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Dudley Lamming 4:27
Associate Professor of Medicine here at the University Wisconsin Madison, and I'm in the Division of Endocrinology, diabetes and metabolism. So we really focus on the biology of aging with a strong interest in how that's regulated by metabolism and metabolic processes and dietary nutrients.
Nick Jikomes 4:48
Yeah, and just starting out like really, really broad for people that don't have a background in this. What exactly is metabolism and what does it mean for someone it just in very general terms to be met? biologically healthier unhealthy? Like what are the major things that scientists and physicians would look for to determine that?
Dudley Lamming 5:06
Sure, I would say I would consider metabolism all the pathways around taking nutrients in from the environment, such as sugar and fats and how protein and converting them into either energy or other building blocks inside the cell that we can use to either repair existing cellular structures or replicate the cell. In terms of what healthy metabolism is, typically, we think of healthy metabolism as sort of the opposite end of a spectrum, where the unhealthy end of the spectrum would be people who are obese or diabetic or insulin resistance. Typically, metabolic unhealthy people might also have high levels of lipids and be at increased risk for cardiovascular disease. So at the other end of the spectrum, sort of the metabolically healthy and we'd assume that people would have good levels of HDL low levels of LDL and triglycerides overall probably have a lower level of fasting blood glucose and be sensitive to insulin. metabolically healthy people are probably able to adapt to different fuel sources and to periods of fasting and overfeeding a little bit more quickly than people who are probably metabolically unhealthy. And our ability to adapt our metabolism to different fuel sources also declines with age. And so we typically think of people who are older might also be more metabolically unhealthy. About a quarter of the people over age 65, for instance, have diabetes.
Nick Jikomes 6:42
In what would be like a good example of someone's metabolism adapting to like a new a new diet or something like that, what exactly does it mean to adapt to a change in the food that you're in taking?
Dudley Lamming 6:55
Well, we see this in mice all the time, when we do these types of experiments in the lab, you could do exactly the same experiment and a person, it's just much more inconvenient, we could put my son in chamber where we measure their respiratory gases. And we can measure how much oxygen and carbon dioxide they're taking in and then breathing out. And that lets us based on some equations that were developed a long time ago, and some sort of very basic observations, let us calculate what fuel sources are being used. So normally a metabolically healthy mouse or person, when they eat food, they'll burn the carbohydrates off, sort of first, they'll start metabolizing them first, they might take some of those carbohydrates and store them as lipids for later when they're not eating. And during periods of fasting or when you are not, don't have food present, you might be focused on burning off lipids and use utilizing lipids, mice that are obese and insulin resistance don't have this fluctuation in terms of burning carbohydrates versus burning fats or not to the same degree. And so the degree at which they adapt to different foods, or to fasting and feeding conditions stories.
Nick Jikomes 8:07
So someone who is insulin resistant and or obese, they don't have that kind of adaptation. So what exactly does it look like in terms of their metabolism when they eat something that say, carbohydrate versus fat rich compared to someone who is healthy?
Dudley Lamming 8:22
Well, at least from the perspective of mouse, there's relatively small fluctuations, we can measure the RTR or respiratory quotient and our metabolic chambers, and we can see that it fluctuates less, make more obese and insulin resistant the animals?
Nick Jikomes 8:39
Why do you think that is? Is there maybe like an evolutionary reason for how we think about this, like our animals, like mice and like, like humans? In our, you know, for most of our evolutionary history, have we just been in environments where we had to constantly like, switch our diet up and adapt to new conditions?
Dudley Lamming 8:55
I think that's probably exactly right. You know, this idea that there sort of food always available in the refrigerator, or in our desk drawer, or, you know, if we're in the office, you know, or just walking home, right, we're constantly surrounded by foods and options to purchase food. And so, you know, that didn't happen evolutionarily. And I think we needed to be able to sort of quickly adapt to make the best, most efficient use of what food sources were available, you know, when, when fruits or vegetables are, are plentiful and easy to get, presumably you need to get those and when you know, you need to be hunting, you probably need to be able to take best advantage of a type of nutrient source as well.
Nick Jikomes 9:38
And so there's a lot of research going on, I know that you've done stuff related to this, that has to do with caloric restriction and the effects that has on metabolic health. So just starting again, in very broad terms, what would you say is sort of the general overall picture we have is today of how caloric restriction tends to affect metabolic health in mice and humans.
Dudley Lamming 10:00
So, first of all calorie restriction, as as you're aware, is this idea that if we restrict the number of calories that an animal or maybe a person is consuming below their ad libitum level, their sort of free feeding level, then that's associated with health. And that certainly seems to be true, generally pretty universally among species. And so organisms all the way from yeast up to fruit flies to mice, and even to non human primates, when their calories are restricted by a certain percentage, and this usually is in the range of 20 to 40%, or so. So that they are have enough calories, but they're not over eating. They sort of metabolically adapt in a number of different ways and lots of different hormones and markers and health change. But generally, these animals live longer, anywhere from 20 to 40, maybe even 50% longer, depending on a lot of factors, including sex and strain and genetic background and exactly how much their restriction is, but they tend to be lean, that's probably not a surprise, right? If you overeat, you're fat. So if you're restricted your calories, you stay lean. And they tend to be insulin sensitive. And that's sort of a universally observed trait in mammals that are calorie restricted. So they're lean, they're insulin sensitive, they tend to live longer, and they're protected from most age related diseases. And so they get less cancer, less diabetes, those animals that are prone to Alzheimer's disease tend to get less Alzheimer's disease. And we see many metabolic benefits, at least in people as well, although nobody knows if it extends human lifespan.
Nick Jikomes 11:48
So So one of the things that it seems like is a consistent marker of good general health is insulin sensitivity. And I think the thing that insulin is typically associated with is regulating your blood glucose levels. So when someone becomes insulin insensitive, Does that just mean that their body's not responding to the insulin and therefore their blood glucose levels are not being regulated properly? Or are there also other things that insulin does that maybe people don't typically talk about?
Dudley Lamming 12:17
Um, there's a lot of things that insulin does. So insulin is what we consider as a signal of the Fed state. Pretty much whenever you eat food, your insulin is going to spike, it might spike more or less, depending on how much carbohydrates are in your meal, but it's going to go up. And typically, right when you eat something your body is, you know, evolutionarily adapted to think that there's going to be not just sugar there, but also proteins and fats. And so insulin stimulates the uptake of all three of those types of nutrients from your blood amino acids. They're based, the building blocks of protein as well as different types of lipids. And it activates all sorts of anabolic processes, where macromolecules are being built from not only sugar, but also from fat and protein. And so wrote pipe protein synthesis goes up, lipid synthesis goes up, cell membranes get made, cells might divide or get bigger, depending on what other developmental programs or signals might be present. But yeah, it's definitely a signal of all different types of foods. And so in insulin resistant state, you don't take up any of those things from your bladder, you take up less of them.
Nick Jikomes 13:29
Okay, so it's, it's not just blood glucose levels, it's it has to do with the uptake of all of these types of major types of nutrients.
Dudley Lamming 13:35
Yeah, we tend to focus on sugar just because it's one of the most apparent things and also, why the easiest to measure, but all of these different things are stimulated by insulin.
Nick Jikomes 13:48
I see. So. So here's a simple question that I feel like I don't have a complete understanding of if you're insulin resistant, and you have a defect in your body's ability to take up macronutrients, including carbs, sugars and proteins. Why is insulin insensitivity associated with being obese than if your body's not taking them up as well?
Dudley Lamming 14:10
Well, that goes into a whole big controversy that you may well be familiar with. And I'm not going to sort of deep dive into that because I'm not, that's not my specialty. But basically, people think that insulin might be obesogenic in itself, and so that as you express more insulin, in order for your body to overcome that insulin resistance, so when your insulin resistance, your body started pumping out more insulin to force your cells to respond to insulin, once your beta cells get tired of making insulin at that level, which eventually they do, then that sort of progression, this type two diabetes, but during that stage where it's pumping tons of insulin out, there's this idea that it might be obesogenic or a dip genic in of itself that might drive other changes in metabolism. So that hyperinsulinemic state might be deleterious as well.
Nick Jikomes 15:02
I see. And what type of molecule is insulin? Is it? Can you just like to describe the type it is and what exactly it's doing.
Dudley Lamming 15:11
Insulin is a small hormone. It's peptide hormone. So it's made from just a small number of amino acids strung together. And that's secreted. And your body has many different hormones that are very similar to insulin in terms of being small peptide hormones that are floating around.
Nick Jikomes 15:28
And, you know, one of the things I know that you've done a lot of research on is amino acids. So proteins are made from amino acids, there's a bunch of different amino acids. One of the key differences between some of them is you always hear about essential versus non essential amino acids. What's the difference there.
Dudley Lamming 15:45
So typically, we think of about 20, common amino acids. These are ones that are the most common by far and food and are directly encoded by your nuclear genome, those of your listeners who might dive into biology a little bit more No, but their price, there are other amino acids as well. But of the amino acids that, that these common amino acids, nine are essential. And so basically, you need them to grow and with if you're any mammal, I think, certainly mice and humans have the same list of essential amino acids. And, but your body can make the other amino acids. There's some other subtleties in terms of, well, maybe some additional amino acids might be essential when you're a baby, because you can't make enough of them. But for the most part, we think of those nine as being the key for a healthy diet.
Nick Jikomes 16:35
I see so so some amino acids your body can produce some you need to get from your diet, because your body can't make them. There's some subtleties there. But that's the basic idea. What about like, how much does the distribution or the profile of essential and non essential amino acids vary from protein source of protein source?
Dudley Lamming 16:55
Um, it varies quite a bit between foods. So almost, I would say, pretty much all foods have all amino acids in them. And it's possible that there's an exception, but I'm not aware of one. But certainly, you know, there's definitely a huge variation. Typically, we think that vegan foods is being low and amino acid, my thymine Muthoni may be low in plants. There's some controversy there as well. And then certain meats might have more have branched chain amino acids, they're very heavy in or concentrated in skeletal muscles.
Nick Jikomes 17:31
And so what would happen in general, if you were deficient in one of the essential amino acids, because you're eating some kind of specialized diet? Um,
Dudley Lamming 17:41
well, I think sort of sort of most familiar, you know, to your listeners might be idea of scurvy, which is, you know, vitamin C deficiency gives you sort of rickets, and all sorts of nasty problems, if you're on a ship without eating enough citrus. And too, it's sort of a broad generalization, the same thing is true, if you are deficient in amino acid, you'll probably be okay for a while your body will use up some of its stores, you know, acids to make up that deficiency, and then various pathological symptoms will start arising. And they'll differ based on which amino acid you're deficient in.
Nick Jikomes 18:14
So basically, it would be that eventually, so So if you were deficient in one, you weren't getting enough of one of the essential amino acids in your diet, your body could initially compensate for that by, I guess, breaking down some of its existing proteins to get that particular amino acid, you know, eventually wouldn't be able to make the proteins that require that amino acid. Yeah, but
Dudley Lamming 18:33
basically, you know, it's very unlikely that anyone's going to be eating a natural food that's completely lacking any specific amino acid. But I'm sure that you know, essential amino acid deficiencies may occur from time to time and people who might be, you know, only eating one or two foods instead of sort of being an omnivore.
Nick Jikomes 18:54
And then you mentioned branched chain amino acids, what what is that?
Dudley Lamming 18:59
Um, three of the essential amino acids have a branch and their carbon structure, and those are leucine, isoleucine, and baleen. They're sort of most familiar to people as being amino acids that people who are athletes or bodybuilders might take supplements of. And there's certainly a lot of commercial supplements of branched chain amino acids that are available on the market. They're also some of the most important components of skeletal muscle and they have a wide range of functions and physiology and metabolism and my lab has done a lot of studying on them.
Nick Jikomes 19:31
I see So is that why they're found in so many supplements that athletes uptake is because they are especially associated with muscle,
Dudley Lamming 19:38
especially associated with muscle? You know, whether they are actually that beneficial in various contexts is sort of a separate question.
Nick Jikomes 19:47
I see. And so what I mean what are some of the other examples of specific proteins whose synthesis requires some of these branched chain amino acids? Is it just like literally like the skeletal muscle components?
Dudley Lamming 20:00
Um, I think, you know, for the most part, any protein is going to require all 20 amino acids. And so, you know, you're, you're definitely going to have some proteins that contain more one and some that contain more of another. It tends to be I believe that, you know, a lot of, of proteins that are involved in skeletal muscle fibers and strength, tend to be leucine, or other branched chain amino acids. But, you know, pretty much all proteins require all the amino acids.
Nick Jikomes 20:30
I see. And so you've done some research that has to do with these branched chain amino acids, either, you know, having a diet that's pretty rich in them, or actually decreasing them in the diet, in the case of rodents, at least. And so what what is the basic sort of takeaways that you've learned in terms of the amount of branched chain amino acids in the diet and how that affects metabolic health?
Dudley Lamming 20:51
Sure, I think we've probably stepped back a little bit to dietary protein. And so when you think about protein, right, you know, protein is generally thought of as being beneficial for people. And, you know, this is this is for a couple of reasons, right? One is that there's this association of protein as something that helps your muscles grow, particularly when you're exercising. It's why lots of athletes take either protein supplements or branched chain amino acid supplements. And secondly, you know, when you think about the major components of the diet, you know, we've had fats that we've been talking about, as being bad for you for many years now. And more recently, you know, for the last 20 years or so, there's been this focus on carbohydrates, particularly maybe the refined sugars, the various types as being detrimental for health in terms of driving obesity and diabetes. For one thing, carbohydrates are insulin, insulin, oh, genic, right, they stimulate insulin early. So if you believe that insulin drops, obesity them, there's sort of a direct causal link there. And so when you eat more protein, you crowd out these other calories. And protein also helps you keep feel full, promotes satiety. And so you might eat less if you're eating a very high protein diet. So generally, there's a misconception that protein is beneficial. And, you know, I like to joke when I'm talking about these types of things that, you know, here, I'm here to like ruin protein for you, too, right. And so what it turns out that when you look at epidemiological studies of people eating dietary protein and other other meals just naturally, you know, the studies are very difficult to do accurately. I think that because people have a lot of trouble writing down what they're eating or recalling what they ate, or even recording in certain real time. But the advantage of them is that they can look at people over a very long period of time and use really large numbers of big populations. And so several of these studies have all come to basically the same conclusion, which is that the more protein that you eat, the more age related diseases you're subjected to. And so your rates of cancer might be higher, your rate of mortality might be higher, if you're under the age of 65, over the age of 65, maybe not. And diabetes is sort of a strongest signal. So people who eat more protein tend to have a higher rate of diabetes, and people who eat less protein, even adjusting for things like body mass index, and everything else that you can think of. And so working with Luigi Fontana, who at the time was at Washington University in St. Louis, he placed people on either a their normal control diet or randomized them to a protein restricted diet that was spent in the hospital cafeteria. So same issue, you know, these are these people, we know exactly what they ate, but their foods are being changed completely, right. Because when you switch from a normal diet where people are eating, you know, burgers and fries to a diet, where they're eating a low protein diet, they're probably you know, eating fish and lagoons and so on. But overall, the people were eating a low protein diet, they lost weight over six weeks. And about half of that was some fat mass. So this wasn't just, you know, changes in muscle mass or water weight, and their fasting blood glucose levels went down to, and actually they're eating more calories, they about 10% more calories than they did at baseline. So they're eating more food, but they're losing weight. And so that's really interesting. Those findings have been reproduced in a population of type two diabetics. Now on a study that came out earlier this year, same general idea, except it seemed even better. Those studies also showed that the protein restricted group had a significant improvement in insulin sensitivity along with some of their other changes. So dietary protein, you know, might be beneficial to reduce this might have effects on all sorts of different age related diseases, particularly ones related to diabetes and glucose metabolism, but maybe mortality as well. And so we want to study this in a mouse. And so there are lots of reasons to study things in mice. You know, one of the things that we can do is we can track exactly what they're eating And we control the composition of their food very precisely. And we can also do lots of tests and study them over a longer period of time, then you can a person on a diet study.
So what did we find? We found that basically dietary protein restriction in mice is very beneficial. And so we weren't the only ones to see this, a couple other groups have been working on those before us and at the same time. But generally speaking, mice that are placed on a lower protein diet, tend to have improve fasting blood glucose levels, they tend to be leaner, they tend to be more insulin sensitive, or glucose tolerant. And overall, they even live longer. And so protein restriction seems to extend lifespan in one of our studied by about 30% in male mice. And so protein restriction overall seems to be beneficial. Since our wrapping this back around to your question about branched chain amino acids, branched chain amino acids are source of one of the important components of dietary protein. And we took the approach to that maybe the reason that low protein diets were beneficial for mice is that they have lower levels of specific amino acids. And one of the reasons that we looked at the branched chain amino acids is that they've been known to be sort of metabolically interesting for a long time. Back in the 1960s, it was shown that they're elevated and people who were obese, subsequently, it was shown their elevated diabetic people and diabetic rodents of various types. And in fact, they've sort of fluctuate with weight as well. So interventions that causes animals to lose weight typically was lower branching amino acid levels. And our protein restricted people that we looked at with Huiji. Fontana, we saw that in the people that were placed on a protein restricted diet, three amino acids changes in their blood. And those were the three branched chain amino acids, while the levels of the other amino acids were essentially unchanged. So
Nick Jikomes 27:04
I'm just gonna say, Have you done the experiment where you take protein restricted mice, and you selectively increase just the branched chain amino acids in them.
Dudley Lamming 27:17
Um, we have, but that's well down the line if you want to, okay, want to start. So um, so we thought the branched chain amino acids would be fun to look at in mice. And so to sort of wrap up quickly, if you restrict just the branched chain amino acids, mice, and we control for everything else, so we keep the carbohydrates the same, we keep the fats the same, we keep the nitrogen contents of the food the same by increasing non essential amino acids, or proportionally, the diets are matched in calories. But what do we get, we get mice that are leaner, we get mice that are more glucose tolerant, they seem to have improvements in probably hepatic insulin sensitivity, so their liver seems to be more insulin sensitive. And the mice live longer, at least if they're male. So branched chain amino acid restriction extends alone extends male lifespan by about 30%. Females doesn't do anything to the Middle Eastern Bloc, six mice. And that's something that we're trying to understand why that is. I'm moving towards, you know, people are always worried about frailty, particularly here, we're talking about reducing a protein that's normally associated skeletal muscle. If anything, our branched chain amino acid restricted mice are sort of just as strong, and they tend to get less frail as they age. So both mice and people tend to get frail as they age, and we can slow that, at least in those mice. And then in our more recent set of experiments, we sort of focus in on one of these amino acids and sort of the most important and that's isoleucine. And so restricting isoleucine, alone recapitulates most of the beneficial metabolic effects of branched chain amino acid restriction in mice. And answer to your question, yes, if we take a have a protein restricted mice, and we add back, either all three BCAAs, or isoleucine, we can essentially block all or most of the benefits of a protein restricted diet.
Nick Jikomes 29:08
So so the effects that you've seen from protein restriction generally seem to be due to just the small number of branched chain amino acids, mostly, at least in the things that you've looked at. Do you guys have any idea yet of why that is? Like, what is isoleucine? Specifically doing that makes it have such an outsized effect compared to other amino acids?
Dudley Lamming 29:29
Well, it's an interesting question. So the first thing I would say is we've looked at all of the essential amino acids at this point. And we think that the most interesting are isoleucine, vailian and histidine, which is not a branched chain amino acid. And so it seems like isoleucine and availing control a lot of effects on body composition and glucose metabolism. isoleucine In fact, in humans, the amount of isoleucine your diet correlates with your BMI. And a study that we did in people here in Wisconsin, and another group did sort of machine learning approach to try and identify factors in the blood that predict mortality risk. And in fact, the more isoleucine in your blood in that study, the greater your mortality risk. And so there definitely seems to be some human relevance seems to be some human relevance to histidine as well. histidine seems to only control body composition, not really glucose metabolism, which is kind of interesting, might be sex specific in mice as well. We're not sure about that. And, again, in humans, it seems to correlate with Body Mass Index pretty strongly. And then we and a few other groups have linked to baleen as you know, potentially being the sort of interesting, particularly an obese mice, you know how far we don't know exactly how far that goes. So those seem to be most metabolically interesting in our hands. As to why those two or three as you know, sort of something that's a little bit up in the air, we know that some of the effects of isoleucine restrict Charon, are driven by a hormone called FGF 21, which is conserved from mice to humans, and is induced by a number of different nutrient environmental stresses, including a low level of isoleucine and the diet. But it's also induced by protein restriction and deuced by cold, and seems to be involved in energy expenditure and sort of ramping up metabolism, when you're cold or one specific nutrients are missing.
Nick Jikomes 31:31
I see. And so, you know, one thing I want to dwell on for just a second is that, you know, I think a lot of people just have this very, very simplistic cartoon model of macronutrients in their mind where they think, Oh, if I eat more fat, I will get fatter, if I eat more protein, I will get more muscular, vice versa. But it sounds like what you're saying is, that's definitely not true, because you can actually decrease protein intake, in particular some of these essential amino acids. And that will actually decrease your fat level. So it's not the simple fatty equals fat protein equals muscle type of equation.
Dudley Lamming 32:05
I should also throw in here, there's a couple other issues. So one is we find that some of these effects vary by genetic background. So the gene exact genotype of the animal seems to matter. Probably, that's true in people as well. And we think that exercise and activity level also matters. So you know, most of the population is overweight or obese, we can assume that, you know, most of the population is not exercising very much, probably, they're a good match for a lot of the mouse studies that we're doing. But we started doing some studies with exercise now as well. And so, you know, I can tell you right off the bat, right? If you are eating a high protein diet, and you're sedentary and you're a mouse, you get fat. And, you know, Exercise seems to eliminate some of those effects, maybe those mice are building more skeletal muscle. So there seems to be a number of different factors that are interacting with the macronutrients in the diet to determine what, you know, the ultimate outcome is.
Nick Jikomes 33:06
Yeah, no, I was going to ask you about exercise and lifestyle, because, you know, in these correlations that you've looked at in human populations, I would presume, but I'd love to know more about like, you know, you mentioned that there was this change in insulin sensitivity that it improved in people who are already diabetic or insulin resistant. In when you look at all these things in humans, what kind of populations you typically look at, is it random sample, the population is it tend to be people that already have certain metabolic disorders, you look at people based on like, how active they are.
Dudley Lamming 33:39
In our initial study, the people were men and about 53 and tended to be a little bit overweight, wasn't originally focused on metabolic outcomes. But I will tell you that there has been two small clinical trials of branched chain amino acid restriction in Europe over the past few years. And one of those looked at people who were sort of in normal good health and the other diabetics, and in both of those populations, branched chain amino acid restriction seemed to improve insulin sensitivity in the course of just a couple of weeks. So this probably applies more generally to, you know, the population overall. But, you know, the population overall is probably pretty sedentary to.
Nick Jikomes 34:24
I see. I see. So yeah, that's, that's something I guess we have to be careful of. And you basically said that in the typical mouse in a mouse study, you would consider these to be relatively sedentary mice compared to like wild mice or mice that specifically get access to like exercise wheels and stuff, is that what we should assume for most mouse studies?
Dudley Lamming 34:43
Um, wild mice have probably had their own issues, but I would say that yes, you know, these mice don't have free access to a running wheel all the time. And you know, if they did, right, they'd probably be thinner, because they'd be running all the time. You know, and same, same with the human. You know, if you got to running well in your office, maybe you do, you know, they probably get more exercise.
Nick Jikomes 35:05
Interesting. Interesting. Okay, so what are so there's a an interesting question I want to ask around the effects of this protein restriction protocol. So it has positive metabolic effects in terms of things like glucose homeostasis, insulin resistance, you said that it actually produces quite remarkable changes to lifespan increases lifespan is, is that generally true of healthspan? To what is this distinction between healthspan and lifespan? And do both of those things tend to go go together? Well,
Dudley Lamming 35:37
healthspan. And humans are sort of associated with the idea of, you know, a lack of frailty, I would say, right, we think of a healthy person as sort of eight who's older, as someone who's capable of living independently can carry on activities of daily living, leave the house, get groceries, get dressed, et cetera, right. And so you know, we can't measure those things directly and a mouse in the same way. Susan Hallett and kind of rock Wood, who are Dalhousie University in Canada came up with this clinical frailty index for mice that sort of matches what's on use clinically, and people as well. And so we could score the animals on a variety of measurements based on how they look how they walk, how they are reflexes react. And we can figure out whether or not these mice are frail. And it's sort of a quantitative way of something that you can see in any animal, right, I ensure that many people have seen frail dogs walking around on the street. And of course, we know that frailty looks like a person. So we measure that are animals, and if anything, they're less frail, on a low protein or low branched amino acid restricted diet. There might be some subtleties, we're trying to see what age of these diets need to be initiated at in order to get these benefits. And in particular, there's a lot of human data that suggests that people who are older might have different protein needs than people who are younger, and so that the elderly might need higher protein diets, particularly for sarcopenia. So that could be sort of another complicating factor that needs to be worked out.
Nick Jikomes 37:22
And you mentioned that you've you've seen some sex differences in mice, Have you have you started to work out exactly why you see those differences? And do we expect? Or do we also see that in humans,
Dudley Lamming 37:34
to the extent that we've been able to look at our human data, there's a in terms of how amino acids correlate with body mass body mass index, there is not a sex effect. So that's kind of interesting. In mice, there's definitely metabolic effects in both sexes, but the effects on aging and aging related phenotypes are always much stronger in males. We don't know why that is. We do know that in our branched chain amino acid restricted studies, we looked at the activity of a protein called mTOR. And so mTOR kinase activity is associated with all sorts of anabolic processes. It's stimulated by amino acids and less protein. And it's lower when we restrict dietary protein. So when we restricted dietary branched chain amino acids, we saw that mTOR activity was down in the male mice that live longer, but not down in the female lines that didn't live longer. And so there's a correlation there with mTOR activity and longevity. Whether that drives these effects or not, we don't know, we also don't know why it is that the females don't have a change and mTOR activity are a response to lower levels of protein. You know, one of the things that we have seen in males, and Jay Mitchell's laboratory also serves on male mice. And so there seems to be a different threshold effect. And so sort of above nine or 10% of calories coming from protein, you're in a sort of non protein restricted zone, and below that you're in a protein restricted zone. And it doesn't seem to matter exactly how little protein you have, at least from the perspective and using this program.
Nick Jikomes 39:13
And when you do protein restriction, or caloric restriction generally, is that are you typically doing experiments where you're restricting the amount of calories or the amount of protein in the diet? Or are you also restricting when the animals have access to food,
Dudley Lamming 39:30
we give them ad libitum free access to food with less protein in it, and so their calorie consumption goes up. So they are actually eating more fat and more sugar. And they actually have to burn off extra energy in the form of heat in order to remain lean. And so energy expenditure is much higher and those animals are their basal metabolic rate is ramped up and trying to understand what actually mediates that has also served something that's I think, quite interesting. Um, but yeah, we haven't done I'm done too much limiting time of day we did a we did a little bit of an experiment there. I think overall, the results were pretty small in terms of time of day effects.
Nick Jikomes 40:12
And how do you start to think about, like, how you interpret mouse studies on metabolism aging, in terms of how they can translate to humans? So like, do you think of my like, obviously, my opinions are different, and we have a lot of differences between us. But I guess we're both sort of similar in the sense that right, we're sort of opportunistic, omnivorous animals, we're not pure carnivores are herbivores. How do you start to think about how, like, similar a mouse is in terms of its general metabolism and like digestive structure, and how that influences how we can maybe think about translating the mouse work to humans.
Dudley Lamming 40:49
So obviously, there's a lot of similarities between mice and humans, sort of all between all living things, my kids on National Geographic book says that we share 50% of our gene movement banana. So, you know, there's definitely a lot of similar cellular metabolic processes are going on. But you're totally right, you know, mice are not very little humans. You know, they're, they're completely different in a variety of ways. But that said, you know, they have lifespan, they have a certain lifespan, we can measure that they seem to have a lot of the same sort of age related deficits that humans do. When they eat a diet that is unhealthy for us, they become unhealthy. When they are on a diet that seems to be healthy for us, typically, they respond in a healthy way. And many drugs and medications work the same, and mice and humans, so we can't necessarily assume that they're going to respond the same way. But overall, it seems like they're a decent model for humans. And it seems like they're decent models for human response to protein, branched chain amino acids, based on the concordance of our experimental data in mice, and a little bit of experimental data and a lot of observational data and people. But there could certainly be differences that matter in terms of translating things, results.
Nick Jikomes 42:09
And, you know, how do we I want to start to ask you some general questions about like, how we assess and measure and determine when a healthy is relative, when a diet is relatively healthy versus relatively unhealthy, and what goes into that. So, you know, other than, you know, like, like, if you give up if you give an animal, a high fat diet, or something that is supposed to resemble an American or Western diet, or you give it this protein restricted diet, how do you determine exactly whether or not that's healthy or not, is it because you're also measuring all these other markers like glucose, you know, resting glucose levels and insulin sensitivity, and you're using those things to determine whether or not something's healthy or not.
Dudley Lamming 42:50
I mean, that's typically sort of what we go with, although, you know, labs, they're more focused on cardiology, you know, I would also notice that, you know, when you feed my serve a Western High fat high super diet that contains cholesterol, that they do become hyperlipidemic have high levels of triglycerides have high levels of fat. If we use modified mice that are a little bit more like humans in terms of their cardiovascular system, we can see athletes sclerotic plaques form when we feed them these diets, and then, you know, not form when we feed them a diet that's healthier. I think the same is true for lots of different systems as well, you know, certainly an unhealthy diet, a variety of ways is going to be deleterious for the heart, it's going to be deleterious for the kidney, and so on.
Nick Jikomes 43:38
So what would be an example of one of the healthiest diets? What what is the composition of one of the healthiest diets that you can give just a regular lab mouse? What does that diet look like?
Dudley Lamming 43:50
Um, that's an interesting question. I mean, you know, from the perspective of the actual healthiest diet, right, the actual healthiest diet is probably still sort of the gold standard, which is calorie restricted diet, and a diet where, you know, they are mostly eating less, rather than eating a sort of something that's slightly different in terms of its macronutrient content. But in terms of, you know, sort of standard diets, I'd say, a diet that in particular, is probably not too high in protein, and, you know, probably overall is relatively energy dilute. So that, you know, not that they're eating all the time. But, you know, when as they're eating, they sort of feel full, not very calorie dense.
Nick Jikomes 44:34
I see. And is there doesn't matter how much doesn't matter. So let's say that your calorie restricted, or you're giving a mouse a calorie restricted diet, how much does you know how much is it the total amount of calorie restriction per se? How much of it is like, you know, if you if you just cut the calories are consuming by 20% per day, and you just do that every single day, versus you cut the same amount, but you put that all into a 24 Read our window where they're not eating, how much do those factors start to matter.
Dudley Lamming 45:04
So that goes into some of our more recent work. But you know, overall, this is something that people have played with for a long time. So, you know, typically we think of calorie restriction in a mouse as mice, they're being fed once a day. And those animals, regardless of whether they're restricted, 20%, or 40%, tend to eat all their food in a couple of hours, they don't have very much restraint, they'll, you know, they see the food in front of them, they eat it, and then they will fast the rest of the rest of the time. But people have actually played with a variety of different regimens. And animals in, for instance, at least one started young, feeding mice every other day, so that they just eat, we get to then essentially normal meal one day and then skip the meal the next day, is very effective at extending lifespan. And there are other regimens as well. And people who did calorie restriction, you know, typically would eat sort of two or three meals a day, and they're sort of spaced out. Nowadays, I understand that, that might be coming less true that people are more focusing on you know, being like a mouse and sort of eating just one meal a day. But we don't know that either of those is beneficial or not, per se, although there's a lot of data that suggests that compressing your feeding window in general and both people and mindset is beneficial. Such and panas work in particular has a look at what happens when a mouse or in some clinical trials people, you know, sort of a westernized diet, but confining amount of time that they eat too. And so mice that confine their Western diet feeding to a 12 hour period tend to be very healthy, and not gain a lot of extra weight, whereas those they're eating, or have food access around the clock, not so healthy. But in our sort of our studies, we've actually found that this fasting period is very important to the benefits of calorie restriction. And so the graduate student who did this work, AIPAC was focused on trying to understand how feeding rhythm in particular was sort of related to health. And so she put mice on regimens where they either were eating a calorie restricted diet, a normal diet, and or sorry, a normal calorie restricted diet, where they're just fed once a day, and they eat their fruit in a couple hours, or a diluted diet, which was very energy dense, and in fact, had a lot of cellulose content far higher than you'd normally find in any diet. And these mice, even though they sort of ate around the clock whenever they felt hungry, you know, those mice actually work calorie restricted as well by about the same amount as our calorie restricted mice. And what was really interesting was that mice are eating this energy dilute diets are eating around the clock, they ate 30% less calories, but they didn't get the benefits of the calorie restricted diet. They did become more glucose tolerant, but they weren't more insulin sensitive, they'd actually tended to be on the insulin resistance side of the spectrum. And they didn't live longer either. They actually had a shorter lifespan about 9% shorter than mice that were just eating a normal Chow. And so definitely, we think that fasting periods very important, and some follow up experiments, she found that if you take mice and train them to eat their entire days worth of food at about two or three hours, those mice metabolically are very healthy, they look very similar to calorie restricted mice, even though they're not calorie restricted, they're just eating all their food at a very rapid period of time. So, you know, parents who say don't rush your food might not be so all that correct.
Nick Jikomes 48:43
What, um, what have been the most effective dietary strategies and humans who are insulin resistant or diabetic and improving their insulin sensitivity? Does calorie restriction work similar to dozen mice, just changing the diet without restricting calories work at all.
Dudley Lamming 49:00
I mean, you may be aware of it some of the more recent work and a Type field of type two diabetes has been concentrated on the fact that, contrary to what people have thought for a long time, that type two diabetes is reversible and about 30 to 60% of people. And basically, that is reversible by severe calorie restriction. And people are placed on very, very heavily modified diets where they cut a lot of calories. And if they can lose about, roughly speaking, I think about eight to 10% of their excess body weight. Typically, you know, a majority of those people will either you know, need less medication or go back to having normal glucose metabolism. And as far as we know, if those people can then keep the weight off, which is its own struggle, right, a lot of people put weight back on, but if they can keep the weight off, then they will remain in remission from type two diabetes for the rest of their life. This seems to only apply To people who are sort of newly diagnosed, the longer that people have been diabetic, the less well, this type of dietary intervention works, probably because fewer fewer beta cells or B, A could be rescued.
Nick Jikomes 50:12
I see. So, type two diabetes can be reversible and a fairly substantial percentage of people with type two diabetes, that tends to be people who've not had it for that long. And I guess the idea here is, the longer you've had type two diabetes, the longer your beta cells in your pancreas have been defective, and their ability to produce and release insulin, and at some point, maybe that just becomes irreversible.
Dudley Lamming 50:36
And I mean, the the beta cells will die. And in fact, you do see a loss of total beta cell mass in addition to progressive dysfunction.
Nick Jikomes 50:45
Why do they actually, why do they die,
Dudley Lamming 50:47
um, that my colleagues here study beta cell, so I won't, you know, try and try and explain that, for the risk of saying something wrong. But I think there are a lot, a lot of reasons that that might be, I think some cytokines that are released in response to inflammation and obesity contribute to that, as well as the incredible stress producing a ton of insulin. So beta cells actually do some of the hardest work in the body in terms of the sheer number of molecules of insulin that they pump out every minute after you eat something that has sugar in it.
Nick Jikomes 51:24
So back on the topic of like, how we assess the, the level of healthiness that we assigned to a given diet, one of the things that I think is super interesting, and you talked about this a little bit in one of your review papers, is that on the one hand, you know, in the Western world, generally, we see things trending in the wrong direction in terms of metabolic health. So you cite in one of your papers that, you know, obesity has tripled in men and doubled in women's since the mid 70s 43%, of Americans between the ages of 40 and 59 are now obese as of about 2016. We're seeing obesity in younger and younger individuals over time. So something like 40% of children are now overweight or obese. And so all of those things are getting worse, those numbers are going up. And yet there's this thing called the Healthy Eating index. And that's been flat, or even improving in recent years. So there's kind of like this mismatch where apparently we're eating healthier, or at least not eating worse, according to some of these indices. But we're in worse metabolic health. So how do you start to think about making sense of that? And what goes into some of these measures for what healthy diets are for humans?
Dudley Lamming 52:33
Well, I would say, you know, one thing is that all of these are age associated conditions, right? And so, you know, you mentioned that and came up with the analogy, right? That, you know, the longer you have diabetes, the worse your beta cells are going to do, they'll die, they'll become more dysfunctional, and so on. I think the same is true from the perspective of insulin resistance and developing diabetes in general, you know, if you are pre diabetic, sooner, when a younger age, I think you have more time as you get older, for age related changes in your body to cause your beta cells to become more susceptible. And we've studied that a little bit about how beta cells, particularly in humans become more dysfunctional, as you age. And so, um, you know, I think some of that may be due just to the aging of the population overall, which has been going on and you know, this country as well as around the world, there are more older people, and so there's going to be a higher rate of obesity, because people have more time to get fat as they get older, there's going to be an increased rate of diabetes, as people are insulin resistant for longer and eventually develop pre diabetes and diabetes. There may be other considerations too. You know, one thing is, it's very difficult to measure what people are eating. And so, you know, I'm not familiar with the details of the, of how the Healthy Eating index is generated. But I would say that, you know, it's notorious, it's difficult to track exactly what people are eating,
Nick Jikomes 54:07
obviously. And so you mentioned that you have at least one kid right? Yes. So you have two kids. So based on like, your background, and everything that you've learned about metabolism, what are some, like the general rules that you use when you are helping them determine their diet?
Dudley Lamming 54:26
For the most part, they are, their their issue is eating enough? And, you know, that's certainly I think, an issue that lots of parents have in terms of making sure that you know, both they eat enough and that they don't eat too much junk food on the other side, right? And so of course, they you know, are always getting, you know, vegetables and so on. And, but they also, you know, and they eat a lot of fruit, so, you know, that's beneficial too, I think. But they you know, also hot dogs and pizza and On so, you know, sort of standard kids food?
Nick Jikomes 55:03
I see. So it's really difficult.
Dudley Lamming 55:07
I think I think everybody knows, who knows that, you know, kids that and kids go through lots of phases. heard lots of stories, you know about kids who only eat one, one or two things for years at a time, and I'm glad we don't have that particular issue.
Nick Jikomes 55:23
Yeah, and when you do. So one thing that I'm thinking about too, is, when you do rodent studies, when you work with mice, typically, you know, I used to work with mice, and we used to give them Chow, which is basically just mouse food, which I guess people can analogize to just pet food or something. So it basically it's not a bright, you wouldn't call that a whole food. It's not like we're, you know, plucking food from nature and putting it in the cage, it's a processed form of food, do you think that affects the outcome of these experiments at all, like the way this mouse Chow is constructed? Or do you think that's probably not a major factor?
Dudley Lamming 55:58
I mean, you know, it's a, it's a limiting and non limiting issue at the same time, right? We typically don't use Chow for our amino acid studies, we use diets that are similar to chow in which are built from the individual amino acids sort of being mixed together in a big vat with, you know, different types of fat and sugar. And then, you know, all processed up probably very similar to, you know, a very hot, very highly processed human food. So, definitely, that might have some health effects on its own. And we control for that, you know, using control diets while we modify different amino acid levels. But absolutely, I think the you know, it does have, it does have issues. And same thing with Chow. You know, there's some other disadvantages with Chow as well is that they're seasonal variations in terms of what goes into it. That's an advantage that we don't have with our amino acid defined diets, where we don't mean we build it exactly. So rarely have seasonal issues. But there's definitely issues with all of these things. On the other hand, you know, the flip side, of course, is that we know exactly what they're eating. And so, you know, and we can control very precisely, which is something that is not possible with food. And, you know, even if, in sort of a, you know, gold standard. Now, I think, for human feeding studies that people take pictures of their plates before and after the meal. And so, you know, you can use a computer or person to figure out exactly what percentage of the food that they ate, and so on. But, you know, there's probably still going to be variation between each egg and the each piece of meat, each vegetable in terms of exactly what its calorie content and nutrient content is going to be. So there's downsides to doing these studies, natural foods, too.
Nick Jikomes 57:50
Yeah. And another thing that I thought was interesting that you mentioned in a couple spots was that you see things like differences between males and females in terms of the effects of protein restriction on their metabolic health, you see differences in metabolic health based on the genetic background of the animals you're working with. And all this stuff makes sense, right? It makes intuitive sense that men and women would on average, metabolize things in somewhat different ways. It makes sense that there's going to be genetic variation in aspects of metabolism that are going to affect how you utilize carbs versus fats versus proteins. I think also, just right, in our day to day lives, we can clearly see that people have different metabolisms, broadly speaking. So what is some of the stuff start to say about the idea of, you know, personalized diets and personalized recommendations and how people can start to figure out from themselves, like whether or not they should be on one diet for versus another? If there's not a one size fits all sort of diet? That's the best for everyone?
Dudley Lamming 58:49
Yeah, I think that's very important. That is, you know, and something that's a field of both nutrition and aging is sort of coming around to this idea of personalized food as medicine or personalized Jerry nutrascience, as Kenny little Sam Hancock goodbye, have sort of dubbed it. But, you know, in terms of our our sort of work in the lab, you know, I think this really highlights the need to, you know, not just study things in one strain and one sex. And so we're having a lot of fun in the lab right now, looking at a panel of genetically inbred mouse strains, each with its own genotype, and sort of figuring out how those strains respond to dietary protein and other amino acids. And so for instance, I can tell you, you know, low protein diet, on average, about 80% of the strain Myo strains that we look at, have about have a reduction and body weight and adiposity when we feed them a low protein diet, but there's, you know, about 20%, where it actually goes in the other direction, and isn't that in and those genotypes It's not only vary among themselves, but the same genotypes don't respond the same way between males and females all the time. And so there's definitely both sex and strain variation, we're hoping to identify genetic variants that might mediate these effects, both to better understand the mechanisms of what's happening, and also to, you know, ask whether those genes in the future might regulate what there's human responses. So can we identify the people who are going to respond very well to a low protein diet? Are there people who would respond better to a high protein diet or keto diet or Mediterranean diet or Palaeolithic diet? And so on? So I think, you know, there's a lot of possibilities there. And I think, although I don't, technically, you know, I'm not aware of a study that's actually looked at this, and it's totally possible. My own intuitive, you know, belief is that people are bad at adhering to diets, but they're probably good at adhering diets are better than hearings, diets, they actually work if they see a difference, right. And so, you know, if we could find that people are going to really respond well to a low protein diet, put them on a low protein diet, and they, you know, very rapidly become metabolically healthier, they're probably going to follow that. And, you know, maybe we can bind personalized diets for other people, too, as well.
Nick Jikomes 1:01:18
And, you know, in the lab, obviously, you guys are very well equipped, equipped to go into the mouse cage, grab the mouse, do your glucose homeostasis tests, and your insulin sensitivity tests and all that stuff. Are there easy ways for the average person to get some indication of those things in themselves? Do they have to go to the doctor to do it? Are there are there things that they can do at home to measure that now?
Dudley Lamming 1:01:42
Well, I mean, you know, certainly type two diabetics use blood glucose monitors all the time, both the sort of traditional fingerprint ones, as well as now continuous glucose monitors, I'm certainly aware that there seems to be a growing number of people who are paying out of pocket to do sort of continuous glucose monitoring at home. And, you know, I, you know, some of those people think that it's very useful for them, and I'm certainly not going to, you know, disagree with it, I think it means remains to be seen whether this is something that really is useful for for most of the population in terms of identifying various factors, at least, and, you know, at least as it regards to the fact that there are genetic causes, right, I think that, you know, in the future, there might be a room for a dietitian to just sequence your genome, right. And, you know, this is something that's come down and cost very rapidly, I think, for the next generation of machines predicted to give something like a 100 to $200, you know, and, you know, certainly that might be in the range of something that, you know, insurance would cover, or a lot of people who are very interested in their dietary health might cover.
Nick Jikomes 1:02:58
Interesting. So what are some of the major questions that your lab is pursuing right now that you think are going to be really interesting?
Dudley Lamming 1:03:06
We're really interested in studying the effect of the individual amino acids on lifespan and trying to understand what the mechanisms of those might be. We're testing a couple of different candidate mechanisms, including FGF 21, that's hormone that seems to be abused by protein restrict gentle, and waterbath strains, but not all of them by by dietary protein restriction, and also isn't used in humans by protein restriction. And then we're doing quite a bit of work on genetic mapping, trying to understand, sir, from a systems biology approach, what alleles and areas of the genomes of a mice might contribute just to these effects. Definitely, we're starting to look at some low sigh. They're becoming statistically significant as we put in more strains, and we're hoping that we'll be able to start focusing on that pretty soon. And a number of projects in the lab are focusing on Alzheimer's disease and looking at how dietary protein and calorie restriction might be used as interventions for that disease.
Nick Jikomes 1:04:09
Is there is there some indication that things like dietary restriction and calorie restriction are going to be beneficial for neurodegenerative diseases like Alzheimer's?
Dudley Lamming 1:04:18
There's a lot of data in mouse models of Alzheimer's disease. All of these models have limitations. So you know whether they accurately model by human diseases, I think something that's heavily disputed, but there are non human primates that sort of spontaneously develop Alzheimer's disease as well. And calorie restriction has been shown to be beneficial in terms of reducing the incidence and maybe severity of Alzheimer's disease, as well. Certainly the flip side is true in humans, we know that humans who who are obese or diabetic have a higher risk of developing Alzheimer's disease. And so there definitely seems to be that same sort of correlation between metabolic health insulin sensitivity how much food is going to seems and the risk of Alzheimer's disease. And certainly the preliminary data from our lab is sort of encouraging, at least in a very limited number of mouse models that there might be some benefit.
Nick Jikomes 1:05:11
Well, Professor lambing, I want to thank you for your time. This is a topic, you know, general area metabolism that I think is very fascinating. It's obviously very relevant to people and their health. It's also super complicated. And there's just always a lot to chew on here. And I think it's really hard for people to grok all of the information that's relevant. Are there any sort of major takeaways or pieces of advice you want to give to people in terms of how they can best, best preserve their metabolic health as they get older?
Dudley Lamming 1:05:40
Um, well, I think, you know, the one thing that seems very clear from both the human and animal studies is that dietary protein is for taking extra dietary protein and eating more diet, dietary protein seems to be not useful for sedentary people who are young. And so, you know, people who are elderly over the age of 65, that might not be the case people are exercising and that's almost certainly not the case. But most people who are sedentary probably shouldn't be focusing on eating a lot of protein or eating a high protein diet.
Nick Jikomes 1:06:17
Excellent. Well, Professor Dudley lambing thank you for your time.
Dudley Lamming 1:06:20
Thank you so much.
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