SPEAKERS
Dr. Bill Evans, Dr. Gabrielle Lyon

Dr. Gabrielle Lyon [0:00:01]

Welcome to the Dr. Gabrielle Lyon show where I believe a healthy world is based on transparent conversations. In today’s episode of The Dr. Gabrielle Lyon show, I sit down with Dr. William Evans. He’s an adjunct professor of medicine at Duke University Medical Center, and human nutrition in the Department of Nutritional Sciences at the University of California, Berkeley. He has played many significant roles and continues to play pivotal roles in advancing the science of aging and muscle health. Not only that, he’s chief of the human physiology laboratory at the Human Nutrition Research Center on Aging at Tufts University. He has more than 75,000 citations. He’s the author or co-author of more than 300 publications in scientific journals and was the first to describe sarcopenia. He is the co-inventor of a non-invasive and accurate measurement of muscle mass, which is strongly related to health outcomes in older people. For the listener, that is a lot of what we talked about.

In this episode, we discussed the surprising fact that we have really only talked about lean body mass versus skeletal muscle mass and made a lot of extrapolations rather than directly measuring skeletal muscle mass. We also talk about what happens to muscle as you age and the age-old question, no pun intended, what is more important, is it muscle mass, or is it muscle strength? How have we thought about this as it relates to health? This episode is critically important because I believe that this changes the next era of research that is going to be coming out on aging, muscle mass, muscle quality, and strength.

I hope you enjoy. As always, if you like this podcast, please like, subscribe, share it, leave a comment, share it with a friend, share it with a family member who needs to hear it. Again, thank you so much for your time and attention.

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Dr. Bill Evans, thank you so much for coming on the Dr. Gabrielle Lyon Show. This episode is going to be pivotal for people’s education, and I’m going to tell you why. For the longest time, we’ve been talking about lean body mass, and we were talking about lean body mass as it relates to the hallmark of health. We have not found that there are many correlations of lean body mass versus skeletal muscle mass as it relates to health and wellness. You, my friend, are creating a whole new paradigm and a whole new era of thinking about skeletal muscle. No pressure.

Dr. Bill Evans [0:06:00]

It’s been an interesting journey, that’s for sure.

Dr. Gabrielle Lyon [0:06:03]

I’d love to hear a little bit about your background. It’s quite extensive.

Dr. Bill Evans [0:06:12]

I did my graduate program at Ball State University, which at the time, and still does, I think, has the premier Human Performance Laboratory. Upon completion, I took a position as a faculty member at Boston University, and at the same time, I did a postdoctoral fellowship in nutrition at MIT under the guidance of Dr. Vernon Young. Then, I guess I was in the right place at the right time. In 1982, there was a brand new facility being built in downtown Boston called the Human Nutrition Research Center on Aging at Tufts University. It was a 13-story facility, right downtown in the medical school, and dedicated to attempting to understand what the nutritional requirements were for older people. There were a number of different human nutrition research centers, one at Baylor, the Children’s Nutrition Research Center. Ours was for aging.

I was very fortunate to be invited to be one of the initial lab directors. My lab at the time was called the Human Physiology Laboratory to understand the relationship between physical activity and nutritional needs, and how they might affect older people. I was there for about 11 years. During that time, we conducted what I think were some really seminal studies. I was the first to describe the condition of sarcopenia, which we can discuss a little bit later. At the time, I defined it as the age-related loss in muscle mass, which I thought would ultimately predict disability in late life and other age-related problems.

I left Tufts and joined Penn State as the director of what was called the Noll Laboratory. I got recruited to the University of Arkansas for medical sciences, which had just received a large gift to establish a Center on Aging in the Department of Geriatrics. I got recruited after about 11 years in Arkansas to GlaxoSmithKline to head up their muscle metabolism discovery unit. I was there for about five years. Now, I’m a faculty member at UC Berkeley and at Duke University. I live in Chapel Hill, North Carolina, and then I commute out to Berkeley to teach when I need to.

Dr. Gabrielle Lyon [0:09:21]

Incredible. I would love to start off the conversation. Why don’t we talk about sarcopenia? Why don’t we talk about the rates of sarcopenia? Number one, the definition of it, and how we can quantify it, I think that would be a great conversation.

Dr. Bill Evans  [0:09:42]

Sure, and it’s a good and important question. Initially, when we were doing research, we were looking at ways to increase muscle strength. We had noticed that one of the primary, if not, the primary functional deficit that occurs as we grow older is weakness. Weakness affects almost everything else that we do. Some of the early studies that we did was we took older people and put them on weightlifting programs and saw that we can double and triple their strength, which was really quite astonishing. We were able to measure how much muscle they had by using the CT scans. We did a study in a nursing home, and it was funded by the National Institute on Aging, in which we took older people in their 90s and were able to triple their strength. No one had ever really shown that before. I think it really demonstrated the power of exercise and the fact that nobody is too old to start. Our oldest was 98 years old, and we were able to really improve his function. At the same time, we showed that his balance was improved, his walking speed was improved, spontaneous activity was improved, and depression was affected. So I thought it’s the amount of muscle that we have that really is the determiner of how strong we are. That was the initial definition, that age-related loss of muscle.

The problem is, since that time in the early ‘90s, there have been dozens and dozens of large cohort studies that have measured lean body mass. Lean body mass isn’t only muscle mass. One of the assumptions has been that muscle mass is exactly the same thing as lean body mass, and we know that it’s not. In older people, muscle is only about 50% of lean body mass. Lean body mass has water, viscera, fibrotic tissue, and other components that are not muscle.

After decades of research, the fundamental conclusion was that lean body mass has very little relationship to outcomes in older people. It’s actually strength. If you measure how strong people are, that is much more closely aligned to risk of getting a disability. If lean body mass isn’t really that closely associated with these outcomes, then there must be some intrinsic quality of muscle that’s changing. All along, nobody was actually measuring muscle mass. It was measuring how much muscle we have.

Dr. Gabrielle Lyon [0:13:08]

Can you say that again, because your work and the work that you’re bringing forward now with D3-creatine is going to change. I think we’re going to have to go back and reflect on all the literature and much of the narrative of what we believe to have been good science is actually, I think, going to change. So if you could just say that again.

Dr. Bill Evans [0:13:31]

Sure. I think it’s fundamentally going to change. It goes back to the initial definition that muscle mass is actually pretty darn important. I can tell you very briefly what our method is. We were trying to figure out, how do you measure how much muscle someone has? It turns out, and probably most of your audience have heard about creatine and creatine supplements, that creatine is really important to how muscle actually functions. About 98% of all the creatine in your body is found in muscle. The idea here is that if we can somehow measure the total amount of creatine in your body, we can actually have a pretty good measurement of how much muscle you have. It turns out that creatine is not made in muscle; it’s made in the liver and the kidney, and then it’s actively pumped into muscle cells. Our idea is we use what’s called a stable isotope. It’s a heavy hydrogen label we put on the molecule, creatine. You swallow it, and it’s a very small capsule with trace amounts. The beauty is that it’s transported to all your muscles. Further, the beauty of creatine is that it’s turned over or it’s excreted by the conversion of creatine into creatinine and then lost into urine. So it’s a very simple idea. You take this label. It gets transported to all your muscles, and then you lose the label through creatinine in urine. We can take a single urine sample, look at how much of this deuterium label is on the molecule, and then know exactly how much muscle you have in your body.

Dr. Gabrielle Lyon [0:15:32]

To frame this for the listener, up until that study, up until this method, what has been used is DXA, CT, MRI. None of those directly measure skeletal muscle mass. I suppose CT is the gold standard.

Dr. Bill Evans [0:15:51]

Yeah, whole body MRI, but they’re very, very expensive and not very practical. That’s why this method that you mentioned, DEXA, has been used in dozens and dozens of studies. Everybody assumes that it’s a surrogate for muscle. We get to the fact that even those who think well, maybe DXA, isn’t that great. We’ll measure what’s called appendicular lean mass. So if we just measure the arms and legs, maybe that’s a pretty good estimate. It turns out that our method is unrelated to the measures of lean body mass.

Dr. Gabrielle Lyon [0:16:39]

What does that mean?

Dr. Bill Evans [0:16:41]

What that means is that all of the data on the relationship between lean body mass and outcomes is simply wrong. We’ve published now about 15 papers in large cohort studies where we first show that cross sectionally, muscle mass is really strongly related to how well you function, what your walking speed is, what your strength is, and how much you fall down in old people, in old men. Then looking longitudinally, we’ve been able to show that muscle mass is strongly related to risk of disability, even what’s called instrumental activities of daily living, which is kind of like your ability to balance your checkbook is related to how much muscle you have. It’s related to a risk of a hip fracture. It’s related to mortality. Interestingly, the estimates of lean body mass are unrelated to these outcomes.

Dr. Gabrielle Lyon [0:17:54]

That’s critical.

Dr. Bill Evans [0:17:58]

So now we have data that has allowed us to convince reviewers, not all reviewers, but reviewers such that we’ve now added this measurement to the Framingham Heart Study. We’re measuring this muscle mass longitudinally in Framingham. We’ve added it to what’s called the Tobago longitudinal aging study, which is measuring African Caribbeans. We just added it to the Women’s Health Initiative, which would be 18,000 measurements in older women. So now for the first time, we’ll be able to say that muscle mass is related to these important outcomes. What that allows us to do is really focus on muscle, perhaps, as the thing that you want to affect. I think everybody probably realizes that muscle is really important, and it’s important for moving around. But it’s the amount of muscle that you have that appears to be the most important thing. So anything that we can do to ultimately help us in that regard is going to prevent disability and keep us independent.

Dr. Gabrielle Lyon [0:19:37]

This is critical that you’re saying that because there’s a large body of evidence that solely talks about strength in the aging population that muscle mass doesn’t necessarily matter because it’s really been grouped as lean body mass.

Dr. Bill Evans [0:19:54]

That’s right, and strength is obviously important, and the reason why it’s been important is because if lean body mass is a pretty poor predictor of how much muscle you have, strength is probably pretty good. The fact that strength is related to some of these outcomes is really an indication of how much muscle you have as you grow older. It’s important to note that obviously, many of your viewers and listeners, we think about muscle as important for climbing stairs and moving around. But it’s important in a lot of other ways. For example, muscle is the primary determinant of your basal metabolic rate, how many calories you lose at rest. As you lose muscle, your calorie needs go down, and your body fat goes up. It’s attached to bones, and it’s called skeletal muscles because it puts stress on bones. Muscle probably helps to prevent osteoporosis. The more muscle you have, the less bone loss you’ll experience. Muscle, we now know, secretes a whole host of what are called hormones or myokines that have a broad array of metabolic effects. We just published a paper recently in older women that shows the amount of muscle that you have is really associated with your risk of diabetes, your glycemic control. Muscle has a lot of really important functional outcomes, but the metabolic outcomes are probably just as important.

Dr. Gabrielle Lyon [0:21:48]

Critical, and the listeners would totally agree. We talked about muscles, the organ of longevity. We talked about myokines, things that are that are very critical.

Dr. Bill Evans [0:22:01]

Your calling it the longevity organ is absolutely correct, probably more so than any other organ system that we have.

Dr. Gabrielle Lyon [0:22:11]

I agree, my friend. One of the things that has become an issue is we’ve always focused on obesity or in the literature, it is all about obesity rather than the preservation of muscle. We are very obese-centric versus muscle-centric. That has created quite a bit of issues as it relates to how do we move forward for people?

Dr. Bill Evans [0:22:34]                                    

Yeah, you’re absolutely right. We published a paper not too long ago. There is a syndrome that some people have called sarcopenic obesity. The idea is that in older people that have low muscle mass, if you have more fat, that’s really bad. We published a paper recently that said, no, that’s not true. The fat is far less important, even in obese people than how much muscle they have. The term sarcopenic obesity is kind of an anachronism. It really doesn’t have much of an effect. I think one of the things we’re thinking about now with the advent of these new GLP-1 agonists, these new drugs that may stimulate weight loss, which is not a bad thing, old people, when they lose weight, almost half of their weight loss is probably from muscle. So we need to really think about healthy ways for older people to lose weight and maintain the amount of muscle they have. We can do a lot with diet, I think.

Dr. Gabrielle Lyon [0:23:50]

How do you suggest people do that with diet?

Dr. Bill Evans [0:23:54]

Your colleague, Don Layman has been a big proponent of thinking about protein and its overall health effect. As I said, when older people lose the weight, they lose a lot of muscle. And partly, it’s because if you think about it, an older person already has a low need for calories. If you think about an older person going on a 200 to 300 calorie a day deficit diet, that means that their protein intake is really low. It’s probably below their recommended dietary allowance for people that are in weight balance, and going on a low-calorie diet greatly reduces the amount of new proteins that are being made in your muscle. The way to stimulate protein synthesis in your muscles is simply by eating more protein. Now obviously, it’s a challenge because a lot of protein-containing foods also have fat. So eating a high-quality low-fat protein is a challenge, and it means not impossible. There are a lot of low-fat, high-quality proteins that are available and/or the use of a low-fat protein supplement, like a whey protein supplement, during weight loss can really help ameliorate the loss of muscle.

Dr. Gabrielle Lyon [0:25:22]

Yes, I couldn’t agree more. First of all, do you believe that there is a normal trajectory to aging? Lots of the quote, healthy sedentary population, the older adults that in and of itself, that inactivity is not healthy. My question to you is, do you believe that there is a natural trajectory of decline? For example, based on what you know now, based on now you’re looking at D3-creatine, which has not been the standard, which I am hoping will now become the standard, do you believe that the rates of sarcopenia muscle mass decline? They put it at 3% to 8% per decade. Do you believe that is accurate? We haven’t even been measuring muscle appropriately?

Dr. Bill Evans [0:26:12]

Yeah, it’s a really good question. It’s a really good question. What I’ve been trying to do is get the public to think that sarcopenia is actually a problem and something that we should be able to do something about. People think about Alzheimer’s disease and write the congressman, and there’s lots of money being spent. But unfortunately, people consider sarcopenia as an inevitable consequence of aging, and I don’t think that that’s true at all. One of the things that we see when we did the first big study that we did using this method, in about 1,300 men about 80 years old, this was a large cohort study that had been followed for a long time and by the time that they were 80. What I was struck by was the enormous variability in how much muscle they had. Some of the men had a lot of muscle. Some of the men had a little bit of muscle. One of the reasons why we’re able to see this striking relationship between the amount of muscle and outcomes is because of this enormous variability in how much muscles people have. I think part of the thing that we need to understand is what accounts for that variability?

I think, obviously, one of those factors is how physically active we are, that’s for sure. That affects a lot related to function. Part of it is genetic. Part of it is diet and a lot of other potential factors. We know that when we’ve done some studies where we looked at what’s the effect of putting an older person to bed, and when we first proposed to do these studies, one of our reviewers says, that’s unethical, you can’t do that. Then I came back and said, well, that’s the number one therapy in the world. Bed rest is the number one therapy to treat everybody, especially old people in the world. Unless we understand what happens, we’re not going to be able to prevent it. What we are able to show is that in 10 days of bed rest in healthy older people, about a kilogram of muscle is lost just from their legs. It’s amazing. When you put young people to bed for 30 days, these are studies done by NASA, they lose about 400 grams. Older people lose almost three times as much muscle in a third the period of time. What accounts for that? Why is that?

One of the things that happens is that inactivity tends to stimulate insulin resistance or the risk of diabetes. That has a really powerful effect on how efficiently your body makes muscle. In 10 days, older people that go to a hospital with normal glucose tolerance can be diagnosed with diabetes due to their inactivity and their illness. Some older people have inflammation, and that’s another area that we really don’t understand. There is this syndrome that some people called inflammation that is some older people have markers of inflammation, even if they don’t have any chronic diseases. The question has always been well, is that because they haven’t been diagnosed with the disease? Or is that because there’s something about aging? I think that that’s probably true, that inflammation, that I think is also variable from person to person, then affects other factors including muscle or muscle function.

There are a lot of other things that happen to us as we grow older. One of the things that I don’t think is terribly well understood is we lose muscle cells as we grow older. Probably around 50 is when we get an accelerating loss of muscle cells, and that’s probably related to how the brain ages. We lose what are called motor units, that you know about better because it’s essentially the connection between the brain and the muscle cells themselves. Whether we can do anything about that is not terribly clear because it’s difficult to measure. But I think that as we do more and more, and more and more molecular tools become available to us, and now that we have the ability to actually measure how much muscle somebody has, we’ll kind of understand what this variability is all about.

Dr. Gabrielle Lyon [0:31:28]

How do you think that the individual listener at home, and we have a lot of practitioners that listen to this, will something like D3-creatine be available to the provider?

Dr. Bill Evans [0:31:40]

That’s my hope. Just as a side note, I formed a company. My partner and I have licensed the intellectual property. We have IP in the US, Canada, and Europe. Our first job is to convince the FDA that this measurement is important and actually mean something. Then we hope that it will be available to everybody and anybody. It’s interesting that when we first published papers, I got a call from a colleague of mine who was at the Bill and Melinda Gates Foundation. They really liked this idea, so they funded us. They gave us a big grant to validate our method in infants and children.

The first study that we did in this regard was taking really small infants, our smallest was about a kilogram, and measured muscle mass, just taking urine from their diaper. We were able to measure the trajectory of gains in muscle mass while they’re in the ICU. We’ve now published papers in boys with Duchenne muscular dystrophy, and for the first time, the Muscular Dystrophy Association is funding us to do a longitudinal study in boys with Duchenne muscular dystrophy, to use this measurement, perhaps, as a marker for disease progression. Again, it’s completely non-invasive. They just swallow up a little liquid or swallow capsule. We take a urine sample, and we’ll know how much muscle they have.

My hope is that if we get the hurdle passed to the FDA that anybody can have this measurement. You can even measure your children, which I think it’s probably a good measurement of healthy growth, how much muscle children make. It’s perhaps a marker for risk of obesity. I think that we’ll hopefully have a new day where this method is inexpensive and non-invasive that people can do it. I think that probably will let us know, especially with older people, that their disability or risk of disability are due to muscle and perhaps not other kind of neurological problems that are also more prevalent.

Dr. Gabrielle Lyon [0:34:32]

Now that we’re able to measure skeletal muscle mass directly, do you think that there will be a way to predict an optimal amount? As you said before, there is so much variation from the individual.

Dr. Bill Evans [0:34:46]

Yeah, that’s another really good question. What we’re trying to figure out, is there a cut point? In our initial studies, what we see is, for example, in men that have less than 30% of their body is muscle, almost all of them have indicators of disability. So I think that now that we have women, and we have the Framingham and we have African Caribbeans, I think, in a couple of years, we’ll be able to do exactly what you say. We’ll know what the level is, the cut point is for serious disability and development of disability over time. Then we’ll be able to, for everybody, do our best to not get there. If we have a marker for whether my mom or whether my grandmother is not going to be able to stand up from a toilet or walk around, then we’ll be able to do something about it. I hope that there’s a lot more research to try to find drugs that may help preserve muscle. But in the meantime, we know that there are things that we can do to help prevent that as well. We know that there are optimal diets. We know that strength training, even, as I said, in people that are 90 years old, we can triple their strength in 10 weeks. There’s a lot that we can do. It’s not always easy, and it would be better if we could give people a pill. But right now, there are things that we can do. There are people that really maintain their function well into their 80s and 90s.

Dr. Gabrielle Lyon [0:36:49]

That’s brilliant. I hope everybody listening, if you have an older family member, you should be sending this to them. But most importantly, if you’re listening, and you are confused, high-quality dietary protein, resistance training, all critical. This is from an extraordinarily well-established scientist. It’s interesting because as it relates to speaking to the public, you’re in the trenches doing a lot of these studies. You’ve played a pivotal role in many, I mean, we’ll link a handful of your studies, but there are so many studies with your name on it. One could spend days and days reading them. But I want to mention something that actually layers another complexity. We’re talking about skeletal muscle mass. One of the things that is seen is that when an individual is obese, they have more quote, muscle mass, but we haven’t discussed muscle quality. I’m thinking about the intramyocellular fat, the intramuscular fat. There has to be another layer of not just looking at the skeletal mass itself, but the quality of that tissue.

Dr. Bill Evans [0:38:05]

Yeah, that’s really important, too. As I said, we have published this paper in obese older people, and showing that muscle mass is an important predictor of how much muscle they have. We also had CT scans where we could look at what we called myosteatosis, which is the amount of fat that’s found in muscle. Aurprisingly, to me, I guess, maybe not to everybody is that it was an independent predictor of how strong they were. For older people, especially for all older people, I think there is this increase in the amount of intramyocellular fat. It’s not just in the spaces between muscle cells, but it’s actually in the muscle cells themselves. So there is an aspect of muscle quality that gets affected, and we’re now just beginning to understand it. For example, we know that weight loss can reduce the amount of fat that you have. Whether or not it can reduce the amount of fat that’s in your muscle is not very well understood and poorly measured. We know that if you lose weight and exercise when you lose weight, you lose more visceral fat, the fat that’s in your liver and in your viscera. Whether or not that translates to loss of fat in your muscle is a really good question that you have, and I think it’s important. We just don’t know enough about it right now.

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Dr. Gabrielle Lyon [0:39:52]

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There’s a lot of complexity that there’s a lot of discussion about intramyocellular fat, also ceramides. There’s a lot of changes from potentially decreased fat.

Dr. Bill Evans [0:42:57]

Yeah, exactly. Fat is also associated with inflammation. These ceramides that are found in adipose tissue and in muscle are thought to be somewhat markers of inflammation that’s due to fat. And as I said, inflammation itself causes insulin resistance and downregulates protein synthesis and accelerates the breakdown of proteins in muscle.

Dr. Gabrielle Lyon [0:43:28]

If you were to target the key, the linchpin, it would make sense that the linchpin would be skeletal muscle.

Dr. Bill Evans [0:43:38]

Exactly, and that’s why muscle is the primary site where glucose is disposed of. When you eat carbohydrate, almost all of it goes right to your muscle. So you drink a 16-ounce Coca-Cola, all of that glucose goes right into your muscle. If you’re insulin resistant, then it causes a rise in your blood glucose levels that would stimulate insulin production and a host of other metabolic effects that are not so great. Muscle is the primary site that I think is the effector of all these age-related changes. As you said, it’s the longevity organ, not just for function, which is awfully important, but for a lot of other things.

Dr. Gabrielle Lyon [0:44:29]

When it comes to tackling insulin resistance, there are discussions on both ends of the spectrum, and the answer is probably somewhere in the middle. There’s some evidence to suggest, I understand that these were clamp studies from Gerald Schulman looking at 18-year-old inactive college students that brought to light insulin resistance in skeletal muscle. Is it about the insulin resistance in skeletal muscle first as the primary site of glucose disposal, or is it a hepatic issue? Is it a liver issue? Is it somewhere in the middle? Have you thought much about where?

Dr. Bill Evans [0:45:09]

We’ve done a couple of studies along those lines. One was an interesting study that was published a few years ago. We took older people that had insulin resistance that were one step away from diabetes that impaired glucose tolerance. We put them on a very low-fat diet that was relatively high in protein and told them, eat however much food you want. Then after three months, we found that they lost about a pound of weight a week, and they were far more insulin sensitive, just from a simple shift away from fat. Most of us eat a pretty high-fat diet or many of us do and a lot of saturated fats. But the fact is, is that it affected both hepatic and peripheral insulin resistance. In our bedrest studies, we did clamp studies, and we measured the insulin resistance in the liver and the muscle, and surprisingly to us is that there was a big increase in hepatic insulin resistance as a result of bedrest. There is, as you suggest, a kind of interaction between the liver and muscle that is complex enough that it’s just important to say that it is, but that’s where there’s a lot of interest right now. There’s a lot of interest in for example, you said Metformin as a way to treat aging. I’m not necessarily certain that that’s a great thing, but Metformin has an effect of reducing hepatic insulin resistance.

Dr. Gabrielle Lyon [0:47:05]

Yes, it is something that we use in the clinic all the time. I mean, again, now with these new GLP-1 agonists that are available, those really make the biggest impact. But Metformin is been around for a long time.

Dr. Bill Evans [0:47:22]

Yeah, Metformin has been around for a long time. It’s the one drug that kind of simulates caloric restriction. We know that caloric restriction does increase maximal lifespan in rodents. We know that in the diabetes prevention trial that Metformin can, and people that are insulin resistant can prevent diabetes, and so it’s an inexpensive drug that doesn’t cause weight loss, but it can prevent some of the complications. The GLP-1 agonist, it’ll be interesting to see how that plays out. I have a colleague who runs the obesity clinic at Harvard. Her name is Caroline Apovian, and I don’t know if you know Caroline. She said there’s a year-long wait right now just for people to come into her clinic because of these GLP-1 agonists. It’s going to change the face of medicine.

Dr. Gabrielle Lyon [0:48:25]

If an individual is consuming enough protein and doing resistance exercise, then they can preserve muscle mass.

Dr. Bill Evans [0:48:35]

Yeah, that’s right. In fact, we’re writing a grant right now to really understand the role that GLP-1 agonist may have on the loss of muscle mass, and how best we can preserve it, whether increasing your dietary protein is sufficient to help prevent it or you need activity as well.

Dr. Gabrielle Lyon [0:49:00]

For the listener at home, the GLP-1 agonists, these are the Ozempic and Wegovy. Mounjaro is a combination product of GIP and GLP. I have not been able to find any mechanism of action that these GLP-1 agonists negatively affect skeletal muscle.

Dr. Bill Evans [0:49:22]

No, there’s not. I’ve been doing a lot of research, and partly it’s because I think that the drug companies have not been terribly interested in measuring it. We know that it causes a pretty significant loss of fat and weight. We hope that we’ll be able to measure muscle loss with these, but it’s very important question.

Dr. Gabrielle Lyon [0:49:48]

Do you think that there are going to be a handful of biomarkers that can look at skeletal muscle health above and beyond mass, for example, myokines?

 Dr. Bill Evans [0:50:01]

Yes, I think that there are some interesting ones that are coming along the way that seem to be associated with longevity that come very specifically for muscle. I think that we’ll find that there are biomarkers that are highly predictive of outcomes. The issue with biomarkers is how strong the relationship is there. But I think that now that we have the ability to look at a host of biomarkers that are, as you say, not just the amount of muscle, it’s interesting. Once we understand the role of muscle mass, then we can begin to explore all the other potential biomarkers and how powerful and strong they are. I think that there will be a new day, and there is a development of new drugs that target some of these myokines that we know have an effect on muscle, bone, and metabolism in general.

Dr. Gabrielle Lyon [0:51:08]

I hope that the listener understands what an important conversation this is that we’re having because up until this point, the majority of the literature has really looked at lean body mass as a surrogate for muscle mass. Because of this, and because of the issues with understanding skeletal muscle, we’ve really downplayed skeletal muscle mass, just the tissue, just the organ, the mass of the organ system, what you’re bringing forth, and one of the reasons I was so grateful that you were open to coming on the podcast is, this information is going to take a decade to come out to the public. If we can collaborate and come together, and I can reach into the academia, to that ivory tower and bring it out to the masses, it will allow individuals to begin to rethink all of the information that they are getting. We always stand on the shoulders of giants, but sometimes a research or group of collaborators come in and actually blow up the way in which it had been thought of in the past. That’s exactly what you guys have done.

Dr. Bill Evans [0:52:33]

Well, I think it’s interesting that I wrote a book, along with my colleague, Irv Rosenberg, in the early ‘90s, called Biomarkers. Our central premise was that all of the things that had been thought of as biomarkers of aging, like bone density, blood pressure, and insulin resistance were not biomarkers for aging, really, at all, but were biomarkers for how we go about living our lives. I think that we now probably understand that what the effect of aging is specifically. I think, for the first time, we can really understand what the role of real aging is as opposed to what you breathe and what you eat and how physically active you are. I think that there’s a lot of interest there.

Dr. Gabrielle Lyon [0:53:40]

If you were to– sorry, I didn’t mean to interrupt. There’s a little bit of a lag, so if the listeners are getting frustrated for interruptions, this is a new studio here. There’s a slight lag. When you think about designing an optimal diet to protect skeletal muscle mass and to think about longevity, for you, what would that be?

Dr. Bill Evans [0:54:02]

I think that there are a couple of pieces of dietary advice that is true for everybody. Number one is reduce the amount of saturated fat that you eat. That probably has the biggest single effect. Increase your consumption of high-quality protein, eat more fish, increase your consumption of Omega-3 fatty acids, and stay away from refined sugars. They’re fairly simple, I think, but nutrition is one of those areas. I know that because you do what you do, you know that everybody has a different idea, different opinion about what the best possible diet might be. The so-called Mediterranean diet is a terrific diet, and it was a diet that was necessitated because the people that were eating it were poor. They had to rely on increased amounts of vegetables and fish. We know that in every society that gets more money, I guess, more affluent, there’s an increase in saturated fat intake and an increase in diabetes and heart disease. Those are the things that I think probably have the biggest effect.

The NIH is sponsoring some large trials, the national study on aging, to understand what the long term effects of caloric restriction might be. There have been a couple of published– they spent about $30 million on a big study called Calorie. Two years’ worth of caloric restriction, and these were in men and women who are not obese and not old. They didn’t have any indices of chronic disease. They found, what you might expect, some improvement in insulin action, but the thing that I thought was an adverse effect is that they lost a considerable amount of lean mass. They didn’t measure muscle necessarily. So I worry that this idea of caloric restriction, however it may be manifested, if it’s not done well, and I think that NIH is going to sponsor some large caloric restriction studies with optimal diets. Protein seems to be really important in that regard. Ideal diets for aging is a big important and moving target because such things change as we grow older. It’s hard to maintain the optimal diet if your calorie needs go down. If you only need 1,300 or 1,400 calories a day to maintain your body weight, or you’re trying to lose weight, it’s more difficult to get all the things that you need especially micronutrients.

Dr. Gabrielle Lyon [0:57:34]

I have two thoughts about what you said; I would love to hear more. The body makes saturated fat. My question is, is it a saturated fat issue, or is it a total caloric load issue? Number one. I’ll let you answer that one, and then I have another question for you.

Dr. Bill Evans [0:57:53]

I think saturated fat in and of itself is bad, and bad in a number of ways. We can make rats diabetic in a week by just giving them a high saturated fat diet. It has a pretty bad effect. We know that increasing your consumption of Omega-3 fatty acids can actually have some improvements in health. Those are large epi studies, and so longitudinal studies are still not terribly well documented. The thing about good fats versus bad fats is that all fats are highly calorie dense as you suggest. Whether you eat saturated fats, if you reduce it, and then replace it with olive oil, you’ll still stay fat. So, I think there are good fats that can really help reduce inflammation, for example. Saturated fat probably increases inflammation, inflammatory markers, but the problem with fats is that they all are calorie dense.

Dr. Gabrielle Lyon [0:59:26]

It sounds as if it’s a combination. It sounds somewhat of a combination. Certainly, some people, it would not be ideal if their diet is high in saturated fat. And quite frankly, I do agree with you, calorie control and potentially choosing leaner cuts of meat and leaner cuts of protein. Then that leads to my next question is you mentioned high quality protein, high quality protein as it relates to aging, high quality protein as it relates to muscle. There is a lot of discussion about of how protein can be detrimental, and it’s easily replaced with lower qualities of protein. I’m curious as to how you see that fitting in as it relates to longevity?

Dr. Bill Evans [1:00:15]

Part of the problem has been that consumption of proteins has also been associated with the consumption of fats. When you think about large epi studies, people that generally have a higher protein diet also have a higher fat diet. And so it’s been difficult to separate the effects of one from the other. As I said, when we did a study where we maintain dietary protein intake at about 20% of calories and reduced fat intake to less than 20% of calories and increase their carbohydrate intake, they lost weights, and they became more insulin sensitive. Every macronutrient has a different metabolic effect. For example, when you eat fat, there’s no what’s called a thermic effect. When you eat carbohydrate and protein, there’s what’s called the thermic effect of feeding that you’re calling Don Layman has done a lot of research. What that means is that when you eat protein, your body processes it. In fact, the protein goes into an increase in synthesis rates in muscle, and that has a caloric cost.

When you eat protein and carbohydrate, some of that, to those calories that you need, increases your metabolic rate. When you eat fat, there is no change. Over the lips and to the hips is absolutely the case for fat. There is no thermic effect of fat. It again makes evolutionary sense, if you think about it. Fat is by far the most calorie-dense food that we can eat. And 50,000 years ago, nobody voluntarily would decrease their food intake. During periods of time when humans went without food, they had to rely on their intrinsic fat stores. We know that humans can go a very long period of time without eating any food because they can rely on their fat stores. Fat has an important evolutionary advantage during times of famine, but it’s not during times when food is plentiful. It’s not so great. As you say, there are a lot of lower quality proteins that are rich in fat, and that’s part of the problem. It’s hard to separate one from the other. And high-quality protein is generally pretty expensive as well.

Well, either I say salmon is almost a superfood because even the fact that it has in it is rich in Omega-3, and it really has a lot of positive beneficial effects. Fish is great, I think, in a lot of ways, because it’s much lower in fat, and the fat that is generally in fish is the kind that has a positive metabolic effect.

Dr. Gabrielle Lyon [1:03:59]

Do you think that there is a certain gram amount? We know that the RDA is 0.8 grams per kg. Prot-Age study came out. I know you’ve done a lot of work with the European Working Group with the sarcopenia. How can we reconcile the actual amount of protein that we give as it relates to recommendations?

Dr. Bill Evans [1:04:21]

First of all, I think that as we grow older, we probably need more protein. We need more protein on a per kilogram basis than young people do. The reason for that is older people generally have lower circulating levels of what we call anabolic hormones like testosterone and growth hormone. Muscle is not as efficient in making proteins, and so the RDA, the Recommended Dietary Allowance, as you know, is 0.8 grams of protein per kilo a day. When we put healthy old people on that amount of protein and give them the calories they need to maintain their weight, they lose muscle. So I think that high quality protein at the level of about 1.2 grams to 1.5 grams of protein per kilo a day is probably a very safe amount. There’s very little evidence that even eating more than that has any detrimental effects on your kidney or any other, unless you have renal disease to start with. Eating more protein probably has very little side effects and bad side effects.

Dr. Gabrielle Lyon [1:05:43]

I would agree, and the evidence would support that. There is likely support also for protein turnover. I haven’t ever seen any data that relates to too high consumption of dietary protein.

Dr. Bill Evans [1:05:55]

I’ve looked at looked at the literature, and we know that some athletes, especially power athletes, they consume massive quantities of protein at 2 grams or 3 grams of protein per kilo a day. Yet none of them really report having kidney disease or any other bad effects because generally, they have an extremely high energy requirements, so they remain pretty lean.

Dr. Gabrielle Lyon [1:06:28]

You mentioned something earlier, as it relates to circulating hormones. You also had mentioned that we don’t have treatments yet for sarcopenia. But the obvious in my mind, and I know that you have a study coming out with a mutual colleague, Dr. Ellen Binder, on the effects of testosterone. You do have a great paper here that is open access. We’ll link it, and this is the effects of testosterone supplementation, body composition, lower body muscle function during severe exercise and diet-induced energy deficit. This was a proof of concept, single centered randomized control trial. I really liked it. This was military based. So the military individuals are always early adopters. But do you think that there is a place for testosterone or some kind of hormone replacement in the treatment of myosteatosis and/or sarcopenia?

Dr. Bill Evans [1:07:25]

When I was at GSK, I worked towards developing what’s called a SARM. It’s a selective androgen receptor modulator. These are drugs that are selective in stimulating the androgen receptor in muscle but don’t have the side effects of testosterone, so that you could potentially give them to women. The problem with testosterone is that it’s only available to men who are hypogonadal and not available to women, only in Europe as a female Viagra. But the SARMs, I think, showed great promise. They’re small molecules that can be taken orally, and they stimulate muscle protein synthesis. They’re not in the market yet. I think there are some other ones that are probably along the way that show real promise. But testosterone is a good one. The one that you talked about, it’s interesting for Navy SEALs and soldiers who are in extreme environments, where they have to do a lot of physical activity and don’t have time to eat or they don’t eat very much. They become hypogonadal. Their testosterone levels go down, and so there’s an accelerated loss of muscle.

So we did this study to simulate that. We took young men and simulated that effect by greatly increasing how active they are, decreasing the amount of food that they did, and gave half of them testosterone and half placebo. During the severe caloric deficit, there was very little effect on muscle, I think, because there was enormous decrease in muscle protein synthesis rates. But when they were allowed to eat ad libitum, the group that had the testosterone gained a lot more muscle back. Testosterone has a powerful effect on muscle. Many men who are hypogonadal, they become sarcopenic because they have low testosterone levels, and those men benefit from the use of testosterone. But I think that there are other potential drugs that are coming along the way that may have very positive effects, hopefully without the side effects.

Dr. Gabrielle Lyon [1:10:10]

Different than the SARM. For example, a SARM would be LGD. I think that there’s a handful of SARMs that are–

Dr. Bill Evans [1:10:19]

Yeah, there have been a number that are in development. There’s one that I worked with called Enobosarm that they went trying to– a lot of the research in muscle, for reasons I won’t get into, except to say that the FDA has been reluctant to consider sarcopenia as a treatable indication, the drug companies that huge was cachexia, which is a loss of muscle secondary to disease. It’s a much more difficult clinical situation, especially in patients with cancer, for example, that become anorectic and with profound inflammation. There was one that, and although SARM seem to have a pretty positive effect there, but the trial didn’t get past the finish line in Phase III.

So I think that there are some along the way. Another one that we haven’t really discussed that is highly prevalent in older women, perhaps due to sarcopenia, is incontinence, urinary stress, urinary incontinence. We know that that’s related to the atrophy of pelvic floor muscles, which is also associated with sarcopenia. These androgen receptor modulators may have some effect on helping to stimulate pelvic floor muscles. But we know that, again, exercises of the pelvic floor muscles can treat this. It’s enormously prevalent. Almost 70% of women over the age of 70 have some degree of stress urinary incontinence.

Dr. Gabrielle Lyon [1:12:12]

Yeah, and what ultimately we’re seeing is there are so many drugs marketed and utilized for obesity, treating fat tissue, and maybe one or two, a handful, maybe five drugs, treating issues of the skeletal muscle.

Dr. Bill Evans [1:12:32]

That’s where I hope that we can get the public to really become advocates because the amount of money that the Alzheimer’s Association has been able to raise has been enormous. They’re one of the largest charitable organizations in the country. The number one health issue that Congress hears about is Alzheimer’s disease. As a result of that, they’ve earmarked a specific amount of research to the National Institute on Aging that has to go towards Alzheimer’s research, almost half of their budget. That’s really because of public pressure. I don’t say that it’s wrong. I think that’s great. There have been new Alzheimer’s drugs that have been approved that have very little effect on cognitive function, but yet they’re approved by FDA, and that’s because of advocacy. As you say, I think that loss of muscle is kind of an existential threat overwhelming almost everything else. The number one risk factor for the development of Alzheimer’s disease is diabetes and obesity. We know that even moderate amounts of physical activity, walking as little as three times a week has an effect on helping to prevent Alzheimer’s disease. So when we get down to it, almost every age-related disease is related to muscle in some way or another.

Dr. Gabrielle Lyon [1:14:17]

Well, Dr. Bill Evans, I think we should close it out there because that wraps everything that we spoke about up so nicely. I am grateful for your time. I feel like you are such an important figure in what’s happening. The work that you are doing and have done is going to change the way that we think about muscle, the way that we now can go forward and research it. Thank you so much for everything that you are doing. If you have not heard it yet today, I know that the world is very grateful for you.

Dr. Bill Evans [1:14:52]

Thank you for having me. It’s been a real pleasure to talk to you today.

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Dr. Gabrielle Lyon [1:14:56]

The Dr. Gabrielle Lyon podcast and YouTube are for general information purposes only and do not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. No patient-doctor relationship is formed. The use of information on this podcast, YouTube, or materials linked from the podcast or YouTube is at the user’s own risk. The content of this podcast is not intended to substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they may have and should seek the assistance of their health care professional for any such conditions. This is purely for entertainment and educational purposes only.