B (3:33)

Yeah. Good to see you. We go back a long way.

A (3:36)

You're still in the. Our same former neighborhood in San Diego.

B (3:39)

I know. And I'm thinking that you found the same feeling here in Austin.

A (3:44)

Yeah, we did. 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 to which 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.

B (4:25)

Let's do it. I do think it's an important topic. You and I have probably talked to all the world's experts on protein and 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 minimalist daily allowance recommended almost sounds like optimal in a way. Like I think people confuse that with the optimal amount of protein. Right. So it's kind of tricky. 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. 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's so many different publications that, I mean, people can start off by reading one of them here by Stu Phillips, Perspective Protein Requirements and Optimal Intakes in Aging. Are we ready to recommend more than the recommended daily allowance? And there's several of these out there. 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, what they are doing is measuring the amount of nitrogen that is excreted in urine after you are metabolizing protein. And some of the flaws that are, I would say 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 the case is, is that it's an incomplete collection. I mean, like when you pee in one of those cups, you don't get all the urine. It's incomplete collection.

A (6:29)

And we lose nitrogen through other means.

B (6:31)

Exactly.

A (6:31)

That is not just urine.

B (6:32)

Yes, exactly. We lose the nitrogen through other means. And so essentially, the signal to noise ratio is pretty low. 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 like more stable isotope studies. The major isotope that's used is the L13 carbon labeling 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. And so now you're getting a quantification that's much more accurate in terms of your protein steady state and turnover. 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. We don't store amino acids like we store fatty acids as triglycerides or we store glucose as glycogen. 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 an intake, daily intake of amino acids to make sure we're able to do all those functions.

A (8:09)

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. Like if we studied biochemistry, and anybody who's studied biochemistry will know this, but we can store fat in unlimited quantities. 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. 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.

B (9:43)

Exactly. For short term and long term health, I think that's pretty clear. And that's where this RDA not being enough is a very important point. So let me go back to this isotope tracer studies, multiple studies, okay, Multiple studies, as you know, have shown.

A (10:00)

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.

B (10:08)

Sounds good. Multiple of these papers have shown that really going up to more like 1.2 grams per kg 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 for 30% more. 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 if we look at the actual protein intakes of adults, 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 kg body weight per day of protein. So pretty close to what that RDA is not what it should be. Older adults, 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. 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 steady state protein balance.

A (11:25)

So here's an interesting question, Rhonda. So 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, is there any way we can estimate what percent of that decay is simply being driven by insufficient amino acid consumption versus other factors? 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. Like 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.

B (12:22)

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, so 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. But when older adults take in 1.2 grams per kg 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 support what you were saying in that if you just increase your protein intake by 50% to this minimum, what the RDA should be 1.2 grams per kilogram body weight per day. I think that's pretty much what most all the experts agree. It's time to change that RDA to that number, 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. 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, for our muscle health, and also is getting us out of that net negative state that we're in.

A (13:43)

So step one is we should move the floor from 0.8 to 1.2.

B (13:47)

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 the new rda and as you mentioned, so you kind of hit on this anabolic resistance. And I think that's also a really, really important point because it does compound 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. Now, anabolic resistance is when your muscle tissue becomes less sensitive to amino acids. And so you're not making as much muscle protein synthesis isn't occurring as much as it does when you're younger. I think it's pretty consensus now that a lot of anabolic resistance is not necessarily aging, the aging process per se, so much as inactivity. Inactivity, yeah.

A (14:37)

And the experiment that Luke Von Loon shared when he was on the podcast, I think was a very elegant way to do this, which is they took young subjects. I don't remember if they were in their 20s, but it was thereabouts, maybe in their 30s. So 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 is, has not escaped me, which is after whatever period of time, the individuals were casted on one leg, not casted on the other. Let's just say it was two weeks, four 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 the stable isotope experiment in these individuals and looked at muscle protein Synthesis rates, and lo and behold, the leg that was uncasted, perfectly normal. The other one, 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.

B (15:47)

I totally agreed. Yeah. I think there's also another study that was done in older adults.

A (15:52)

Can we explain what anabolic resistance is? I think it's worth people understanding why this idea matters.

B (15:56)

Yeah. Anabolic resistance. When we eat protein, we're breaking down amino acids, and the primary amino acid that is anabolic is leucine. Leucine are getting into the muscle tissue and that is instigating. It's a signal to increase muscle protein synthesis. So you're making more protein in your muscle, and that in turn increases muscle hypertrophy. The other major signal to do that is mechanical force. So that would be the resistance training working of the muscles. So as we get older, our muscles do become less sensitive to those amino acids. The leucine transporter being one of the major ways, but I think there's others as well. And so what happens is, is that for this same amount protein dose, and this study has been done, and if you compare younger adults and older adults 65 years age and older, you give them the same exact protein dose, 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 double that amount of protein. That's because again, you need. It's just your muscle tissue's not as sensitive to the amino acids. And so to get more of them in, you have to increase your intake of the protein. Now, to your point about physical activity being the major driver here, I think that's 100%. I agree. I think it's totally true. 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.

A (17:29)

So in other words, the activity makes up for it.

B (17:32)

It does. As you're aging, if you're a 65, 70 year old male listening to this episode and you're engaging 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 in 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, you should be training.

A (17:59)

Yeah. And think about the impact that physical training has on insulin resistance as well. Completely different mechanism of action. Probably ties 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. It's been demonstrated so conclusively that actually nobody really talks about it. It's just taken for granted.

B (18:21)

It's a good point. So the anabolic resistance, if we're talking about general population, again, we're going back to these surveys that are done looking at how physically active are people. Cause those numbers are out there, Right. We know that, generally speaking, adults, including young and old adults, about 32% of them engage in resistance training.

A (18:40)

How much?

B (18:40)

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 resistance training. Physical activity kind of mirrors a little bit those numbers. But I think the bottom line here is that putting in the effort, it's harder for people. Putting in the effort is harder. It's easier for them to just increase putting something in their mouth. That's why pills are so popular. People always gravitate towards the easier thing to do, which is, I'm gonna eat something, I'm gonna put something in my mouth, versus putting in the effort. It's unfortunate, but it's a reality. And so I think that even just going back to this RDA being too low, it's just so important. It's so important because people are out there thinking they're getting enough protein. Older adults, younger adults, it's really more important with older adults. You have a little bit of wiggle room when you're younger. And then 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's all these compounding factors that's really just digging into their muscle. It's taking away this insidious sort of taking away each year, each year. And then the next thing you know, you're frail, you have sarcopenia.

A (19:57)

My patients are obviously indoctrinated into this, but I'm a bit surprised that there aren't more people that 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 four horsemen, I talked about cardiovascular and cerebrovascular disease, cancer, neurodegenerative and dementing diseases, and metabolic disease. Because, of course, those are the things that are the main assault on your lifespan. And relative to those. Frailty is not as big an assault on lifespan. It is, as you know, the risk of falls are enormous and the 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 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. I think along with cognitive health and minimizing too much cognitive decline, frailty is the thing that seems to determine the quality of your final decade on this earth. 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 who are 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 somehow still seems abstract because it's so many years off. I mean, what's your take on this overall challenge?

B (21:43)

For one, I completely agree with the frailty risk being as important, if not more, and witnessing it with, like, family members. What I think it is is that it's like this incremental thing where something happens. Maybe there's a fall, or maybe there's just a surgery, a planned surgery, or a hip replacement or a knee replacement. Your parents or your grandparents are inactive for many weeks, and they lose a lot of muscle mass. So this happens. If this is a younger person, 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. There's a planned surgery and there's a fall, and maybe there's another surgery, or maybe there's Covid or the flu or whatever it is they keep hitting. And you. You reach this, what's called disability threshold, where all of a sudden, your parents, they just can't walk much at all anymore. And it's like all of a sudden, it's like, when did this happen? Well, the evidence was mounting over the last five years when they had these points of inactivity that were occurring. And so I think people just don't follow the timeline where it's like, they see what's leading up to it before this 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 observed the timeline and said, oh, A plus B plus C is getting me to this point. 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.

A (23:24)

Yeah. 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 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 as 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.

B (24:44)

The cliff is coming for sure. I mean, it's like your retirement fund. 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 going to be screwed. And so with the muscle mass, you're right. You have to bank as much as you can while you're young. And we haven't even talked about optimal.

A (25:02)

We've just talked about not going backwards, right?

B (25:04)

Yeah, we've talked about not going backwards, which is what most people are doing, because this RDA is too low, for one. I think that's the big problem. But optimal is a whole other story. And that's, again, where it's hard to kind of 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 approach to looking at how protein affects the way we age. And I think some of that data has biased researchers and people to think that protein is bad. I think some of it's coming from that evidence, which we.

A (25:39)

That's an interesting point. Yep. Yep.

B (25:41)

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.

A (25:54)

Yeah, I mean, I'd like to talk about harm down the line as we get further up the chain, because we've now just. I like the way we're talking about this, where we're going from sort of the.08 up to 1.2. And now let's talk about going from 1.2 to 1.6 and 1.6 to 2. And as you continue this journey, let's say you look at the data of which there are some studies looking at 3 grams per kilogram per day, 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. The curve is saturating. 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, let's leave bodybuilding out of it, you're sort of hit the saturation curve, but can't seem to find the evidence that it's causing any harm. This is experimental evidence, even epidemiologic evidence. Just no evidence. But that said, let's not get ahead of ourselves. Let's go back to we've established a new floor. 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?

B (27:05)

This again is 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 controlled trials. Resistance training alone or resistance training plus supplemental protein. And the supplemental protein went up to 1.6. Well, actually it went up above that. But 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. That's pretty big.

A (27:53)

I was gonna say that is bigger than I would expect.

B (27:56)

Yeah.

A (27:56)

Especially on the strength side, in the strength side.

B (27:58)

So the protein itself. But if you think about it in a way, we're talking about supply and demand. 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. And then 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. But yeah, I was surprised by the strength as well, really. Once you went above 1.6 grams, there was still increases in muscle protein.

A (28:33)

The curve is slowing down.

B (28:34)

I like the analogy that Stu Phillips uses. He says like if you have like a wet washcloth, you squeeze it to get all the water out. Most of that water's 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 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 high level athlete. Definitely going to have to go above 1.6. That's when you get into the more 2. 2.2 grams per kilogram on body weight. So people that are doing a high level of training, whether that's endurance or strength training, resistance training, because endurance athletes, I mean, they're. You are battling being catabolic. I think the evidence for more optimal. You're talking about 1.6 grams per kilogram body weight. You can get marginal benefits above that up to like 2.2.2 grams per kilogram body weight. But again, that's people that are really training.

A (29:31)

Yeah. To me, there's an analogy here with APOB and cardiovascular disease. So if you look at the three bodies of evidence, so 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, again, ldlc, apob, easy to view them together. So on the X axis you have LDLC going down. So from 160, 140, 120, 180, 60. So descending LDL C. 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 in 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 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 30mg per deciliter. 30mg per deciliter is really low by most people's standards. For context, 60 milligrams per deciliter is about the 5th percentile. At the population level, 30 milligrams per deciliter IS about what a child is. So we're born with relatively low levels of apob, 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 is this rise in apob. 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. It probably depends on your previous exposure, though. 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 APOB, 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 APOB 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 APOB of 60 milligrams per dec, I don't think you need to do a thing. I think they're just fine. And again, it's the inability, I think, 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. It's very frustrating for a person like me who craves nuance.

B (32:12)

Agreed. I love that analogy. I think it's perfect because 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, certainly when you start to get into that energy deficit phase as well. 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, gain muscle. If you wanna lose fat and gain muscle at the same time, you're gonna have to take in a lot of protein.

A (32:47)

Yeah. So that's another very important point. Another point I wanna make is you're still dealing with an asymmetric target. We tell our patients to be closer to two. Now, I know that's just gonna get a whole bunch of people on the antiprotein 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 point 5, another day they're at 1 dot 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. If you're sitting there listening to this and you're confused and you're asking, oh my God, should I be eating 2 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.

B (35:09)

Day, I can just tell you from personal experience, it's actually smarter to aim higher because I constantly not meeting the one thing I am not.

A (35:17)

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. We literally have pasta and sauce. There's no fricking 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.

B (35:47)

Right. I was thinking about this because we mentioned the 1.2 being the sort of the minimum buy in the 1.6 grams per kilogram body isn't necessarily just for people training a little bit. It's also older adults that are not training because we talked about the anabolic resistance. I'm eating twice as much protein as well. And so what you're talking about here is going up to two so that you can really have an average at least of 1.6. You're getting that average.

A (36:13)

I never want to fall below that. That's really the point is I know I'm training every single day 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 gonna take steps backwards if I'm below 1.6, so I'm gonna overshoot so that my down day is 1.6, 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 meet these criteria. Human clinical trial of this duration. Da da, da, da, da. Nothing but crickets.

B (37:05)

Yeah, I mean, I haven't seen any human data either for sure.

A (37:08)

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.

B (37:22)

Yeah.

A (37:23)

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

B (37:35)

Yeah, exactly. I haven't seen that data either.

A (37:38)

We haven't spoken specifically about pregnancy or adolescence. What do we know about protein requirements? Because there are clearly women listening to us right now who are pregnant or who will be pregnant. And I don't think there are any adolescents listening to us, but I bet there are parents of adolescents. So what kind of Guidance would we want to give these folks?

B (37:55)

It goes up with pregnancy and also adolescence.

A (37:58)

I mean, so are there formal recommendations?

B (38:01)

I don't remember. Again, it's all about like going a little bit above what's the rda. And we've already established that's not enough. 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.

A (38:16)

So if we accomplish nothing else, that's the single most important take home message here.

B (38:20)

I really think it is because everyone looks at those guidelines.

A (38:23)

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 percent of daily requirement. But it was obviously baked to a very low number because I remember my son was looking at it with me and he goes, 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.

B (38:49)

Growing is also an important time for protein. Right. Because these amino acids and the essential amino Acids are activating IGF1 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, kids are more physically active, they're doing sports and things like that, adolescents. So it's really important to get the protein requirements. I haven't dug into all the nuance of that data. The way I look at it is it's got to be like a 1.2. Even though that's an adult, it's more like a 1.2 gram per kilogram for an adolescent who's pretty close in body size to an adult, generally speaking, they start growing pretty tall.

A (39:46)

Yeah. I mean, I would think for kids it should be at least the 1.2 to 1.6. Just look at the activity level of my kids is they make me look sedentary. 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.

B (40:11)

I would say the other thing would be the 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 group of population of people where the high protein intake is critical 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 gonna gain muscle. And we just talked about wanting to bank as much muscle as possible as 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 that's where you start to get really high numbers. 2.2, even higher. You can find studies out there. It's like 3 grams per kilogram per body weight. Going above the 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 it's like you mentioned, it's satiating a little bit thermogenic. I don't know that's the big mechanism here, but I think the big mechanism here is just you're really wanting to prevent this catabolism. So I think that's just another important point because there are a lot of people that do intermittent fasting, time restricted eating. They're trying to do body recomp, gain muscle, lose fat. I think a lot of people are interested in that.

A (41:36)

There was one period in 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 like 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. That seems counterintuitive because I wasn't intermittent fasting because I believed that a fasted state was producing some benefit. There's some people who think that, well, if I don't eat breakfast I'm kicking off some autophagy or something. No, no, it was, it was purely a 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, but 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 in amino acid excess. And again, you can actually do that with liquid protein pretty easily because basically all you're getting is getting relatively few calories because you're just consuming whey protein.

B (42:47)

Did you have any like GI problems consuming so many shakes?

A (42:51)

No, but I did a lot of experimentation. 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. A scent maybe, does that ring a bell? 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 like 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 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 didn't like the feeling on my gut. So for whatever reason that worked for me. But to your point, it's another level of challenge if you're trying to recomp.

B (43:48)

In that way or people on GLP1 right. Receptor agonists. Right. And I don't know how difficult it is to eat a meal versus like take a protein shake. You're satiated pretty much all the time. You don't have a real appetite, but also digestion is slowed. So if you're like consuming more protein, I don't know how that all affects.

A (44:06)

We'Ve seen in our patients. 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. By safely, I don't just mean in the obvious sense of the word, I mean safely for long term muscle health as well. 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. And if you're on tirzepatide, you don't really want a steak, you don't really want to have a big chicken breast. You might not want to even have an omelet. But if we have to make sure you're hitting that 1.6, you might be doing a bunch of liquid shakes. And 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, we also know the downside of that.

B (45:23)

Well, the answer's clear, right? You don't want to be losing muscle mass for sure.

A (45:26)

My point is we do Dexa before and after. We're not seeing the type of muscle loss we saw with our V1 approach to this.

B (45:35)

What kind of dose are they on? Like a higher dose?

A (45:37)

No, I mean, I think for tirzepatide starts at 2.5. Some people are getting enough benefit there. I mean, the other thing that I think our approach has been is that slow and steady wins the race. 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. The idea of being on a saw is probably a bad idea. I think the data suggest 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 benefit. I'D much rather a patient be sort of slow and steady on it as opposed to try to go for maximum and rapid weight loss.

B (46:42)

What do you think about some of that data on like, heart issues or bone loss? Does that concern you at all?

A (46:49)

Sure, I think it all does. I mean, I think all of this stuff has to be paid attention to. And I think the question again comes back to how much of that is occurring due to training? How much of that is happening due to the loss of amino acid intake and the loss of training or the neuropsychiatric.

B (47:04)

That's another one on the eyes. What I'm interested in is we have these GLP1 receptors, like on so many different tissues systemically. Like, how is it beneficial? Is it not beneficial? I don't know that we really know. We have data where there's obviously positive effects, you see, like reduced Alzheimer's disease incidence with people taking these GLP1 receptor agonists. But how much is that is due to, like, weight loss?

A (47:27)

We've looked into this a lot because it's funny, we did a podcast on this somewhat recently where I went through this particular question, which is will GLP1 receptor agonists ultimately prove to be zero protective? I came up with a very obscure way to define that which is independent of weight loss, because obviously at the macro level, they're going to be zero protective, 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 geoprotective 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 obscure metabolic condition without obesity. So we have patients who have diabetes but are already at very low body weight. We have two patients actually in our practice in this regard. After lots of detailed back and forth machination with Ralph DeFronza, who's a previous guest on the podcast, we sort of realized that at least one component of the drug regimen for these patients was going to be a GLP1 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.

B (48:55)

They're looking more metabolically healthy.

A (48:56)

Oh, my God. These are really interesting cases that 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, like, 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 three months of being on 2.5 milligrams of tirzepatide, this individual's OGTT had almost normalized and I suspect by about six months it will.

B (49:35)

That's fascinating.

A (49:36)

And we've managed to do this without any weight loss. So this, to me is the interesting question, which is when you look at some of the Alzheimer's biomarkers which are improving, 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.

B (50:02)

Or like you said, if you're doing this microdose, 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 effect.

A (50:14)

We've also seen some other weird things. Anecdotally, patients have told us that when they inject in the abdomen the fat, the sub Q fat of the abdomen, basically 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. 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. For some people, that would be a bug as opposed to a feature. So you have to understand how to use the tool.

B (50:50)

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

A (51:00)

Overweight. Yes. I'm glad you brought this up.

B (51:02)

Yeah, exactly 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, you know, and I've talked to a variety of experts, Brad Schoenfeld, Stu Phillips, they agree that really if you're someone that's overweight or obese, you shouldn't be calculating it based on your actual weight because your protein requires way too high. It's more like your target weight. If you empirically could measure your lean body mass, that would be better. But yeah, I just wanted to point that out.

A (51:26)

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 pounds right now and your ideal body weight is 220, you don't need a DEXA to figure that out. A DEXA can help. But most people who are £300, remember, gosh, at the end of high school I was 220. That was my good weight. Or maybe, you know, at the end of high school I was £200, which is, I'll probably never get back into those genes 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 had this orthopedic, there's the story of how you got to be £300. Yeah, most people can figure out 220 is probably my goal and that's what I should be targeting. Yeah, so you made a great point, which is how do we reconcile the following. So caloric restriction as an intervention, as a zero protective intervention is the oldest one in the book. I'm not really aware of an intervention where a non genetic intervention that has from a longer standing perspective 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 models of 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, in the downregulation of mtor. 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, I'm being very facetious. I know, I know the answer to this question.

B (53:27)

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 the rodents, it's a stretch. You know what else turns on mtor? Exercise. Physical activity. Mechanical force turns it on in our muscle. And we know exercise is like one of the best things that we can do for our health. I think here, I think 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 in your protein, it's going to your muscle. We know that for a fact. I talked about anabolic resistance and how exercise can counter that. While it's increasing the leucine transporter, the expression of 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, increases muscle protein synthesis. When it comes to deactivating mtor, whether that's through protein restriction or rapamycin, that would be like an hours long podcast. Talking about all the nuanced data there because there's all sorts of differences with sex differences in rodents. You're aware of all this data. My biggest thing here with the protein restriction. Let's talk about one. I did spent six years in grad school working with mice. I did a lot of animal studies. These mice are in a small cage. They are not physically active, they're not running around. I mean, they move a little bit.

A (55:11)

They're not under threat.

B (55:12)

They're not under threat. They're being fed ad libitum. They're just being fed as much protein as they want.

A (55:17)

Perfectly thermoregulated.

B (55:18)

They're not being exposed to influenza or Covid, whatever, viruses, anything that's going to take them out for a period of a couple of weeks. They're in a sterile environment. They're happy, they're happy, and that's it. People are not mice we talked about earlier. As we get older, we're being exposed to infectious diseases. Things 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 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 catabolic crisis events 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's kept you inactive. That doesn't happen to these mice. So protein is much more important to humans because we, of course, need that muscle mass and we need to bank it early. We establish that. And I think that's a really important difference here, is that 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 for, like, losing all this muscle mass and then not happening, and they reach this disability threshold, and then it's very different. So I think that's first and foremost important to point out. The second thing is, 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. 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?

A (57:14)

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 don't want to do anything, I just want to sit in front of my computer. You know what, it probably makes sense to be a little bit caloric restricted because I can't solve your metabolic challenge through activity. But what if I could at least solve it through nutrition restriction? Again, I think it's the inability of people to understand that those are very different states. You cannot treat those two people the same way.

B (58:01)

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

A (59:09)

Yeah. And the other thing I think that is missing from this discussion, this is where I think inflammation serves as a great analogy. 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 be also 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, 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 zero protective, 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, but 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. Cortisol, great example. So cortisol, 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. That would be Cushing's disease. So both extremes bad. It's do you know when you need it and what it's supposed to do? And I think the same is true with mtor.

B (60:42)

I'd also like to see data comparing, even if it's animal data comparing giving rapamycin or inhibiting, somewhat inhibiting MTOR versus physical activity, making them run on a treadmill, being physically active. Because if you look at a lot of the protective effects of rapamycin, 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.

A (61:09)

Well, Eric Verdon made a very interesting comment on my podcast a while ago. And so Eric is in the camp that he does not believe Rappa will be geoprotective 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. So 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. Eric argues. I think this is a very interesting argument. Rapamycin disproportionately works well in animals that are below the longevity quotient. So that's why it works so reproducibly in mice. 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, as 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.

B (63:10)

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 rapamycin. It wasn't super, super high, but to me that was like, enough to be like. Well, yeah.

A (63:27)

And then the question, of course, is, is there a way around that? 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 about a resistance training by a couple of days or something like that. But yeah, there's a lot there. Great expression I heard recently, which is mice usually lie, monkeys sometimes lie. It's humans we care about. It was just fantastic.

B (63:51)

Well, to get back to the MTOR story, I think 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 MTOR was activated in macrophages. And it was like this whole story.

A (64:04)

Was pieced together about 25 grams of protein.

B (64:07)

Sorry, maybe it was the equivalent dose.

A (64:09)

Equivalent. Okay, okay, yeah, the human equivalent dose. I was like, wow, that's. They're eating their body weight.

B (64:13)

Human equivalent a dose was 25 grams. Yeah. But it was essentially like arguing that atherosclerosis was being caused by protein. I'm like, are you kidding me? Like, for one, we know atherosclerosis. The bigger story there is not protein. But again, it comes down to this whole activating MTOR in systemic circulation versus the leucine going to the muscle because you're physically active. And keep in mind those transporters, the leucine transporters, they're pretty sensitive for quite a while. I mean, you're talking about at least 24 hours, maybe even longer, but definitely 24 hours.

A (64:49)

I think the mice atherosclerosis studies are very dangerous. 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 really wary when I see these studies that are using the mouse model of atherosclerosis. I understand why we do it because it's much easier and cheaper than looking at primates. And obviously 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.

B (65:24)

So then there you have it. I mean, that's a lot of the controversy around protein being bad for you. And activating MTOR is coming from that study. And then there's countless studies on cancer increasing with IGF1 and MTOR. And again, same deal where IGF1 exercise is causing IGF1 to go into the brain, to go into muscle.

A (65:42)

People also don't appreciate how short the half life of IGF1 is. It's a staggeringly short half life molecule.

B (65:49)

Oh, really?

A (65:50)

Oh, yeah, yeah. It's insanely short half life.

B (65:51)

What's the half life?

A (65:52)

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. You want to think of it almost as a paracrine thing where it has to be delivered into the muscle. So 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, but exercise is the most important drug. 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.

B (66:28)

It's not.

A (66:29)

There might be several pills that come out of it. We might figure out a way to make Clotho. 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.

B (66:41)

There's like 500 molecules.

A (66:43)

I don't know if you remember this. I'm dating myself, but I don't know if you remember Irisin. Yeah, yeah. Like, I mean, there are no shortage of these things, right?

B (66:50)

There's so many things going on for sure, that is beneficial with exercise and just kind of bring it back to the protein. I think that they go hand in hand. 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. Athletes, they're some of the longest lived individuals on the planet. We talked about this in our last podcast. Olympic athletes live, on average five years longer than the gen 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, Major League Baseball, a lot of these big professional sports leagues. They're taking in at least 2 grams per kg 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. Exercise is the king, right? Exercise is the most important thing, but you need protein to support that physical activity. And I don't understand why anyone's arguing about that. What's the argument?

A (67:56)

Despite all the flak I'm taking, I'm gonna just defend this one and continue. 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 GLP1s. 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. 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 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.

B (68:55)

Yeah. Is there anything else with the protein, I mean.

A (68:58)

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 should we start with. Well, first of all, just tell me what got you interested in this topic. You're not the typical demographic, no offense intended by that, but when I was in high school, right, and I'm probably 15 years older than you, 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. It must have been because your friends were doing it. Well, no, no, but it must have come from bodybuilding magazines. Like, I don't know where we got the information. I was thinking about this the other day because I knew we were going to talk about this and I was like, okay, there was no Internet. What was our source of truth? It was muscle and fitness. So there must have been something in muscle and fitness that told us this. And then you know what I realized we did? We would hang out at supplement stores. 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 yoked 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 two weeks. Then you go into your maintenance phase at 5 grams a day, and then you repeat the cycle every eight weeks or whatever it was. And we were like buying this stuff by the truckload. And this is like almost easily 35, 40 years ago. Fast forward, I don't know, a few years ago, we're paying attention to creatine.

B (70:41)

Again, 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. 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 the brain, which is my interest, but 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. That's an important point. My journey with it began with my obsession with increasing my resistance training.

A (71:16)

Like your performance or your hypertrophy or your recovery. What specifically?

B (71:19)

Everything that we talked about in the first 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.

A (71:36)

You've chronicled this pretty well on your social media. You've got videos of you deadlifting, like you're really embracing this.

B (71:41)

Yes, yes.

A (71:42)

Awesome.

B (71:43)

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. I want to be in it and it's part of the fun. I love it. 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. I have a personal trainer now. I'm doing resistance type training. I do like a crossfit type training for at least three 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. And that's when I became really interested in creatine where it 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. 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 creatine phosphate is able to help rapidly recycle that so you can make energy quicker. Very relevant for a lot of scenarios, including high intensity naval training, resistance training, even endurance training because it decreases recovery time because you're 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 this is a molecule that we make in our body. It's not like a dangerous thing that I'm really scared of. We make about 1 to 2 grams in our liver. Our livers make about 1 to 2 grams a day and then we can take in another depending on how much meat we eat. Meat is the major source of dietary source of creatine. So vegetarians 100% rely only on their one to two crams a day. And they're probably the population that benefits the most with supplementing with creatine. And there's just countless studies out there showing this because they are just not getting anything from their diet essentially. I mean there's like negligible whatever is in plants.

A (73:45)

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

B (73:49)

There are, there are differences. Like beef.

A (73:51)

Beef would be the most.

B (73:52)

Yeah. It's probably why people on a carnivore diet, they just get so jacked. Right. They're getting the creatine, they're getting the protein and they're working out and it's like this combination, right. They're just getting so much.

A (74:03)

And do you have a sense of if you eat a 12 ounce steak, how many grams of creatine would you get in there?

B (74:09)

People can figure that out with Google, generally speaking, that like on average people are getting in their diet probably like 1 to 2 grams additional.

A (74:17)

So you've got your endogenous plus.

B (74:19)

Yes. Yeah. And then you can supplement on top of that. And this is where I would say for many, 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 the muscle. And so I'm totally just summarizing this. I'm not going into every single detail. But generally speaking, five grams a day of creatine is enough to saturate your muscle tissue. It takes about a month, maybe three weeks to actually fully saturate it if you're doing five grams a day.

A (74:54)

Hence the bros that were telling me to take 30 when I was 13, that might have been overkill.

B (75:00)

Yeah, it's coming from the fact that in these studies that have been done, because people haven't been taking the five grams a day for like three weeks and they're doing this short term weeks long study, they want to like quickly get their muscles saturated and that's why they do that loading phase. And so most people don't have to do that. Unless you're, like, doing some competition and you, like, knead right then and there, generally speaking, it's just not necessary. And you really just increase the risk of GI distress.

A (75:26)

And our thinking today is just take five every day and then you should be all right.

B (75:30)

Well, that was my thinking up until a few months ago.

A (75:33)

All right.

B (75:34)

And I was taking. For the last year and a half, I was taking about 5 grams a day. The evidence there is that the creatine is essentially improving your exercise performance in that you can do one to two more reps, or essentially the volume of training goes up because you're recycling that energy quicker, you're able to do more. And that is why you then get gains in muscle mass and strength. It's not like the creatine itself is acting like protein. It's not increasing muscle protein synthesis if you're just a couch potato.

A (76:05)

Yep, you have to do the work.

B (76:06)

You have to do the work. Right. And the reason that you do increase the muscle mass and strength is because you're able to do more work. It's pretty obvious anyone that for me, with my CrossFit, it really is useful because there's a lot of explosive training, a lot of hit. So for me, it was pretty obvious that it was having an effect. And 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, anything that can improve cognitive function in a safe way, like any kind of safe nootropic. And that's where I really started to get interested. And this has built up over years where I was getting interested in the brain effects, even though I hadn't been supplementing with it. I had been keeping an eye on the literature. And finally when I started using it, I got pushed over. I'm like, okay, I'm all in. And I want to get into this.

A (76:57)

You felt like you got all in because you actually felt a difference, or you were like, well, look, I'm already taking it for these muscle purposes. Let me really now go deeper on the cognitive science.

B (77:07)

Yes. I was already like, first of all, the literature was clear with the muscle. There's a lot of literature. You can't deny it. You just can't.

A (77:14)

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

B (77:27)

Exactly right. And when we're talking about 40 years or whatever of research, that's a lot of data with the brain. So for one, your brain does make a little bit of creatine as well. Something I don't remember. I think it's somewhere between one to three grams a day. But the data on the effects of supplemental creatine on the brain isn't dating back as far. And so you do have to kind of take the data with somewhat of a grain of salt because there's a lot of small studies and they're not like you can't hang your head on it. This is the end all be all.

A (77:58)

And let's talk about some of the measurements. I think one of the advantages of studying the effects of creatine on physical performance is we have really good objective measurements that you can demonstrate in a short period of time. You could do a 12 week study and in just 12 weeks you could objectively unambiguously determine if there was hypertrophy and if there was an increase in performance. How do we do that? On the cognitive side, what are the data that you've been looking at that have given you an increasing level of confidence?

B (78:26)

Okay, well, first let's talk about dose, because that's important. And I think that that was where initially when researchers were looking into like the effects of creatine on the brain, the five grams a day didn't seem to be doing anything in terms of getting creatine into the brain.

A (78:42)

Creatine is crossing the blood brain barrier. That's established.

B (78:45)

It is. However, the muscles are greedy as hell.

A (78:48)

Ah, those lovely greedy muscles.

B (78:51)

Yeah, the greedy muscles. When you're taking in up to about 5 grams of creatine, they're consuming it, they're taking their share.

A (78:58)

Especially if you're training.

B (78:59)

If you're training, it's like. 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 that was published a few years back that did dose dependent effect and looked at creatine levels in certain brain regions.

A (79:15)

Naive question. Are they using an isotope? Are they labeling the creatine?

B (79:18)

I believe they were using an isotope.

A (79:19)

They're not using CSF levels or anything.

B (79:22)

I believe it was an isotope. Okay, but don't hold me to it because I don't remember exactly.

A (79:26)

You need more creatine.

B (79:27)

I know, but 10 grams was where.

A (79:31)

Creatine was now, was not Rate limited.

B (79:33)

Yeah, exactly. Now you were increasing levels of creatine in the brain. Pretty sure it was isotope labeled, essentially 10 grams. You have to double that. And that's where I was like, okay.

A (79:44)

Does that mean that 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, and if you have a study that was done at 5 and it shows no effect, you're gonna come to the wrong conclusion, potentially.

B (79:56)

Bingo. Just like with any supplement and. Or drug dose matters. So, yes, that is the case. But also it's important to point out, just like with muscle, you have to be stressing your muscle for creatine to work. 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 you can increase strength with the brain. It works in the background of stress. And what I mean by stress is sleep deprivation. Psychological stress. Like you have an exam, marital, I mean, whatever. Psychological stress, emotional stress. Sleep deprivation's a big one. Neurodegenerative disease, or anything that's compromising brain function. That's where creatine really shines in terms of cognitive function. And we'll get into measurements. But I think that's important to point out. This is my argument. I feel like I'm constantly under stress. I think most people are constantly under stress.

A (80:50)

Anybody listening? If you're not under stress, I'd like to hear from you. I want to know what you're doing.

B (80:55)

Same, same. Even just like diving into the scientific literature, what we do every day, learning that is the stress, the brain consumes a lot of energy as well.

A (81:06)

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.

B (81:17)

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. If energy is being triaged to whatever stress and the hormones and the whatever, whatever's going on, fill in the blank. And so the studies that typically are looking at the effects of creatine on cognitive function are looking at processing speed. They're looking at a battery of tests that are typical of any fill in the blank supplement or treatment that is either gonna improve cognitive function, memory being another one. Right. Processing speed's a Big one too. I would say that creatine's been shown to improve, but again, really it's in the background of stress. Whether that's stress being aging. So older adults, so aging is kind of a stress brain aging. So older adults seem to benefit from taking exogenous creatine or supplemental creatine. And people that are sleep deprived, that's another one. That's a really big one. In fact, there's been a few studies that have shown people that are sleep deprived if you give them this was on a per kg body weight basis. So I think total, it was like 20 to 25 grams of creatine that were given just based on their body weight. But if they were sleep deprived and given that creatine, not only did the cognitive deficits that usually occur when you're sleep deprived not occur, but their cognitive processing speed was improved more than baseline. Now, this is a small study. If you, Peter, were to go to the study and look at this, you'd be like, this is a small study. And I agree. We can't just hang our hat on.

A (82:54)

This one study who's doing these studies, because there can't really be any financial incentive to do them. Creatine is ubiquitous. There's no IP around it. I want to give people some advice on how to go buy creatine because if you go to Amazon, it's like, which one do I buy? But who's sort of taken the mantle on trying to understand this? Because it is an important question. And if you've got something that's insanely cheap, completely safe, has other benefits in the body anyway. And all we're really trying to figure out is, hey, should we all just be doubling our dose from 5 to 10? It'd be great to quantify the effect size and stratify patients that we need to be reaching out to. Because again, not everybody listening to us is doing this anyway. And it's just one more thing to ask somebody to do which comes at a cost. There's a psychic cost to just asking people to do more stuff. And it's one more thing you gotta do. Again, this is like low hanging fruit in the world of biomedical research.

B (83:46)

It is. Darren Kandao is someone who, he's getting into the brain stuff. I think there's quite a few people that have been doing muscle research who are now it's opening doors for them where they're like collaborating and they're reaching out to like people that are doing more neuroscience. And it's kind of exploding this has.

A (84:04)

Got like Dom d' Agostino's name written all over.

B (84:05)

That's a really good point. It totally does.

A (84:07)

We gotta talk Dom into doing this.

B (84:09)

So there was like a pilot study that came out. These are researchers that I don't know necessarily, and some of them are pretty junior, but there was one that came out with 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. And I think there was also placebo control as well. And then they took those same patients and then had them exercise and improved strength and improved lean body mass.

A (84:33)

I'm just going to be skeptical. I still think that the name of the game is prevention where I'm most interested. And of course that's the hardest thing to study. But 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 ad. 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.

B (85:16)

Totally. Prevention is the name of the game for sure, 100%. Unfortunately, there's a lot of people's parents out there that have it right now because they missed the boat on prevention. Right. Those people are obviously their kids are willing to do anything to help them. It's terrible. Right? 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 sleep deprivation, like I just got back From China about five days ago, I've been like doing 20 grams a day, 15 to 20.

A (85:52)

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.

B (85:59)

It would probably affect a lot of people's GI. I do 5 gram doses and you'll.

A (86:05)

Just put the 5 grams into water.

B (86:06)

And I'd put the 5 grams into water or like tea and then I just take it like that and I do it mostly before noon. 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?

A (86:27)

If the placebo's working for you, take it.

B (86:28)

Exactly. Because it's physiologic. Right? I mean, it's a biological mechanism that's working for me. 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 gonna get more and more evidence out there that it's gonna be beneficial. And 10 grams is gonna be the new.

A (86:44)

The new baseline.

B (86:45)

Five grams. Yeah, it's gonna be the new baseline.

A (86:47)

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.

B (86:53)

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

A (86:54)

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. 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 Korea Pure is the active ingredient within it or does it matter?

B (87:15)

I think the most important thing is that it's creatine monohydrate.

A (87:18)

Yep.

B (87:18)

The reason people like Korea Pure is because it's like 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 these heavy metals and things that sort of hitchhike on a lot of these supplements. Personally, that's what I look for. I think Creapure is great too, depending on whatever brand is using. Creapure.

A (87:40)

Yeah, lots of brands are using it.

B (87:42)

So NSF is what I look for. I use the thorium and there's no.

A (87:44)

Reason you can't have both. You could have Creapure NS certified product, totally for sure. 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?

B (88:04)

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. And you're heating it up. So there's the heat component that's degrading things. So gummies, unless you can find a third party tested gummy that actually has the amount of creatine monohydrate in it that says on the nutrition facts label, I would avoid a gummy.

A (88:44)

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? What am I doing to my teeth?

B (89:07)

Yeah. What else is in the gummy?

A (89:08)

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

B (89:21)

Don't eat the gummy. Like, you need the powder. Thanks for bringing that. Because also, capsules, you're gonna have to take so many capsules to get. I say the 10 grams or even the five. If you're just looking for the muscle effects, you're just gonna have to take a lot of capsules. And so that's also an important point. I also think that the vegan thing and vegetarian is another really important aspect.

A (89:40)

If you take them to 10, they should be fine because they're at least offsetting the couple grains. Yeah.

B (89:44)

I'm just saying it'll change. Like, I have so many vegan friends that it 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 outsized compared to what I was getting. And I noticed effect. I mean, it was, like, unreal.

A (89:59)

And how long had they been vegan?

B (90:01)

One of them, not that long. Maybe like two years. But the other one just most of her life. Yeah.

A (90:07)

Yeah. And so I'd be interested. The one who had been vegan for two years, 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 variables.

B (90:18)

She's always kind of calorically restricted too. And I don't know how much protein she was really eating when she wasn't. It wasn't. Yeah, but that's a good question. Question.

A (90:25)

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. Is she too young? Should she be taking creatine?

B (90:36)

Yes. There's studies out there on kids, children like, younger than 17.

A (90:41)

My boys who are.

B (90:42)

I'm giving it to my son. Okay.

A (90:44)

How much?

B (90:45)

If I remember correctly, it's like 0.1 grams per kilogram body weight. I give my son two and a half grams.

A (90:51)

Okay.

B (90:52)

Again, there's studies out there. It improves agility, is a big one. And speed. So a lot of these studies were done more like an endurance because kids aren't like lifting weights. So it improves agility and speed.

A (91:03)

And would you, for my daughter, give her five?

B (91:06)

Yeah, she's tall, too.

A (91:08)

She's studying hard. Like, does she just need the full 10?

B (91:10)

Exactly. She is almost an adult.

A (91:13)

I think she's done growing.

B (91:14)

If it were me, I would do 10.

A (91:16)

All right.

B (91:16)

If it was my daughter. There's actually some studies that have been done in college students who are 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 all in on the creatine.

A (91:29)

My creatine budget, literally the household creatine budget just went up by 4x.

B (91:33)

Same happened to me like 6 months ago or so. Again, the harm that people claim is unfounded. The kidney problems. First of all, as a physician, you know what the problem is? People are looking at creatinine. If you're like supplementing with creatine, you got to tell your physician.

A (91:48)

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. 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 something about a topic that is near and dear to both of our hearts, which is temperature. You know, my journey on the sauna train. I was probably the biggest sauna skeptic for many years. Not because I didn't love it, I love, I've always loved a sauna. I just had a hard time believing that the data were causal. I was just like, there's too much healthy user bias in here. But over the last five years, as I've looked closer and closer at the data, 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. 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 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 you're one of the people who I think keeps up with this literature more than anybody. Tell us if anything has changed in your mind one way or the other, both in increasing confidence, decreasing confidence, just update us on where you are.

B (93:41)

Yeah, 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 are somewhat 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 anything that Improves cardiovascular health, is going to improve brain health. But there's another aspect to this story here, and this kind of dates back to like the origins of one of my first biology experiments I did 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 stand there a long time to get a real heat shock response. But if you're in like 163 degree Fahrenheit sauna for 30 minutes, we know that heat shock proteins increase about 50% over baseline.

A (95:07)

And what would be the equivalent exposure in steam or water?

B (95:11)

In the water it's about 104 degrees for 20 minutes, shoulders down.

A (95:17)

20 minutes?

B (95:18)

Yeah, about 20 minutes.

A (95:19)

And then presumably if you're in a hotter dry sauna, less time is needed.

B (95:24)

Presumably. We don't have that data. I'm just quoting the empirical data that we have.

A (95:28)

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. Whereas in dry sauna we can look at time and temperature and humidity. If I know the temperature of the sauna, the humidity of the sauna and then 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 number, so I don't want to get it wrong. It was either 5 or 8 degree increase in skin temperature was necessary to produce similar benefits. Do you know about this?

B (96:12)

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 to a regular hot sauna to 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 auna could be 160 or it could be 175 or 180 and the infrared is like 140 or something like that. 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, like the title is something like Infrared saunas does not mimic cardiovascular effects of exercise or something like that. And that's because the given dose, if you're just doing like 20 or 30 minutes, it's not gonna be the same. Your heart rate doesn't go up as much. You don't feel as hot because the temperature's 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 duration. Yeah. So rather than spending 20 minutes in 175 degree, 180 degree sauna, you're gonna spend 40 minutes. 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.

A (97:54)

Is she awesome?

B (97:55)

She's awesome.

A (97:56)

I just love her.

B (97:57)

She's awesome. And we collaborate on a variety of sauna studies. She wears a lot of hats and her data looking at, she's a psychologist by training and she looks at depression and she's looking at depression as an endpoint in terms of these infrared saunas. And she's looking at core body temperature increases. 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 infrared sauna for like 85 minutes. They're in there a long time and they are getting hot. She'll talk about it. She's got assistants that are cooling them down on their head. Cause it's a head out infrared sauna. It's like basically like a bed. 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 a kind of funny, it's called hyperthermia. So like you're inducing hyperthermia and there'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.

A (99:00)

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, and I'll run it pretty hot, at least 190.

B (99:09)

Okay.

A (99:09)

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. 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 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?

B (99:38)

To answer that question, it'll take me in a whole other direction. Should I go there right now, or should I finish?

A (99:42)

No, finish, because I want to go.

B (99:44)

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.

A (100:00)

Not single treatment.

B (100:01)

Single treatment. Now Ashley has gone out and she's done four to eight treatments, depending on the person, whether or not they've completed the whole study. And she didn't have a sham control, but she's got just phenomenal.

A (100:12)

How do you sham control that.

B (100:13)

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.

A (100:22)

Didn't hit the threshold.

B (100:23)

Yeah. Raising their core body temperature by 2 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, like, every day. I lived across the street from ymca. I was going into the sauna in the morning. It was freezing in Tennessee. And I was going to the sauna in the morning before I would go into the lab to do my experiments, I was going every single morning and saying it a long time because I was like, go hard, 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, was 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 in this whole field of sauna depression. I think just she's opening the door. So that said, the effect on the head, if you think about, like, hot tubs, Jacuzzis, we're all sitting with our head out as well. We're in there. And it's a good question, because I agree with you. When I'm in a hot sauna and I'm also on the top and it's the same deal, I want to get out in 20 minutes. If I stay in too long, I will get a headache. I know my threshold now. I know the temperature and the duration and the amount of water. I know all those variables.

A (101:46)

Isn't it amazing how much water you can drink in a sauna?

B (101:48)

Like, I. I know.

A (101:50)

I worry I'm gonna get hyponatremia. I'm like, you gotta slow this down.

B (101:53)

So. So the interesting thing is, is that talking about dementia risk, I talked about heat shock proteins, and I kind of went off on this tangent. Sorry, but the heat shock proteins, what they do is they prevent proteins from misfolding and forming aggregates. And so 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 effect where you're now just improving the folding of proteins in general even after you're out of the hot sauna. So there's a lot of animal studies that have been done. I did a lot of studies in worms 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 prevents the aggregation and it prevents the muscle 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. You know, the data coming out of Dr. Yarielkunen'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.

A (103:16)

And that was at 170, 79 degrees or greater for 20 minutes or greater, right?

B (103:19)

Yeah. Like 175 or 179 exact for 20 minutes. Now, here's where your question comes in. And that is like, what about the head? There was another study out of Finland. It was not Yari's lab, It was another professor that I'm not aware of. But this study looked at sauna use and dementia risk, and then 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're on average, it was like, if they're 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 really hot. My concern is the head at that high of a temperature.

A (104:09)

I've started wearing one of those sauna hats. The sauna hats. I don't know why it works, do you? It's not logical to me why it's helping rather.

B (104:16)

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?

A (104:21)

Yeah, I suppose. But the fact that that's a net benefit because it's also gotta be preventing you from dissipating heat. Clearly what it's preventing coming in exceeds what. But it makes such a difference. I've also dialed mine down a little bit. I used to be consistently going to at least 250. Now I'm like, you know what? 185 to 190 is good enough.

B (104:41)

I do. 180.

A (104:42)

My wife is going to be very happy if we dial it down to 180. She seems more sensitive to the heat than I am.

B (104:47)

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, it's definitely like, I'm more sensitive.

A (104:53)

To it, but this is important. So you really think that we could even dial it to 180?

B (104:57)

Absolutely.

A (104:58)

And just totally get the same benefit.

B (104:59)

I mean, the data is showing that.

A (105:00)

Yeah, yeah, I know. I just, you know me. More is better.

B (105:02)

More is better. I'm not just you. It's the go hard, go home. But I do think we're talking about a type of stress here, right here.

A (105:07)

And you have to get it hormetically correct.

B (105:09)

Exactly. Exactly. I don't know that the 212. And I hope people that are out there doing the 212 are listening to this, because it's too hot. There's no need for it. There's no evidence you're getting added benefit. And if anything, there's potential risk that you're getting. Exactly. Potential risk. Downside. That's just one study.

A (105:25)

Yeah, yeah.

B (105:26)

But it's enough to make me go, hmm. There's no data showing we need that, so why are we doing that?

A (105:31)

Rhonda, I know you gotta go, but I want to end with just one question and topic, which is what year did you launch your podcast?

B (105:38)

I launched it in 2014.

A (105:41)

So here we are. We're 11 years in. You are the OG in this space. You have an incredible podcast. Are you still enjoying it, and what are you most excited about?

B (105:53)

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 these superstars on my podcast, and they get to, like, learn so much. I read their papers first, but I also learn so much from the conversation, and people get to, like, benefit from it. I mean, it's so rewarding. So I get to, like, scratch my own itch. And then I also get to, like, help people.

A (106:29)

I just want to make sure that everybody listening kind of understands your place 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, 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 gotten to know Ben especially, and Ben is putting at least 120 hours of preparation into each podcast, and therefore, you can only do one a month. And it shows. So, in many ways, I think of you as the acquired podcast version in our space, which is just the breadth and the depth of what you're doing is awesome. It's such a treat. And it's just. 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. Anyway, I'm 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 insane.

B (107:32)

You were, like, one of the first 10 guests.

A (107:35)

I sort of knew what a podcast was because 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.

B (107:47)

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

A (108:05)

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. This creatine stuff is new. It's going to change what I do. And also, you've already made a change to what I'm going to do in the sauna. So thanks again. This was awesome.

B (108:38)

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

A (108:41)

Thank you for listening to this week's episode of the Drive. Head over to peterattiamd.com shownotes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram, and Twitter, all with the handle Peteratti. MD. You can also leave us review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or Advise, please visit PeterAttiaMD.com about where I keep an up to date and active list of all disclosures.