if you're not training, it's still going to muscle. But yes, especially if you're training.

And so there was a German study published a few years back that looked at a dose-dependent effect of creatine levels in certain brain regions.

>> So naive question, are they using an isotope? Are they labeling the creatine? >> I believe they were using an isotope. >> They're not using like CSF levels or anything? >> I believe it was an isotope. Okay. Um, but don't hold me to it because I don't remember exactly. >> You need more creatine. >> I know.

But the 10 grams was where creatine was now... >> Was not rate-limited. >> Yeah, exactly. Now you were increasing levels of creatine in the brain. Pretty sure it was isotope-labeled.

So essentially, 10g... you have to double that and that's where I was like, okay... >> Sorry, just to be clear—I'm sorry to interrupt you. Does that mean you're going to get mixed results if you look at the cognition literature, because you're going to have some studies that were underdosed? If you have a study done at five grams and it shows no effect, you're going to come to the wrong conclusion potentially. >> Bingo. Just like with any supplement or drug, right? Dose matters.

So yes, that is the case. But also, it's important to point out that just like with muscle, you have to be stressing your muscle for creatine to work, right? You're basically putting in the work and you're able to put in more work, and that's why you can increase muscle mass and strength.

With the brain, it works in the background of stress. And what I mean by stress is:

• Sleep deprivation
• Psychological stress (like having an exam, or marital or emotional stress)
• Neurodegenerative disease or anything that compromises brain function

That's where creatine really shines in terms of cognitive function. And you might—this is my argument—I feel like I'm constantly under stress. I think most people are constantly under stress. >> Anybody listening, if you're not under stress, I'd like to hear from you. I want to know what you're doing. >> Same, same.

Even just diving into the scientific literature, like what we do every day learning, that is the stress, right? The brain consumes a lot of energy as well. >> 20% of our total caloric intake goes to an organ that weighs less than 2% of your body weight. It is the most insane statistic of the human body. >> Totally. Which is why it makes sense that giving your brain extra creatine, which can recycle that energy quicker, would help—particularly in the background of when you're using more of that energy.

The studies that look at the effects of creatine on cognitive function are looking at processing speed, memory, and other metrics typical of any supplement or treatment intended to improve cognitive function.

But again, it's really in the background of stress—whether that stress is aging. Older adults seem to benefit from taking exogenous or supplemental creatine.

And people who are sleep-deprived. That's a really big one. In fact, a few studies have shown that in sleep-deprived individuals given creatine (calculated on a per-kilogram body weight basis, totaling around 20 to 25 grams), not only did the usual cognitive deficits not occur, but their cognitive processing speed improved beyond baseline.

Now, this is a small study. Peter, if you were to look at this, you'd be like, "This is a small study," and I agree. We can't just hang our hat on this one study. >> Who's doing these studies? Because there can't really be any financial incentive to do them, right? Creatine is ubiquitous; there's no IP around it.

I want to talk a little bit about Creapure and give people advice on how to buy creatine, because if you go to Amazon, it's like, which one do I buy?

But who is taking the mantle on trying to understand this? Because if you've got something insanely cheap, completely safe, that has other bodily benefits, and we're just trying to figure out if we should all double our dose from 5 to 10 grams, it would be great to quantify the effect size and stratify patients. Not everybody listening is doing this, and asking people to do more stuff comes at a psychic cost. It would just be low-hanging fruit in biomedical research. >> It is. Darren Candow is someone getting into the brain stuff. There are quite a few people doing muscle research who are now collaborating and reaching out to neuroscience folks, and it's kind of exploding. >> This has got Dom D'Agostino's name written all over it, right? >> That's a really good point. It totally does. >> We've got to talk Dom into doing this.

There was a pilot study that came out—and these are researchers I don't necessarily know, some of them pretty junior—on people with Alzheimer's disease, and they were given 20 grams of creatine.

And it improved cognitive function in these patients with Alzheimer's disease. I think there was also a placebo control as well, and then they took those same patients and had them exercise, and it improved strength and improved, you know, lean body mass.

See, I'm just going to be skeptical that—I still think that the name of the game is prevention, right? Like where I'm most interested, and of course that's the hardest thing to study.

[1:34:4] >> But you know, when we think about the energy crisis that is happening in a brain with Alzheimer's disease, and while there are—I think you and I would agree—there are probably many paths towards Alzheimer's, right? There are inflammatory paths, there are lipid-mediated and vascular paths, and then there are sort of these more metabolic paths. But when you take that individual who is most susceptible to the metabolic path towards dementia and, 10 years earlier or 20 years earlier, you're giving them a substrate that is augmenting ATP creation—

Yeah, I get it. That's the hardest thing to study. That's also the single most important question in my mind.

>> Totally. I mean, prevention is the name of the game for sure, 100%. Unfortunately, there are a lot of people's parents out there that have it right now because they missed the boat on prevention, right? And those people are, you know, obviously their kids are willing to do anything to help them. It's terrible, right?

[1:34:3] But I mean, I think the reality here and the point I want to make is I think that creatine for the brain is the most interesting aspect of this area of research right now, at least for me. I certainly think that there's really no downside to doing 10 grams a day.

Now in some cases—with sleep deprivation, like I just got back from China about 5 days ago—I've been doing 20 grams a day, 15 to 20.

>> And are you having any... I remember as a kid I never had the GI side effects with even 30 a day, but for some people, is 10 to 20 in one dose—

>> It would probably affect a lot of people's GI. I do 5-gram doses.

>> And you'll just put the 5 grams into water and just—

>> I put the 5 grams into water or like tea, and then I just take it like that. And you know, I do it mostly before noon. So I like to take it in the... because for, you know, like I said, I don't know if this is placebo, but I don't get sleepy in the afternoon anymore. If I only get 5 grams, I get the sleepiness.

Now again, it could be complete bias, and who cares if it's not like—

>> If the placebo is working for you, exactly, because it's physiologic, right? I mean, it's a biological mechanism that's working for you. And if you listen to this episode and it works for you, that's great, because there's really no downside. And in fact, I think we're going to get more and more evidence out there that it's going to be beneficial, and 10 grams is going to be the new—

>> 5 grams. Yeah, it's going to be the new baseline.

>> But if you aren't in this state of jet lag, 10 grams per day—you do two shots of five and you're feeling great.

>> That's what I do. 10 grams a day.

Let's talk a little bit about brands. Are most of the companies out there that are otherwise very reputable in making supplements—so whether that be Thorne, Momentous, like I've lost track of all the names of the companies out there that make supplements, but there are a handful of supplement companies that actually really seem to be credible. Do you have any difference between them? Do you always look to make sure that Creapure is the active ingredient within it, or does it matter?

>> I don't. I think the most important thing is that it's creatine monohydrate. The reason people like Creapure is because it's pure.

>> But what I like even more than that is NSF certification, because there's rigorous testing to make sure there's no lead contamination and heavy metals and things that sort of hitchhike on a lot of these supplements. And so I personally—that's what I look for. I mean, I think Creapure is great too. I don't know if, depending on whatever brand you know, is using Creapure—

>> Yeah, lots of brands are using it.

>> Exactly. So NSF is what I look for. I use Thorne.

>> And there's no reason you can't have both, right? You could have Creapure in an NSF-certified product. One thing I want to call out that one of the members of my team was sharing with me yesterday: apparently there are a whole bunch of creatine gummy products out there. And for the obvious reason, they're very popular. But there was a third-party test... Well, why don't you tell what they discovered?

[1:37:1] >> Yeah, I mean it was essentially there was third-party testing looking at actually quantifying the levels of creatine monohydrate in these gummies, and there was essentially none in 95% of them.

And that does, I think, translate to gummies in general. I've talked to vitamin manufacturers and they've said it is incredibly challenging to get an active ingredient into a gummy, plus you're heating it up. So there's the heat component that's degrading things. So gummies—yeah, unless you can find a third-party tested gummy that actually has the amount of creatine monohydrate in it that's labeled on the nutrition facts label, I would avoid a gummy.

>> Yeah. And also the thing about this whole gummy craze that drives me bananas is you have to ask the question: how many gummies do I need to eat? So look at the chalky white creatine powder, look at what 5 grams looks like, and ask yourself, how many gummies would I need to put this into such that they would be palatable? And then the question is, do I really want that many gummy bears? Like, what am I doing to my teeth?

>> Yeah. What else is in the gummy?

>> How much sugar do I need to eat that's totally unnecessary? Like, if I'm going to have sugar, let it be good. Give me a nice piece of chocolate, right? Give me a piece of carrot cake. I'm not going to squander my sugar calories on gummy bears that aren't even giving me creatine.

Don't eat the gummy; you need the powder. Thanks for bringing that up, because also capsules—you're going to have to take so many capsules to get, let's say, the 10 grams, or even the 5 if you're just looking for the muscle effects. You're just going to have to take a lot of capsules. And so that's also an important point.

I also think that the vegan and vegetarian angle is another really important aspect here.

>> But if you take them to 10 [grams], they should be fine because they're at least offsetting the couple—

>> I'm just saying it'll change. Like, I have so many vegan friends, and it just literally changed their lives. My phone blew up! I mean, I couldn't believe the magnitude of effect that these women were experiencing was way out compared to what I was getting. And I noticed an effect, but they were just... I mean, it was like unreal.

>> And how long had they been vegan?

Um, one of them not that long. One of them like not that long, maybe like two years, but the other one just like, you know... >> Most of her life. Yeah. And so I'd be interested—the one who had been vegan for 2 years, like when she all of a sudden got creatine back, I wonder if that was a short enough period of time that she was like, "Oh my god, this is what I used to feel like just two years ago." Or there's probably too many confounding... >> She's always kind of calorically restricted, too, and I don't know how much protein she was really eating when she wasn't... yeah, but that's a good question. >> Talk to me about kids. So, my daughter is 17. She's really training hard. I mean, she runs cross country. She does track. She's in the weight room. Um, is she too young? Should she be—should she be taking creatine? >> Yes. There's studies out there on kids, and so like children like younger than 17 that are doing like... >> My boys—I'm giving it to my sons. Okay, how much? >> It's, if I remember correctly, it's like 0.1 g per kilogram body weight. I give my son like 2 and a half grams. >> Okay. >> And um, it again, there's studies out there that it's—it improves agility is a big one, and speed. So a lot of these studies were done more like in endurance, like because kids aren't like lifting weights, but so it improves like agility and speed. >> And would you for my daughter give her five? >> Yeah. >> Of course. Also she's she's studying hard, like does she just need the full— >> Exactly. Um, good question because she is almost an adult, right? >> I mean, I don't—I think she's done. >> If it were me, I would do 10. >> All right. >> If it was my daughter, um, that—yeah, there's, you know, there's actually some studies that have been done in college students who are undergoing like taking a test and stuff. And of course, you're sleep deprived when you're studying for the test, and the creatine improves test scores. So... >> I'm—I'm all in on the creatine. My creatine budget literally—the household creatine budget just went up 4x. >> Same with—same happened to me, like, you know, like 6 months ago or so. Um, but there's no, again, the harm that people like claim, there's just—it's unfounded, you know, like the kidney problems. It—it doesn't cause—first of all, as you as a physician, you know what the problem is: people are looking at creatinine. If you're like, if you're supplementing with creatine, you—you got to tell your physician... >> Well, the other thing is, physicians listening to this, please make this another reason to just look at cystatin C, please. I'm sure the test costs an extra dollar, it's worth it. Cystatin C is a far more accurate way to measure and estimate GFR, and you don't have this problem of getting the confounded creatine levels increased. Um, I know we have to get you out the door relatively soon because you were giving a talk today, but if we have a little bit more time, I want to talk about a topic that is near and dear to both of our hearts, which is temperature. Um, you know, my journey on the sauna train, right? I was probably the biggest sauna skeptic for many years. Um, not because I didn't love it. I love—I've always loved saunas. I just had a hard time believing that the data were causal, right? I was just like, there's too much healthy user bias in here. Um, you know, over the last 5 years as I've looked closer and closer at the data, um, while I can't comment on the effect size—I think it's very difficult to comment on the effect size from all the epidemiology—it's very difficult for me to believe that there isn't a positive effect in terms of at least cardiovascular disease and dementia. Um, so those are my priors. My priors are I'm now in a place where I actually view sauna as an intervention that can help an individual reduce their risk. And for me personally, because I don't really worry about cardiovascular disease anymore—it's so easy to manage the risk around that otherwise—but dementia is a very difficult risk to manage, because you know, there's fewer things we understand about the causal pathways to get there than we do ASCVD.

So, in many ways, I'm in the sauna not just because I enjoy it, not just because it's a wonderful social opportunity to be with your spouse, if that's how you choose to do it, but because I'm also banking a little bit on, hey, I want to get some benefit to my brain. So, tell us where you are currently, because I think you're one of the people who keeps up with this literature more than anybody. So tell us if anything has changed in your mind one way or the other, both in increasing confidence, decreasing confidence... you know, just update us on where you are.

>> Yeah, I—I am still a huge proponent of using deliberate heat exposure to improve your health, both cardiovascular and brain. I do think that the physiological mechanisms, um, are somewhat—in many—in some ways, mimicking some aspects of moderate-intensity cardiovascular exercise, and that is how it is improving cardiovascular health and also an aspect of that brain health... cardiorespiratory fitness, that's been shown. There's been not only like observational data, but there's been intervention studies looking at endurance, getting someone on a stationary cycle, and then adding the sauna on top of that, and VO2 max improvements were greater in individuals that are also doing the sauna right after their training. So, um, anything that improves cardiovascular health is going to improve brain health. But there's another aspect to the story here, and this kind of dates back to like the origins of my—like one of my first biology experiments I did in, um, when I was actually a technician at the Salk Institute before I went to graduate school. And that has to do with the heat shock protein response. And so we do know that heat stress in the form of either hot baths or going into a hot sauna—infrared sauna, a little different, you'd have to stay in there really long, like a long time to get a real heat shock response—but if you're in like a 163-degree Fahrenheit sauna for 30 minutes, we know that heat shock proteins increase about, uh, 50% over baseline. >> And what would be the equivalent exposure in steam or water? >> In the water, it's about 104° for 20 minutes, like shoulders down. So you're— >> 20 minutes. >> Mhm. >> Yeah, about 20 minutes. And then presumably if you're in a hotter dry sauna, less time is needed? >> Presumably, uh, we don't have that data. I'm just quoting the data we—that we, the empirical data that we have. And what—tell me more about the IR, because there are no questions I get asked more than, "Hey, are all the benefits you're talking about, which all seem to come from studies in dry sauna, are they also applicable to infrared saunas?" To which the only data I can find is if you're using infrared, you actually have to rely on the change in skin temperature to know you've hit the...

Whereas in a dry sauna we can look at time and temperature and humidity, right? Like if I know the temperature of the sauna, the humidity of the sauna, and the duration that you're in there, I know how to measure the effect size. We can't do that in IR.

So we looked at some data that looked at basically thermal skin change—and I can't remember the exact number so I don't want to get it wrong. It was either a five or eight-degree increase in skin temperature that was necessary to produce similar benefits. What do you know about this? Do you know about this? Not that I don't know specifically about that, but I do know most of the studies that have been done comparing—and there have not been many, maybe three or four that I can think of—they have compared a regular hot sauna to an infrared sauna at the same amount of time. So in other words, the dose is the same. Obviously, the temperature difference is pretty vast depending on the study. The hot sauna could be, you know, 160 or it could be 175 or 180, and the infrared is like 140 or something like that, right?

So a lot of variation in terms of the temperature of the saunas. If you're looking at... in fact, there's like one study, the title is something like Infrared saunas do not mimic cardiovascular effects of exercise or something like that. And that's because at the given dose, right, if you're just doing like a 20 or 30 minutes, it's not going to be the same. Like your heart rate doesn't go up as much, you don't feel as hot because the temperature is not as hot. Now, you will sweat based on a different mechanism. But as far as my take of the literature, it's pretty clear to me that infrared saunas, if you want it to mimic the cardiovascular exercise response, you might have to double that. You might have to... Yeah. So rather than spending 20 minutes in a 175-degree or 180-degree sauna, you're going to spend 40 minutes.

>> Wow. >> Right. So you're giving up your time if that's the kind of sauna that you either have or enjoy, because if you do—and I've been in infrared saunas many times—if you stay in long enough, you get that... you feel hot and you feel that heart rate going up just like you do when you're in a hot sauna. It just takes a lot longer.

Now, I know you've had Dr. Ashley Mason on your podcast. She's been on my podcast as well, we collaborate. >> Is she awesome? >> She's awesome, I just love her. She's awesome, and we collaborate on a variety of sauna studies. She wears a lot of hats, and her data looking at... you know, she's a psychologist by training, and she looks at depression as an endpoint in terms of these infrared saunas, and she's looking at core body temperature increases, right? So people, their core body temperature is going up by like almost 2 degrees.

And in that case, I mean, she's got them in an infrared sauna for like 85 minutes! They're in there a long time, and they are getting hot. And she'll talk about it, you know, she's got assistants that are cooling them down on their head because it's a head-out infrared sauna. It's like a bed. And anyways, that's a whole other area looking at the effects on mental health.

And this actually stems from her mentor, Dr. Charles Raison, who I had on the podcast many years ago. He did this really phenomenal pilot study looking at... it was kind of funny, it's called hyperthermia—so you're inducing hyperthermia, right? And it's like this funny chamber where it's increasing your core body temperature. But Ashley's not using that anymore; she's established the heat bed as a safe...

>> And what do you think is the role of the head being hot? So when I am in our sauna, which is a dry sauna, I think... and I'll run it pretty hot. I mean, I'll run it above, like, at least 190. >> Okay. >> And again, part of it is I don't want to be in there for more than 20 minutes because time is tight. Time is my most precious commodity. So I'd rather do 190 to 200 for 20 minutes than go longer. But I will tell you, the most discomfort is in my head.

Now, of course, part of that is I'm sitting on the top bench, and so temperature is hottest at the top. So I think my head is exposed to more heat than my torso just based on that difference. But is there harm or benefit, or do we know anything that's happening from any of these other metabolic parameters? >> I will... okay. To answer that question, it'll take me in a whole other direction. Should I go there right now or should I finish? >> No, I'm sorry, then finish because I want... >> Finish and then go there.

All right. So basically, the only point I was getting at was the pioneering study where people with major depressive disorder were exposed to this device where they're heating up their core body temperature by about 2 degrees, and they had an antidepressant effect that lasted six months compared to a sham control—which was also heating people up, but not... >> Single treatment? >> Single treatment.

Now Ashley's gone out and she's done four to eight treatments, depending on the person, whether or not they completed the whole study. And she didn't have a sham control, but she's got a... just phenomenal... >> How do you sham-control that? >> So, what he did in his study was he had the same device that just got people a little bit warm enough where they were thinking they were getting the active treatment, but it was not... >> Didn't hit the threshold. >> ...of raising their core body temperature by two degrees. It was a phenomenal study.

And this is, by the way, Peter, what got me interested in the sauna back in like 2008 when I started doing it every day. I lived across the street from the YMCA, and I was going into the sauna in the morning—it was freezing in Tennessee—before I would go into the lab to do my experiments. And I was going every single morning and staying in a long time because I was like, you know, "Go hard or go home," kind of thing, and I love the heat. And it was incredible the effect it was having on my mental health and my ability to deal with stress and anxiety, so much that I was like, "This is insane. What's going on? Nothing has changed other than I'm going to the sauna every day before I go and do all my failed experiments."

And that's kind of what got me into the whole sauna thing—actually the effect on my mental health. So it's kind of fun to go full circle and team up with Ashley on some of this research as well. And she's amazing, by the way, and she's got some new studies coming out that are really in this whole field of sauna and depression. I think she's just opening the door.

So that said, the effect on the head—and you know, if you think about hot tubs, jacuzzis, right? We're all sitting with our head out as well. It's a good question, because I agree with you. When I'm in a hot sauna and I'm also on the top bench, it's the same deal. I want to get out in 20 minutes if I stay in too...

long, I will get a headache and I—I've know my I know my threshold now. I know the temperature and the duration and the amount of water and all that. Like I know all those variables. >> Isn't it amazing how much water you can drink in a sauna? Like I >> I know, it's—it's >> I worry I'm going to get hyponatremia. I'm like, you got to slow this down. Um, so the interesting thing is is that talking about dementia risk, I talked about heat shock proteins and I—I kind of didn't even I like went off on this tangent. Sorry. But the heat shock proteins, what they do is they prevent proteins from misfolding and forming aggregates, right? And so, um, you know, it's—it's obviously when you're getting into a hot sauna, you are denaturing some proteins. And so, your heat shock proteins are a stress response that's activated to help with the proper folding of those proteins that were kind of denatured somewhat from the heat that you were exposing yourself to. Well, it turns out the heat shock proteins stay active for a long time. And so they end up having this like effect where you're now just improving the folding of proteins in general even after you're out of the hot sauna. Right? So, um, there's a lot of animal studies that have been done. I did a lot of studies in worms like many, many years ago where you can take amyloid beta 42, inject it into a worm muscle tissue, and then activate heat shock proteins and it like prevents the aggregation and it prevents the—the muscle sort of paralysis that occurs in these worms. Animal studies have been done looking at amyloid beta and heat shock proteins and Alzheimer's disease. Again, it's having a protective effect. Now, is that the whole story? No. The cardiovascular effects are also important for brain health in my opinion. Right? You know the data coming out of Dr. Jari Laukkanen's lab showing that dementia and Alzheimer's disease risk is 66% lower in people that are using the sauna four to seven times per week versus just one time a week. Of course, all >> that was at 179 degrees or greater for 20 minutes or greater. Right. >> Yeah, like 175 or 179 exactly for 20 minutes. Um, now here's where your question comes in, and that is like, what about the head? And there was another study out of Finland. It was not Jari's lab. It was another professor that I'm not aware of. But, um, this study looked at sauna use and dementia risk. And then it sort of—it stratified the data based on temperature. And it was protective. Again, people that are using the sauna, again, they're getting a protective effect against dementia. But when people were going extreme—so if they're going above 200 degrees Fahrenheit and they were on average it was like if they were getting to like 212—people do this, by the way. This is like you can go on Instagram and see, it's not an uncommon thing. >> Their dementia risk was actually increased with that temperature where it was like really hot, and my concern is the head at that high of a temperature. >> I've started wearing one of those um >> sauna hats. >> The sauna hats. Yeah. I don't know why it works. Do you >> It's not logical to me why it's hurting—why it's helping, rather? >> I don't know. It does seem to help. I mean, it shields probably some of the heat that you're being exposed to, right? Cuz there's got to be—but the fact that that's a net benefit because it's also got to be preventing you from dissipating heat. >> But clearly what it's preventing coming in exceeds... but it makes such a difference. >> Um >> those, I mean, these cultures, and like—I've also dialed mine down a little bit. I used to be consistently going to at least 200 and now I'm like, you know what, honestly, like 185 to 190 is good enough. >> I'm 180. I do 180. >> Well, my wife is going to be very happy if we dial it down to 180, cuz she—she's more >> uh she seems more sensitive to the heat than I am. >> I'm more sensitive to the heat than my husband is as well. I wonder if there's some kind of sex thing where—yeah, if it's—it's definitely like I'm—I'm more sensitive to it. >> So that's great. So, but this is important. So, you really think that we could even dial it to 180? >> Absolutely. >> And just totally get the same— >> I mean, the data is showing that. >> Yeah. Yeah. I know. I just, you know me, more is better. >> More is better. And not just you, it's—it's a common, you know, it's go hard, go home, right? Um, but I do think we're talking about a type of stress here, right? >> And you have to get it hormetically correct. >> Exactly. Exactly. You know, I don't know that the 212—and I hope people that are out there doing the 212 are like listening to this because >> it's too—it's too hot. There's no need for it. You're not—there's no evidence you're getting added benefit, and if anything there's >> potential benefit risk that >> exactly, potential risk, downside. I don't—you know, that's just one study. >> Yeah. Yeah. >> But it's enough to make me go, hm, I don't—like there's no—there's no data showing we need that. So why are we doing that? >> Rhonda, I know you got to go, but I want to end with just one—one question and topic, which is what year did you launch your podcast? >> I launched it in >> '14. >> 2014. >> So here we are. We're 11 years in. You are the OG in this space. You have an incredible podcast. Um, are you still enjoying it, and what are you most excited about? >> I love doing the podcast. I don't do it every week like some people. I like to find the guests that I'm really interested in learning from. What I love the most is I've always learned more from the conversations I would have with my colleagues or professors than I would from reading a paper. And now I get to do that for a living, where I'm just having like these superstars on my podcast and I get to like learn so much from—I read their papers first, but I also—I learn so much from the conversation, and then people get to like benefit from it, right? I mean, it's so rewarding. So, I get to like itch my own, you know, or scratch my own itch, and then I also get to like help people. >> Well, you know, I just want to make sure that everybody listening kind of understands your place in the—in the podcast landscape, which is—I've talked about one of my favorite podcasts, probably my favorite podcast, or one of my two favorite podcasts in the world is called Acquired. So, Acquired is a podcast about companies, great companies, and what makes them great. And the hosts of that, uh, Ben Gilbert and David Rosenthal, they only put out one a month on average. But the reason is the amount of work that they have to put into the preparation is insane. And I've—I've gotten to know uh Ben especially, and you know, I think Ben is putting at least 120 hours of preparation into each podcast, and therefore you can only do one a month. Um, and it shows. So, in many ways, I think of you as the Acquired podcast version in our space, which is just the—the breadth and the depth of what you're doing is—is awesome. It's such a treat. And, um, it's just—it's always it's always

Quality over quantity. And yeah, I'm sure if you could put out one a week, you would, but the reality is you wouldn't be able to put in the quality if you were trying to bang one of these things out a week. And anyway, I'm just glad to hear you're still loving it. And it's hard to believe how fast time has gone. I remember being on your podcast in 2014, so that's kind of insane.

You were like one of the first 10 guests I had. I don't think I knew what a— I mean, I sort of knew what a podcast was 'cause Tim Ferriss had had me on his, but it was like I didn't really understand what this was. I was like, I wonder why does she want to talk to me? Like this seems kind of random, but look at how much it's evolved, right?

I know. Well, thank you for the kind words. And I feel the same about your podcast. You know, when I'm looking for information that I know I can trust, it's always like, what? Peter, what's Peter? Peter is someone that I've always been able to trust for being rigorous, right? And really like, like you said, if something changes, then you change. And I respect that.

Well, Rhonda, this has been super interesting. As is always the case, there were about 80% more things we were supposed to talk about today, but I'm really glad that we got to the topics we talked about. I think the protein question, the creatine question, and this nuance around temperature are all things that matter to everybody and in two of the three cases, I learned a lot. Obviously, on the protein side, it was more about you and I trying to set the record straight. But this creatine stuff is new. It's going to change what I do. And also, you're going to—you've already made a change to what I'm going to do in the sauna. So, anyway, thanks again. This was awesome.

Thanks, Peter, for having me on. I really appreciate it.