SPEAKERS

Dr. Robert Wolfe, 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 the legendary Dr. Robert Wolfee. For those of you in the protein world and in the nutrition world, then Dr. Robert Wolfee is no stranger to you. Dr. Wolfe has served as a faculty member at Harvard Medical School, and the focus of Dr. Wolfe’s 40 years of medical research has been primarily on aging, metabolism, and muscle performance. He has really done legacy-type work. He’s published over 500 peer-reviewed articles, three books, and holds many active patents.

In this episode of the show, we talk all about the potential use of individual amino acids, who should use a branched-chain amino acid versus an essential amino acid, and what  diet is most disruptive to metabolism. Is it high fat? Is it high carb? Finally, are you working hard enough to justify that large fruit smoothie you’re about to have? As always, we appreciate your time. Please take a moment to leave a review, a comment, rate it, share it. We understand how precious your time is, and we greatly appreciate it. One last thing, if you have not had a chance to head on over to my website, please head on over to drgabriellelyon.com. Check out the pre-order page of my book. We are offering a ton of free perks. Head on over to my website, check out the pre-order page, and check out all the free things that we are offering. Alright, let’s dive in.

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Bob Wolfe, I’m so excited to have you here. By the way, do you know that your work has made some of the biggest impact on my trajectory in my career?

Dr. Robert Wolfe [0:04:50]

Well, that’s great to hear. You’re around long enough, and there have been somebody that has listened to you. One of the things is that in my career, I had over 50 postdocs and about 20 PhD students. It involved a lot of hassle because the programming and metabolic physiology wasn’t existent, so I had to start it and go through all the administrative hoops, but I  realize that by yourself, you can only do so much research and make whatever contribution you can. But through influencing other people, you have a much broader chance of actually making contact and influencing people. It’s just great to hear that you actually felt that I had some impact on the direction that your work has gone.

Dr. Gabrielle Lyon [0:05:46]

You’ve actually had quite a significant impact. Don Layman has trained me for the last 20 years.

Dr. Robert Wolfe [0:05:53]

Oh, okay. Don just probably told you that we’re very good friends. In fact, Don came down to Galveston when I was at UTMB for a sabbatical, and we worked together then. That’s a small world, so it’s great.

Dr. Gabrielle Lyon [0:06:07]

It’s pretty amazing. I have a lot of questions for you. But before I get into some of these questions, I really want to highlight some of the massive contributions that you have made in the scientific literature and really in the science space. Number one, stable isotopes, you’ve really brought that to the forefront. This is the way that we look at metabolism, so thank you for doing that. The other thing is there’s a lot of discussion about the Randle hypothesis. The Randle hypothesis, and I’m sorry that this may be a little technical for some of the listeners, but the glucose fatty acid cycle, you came out with a very pivotal paper in the ‘90s where you wrote about it that really this glucose fatty acid cycle is that we’ve got it wrong. That was just so significant. Finally, and certainly not in this order, your work has really inspired so many others, that your paper, The Underappreciated Role of Muscle, has just inspired so many people. Thank you for all the massive contributions that you’ve had.

Dr. Robert Wolfe [0:07:25]

Oh, thank you. That’s very good to hear. But interestingly, I was just in the process of doing a talk. I’m giving a talk in Korea in a month or two, a plenary lecture at a big metabolic meeting. They asked me to give a review of 50 years of research, but I said definitely only a few highlights. One of the things that is interesting that I focused on the Randle hypothesis because the glucose fatty acid cycle, I think, people have always just blithely referred to that as this is the way it is without really understanding exactly what controls the balance between fatty acid and glucose metabolism. In this talk, I went through all the background and research and realized that most of the people in the audience hadn’t been born when I was doing that work. So it goes to show that hang around long enough, and somebody is going to appreciate it. But thanks for bringing those points up because it means a lot that that had an impact on you.

Dr. Gabrielle Lyon [0:08:38]

My goal at the end of this podcast is really for you to highlight some of this pivotal work that you have done because this is where you absolutely excel is in metabolism. As a metabolic researcher, you are exceptional. With many researchers, your work is not necessarily accessible, and you are not necessarily accessible to the general public. They’re the things that I think are so important. For example, this glucose fatty acid cycle, can you explain a little bit about the Randle hypothesis, what its impact is if we believe that fats dominate metabolism versus glucose, and  how that changes our perspective from the Randle hypothesis to the reverse, which is what you highlighted and what that means to the listener, to the patient?

Dr. Robert Wolfe [0:09:39]

The basic hypothesis put forth by Randle and Newsholme back in 1963, based parenthetically purely on in vitro enzyme analysis, it wasn’t ever any kind of metabolic study that led them to this conclusion. But the general topic was, what controls the balance between carbohydrate oxidation and fatty acid oxidation to provide the metabolic energy to perform functions even like physical activity or just daily functions? Their theory was that the availability of fatty acid dominated and that as fatty acid levels became more abundant, this had an inhibitory effect on the oxidation of glucose. As the fatty acid levels decrease, the glucose oxidation rose.

We did a series of two fairly straightforward experiments in human subjects testing the hypothesis. In which case, one we had a high rate of carbohydrate oxidation dictated by glucose infusion, glucose intake so that 100% of the energy was coming from glucose oxidation, and then had a 20-fold increase in fatty acid availability. According to the theory, it should have inhibited glucose oxidation when in fact it had no impact at all. Then we did the reverse where we had normalized the high level of fatty acid oxidation by infusing a substance called intralipid, which is a lipid emulsion, and in that case, we raised the fatty acid concentrations to very high levels. 100% of the oxidation balance between the two came from the oxidation of fat, and then infused glucose and as glucose was infused, there’s a direct inhibition of the fatty acid oxidation.

We followed that after with more mechanistic studies where we showed the exact place in which our metabolic site where this occurred that as fatty acids are transported into the mitochondria, that the enzyme responsible for that is actually directly inhibited by glucose, so that not only was the general concept shown to be exactly the reverse, that the availability of glucose dictates the substrated metabolism, but actually, we demonstrated the specific side of control. The upside of this was that in situations where we’re trying to lose fat, if we take it to a more generic thing that everybody’s interested in, as long as the carbohydrate intake is prevalent or high, the oxidation of fat is going to be completely shut off. Even in cases like exercise where the goal is to be oxidizing fat, it’s only at a low level of activity that you get a very significant contribution of fat oxidation because as the intensity of exercise goes up, the oxidation of glucose becomes more prominent and that inhibits the fatty acid oxidation. At higher levels of exercise, the oxidation of fatty acid actually goes down as compared to where it was in the lighter exercise. This led that fundamental observation.

Now the paper that specifically described that an exercise has been cited over 4,000 times, and it really was the foundation for the concept of the fat burning zone that you get, like if you get on the elliptical, you will see if you’re working in the fat burning zone, and it’s usually well below the highest intensity. I think that did kind of change people’s perspective on exercise for weight control because what it showed was that to maximize fatty acid oxidation, you really didn’t need to have a tremendously high exertion, but rather the length of time at a low level of energy expenditure more directly fueled the oxidation of fat. I think more generally in the context of diabetes, the idea that increased fatty acid availability was causing insulin resistance and increasing blood glucose turned out to really be not the case at all. That has been followed through with studies for the last 30 years since those initial studies that we did. The whole concept of how the blood glucose level is controlled, I think, has been affected by the realization that the availability of glucose, not fatty acids are really what dictates substrate metabolism, and that’s why we coined it the glucose fatty acid cycle reverse because it actually works the exact opposite.

Parenthetically, Eric Newsholme, that work was his, the original glucose fatty acid cycle was his PhD thesis. I got to know him quite well, really not through academics, but because we were both marathon runners. He ultimately conceded that he had it wrong. Unfortunately, he’s deceased now, and he never really published that. I think that the real take-home message is that the physiology in human subjects dictated exactly the opposite response of what was dictated by measurement of enzyme activity and presuming that related to some sort of metabolic flux in vivo. I think that we could take a broader picture of that whole thing with the glucose fatty acid cycle and realize that using in vivo intact human subjects, that even though much less invasive procedures are possible, nonetheless, that it really has to be done in human subjects because that’s really the only circumstance in which you’re really get at true picture of what the metabolic control mechanisms are.

Dr. Gabrielle Lyon [0:15:45]

First of all, thank you so much for that history. Again, you are the person that really this came out of your lab. This understanding, which I think is so fascinating, is that there’s this conversation about how we’re eating too much fat. Maybe it’s not that it’s an excess fat issue or excess glucose issue, potentially, is it an excess calorie issue?

Dr. Robert Wolfe [0:16:14]

I think that’s absolutely a take-home message of what I’ve just said. A deep dive at that point is that, whether it’s carbohydrate or fat, the caloric balance is really the dictator of whether you have a positive energy balance or a negative energy balance, and there’s really no escaping that. Whether it’s fat or carbohydrate, it really doesn’t make a difference. I think that’s a lot of misconceptions is the idea that a low fat diet is going to be beneficial; if it’s a high carbohydrate diet, realize that the high carbohydrate is going to inhibit fatty acid oxidation, so it all comes out in the wash. It’s just how many calories you eat, whether it’s carbohydrate or fat, that’s going to be the predominant factor in energy balance.

Dr. Gabrielle Lyon [0:17:03]

I’m so glad that you brought that up because my next question was, how do we place the Dean Ornish Diet? Dean Ornish is 10% fat versus a ketogenic-style diet? Where does all of this fit into health?

Dr. Robert Wolfe [0:17:18]

I think it’s like people ask, what’s the best exercise? And the answer is really, whatever you’ll do. I think that when we just discussed the fact that the caloric balance is really the bottom line, that these different diets are just different ways to approach eating so that people might find it tolerable to live in a hypocaloric state because it’s really not a natural physiological state to be eating less calories than you’re burning. People have a really tough time staying with that. Whatever the type of diet is, the ultimate deciding factor in its effectiveness is the caloric balance. That being said, though, I think there’s another sub-component that we want to think about, and it really touches on that third issue that you’ve pointed out at the beginning, and that is the role of muscle in metabolic regulation beyond just physical function.

The energy balance is the key thing. Realize that the muscle protein is at a constant state of turnover, meaning synthesis and breakdown is occurring constantly, and there’s an energy cost of that turnover, which is about 1/3 of the total resting energy expenditure, so that if you have a large muscle mass, large, active muscle mass, that metabolic expenditure of that protein turnover is going to contribute to the energy use in that individual, so that the energy balance will be helped not only by just the calories during exercise, but just the fact that you have a larger muscle mass, then the energy expenditure just related to the basal turnover, that protein will contribute to an energy expenditure side of the equation, so that within the context of diets that promote usually the fat or carbohydrate, really the crucial factor is how much protein is in the diet that gives a higher rate of protein turnover and energy expenditure in response to the meal intake as well as maintaining a greater muscle mass, which will maintain a greater energy expenditure over time in the basal state and contribute to an energy balance over a long period of time.

Dr. Gabrielle Lyon [0:19:36]

First of all, thank you so much for talking about protein because we’re definitely going to do that. I’ve got a handful of questions. Number one, how much protein do you recommend or do you think is necessary?

Dr. Robert Wolfe [0:19:56]

Well, I spent a lot of time over the past several years working with the FAO/WHO on quantifying protein quality, and I think that the question of how much protein should you eat is just really a sub-topic and that is, that it makes a big difference what the type of protein is. And what we’ve been working on is developing and validating a system of evaluating protein quality that’s dependent not only on the amount of protein you eat, but the specific nature of the protein, namely, the profile and amount of essential amino acids in the protein as well as how well it’s digested. For example, wheat protein is not a very high-quality protein in the context of its amino acid structure with its content, but it’s not that bad. But then when you couple the fact that only 50% of it is digested as true amino acid absorption, then you can see that it is a very weak protein as compared to a high-quality protein such as whey protein or milk protein that not only has a better profile of essential amino acids, but also is digested faster.

So keep in mind when I say that the average intake of the dietary protein is the official recommendation is 0.8 grams of protein per kilogram per day. But what people have forgotten about that recommendation is that that’s of high-quality protein, meaning that it’s fully digested and has a profile of amino acids that is very beneficial. But in most circumstances, the dietary intake of protein, it will be beneficial to have a higher protein intake in that basal amount. The dietary requirement of protein or the RDA for protein is predicated on the amount of protein intake you need to avoid deficiencies, so that you don’t start losing hair and having other problems, so protein deficiency, if you eat 0.8 grams of protein per kilogram per day, that’s a very low level of protein intake. And in fact, when we look at it in comparison to the American diet, most people are eating well in excess of that, and yet still benefit from increasing their dietary protein intake. So at a very conservative level, I think that there’s a general consensus that as you get older, you need to eat a higher level of protein intake at least 1.2 to 1.5 grams of protein per kilogram per day. If you’re in a very intense physical circumstance, such as exercise, or military training, or anything that really requires a lot of physical activity, it will be beneficial to eat a higher protein intake as well.

We did a pretty large study in weight loss showing that to maintain muscle mass and weight loss that you have to have at least 1.2 grams per kilogram per day of dietary protein, which, when you multiply it out, presents a big problem in age and obesity because if your BMI is 35 or 40, you have so much body weight that the amount of protein necessary to maintain your muscle mass at 1.2 grams per kilogram per day will mean that it’s almost impossible to lose weight because you’re going to have so many calories just to meet protein requirements that you can’t maintain or you can’t meet the caloric requirements of caloric restriction weight loss. And that’s one of the big dilemmas of caloric restriction weight loss diets is that you can’t really eat enough protein to have a great success in maintaining muscle mass, and so almost all diets result in some degree of loss of muscle mass, and then that works against you because as your muscle mass goes down, your basal metabolism goes down, and your amount of calories you eat to balance your energy expenditure actually goes down over time. So all of it is a cycle that really is a difficult challenge. And that’s where the specific dietary intake of certain proteins that are high in essential amino acids that have direct anabolic effects is really an important factor.

Dr. Gabrielle Lyon [0:24:30]

Let’s say an individual is looking to lose weight, and their diet is higher in protein. How difficult is it to gain weight on lean forms of dietary protein?

Dr. Robert Wolfe [0:24:55]

The loss of weight is very difficult to accomplish without losing muscle as well. The biggest example and most controlled is bariatric surgery where a big study was done pulling data from many institutions and maybe several 100 people, and the average loss of lean body mass was something like 27 kilograms. So that it’s really a challenge to lose weight without losing muscle mass. And the idea of doing it with a high protein diet is that you’re going to reduce the rate of muscle loss, and then that will have a lot of beneficial effects. And so it’s the best you can do. If you’re going to try to lose weight with a diet, a high protein diet is clearly the best route to accomplish that with.

That being said, it’s a challenge because as I said, when you have a high protein diet, that doesn’t leave much room for the other calories that you tend to eat in your diet. So that’s why things like the Atkins diet, if you eat that much protein, you get calories come along with it because of the content in food products, and it’s a real challenge. And I think that people are finding this, that it’s very difficult. It’s not a newsflash, it’s very difficult to sustain weight loss with caloric restriction because you lose muscle mass. And as you lose muscle mass, your metabolic rate goes down, and the amount of calories you can eat in a day to maintain energy balance goes down, so that it’s really tough. But the best you can do is a high protein diet, but I just think it’s necessary to appreciate that really no matter what you do, it’s closing the barn door after the horse got out. And everybody’s interested in weight loss, but what we really should be more focused on is preventing weight gain because that’s where we’re still at a point in the dietary balance that we can accomplish that goal. The weight loss is proven to be a real challenge.

Dr. Gabrielle Lyon [0:27:10]

When you’re talking about preventing weight gain, this paper, The Underappreciated Role of Muscle, you started talking about muscle decades before people even thought about it. Everyone has been focused on adiposity for decades. Why muscle? Why did you write that paper, The Underappreciated Role of Muscle?

Dr. Robert Wolfe [0:27:29]

Well, I think we think about muscle entirely in terms of physical performance. And yet, muscle plays a key metabolic role in a lot of respects. All proteins in the body are in a continuous state of turnover, meaning they’re being broken down or replaced by newer, better functioning proteins. And this process of protein turnover causes energy, and it requires energy that is responsible for the basic metabolic rate. And a lot of these tissues that are constantly breaking down their protein and regenerating it can’t afford to lose mass, you can’t afford to lose that much of your heart muscle, you can’t afford to lose your skin. There’s certain tissues and organs that are really dependent on a constant supply of amino acids to maintain their mass and function. And yet, that’s not the way we live.

We eat dinner at night, we might be 15 to 20 hours before we need more protein as adjusted the next day. So we have a long period of time with no amino acids coming into the blood from the diet. And the amino acids are maintained at the normal level by the result of net protein breakdown. So that the protein and muscle really serves as the reservoir to provide the precursors for these other tissues and organs. They can’t afford to go any significant period of time. And in fact, it’s so striking that even after two to three weeks, so total starvation, the plasma amino acid levels are still maintained. In the Belfast studies where the Irish hunger strikers were asking to have their blood measured every day just as hope that some scientific benefit would come out of their sacrifice of starving themselves to death, and the most striking aspect of those studies was after 40 days of starvation was the first time that the blood levels of amino acids started to drop. And once the muscle had been so depleted that they couldn’t maintain the breakdown of muscle protein, was too depleted to maintain normal blood levels of amino acids for things like the heart and brain to utilize for protein synthesis, that was the time at which they died. And obviously, we don’t go to that extreme in our daily lives, but it may be at least 20 hours between protein intake in a person’s daily activity. So the muscle mass is important in being able to provide those amino acids that have to be used by tissues to actually maintain their function, even in the absence of dietary intake of protein or amino acids.

Dr. Gabrielle Lyon [0:30:11]

Which would then lead us to the conversation about dietary protein and dietary protein distribution. What are some of your thoughts on dietary protein distribution?

Dr. Robert Wolfe [0:30:23]

The idea is that there’s only a certain amount of protein synthesis that can be generated in any particular meal. And it does make sense, but it’s been a tough concept to prove. The idea would be that you’d be better off eating 30 grams of protein with each meal than eating a low-protein breakfast, a low-protein lunch and a lot higher amount at dinnertime. I think that in terms of protein synthesis, there is a pretty good basis for that theory. In terms of the total gain and loss of protein, if you take into account the breakdown effect as well, what we found was that up to a certain level, the primary action of dietary intake of protein is to stimulate protein synthesis. And there’s a certain limit to that, and people have put that around 30 grams of protein, but I think it depends a lot on what else was in the meal and what type of protein you eat.

But let’s just say 30 grams of protein maximize the protein synthesis. But as you go to higher levels of protein intake in the meal, protein breakdown begins to be inhibited. And so the gain in body protein can still be augmented beyond that amount of dietary protein by suppression of protein breakdown. So it depends what your goal is. The argument is that slowing protein breakdown is not really advantageous because the turnover of proteins, as I said, is how the older ones are broken down and they’re renewed with better functioning proteins. And that’s not going to occur by virtue of a suppression of breakdown. So that the net gain of protein is not really dependent on the pattern of eating. But it may well be that, and there’s a good theoretical basis still for assuming that, by better distribution throughout the day that you maintain a higher synthetic rate, and then at a greater functionality of the protein turnover.

So I say the jury’s still out on that. It was a theory that was very attractive when it was first put out. And it’s been a challenge to directly confirm it. But I think there’s still some merit and some aspects of it that are worth thinking about. I think just common sense tells us that eating some protein at all meals, that kind of distribution is going to be more effective than eating most of your protein at dinner, which is the general pattern that people follow. It’s just been a little bit difficult to prove conclusively that it really makes a difference.

Dr. Gabrielle Lyon [0:33:03]

Don was also talking about that as well. What about the first meal? So most of the studies are done at breakfast, as opposed to a lunch or dinner meal as it relates to protein intake, protein distribution. Why is that?

Dr. Robert Wolfe [0:33:23]

Well, it’s purely a methodological thing, and that is you’re going to have a period of a real basal state, and then you give the meal and you get a response over the next several hours. The problem with looking at lunch and dinner is that what you had for breakfast will affect the response to lunch because the blood levels of some of the things you’ve eaten will still be elevated. And then what you eat for lunch, and when you ate lunch, it will be affected and will have an impact on dinner. But I think it does have an impact. And it’s difficult to sometimes sort out what it’s due to because we did a study a few years ago which showed that eating the same diet at 6:00 p.m. or 10:00 p.m. had a significant difference in terms of the metabolic response overnight during sleep, so that eating a diet late at night had, as I said, a different metabolic response than eating it earlier, which could be due to the fact that you’re closer to sleeping or it could be due to the fact that the previous breakfast and lunch are still having an impact on the deposition of the dinner.

So I think it’s a methodological thing, but it’s an important point you mentioned and all our studies are done in the morning because it’s the most convenient time where you don’t have any impact of the previous meals. But we know, for example, we did a study several years back. Stu Phillips did this study in our lab and that was doing an exercise study and showing that the effect of the exercise, the anabolic effect of amino acids after exercise was still enhanced two days after the exercise. So you get this building up and compounding of the effects of one meal and the next. We’ve tried to circumvent this more recently by focusing on at least one day or even three days total protein turnover. But it’s a real challenge because you got a lot of permutations of diets and timings and amount of each meal and everything to deal with, which is one thing we don’t like about doing human studies.

Dr. Gabrielle Lyon [0:35:38]

It is challenging, and you’re bringing up a really good point. I just want to highlight it for the listener. Some of this conversation is a bit technical, but it’s really important, just this concept that many of the studies are done for in the morning because of that basal rate where there’s no influence directly of food the night before. The other thing that I think is really important to point out is that protein research, muscle research is definitely very challenging, the metabolic dynamic of the human is very challenging. It’s interesting, because as individuals age, it seems as if the protein requirements go up, anabolic resistance potentially happens, and there’s a whole host of things. What role does exercise play in the relationship of substrate utilization? Oftentimes, people think about aerobic activity and carbohydrates, but what about aerobic activity and protein?

Dr. Robert Wolfe [0:36:44]

The exercise is the most effective way to stimulate this process of breakdown of amino acids and proteins that are not functioning as effectively as when they’re new and replacing those with newer proteins. And so this concept of protein turnover, and acceleration of protein turnover is really the key thing that degenerates as we get older. The muscle mass goes down, and a lot of people would pay most attention to that. But really, it’s this functionality of the muscle as you get older that matters. As you get older, the amount of muscle you have is of much less concern to most people that whether you can actually walk out to the mailbox and get the mail.

And so I think that the exercise is really the most effective way to stimulate this process. Any adequate high-quality protein will amplify the response so that it’s not just an added effect. Actually the beneficial effects of exercise, aerobic exercise or anabolic or weightlifting has an acute effect, which really helps the muscle. But there has to be an increased supply of amino acids from dietary fat or protein to provide the building blocks to replace the proteins that are broken down at an accelerated rate. So that there’s an interaction that when you do the exercise and add high quality protein intake, then you get a bigger response than the individual effect of either one alone.

Exercise has a beneficial effect, but the high protein does as well because of the fact that you got to have building blocks to make the new protein and that’s what the dietary protein provides. So you really need both. And unfortunately, as people get older, for whatever reason, dietary patterns indicate that people tend to eat less high-quality protein as they get older, which is a big mistake, and it’s just about equal in problems to cutting down the exercise, both of which are important and both work together synergistically.

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Dr. Gabrielle Lyon [0:39:00]

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This is the biggest challenge I think when people are talking about going plant based is it’s not the younger individuals per se that it impacts. It’s really the older individuals because if they’re getting this information, and they’re hearing these messages to cut back high-quality protein, I worry about their ability to address protein turnover, not necessarily that they would feel it, but over a period of time thinking about how they’ll be able to recover and just muscle quality. And as their appetite decreases, if they’re going to reduce high-quality protein, then the protein sources that they’re going to pull upon and rely on are going to have a lot more carbohydrates, slower digestibility, poor digestibility. Is this going to become a real problem?

Dr. Robert Wolfe [0:42:28]

What you said is just right on the money, and I think that it’s underappreciated. Working at Center for Aging, I’ve had a lot of impact or influenced by people just asking them about their diet and what they’re trying to accomplish. And that’s certainly the most common thought is that I’m cutting down red meat intake for health purposes. And then yes, what is it about the red meat? Well, it’s just what we’re told, that we should be eating less. But the problem, like you said, is that there’s aspects that people don’t appreciate. For one, if you maintain the same protein intake of a plant-based diet, you’re going to eat many more calories and mostly in the form of carbohydrate. And as you get old, the insulin resistance is an issue which is amplified by high carbohydrate intake so that the plant-based diet really has the potential to have detrimental effects, not only in not to being beneficial in terms of health, not only not beneficial, but actually detrimental to a more well-balanced diet.

I think that the other thing that is important to realize is that eating is, from a totally non-physiological perspective, is an important function for older people. Because as your world  narrows, having meals and eating with other people and enjoying eating and so forth is one of the main pleasures that older people have. And this notion that we should be forcing them to eat– I say them as if it doesn’t include me. But the point is that to make dietary sacrifices that aren’t even rational, but when even if they are, unless you really can document that this is going to make a major impact on people’s lives as they get older, then you should really think twice about recommending that they should have it. But I do think that the heart of what you’re saying is people that are young that live on a plant-based diet will point to what they do and say, well, there’s no problem. And I think what we have to appreciate is there’s metabolic flexibility as you’re younger that enables you really to make do with almost anything. And then as you get older, that becomes more and more restricted, and when you get to over 65 or 70, becomes a real limitation that the exact nature of the dietary intake becomes very important. That’s why we really should be paying more attention to what the health consequences of some of the recommendations that are out there.

Dr. Gabrielle Lyon [0:45:10]

Yeah, the unintended consequences of reducing high-quality protein for an aging population or a sick population, I think, is going to be devastating. And ultimately, if I was a betting woman, I would say we’re going to have an epidemic of sarcopenia and osteoporosis like we have never seen.

Dr. Robert Wolfe [0:45:27]

People are living longer, but the problem is that, as you said, with loss of muscle mass and bone strength, the incidence of crippling diseases and lack of independence is going to become much more important.

Dr. Gabrielle Lyon [0:45:46]

I’m just going to mention this one point is that it’s not even just all about the macronutrient protein, but there’s low molecular weight bioactive compounds like creatine and carnosine, and then of course, vitamins and minerals, which the nutrient density aspect of high quality protein is critical, so there’s that, which moves us into exercise, not exactly, but we’re going to go right into exercise, as it relates to fuels for exercise because this is definitely within your strike zone of work that you’ve done a lot of. Oftentimes, people who do aerobic activity always think that they need carbohydrates. Maybe true, but what about their protein need?

Dr. Robert Wolfe [0:46:35]

The general concept has long been that it doesn’t matter how much protein you ate because you really don’t need much protein. And if you look at the top endurance athletes, they don’t eat much protein. What people miss is that the caloric requirement of world class endurance training, maybe 5,000 to 6,000, even 8,000 calories a day, so that if you eat a very low-protein diet, that you’re still eating a whole lot of protein. The Kenyan runners that eat this gruel for their main substance have been cited as though they look at how well they do on a low protein diet. And if you look at the actual amount of protein they ate, it’s over two grams of protein per kilogram per day because they eat so much. They’re usually 5,000 or 6,000 calories a day. It’s nothing new to advocate that you have to have a high-quality protein as a component of the dietary intake. Particularly, if we’re not world class athletes, there may be certain sports that you want to have an unusual diet in terms of maximizing performance relative to body weight or something.

But for most people that are just recreational athletes, the whole benefit of exercise is more on the quality of muscle and its action and metabolic regulation and its function physically, than is the case with the extra calories. Because the problem with exercise as a caloric, for purely for weight loss is that you definitely have your appetite stimulated by doing aerobic exercise. If you have the willpower to go through the exercise and not eat as much, then that will enhance your rate of loss, certainly, but that can be harder than it seems. So I think the main thing we need to consider in supplying the energy for exercise is that dietary protein should be a central part of the dietary intake. High carbohydrate is particularly helpful in exercises where you’re really depleting your glycogen stores, but realize that that’s really extensive exercise, and most people are not even touching their muscle glycogen stores.

Dr. Gabrielle Lyon [0:49:08]

What would be an example of exercise that would deplete muscle glycogen?

Dr. Robert Wolfe [0:49:13]

Working at about 70% or 80% of maximum for at least an hour. And it could be even more than that. In a marathon probably or the well-trained subjects, maybe as long as an hour and a half of racing before the muscle glycogen is depleted. So that if you look at the breakdown of substrate metabolism during exercise, at 50%, of maximal effort, you’re really not using much muscle glycogen at all. It’s only when you start getting really high-intensity exercise that you start using the muscle glycogen and most people that aren’t highly trained can’t really sustain that high level of intensity for very long so that I think that the concept of lots of carbs has been overstated. I think that the most important thing is to maintain a balanced diet with a healthy amount of high-quality protein as a component of the diet with the aerobic exercise.

Dr. Gabrielle Lyon [0:50:11]

What role does leucine play in substrate utilization in aerobic exercise?

Dr. Robert Wolfe [0:50:19]

Well, leucine is the specific amino acid that is cited to have not only importance with regard to the fact that it’s the most abundant essential amino acid in muscle protein, but also that it may have, in a lot of circumstances, regulatory role beyond just its component of muscle protein. So that dietary intake of proteins that have a high proportion of leucine may stimulate the whole molecular mechanism involved in the activation of the [protein? 0:50:51] synthetic process so that leucine as a specific component of dietary protein may be able to actually enhance the metabolic response more than just as the fact that you’re supplying a component of protein but that it plays a metabolic regulatory role. Keeping in mind, though, that the amount of protein that needs to be eaten to get the plasma level of leucine up high enough to exert this regulatory role is pretty significant.

So that this is why as you get to a higher level of protein intake, you start seeing maybe unexpectedly disproportionate beneficial effects because now you’re getting up to the level of intake where the blood levels of amino acids, including leucine, get high enough to activate the whole molecular process of initiation or protein synthesis, which low levels of protein intake really aren’t activated by a dietary protein intake.

Dr. Gabrielle Lyon [0:51:44]

This all, I would say, probably lends itself to distribution being important.

Dr. Robert Wolfe [0:51:51]

Yeah, well, I think it’s definitely the idea that if you hit that level three times in a day that you’re going to activate protein synthesis, you got to eat a fair amount. If you have a small amount of dietary protein for breakfast, you’re not activating any kind of activation of the whole molecular process supporting protein synthesis because the amount of leucine in the diet is just not high enough to activate that process.

Dr. Gabrielle Lyon [0:52:21]

Yes, that definitely makes sense. Arguably, I always wonder is the middle meal very important, because potentially initiation factors are already up at that middle meal. But clinically, what we do in our clinic is that first and last meal are very relevant, and then the middle meal, we think, okay, could it be an even distribution? Yes, potentially, because that allows for mitigating hunger and all the things that you have said. What is the role of branched-chain amino acids as a supplement?

Dr. Robert Wolfe [0:53:01]

Well, I think that the branched-chain amino acids are important. Really, the leucine is the one that has been demonstrated to have some specific regulatory roles, but the metabolism or breakdown of dietary leucine is occurs because of the activity of an enzyme which also breaks down and oxidizes the isoleucine and valine, the other two branched-chain amino acids. So when you provide leucine alone, you can have a deficiency in both isoleucine and valine because you’re activating the oxidation of all of them. So the concept came across to provide all three branched-chain amino acids and get the stimulatory effect due to leucine and not develop a deficiency in the other branched-chain amino acids. The shortcoming of this approach in humans has been that you really need all the rest of the essential amino acids as well. But if you activate the process of initiation of synthesis with leucine, the only increase in synthesis you can get is a more efficient utilization of what amino acids are available for breakdown. So that when combined with the other essential amino acids, as exogenous precursors, then that combination of the BCAAs and the other essential amino acids becomes more effective than just the branched-chain amino acids alone.

Dr. Gabrielle Lyon [0:54:38]

You did a really great paper. I don’t know how long ago it was, but it really talked about how there was no utilization for branched-chain amino acids as a dietary supplement.

Dr. Robert Wolfe [0:54:52]

I wouldn’t say no utilization. I think that it’s an important component, but very limited without extra amino acids in the diet, because if you just think about it, essential amino acids are very effectively utilized to begin with. And that’s all you got to be as precursors for new protein synthesis, it’s going to be quite limited. But then if you combine those amino acids with other essential amino acids, a high proportion can be particularly useful in aging or other anabolic resistance states. So I think it’s important to recognize that my take on that was not that there’s no value, but only that the value of the BCAAs alone or leucine alone is quite limited as compared to utilization of a balanced mixture that has the BCAAs as a prominent component, but also all the other essentials as well.

Dr. Gabrielle Lyon [0:55:50]

Well, in terms of supplementation, what I’m hearing you say is that branched-chain amino acids can be helpful if someone is eating potentially a lower protein diet, as long as all the essential amino acids are available. So you wouldn’t have a BCAA drink on its own or a branched-chain amino acid mix on its own. You would have it with a complete protein, essentially. Is that what I’m hearing you say?

Dr. Robert Wolfe [0:56:16]

Yeah, I think in that circumstance. I don’t know the extent to which that’s been demonstrated. But I think that in theory, that’s the case. The limitation with the way you proposed there is just the timing that the free amino acids are absorbed so rapidly as compared to the dietary protein, that what you said makes sense, but it hasn’t really been demonstrated to be true. And I think before I was really agreeing to what you said, I’d have to see data demonstrating that it made a difference, because you got a spike in the BCAAs with a dietary supplement of the free amino acids. And it’s back down to a low level when the slow rise of the amino acids from the dietary protein occurs.

So I think it should work. We’ve done a study showing that a balanced mixture of essential amino acids can amplify the effect of dietary protein quite well. So I think, probably true, if it’s with the BCAAs, but you’re still going to be limited at the end of the day by the availability of all the essential amino acids. So I think that by itself, I think there’s little doubt that the BCAA supplementation is limited, but in combination with a meal or dietary protein supplement, may still have a place as an effective anabolic agent.

Dr. Gabrielle Lyon [0:57:39]

Would whole foods be better? Or is there a place for an essential amino acid mixture, and when would that be beneficial?

Dr. Robert Wolfe [0:57:55]

Well, actually, I think that the whole foods are crucial, but the amino acid supplementation has quite a different response because free amino acids are absorbed directly. There’s no digestion involved, so that you have 100% absorption and also that the composition can be controlled to whatever you want it to be for whatever the optimal circumstances so that the spike in the concentrations of amino acids in the blood from a free amino acid supplement reach a peak way before you get with a dietary protein and also at a much higher level. So you can provide a dietary supplement that will accomplish certain metabolic goals. Both the speed of absorption as well as the composition, will have specific metabolic targets, which are not really feasible with a dietary protein that comes in much slower and you can’t change the composition of a dietary protein.

So in that light, I have patents on 14 different formulations that at least in theory are targeting specific metabolic effects or actions that are benefited by having a particular formulation not only just the quantity of essential amino acids. For example, we have a formulation for reducing liver fat that blocks the methionine uptake in the liver by competitive transport. So we couldn’t do this with a dietary protein because of the fact that all dietary protein has methionine in it. It’s the first amino acid in the translation of mRNA. So you’ll never have a diet that’s sufficient at methionine, but you can make a formulation of essential amino acids that is deficient in that specific amino acid in order to get a selective reduction of inactivity [unclear 1:00:01]. They’re different things. I think that while I’ve been involved in developing different amino acid supplements, I never would want to lose the focus on the requirement or necessity of having a well-balanced dietary intake of high-quality proteins. The two things are actually a little bit separate in what their mechanism of action is.

Dr. Gabrielle Lyon [1:00:26]

That’s very interesting to think that you can create different amino acid mixtures for very specific things, something like methionine, which sounds as if it’s a methionine restriction, which would model a say, vegan-style diet. And to think that there are potentially other kinds of formulations would be pretty powerful and interesting to see. You’ve spoken about central fatigue hypothesis as it relates to whether it’s a depletion of amino acids. Can you talk a little bit about that?

Dr. Robert Wolfe [1:01:06]

Well, that’s a little bit right along the line of another example of how the formulation can make a difference because the feeling of alertness and fatigue is governed to a significant extent by the neurotransmitters of dopamine and serotonin in the brain, both of which are produced from essential amino acids. The dopamine is produced from tyrosine, which is a derivative of phenylalanine. And the serotonin is derived from the metabolism of tryptophan. The idea is that as you get fatigued, that they branched-chain amino acids are oxidized at a faster rate during intensive long-term exercise, so you start getting depletion in the branched-chain amino acids relative to the tryptophan so that the dopamine level drops relative to the serotonin and your brain tells you you’re tired, even though your muscles may still have something left.

So the idea is to competitively inhibit the tryptophan uptake by giving a formulation that’s high in the branched-chain amino acids and phenylalanine, which are all transported into the brain by the same transporter as the tryptophan. But you provide all of those and you don’t have any tryptophan, you restore the normal ratio of the of the branched-chain and large-chain amino acids relative to tryptophan, and this will restore the balance between dopamine and serotonin, which not only will help prolong exercise, but it will actually give you a greater cognitive capacity and an enthusiasm for getting started with workout as well. It’s another example where there’s a specific formulation, which isn’t designed, particularly to promote protein synthesis so much as the production of neurotransmitters, which are also functions of essential amino acid intake.

Dr. Gabrielle Lyon [1:03:11]

Do these large neutral amino acids cross the blood brain barrier?

Dr. Robert Wolfe [1:03:17]

Yeah, that’s the whole point that they’re transported by a specific transporter, and all of them tryptophan, phenylalanine, leucine, isoleucine, or valine are all transported by the same transporter across the bloo brain barrier into the brain, and there’s a limited amount of them so that if you give a high amount of one, you’re going to limit the transfer of the other because there’s just not enough transporters available to get them all into the brain. So that’s the general principle that by giving a balance that favors the dopamine precursors, that you’ll continue activation of enthusiasm or lack of mental fatigue. And, of course, this is a tough one to show beyond the theory because of the fact that people quit exercise for a lot of reasons. It’s not just because your dopamine level is dropped, but your legs going to feel tired or you just don’t feel like going on.

The idea, though, is that by optimizing the dopamine and the serotonin ratio, that you can improve this. It’s the same thing in a different circumstance with delirium, which is in short-term cases in hospitals where people have a disruption to their normal amino acid levels. This is a short-term response to a complete alteration of the balance between dopamine and serotonin, and that’s another area in which the provision of a formulation heavy in the branched-chain amino acids that are precursors to the dopamine is much more important than blocking the uptake of tryptophan, which is the serotonin precursor. This will help reduce the incidence of delirium.

There are just a lot of different applications that are possible. I think the thing that’s most important to recognize is that this is a really rapidly growing field that I described the first use of these essential amino acid stuff in about 2000. And in 2015, just to what I found there are almost 150 clinical trials worldwide and essential amino acids that have all shown some sort of positive effects. So it’s a growing field, and we’ll see where it goes, which it’s very difficult. One of the questions is, does it really make a difference which way your exact formulation is? And of course, those are difficult questions to answer because you’re an intact human, so there a lot of variables, and so forth. So that as more studies are done, I think we’ll learn a lot more about the applications and the limits of dietary essential amino acid supplements. But I think we can be pretty confident that there will be a place for them in terms of nutritional guidance, but that they put a different role to dietary protein and there’s both a limitation to their utility, but also an advantage that can’t be achieved through dietary protein alone.

Dr. Gabrielle Lyon [1:06:36]

They have tests where you can look at blood levels of amino acids, but that doesn’t necessarily translate because depending on the amino acid, that’s not where it’s primary location is.

Dr. Robert Wolfe [1:06:54]

We know that it’s maintained pretty constant, so that it makes the interpretation difficult.

Dr. Gabrielle Lyon [1:07:01]

I think it was Fernstrom that did a lot of some of the earlier research in tryptophan and serotonin? You guys listening are ready to nerd out on some of that stuff, but Fernstrom did some of these work.

Dr. Robert Wolfe [1:07:16]

That was done way back in the 1970s. He didn’t really ever capitalize on it and coming up with a formulation that people could benefit from. But the concept definitely originated with him.

Dr. Gabrielle Lyon [1:07:28]

I was very interested in it because I had been thinking a lot about is there a way in which we can create a nutritional plan that leverages some of these various amino acid profiles? But I finally gave up in the way that not necessarily, and it’s very difficult. Like you said, there are limitations to leveraging whole foods versus very specific amino acids and what is that utility and how can that be utilized. The next question would be, well, what about dosing? For example, what would the appropriate dose be to impact dopamine levels a certain amount? Have you thought about that?

Dr. Robert Wolfe [1:08:10]

Well, it’s a difficult question because the end product of the dopamine and serotonin is in the brain. There’s something called the DaTscan now, which scans for intracellular dopamine in the brain using the CAT scan. Over a long term, like months of treatment, it’s possible you can see an effect. This approach is used for diagnosing dementia and Alzheimer’s now, and that may be possible. It’s just a real challenge because with muscle, we can take a biopsy and look at the intracellular concentrations and rates of appearance and so forth. We don’t really know that there’s a very direct relation between blood dopamine levels and an intrabrain level so that some of them are limited then to performance outcomes, which as I said, are touch and go because they’re a little squishy in terms of how precise they are. It’s been mostly animal studies that have really been the basis of this theory, and then as they extend to human use, it’s been more a matter of faith on the rationale provided for the animal studies than being able to directly measure effects because we can’t really get inside the brain to measure the endpoints we’re working towards.

Dr. Gabrielle Lyon [1:09:37]

That would be not ideal. Have you thought about certain foods, for example, that are unbalanced in their amino acids, like bone broth or collagen, things that are actually found in nature? Do you have any thoughts about where potentially that can play a role in some of the facts that you pointed out?

Dr. Robert Wolfe [1:09:55]

I think that what we’re seeing with collagen is that there are some benefits that wouldn’t be predicted from the composition of the collagen amino acid structure. The most likely explanation is that they have some bioactive peptides resulting from the digestion that they, themselves have a direct regulatory role. That’s all been proposed. And I think that if that turns out to be true, then it opens the door for incorporating that kind of approach, whether it be dietary collagen alone or hydrolysates that have that peptides in combination with other formulations, such as essential amino acid formulation, that would stimulate protein synthesis might be an avenue. But there does seem to be benefits to collagen that wouldn’t be predicted, so I think that’s an interesting one to keep an eye on.

Dr. Gabrielle Lyon [1:11:03]

Anything else? There are micro proteins and trying to make proteins out of all different kinds of things. Do you think that there is anything else on the forefront?

Dr. Robert Wolfe [1:11:16]

Well I can really only speak to myself. I think it’s certainly possible. I mean, people are always looking for something. But the field of protein in nutrition is well over 100 years old. So you have to work pretty hard to come up with something that’s completely novel, particularly just relying on dietary protein. So we’ll see. It’ll be exciting, if it does. And I think that when I think that ultimately, where we might be heading is a combination of therapies put together into the same  approach, but this all hinges on actual experimentation and real data, which unfortunately, a lot of what we deal with in this field is a theory without much substantiation. I think we have to proceed with optimism, but a little bit of caution as to relying on actual experimental data to make any conclusions.

Dr. Gabrielle Lyon [1:12:12]

Well, I just want to thank you so much for your contribution to science. You have really impacted so many people. I know that you’re up to all kinds of things, if you would love to share, we would love to hear it.

Dr. Robert Wolfe [1:12:26]

I’m still active at University of Arkansas Medical School on a 30% basis, but most of my efforts have been directed towards research projects to develop amino acid supplementation via The Amino Company, which I’m a founding owner of so that my comments on the amino acids I’ve kept in a general sense so that I haven’t been specifically touting anything The Amino Company sells. But that’s been a major focus of mine, and we’ve been able to get quite a few NIH grants to specifically develop products to enhance or target specific metabolic circumstances that can benefit from formulations that can’t be duplicated with normal dietary protein. But as I said, at the same time, I’m still quite involved. In fact, I’m in New Zealand most of the time. My associate [unclear 1:13:23] who’s the head of this WHO/FAO program to develop the diet score. That’s taking some of my time as well because I think that there’s certainly a major role of dietary protein in proper nutrition, a major role. So I’m trying to stay active in that aspect as well.

Dr. Gabrielle Lyon [1:13:42]

Well, thank you so much for your time. We will link everything here. We’ll link The Amino Company; I don’t know if you have a website, but if you do.

Dr. Robert Wolfe [1:13:52]

Yeah, there is an Amino Company website.

Dr. Gabrielle Lyon [1:13:54]

Yes, you personally, and then if anyone is interested, they can Google you, do a PubMed search on you and you publish a tremendous amount of research. Dr. Bob Wolfe, thank you so much for your time.

Dr. Robert Wolfe [1:14:10]

Okay, well, thanks. This has been really enjoyable. I may have gotten too technical at times, but you got me going on some things I hadn’t thought about for a while. So that was really fun.

Dr. Gabrielle Lyon [1:14:19]

Well, my audience really likes the technical details, so thank you.

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