Dr. Patrick: Hi, everyone. I'm very honored to be sitting here today with our podcast guest, Dr. Stuart Phillips. Dr. Phillips is the director of the Physical Activity Center of Excellence at McMaster University in Ontario, Canada. As we are going to learn today, his research and his lab has made pretty big contributions to our understanding of muscle protein synthesis. And I'm pretty excited to dive into all that research. I've spent the last week reading review articles and studies.

Dr. Phillips: Cramming. Cramming, yeah.

Dr. Patrick: Yes. I feel like I've just learned a tremendous amount compared to, I mean, what I knew last week. So, I mean, you know, it's just...

Dr. Phillips: Excellent.

Dr. Patrick: So, or maybe we can just start off talking about muscle mass and why, you know... We hear often times physicians, almost everyone knows about body mass and body fat percentages and BMIs and what's a healthy BMI and what's not. But, you know, muscle mass is also important. So maybe we can talk about why.

Dr. Phillips: Sure. Yeah. I mean, I think when you step on a scale, everybody at least should realize that the sum of all of your body, so we say compartments, is what you see on a scale. And most people can appreciate...obviously, they're worried about their body fat content. But a large part of what's registering on the scale is actually what we call lean mass or some of it is muscle mass and then obviously your bone mass as well.

So, I think, most people will probably understand we're about almost 70% by content water. And most of that water is inside our cells, and a lot of it is inside muscle mass. So what we call muscle mass or lean mass is very hydrated tissue. Fat mass is actually not, and its preservation, muscle mass at least as we get older, is critical for health. I think it's one of the things that's lost on a lot of people to say, "Well, that's great that you're maintaining your body weight." But if we don't maintain our muscle mass, it has some pretty deleterious consequences.

Dr. Patrick: And muscle mass correlates, I mean, specifically with mortality, right? I mean, there's an inverse correlation.

Dr. Phillips: Yeah. Absolutely. I mean, I think, that the outward manifestation of muscle mass is obviously, you know, our ability to move around strength, getting up out of a chair, that sort of thing. And at some stage in your life, you're going to have to be able to do these, sort of, rudimentary activities of daily living. And once you can't do them, then, you know, you need somebody to care for you. So, it's not surprising that there are, as you say, correlations between muscle mass and mortality. It's a vitally important organ if you look at it that way.

Dr. Patrick: I think the frailty index, which is...there's a lot of measures that go into that, you know, in frailty indexes. As you get older, at least over 65, it's a pretty good predictor of mortality. And muscle mass is an important component of that. Am I right? Yeah.

Dr. Phillips: Absolutely. Yeah. I mean, I think, all of these definitions. You say frailty, I mean, the precursor would be sarcopenia or loss of muscle mass as we age. All have a component of measuring lean mass or muscle mass, and it's predictive of a downward decline as we get older, for sure.

Dr. Patrick: I've seen some studies that have also correlated specifically lower body...I think strength of lower body with improved cognition. And I was wondering just... For me, I don't... Like, why not upper body? Why lower body? Is there a, you know, potential like people that are also doing cardio or getting some lower body strength? Do you have any ideas?

Dr. Phillips: Yeah. I'm not sure I can answer the question, but it's interesting to note. You know, some of these correlations come up and the...you know, when it's a correlation, obviously, it's association, and people want to know, you know, is it causative, right? So you always, kind of, hedge your bets. And what I say to people, I said, "I don't know." But it's not a bad goal to aim for to have stronger legs and be able to move around and, yeah, if it correlates with, you know, improved cognition and mental function as you age, you know. If that's a connection between the two, it's not a bad goal to aim for. Whether one causes the other, I can't say. But, yeah, I'll take if it's a causative relationship for sure.

Dr. Patrick: What percent of muscle mass do humans lose, like, per year? And when does that start? Like, you mentioned sarcopenia.

Dr. Phillips: Yeah. This is the, you know, I would say $64,000. So that wouldn't get you much these days probably more question I suppose. Most people will say that somewhere in your 30s or 40s, you're beginning to lose muscle mass. My own personal opinion is it's somewhere probably closer to about 56 or thereabouts, but that's personal. But something, you know, probably for most people that you can see in their 40s. And usually, what we say, on a population level, it's about a 1% loss of muscle mass per year and about a 1% to 3% drop in strength or power. So, the muscle mass decline is actually slower than we lose strength. And strength as they say is the upward manifestation of muscle, but it must speak then to the quality of the muscle you have and your brain's ability to be able to talk to muscle and get you to do things. So, as much as we can do to try and slow that, that would be beneficial as we get into our older age for sure.

Dr. Patrick: Yeah. And I definitely want to get into all that stuff, you know, how we can counter sarcopenia, loss of muscle mass. The building up of the muscle reserves, not like that's something I've heard you talk about or... You know, it's something that's, like, common knowledge to some degree. What does that mean? Is it, you know, really important to do that before a certain age? And if you don't do that, can you still start later in life?

Dr. Phillips: Yeah, great question. I mean, I think, the parallel that most people are most familiar with that we can, sort of, pick on and say, you know, women, in particular, are told that we can build bone mass up until probably about 30, men, it's about the same, that when women head towards the menopausal transition, that they're definitely going to lose bone mass. You want to start at a higher level as possible. I mean, everybody after the menopausal transition loses bone at about the same rate. So you really would like to be on a higher plateau before you get there.

I think the concept is entirely similar with muscle. The good news is, is that probably, even past your 30s into your 40s, 60s, probably even into your 70s, we can still gain a little bit of muscle. We can definitely gain strength by concerted, you know, resistance exercise, usually. So you probably have a much bigger window to accumulate the muscle that you have. But it's the same concept. You'd like to go into older age when you're beginning to lose muscle at a higher level because then you're starting to decline from a higher plateau. So, it's a similar concept.

I don't know that we know exactly how much and when. But there are even studies in nonagenarians, you know, people in their 90s lifting weights, and they can get stronger. Now, gaining muscle, not so much, but they get function back. So there's some adaptability left in the system in a muscle sense that isn't there with bones, for example.

Dr. Patrick: And at the end of the day, as you're mentioning, you know, being able to get up out of your chair. These sorts of important little, like, everyday activities that we take for granted when we're younger can make a difference when you're older, and you, like, fall and break a hip, and then you, kind of, go into this downward spiral. So, strength does make a difference with that, right?

Dr. Phillips: Yeah.

Dr. Patrick: Like, just having...even if you're not gaining muscle mass, like, being able to have the strength to do that.

Dr. Phillips: Yeah, absolutely. I mean, I think that that's maybe a little bit overstated, the importance of muscle mass. Not that it's not important, but the function and the outcome. So the strength and the power is really the key point, even something as simple as walking speed, what we call normal gait speed. And, you know, the example I like to give is to say, you know, you're standing at an intersection. The walk signal comes on, and, you know, there's a certain distance you got to cross in a certain amount of time. So you need a certain gait speed. You know, not that the motorist hopefully wouldn't stop, but, you know, you're under pressure to make it across an intersection, let's say. It's important. And we know, you know, fully that once you get to a certain level of strength, your gait speed drops. It becomes more difficult to do activities of daily living, and then you're looking at full-time institutionalized care.

Dr. Patrick: Right. Quality of life going down. And it, kind of, goes back to that concept of, you know, improving health span, right?

Dr. Phillips: Yeah.

Dr. Patrick: You know, basically, being able to delay the onset of these age-related diseases and diseases that hit us later in life in any possible way that we can, even if we don't necessarily live much, much longer. But in some cases delaying those diseases, you might get a year or two, right?.

Dr. Phillips: Yeah. It's not trite to say, but, you know, everybody say, "Well, what's exercise going to give you?" And we do have, and again, it's observational data, of course, that, you know, once you hit that, sort of, 150 minutes of moderate to vigorous, whichever... Okay. That's the guidelines. And, I think, you know, you maintain your strength, and so make sure you do those two days of strengthening exercises a week. Obviously, we get...on average, when you look at, you know, population data, about four extra years of life. So, I think, most people would take that. If that were a pill, you know, I wouldn't be sitting here. I'd be skyping in from Tahiti or something. And most people obviously realize then that your health span that's associated with that is longer as well. So it's time in your life that's longer, but it's time in your life that is spent in good health. And for most people, that's a better quality of life.

Dr. Patrick: Absolutely. So let's talk about some of the major signals and inputs that regulate muscle protein synthesis, which... I guess we can talk about how much that correlates with muscle mass and strength. Let's first talk about recommended daily allowances for protein intake for adults. In the United States, in Canada, it's about 0.8 grams of protein per kilogram body weight.

Dr. Phillips: Correct. Yeah.

Dr. Patrick: And I don't know what people are actually consuming. Maybe you can shed some light onto that, what they're actually consuming. I know you have thoughts because you've published them on whether or not it's scientifically sound that number specifically.

Dr. Phillips: Yeah. So, I mean, one of the things...the precursor I'd like to start off with is to say people say, you know, "How is protein different than everything else that we eat? What does it do?" And so I often explain to people that carbohydrates and fats, that's fuel. You put that in, and you burn it, or we store it. Unfortunately, we're really good at doing that. But protein is something that when you ingest it, your body has to use it. There's not, like, a little, sort of, place that you can store away the building blocks of protein, which are amino acids and, kind of, use them for later, although your muscle is, sort of, a reservoir of that. So it does turn over a little bit. So when we think about it from a daily recommended intake or what we call the recommended dietary allowance, it's the amount of protein that you need to ingest to replace all of the protein and amino acids that your body loses. And most of it is lost in urine as urea. And I say to people is...

I've stopped trying to fight too much against this because I would actually be happy if they just changed the name from recommended dietary allowance to minimal dietary intake. So first, I don't think it should be recommended because it's too low. And, I think, you should be allowed to eat more. So 0.8 I think is...to me, that's the, sort of, bottom level buy-in. That's where you need to start and then build up from there.

So, most of the data that we have, and it's not ours, there's lots of other people who have contributed to this as well, suggest that a minimum might be closer to about 1.2 grams per kilogram of body weight per day. And, you know, athletes and even older people could probably benefit even from going up from that level up to about 1.6. At a certain point, I don't think you can put too much protein back into the system, and the system would hang on to it. So, every species has evolved a way of getting rid of extra protein, fish, it's ammonia, birds, it's uric acid, mammals, it's urea. So there's an upper limit.

But most people, depending on what surveys you look at, when they're younger and even middle-aged are probably doing okay in terms of protein. So I'll, you know, put hand on heart and say probably not a big issue. When you get a little older, people's appetite goes down. People tend to gravitate towards different ways of eating, and protein actually becomes a much smaller percentage of their diet. So, at the time when I think you need more protein and you want to support muscle mass and lean mass as you age, most people's protein intake is actually going down to levels where it becomes limiting to the amount of muscle they can hang on to. So, that, I think, is an important, sort of, distinction between, let's aim at the minimum and let's go into what we call a more optimal protein intake range. And I don't know where and at what age that begins. But I think it's an important consideration as most of us, myself included, transition towards, you know, I'm looking at the rest of my life and thinking, "I want to be in as best health as I can." And so I have to be a little bit more cognizant about the protein that I eat.

Dr. Patrick: What went into your determining 1.2 grams per kilogram body weight? So, you're saying most young adults are consuming that probably. And then also, like, you know, I guess, you know, talking about the audience. Like, are we talking about like...to people that are in, you know, a big caloric excess? They're probably already getting that protein, right?

Dr. Phillips: Yeah.

Dr. Patrick: I mean, like, if they're in a huge excess of, you know, eating more calories, they're probably getting more protein and everything else. Is it relevant for, you know, every age or maybe people that are really physically active, like you said, go up a little more? So why 1.2? What was the science behind that?

Dr. Phillips: Yeah. So, the original studies that led to the derivation of the recommended dietary allowance are what we call nitrogen balance...and as the name implies, it's measuring all the nitrogen or protein that goes into our body and collecting everything that comes out. I mean, so wonderful, delightful studies to do. Those studies we've known for a long time are problematic because of incomplete collection, overestimation, etc., of losses. So, one of the things that we do know is that the closer you get to your requirement, your body actually gets much more efficient at utilizing protein. And that's not really taken into account in the way people have modeled that data.

So without, you know, going too deep into the weeds, let's just say that there are alternative approaches using stable isotopes that have consistently shown that people actually need...when I say need, to maintain the balance that we talk about, higher intakes. And so that's the 1.2. It's not that, you know, 0.8 really, you know, does it for a lot of people. We need to come up to 1.2. And then from 1.2 and above, we're talking about optimal intakes.

And, I think, the example, the one that people can maybe relate to a little bit is that up until probably about 25 years ago, we aimed at a vitamin C intake that prevented scurvy. And that was good because who wants scurvy, right? But then we've done some science, and, you know, not me, but obviously, lots of other people, to show that intakes above the vitamin C intake that prevented scurvy were actually associated with health benefits. And so we make that recommendation.

We haven't done that for protein. We're still aiming at the prevention of deficiency as opposed to the optimization of processes that are important. And there's still a lot of people who push back against my viewpoints, and, you know, I'll take the heat. I think what hasn't been considered is this maintenance of muscle and mobility as we age that is in part driven by protein intake. I mean, the other half is we can't get away without talking about exercise, right? So that's the other side of the equation.

Dr. Patrick: Right. Let's talk a little bit about protein intake, and you're talking about people giving pushback. There definitely are animal studies that have looked at, you know, caloric restriction and protein restriction and its effect on how lab rodents live and how healthy they live. I think that...as you and I have talked off-camera, you know, there's a lot of different types of people that are in different life stages. We've got obese people like sedentary that could probably benefit from caloric restriction. We've got young healthy, physically active people that are probably needing more protein intake. We've got the older people that are battling sarcopenia that probably need more protein intake.

And then we have the whole fasting community. I've had a lot of fasting experts on the podcast as you know. A better job that needs to be done is basically just talking about the audience, talking about, okay, who are we speaking to here with this specific thing we're talking about? Because it's important. There's people in different stages of life. And then, I think, also with some of the protein restriction as well, very similar.

And I've listened to some of the things that you've talked about with, you know, extrapolating data from lab animals, specifically on caloric restriction and dietary restriction, protein restriction to humans may be a little murky because of something called disuse and disease that humans are just so susceptible to. So can you talk a little bit about it because it makes so much sense?

Dr. Phillips: Yeah. I mean, the writer's statement, I think...and the disclaimer right at the start is to say tremendous amount of respect for the science of the people that do the studies around caloric restriction, protein restriction, etc. Most of it is done, as you mentioned, in lab animals, mostly small rodents, so usually mice or rats sometimes.

And, you know, I think, one of the things that's important to point out is when we compare primates head to head, so this is in caloric restriction, arguably, the most robust model of survival, extending lifespan, the data is actually conflicting. It's only been done obviously in two different locations. And so, if you were a primate, you know, in one location, you did better than primates in the other, but the net result was, it actually didn't extend lifespan. So, that, sort of, makes you think, okay, maybe there's...it's not as clear-cut as you might think. Obviously, small rodents, they're mammals, so the extrapolation to us is often done. Drug companies do it all the time, I understand.

I think the thing that I focus on the most is around, there's a caged animal that lives in a very controlled environment, and food is...there is no fluctuation in food. It, sort of, held at it here or here because it's given or taken away from the animal. So, you know, choice is taken away from the animal. The human beings are notoriously, sometimes great, sometimes not so much at making. And, you know, these animals aren't exposed to a lot of the same stressors.

So, one of the concepts that we...and it was something in reading....a good friend of mine, Doug Paddon-Jones, who sadly passed away really early in his life, pointed out at these catabolic crises that we have. And for him, it meant a period of hospitalization. And during this event, the de facto treatment in hospital is you go into bed rest. And we've known for years that, you know, putting people in bed rest, and you can ask any clinician, it's a bad situation. You're not using your muscles. You become instantly sedentary, obviously. It would exacerbate a lot of other issues if you went into bed rest with type 2 diabetes. You're overweight, etc. So these events...you can appreciate bed rest in a catabolic crisis if you've got a hospital event is, yeah, that's going to be bad. I get that.

So we, sort of, said, well, dial it back a little bit. Maybe you get flu, and you're an older person. You get some respiratory distress, you go in the hospital for a few days, you're on oxygen. Now you're fine to be released from the hospital, but you go home and convalesce for two weeks. So this is a disuse event, relatively speaking. But you're okay but you sit around for two weeks. And we think as you get older, even those types of events are a disuse event that we think precipitates an issue.

And I was fond of saying that, well, you know, this happens every year, and what happens everywhere, most people get the flu. And I said, "But there's maybe a uniquely, if not, Canadian, but Northern U.S. phenomenon that when it's freezing cold outside, you also as an older person, you don't go inside. You don't want to shovel your snow. You could slip."

And clinicians would say, you know, "How often does that happen?" Then COVID comes along, and I said, "It happens a lot." So, I feel a little bit of vindication, I said, "This is a relevant model." And what happens is if you can imagine somebody's...they're already going down because sarcopenia is happening. When they have a disuse event, they bend the curve dramatically. So there's an accelerated rate of muscle loss. And what happens...when you're younger, you go down, but you're able to bounce back up. At some point and this is universally, I think, understood by clinicians is that an older person that has an event like that is actually now on a different downward trajectory. So they've actually hopped. You know, they've accelerated the loss that they have with aging to a fairly large degree.

The best, you know, way to explain it to people is to say, you put somebody up in space because there's no gravity that's effectively disuse because you can't really generate any force with your muscles. And we know that, you know, six months or a year standing up at the space station is about 10 to 15 years of skeletal and muscle aging. And it's tough to get back. In fact, most of those astronauts, I'd be willing to bet, don't get much of that back when they come even down to earth. So, that's the price you pay for a little bit of weightlessness for about six months to a year.

Dr. Patrick: Wow. Yeah, that's incredible about the astronauts. But just speaking to, like, what you were saying with the disuse and disease, again, it makes a lot of sense because laboratory rodents are not really exposed to that. They're in these little sterile environments. Again, at the end of the day, just to, kind of, get this...I think to make it clear to people listening here today. I still do think there are benefits to different types of intermittent fasting for different people, whether we're talking about someone that's obese and overweight, you know, having a form of caloric deficit, which can be achieved a lot of ways, including probably the best, I mean, like, exercise. Exercise is probably the cornerstone of health span right?

Dr. Phillips: Absolutely.

Dr. Patrick: I think we agree there.

Dr. Phillips: Yep.

Dr. Patrick: But also, like, there's different types of fasting. You know, there's the constant caloric restriction like we're just talking about. But there's also just not eating two to three hours before bed, and that's something, I think, most people can benefit from, honestly, because you're not as insulin sensitive later in the evening. And it's nice to have a period where you do have some rest, digestion, and everything. So, lots of types of fasting, and, you know, that all gets lost, again, when we just, kind of, talk about it in this big umbrella type of generalization.

So, I think, we're going to talk a lot about protein here and muscle synthesis. But to be honest, I think, people that are overweight and obese, they have to start there. They have to, like, lose the weight, and, you know, there's ways to do that, exercise and caloric restriction both really effective. But getting back and speaking to the RDA for protein, it's funny because you mentioned the micronutrients. You mentioned vitamin C. I did my post-doc with Bruce Ames, and I studied micronutrients. His whole stick was RDAs are like to prevent deficiency, you know, and that they're just not adequate, you know. So like vitamin D, etc.

Dr. Phillips: Yeah.

Dr. Patrick: It goes on and on. Right. And so I'm very familiar with that where it's like, "Well, look, yeah, who wants to..." Like, preventing scurvy is one thing, but like, you know, not having DNA damage that's accumulating over time that's going to lead to mutations, lead to cancer, well, that's important. So maybe we should be thinking long-term, right?

Dr. Phillips: Yeah. That's pretty big, too.

Dr. Patrick: So it's, kind of, like the same concept. With respect to the 1.2 grams of protein per day, let's talk a little bit more about like specifics with people that are physically active. So you mentioned 1.6. Now, there was the study that...I think it was a meta-analysis out of your group that you guys looked at resistance exercise in adults younger than 65 and adults older than 65 and their protein intake. Can you talk a little bit about...? Like, you looked at lean body mass and what was found there. What were the major findings?

Dr. Phillips: Yeah. So, I think, it's fair to say that our lab has contributed to maybe some of the overstatement of the importance of protein for muscle mass. And I'll, you know, throw my hands up and say, okay, some early studies that we did, particularly where we were measuring rates of muscle protein synthesis, we saw these enormous changes with protein. And everybody was like, "See, it's important." And I'm like, "Absolutely." You begin to accumulate evidence. You begin to accumulate longer-term trials where people are fed higher versus lower protein intakes. And the data looks, sort of, promising, but the more trials you get, it's, sort of, the effect tends to become a little bit smaller, the nuance, let's say. So I think that it's important that 1.2 is still the basal level, that's the buy-in. I think 1.6 grams per kilo... And I know people like to talk in pounds. So, you know, it's something around, sort of, 0.6 to 0.7 grams per pound.

And those levels after that...you can digest and eat lots more protein. Your body just can't use it. But if you're a physically active younger person, we refer to protein turnover. And the concept, I think, that's easiest is to say, you know, your muscle or your proteins in your body are like a brick wall. The amino acids are the bricks going in. Protein synthesis is the bricks going into the wall. But at the other end, there's a process of bricks, you know, bad bricks, damaged bricks, old, worn-out bricks being taken out of the wall. So we're turning protein over constantly.

And if you're performing exercise, and you're going out, doesn't matter if you're running or lifting weights, then that protein turnover process is accelerated. So you have to put more bricks into the pool to replace the ones that are coming out. It sounds like a really inefficient process, but you can imagine, if you did that every day to the walls around your house, they'd be in great shape. So, it's a good thing. I think as you get older, what happens is that the bricks that are coming in aren't used as efficiently. But we're still pulling bricks out of the wall, and that, sort of, tips the balance and we begin to lose muscle mass. If you go into bed rest, we tip that in the opposite direction in a really severe way.

And, you know, most people have experienced... And we use this as an experimental model, a period. You put a cast on your leg or your arm, you take the cast off, and then you look and you say, like, "Where did my leg or my arm go?" Well, that's local muscular atrophy. When you're young...most people ask, "Why don't we do rehab for young kids if they fall out of a tree and break their arm?" The answer is we don't have to because kids just go back and keep doing and playing. Like, that's their rehab. As we get older, we don't tend to do that. So we need active rehab. And, I think, that that's then the period where you need to put more protein back into the system to try and restore that. It just becomes ridiculously difficult as you get older.

So, young people, physically active, I'm an advocate for higher protein intakes. I would agree that most of them, if they're particularly eating to cover their energy needs and consuming a mixed diet, they're probably good. Middle-aged people, and I'll be the first person to admit this or probably not the first, we don't have a lot of data. And people ask why. And I'll give you a simple explanation. We can conduct lots of studies on university campuses as academic research institutions on young college-age people. There's lots of them around, willing participants in research. And we can conduct lots of research on people over the age of 65 as the meta-analysis, sort of, implies. The people in the middle, they're busy people. They've got kids, jobs, lots of things going on. And we say, "Hey, you got to come into the lab for a whole day. You got to do this." And they're like, "I can't do that." So, they're not studied often.

I think the assumption, and this is a reasonable one, is you can draw probably a line, you know, from young to older people, and the middle-aged people would be in the middle. So the meta-analysis was essentially then an attempt to reconcile, you know, "We've got all of these studies. What does protein do for lean body mass?" And the answer is, if you're younger and you're resistance training, so you're lifting weights, you want to get a bit bigger, a bit stronger, 1.6 grams of protein per kilo per day was the type of intake that you need to consume. But the effect is small.

So in other words, I like, you know, to put it practically, I say, you get most of the benefit from just going to the gym. And then the protein effect is a thin layer on top. And it's the same story as you get a little bit older. The bad news, like a lot of things, although aging is great, you know, you're more wise, you're...everything else like that, but things slow down. And so the protein begins to add incrementally, sort of, smaller amounts, and so it's a small nudge. You get a little bit of extra strength. You get a little bit of extra muscle. But it's really the lifting of the weights that is the big driver of all of the benefits and all of the gains. So, you know, simply put protein is we talk about sufficient and necessary for a little bit of extra strength, but it's a thin slice on top of what lifting weights provides in terms of strength and muscle.

Dr. Patrick: That makes sense. So the 1.2 is, kind of, going back to that number. It's like...

Dr. Phillips: Yeah. You kind of need to start there, and then you can move up, but there's obviously...there's a ceiling. And, you know, we could, obviously, have a discussion about, should it be 1.6 something here, or if you're in a caloric deficit, and I'm like, "Yeah, you could probably stand to eat a little bit more," because, you know, in a calorie deficit, again, you're, sort of, tipping the scales in the favor of the breakdown side of things. That's just, you know, calorie deficits are catabolic stimuli, and it's catabolic for muscle too. So, yeah, there are probably situations where we need a little bit more. But how long, how much? Those are really, let's call them fine details.

Dr. Patrick: Is this also a fine detail? The protein timing. Probably one of the most common questions is, "Should I split my 1.2 grams into, you know, 3.4 grams per kilogram?" Is the stimulus...? And we'll talk more about why protein's a stimulus for muscle, you know, mass. But you know, does it have to be higher or...?

Dr. Phillips: Great question. Again, I'm drawing as much from evidence as I can here in a little bit for my, sort of, own sense, so, you know, take this with a grain of sand. I think the way your body is set up and your muscles, in particular, prefer to be fed regularly, so pulsed, you know, breakfast, lunch, dinner, and a snack or whatever it is. So when I'm talking to athletes who are the crème de la crème, pro-level, Olympic level, I get to talk to them every now and again and I always say, you know, "You guys are clearly..." We've skimmed off everybody who is, sort of, a mere mortal like me. And now we've got these elite specimens, and they probably should eat that way. Now, I appreciate that sometimes training is difficult for them to do and everything else like that. But, I think, they could benefit from even distribution, whether it's a huge effect, I think, for most mere mortals, it's not a big deal.

I think if you're the top-level athlete and you're probably looking to medal or, you know, win this or win that, then maybe some of those small differences, that's the sort of the last little part that you need to turn the dial that is the margin of victory at the top level. So, we talk about even spacing of protein. I think for most people, it's not that big a deal. There's also the timing with respect to exercise, and I lived through that craze, not as big a deal as we once thought.

So it's really about the total amount of protein you're going to get in the day. And then the next one would be, you know, even spacing, and I'd say, yeah. And then the next one would be, sort of, protein quality where, you know, we get into some of the more nuanced talk about protein. And then you can dial it down from there.

Most people I talk to, I just say, you know, "Do you go to the gym?" And they're like, "Yeah, yeah." I'm like, "How many times?" They're like, "Well, you know, once or twice." I said, "Maybe you could go two or three times." That would probably be a much bigger benefit than I need to divide my protein three times across the day, so.

Dr. Patrick: Good point. What about 65 years and older?

Dr. Phillips:Yeah. This is where what we call a skewed protein intake, and the traditional intake is lowest at breakfast, moderate lunch, and then most of it at dinner. I think it's probably correct to say, first, that breakfast time meal, you could really stand to push the protein intake a little bit higher. Most people say, heart-healthy breakfast, whole grains, that sort of thing, and so that's where they focus. When we've looked at intakes of older, particularly older women, they consume a ridiculously small amount of protein at breakfast. And, I think, they could handle, you know, some Greek yogurt.

We take eggs off the dirty list and we say it's okay to eat an egg, good high-quality nutrient-dense source of protein. And then they say cholesterol. I'm like, "Probably not as big a deal as you've been taught." And, you know, you're 85. I'm like, "Have an egg, for goodness sake, you know, or a glass of milk." You know, most people say, "Well, there's not much protein." And I say, "You're right," but it's more than the 6 to 8 grams, you know, most of which comes from wheat gluten, which is...you know, it's not a particularly high-quality protein that these older folks should probably aim for. And it doesn't necessarily, again, have to be enormous amounts.

People say, "What about protein supplements?" I'm like, "Very convenient." If you can't do it with food, absolutely a protein supplement is probably useful. But, you know, whatever suits your lifestyle. But I do think that older people particularly, instead of having the skewed distribution, could stand to, sort of, have a more even distribution throughout the day.

Dr. Patrick: Okay. Maybe we should talk about why protein is such a strong stimulus for increased muscle protein synthesis. I mean, what is it about protein, the essential amino acids?

Dr. Phillips: Yeah. So you said it. I mean, go back to the brick wall analogy if that's muscle protein. It's made up of 20 different types of bricks. Those are the 20 amino acids that we have, 9 of which are essential. We need to get them in our diet. And in particular, they're a group of what are called branched-chain amino acids that are three of the nine. And the most potent, if you like, of the three branched chains is an amino acid called leucine. And the way I like to explain it to people is that it's, kind of, like the brick that when it arrives, it turns the process on. I'm intentionally doing that because I always just like to remind people, it's like a dimmer switch. So it's not, you know, click on, click off. It's really like your...you know, leucine comes along, and you see the lights begin to come on. And the lights obviously are the process of making new muscle proteins.

So, once you have sufficient leucine there, you can turn the switch up as bright as it can go. Once you put more leucine there, you can't go any higher. For older people, for reasons that we're beginning to unravel now, I think, what happens is now the sensitivity of that dimmer switch. The leucine comes and you, sort of, get this response. In a younger person, you might get that. So we need more leucine or more branched chains or more essential amino acids, which translates into more. You need more protein to trigger the whole turning the protein synthetic process on. So, it's a pretty nuanced level, I think, of understanding. But we're beginning to see on, when we look at diets, the people who consume higher-quality proteins or sufficient lower quality proteins, which I'm sure we'll get to, it's really about the leucine that they consume, particularly for their muscle, that's important.

Dr. Patrick: So I have a question about that. But before we get there, the higher quality. Obviously, animal meat is higher in essential amino acids than plant protein. Can people that are on a plant protein diet then get sufficient essential amino acids to foster muscle protein synthesis?

Dr. Phillips: Great question. And, you know, this is one area we chatted a little bit before. I came on to say that my understanding and even the studies that I've been involved with has changed. You know, so 20 years ago when I first came to McMaster, I'm like, "Here's a fundamental truism. Animal-derived proteins are higher quality than plant-derived proteins." Plant-derived proteins have anti-nutritional, fiber is one, phytates, lots of other things that can inhibit protein breakdown enzymes. And, you know, I use to say, "That's a big deal. It's going to lower the quality. You're not going to get as many essential amino acids." And that's true.

But, you know, fast forward, 20 years, we've now got processing methods that can lower or change the fiber content. We've got foods where we've isolated plant proteins, etc. So we've taken a lot of that out of the equation. And then everybody says, "But the essential amino acid content is lower in plant proteins than is in an animal." I'm like, you know, "Essentially, you're correct." The top of the list in the plant kingdom would obviously be soy. It's, you know, plant-derived protein and probably been the mainstay of 20th and 21st-century vegans or vegetarians.

But now we're looking at a variety of plant-based protein sources that are...they are contrived. They're manufactured foods, but they're very high-quality proteins. They're not something that people need to worry about in terms of on getting an inferior "source of protein." So, I think that the way you can make up for the difference is you either eat a little more over here in terms of protein, or you go towards supplements or foods that actually have taken some of the anti-nutritional out, or and this has been something that we're keenly aware of and trying to study is that a lot of the prep methods of plant proteins like beans and legumes, you cook them. And cooking actually liberates a lot of their proteins and makes them more bioavailable, and so reduces the anti-nutritional effects. So sprouting, cooking, fermentation, all kinds of things that are commonly done with plant-based proteins, beans, legumes, I think, are making the two proteins much more close in quality inside us than we once thought. And so, I tend to worry less about protein quality than I once did.

And I know that probably upsets a lot of people because they're like, "Well, you used to say..." And I was like, "You're right. I used to say that, but the evidence is evolving." And even in our own hands, we've been...I think I've been surprised actually at how good plant proteins have been in stimulating muscle protein synthesis, so.

Dr. Patrick: That's really good to know. And I'm going to ask you this because I know people listening or watching this are going to ask. And when you're talking about fiber and the effect of fiber on, you know, being able to absorb proteins, you're talking about within a plant. You're not, like, talking about eating your plate of spinach with your steak. It's inhibiting the absorption.

Dr. Phillips: Yeah. That's right. Yeah. I mean, the steak and the spinach still good mix, great if you enjoy to eat that way. But, you know, I'm talking about... I mean, here's the other, sort of, knock on some of the studies that we use to make these generalisms. People are fed individual foods, and that's really not how we eat. We tend to...you look at a plate and it's got something like this. But when you do that...

I think the point I'm making is the fiber that's intrinsic to the plant or the fruit or whatever it is is inhibiting, to some small degree, your absorption of the protein that's there. But those effects. Again, you cook a bean or a pea, and a lot of that goes away. So, raw peas, you know, if you eat raw peas. Okay. But if you cook the peas, they're a lot more digestible. And so, you know, a lot of the studies that we have to look at protein digestibility and the amino acid scores, and there are lots of them, but I don't think are as big of a deal as we once thought.

Dr. Patrick: Yeah. Talking about the leucine and, kind of, circling back to that, I... And I want to get into, you know, underlying causes of sarcopenia and... But, kind of, before we get there, the leucine supplementation does come up in my mind and probably in a lot of other people's minds. It's like, "Can I supplement with leucine and not have to take in so much protein and have a similar effect on muscle protein synthesis?"

Dr. Phillips: Yeah, really great question. And we have done some studies where we haven't... Well, at proof of principle, we supplemented people with leucine, and we did find that it improved the response. A little...you know, the caveat statements. First of all, leucine is of all of the 20 amino acids...and I know everybody hasn't, you know, done this, sort of, thing. It's extraordinarily bitter. So it doesn't taste great. So you need a bit of food science to take that edge off, I think.

From my perspective, that would be, sort of, a last resort because it's really...it should always be a food first approach and then maybe a supplement. And now you're bringing it down to the individual component. And, you know, you probably get a sense of this from some of the studies that we've seen with individually purified components of like a tomato, and it was, "Oh, it's lycopene. That's really important," when actually, there's things in the whole tomato, the matrix and other things, and lots of bioactive compound. We have no idea what they're doing. And probably the tomato is better for you just like lycopene alone.

That's my, sort of, ethos statement to say, you know, leucine supplementation, if you must, buyer beware, make sure it comes from a reputable company. The internet is rife with crummy supplements, and you just need to know where it's coming from. So usually look for third-party testing. I tend to like domestic production, so, you know, North America if you can.

Then a lot of people say, "What about branched-chain supplements?" And I'm like, "That's really interesting." Like, they stuck around as a sports supplement for a long, long time. I think the message is fairly clear now that they're largely...I won't say useless. But from useful to useless, they're a lot closer to the useless end. But it's only the leucine out of those three amino acids that's the important branched-chain amino acid. So, they work because of the leucine.

So, then people say, "Well, I'm on a high protein diet supplemented with the right whey, and I'm taking branched chains." And there's a great Instagram meme where I see a guy in, you know, a pool. It's raining and he's drinking water. So it's, sort of, like that's where the branched chains are. I'm like, you're surrounded by good stuff. The branched chains are probably not a big deal. But for older people, we've done some work. It's possible, you're going to see products. They're fortified with a little bit of extra leucine.

Dr. Patrick: Do you absorb leucine, like, in free form? And it doesn't have to be a certain form?

Dr. Phillips: No.

Dr. Patrick: Okay.

Dr. Phillips: No, you absorb it in free form. In fact, it's really readily absorbed. The big barrier in all the studies we've ever done is how to mask its taste. So, you can imagine, given its taste profile, we mix it with some, sort of, citrus and legumes...excuse me, citrus fruit flavor and try and sort of blend that sharp bitter edge into like, "Oh, it's lemon. It's orange. It's grapefruity, you know, something." And that tends to be a good mix. But, yeah, I'm not a food scientist.

Dr. Patrick: Pineapple juice will be fine.

Dr. Phillips: Pineapple, yeah, something like that.

Dr. Patrick: So you said four to five for older individuals, let's say, that are...you know, as you mentioned, when you get older, your satiation...those hormones are all different and that people don't eat as much. They're not hungry as much, and they certainly don't chew as well. I mean, all sorts of factors, right?

Dr. Phillips:Absolutely.

Dr. Patrick: You know, if you can get someone who's having a hard time, like, there's just no way they're going to get 0.4 grams of protein per kilogram body weight. The leucine supplementation may help with that older person.

Dr. Phillips: Yeah. We've shown that. And, I mean, I think, it's not just our work. Lots of other people, collaborators of mine, good friends of mine have shown the same thing that if you take even a small protein dose, and you add a little bit of extra leucine, you can make it look as if it's a bigger protein dose. And so, you know, our dimmer switch analogy is that, you know, "Here's a small protein dose," and you get that response. Here's the small protein dose with leucine, and now you get a slightly greater response.

Dr. Patrick: And you said was a 4 to 5 grams? What was it?

Dr. Phillips:You know, the per meal leucine dose is probably somewhere in the range of, sort of, 3 to 4 grams for an older person, probably 2 to 3 for younger, and that's just because the younger person is really sensitive to the effects. But we can make a younger person. When we put a brace on their leg, and we get local atrophy, their atrophied muscle looks like an older person's response. So the disuse response we think is sort of...it's almost a model of premature aging in terms of your muscle anyway. The difference is a young person does this, and they just bounce back. An older person does this, and now they're down here.

Dr. Patrick: So why? Can you talk a little bit about this, as I've heard or read in your publications, and I'm sure others as well, this anabolic resistance decline? What is that?

Dr. Phillips: Yeah. It's a great question, I mean, I don't think that you can discount inactivity with aging. You know, everything as it gets older, you know, from earthworms all the way up to, you know, humans, we do less as we age. There's no question about that. We have done some studies where we've used step reduction like abrupt step reduction as a model of, sort of, abrupt sedentarism where we can make older people much more anabolically resistant as a result of that. So, clearly, activity is a driver of it.

At the same time, I think, there's probably aspects to do with insulin resistance, and it doesn't need to be overt insulin resistance to the degree that you have type 2 diabetes, but maybe you have what we call vascular insulin resistance. And what this means is that when you turn on insulin, you usually open up blood vessels to allow flow to happen. And what we think happens with aging is that response becomes just a little bit less sensitive. You're not insulin resistant from the perspective of blood sugar, but from a protein perspective, we think that opening up local capillaries and allowing good blood flow in older people just isn't quite as sensitive.

So, again, people say, "Well, you know, what can I do?" And the number one answer is to be as physically active as you can, and that maintains that vascular level sensitivity as you get older. Aging is going to get you at some point, there's no question. But clearly, as you said, the cornerstone is to maintain your physical activity levels. Be as active as possible. Aerobic exercise, absolutely. Resistance exercise, it's got to be there.

Dr. Patrick: And what about in terms of how many times a week resistance exercise? You mentioned, you know, the 10,000 steps. People talk about the 10,000 steps, right? Is there something people can think about? And is it age-dependent? Does that change as well? Right? I mean...

Dr. Phillips: Yeah, yeah, that's a great question. I mean, the origins of 10,000 steps is also probably...you know, people go, "Where does that come from?" And you're like, "That's a good question." I mean, it's a great round number. You know, when you go back to the history of those little pedometers, it was just...you know, that's a good number. And it's probably true. You know, the closer you get to around 6,000, 7,000, and 8,000, 9,000, 10,000, you start to see health benefits. So I'm not going to dismiss that.

Resistance training, it's a little bit more difficult. Most of the guidelines you look around the world, there's a recommendation for two times a week of strengthening activities. My own feeling is that it should be more than recommended. It should be a de rigueur part of the guidelines like 150 minutes. And I do think two days a week is sort of...that's the buy-in level. I mean, if somebody's doing nothing, and they do one, big change. They do two, big change. I think three, bigger change. Four, I'm like, "I don't know." You're probably starting to see the plateau. Five, I'm like, yes, if it's your thing. Six, you go. Seven, you're mad, but go for it. It's a dose-response like a lot of things, right? 150 minutes is, kind of, where we tap out a lot of the benefits, and then you go from there to say double in 300 minutes. And you can squeeze a little bit more out of the cloth, but you've, kind of, got a lot of the benefits with the first 150.

Dr. Patrick: Let's say you're doing... So that's 150 minutes of strength.

Dr. Phillips: That's aerobic exercise.

Dr. Patrick: Aerobic?

Dr. Phillips: Yeah.

Dr. Patrick: When you're talking about...let's say you were doing a two days a week of resistance training. What's the duration for each of those? Is it...?

Dr. Phillips: Here's where we climb inside the really, kind of, nuanced things. Then it's, sort of, like, do we do free weights? We do machines, we do sets, we do reps, and everything. And this is actually, I think, one of the barriers for a lot of people is that the...you know, most people, I say 10,000 steps, they're like, "Oh, walking. I could do that." And then you say weightlifting. They're like, "Oh, I hate going to the gym." And then you're like, "Okay, well, have you ever done a push-up?" And they're like, "Yeah, but I hate push-ups." And most people hate push-ups because they were used as a form of punishment when you're a kid, at least that's my feeling.

But, you know, you don't need a gym to do resistance workouts. You can do bodyweight workouts just about anywhere. You can do like an air squat up and down, and you don't need a weight. But, you know, sets reps for, you know... My main point is getting to do that at least twice a week for, let's say, 30 to 45 minutes duration. There's a lot of benefit associated with that. I think three times, you can get a little bit more.

But it's about making clear that the biggest reduction in risk bar none is always going from nothing to doing something. And not that we should aim at, you know, the smallest or the lowest bar or anything else like that. But as we mentioned...I'm saying before we got on camera, these nudges of people that are really sedentary at a population level, if we got everybody to walk for even 10 minutes a day, and then maybe they did, you know, push-up, even if it's...they can't do a floor push-up. Let's say a wall push-up and, you know, maybe went how to walk outside, how good they would feel, mental health, physical health, and everything. And the population effects would be pretty substantial.

So I'm good. You know, if you're like me, and you like to go to the gym, and you like to lift some weights... I don't lift heavy weights anymore. I think that's, sort of, a diabolical pursuit. But if that's your thing, go for it. But, I think, it's more about getting to the gym, performing a workout with pretty high levels of effort, which is the...I stopped prescribing percentages of your maximal lift. I just say lift until you're pretty fatigued at the end, and you should do pretty well.

Dr. Patrick: And when you're lifting or you're doing any type of resistance and/or strength training, you are also causing muscle protein breakdown, right?

Dr. Phillips: Yeah.

Dr. Patrick: But then the mechanical force on the muscles are increasing protein synthesis. Or what are they doing?

Dr. Phillips: Yeah. No, that's great explanation. Yeah, I mean, I think, you know, our wall analogy, again, is to say that actually, exercise, physical exercise and particularly some forms, but weight lifting is a really potent one, turns up the rate at which we're pulling bricks out of the wall. You're creating damage. You're creating a stress on the muscle. Successful adaptation to stress is that you're able to repair that damage and replace those damaged proteins. And that's the synthesis side of things.

And then, you know, clearly, what we're aiming for is, you know...so we have damage, and then we have synthesis. But now you've gone up a little bit and we have damage synthesis. And over time, you know, it's, sort of, down up, down up, down up, but the trend is that you're getting better and better. The same with aerobic exercise. I mean, it's...

You know, I'd say to people, like, the exercise is great, but it's in recovery that we...that's where all the good stuff happens because we, you know, as a result, repair any damage, recover from the stress and hopefully recover fully so that we're at the better starting point. Again, sometimes it's small changes. Then over time, you know, people say, you know, "When I first started, I was so tired." And I'm like, "Yeah, it's hard work when you first get started." Get past month one, month two, month three month, you know, and then now you're six months later, you're like, "I'm so much stronger and so..." you know, etc. It takes time, and stress is stress. You have to overcome it. But the benefits are massive.

Dr. Patrick: Does the recovery...? I mean, is there a certain...? Like if you're doing the strength training, let's say you do 30 minutes one day. Do taking the next day off matter, or can you like do it two days in a row and then recover? Is that just...

Dr. Phillips: Again, these are the sorts of things that, I think, you know, when you become more advanced. So now you're go... I'm like, "Okay, I've got three days in the gym a week. I've got that down, no problem." And it becomes, you know, "What more can I do to, sort of, maximize what I'm getting out of the workout that I'm doing?"

Most people split, say, a resistance workout. They might pair exercises. The most rudimentary one is, sort of, say, there are pushing exercises, so that above your head. There are pulling exercises or a bicep curl. And then there are leg exercises, so pushing, pulling legs, and you're working different muscle groups. And that's three days a week. It gives you...the muscle has lots of time to recover.

Some people do it really differently. The bodybuilding culture gets into, you know, individual body parts. So today is a bicep day. The next day is a tricep day. You know, Monday is usually always a chest day, and you're under the bar doing a bench press. You work on your legs. You work on your lower legs. You work on your upper legs. You know, all of those are things that are...ways of splitting it up.

I think, you know, my advice to most people is to say, you can probably break most exercises, resistance exercises down into some pretty basic ones. You know, there is a push from your back that's a bench press. There's a shoulder press above your head. I'm not a big fan of isolation exercises. But, you know, squatting or a leg press if you don't want to squat is really...you know, those are the three sort of...if you walked away and remember nothing, those are great exercises. You don't need to do too much more to be honest with you, but you branch out from there.

I do think some people can handle a lot more. I know from my own experience, when I was younger, I could do a heck of a lot more, and the recovery came a lot easier. Now, not so much. And the goals are different. My goal now is...you know, it has a 20-year horizon, 30-year horizon. You know, that's something. I'm like, you know, How long does it take to recover? I'm like, "Well, I don't know. I took a day off yesterday. I was okay."

Dr. Patrick: Does protein help with recovery? I mean, how much of a role does...? For example, we talked about leucine. How much is, like, you know, essential amino acids like that activate IGF-1? Does IGF-1 playable in muscle repair?

Dr. Phillips: Yeah. You know, good question. I mean, I think as I said, you know, it's in recovery where all the good stuff happens. Like, the workout is putting the stress on the muscle and the bones, the joints, etc. And then the recovery part, the stress is removed, and it's like, "Okay, now it's repair time, recovery time, three hours, rehydrate, refuel, repair." So you got to get fluid back in if you've lost that. It's a primary one. You got to get fuel back in, particularly if, you know, the next day you're going to do another workout. The repair part, that's where the protein comes in.

There's a lot of thoughts that the regenerative process also involves, you know, hormones going up and everything else. And I think for a large part particularly when you're an adult, that's a non-issue. The restorative process and the recovery process is driven almost exclusively by macronutrients. And so, IGF-1, and I'm like, "Yeah, needs to be there." But it's not a stimulatory or an inhibitory hormone for repair or recovery.

Dr. Patrick: Okay. Let's talk a little bit about mechanisms and...there was definitely some surprises and interesting, you know, findings when I was reading a lot of the literature, including predominantly yours. Leucine, its major role in activating muscle protein synthesis is through mTOR?

Dr. Phillips: Yes, through mTOR. Very good.

Dr. Patrick: Okay.

Dr. Phillips: Yeah. I mean, mTOR is one of these...you know, it's a highly conserved protein. It's, sort of, an integrative nexus of all kinds of anabolic stimuli, including resistance exercise, or any form of exercise is actually running through mTOR. Leucine goes through mTOR. Its dysregulation is involved in all kinds of processes, including cancer and lots of other things, so has a really essentially important role in integrating all of those anabolic signals.

There are some thoughts now that there are actually two complexes of mTOR, one that's sensitive to nutrients, one that's actually more sensitive to exercise. And, you know, one functions a little bit different than the other. But the ultimate culmination is that the downstream signals after you've stimulated mTOR are to turn on protein synthesis and all of the regenerative or anabolic processes to repair any or recover from any stress that's been exposed. So, yeah, it's essentially important protein. We study it a lot. We're by no means experts in it. There are people that are far better at it than I am, so.

Dr. Patrick: Yeah. So, inhibiting like mTORC1, which is the nutrient-sensitive complex. Something like rapamycin could affect muscle protein synthesis but not... because there's also mTORC2 activity going on. If a person is resistance training, is it not as big of a deal or is it still does affect it?

Dr. Phillips: I mean, I think, like I said, you know, the benefits of the resistance training probably through mTORC2 are like this. You still get the protein synthetic response. Within mTORC1, I mean, that's where the, sort of, thinner layer of the nutrient added stimulation goes on top of resistance training. So, as you say, one's sensitive to rapamycin. The other one actually isn't.

So, you know, the more we uncover with this, the more we realize we probably...you know, 10 years ago, we thought we hadn't figured it. Now we're not even close. And so now we're beginning to understand that mechanical stress from exercise is routed through a different process, the nutrient stimulation of protein synthesis. So, you know, maybe that's the underpinning mechanism why a lot of people talk about, you know, restricting protein and not wanting to turn on the overly or overly turn on the anabolic side of things, you know, because uncontrolled growth and, well, you know, cell level, that's cancer.

But as I point out to people, you know, persistent exercise also activates mTOR on an almost chronic basis if you exercise every day. And now we're like, "Well, actually, it's signaling through a different process." So maybe that's why it's beneficial. And this one if it's chronically turned up is not so good.

Dr. Patrick: Yeah. And it also goes back to some of the observational data we were talking about also a couple hours ago, whenever it was, when you're looking at protein intake, specifically animal protein versus plant protein. And animal protein as you pointed out is higher in essential amino acids, including leucine. So, you look at these all-cause mortalities and these cancer-related mortalities, and there is definitely conflicting data for sure. But there is an overall...

Like, there's a lot of studies showing that there's a lower all-cause mortality and a lower cancer-related mortality in people that consume plant proteins. However, when you start to look at the largest observational studies that have been done, those studies that have looked for any like unhealthy lifestyle factors or confounding factors have found that, oh, actually, people that have no unhealthy lifestyle factors, so they're not obese, not sedentary, not smoking, not excessively drinking alcohol, they have a similar all-cause mortality as a plant-eating person.

So, you know, again, it goes down to that, okay, well, maybe if someone is obese and smoking or sedentary, before you start eating a lot of protein and worrying about that, like let's get rid of those unhealthy lifestyle factors, right? Let's get physically active. Let's lose some weight, some fat. Then things can, kind of, fall into place.

Dr. Phillips: I couldn't agree more. I mean, I think, in, sort of, the broad checklist, and people say, you know, "So what are you doing to age well?" And I said, "Well, I'm trying to stay at a body weight that's, you know, not excessive." I weigh more now than I did when I was, you know, 13 14, no kidding. I'm more than I did when I was 23, 24, but not much more.

I'm physically active. I pay attention to what I eat 80% of the time. And people say, "Well, what about the other 20%?" I said, "That's why I exercise. So, I can indulge myself 20% of the time." I don't need a vegan diet. I don't need a vegetarian diet. But I eat less meat, particularly red meat than I used to. I eat more fish. I don't eat as many, you know, unrefined or excuse me, refined carbohydrates. I don't really have a sweet tooth, so I was kind of lucky in that way. So I don't feel compelled. I'm weak in the presence of chocolate. Maybe that's my one indulgence. But I don't smoke, never have. I don't drink as much as I used to, you know, all of those things when you're going check, check, check, check.

And then people go, "Well, what about intermittent fasting?" And I'm like, "You know what..." And again, it's my...this is the analogy, I love this, is to, you dip the water or you dip the cloth in the water. And, you know, the first ring is, like, you get a lot of water out. I'm like, "That's maintaining your body weight." I'm like, the second one is physical activity. The third one is watch what you eat. The fourth one is, you know... And then you could add subtle nuanced things more on that. You know, it's only little drops that are coming out of the cloth. That's where, I think, a lot of the finer details, the vegan versus, you know, omnivorous diet, if you're judicious about how you plan your omnivorous diet, can make a difference. Yeah. if you're smoker, that's a great thing to give up because that's a bona fide, a shortened lifespan, poor quality of life, etc. But I understand the power of addiction and particularly if you started early, which is when most people take it up, man, it's a tough one to break.

Dr. Patrick: Yeah. Lose the weight, physically active. I think what you said is pretty fair. Like, the most important things.

Dr. Phillips: Yeah, some broad strokes.

Dr. Patrick: And then the little drops that can come out. Hormones, growth hormone, testosterone, I mean, getting to the sex hormones. I was quite surprised by, you know, some of the data coming out of your lab that showed... maybe you can explain it because you'll explain it better than I do. But, you know, looking at what effect, for example, growth hormone has on muscle protein synthesis.

Dr. Phillips: Yeah. You know, to give you the origins or the genesis of this story, I was early in my faculty appointment. And we were doing these studies where we were infusing people with labeled amino acids to measure the rate of muscle protein synthesis. So we were measuring these...the incorporation of these amino acids. And we had people exercising. These are mostly young men, freely admit that. We're making a push to do younger women and older women and middle-aged women, perimenopausal women. So, stay tuned. It's coming. And we would send it in for publication, and they said, "You haven't measured, you know, testosterone, growth hormone,or insulin like growth factor." And they go up after exercise, and they're driving this protein synthetic response.

And my training is as a biochemist. I'm not an exercise physiologist. I'm a varsity athlete. So, you know, pairing the two seemed logical to me. And I'd actually worked with, you know, some people that were pretty good with steroid biochemistry. And my understanding was that steroid hormones, testosterone, that sort of thing, slid across membranes, bound to receptor, receptor went into the nucleus, modified the expression of genes. And that takes a long time. That's not a transitory, you know, testosterones up, and 15 minutes later, it's back down. And growth hormone, the same thing.

So, we thought, you know, "We need to test this." We either need to show that those hormones are important or they're not. And so that's why we don't think we need to measure them. And it's a journey that we...it's taken us, you know, 20 years, probably about four Ph.D. students, a couple of good post-docs. So it's been a good one. Lots of people have chipped in.

We've tried very, very hard to show that those hormones have an anabolic effect. And we've never been able to see it. And we've manipulated all kinds of experimental conditions, and we just don't see an impact. I think the most damning evidence against testosterone as a big driver of muscle protein synthesis is to say, you know, if you take men and women, and agree, like, men start out with more muscle mass than women, and you resistance train them... And this is a meta-analysis now. A guy named Brandon Roberts did this one. And you resistance train them relative to what they started with. Everybody goes up the same amount. Women get the same amount of muscle growth as men do. But they had less muscle to start with because, you know, boys and girls are like this. Puberty happens, boys become mannish, and that's the testosterone surge. But after that, they follow each other. So, the big T, not so important.

Now, this is where people say, "But steroids work." I'm like, "Absolutely." And so this is the normal diurnal variation in testosterone. This is steroids. It's about two to three standard deviations away. And if the person is taking it either orally or as an injectable, it's up all the time, whereas we're talking about transient fluctuations and hormones throughout the day. If you take men and they have a diagnosis of prostate cancer, they're often put on androgen deprivation therapy. They're taken from a normal testosterone state to a hypogonadal state. And, yeah, they lose muscle mass. It's almost a feminizing process for these guys, but it's good news for the prostate tumor, which is a reproductive hormone-driven tumor. And, you know, the dirty secret that we're trying to sort of...

You know, our lab and lots of others are trying to, sort of, convince and talk to women, particularly around menopause, is, it's not just bone that drops off. It's muscle too. And that's the loss of estrogen-mediated stimulation of protein synthesis. So, you know, that's the sort of the testosterone story. And, I think, it's pretty much we can put that one to bed.

Now, I will say this is...there's a lot of people making a lot of noise and lot of water about certain supplements that boost testosterone, and do this, that, and the other. I just came from the American College of Sports Medicine meetings and listened to a great talk. A good friend of mine, Eric Rossen, said, you know, this is a case of what's old is new.

There have been in my 25-year career now at McMaster probably about two dozen testosterone-boosting supplements that I've seen come and go. And then it seems like we just can't get rid of them. You know, there's two or three hot ones out now, and I won't name them. But let's just say, you know, I get DMs on Instagram, "Which one should I take?" I'm like, "Save your money. Why bother? Like, just get to the gym and lift." And that tends to upset a lot of people. I do think, however, if you go and you look back at...you know, it was androstenediol. It was a hormone precursor. Having trouble getting my tongue around here. It was plant-based hormones, etc. None of this fenugreek...none of these things have worked.

Again, look at the sum totality of the research. Not one study, not one person talking about this on an Instagram Reel. I think you just need to step back. And, you know, Phillips' "three rules of supplements" taken from a good mentor of mine, Ron Rahman, "If it sounds too good to be true, it probably is. If it's too good to be true, it's probably banned, or you need a big prescription for it." There may be some exceptions as rule number three, but there are very few.

So, the growth hormone story is another one, and the easiest way I, sort of, like to try and explain that to people is, the lack of growth hormone when you're young, so hypo classical hypopituitarism leads to shorter stature, dwarfism. Those individuals have an amount of muscle mass that's directly proportional to their stature. If you have hyperpituitarism, you're a giant. You're just tall. You don't have excessive muscle mass. You have it directly proportional to your stature.

So growth hormone is a stimulator of stature, you know, your height. It's good for bones. It's actually really good for collagen. And everybody goes, collagen. Your bone is actually about 40% by composition protein. It's not just a stick of chalk. There's a layer of collagenous protein around it. But this may be where collagen has achieved its, sort of, notoriety, particularly in the supplemental form for athletes is it stimulates collagenous tissue synthesis. And if you think about it. So you take testosterone, your muscles get bigger. They probably get big enough that you can do ridiculous things in terms of lifting really heavy weights but to the degree that you can tear your muscle right off of a tendon. And it happens.

And so, where the growth hormone comes in, this is my own personal theory, is it stimulates collagenous synthesis, and so the tendons become stronger too. And laced throughout your muscle are collagenous proteins. So that's where growth hormone is beneficial. So, we're in California. I'll invoke, you know, Victor BALCO and say, you know, "You have to get the cream and you have to get the clear." And that's the steroid hormones and the growth hormone. You need both of them to be a big, strong guys.

But, you know, both of those hormones are pro-anabolic and therefore pro-cancer hormones. Chronic elevations of those hormones mess with a lot of systems that we just...we're only beginning to understand. So, excessive testosterone or high levels, great driver of prostate growth, excessive growth hormone, a great driver of lots of different tissues. But it's lack...and this is where you've had Dr. Longo on the show before. He shows in certain populations of dwarves, for example, who have a particular type of dwarfism and lack of growth hormone receptor. They actually don't get cancer.

So, do we really want to mess with that system is my question. And, I think, that, you know, us showing that they don't have a particularly huge role at least within the normal variation is a lot different than people coming out to the extremes down here. And if you're clinically low in those hormones, by all means. But for most guys, I'd stay away from that stuff.

Dr. Patrick: You have shown that androgen receptor content increases with resistance training and is correlated with muscle protein synthesis. Do I understand that correctly? What do you think then because the androgen...? Does testosterone also increase androgen receptor? I mean...

Dr. Phillips: So it probably does a little bit as, sort of, a feed-forward mechanism. But I think that there's a little bit of a feedback mechanism, the nature of which you're not entirely sure, but that you can only get so much androgen receptor. You're entirely right. You know, as I said, the testosterone or other steroid hormones, estrogen as well, bind to receptors. And those receptors turn on genes. And so the content of the receptors may be...we think anyway, and others have shown the same thing, the rate-limiting action of where the testosterone probably is having any action if it's having any action at all. And the same for estrogen, so.

Dr. Patrick: Okay. So there could be some...and maybe other metabolites that are binding to it.

Dr. Phillips: We're scratching the surface with the big ones. There's lots of other downstream hormones that we're not looking at for sure.

Dr. Patrick: Well, that makes a lot of sense with the extremes because those were... You pretty much answered my questions, which were, you know, you inject, you know, people with testosterone, and muscle growth goes up. But it's super-physiologic, same with growth hormone though, right?

Dr. Phillips: Yeah, absolutely.

Dr. Patrick: Super-physiologic. So it's not just so much of the transient increase that you're getting from the exercise but this constant like where it's just elevated for like hours and hours and hour.

Dr. Phillips: Yeah. Like I said, the diurnal range is so ridiculously small as opposed to, you know, where steroids are or where growth hormone administration is. The comparison of like normal changes, you know, "I'm a high testosterone responder, I'm a low testosterone, or I'm a high growth hormone...you know, etc." It's not the same as talking about somebody who's taking exogenous supplemental hormones. They're completely different paradigms. So you can't invoke this as proof of that if you like.

The deficiency end is interesting, and I can see the clinical case for treating hypogonadal men if they have low testosterone or kids with, you know, classic type of pituitarism to get them to it. Probably not the stature that they would have if they're completely normal, but certainly not short. Some people choose not to do it. Some people just say, "No, that's how I was born. That's the way it is." I can respect that, but at the same time, you could make a case.

Where I differ with some of these, sort of, exogenous, they call themselves anti-aging clinics, is that the anti-aging that you get as a result of taking the hormone is maybe at the expense of overstimulation of anabolic or cell division cancer, etc., to the degree that it's doing you more harm than good. And, I think, unless it's closely managed, you need to be aware of that.

Dr. Patrick: Are you talking about like hormone replacement therapy? What about people that are doing hormone replacement therapy that are mimicking more what your physiological levels would be...?

Dr. Phillips: That's the paradigm. This is the normal range of testosterone, and most guys they point out that it's quite wide. And it is. So you can be just this side of it or just this side of it, and you're at the low end of normal. And bringing you into the normal range, that's clinical treatment. And it's the same for women at menopause taking supplemental estrogen to bring themselves back to where they were pre-menopausally. I understand that. Those are closely monitored clinical situations, or bringing you, you know, with growth hormone injections back to here.

I think where the difference is, is, you know, this sort of...I'll call it the Wild West of these anti-aging clinics where people just go take this, and there's no monitoring of what happens, or it's a physique-driven process. And so, you know, older guys say, "Look at me now." And I'm like, "That's great. You look great. I hope there's nothing, you know, with your prostate or elsewhere that's growing. That's all."

Dr. Patrick: And that again comes down to our lifestyle and physical activity, you know, which, as you said, 20%, you don't...you're eating your bad stuff, but you're physically active. I mean...

Dr. Phillips: I indulge.

Dr. Patrick: You. Indulge. Okay. You know, but...

Dr. Phillips: A slice of cheesecake is okay. A hot dog at a ball game is okay in my opinion.

Dr. Patrick: Yeah. I mean, you know, especially if you're a physically active person, and you're not eating it for every meal every day, right? So, you know, again, it comes down to, I think, also, you know, back to some of the observational studies where, you know, if you are going to do hormone replacement therapy and...like maybe there's a reason evolutionary speaking that our bodies start to make less of those growth factors and hormones as we age, maybe because cancer incidence goes up. And so if you're not taking care of the other factors that can lead to cancer... Exercise, you know, is one of the best known ways to lower risk of many different cancers, including hormonal ones. Then you probably shouldn't be thinking about hormone replacement therapy until you figure out the physical activity part first, right? So, you know...

Dr. Phillips: Great to inquire. Yeah, great. No, no, I think it's a really relevant point to say that, as you say, the benefits of exercise never stop. It's almost embarrassing to talk about how good it is for you. You talked about cancer. Yeah, 13 of the 26 most common types of cancer are lower in people who have higher levels of leisure-time physical activity. And so that's not exercise. That's gardening. That's walking. That's like...you know, just the general day-to-day, you know, not...

Dr. Patrick: Moving.

Dr. Phillips: Yes, moving around, yeah, not sitting down all the time. And we were talking before the show to say...I have a colleague. I'll give her a shout-out. Jen Heinzs just wrote a great book on the mental health benefits of exercise. And, you know, 15, 20 years ago, if you said, well, you can change the size of your hippocampus in your brain with exercise would have been like, "Right." You get, you know, improvements in mood. You get improvements in depressive symptoms, anxiety, and everything, you know, almost of the magnitude similar to people, you know, taking pharmaceutical, you know, interventions for those things. So it's just a win-win-win-win-win. If it's a pill, everybody will be on it.

Dr. Patrick: Absolutely. I kind of want to just...because it's a good transition into the sauna, the growth hormone store because, you know, I've been a routine sauna user since about 2009, a long time. I used to go every day. You know, it was like really, really...for me, it was like... In grad school, I would go into the sauna before I go to the lab. And it really seemed to help with my anxiety. And so I started to read about it. It was like, "Something's going on here," right? And I came into this whole growth hormone literature where, holy crap, you could do like two or three back-to-back sauna sessions separated by, you know, 5 or 10 minutes of cooling. And you could get up to like a 16-fold transient elevation in growth hormone.

And so, at the time, I was thinking, oh, you know, because I had used it so much through periods of injury and when I usually lose muscle mass. And it was very apparent to me, subjectively speaking, that I was not losing muscle mass. And so, at the time, you know, I was like, "Growth hormone, that's it," because it's an anabolic hormone, of course. You know, net protein synthesis will be increased. And it turns out I was probably wrong about that part.

Dr. Phillips: Yeah. The way you think about these hormones is that when we're kids and we're growing, you need growth hormone to grow. IGF-1 is a pro-growth factor. Once you're finished, your linear and, you know, sort of broad growth, these hormones are mostly...in the case of growth hormone, it's actually a fat mobilizing hormone. That's one of its great side effects. If you're taking exogenous growth hormone, you notice you get leaner. It probably doesn't do much for your muscle. I do think that there's something to the heat exposure probably outside of growth hormone that, you know, at the local level, we're beginning to appreciate the stress of the sauna. So it is stressful. It's a thermal stress but, I mean, it sort of, recreates, "mimics some aspects of exercise."

And we talked about, you know, hot yoga is one of this great sort of not only relaxing therapeutic, but you're physically active. You're stretching muscles, but you're doing it in the heat. So there's a big thermal stress, and your cardiovascular system absolutely is like, "Wow, we're under siege here." You know, heart rate goes up, everything else like that. But our muscles begin to turn on what we call heat shock proteins. So these heat shock proteins are...as the name implies, they were discovered when we...people applied local heating. And for a long time, they're like, "I don't know what these proteins do."

But what we understand now is that they chaperone or they act as essentially little proteins that bind to other proteins to prevent them from being what we call misfolded. And part of the stress response, and so as the name implies, could be stress due to exercise, could be stress due to sickness, could be stress... you know, you name it, is that more proteins are misfolded.

And people, you know, "What about misfolded proteins?" And I said, "Well, you know, a protein is a string of amino acids," and then it, sort of, bends in on itself, and then it does, you know, all kinds of things. And it twists into a shape that is its final shape for it to be useful. But sometimes it doesn't do that, and it does something else. And let's say it just...it doesn't fold into the shape it should be. And stress proteins help those proteins maintain and get into that appropriate folded structure.

So, yes, I think, you were getting benefits. You know, I don't know that the growth hormone was a big part of it, but definitely, the heat shock protein response is, I think. And we're beginning to see more and more that you can alleviate muscle atrophy and even in some patient groups with various forms of muscular dystrophy that actually...you know, heating and exercise could have synergistic benefits. So, again, pulling away some of, you know, the covers on this, it's a fascinating area.

And the other part, and we talked about this too, you feel good afterwards. And as I said, the top levels of athletic performance like the feeling good part is you can't undervalue that, even if the physiologists go, "Ah, there's nothing to it," and the athlete says, "I feel good." And the physiologist goes, "Oh, okay, well, you know, you scored three goals last night. So who am I gonna... you know, I can't argue." Yeah. So I feeling good is big.

Dr. Patrick: It is. I'm glad you brought up the heat shock proteins because that... To my credit, I did publish a review last August where I talked all about the heat shock proteins being responsible for preventing and, you know, much muscle atrophy with. There's been animal studies that I cited, you know, many years ago, and they've been sort of redone in a sense in some local applied heat therapy studies where they're preventing, you know, atrophy disuse.

Again, back to this elderly population. So I've been able to get my mother in the sauna. I have a sauna. There's only so much you can do with someone who has not spent their entire life being physically active. And I find that it's easier to get her in the sauna. And so I'm mimicking to some degree a little bit of moderate aerobic exercise and then hopefully also getting some heat check proteins to help with muscle atrophy, which she's battle...everyone, you know, as we're getting older battling.

So it's really nice to hear that you said that on the feeling...depression. I'll send you my article. You'll read it. But there's a whole section because there's been a sham-controlled trial looking at the effects of heat stress on major depressive disorder. There was a sham-controlled. And basically, it had an antidepressant effect. And I'm working now. I'm collaborating with someone. I'm a small collaborator. I'm the biomarker person. But Dr. Ashley Mason, she's at UCSF. She's now running more large randomized control trial on this. And so that's in the works right now.

Dr. Phillips: But the thermal stress side of things, you wonder, you know, so here's exercise. There's thermal stress, but there's muscular activity. So you're talking...I'll call it passive thermal stress. I mean, they must cross over. And so it wouldn't be surprising that, you know, one sort of mimics part of what the other does. So, yeah.

Dr. Patrick: I have a question for you because, as I was reading some of your reviews, something that came up was, you know, looking into the causes of sarcopenia, the many causes, but even down to like looking at the molecular and the muscle tissue level, there was this degradation or a proteostasis. Basically, proteostasis was messed up in type two...was it type two muscle fibers?

Dr. Phillips: Yep.

Dr. Patrick: And I was wondering if the heat shock proteins and sauna may play a very specific role in countering that type of sarcopenia.

Dr. Phillips: So, if you'd asked me that...and here's where, you know, never stop learning begins. Even three or four weeks ago, I would have to say, you know, "I'm not really sure." I had the pleasure of attending the International Biochemistry of Exercise Conference in Toronto, so, it was an easy one for me to get to, just two weeks ago. And there was discussion about this sort of heating aspect of things and heat shock protein response and what it could do in terms of a protective measure against atrophy. And maybe it's important.

And it was in the context of somebody who was talking about the benefits of exercise for people with various forms of dystrophy. But, you know, let's just say it's muscle loss. And, you know, the heat shock protein response as in the role that I described as a chaperone protein but also in other ways that we're probably not understanding as well could be beneficial. And I definitely wouldn't want to dismiss that.

I do think that there is enough evidence to be at least interested and raise your eyebrows say, "This is deserving of a greater and deeper study." So, again, like I said, honestly, three or four weeks ago, I'm like, "I don't know." But I heard a great exchange between a former mentor of mine and a good friend who is an extraordinarily bright individual. And they both, sort of, nodded and thought, "You know what, this is something...there's something going on." So, I'm still learning. We're all still learning. So, yeah, never say never.

Dr. Patrick: Yeah. I mean, if you ever want to... like, you know, I got Dr. Jari Laukkanen. He's in Eastern Finland. He's a friend of mine, and, you know, he's got lots of samples and looking for collaborators always. So there's, you know, lots of possibilities there because...I would love to, sort of, connect people and try to, you know, ask the right questions and see if we can answer them. I mean, that would be...

Dr. Phillips: It's an interesting one to answer because it seems that the heat shock response is something you can locally induce, right? It doesn't have to be a sauna. So you can heat one leg and not the other leg, for an... These are always the things that kind of pop in my mind. I'm like, "How could we study that in the most efficient way possible? Do we need to put people in the sauna?" Not that that wouldn't be good, but maybe we could do local heating. And again, the cardiovascular effects to do with that and opening up capillaries, and so more perfusion at the...I mean, there's all kinds of things that suggested that there could be something going on there, yeah, for sure.

Dr. Patrick: Yeah. Well, before we wrap this up, this has been a really...an interesting talk, Stuart, I want to go back to your three...if it's too good to be true, it probably is. There was the third one, which is there's exceptions. Here's my jam.

Dr. Phillips: Go for it.

Dr. Patrick: Omega-3 and vitamin D. Okay. I...

Dr. Phillips: Check, check. So, my supplement shelf is small. I live a lot further North than you do, so we get less useful sunshine. Definitely, in the winter months, vitamin D is, yep, absolutely.

Dr. Patrick: So my question to you being a muscle expert, and me, you know, I guess people would call me an enthusiast. You know, I definitely try to follow the science. But there's widespread deficiency with vitamin D, no doubt, you know, across North America. And, you know, it is a steroid hormone that is doing similar things like testosterone in the sense where is a binding receptor going into the cell nucleus and regulating...

Dr. Phillips: Changing all kinds of genes. Absolutely.

Dr. Patrick: Yeah. Like, 5% of the protein encoding human gene a lot. So it's not just about bone homeostasis back to the RDA. But with omega-3... I do read a lot of the literature, and I certainly don't always get things right. But I've seen more than one. I've seen probably a handful of studies now looking at omega-3 supplementation and muscle mass, specifically, I think, there's older women...usually an older population. But it helping with...I think it may be helping prevent some of the atrophy or helping with lean muscle mass. Is that a real thing?

Dr. Phillips: It's a real thing. Like in our hands, I had a postdoc, Chris McGlory. He left the lab. He has a faculty position now at Queen's University. But when he came, he was an omega-3 guy, and he said, you know, "We need to study more of this in human muscle." So we ran a trial, and we ran it actually younger women. And then a bunch of people said, "Why do you run it in women?" I'm like, "Nobody ever asked you why you only run in men," right?

So we did it in younger women for a number of reasons. There's not much research in younger women. And we did actually think that it might be more effective in women than men for reasons I don't fully understand, as you mentioned older women there as well. We supplemented one group with very high dose of omega-3 fatty acids, and we supplement the other group with, sort of, a corn oil placebo. And then we braced one of their legs for local disuse atrophy model for two weeks.

And the women on the omega-3 supplement saw a really mild disuse atrophy response and then returned to normal much quicker than the other group who saw a much greater atrophic response and didn't get back to normal after two weeks of what we call passive remobilization. You remove the brace. You don't actively rehab. You just, like, go back do all your normal things. It's anti-catabolic for sure. You can have a nutritional intervention that can affect disuse like that. That's a profound finding. So you can imagine with respect to our disuse, you know, a catabolic crisis model, lots more work to be done. That's more Chris's area. He left. I'm like, "That's yours, man."

Dr. Patrick: Is he still doing it? Yeah, because...

Dr. Phillips: He's still doing it.

Dr. Patrick: I mean, you know, here's the thing is that we have this aging population. And it is much easier...as much as we want to get them to...first and foremost, can we get them to do any sort of resistance training? Obviously. But that is a struggle, especially for people that are much, much older. You know, getting them to take a pill is one of the easiest things that you can do.

Dr. Phillips: Yeah. One would think.

Dr. Patrick: Yeah. Omega-3 is... I think there's just been more and more evidence that, you know, there's many benefits. I've talked about a lot of those. But, you know, I mean, the anti-inflammatory resolving inflammation in so many different ways. I mean, there's like the specialized pro-mediating molecules. There's the resolvans, the protectins, the maresins. I mean, it's doing...you know, it isn't just prostaglandins. It's not just, you know, this one, you know, pathway. I mean, it's doing a lot of things. And what role does inflammation...? So inflammation, I know from reading your work, inflammation in a diseased state like cancer or, you know, type 2 diabetes or things like this. I mean, it can be catabolic, right?

Dr. Phillips: Absolutely.

Dr. Patrick: What about the low-grade chronic inflammation, the unhealthy sedentary?

Dr. Phillips: Yeah. You know, the disclaimer is, you know, we've learned a lot about how to make muscle more anabolic in young individuals, and then we've extended that to healthy older individuals. We don't have older individuals participate in our study. If they're on, the list of medications is relatively long. So, they're probably the healthiest of the older population. We'd like to think that's a truer effect of aging rather than some meds that they're taking.

But let me just say that chronic low-grade inflammation and what people call inflammaging is problematic. It's probably responsible for some of the anabolic resistance we talked about. So dampening the inflammation beforehand could help you get more anabolic. In extreme situations of, you know, so ICU or cancer or, you know, particularly cancer cachexia where people are...you know, they're swimming in inflammatory cytokines. And, you know, COVID gave us a little glimpse of this cytokine storm that some people experience. The prognosis becomes very poor.

So we think a lot of things, you know, nutritionally can combat muscle disuse. But if you have a patient that's on bed rest and in an ICU, and they're, you know, massively inflamed, you can throw a lot of things nutritionally at these people, and it's just dust in the wind, nothing really happens. So, you know, the message is you've got to get inflammation under control before you're able to see the full and robust effect of a lot of the anabolic stimuli that we're talking about. It is an issue. And it's clearly something that people need to think about as they get older.

I'm actually of the mind that, you know, the low-dose aspirin that a lot of people are taking to, sort of, tamp down inflammation is probably a good thing. But then also the flip side is to say, there is some degree of inflammation that needs to happen. So if you keep chronically suppressing inflammatory responses in younger people even, I don't think you get a full adaptation. So, some inflammation good and necessary, chronic low-grade inflammation, probably not good, definitely rampant inflammation in all kinds of clinical states. Yeah, that's really going to take the edge off of anything you do, both nutritionally and probably from an exercise perspective too.

Dr. Patrick: Yeah. What you said makes a lot of sense. But obviously, you do want an inflammatory response when you need it, right, I mean, when you see a pathogen. And that is also why I think omega-3 is one of the best ways to kind of lower the chronic inflammation because it has to do with resolving in so many ways the resolving of the inflammation.

Dr. Phillips: It's almost if you're turning down the burner, right? You know, it's taking the edge off of that. So, no, I agree. Yeah.

Dr. Patrick: Right. Yeah. And then my last supplement to ask you about creatine monohydrate. There's evidence that it seems to be beneficial for muscle growth, for brain health. Like, is there side effects? Is there worry? What are your thoughts on it?

Dr. Phillips: Yeah. So, again, short supplement shelf that's on there for me. I don't take it all the time. I have periods where I'm doing a lot of work. I try and, sort of, you know, ramp up the volume of work that I'm doing, and I will add creatine at that time. Now, I know a lot...I got friends who are saying, "Why aren't you taking it all the time?" And I get it. Probably about 40 years old now. So supplements go. It came and stayed, which makes it one of the number three categories. It sounds too good to be true. Its effects are pretty mild on muscle, but they're there. They're potent. They last. Now the brain and the cognitive side of things is...you know, the evidence is growing in that area too.

If there were a danger with it, you know, that it was having...there was a lot of talk about "It's damaging your kidneys. It's doing, you know, this. You know, it's a guanidino compound, etc," we've got 40 years' worth of data with people on the supplement now. And we're not seeing some, sort of, rife wave of people who used it getting various forms of cancer, etc., which you would expect. Forty years is enough to see the effect.

All the data reviewing it from a safety standpoint has given it two thumbs up. The adverse events are rare usually in combination because people are taking not only that supplement but several others. So, you know, pinning it on creatine per se hasn't shown any credence. So, it definitely gets an A grade from the effectiveness standpoint. I think it's good for younger and older people.

I'm good with the health or the safety side of things as well. I do think people if they're going to try it should do it, sort of, gradually. It used to be you take these big loading doses. And I think most people now... A good friend of mine, Mark Tarnopolsky, neuromuscular physician, has all of his neuromuscular patients on it. So I think that that's a fairly robust endorsement of what it can do for people with compromised muscle function. And he recommends that these people just start with a dose of above, you know, 4 to 5 grams of creatine a day.

Dr. Patrick: What is he using it like exactly for?

Dr. Phillips: Well, I mean, all these people have is one of the overriding symptoms no matter what they have, whether it's a mitochondrial myopathy or some, sort of, dystrophy condition is muscle weakness. So, people do get a little bit of a boost. It may not be, you know, something that you or I would consider worthy. But if you're somebody who's close to that line where, you know, disability is here and ability is here, then creatine could be what it is that pushes you over that line.

And again, you can go and read his papers. They're pretty robust studies done in all kinds of populations. So, yeah, try it, see what you think. Most people tolerate it very well. You don't need a fancy brand of it. The stuff they sell at Costco or whatever is just as good as anything else. The monohydrate form is the one to aim for. Don't be fooled by...creatine, insert your favorite derivative, monohydrate is the one that's been most studied and so probably the one you want to go for sure.

Dr. Patrick: And it's good to know. So you don't actually have to be physically active to reap any benefits from it. That was the question I had because...I mean, again, thinking of parents and grandparents, right? That's the issue with the ones that are not physically active or that... I mean, there's people that walk their dogs and stuff, which is good that at least gives them some physical activity. But you don't have to be pumping iron and stuff to...

Dr. Phillips: No, you don't.

Dr. Patrick: Because I always thought about it that way. I'm like, "Well, I'm not like a gym rat. So do I need it?"

Dr. Phillips: Yeah. No. You know, the stuff now with creatine that they're uncovering that makes me think, "Maybe this should be part of my regular routine" actually has less to do with the muscle and more to do with the brain and the cognitive performance that it...you know, it's come back several times now and improves. And, you know, you mentioned, I'm the director of PACE. It has a special place in my heart. And the truth is, is that you talk to people in PACE. Our oldest participant is 104. So I consider him to be the icon of wisdom. And people talk about when they get older from a health standpoint, they don't want to be a burden. And that always when you unpack it, it is round, "I don't want for somebody to have to take care of me because my physical capacity has gone down or that my mental capacity has gone down." They all fear that. So it's dementia and then it's physical inability to do things. And so I say, "Well, you're here working on the physical ability. But you're working on the dementia too." And they say, "Well, what else can I do?" I say, "Well, here's a list of, sort of, things." And by no means a dementia expert, but creatine might be something that older people might want to talk about for sure.

Dr. Patrick: That's awesome. Really appreciate this conversation, Stuart, and I look forward to continuing to follow your research. You're quite active on Twitter. So can you tell people what your Twitter handle is on...

Dr. Phillips: Twitter handle?

Dr. Patrick: Yes.

Dr. Phillips: Yeah. I'm mackinprof, M-A-C-K-I-N-P-R-O-F, the same on Instagram. I'm much better on Twitter. I'm just much more comfortable with that rather than a picture of me doing something on Instagram. And I do have a Facebook page as well. It's snp.phd, and that's a professional page you can find me on Facebook. And I'm on LinkedIn as well, so.

Dr. Patrick: Awesome. Well, I follow you on Twitter. You're tweeting useful things. So I encourage others to follow you as well. And again, thank you so much, Stuart.

Dr. Phillips: Yeah, my pleasure.

Dr. Patrick: And look forward to chatting with you again sometime.

Dr. Phillips: Yeah. I'd love to come back to this [crosstalk 01:49:41] because it's awesome. Yeah, it's awesome.

Dr. Patrick: All right. Sounds good.

Dr. Phillips: Yeah. Thank you.