#224 ‒ Dietary protein: amount needed, ideal timing, quality, and more | Don Layman, Ph.D.

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My guest this week is Don Layman. Don is a Professor Emeritus of Food Science and Human Nutrition at the University of Illinois, Urbana Charlotte, Champaign, where he served as a member of the faculty as well as the Chair of Foods and Nutritions, the Director of Human Ecology, and the Associate Dean of Agriculture. He earned his Bachelor's and Master's degree in Chemistry at Illinois State University and his doctorate in Human Nutrition and Biochemistry at the University of Minnesota. His research has focused on muscle development, protein and amino acid metabolism and nutrition in the context of athletic performance, obesity, diabetes and cardio metabolic health. Don currently consults for many food industry companies including Kraft, Nestle, Hershey, the Dairy Council, the Egg Board, the Beef Board. Among this episode and discussion with Don really focus around the concept of what he calls a muscle centric nutrition view, which is how should we think about nutrition protein and various amino acids if our goal is to maintain or maximize and build muscle, especially as we age. In this episode we talk about Don's background, his interest in protein, muscle, insulin, anabolic factors in general. We explain what the RDA for protein is, how it came about, how it's clearly being misunderstood by people as a recommended amount of protein versus a barely minimum protein amount for survival. Talk about the nuances of animal versus plant protein. We talk about the difference in protein requirements between children and adults, even normalized to mass of course. And we talk about what happens to children who are protein deficient early in life. And then we look specifically at protein needs under various circumstances. So for example, what's the maximum amount of protein that can be consumed in and used in one sitting, meaning the most amount of protein that you can consume in one sitting, which still contributes to muscle protein synthesis? Talk about the ideal timing of consuming protein throughout the day and around exercise. We talk about the importance of protein quality when looking at how much or how little a person consumes. And then we talk about how these things change as you age. So without further delay, please enjoy my conversation with Don Layman. Hey, don't. Thank you so much for making time to sit down today. I've heard a lot about you over the past couple of years from our mutual friend Lane Norton, who suggested that we sit down and go even deeper down this nutrition pathway. What you may not know about me is nutrition is my least favorite subject. I say that only because I'm so tired of the religious aspect of nutrition. I enjoy talking about nutrition through the lens of biochemistry, but thereafter, my patience for it has dwindled over the past decade. I have a feeling we'll get along just fine because your entire background is based on nutritional biochemistry as opposed to nutrition, religion.

Well, first of all, it's great to meet you, Peter, even electronically. And my interest was a little sort of the opposite. I was interested in biochemistry first, and studying organic chemistry just seemed so boring and esoteric that nutrition. I could actually apply my biochemistry to things people were interested in. I kind of like that split, But I totally get your aspect of the zealot ends of the spectrum.

You grew up on a farm, if I'm not mistaken, correct? In Illinois.

Yes, that's correct.

And before we started recording this, you mentioned to me that your parents, your dad lived to 97, your mom to 102. So you're at the midpoint of your life right now, essentially based on your good genes. But what was it like growing up on a farm 70 years ago?

It was a great experience. Back in the 50s, when I was born, agriculture was very poor in the United States, and so you sort of grew up in that background. But I think I learned about animal growth. I learned about reproduction. I learned about growing corn and soybeans. I learned about life cycle, and I just got an interest in food. We were growing it. We had it there on the farm, and so it just made me interested in it. And then combined with that, I always had an interest in science and evolved to be kind of a natural marriage, I guess.

When you're going to college, did you study biochemistry and organic chemistry first? That was your undergrad?

Yeah. The serendipity of how I got into nutrition, it certainly wasn't anything I knew about. I was in a small town. I went to a school that had like 400 people in it, and so certainly wasn't anything I knew about, But I knew I liked science. So I went to First Illinois State University to study Chemistry. And I pretty quickly realized I had no aptitude for inorganic chemistry. But I sort of understood biochemistry pretty well. I got to the end of it, and it was actually during the Vietnam War and I was scheduled to go into the military, so I was totally unemployable. And the university said, hey, you're doing really good at this chemistry stuff. We'll give you a graduate assistantship. And you go when you go. And all of a sudden I ended up with a deferment, getting a master's degree in biochemistry. And my mentor at that time says, you really have a knack for this nutrition part of it. Why don't you do a PhD? And I sort of said, oh really? And so I ended up at University of Minnesot doing a PhD in nutritional biochemistry and fell in love with all of it. Certainly was no grand plan, but it fit my background of agriculture, food, sports, nutrition. I fell into a group that was doing muscle metabolism and it just kind of all fell together for me.

Was Ancel Keys at the University of Minnesota at that time?

He was not he had left, but his legacy was there with George Blackburn, Ivan France and some of those individuals. So I certainly got that background while I was there and certainly invested a lot of my early thinking of nutrition. And Lane Norton, who you've talked with before, has talked about how our thinking of nutrition evolves. My certainly has evolved.

Tell me a little bit about, at least as far as you can remember, what was your underlying philosophy of nutrition circa 1975, which is probably when you were doing your PhD.

I'm guessing one of my earliest thinking about nutrition. Again, it sort of dates to my interest in animal growth, but also sports nutrition. I very early developed the philosophy that nutrition was really about two tissues, the brain and skeletal muscle. If those two tissues were healthy, you were going to live a pretty good life. Everything else is regulatory. The liver, the heart, the kidney, the gut. Everything else adapts to your environment. But you have to focus on those two. And I think if you tailor your nutritional requirements around that thinking, you end up with a much more sensible approach. I sort of coined the concept that my colleague Dr. Gabrielle Lyon and I always use of muscle centric nutrition. If you keep muscle healthy, you've got a good shot at avoiding obesity, avoiding diabetes, avoiding cancer, et cetera, et cetera.

Let's go into that a little bit. I mean, I want to get into some weeds on a whole bunch of other really nuanced stuff, but let's follow this thread for a moment. So when you say that I Assume you're at least in part referring to the following two facts. One, muscle is the largest sink for glucose. 75 to 80% of our glucose storage capacity exists within skeletal muscle. And then there's another factor of muscle, which is it's a very early depot for excess adipose tissue. So once we start to let little droplets of fat accumulate within muscle cells, it leads to this process of insulin resistance that then creates a problem for the first point that I made, which is you now make it harder for your carbohydrate storage unit to accept carbohydrates. And of course that leads to hyperglycemia and ultimately diabetes. Is that part of why that formulated your thesis or is there more to it?

More to it. I think what you stated is correct, but I do think about it differently. I think about muscle really serves two functions. One, the obvious one is mobility. Most people get to the age of 65. Beyond that, most people actually die from some form of immobility, falls, breaking something, hospitalization. So functional mobility is critical, but the other aspect is metabolism. And muscle is a primary site for insulin activity. You mentioned glucose storage. I look at it more as an issue of glucose utilization and also fat utilization. So basically your blood glucose and your blood lipids are heavily. Obviously the amount you eat makes a difference, but the actual level is heavily dependent on your muscle metabolism. And you sort of comment about insulin resistance being associated with fat. Actually insulin causes insulin resistance. So if you chronically elevate insulin too long, that is the definition of type 2 diabetes is that basically insulin causes insulin resistance.

Say more about that. It's hard to untangle some of the causality here. I spoke with Jerry Shulman. God, probably it's been two years ago. And in his paradigm, you have the accumulation of diacylglycerides within the actual myocytes. So not interstitially right or not between them, but it's the actual accumulation of lipid within. And it's funny, I'm blanking on which enzyme now that inhibits, but it's basically down the Pi3K pathway, the Pi3 Kinase pathway, where you basically render the muscle cell less sensitive to the signal of insulin, telling the GLUT4 transporter to come up. And so this hyperinsulinemia is effectively the first way that you can externally measure insulin resistance. Is that in line with what you're saying?

Yes and no. So Jerry Solomon's great. I definitely followed his research a lot. The thing to understand about the biochemistry is you can create the models to give you a negative Feedback. So he's absolutely correct that diacylglycerol or ceramides will feed back to the insulin receptor, the GLUT4 transport and the insulin receptor and cause insulin resistance. That's true. That is a philosophy of fat centric, that fat causes all the problems. On the other hand, you can do the exact same thing with glucose. Too much glucose will also inhibit the insulin receptor and cause that same exact feedback. It doesn't accumulate the ceramides or the diacylglycerol. I did some research with diacylglycerol, and if you do it in the issues of high carb, low carb, you won't find those effects. So the question then begins, which one's more likely to be physiological because people are eating 350 grams of carbs per day, or because they're eating 90 grams of fat per day, which one's likely to cause it? Bob Wolf, There's a philosophy called the Randall Hypothesis. I don't know if you've heard of it, but basically the philosophy is the Randall hypothesis was that fatty acids, diacylglycerol, cause all the problems. And what Bob Wolf did was basically run that experiment with stable isotopes and he showed it's actually the reverse, that fatty acids are not inherently toxic, but glucose is. It has its own disease. We call it diabetes. And so when you eat excess carbs, you must get rid of them. You absolutely have to dispose of them in the next two hours, where fat basically can hang around for much longer. It's just simply not that toxic to the body. In fact, the body always wants a certain level of free fatty acids in the blood because that's the fuel for the heart. Okay, so it's always high.

What about the ability to turn that excess glucose into fatty acid via de novo lipogenesis? Are you saying that doesn't happen quickly enough to alleviate some of the toxicity of acute hyperglycemia?

It doesn't happen super quick. I mean, that's a great question. There's a lot of people who argue how much de novo lipogenesis actually occurs. But basically when you get into requiring high amounts of de novo lipogenesis, now we start talking about fatty liver. And so now you start seeing triglyceride problems. People who are actually doing a lot of de novo lipogenesis typically have elevated triglycerides. So that's one of the first signs that you're disrupting that flow. Triglycerides in general are there to recycle free fatty acids. So the adipose is always dumping free fatty acids out for the heart and other tissues. The problem comes in is when you start blending that with too many carbs and too many fats. So first and foremost, calories are always the problem. But when you have excess calories and then you start rebalancing these macronutrients is when you get into trouble.

You're obviously intimately familiar with this, maybe even some of the listeners are. But there's a very famous paper by Mark Hellerstein circa mid-90s, 94, 95 that demonstrated really a very small amount of de novo lipogenesis taking place with carbohydrate feeding. I absolutely believe the results of the paper, but I also think it's a very narrow context and it's not necessarily the context of an overfed individual. Therefore, I think our capacity for de novo lipogenesis depends heavily on total energy content or total energy balance. And therefore I think there is a scenario where in the Hellerstein paper you can feed a high carbohydrate diet, but within the overall composition of a low energy diet or a balanced energy diet. And D N L is actually quite low. Conversely, you can feed a high carbohydrate diet in the context of a high energy diet. And I think we would probably see a much greater amount of dnl.

Totally, you're exactly right.

I think the context matters. And I do think that the first, if we were describing this as a polynomial, right, like the first order term is energy, the first order term is how many calories are coming in. And that probably matters more than the ratio of carb to fat.

Go back to that Randall hypothesis or Wolff discussion. You always want to think about it as that carbohydrates, excess glucose is toxic. If the blood level is high, you'll damage basically every tissue from your eyes to your toes. And so you have to dispose of the glucose. So Hellerstein's, what he showed was that if you have a diet, say the American diet, 50% carbs, 35% fat, and you take in 1,000 calorie meal or 800 calorie meal, which one are you going to put into fat quickest? You're going to put in the easiest one, the one that's already fat. And so the carbohydrate is going to get burned and the fat's going to go to fat. It just simply the body is selecting the easiest pathway. But if you switch that, and Jules Hirsch did it and then Jeff Volek did it later, if you switch that to a 80% carb, 10% then you'll see that de novo liposynthesis. And one of the interesting things out of it is when the body makes fat, the only thing it can make is saturated fat. So we have a lot of saturated fat in the blood that actually doesn't come from eating fat, it comes from eating carbs.

Again, in the context of how much we're eating, Right?

Yeah, exactly. It's important for people to realize we burn around 100 calories per hour. That would be 2,400 calories per day. So 100 calories per hour in a two hour period, you're only burning 200 calories. So everything else has to be stored. Average American meal is 400 to 1,000 calories. That means you have to store all of that.

Is that an argument, you think, for spreading out calories more over the course of the day?

That takes us into a protein discussion, and I would say absolutely not. Two angles to that. One was there was a theory back when I was early in my career, back in the mid-80s, by Gil Leavelle, and he was arguing that lots of small meals was good for less fat. Deposition. And it was an artifact of how he did the study. He did it with animals and basically showed that when you made the adaptation to lots of small meals, the animals did gain as much as if you adapted them to like two meals per day. But the artifact was when you adapt an animal to two meals per day, they go through a starvation period because they have to learn to do it. And when you come out of a starvation period, you're making more fat. So we redid it with a longer adaptation period. And what we found was that reducing the number of meals per day actually is thermogenically advantageous. You actually waste more calories. So we actually redid that and published it. The other aspect we can get into is protein. Protein needs to be distributed at specific meals. The distribution needs to be high. And eating lots of small meals is a really bad choice for a lot of reasons. And we can get into that.

Yeah, and I definitely want to get into that because if there's one area I really want to double click on today, it's everything from protein timing, protein type, animal versus plant protein efficiency, amino acid variability, all that kind of stuff. We're going to go deep on that, but let's go pick it up. Back in University of Minnesota. You've got the legacy. And I'm guessing at the time, Keys is really famous for two things in the mid-70s. I think by that point he's probably already published his seven country study and the hypothesis now is a very fat centric view of the negative consequences of dietary fat, specifically dietary saturated fat in the American diet, especially as it pertains to ascvd. And then I suspect the second thing that he's probably still famous for is the starvation experiments, I'm guessing done in the 1950s. I mean, these were done on conscientious objectors, so they're probably in the 40s or 50s, right?

I can't exactly date that, but you're exactly right. I mean, we learned a lot about starvation at that point. For obvious reasons, we can't do experiments like that before, but we learned a lot about body composition and how the body starves. So those were good, but certainly the legacy was there. And when I got to Minnesota, I sort of bought into the cholesterol and the saturated fat and total fat and okay, this is what everybody's teaching and you know, that's what I was forced to learn, that's what they were teaching and so I bought into it. But as I slowly started doing experiments and early in my career we did a lot of fasting type of experiments with animals to look at composition changes. And I did malnutrition work in Northern Africa and I sort of got into all of that and I started realizing, you know, I don't really believe that. And one seminar I will always remember at Minnesota was individual by the name of Fred Kumaro came to Minnesota and gave a seminar about the dangers of cooking oils and specifically trans fats. And Blackburn and France just ridiculed him. Basically said, this is the craziest thing we've ever heard. All these plant oils are great. I 20 years later we banned trans fats from foods literally as the most dangerous fat that you can encounter. I always remember that, just sort of thinking, well, people who have bought into this dogma aren't necessarily right and we need to keep questioning it.

Speaking of Franz, obviously, in 1973 he completes a study, the Minnesota Coronary Experiment. I actually find this to be one of the most difficult studies to interpret. Not so much the one that he published 16 years later, by the way, in 1989, but the one that Chris Ramsden republished just a couple of years ago based on all of the data from Franz's study, plus data he never published. This to me is one of the most complicated stories I will tell you. I have posed this question to every friend of mine who is more steeped in nutrition than I am, and I still don't have a great sense of how to explain these results. So I'll explain it for the listener and the viewer and I'm curious to your thoughts. So the experiment was done in basically institutionalized patients. So again, maybe not a study that could be done easily again today for ethical reasons, but had the advantage of being so well controlled. You basically had patients that were randomized into two groups. Their total energy was identical, their total split of macronutrients was identical. The only thing that differed was that in one group it was high saturated fat, and in the other group it was high polyunsaturated fat. The hypothesis being tested was is saturated fat intake leading to increased major adverse cardiac events, heart attacks and strokes? The experiment, I can't remember exactly, I think it ran about five years in 1973, showed no difference. There was no difference in cardiac events, despite the fact that the group that was on the higher polyunsaturated fat group did indeed have much lower cholesterol levels. This predated the sub fractionation. So they weren't measuring LDL and hdl, they were just measuring total cholesterol. And at the time there was some correlation between cardiovascular disease and total cholesterol levels at the extremes. That was certainly true. Again, because I didn't think we'd be talking about this. I don't have the numbers all in my mind, but we'll link to it all. But directionally, I believe that the higher PUFA group relative to the saturated fat group was about 30 milligrams per deciliter lower in total cholesterol. And based on everything we know today, we would assume that much of that was in LDL cholesterol, indeed being lower and non HDL cholesterol. And yet there was no difference in events. And of course, it's become a very famous and unfortunate story in nutrition research in that Franz chose not to publish it because he didn't like the results. It didn't match his hypothesis, which was that the group on lower saturated fat would have fewer events. Ramsden went and published all of these data, plus a whole bunch of sub data, as I said just a few years ago, I believe in the British Medical Journal, and actually found something that threw a wrench in my initial hypothesis. My initial view of the Minnesota coronary experiment was it probably wasn't a long enough intervention. It might be that five years was not long enough to appreciate a difference. And so it was underpowered or too short in a duration to see a benefit if there was a benefit. But in Ramsden's analysis, you actually saw the opposite because he now looked at some subgroups and you actually saw a higher incidence of coronary events in some of the people that were consuming the high polyunsaturated fat diet. And I can't remember what the dominant oil was. I'm blanking on it. I don't remember if it was canola or safflower. I think it was safflower. So how much of that do you remember, Don, from your time there? And can you shed any light on this or do you have any thoughts on how to interpret that experiment?

Well, first of all, I am definitely not a lipid expert, so I sort of remember the study, but I can't put any more numbers to it than you did. I actually did some research with Ivan France and Penny Chris Etherton when I was at Minnesota. So I sort of was in the loop at the time, but that's been a couple of years ago. I think if one really looks at the literature on saturated fat and is fair about all of those studies, you find a very mixed bag. The Women's Health Initiative and all of those kinds of things. And unfortunately, the people who believe the hypothesis have either delayed publishing it or said, well, it could have been wrong. And they tried to find all kinds of excuses as opposed to. To just believing it. You know, there's an old theory in science that the theory is correct, it'll get stronger over time, and if it's not, it gets weaker. And I think one would have to realize that a the cholesterol theory, the total cholesterol theory has definitely gotten weaker and the saturated fat hasn't held up very well. We still believe it, but your comment a little bit ago, it's first and foremost calories. If you put excess saturated fat on top of too many calories, that's probably a problem. But if you're at or below your calorie needs, I don't see any data that suggests it is. So my sort of joke or comment all the time is that if you're committed to being obese, you probably ought to pay attention to the quality of your fats. If your goal is to be lean and healthy, calories is what you're paying attention to in the macro distribution is sort of your personal preference.

So let's talk a little bit now about how your interest in protein came about. Because of all macronutrients, this is the one I have to pay the most attention to. And it's honestly the one where I feel like I fall the shortest. I feel like I have some days when I nail it and I have too many days when I come up short, I never go overboard. I never go to bed at night thinking, God, I ate too much protein today. But I do go to bed sometimes thinking, I don't think I ate enough for my goals. My goals are to maximize muscle protein synthesis. My goals are to preserve lean tissue as long as I can. And frankly, that's the goal for my patients. So how did this become a strong interest of yours?

Well, the real interest started in my master's degree because I got interested in studying protein turnover, protein synthesis. And I was working with Arlan Richardson, who was an expert in aging and we were studying age related changes in protein synthesis and we actually discovered the changes in MRNA over time that the poly tails on MRNA get shorter. Your ability to put ribosomes on the message goes down and you have lower synthesis. So that efficiency of change of protein synthesis over time is a theme that runs through all of my research. And we'll get into efficiency in adults and things like that. So that was sort of the beginning when I went to Minnesota, then I sort of got a muscle focus on it. And one of the first things I learned in graduate school is we don't really have a protein requirement. We have a requirement for nine essential amino acids and organic nitrogen, organic amines, which all translates into the fact that we can make 11amino acids and nine we have to have in the diet. And one of my favorite quips I use when I'm talking to groups on stage is that protein we should think of as a vitamin pill. We don't have a daily requirement for a vitamin pill. We have a requirement for 12 vitamins inside the pill. We don't actually have a daily requirement for protein. We have a requirement for nine or 20amino acids inside of it. And so talking about a protein requirement just reflects ignorance. We have specific requirements for nine essential amino acids. And that gets into the complexity then, because these amino acids are essential for building blocks for new protein. But every one of them has a metabolic role like leucine and MTOR or arginine and nitric oxide, or lysine and carnitine, or cysteine and glutathione. And all of those roles are vastly above the minimum that is detected for nitrogen balance for the rda. And so that's where people fall apart, is that we think about vitamin C and we know There's a minimum RDA to prevent scurvy, but people will take five or 10 times that during COVID for immune response. But we resist thinking that way about amino acids, and it's exactly the same.

You know, that's a great point, Don. Maybe we should spend a minute helping people understand what an amino acid is. Because, you know, I took biochemistry, I have my little cue cards. I can draw every one of the amino acids. Not anymore, I can't. Yeah, I was going to say not anymore, but there was a day when I could draw all nine of them. But let's help people understand. I think most people understand what glucose looks like. If you've listened to this podcast, you're no stranger to the idea that glucose is a six carbon ring, and each one has a couple hydrogens on them, and one of them's got an oxygen and a hydrogen on it as well. I think most people who have listened to this podcast have a decent sense of what a fatty acid looks like. Long stretch of carbons. If it's saturated, there's no double bond, so it's just littered with either two or three hydrogens, depending on where it sits in the chain. And then, of course, you store them by putting three of those onto a nice little three carbon glycerol backbone. But I actually think most people understandably have less clarity around what an amino acid is. And you've already alluded to the fact that there were 20 of them and nine of them we can't even make. If we were deprived of these things, we'd be dead. So we gotta eat them. But can you give folks a sense of the nomenclature? What is an amino acid? What do these things look like?

A little bit like a fatty acid. An amino acid has a carboxy end connected with a carbon, and then it has a nitrogen end. So when we eat protein, we get these amino acids in some sort of a string, but we totally digest them down to probably individual amino acids, maybe di or tripeptides, and we absorb them. That way they get to the blood as single amino acids for the most part, and then the body begins to reconnect them based on the messenger RNAs. Our DNA tells us how to reconnect them. And so we connect that carbon to a nitrogen and we string them together. Of these 20amino acids, though, they all have that acid and nitrogen part, but they also have a side chain ranging from very simple one, like glycine with just a hydrogen, to ones like tryptophan that have a big aromatic part to them. And so all of these are different, and they go into proteins in different structures. The DNA tells us how we put them together. And proteins can be simple, like insulin with 51amino acids. Or they could be like myosin with thousands. And then every protein in the body has a different turnover rate. Some of them, like insulin, might last 15 minutes, and some of them, like myosin, or we'll just take collagen, might last 250 days. And so they turn over at different rates. So that's sort of what they are. But beyond that building block structure, then every amino acid has other kinds of structures. It might be like lysine, where part of it becomes the molecule known as carnitine, which is for fatty acid metabolism. Or it might be the nitrogen off arginine that goes to nitric oxide for vaso restriction. Or it might be cysteine, which goes to part of creatinine or glutathione. So we can get the leucine, which is sort of my favorite, which is a signal, which really got me interested in protein and metabolism, is a signal for muscle protein synthesis. So again, they all have this building block structure. They get strung together in different links, but they also have other metabolic functions. And that's what people don't recognize when they're talking about protein requirements.

So let's talk about that rda, because when we look at our patients and evaluate them from a nutritional standpoint, almost without exception, we come to the conclusion that they are not getting enough amino acids based on how much protein they're consuming. Now, I don't know how much of that is the nature by which food is prepared these days, the nature by which protein makes up a certain amount of the caloric intake based on various types of prepared foods and things like that, and how much of that just is based on a belief system of what people need, perhaps coming back to the rda. So, first of all, let's tell people what the actual RDA is and how it came to be.

So the RDA is a Recommended Dietary Allowance. Some people think it's daily, but it's a dietary allowance. So it's sort of a generic number. And the argument is that for all RDAs, we sort of test a population and come up with an average number. And then for a safety factor, which average would be 50% would be deficient. And so we add a safety factor of two standard deviations, which supposedly 97.5% of the people would be adequate to prevent any signs of inadequacy at that point. But that also means 2.5% of the people are actually deficient at that point. That's sort of the definition. Where does the RD come from? I think it's useful to go back in history just a little bit then on protein. How did we begin to evaluate protein needs? Well, it all came out of animal sciences back in the early 1900s, before we even knew all the essential amino acids. Farmers were trying to say, how do I get animals to grow best? You know, and different kinds of proteins and things like that, and they develop protein quality scores and things like that. How much growth did I get for what I fed? How much nitrogen did I deposit for how much I fed? So these are all rapidly growing animals. And we developed this concept really of nitrogen retention that basically we've now translated into what's called nitrogen balance. And that's how we determine the protein requirement. Basically what's important in all of that discussion, that long winded explanation, is that all of the concepts were developed for growth where nitrogen balance was positive. You could measure a change over time. And as we've now tried to start applying that to non growing adults, it gets a lot more vague. So it's important to recognize that what we think about protein requirements is a developed from nitrogen balance, where you measure all of the nitrogen you're eating, which you can do pretty good, but then you have to measure all of the nitrogen you're losing, which we're really bad at. And we call that nitrogen balance.

Can you explain how that's done? We're going to talk so much about it. I think it's worth getting into the details of how nitrogen balance is calculated. And let's do it in a human. If I came into your lab, how would you do this?

So let's start with the front end. Let's start with nitrogen in. So that's basically you just take a bunch of food and you do a chemical analysis and you measure the nitrogen and you multiply it by a factor of 6.25. So a you're measuring nitrogen, it's not really protein, it could be nucleic acids, it could be anything. With nitrogen, you're calling it protein. And then you're measuring, multiplying it by 6.25, which says, I believe that protein contains 16% nitrogen, which also isn't always true. So now we've got this error on the front end and now on the back end we're going to try and measure losses. So the primary loss of nitrogen in the body is in the urine, urea. So that's pretty easy to measure. You can collect that. Second would be the stool. So you can collect that, but then you get into things like sweat, skin loss and Hair loss and respiratory nitrogen, ammonia and the breath. And those are all incredibly vague. So everyone who knows nitrogen balance says that nitrogen balance underestimates requirement. Everybody, uniformly. But that is where the RDA comes from. When you do short term studies, what you find is most people. And again, all these studies were done with college age students. So they're kind of right at the end of their growth. Basically, in a short term, seven day study, they look okay. So that's where we're at. In the last 20 years, those of us who study protein have gone beyond that and said, well, nitrogen balance is one outcome. But like the vitamin C argument, there are other outcomes based on amino acids and metabolism that may be more important than minimum nitrogen balance. And we now know that protein handling, the efficiency goes down as we get older. So now we have much higher requirements that most of us talk about for adults.

So just to be clear, Don, going back to something you said, the reason we all agree that standard nitrogen balance underestimates the requirement is it's easier to measure the sum of the ins than the sum of the output.

Yeah, exactly. And the chances are you're significantly underestimating.

The outs, especially if you do. I mean, when I was a surgical resident, there were times we did nitrogen balance on patients who were on long term tpn, total parenteral nutrition in the icu. These were patients that it wasn't clear how long it would take for their guts to start working again. So they had to be fed all of their nutrition through a central line, which is very complicated feeding to do. And when we would have the nutrition team come and do a consult and do a nitrogen balance, I mean, they literally had to put a tent over that patient. They were doing the best that they could in the ICU to basically create a laboratory environment to calculate nitrogen balance, which turns out you're not surprised. Very important. For critically ill patients, that is a hyper, hypercatabolic state. And if you're trying to create an anabolic state in that person to keep them alive, it's imperative that you understand how much nitrogen they have or how much nitrogen that they require. So the simple idea of I'm just going to tell you how much protein you're eating and I'm going to measure the nitrogen that's coming out in your urea, that's just not going to cut it. That's just too simple. Yeah.

And currently a lot of those studies are simply done with a factor. So they don't put them in tents or buildings or what they just measure Urea in the urine and everything else is just sort of.

Well, we think it's a one bladder.

Yeah, exactly, exactly. And so obviously we're perpetuating an error based on ignorance.

So then let's go one step further, Don. How do you use isotopes to now really get into what's happening, not just on the boundaries, but how that nitrogen. And by the way, I think there's one point we should make for the listener who might be still lost as to why we're talking about nitrogen. Proteins have nitrogen, amino acids all have nitrogen, carbs and fats don't. So this is where we can really speak to the source of the nitrogen. Now, as you mentioned, anything with a nucleic acid is going to have nitrogen as well. But the majority of the nucleic acids.

Come in proteins, come in protein. Foods.

Yeah. Would be found in protein based foods.

You're exactly right. I mean, fats and for the most part, annoying, essential fatty acids, Carbs and fats are basically energy sources. They're carbon, carbon bonds that provide energy, where amino acids have a very different purpose and structure and that nitrogen is part of what makes them different.

In other words, we consume carbohydrates virtually exclusively for their energy content, fat mostly for its energy content. There's some structural importance that comes with fat and cholesterol. But really, you don't want to be consuming protein for energy.

Right. The only caveat I would say to that is that there might be reasons that people are hypersensitive to carbohydrates, where taking in more protein beyond what you might actually need for protein metabolism, might be a substitution for carb calories. We can get into that conversion and things like that. But I talk with people and they say, how much protein? What's your high end? And I sort of give them one number. And I say, but, you know, the caveat is you might want to take more if you're really trying to struggle with a carbohydrate issue.

So now let's talk about that measurement of what's actually happening with those amino acids. Actually, there's a question I want to ask you. Even before that, when people think of protein, they think of meat. That's going to be a great source of protein. Obviously there's protein in. Most foods have some protein in them. But if you were eating a piece of steak, how many of those 20amino acids are in there? Are they virtually all in there?

If you're looking at animal source proteins, whether it's meat or eggs or milk, basically all of the Amino acids that a human would need are in those because they're basically. Obviously a chicken's not a mammal, but the others are mammals. And basically we have the same amino acids, the same protein. They're all there. Meat is a good example because they're all pretty much in the right balances. But every protein has a little different balance of essential amino acids. You can look at dairy proteins, and dairy proteins are something we can fractionate because they're all water soluble. So we know a lot about alpha lactobumin versus lactoferrin and lactoglobulin, et cetera, et cetera. We know that a lot of differences about amino acid compositions of individual proteins.

Going back to what you just said then animal protein we typically think of as meat. Mammals, beef, pig, stuff like that. And then of course, you've got sort of bird protein, mostly chicken for folks, and then fish protein. And then you have eggs, dairy.

The first three are exactly the same for protein. So whether it comes from a cow or a pig or a chicken or a fish, muscle protein is still muscle protein.

And how do we think objectively about the quality of a protein? This is a topic that you've talked about extensively, but. But there's a way, there's a numerical way to talk about that, isn't there? An efficiency of that protein versus tofu versus soybean versus rice, all the way down to lower and lower protein density foods?

Yeah. Protein quality is something that I think a lot about, and I'm actually working with a group now to sort of reinvent how we think about that. But I think you're referring to protein quality in a sense of PDCAs or DIAZ or something like that. Basically, we realized that when you look at a protein, there are two factors. One is what's the composition of those nine essential amino acids, and the other is what's its bioavailability. How well do we digest it and absorb it? With animal proteins and most isolated proteins, you know, even soy protein isolates, the digestion absorption is pretty close to 100. It's usually 95% or higher for all animal proteins. For plant proteins, though, it gets into. You need to realize that in a plant, the protein is there for the purpose of the plant. And so a lot of it is attached to fibers, to structures. Plants have proteins attached to the leaves and the stems and the roots and the flowers and the seeds. And when you start to isolate that, if you just eat it in a raw form, it may only be 60, 70% available because we can't digest the fiber. So those are the two factors. We can put those two together and get a protein quality score, and we can determine that a whey protein isolate, because of its essential amino acids, is 20% better than a soy protein isolate just because of the amino acids. Or we can compare a wheat protein, a wheat bran, and we realize that it's only 40% available. So if you look at wheat bran on a cereal box and say it was a wheat flour and it says there's 4 grams per serving, there's actually less than 2 that you can actually absorb. That's how we look at it. In my opinion. Some of the problems with those right now is it's hard to compare across foods and it's hard to build a meal that way. We can say that whey is better than soy. And so if you're only eating those two things, that's okay, but what happens happens when you start putting them together. And so I am working with a group trying to build a protein quality score that really based on three amino acids, lysine, methionine and leucine, which in my opinion are the key markers for adult health. And so we're trying to restore it differently. Again, long winded story about protein quality, but that's how it's measured.

No, that's very interesting, Don. So what you're saying is, if I'm understanding you correctly, you could brute force your way through life by looking at every single thing you eat and trying to figure out the dyas score for its protein. Okay, I'm about to have a rib eye. That's going to be about a 96% dyas. I'm going to have my soybeans over here, that's about an 80% dyas. I'm going to have my whey isolate, that's 100% dyas. I'm going to have my shredded wheats, that's a 40% dyas. That's a tough way to go through life because you can't just add up the protein.

Yeah, they're not truly additive. You can't really figure that out. And the average person doesn't even have that data. I mean, if you go into the USDA database with whatever 7,000 foods, there are 4,000 that actually have amino acid scores. And of those, there's probably less than 300 that have Dias scores. And so you can't put it together. There's no way. And so we're trying to develop a system that allows people to get better than that. If you look on a label on a package and you see, again, a wheat cereal that says it has 4 grams of protein. Well, again, that's a nitrogen analysis times 6.25 for all the problems I've said. And then if you look over in another column, it'll say daily values. Almost no label have daily values for protein, because that would require a PDCAS or Dyas score, and nobody has them. And so that 4 grams really would translate into less than 2. But nobody's being told that.

And by the way, just for folks who are hearing us use the term, Diaz, that's digestible indispensable amino acid score, correct?

Right. And I have a big problem. The digestibility is where a lot of people have been focusing. But I have a big problem with the amino acid scores because they're incredibly low. They're way too low. They're established by the World Health Organization, by the fao, which is really designed to prevent malnutrition in Africa, where we know from our Institute of Medicine that the essential amino acid scores are much higher than that should be. You mentioned stable isotopes a little bit ago, or tracers. We know from stable isotope studies that all those FAO amino acid scores are too low. And so that's part of the equation that we're not telling people either.

I want to come right back to that, but I'll finish this one point, which is what you're offering as an alternative to people living in spreadsheets to calculate how much actual indispensable amino acid they're getting is, hey, what if we make this easier and you focus on the actual content of three amino acids? So we're going to take a subset of essential amino acids, and if I recall, I remember, leucine was clearly one of them. Lysine was one of them. Was methionine, the other one?

Methionine's the other one. Yeah.

So we're going to take methionine, leucine, lysine, and we just want you, Peter, to walk around and make sure you get enough of those with each meal. If you do that, the rest will take care of itself. Is that effectively what you're saying?

That's exactly what I'm saying. If you look at Dyas scores right now, the amino acid scoring A, I've already said is too low. But if you look at how they're scored, they're not scoring apples and apples, they're scoring apples and oranges. So if you look at the soy deficiency, all legumes like soy or pea are limiting or deficient in methionine. And you score that against whey, what you end up is the limiting amino acid in whey is considered histidine. And no one has ever shown histidine to actually be a limiting amino acid in an adult. Result, it's a limiting amino acid in children and babies. So now we're comparing apples and oranges. They're not fair. So if you compare methionine to methionine, it's not 20% higher, it's 250% better. Comparing soy and whey, we need to compare apples and apples. We need to compare them across the three essential amino acids that are actually likely to be limiting, where histidine, phenylalanine. To my knowledge, no one has ever shown those to be limiting in an adult. So why do we consider them limiting?

So you've already mentioned the importance of leucine, and listeners of this podcast are no stranger to leucine because we've had David Sabatini on, we've had Matt Kaeberline on. I mean, we've gone deep in the weeds on mtor. In fact, it was one of David's postdocs that actually discovered the leucine sensor on mtor. So we know now, pretty unambiguously, leucine is an amazing trigger for mtor. Of course, there's gonna be a subset of people listening to this who are confused. But wait a minute, Peter. If rapamycin is good and rapamycin inhibits mtor, how can leucine be good if leucine turns it on? And of course, they're forgetting the chronicity of the state. Sometimes you want it on, sometimes you want it off, but when we're talking about eating, we want it on, right? We want to be able to turn MTOR on for muscle protein synthesis.

So let's circle back to our earlier comment about how often you eat. So now we've got an issue of MTOR and whether it needs to cycle on and off. And not only does leucine turn it on, but so does insulin. Probably the worst case scenario, and you can use a lot of animal studies to back this up, would be people who eat a lot of small carbohydrate meals that continuously activate mtor. What we want to do is use specific meals with the right amount of insulin to activate the muscle centric mtor. MTOR is in every tissue, and what you don't want to do is continuously activate it in liver or some other tissue. And so that's where the confusion gets into it Is people ignore the fact that insulin is just the biggest trigger in other tissues, where leucine is a very unique trigger in muscle.

Let's go back to the practical application of this so we know why leucine matters. Can you say a bit more about methionine and lysine and why raising them to the level of leucine becomes a great proxy for overall protein load?

If you look at limiting amino acids actually in food, lysine is always limiting in grains, and that has been shown in animal science over the years. That's a major limitation in how you feed what, the minimum amount. So that one is probably limiting for protein synthesis. It's also in carnitine and some other things. But lysine is probably mostly for protein synthesis. Methionine. If we look at the amounts we need, we need about 3.4 grams of lysine per day. We need probably a little less than one gram of methionine. So they're not in the same proportion either. But the methionine is what we call part of the one carbon pool. And so basically, for the body to make and repair DNA, to make and repair rna, to make taurine, downstream, to make nonessential amino acid cysteine, to make glutathione, the oxidant methionine is the key to all of those pathways. Methionine is one of the most limiting and it's limiting in all legumes. So we think of soy and pea and lentils and things of that nature as higher quality protein. They are, but they're still limiting in methionine.

What are some of the natural sources of food that are high in methionine?

Classic. One of quote sulfur amino acids is eggs. Eggs are quite high in the sulfur amino acids, which are methionine and cysteine. But all animal products are adequate in them, and basically all plant products are pretty low in them.

You grew up on a farm?

Yes.

We look at animals like cows, which are quite muscular, eating basically just hay and grass. For them to be able to be as catabolic as they are and produce so much muscle, does that just speak to the incredible volume of that plant that they have to chew to make sure they're getting enough methionine, enough lysine and enough leucine.

I think you meant anabolic, not catabolic.

Sorry, anabolic. Yeah, yeah, yeah. In such an anabolic state, I mean, what volume of total protein in the form of grass and hay and things like that do they need to Get a sufficient amount of those muscle building amino acids.

That sort of wanders us into a sustainability argument, which I really love to wade into. But cattle, ruminant animals are a very important part of the food chain because of their stomach, which is full of bacteria. One of the things to think about for essential amino acids is really the only place they come from in life is bacteria. Nothing else can make them. Our primary source of them in nature is the bacteria on roots of plants. So the bacteria on the roots will take the nitrogen. Why do we fertilize our garden as nitrogen? The bacteria will take that inorganic nitrogen and form organic amines with it. And those organic amines then can be made into proteins in the plants. But as I said earlier, the problem with plants is that they don't have the same balance as we need. They have the plants to make roots and flowers and things like that. The beauty of a ruminant is they can take that plant and they can digest it. And the bacteria then will rebalance all of the amino acids, they'll capture inorganic nitrogen and they make the essential amino acids that mammals need and they concentrate it for us. So basically humans, one of the arguments is humans evolved by being able to use more concentrated protein. If we gestate plants, it's hard to get enough. But if the ruminant animal can actually digest all of that, form it into appropriate amino acids. So, so Basically, for every 60 grams of protein an animal eat, they'll make 100 grams of essential amino acid balanced protein.

Wait a minute, say that again.

So for every 60 grams of plant based proteins and nitrogen that they'll take in, they can upcycle that to 100 grams of amino acid balanced protein. So ruminants are called upcyclers. So whether it's in dairy or meats or goats and sheep and deer, all of those ruminant animals upcycle by eating grasses, they produce great quality protein. No other animal can do that.

And just to make sure I understand the mass balance of that, the bacteria are obviously the engine of that upcycle. But you can't make nitrogen out of nothing.

So you're saying they're making protein out of nitrogen?

That's right. That's what I was going to say. So they're getting the nitrogen from the fertilizer that went into the grass?

Not quite. They're getting nitrogen that's inorganic in the plants, but it's not actually in protein forms. And so it's in the fibers and other kinds of things. So they're able to upcycle that they're able to increase the value of non amino acid nitrogen, plus they capture all of those other nitrogens.

So, first of all, I had no idea that was happening. I had never heard of that phenomenon. So that's incredibly fascinating. Secondly, are they also disproportionately creating amino acids that weren't necessarily there in the plant? So, in other words, if you use the example you gave earlier, which is you eat a hundred grams of cow protein, you're going to probably get quite an amount of methionine, lysine and leucine. Is it true that that amount of amino acid was not even present in the 60 grams of grass protein that they consumed?

That's exactly what's happening. So the bacteria, if you look at the flora in the cow, they have certain bacteria that will produce methionine or lysine. So they can basically take an amine nitrogen, or they can take glycine, a non essential amino acid, and they can make it into amino acids. One of the supplements that you can actually feed a cow is urea, a human waste product type of thing. We excrete nitrogen waste as urea in the urine. You can actually feed urea, a nitrogen source, to a cow and they can make it into methionine or leucine or lysine.

Unbelievable. So it's an interesting argument. Now we're venturing from nutrition into religion because there's certainly a group of people who would argue that we should not be eating any animal protein whatsoever. We shouldn't eat eat meat, we shouldn't eat eggs, we shouldn't eat dairy, et cetera. A counterargument to that would be it's awfully difficult without these animals to get adequate amino acids, especially if you stop thinking of it in terms of an RDA and start thinking of it in terms of essential amino acids.

I try and stay away from the religious argument of it. That's a personal preference, as you said. I grew up on a farm where we raised cattle and pigs. We raised cattle, corn and soybeans. And so I saw it as a life cycle type of thing. I think of it as a biochemist. And there's just no question that ruminant animals play a very important role in our food system and one we can't really replace. We can't just idle millions of acres of grassland and pretend that we can grow avocados on them or broccoli. Cattle basically spend a year of their life on basically nothing but grass. Sheep and goats, the same. But those are amazing contributions to our food system.

I was completely unaware of this capacity to concentrate and almost up produce both in quantity and quality of amino acid. That's a very interesting finding. So where were we before we went down that path? Because I was just trying to understand how it happened. So also didn't appreciate the role of the bacteria. Oh, I know where we can go back to. You mentioned that you have spent some time studying the difference between, call it 20 year olds and 60 year olds in terms of the efficiency of muscle protein synthesis. And this is where you probably have to get into the isotopes. Now you're getting into sort of nuanced stuff. But what do we know about a 20 year old versus a 60 year old who puts their muscle under a progressive overload? They're doing resistance training. They're being provided with adequate amino acids. And let's assume they're being provided with not just the right quantity but the right quality of amino acid. What do we know about the assimilation of that amino acid into new muscle tissue across. And you pick any age you want. I just use 20 and 60. I know you've studied this at very specific age points.

Piece of background. Before we get into that, it's important to recognize that whether you're 16 or 65, your body needs to make nearly 300 grams of new protein per day. So there's a protein turnover. Every tissue in the body is turning over, some as fast as liver enzymes, where you replace every hour. Muscle proteins we replace with half lives of around 15 to 16 days. So every 30 days collagen turns over at about half life of 100 days. Which is why if you have hurt your knee, it takes so long to repair it. But basically if you put that into thinking the body replaces literally every protein in it about four times a year. That's a pretty remarkable number. And then if you think of we have to make 300 grams of new protein per day. The average American intake is around 80 grams or less. Women 70, men 90. That means that there's a recycling thing going on. So of every new protein that's getting made in the body, about six out of seven amino acids are getting recycled. All of that sort of feeds into this process of protein synthesis, protein turnover and what, remember I said what I was doing with my master's degree, we were studying the age related changes. What we now know is that as you get older, the efficiency of that protein turnover goes down. So where a 16 year old, you give them a certain amount of protein, they'll have a very good response. A 65 year old will have maybe no response at all or 10% or something. But what we have learned with the study of leucine and initiation factors and all of that is that if you give an enriched source of essential amino acids more protein, you can actually make the adult look just like the 16 year old. So what we know is that the efficiency goes down, but the capacity to respond doesn't. And so what we're now thinking is that what we now know is that if you have a requirement that's about twice the minimum RDA, so instead of 0.8, it's 1.6 grams per kilogram, we can get the adult, the 65 year old, to respond just the same as the 20 year old as far as muscle, muscle protein synthesis.

You know, a moment ago, Don, we talked about how it's a slippery slope if you just focus on total protein. So when you say 1.6 grams per kilogram, does this assume it's from a whey like product and an animal based product? And if that person says, hey, I'm 65 years old and I'm on a plant based diet, are you going to say that number is going to need to be higher?

That's a great question, a great way to ask it. What we know is that most people who go to a plant based diet, a vegetarian diet, decrease both the quantity and the quality. So your point is exactly right. If you're on a plant based diet, you'll need more protein and that means you'll have to have more calories. But what's the threshold for that? What we would probably argue is that if you have 100, 120 grams of protein per day, it probably doesn't matter the distribution between animal and plant because you probably have enough to cover it. Okay, if you're only eating 50 grams of protein per day, then it makes a big difference. You'll never catch up to your essential amino acid needs. So somewhere between 50 and 120, it depends on what you choose. If you're going to be plant based, have 125 grams of protein per day and you're probably fine. But if you're going to be vegetarian and you think you're going to get along with 56 grams per day, you're going to get in trouble.

Going back to this difference earlier about the call it anabolic resistance between the 65 year old and the 16 year old, the obvious thing that comes to mind is there's a huge difference in androgen level between those two. What are the other things that might Explain this anabolic resistance that, by the way, I think it's very interesting that you can overcome that by a higher amount of protein. But. But prior to that workaround, what else do you think explains anabolic resistance?

Clearly, the hormone issues are first and foremost. So I always make the comment that when you're growing, hormones are your friend. They're sort of driving it. And you look at malnutrition in Africa, and children will grow on really lousy diets. They may not grow as healthy, they may not live as long as. But there's a survival reproduction nature to that. Now we switch to talking about healthy aging. And I want to live to where my parents. I want to get to that century mark. Now we talk about healthy aging, and now we change the criteria that we're looking for. Let's just think about MTOR for a second and try and put that in framework. There are four different signals that regulate mtor. We've mentioned leucine. We also mention insulin, an enzyme, a factor known as AMP kinase, which is carbohydrate sensitive, is energy sensitive. And then another molecule known as RED one, which is stress sensitive, particularly resistance exercise. So there are four different things the individual balances when you're young and growing, insulin and IGF1 dominates that. And insulin, first and foremost, is growth hormone. And when you stop growing at 25, it ceases to have an effect on protein synthesis and muscle. And so now the shift, the whole thing shifts to protein quality. Protein quality is not nearly as important when the system's dominated by hormones. And so now what we know is as we get older, we can buffer that loss of the hormones by higher quality protein, mostly leucine, and. And resistance exercise. Those two factors will balance out the growth issue that young people, the benefit of the growth part. So that's the way you have to think about the change in efficiency with aging.

Speaking of aging, at the front end of what you just said, I want to go into that a little bit more. And I think most people will recognize that this is an enormous problem in the developed world. And we should talk about it through that lens, because I think that's where it's most stark. But I'm curious as to whether or not you think this could become a problem or even plays a role in childhood obesity rates. So let's talk about what happens to a child that is protein deficient at the beginning of their life. What is the implication of that later in life?

So when I got into protein, John Waterlow and Joel Millward and Peter Garlake and Vernon Young were the godfathers out there that I learned from. And I got involved with some international malnutrition with the US International Agency for International Development, USAID project in Morocco. And so we looked at that and that led us to doing some animal studies. And basically we used the animals to look at malnutrition and recovery. And what we found was that malnutrition, starvation insults early in life would stunt muscle development, basically limited the DNA development, limited to cellular development, and basically stunted lean mass in the children and in the animals. And if that was stunted, basically what happened is the individual as an adult was always predestined to have low lean body mass and high body fat obesity. And that was really the origins of how we started thinking about muscle centric health. If muscle didn't develop right, if it wasn't metabolically correct, you are predestined to some of these other things. And I mentioned Dr. Gabrielle Lyon, that's sort of how we put that concept together is muscle centric health. We've got to have the correct development and we have to have the correct protection as adults, because that's kind of where both your mobility and your metabolic health start.

Dawn, what's the mechanism? Do we have a sense of why? You know, for example, maybe people are aware of this, but when you look at children in places like Africa who are really malnourished, at first glance, you almost pause and think, well, why are their bellies so big if they're malnourished? And yet they don't realize that's an actual. That's an extreme. And I don't even remember. It was Kwashiorkor. Was that the name of.

Exactly.

Yeah. And what's the pathophysiology of that? Why does the extreme malnourishment lead to that protruded abdomen and things like that?

So there's sort of two terms, two directions that childhood malnutrition goes. One is called marasmus, which is sort of the skin and bones look, and the other is kwashiorkor, which is that inflated belly looking. The belief of those two differences is that in Kwashiorkor there's disproportionately poor protein, and that leads to changes in water balance and edema. People have argued, is it cortisol based? You know, is it stress based? It appears to be an imbalance in the protein to energy relationship, where in marasmuth they're just short of total calories and total protein and everything. But in Kwashiorkor, it appears that the quality of the protein they're eating, these starchy porridges and things like that, totally deficient, probably in lysine and methionine. And that leads to water imbalances and other things.

And what is it about this critical window of development where this protein deficiency makes it very difficult for them to put on lean mass later in life and creates a propensity for adiposity?

We actually did some of that original research stuff we did way back in the late 70s, early 80s. Muscle is a very unique cell structure. We have what are called muscle fibers. And unlike a liver cell, which has a DNA, a nucleus in each cell, muscle cells are multinucleated. They have what are called satellite cells around them. And so as the original fiber begins to develop, the satellite cells will put DNA, these nuclei into it. And what we determined was that each DNA has a certain amount of protein it can handle. And so what the DNA ultimately determines how big your muscle can get. And so what we determined was that late in pregnancy, early in lactation, if the insult occurs during that, you stunt these satellite cells and you don't develop enough DNA. So the muscle is always limited in its potential size.

Wow. I was aware of the propensity for adiposity later, was not aware of the limitation in lean growth. So this is really the double whammy. It's effectively lifetime sarcobesity.

Yeah. So basically you're decreasing your lean mass, you're decreasing your metabolically active tissue, and so you're sort of stuck with minimal calories with deposit fat.

In the US it would be hard to imagine a child developing kwashiorkor, but clearly there are kids in the United States that are disadvantaged enough that they're not going to be exposed to high enough protein in either quality or quantity. Do you think that there's to a lesser extent some of this problem that's going to happen in developed nations like.

The U.S. i think it's possible. Frankly, these are the kinds of things I worry about with the advocates of plant based diets. We're starting to see New York City taking animal proteins out of school lunch. I mean, what is that really going to do? We're conducting a public health experiment without actually having any knowledge of that. I think that's frightening. The issue is public school lunches, nursing homes, daycares, these are all under these federal guidelines where we're diluting out the quantity and quality of protein at the same time with no knowledge of what that's really going to mean. So I think that's Pretty frightening to be doing that kind of public health experiment without knowledge of it.

I hadn't even considered it through that lens, actually. Let's talk about something else that we alluded to briefly. But now I want to get back to which is maximum protein usability or assimilation in a given sitting. So I'll tell you where I come at this. One of the challenges that I've observed in taking care of patients is when they get into a very heavy regimen of time restricted feeding. You're probably aware of this, Don, but there are ideas that say, look, if you can just limit the amount of time that you eat, but not place any limits on what you eat or how much you eat or what you're eating from into this sort of intermittent fasting window, it produces some health benefits and it's certainly an effective way to reduce calories. So if the goal of the exercise is to reduce total energy expenditure and you create a narrow enough window, you will indeed do that. But what we've seen repeatedly is people who, after say six months of adopting a very narrow feeding window, say one meal a day, will lose weight, but disproportionately will lose lean tissue. The diagnosis here is pretty straightforward. They clearly reduced energy intake, but they probably reduced protein intake too much. And so body composition actually got worse, despite the fact that weight went down. Which then gets to a point which is, well, can't you just eat all of your protein in one meal? So if a person says, I'm just going to eat one meal a day, let's just say this is a very active person, right? So they're going to eat 3,000 calories in one sitting, which I will raise my hand to, saying I can do that quite easily. I'm quite a glutton. Even if I was able to eat 150 grams of protein in one sitting, is it clear that my body will get the benefit from that? That it would if I ate 50 grams three times a day?

Yeah, it's quite clear that you won't get a benefit, that there is a limit. So now we need to think about the body as muscle versus everything else.

We're going back to the muscle centric view that I like.

You're probably sensing a theme with me at this point. The muscle. There's a lot of data now that muscle can handle protein meals for an optimum and anabolic response, between about 25 and maybe 60 grams. Then you start getting into distribution. If you're going to have 150 grams per day, how should you distribute it one of my pet peeves in nutrition, I'm slightly getting off track here is people refer to protein as a percentage of calories. Protein is not a percentage of calories. Protein is an absolute number. You need to decide on what you're going to build your diet around. So right now we're building it on 150. The issue with protein is being an absolute number. If your calories go down, say you're now a 75 year old woman and your calories per day is now 1200 calories, you still have 100 gram per day protein requirement. So now your protein needs are 35 to 40% of your calories. If people are doing weight loss, it's an absolute number. So people should never talk about percentage of calories. That's basically people who don't think protein is important say, well, fat should be 30%, carbohydrates should be 50% and that leaves 15%. You have to think about protein first. So that was the issue as far as distribution from my research. One of the things that we believe is the most critical meal of the day is the first meal of the day. When you have had an overnight fast, your protein synthesis is down and that MTOR signal molecule is down, regulated, it's inhibited. And until you have enough leucine, around 3 grams, which translates to about 30 grams of protein for most people. Until you have a meal that has 30 or more grams or protein, your muscle stays catabolic. So you're continually breaking down protein. We think that's a significant aspect of aging, that people have lower and lower protein. They don't eat protein at breakfast, and we know the efficiency is going down in the first place. So we want to front load protein in the day. So we want at least two meals that are well above 30 grams of protein. So I always have people shooting for 40, 45 at the first meal, another 45, 45 at their last meal, and then in between, if we're talking with people who are say an elderly woman trying to maintain minimal muscle, I'll concentrate on those two meals. If I'm talking with somebody who's trying to do weight loss, I'll concentrate on three because I don't want them getting hungry. If I'm talking with someone who's trying to be hypertrophy, a muscle builder, I'll concentrate on four. So how many meals per day do I make anabolic and muscle? And by anabolic I'm thinking 35 grams or more. And the data that we know for absolute certain is the first and last meal are absolutely important. The middle meal. I'd be hard pressed to show you a single study where anybody's ever looked at lunch.

And so the reason that you're saying for the anabolic person we need four meals is we know we need it for positive nitrogen balance. We're just going to have to get the two aspects.

There's one is MTOR signaling muscle protein synthesis, leucine effects, and the other is total protein per day. So those two lead say, well, if I need more protein and I max out at 50 grams, I need another meal.

And what about timing? Let's just talk about someone who's doing their strength training in the morning. So let's say someone's going to do strength training from 8am to 10am do you want them having that first bolus of protein before the workout?

There's some debate about that. You'll find some people and trainers who believe that. We did some studies and most of them were with animals where we looked at different timing and we find that exhaustive exercise is catabolic no matter what. So having protein ahead of it doesn't make it. We find the benefit is after the exercise when the system is now finely tuned, we've inhibited red one, the system MTOR is ready to go. So we find the benefit is after exercise, not before.

And just to be clear, what you're saying is, look, you can take all those amino acids before, but it's not going to prevent you from becoming catabolic during exercise because again, exhaustive exercise is a catabolic activity. So you are going to be breaking down muscle no matter how many amino acids are on board while lifting. It's more important after the lift that you have a good meal.

You'll find some disagreement in that in the literature, but I strongly believe that what you just said is correct and my research supports that.

And talk about the efficiency or the window in time post a workout in which you want to make sure you're getting that first big meal of protein. I'll tell you a funny story. My youngest son, who's now 5, but when he was like 3, for whatever reason, he just fixated on protein, probably because we kept telling him to eat this and eat that because there was protein in it. Hey, eat your salmon, it's got protein. Eat this cause it's got protein. And basically he has become the protein police of the preschool. He walks around and he looks at kids snacks and he's like, that doesn't have protein. That granola bar does not have protein. That has protein. And you can imagine what these people who work at the preschool say to my wife when she drops him off and picks him up. She's like, are you a nutritionist? And she says, no. Oh, okay. It's just your son really fixates on everybody's protein consumption. So we joke about how he's going to be like one of those bro protein guys who's just going to be all obsessed with his protein and when he's eating it and stuff like that.

I've lost our train of thought here for a minute, but just to focus on the children for a moment. So we're talking about adult protein needs and I don't want everybody to walk away thinking, gee, I need to get 50 grams of protein in my kid. Children will be very efficient at maintaining growth with small snacks of 8 to 10 grams of protein where that will have virtually no impact for an older adult. So a protein bar that had 10 grams of protein is a perfectly legitimate snack for a child where essentially the only thing it would do is probably increase liver enzymes in a 70 year old. So don't want all the mothers think they're doing a bad thing by giving their child a 10 gram protein snack.

I remember what we were going to come back to, so I'll take us back there. But let's talk about that a bit more because that's actually news to me. I didn't realize that there was minimal benefit in smaller quantities of protein. So this is another argument for don't dribble out your protein, commit to it. It's binary. You eat it when you eat it and then you don't when you don't.

Yeah. So again, children versus adults. In the adult, if we have every meal of the day, let's say we have 100 grams of protein, but we take it in in very small meals. 15 grams trickled in all day long. You will never stimulate muscle protein synthesis, but your liver will be perfectly fine. Your gut will respond to that amount of protein. Your gut, your liver, your heart, your kidney, all of those organs will respond to the net protein per day, no matter when you ate it. But muscle doesn't. Muscle is specific. Muscle is such an energy, as you mentioned earlier, there's so much, much mass to muscle. Muscle isn't triggered unless the diet is exactly right. And we could get into teleological arguments about leucine at this point. Branched chain, amino acid. Why does the muscle sense that? But basically the muscle senses energy, insulin, protein before it triggers. And if all of those aren't balanced, it won't trigger, but your liver will.

To your point, teleologically, you might make the case that, that the liver has more concern for the brain than the skeletal muscle. And maybe it gets priority over being happy because it has to maintain glucose homeostasis. And without glucose homeostasis, the brain would literally die within 20 minutes.

Your liver, your heart, those have to function. Middle of the night, your liver still has to be making protein, but your muscle doesn't. While you're laying there in bed, your muscle is catabolic and it's supplying amino acids, so all those other organs work. So while I argue about muscle centric health, the reality is moment the moment it's organ based. But long term, your overall health is determined on keeping the muscle healthy because it keeps everything else healthy.

Just because I want to keep talking about this before we go back to where we were before I distracted us, is the reason that it's okay for kids to be eating much smaller amounts of protein? Is it simply just the mass? My youngest weighs 25 kg, right? Is it basically just saying, look, he probably doesn't need more than 40 grams of protein a day. So for him to have a 10 gram serving is 25% of his protein. That's like me having 40 grams.

And plus his protein synthesis, as we mentioned earlier, is driven by hormones where yours isn't. So his growth is highly efficient. It's driven by hormones and he will accommodate it in small doses. And you're right, he probably only needs 45 for the day anyway.

So I'll take you back to where we were before I sidetracked us. It was now asking about how big a window you have to refeed to maximize muscle growth.

So we actually did that first experiment in rats. So Josh Anthony and Tracy Anthony were in my lab just before Lane came. And what we were looking at was exhaustive exercise, again of rodents. We were looking at this catabolic state. We were trying to look at how the muscle regulated recovery. And so we were looking at what were called initiation factors. And we discovered the link between leucine and an initiation factor called EIF4 that is sort of the downstream effect of MTOR. MTOR is the regulator and it stimulates EIF4 and S6 and other initiation factors. And so what we found was that when you came out of an exhaustive exercise, muscle is catabolic until you took in enough leucine to reverse it. And so we started looking at feeding right after exercise. And Stu Phillips, Doug Patton Jones and Luke Van Leeuw, a lot of people sort of picked up on that. Okay, so now the caveats. The biggest effect of feeding right afterwards is about a two hour window, but that's in untrained individuals. If you begin to look longer, you can have a bout of resistance exercise and you'll detect the difference. You'll start regulating that red one protein factor and you'll see an anabolic effect the next day, 24 hours, 36 hours later. So when does your protein effect? Well, it makes it more effective all the time. The more trained you get, the less you're going to see a post exercise effect. So if you're beginning training during the first four weeks post exercise, protein probably makes sense. If you're well trained, you're basically training the same way and you've been doing it for six months. I don't see any effect difference between having protein within two hours after exercise versus just having your three or four meals per day. You won't see any difference in either mass or strength.

I remember having this discussion with Lane as well and being very surprised by that, being pleasantly surprised by the way, because it says, hey, look, once you get to a point where you're well trained enough, you don't have to be so maniacal about meal timing. You can just focus on the big picture, which is total protein, protein quality and spreading it out such that you don't exceed the metabolizable fraction of it at any one sitting.

Exactly. You'll hear trainers take that last statement, metabolizable energy, and you'll hear trainers say, well, you can't use more than 30 grams at a meal, you won't digest it or whatever. That's not true. I mean, you'll digest and absorb 100 grams of protein at a meal, but muscle in particular only has a window of around 25 to 60, depending on protein quality, where it can use it. The liver will use all of it. I mean, it doesn't matter. We have what is known as first pass metabolism of protein, which confuses the issue even more. When you eat a meal of protein, approximately 50% of the protein is degraded to nitrogen and carbon before it ever gets to the blood. Almost 50%. The exception to that are the branched chain amino acids, leucine, isoleucine, valine, and almost 75, 80% of those get into the blood. And we're back to that teleological argument. Why did muscle learn to sense that? Because that basically shows up in the blood in direct proportion to the meal. And the muscle learned to sense that as A meal quality. It says, oh, wow, this meal has adequate quality for me to trigger this very expensive process of protein synthesis, protein turnover. And until it sees that signal, it won't do it.

While we're on the topic of muscle, don't. Another thing I've learned somewhat recently that surprised me was the importance of leucine in fatty acid oxidation by the muscle. One of the things that is such an important pillar of our practice is low end aerobic training. We call it zone two, so zone two, mitochondrial efficiency. So this is basically pushing your muscles to the maximum point at which you can keep lactate below 2 millimole. And in a very fit individual, you can generate a lot of power while still keeping lactate below 2 millimole. I mean, the best in the world can produce more than 4 watts per kilo while still keeping lactate below 2 millimole. And they're doing so virtually exclusively with fatty acid. So we will pair this type of analysis with CPET testing and we will look at fat oxidation rates. And again, you will see the fittest of the fit have insanely high fat oxidation rates. They're over a gram, roughly a gram per minute. Point of that is look, a really good muscle doesn't just rely on glucose. A really good muscle can oxidize fats very effectively. What role does leucine play in that?

That's a great question, and I don't think it's been researched well enough. I mentioned earlier, we talk about amino acids and every amino acid has a different side chain. Well, leucine is one that's referred to as a branch chain amino acid. And its side chain is purely carbons. It's a carbon chain that looks a lot like a fatty acid. And so leucine is one of really two amino acids that are ketogenic. It is metabolized as a fatty acid. And what we know is that leucine will also activate the CPT1 enzyme, the carnitropomatin transferase enzyme, which is the link of bringing fatty acids into the mitochondria for oxidation. So there's a benefit there. It gets even more complicated in that when you have higher leucine, it also begins to inhibit pyruvate from going into the mitochondria. So when you oxidize a leucine, the nitrogen that comes off of it is put onto pyruvate, generating an alanine. And so the body begins to recycle glucose. So it becomes kind of steady state on glucose and emphasizes fat oxidation. So back when you were Talking about Schulman studies early, if you overload all of that, basically you can make the leucine inhibit carbohydrate oxidation. So if you have huge amounts of carbs coming in and then you overload the system with leucine, you'll inhibit pyruvate oxidation. And so that could look like insulin resistance. But if you look at the physiology of how it's supposed to work under conditions where you'd be burning fat like you just described, leucine actually stimulates fat oxidation and spares glucose for the brain and other tissues. So, again, you really have to think about how the experiment's set up, what's getting inhibited and what's getting pushed.

You've recently taken an interest in weight loss, right? So the dietary interventions that can be efficacious for weight loss and treating things like metabolic syndrome. So let's build off this idea a little bit. How do you incorporate the strategy around reducing energy intake? This is sort of how I think about weight loss. You gotta reduce the intake. But I think of three broad ways that you can approach that. So three strategies, right? One is you just reduce calories, and that becomes the only focus. So, so you pay attention to the total energy content of food without thinking about the timing of food or the macro distribution of food. The next approach is you spend less time thinking about the total number of calories, spend more time thinking about the macronutrients. I describe it as sort of create a boogeyman in the diet, things that you avoid. And the restriction of certain things becomes a roundabout way to restrict total energy. And then we talked about time restriction as well as another strategy. How do you think about manipulating that middle bucket of changing macros to achieve energy deficit?

I totally agree. Weight management is a calorie issue, and it's not the same for every individual. Everybody's got a little different efficiency. So we understand you can't be an accountant and expect to just count calories all the time. But let me build it as a story of how we thought about it back in the late 90s. Atkins and the Keto Diet were out there, and Barry Sears and the Zone Diet and Mike Elites and Protein Power. And I was looking at all of those things, and we were doing those leucine experiments and we had discovered this effect of leucine on muscle protein turnover and some of these metabolic things with fat metabolism. And I basically took the leap of faith and said, you know, well, I think the underpinning of all of these diets is really the protein Carb ratio and how can we manipulate that? And so I started thinking, well, if we're going to create diets, one, we know that from a satiety standpoint, protein is probably the most satiating. Lower fat would be next carbohydrate the least. We were concerned about big insulin swings. So we wanted to sort of balance out our carbs per meal. We know that if people are overweight, they tend to have big post meal carbohydrate and insulin swings where they get two hours later they'll have carbohydrate lows. And so we started trying to think about that and we said, okay, so we think the first meal after an overnight fast is critical, so we're going to correct that. So we basically started saying how much protein do you need? 30, 40 grams of protein to get both satiety, protein synthesis effects. We knew that protein had a higher thermogenic effect, burns more calories, more heat than either carb or fat. So we wanted to front load that effect. People have argued that, well that's because protein is a nitrogen, it's harder to digest and absorb. We don't think that's true at all. We think the thermogenic effect is stimulating muscle protein synthesis. We know that that is a massive ATP expenditure. And so what we want to do is maximize that at every meal. So our first meal we wanted to be 40 grams of protein. We wanted to have a carb level that would not overstimulate insulin. So we kept that under around 30 grams for what we created a carbohydrate threshold concept. We could go into and then fat sort of around out the calories. And we basically developed three meals a day to distribute like that. We basically increased the protein to about 1.6 grams per kilogram. And we ran the study comparing it to the food guide pyramid with 0.8. So as far as we could tell, we did three different studies. One, a total feeding study where we fed everyone. A second study with diet and exercise that was four months. And a third study was multicentered with 120 subjects that lasted 16 months. And so we did three studies.

And the last two were free living where they were responsible for the food. But the first one they were fed.

The first one we fed them in the lab so we knew exactly what they were eating. The second one we actually fed them for the first two weeks for a few meals so they really saw what it would look like. And the last one was totally free living based on the diets and manuals that we develop.

And each of these was two arms where the only difference was protein.

So in the first one it was two arms, Food guide pyramid, high carb, low protein versus higher protein, low carb. The second one was two by two. So we basically had the diet treatment and then we had a resistance exercise treatment. So high protein, low exercise, high protein, et cetera. And then the last one was diet with a generic recommendation for exercise, but just a two treatment fact.

So what did the first experiment show? The really well controlled one?

The well controlled one, what we found was that with the higher protein, and as far as we could measure exactly the same calorie intake, the people on the higher protein, low carb, lost more total weight, more total fat and less lean. And that stabilized their insulin and glycemic regulations and lowered their triglycerides across the board.

Do you remember what the difference was in weight and fat mass? And was it all explained by the thermodynamics of the difference in protein?

It was close. We found that if you assume that body fat, 3,500 calories, and you can make that calculation, we figured out that the people on the higher protein diet were getting a benefit of a, I think it was around 170 calories a day, eating the same calories. So that could be about the thermodynamic effect.

So in other words, that amount spread out over the duration of the study explained the difference in weight loss.

Right. So both groups lost weight. They were both on weight loss diets, but the protein people lost, I didn't look those numbers up, but they lost around eight pounds more and something like, like six and a half of it was fat.

And did they also complain less of hunger or was there a difference subjectively between the groups?

We did a satiety check using an analog scale. We just asked them to rate how they felt and stuff. And one of the things that the dietitians who were running the study always came back is they said that the protein people were never talking about food and snacks, but the people on the high carb diet were always talking about being hungry and snacks. There's definitely a different satiety and compliance issue to it.

I assume the fat was constant in.

That study, first study, which was only 12 weeks, basically all subjects in both groups finished the study. And the longer studies would got into four months and longer. We found much higher dropout rates in the high carb group too.

So did the results of all three studies point in the same direction, which was that a higher protein weight loss, so a protein sparing weight loss diet, which gets back to your point earlier. Stop thinking about protein as a percent of total calories. Protein should always be absolute. And if you want to think about it that way, as you reduce calories, protein should increase. The total fraction of calories is going to preserve lean tissue better, maintain satiety better. And plus, there's potentially this bonus of the thermogenic effect of protein, right?

It definitely partitions the weight loss toward fat, protects muscle. Malignant tissue definitely has higher satiety. One of the things we know, in fact, for a long time there was a lot of debate whether people over 60 should ever practice weight loss because they would lose too much mass and they can't gain it back. Doug Patton Jones had the theory that sarcopenic aging isn't a gradual decline. It's a series of acute effects that you injure yourself, you're in bed, you have a surgery, whatever, you acutely lose lean mass and you can never gain it back. So we were concerned about that. We want weight loss, but we don't want people to lose any lean mass, especially if they're adults. If you're a 20 year old, it probably doesn't matter so much. But if you're older, you're beyond 40, it does matter.

It's a scary thought, Don, if you think about it, right, 40 is not that old. And yet I recently had shoulder surgery. The time that we're recording this, I'm probably about five months out from that shoulder surgery and I still have not gained back all of the muscle mass. Now I think I will gain it back, but I look at how difficult it has been and how acutely I lost it. I mean, within three weeks I was 10 pounds lighter. I lost 10 pounds of body weight. And it's obviously not just from the shoulder. It's when you don't have have an arm, you can't squat, you can't deadlift, you can't do all of these other things. So obviously some of that was water weight, But I think seven of those 10 pounds was lean tissue that I lost in a span of three weeks.

There's some tremendous research by my colleague Doug Patton Jones, who unfortunately passed away this last year, who did a lot of that kind of bed rest sort of study. And looking at older adults versus younger, and in the same period of time, an older adult in bed rest will lose four times as much muscle as a younger adult. It's frightening how fast you can lose it. And to your point, if you're diligent and do weight training you can begin to gain it back, but it's hard to ever get back to ground zero if you lose it in aging. And people ask me, well, all this leucine stuff, when does it really come into play? It's not as important for a 20 year old as it is for a 60, but where's the middle ground? Where does it change? And I think it's a little like bone health. Once you're 40, you're sort of on the back end of that, and you need to be much more careful. Doug and I ran a study, which everybody quotes now, where we took 90 grams of protein and looked at it distributed as three meals per day, 30, 30, 30 versus 10, 20, 60. And we found that with the same amount of protein, the same overall overall diet, you would have higher net protein synthesis with the distribution to breakfast. So that's kind of where all the distribution data came from. Was that study. We ran that study in 37 year olds. The average age was 37, so we think that by mid-30s, you can detect the distribution effects.

And just to be clear, Don, do you think that the reason 30, 30, 30 was better than 10, 20, 60 because you started the day at 30 or because you had three meals where you cleared the hepatic threshold?

That's a great question, one that I wish the Twitter world would understand. I think the effect is moving at the breakfast, the first meal. I think that frankly, we'd have been better off.

You should have done it 60, 20, 10 as the other arm, right?

No, I think it should have been 40. What's the math? 40, 10, 40. I think the first and last meals are the key. And I'll give you the reason for that. We've done a number of studies in animals. Other people, Mike Rennie and Phil Atherton, have done it in humans. But when you trigger MTOR at that first meal, we know that it's still stimulated five hours later. So why do you need leucine for MTOR at lunch if it's still stimulated? You don't. So there's. Nobody has actually studied that at this.

Point, unless you're the person who just is so big. Like if you're laying and you're £200 and you're a bodybuilder.

But the key to what you just said is now you're talking total protein per day, not a leucine effect. It's not a leucine tor effect. There's not this thing to it. It's okay. Lane needs 250 grams of protein per day. He'd be better off putting that in four or five meals than putting it in two. So that's the difference that people need to understand is that distributing across all the meals, if it's for weight loss and appetite, that's great, but it's not an MTOR effect.

So, Don, this kind of brings me to something we've talked about before, which is so much of this research that you've done has been funded by industry and a lot of people are going to say, well, we're going to discount everything Don just said because. So give us the names of some of the organizations that have funded your work over the last last four decades.

So let me backdrop that for you. So I had the leucine concept that leucine was going to be key to protein synthesis in muscle. We ran a study in the early 80s where we realized it was initiation effect. We started looking for what those initiation factors were going to BE and it's EIF4. So we sent that as a proposal to NIH, National Institute of Health. For 10 years it was continuously turned down. And they said, well, we only study disease and we don't know of any deficiencies of protein, so it's not a priority to us. And so basically I was left with what turned out to be a revolutionary idea of reinventing protein that NIH wouldn't fund. I finally went to Kraft Foods, the National Cattleman's Beef association, the National Dairy Association, American Egg Board and some of the other groups who were inherently interested in protein. We had some from the usda. I was at a land grant university. So those were the funding sources that basically unlocked all of this knowledge about protein for adults. Leucine, mtor, muscle centric health. All of that was unlocked simply because we could get funding from Kraft and Beef. Am I biased? You know, everybody who eats is biased in some way. If you look at research, and I think maybe Lane said this with you. I never believe research when I read it until I see it in three more labs. So I don't mind if people look at my research and say, I don't believe it. But my research has been out there, very clear theories for 20 years now. And every test makes it stronger. And so that's how you believe it. The fact that Kraft or Beef funded it's irrelevant. The issue is everybody who's ever run the study after me shows the exactly same thing.

Do you think NIH has? I know you've been semi retired now. You're kind of not really retired, but you're retired from the Grant cycle.

Exactly.

But do you have colleagues that are still in it, or do you see any evidence that NIH has taken a broader purview to health? If nothing else, they should be able to look at the fact that 2/3 of Americans have metabolic syndrome. And that should at least give pause to think we might need to revisit the way we're approaching nutrition and therefore maybe we should be funding, quote, unquote, non diseased research in nutrition.

I think they definitely have. Chris lynch, who's director of nutrition at nih. Now, that position didn't even exist.

Is that within niddk? Where does that sit?

I think it's across multiple institutes. So which one actually funds the most? I think NIDDK might be the one, the Cancer Institute. I think his unit actually goes across multiple institutes. But again, that didn't exist back in the late 80s, early 90s. You know, I think it may be a little bit. But there is a general philosophy still at NIH that NIH does not do applied food research. That industry should fund it. So that becomes a catch 22. You know, if we're going to study the difference between whey and soy, unless you can say, well, that's going to cure heart disease, they're not going to fund it. And so you have to then go to the Dairy council and say, I want to do this study. And then people say, well, you were funded by the Dairy Council, or I go to the soy board or whatever. It's a catch 22. But basically the alternative is we put our head in the sand and we don't do the research. I look at people in nutrition right now and literally I don't know anybody in nutrition who doesn't get industry funding. It's just simply how you have to get funded. One of the things I'd also point out in this whole issue of biased, it's important to recognize that the animal commodities are all under the USDA supervision because they are animal commodities and they have checkoff boards. So that means everything they say in advertising has to be screened. Where the grain industry has big companies like Kellogg's and Pillsbury and Coke and Pepsi, and they can literally go out and say anything they want. And so you'll see a product out there that pretends to be an egg and they'll claim that there's better than eggs, but egg can't come back and refute it. So you've got two different playing fields. One that's highly restricted and supervised and the other which is fair game. First Amendment.

I can Say anything I want on that topic. Don, how closely have you paid attention to both the plant based meat and the synthetic meats? I. I've paid a little bit of attention because obviously there's two companies that are pretty popular. I can never remember their names. I think it's beyond meat and impossible meat or something like that.

Exactly. Got it.

And they're plant based meats. So they're making meat out of plant. And then you have a whole host of companies, none of whom I can remember the names of, that are actually trying to make synthetic meat. The little bit that I've read about that, which really amounts to reading two scientific articles left me with the impression that that will not be technically feasible. Just from an energetics cost, mass balance, sanitation, GMP standpoint. That's not going to happen. That's my way of saying either I'll be proven wrong or that will turn out to be one of the biggest boondoggles of industry in some time. Do you have thoughts on either of those two, including nutritional composition and how it feeds into an amino acid perspective.

First is an overview. I think that as the world continues to expand in population, we're probably going to need additional protein sources. We may be near our capacity for animal based protein. I don't think we can double it again. So we may be near. So we're going to need other sources. So I accept that plant based proteins are important to us. I totally agree with your comment about synthetic proteins. I don't think that will ever be economically or environmentally feasible. I don't think that's true. Then we get into the popular versions of plant based beyond burgers and things like that. And the reality is it looks like a flash in the pan. People tried it and basically if you go to a Burger King and look they had a good sales for a few months and you track that. It was all people who don't normally go to Burger King. It was people who were interested in a plant based burger. They went and tried it once and never came back. So basically we know the stock has fallen through the bottom. Now we know that nobody's using it. The problem with it is. Let's take beyond Berger. Basically it's a pea protein that's produced in Canada. It's shipped to China because we can't process it. In the United States there's no processing. For the most part they're beginning to develop it, but when it came out there was none shipped to China. China processes production. Protein ships us back to the US we know transportation is the Number one cause of greenhouse gas in the world. And so now we've shipped it all over the country, comes back to the US and they process it into something with like 25 ingredients. Probably five or six of them are not FDA approved. And so now you have.

I wasn't aware of that.

They have multiple products, they have multiple components in synthetic that have never really been studied and they're not FDA approved. So they're basically relying on safety without ever proving it. Will that ever come back to haunt them? I don't know. In the spirit of having natural foods, there's certainly not anything natural about them. Anyway. I think that plant based proteins have been around a long time. I think trying to pretend that it's meat calling soy drink milk or almond drink milk, I think those are travesties. I think those are standards of identity. Almond milk has what, one gram of protein per eight ounces where cow's milk has eight. Calling that milk is pure deception. And that's why there are lots.

I love cashew milk, by the way. That's how I make all my smoothies and stuff. My wife calls it nut juice.

I do too.

You're going to have some of your nut juice.

You know, I'm not against using them, but I think the.

You just think the nomenclature needs to be correct.

One of the examples I like to use is that if you look at a wheat cereal, pick any, but take a wheat cereal that has 4 grams of protein per serving. We always said that's only two. Probably on the label it says you mix it with 3/4 of a cup of milk. So now we have 10 grams. And if you look at the lysine balance of that, it's exactly balanced. But if you go to soy milk, a soy milk only has 6 grams per 8 ounce per cup instead of 8. So now you already have less protein and it's also deficient in lysine. So it takes almost a quart of milk, takes almost 30 ounces of milk to balance that cereal. So if you're a mother feeding this to your child and thinking, well, I doing a plant based thing and I'm feeding them a totally deficient diet with 6 ounces of soy milk for breakfast, I'm feeding them a totally deficient diet. How many mothers know that?

Look, if I don't know that, I'm guessing a lot of mothers don't know that.

And so those are the kinds of things that we think need to come out about protein quality. We want a system where we can show people an additive Value and that at the end of it and I put, put that meal together. This is a company called wisecode that I'm working with. We think that we can show with using QR codes and your phone will simply add them up and you can tell what your total meal looks like.

Yeah, that would be incredibly helpful. As I alluded to earlier. Still something I have trouble with is doing it especially on days when I don't have access to as much meat. What it comes down to for me is just how much did I have from leftovers the night before. So I've got a meat based meal which is my dinner. Wild game is sort of our routine, right. So elk and venison and stuff like that. And if I'm smart enough and thoughtful enough to make a lot extra, I can basically have it for breakfast and lunch the next day. But sometimes I'm not. And then I'm making protein shakes. I'm eating a venison bar here and there. But it gets a lot harder and I'm having a hard enough time just making sure I hit the total grams per day of protein. There's no attention on my end going into hey, how much methionine is here, how much leucine is here, how much lysine is here.

If you've got 125 grams of protein in your diet per day, chances are you'll hit those numbers where leucine is a meal to meal number, lysine is a daily number. It doesn't matter. Meal to meal. It's a total yes.

For me that's probably okay. But then I think about it for my wife or my female patients where it's hard to get them up to 120 grams per day.

We struggled with all of the adult women we had in our studies. We had whatever, 3, 400. It's a real struggle to keep a female at 100 grams of protein per day. It's just a struggle. Then quality becomes an issue. That's my concern with the whole plant based movement is that do people have the resources to can you make that healthy? Sure you can. But you a need a lot of knowledge, you need a lot of food skills and you're going to have to eat synthetic products because you can't get it from eating lentils and rice. You just can't eat enough of them. And so you're going to have to have shakes or supplements or something to get to that kind of level. Otherwise the track record says that vegetarians will end up somewhere in the 60s for their protein per day and quality does make a difference at that level.

Well, Don, this has been really interesting. I'm so glad that we were introduced. I can talk about protein all day because it's an eternal interest of mine personally, but also in terms of helping as many of my patients as I can, it's not the macronutrient that gets the most debated on Twitter. That's reserved for carbs and fat. But this is the one that I think we need to be paying more attention to. So I'm grateful for the work you've done and for the attention you brought to it today in our discussion.

I appreciate the opportunity to do that. One thought I'd leave you with that we haven't touched on is people talk about high protein, and I think it's important to try and come to grips with what that means. If you look at all of the epidemiology, which I think is pretty bad science, the definition of high protein is about 1.2 grams per kilogram, and low protein is actually below 0.8. And so a lot of them will express it as percentage of calories, and they'll say less than 10%. And so when you look at the epidemiology, you need to realize they're talking about very narrow ranges of protein intake. And it really isn't the protein that's making a difference. It's the calories and the other things that are going with it. One last thought. For four years, I was director of research for the American Egg Board. So I funded all of the research that basically got the cholesterol direction eliminated from our guidelines. One of the things we funded, though, was there was a lot of research suggesting that eggs had a high correlation with obesity and diabetes and heart disease. And so we funded some research with Teresa Nichols and Vic Vergone, who are experts in the NHANES data. And what they looked at was that but in the epidemiology, the difference between the first quartile and the last quartile for egg consumption was three to three and a half. So they were basically saying that a half an egg per week was a difference in causing obesity, heart disease, and diabetes. And so what they did was they went into the NHANES data and they factored out all of the eggs that were eaten at fast food versus the eggs that were just eaten at home in a, quote, good nutrition setting. And what they found is in every case, eggs now became a positive. They reduced obesity, they reduced. So basically, it's not the egg, it's the egg. In the company it keeps. And you can make anything a bad diet.

To your point, when we talk about epidemiology pointing at high protein being a problem, you realize anybody who's tried to actually consume high protein realizes it ain't high protein. It's high calorie. That's the problem. And the protein is along for the ride because again, and 1.2 grams per kilo is actually kind of low protein in the context of a high calorie diet.

If you look at epidemiology and you do any food surveys, what you realize right away is that the data for protein is pretty good. If I ask you how many eggs you ate yesterday, you'd give me the number. If I ask you how many ounces of milk or how many grams of meat you'd give, because we sell those by ounces and weight. But if I ask most people how many carbs they ate yesterday, they miss it by 200 grams. And so that's the problem with epidemiology is that the errors are not homogeneous, they're not spread out, they're not equal. So anyway, I ramble on, but a great pleasure to chat with you, Peter.

Thank you Don. This was fantastic.

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