#324 ‒ Metabolism, energy balance, and aging: How diet, calorie restriction, and macronutrients influence longevity and metabolic health | Eric Ravussin, Ph.D.

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My guest this week is Eric Rabisen. Eric is the Director of the Nutrition Obesity Research center at Louisiana State University's Pennington Biomedical Research center where he also serves as the Douglas L. Gordon Chair in Diabetes and Metabolism. Having published over 600 peer reviewed manuscripts, Eric is regarded as a world expert in obesity, metabolism and aging and has received numerous awards for his contributions to these fields. As discussed at the beginning of this podcast, Eric and I worked together for about four years, roughly 15 years ago, and during that period of time I just came to have such an admiration for Eric, his curiosity and his intellect. When it comes to this field, we talk about Eric's background and his extensive experience in metabolic research. In particular, when it comes to measuring energy expenditure, which turns out to be a very technically demanding problem, we go through the various methods that this has done, including what is today regarded as the gold standard. This of course is necessary because if you want to understand energy balance, you must clearly be able to measure energy expenditure. We of course discuss energy balance, energy expenditure and food intake, how we regulate appetite, and the findings of a very important study that Eric did which look at the impact of manipulating the ratio of macronutrients to see if it would indeed change energy expenditure. Disclosure I was involved in the funding of that study. We then delve into the calorie study which looked at caloric restriction, and discuss its insights as it pertains to the biomarkers of both primary and secondary aging. We speak about the implications of GLP1 agonists and similar drugs in replicating the benefits of caloric restriction and look to the future of this research and see how new technology advancements like AI might come into play. So without further delay Please enjoy my conversation with Dr. Eric Ravison. Well, Eric, thank you so much for joining me. Sorry that we can't be in person, but given that you're in the south of France and I'm over here in Texas, that would have made it pretty difficult because normally we're quite a bit closer. You're obviously in Louisiana. But anyway, it's wonderful to see you again. It has been close to 10 years, right?

I think so. I think so. But I have found memories of our interactions.

Yes, as do I. I guess by way of background, maybe we can even just give people a bit of a sense of how closely we did work together. For four years at the time, I was part of an organization called nusi, and you were one of the six principal investigators for what was a very audacious experiment and part of something called the Energy Balance Consortium, along with Kevin Hall, Steve Smith, Rudy Leibel, Mike Rosenbaum and God, who am I missing? Mark Reitman. And nevertheless, this was a once in a lifetime opportunity to do something that had never been done before, which was a multi center indirect calorimetry inpatient study that was really aimed at trying to at least pilot what would be necessary to do the definitive experiment to answer a question that I'm sure we're going to talk about a lot today which has to do with the nature of calories and weight gain. So I will leave it at that. Only by way of background to say that we had the incredible pleasure of working together and really getting into the weeds of how one technically tries to measure these things and how difficult it is on all of the challenges and potential pitfalls of this. But let's just take a step back and maybe give folks a sense of your life's work and your life's passion. You've been the head of Pennington Biomedical Research for how many years now is it? 20 years?

I have been for 24 years at Pennington. I was associate executive director for Clinical science. I'm not the head of the Pennington. I joined after spending two and a half years at Eli Lilly and before I was 15 years intramural NIH. And the reason I came to this country was to build the first metabolic chamber or indirect calorimetry chamber to measure energy expenditure in people over periods of hours and days.

Tell folks a little bit about what it means to be intramural versus extramural nih. I think when people hear nih, they sort of have a vague sense of what it is, but maybe that distinction isn't clear to most people.

Yeah, the NIH budget is about 33 to 35 billion dollars. But there is a group which is intramural, but most of the money, 80 to 85%, goes to all the academic institutions doing biomedical research in the country. I like to be intramural, just so.

Folks understand what that means. That means you are an employee of the nih, you work at the NIH campus, and your funding comes from the organization that you work for, unlike someone who's at Stanford or Harvard who's receiving extramural NIH funds correctly.

And I was intramural, but based in Phoenix, Arizona, because I worked a lot with the Pima Indians, who have, as you know, the highest prevalence of type 2 diabetes and the second highest prevalence of obesity in the world. But intramural, what I like, you are judged after the facts. You have a budget and you can do whatever you want, but every three years you are judged. Whereas extramural, as you know, we chase these grants and you have to basically provide preliminary data, hypotheses, and you are judged before doing the study. And I think you can be much more creative being intramural than extramural. I'm sure that my colleagues, intramural, are going to hate me that I say that, but it's true. They should enjoy to be judged after the facts rather than before.

So tell us a little bit about Pennington. It's obviously a pretty unique institution. You've been there, as you say, for 24 years, but yet I suspect it's a place that most people listening to us won't necessarily be familiar with.

It's becoming, I think, the largest institution for research in nutrition and obesity. We concentrate mostly on nutrition and obesity. We have about 500 people working at Pennington and everybody is doing research. We have no teaching. I mean, yes, I have postdocs and things like that, but no formal teaching. And we do research and we chase. We have maybe a budget of functional budget of 80 million per year. 50% or 45% of that is NIH extramural money coming to Pennington. We do some sponsored project for pharma or biotech. We have grants from association like the American Diabetes association or American Heart association and so on. And we do basic science, clinical science and population science, basically, which is to reach the community and implement some of the discovery into the community.

Yeah.

So the other thing you mentioned a few minutes ago, Eric, was the words metabolic chamber and indirect calorimetry. And I think at some point, because this is going to come up in our discussion as we get into the weeds on metabolism, it's going to be necessary, I think, for the listener to kind of understand how those techniques work. I know I've discussed this on previous podcasts. There's at least probably half a dozen episodes where I've explained how one uses the ventilation of oxygen and CO2 to quite accurately estimate energy expenditure and substrate utilization. But it can never be a bad thing to explain it one more time. So why don't you explain how it works and you can even use the example of when I was in the chamber for a couple of days 10 years ago when I was out at Pennington as a subject or pretend subject.

Yeah.

There's two things, indirect calorimetry and direct calorimetry. You generate your energy metabolism, or ATP by oxidative process and you oxidize carbohydrate, fat and a little protein. You don't want to oxidize too many proteins. And this basically build up these ATPs which are used online for generation or maintenance of the cells or activity and so on. Now, when you have this metabolism, you produce heat. If you have no exercise, no external work, all the energy which is provided in generating this ATP is lost as heat. And this is direct calorimetry. And I was fortunate when I did my PhD back in Lausanne, Switzerland, to have access to both indirect and direct calorimetry. You can really do fantastic studies. We did a study of measuring in vivo what we call the PO ratio, how many oxygen do you need to generate one, one ATP, and all these kind of things by the combination of these two techniques. Now going to indirect calorimetry, this is an easier one than direct and.

Sorry just to interrupt you for a second, Eric, when you're doing direct calorimetry, obviously when it comes to something like food, if you want to know the energy content of food, you can burn the food and measure the heat when you're doing it otherwise on a living organism. Is it possible to do direct calorimetry on something as large as a human? Or is that something you're typically doing on a mouse or something that is small enough that the chamber in which you can measure changes in heat is much smaller and easier to manage?

No, we can do that in humans. I was fortunate to be at a place which had one of the two direct calorimeter at the time there was one in Bethesda doesn't exist anymore. The one in Switzerland doesn't exist anymore. I wish I had picture to show you, but this is a. Basically, I would say 1.2 meters by 1.2. It's a little bit bigger than a cubic meter box. And you recover all the heat and you have dry heat by convection, and you have a layer gradient layer, capturing the heat production. You collect the evaporative heat losses from perspiration, expiration and so on, and you merge all that and you have a complete heat balance of the person. And we measure these two kinds of heat, and this is basically equal to your metabolic rate. You generate energy by oxidation of substrate, and the byproduct is heat. And with that exercise or external work, energy in is equal, energy out. And this is what we measured. And I did a lot of these studies during my PhD, but then at that time, we decided to build a metabolic chamber, which is like an hotel room in which you can live one day or two days. And I think you stayed for two days in one of these rooms at Pennington in Baton Rouge. And here we measure oxygen consumption and CO2 production. Oxygen is used to oxidize a substrate. It produces CO2 and water. And knowing oxygen consumption, CO2 production, you can calculate the energy expenditure or the energy generated by this oxidative process. And you can also calculate the substrate that you oxidize. If the ratio between the VCO2, the CO2 production and the oxygen consumption is 1, you oxidize carbohydrate. If it's 0.7, you oxidize. Fat and protein is something in between. 0.82, depending on the protein.

Yeah. And so, basically, by measuring just these two things, the actual concentration of oxygen that's being consumed and the rate at which it's being consumed. And the same with production of CO2, you can really infer two things. One, the total energy consumption, total calories consumed, kcals. And by looking at the ratio of the VCO2 and the VO2, you can calculate what fraction of that is coming from oxidizing carbohydrate versus fat. Having spent probably a total of eight days of my life inside metabolic chambers across a period of a couple of years, it never ceases to amaze me, never, just how accurately these rooms work. Because I use an indirect calorimeter all the time, measuring VO2 max. It's basically the exact same technology, but it's easier because you're strapping the mask to your face so you have perfect access to exactly the O2 consumption and the CO2 production. But it's doing the exact same calculation. It's going to tell you exactly how much energy you're utilizing and where the substrate comes from. And, of course, in that situation, you're interested in knowing the maximum amount of VO2 or O2 consumption. So what would you estimate is the error on the hotel room sized indirect calorimeter where you don't have the luxury of just slapping a mask to the person's face for a few days?

Yeah.

When I was at nih, we did a lot of reliability testing in the same person. Or you can calibrate the system. You calibrate the system with standard gas that you know the exact concentration to calibrate the analyzers. But you can also mimic someone by burning alcohol or propane and you can vary the rate of burning. And this is what we did when we did this study with four different chambers. We validated the chambers once against the other one and we accepted to have 3% deviation for CO2 or oxygen based on stoichiometry. You know exactly how much alcohol or propane you burn, you know how much CO2 should be produced and how much oxygen has been consumed. And this is what we did. And you are right, they are very, very precise. And you don't have the inconvenience of the mask. I mean, you couldn't measure with a mask for 24 hours or two days.

Right. Because when I was in that chamber for a couple of days on separate occasions, we were trying to replicate as much as possible my life. So I had three meals prepared, I had an exercise bike, I had weights in there, equipment to do everything. And we were very interested in seeing how that would compare with, for example, what we knew I was experiencing in the outside world based on when we could put a mask on me. And also separately, if you may recall, Eric, we also did spent about 10 days using doubly labeled water, which I'm sure we'll talk about at some point, as well as a more real world example of this. So all of that is to say that scientists such as yourself have some pretty high fidelity tools to measure energy expenditure. But it comes with a caveat, which is it has to be done under this very controlled setting. These people need to be in the hospital, and not just in a hospital, but in a metabolic ward and inside a chamber, which is basically a NASA grade gas chamber. With how many sensors, by the way? Just out of Curiosity, how many O2 and CO2 sensors would be in a particular chamber?

We don't need many because we need to homogenize the air in the room.

And I see, so that's the bigger effect.

So the corner of the room is the same as the other corners. That's why. But we have to measure Humidity, you have to measure temperature because you have to do this correction, what we call stpd, which is standard pressure, et cetera, to calculate the energy generated by this oxygen. But yeah, I mean, it's quite phenomenal, the accuracy of those. And to go back to your question, the accuracy or the precision is about two and a half percent. Now, if you repeat yourself five times or, and myself, there's a little bit more variability because we vary from one day to another one and so on. But I mean, this is quite amazing that we can calculate so precisely your energy expenditure during a day or two days and so on. I wish we had the same system to calculate the energy that we put in.

Yeah, that's a great point. Outside of having food prepared in a metabolic kitchen, which of course was also done for this experience, I think at best we're probably plus or minus 10%. Right. I mean, it's very difficult to estimate.

Energy intake when it's in free living. It's worse when you do that under supervision and you provide all the meals like Kevin hall is doing, like we're doing, then you have a good estimate and you subtract what is returned on the plate or these kind of things. But it's not normal life. As soon as you go to normal life and free living conditions, things are falling apart.

I think that is a really nice intro into kind of a philosophical question that will take us towards some of the experimental work. So I was actually going to launch into the explanation of the energy balance model and talk about the work that you and the other folks that we just talked about did a decade ago. But let's pause for a moment on the statement you just said, which was, look, in the free living environment, we cannot estimate energy intake worth a damn. Which is to say that 99% of people out there who aren't weighing every single morsel of food they eat every single time they open their mouth, which again is virtually nobody, are going to have enormous variability in what they're eating. And so I put myself in that category. Right. I pay no attention to how much I'm eating in terms of weight. I'm just sort of eating by kind of my appetite. Sometimes I overeat too much, my appetite gets the best of me. I'm surrounded by highly palatable foods that I overeat. And other times, you know, I'm just really busy. Like yesterday I just didn't get around to eating that much. But here's what's interesting, Eric. My weight lives within about a two pound variation for years And I don't think I'm unique in that. I would guess that you're pretty similar as well. I think many of us find ourselves in kind of a couple of pounds of variation, most of which is probably water weight varying over years, and yet we're not really paying attention in excruciating detail to how much we eat. So first of all, do you agree with the assessment that that's not an uncommon phenomenon?

Yes. But on the other hand, if you take your lifetime history, maybe you are an exception. But I have gained some weight. When I got married in 1975, I weighed 69 kilos. Now I weigh close to 77. Now it's 50 years later, of course, but you have this change. You have also a change in your body composition. And it's very rare that people are staying the same constantly. I mean, you may be an exception.

No, no, I would not suggest that I'm an exception. I've had probably more variation in my weight than even what you're describing over the period of time. But I guess the question I'm getting at, Eric, is how does the body regulate energy storage, which is effectively what is determining our weight. It's how much are we storing as fat, how much are we storing as lean tissue that seems very, very regulated despite very little control over the input and the output. We're free living animals who live in an environment with endless inputs. So we have to somehow regulate that and frankly, very little reason to do deliberate outputs. Right. Obviously the majority of our energy expenditure is based on essential function of life, just the necessary ATP production as you described it, for cellular function. But it's not like most of us are out there expending energy deliberately, that is exercising and moving necessarily to expend energy. So as we enter this discussion of the energy balance model, let's just talk about energy balance. Why are we so largely able to conserve mass despite very noisy inputs and outputs? Into the black box?

I think I had an answer. I hope that I had an answer, but I don't. You know, when leptin was discovered, it was a ha ha moment. We have a signal which comes from the energy storage and therefore, you know, it seems to regulate food intake, also energy expenditure and all that. I was fortunate to have access to the three Turkish leptin deficient people that we measured in these chambers in Baton Rouge. We thought that we would have a clue and it was not the case. We know that leptin is very good to defend against the loss of weight when it becomes extreme, but it doesn't work on the other side of the equation when you creep up with your weight because you become leptin resistant and your leptin is not telling you stop to eat. I think that we learn a lot about the biology of energy balance thanks to leptin. But then we need to think that we have also signals coming from the fat free mass. Now what is the fat free mass? We measure it as everything but the fat and we call that fat free mass. But it's liver, it's skeletal muscle, it's everything but the fat. And I think that there are signals that we are still chasing. John Blundell showed that we eat according to our fat free mass, which is basically we eat according to our resting metabolic rate, because fat free mass is the major determinant of your resting metabolic rate. But what are the signals? I don't know. I still don't know. We have to be modest here and say there are still things that we don't understand when it comes to this energy balance. Now I can understand that why you don't gain 5kg over this coming year, because in response to creeping up your weight, you burn more energy. If you do the same physical activity, this extra 5 kilos or 10 pounds is going to cost you more energy. Your resting metabolic rate is creeping up and basically you offset that. But why are we so good at maintaining, like you said, within a couple of pound over a year or two years or three years or five years. And I think that we are still missing some signals. But I think that there are signals coming from when FGF 21, which is a signal coming from the liver, was discovered. I said, ah, maybe that it. Or when you have some of the myokines coming from the skeletal muscle. I said, maybe this is it and it's not been it. And I think that we have to be modest and say, hey, we still have things to discover when it comes to this regulation of energy balance. But as a population we have not been very good. I mean from the 1980s to 2010, the American population has gained 10 kilograms. It's 22 pounds in 30 years. It means that there is still the major driver is this environment. And the change in the environment has been the trigger of this weight gain. But of course people, some people are successful, some are less, and this is a problem. And of course now we have an epidemic of obesity. It has replaced the contagious disease of the past. And now we have all this constellation of conditions which are associated with obesity.

Eric, if you were to guess which I think is the best we can do. Although I think it's informed guessing, I don't think we're just guessing in the dark. How much of the regulation do you think is occurring on the appetite side, meaning feedback from whatever is happening in the system. And let's just posit, as you said, that it's coming from the lean part of the system, so the organs, the skeletal muscles, all but the adipose tissue and that that is working to feed into the appetitive system. Or do you think the balance is more on the expenditure system where those signals are feeding to make us move a little bit more? Or simply as you say, it's the extra weight you have to move around if you're going to carry. People should pick up what 10 kilos is. That's an awful lot of weight if you have to carry an extra 10 kilos up a flight of stairs and every time you get up and move around you're going to expend more energy. So do you have a sense of the balance of that regulatory pressure?

Yeah, Peter, When I first joined the nih I did a study in Pima Indians who are very prone to weight gain, as you know. And we measure in 150 people the 24 hour energy expenditure as well as the resting metabolic rate. And we found that there was large variability between people after adjusting for their body size, fat free mass and fat mass. Now we do better because we have organ size and we do MRI and all these kind of things. But there is variability and this variability is associated with family membership. In other words, we can say that there is a genetic background to that. But what we found was that those people in the lower third tile of this metabolic rate adjusted for body size were at much higher risk of gaining weight. But when we tried to attribute the weight gain either to energy expenditure being low or, or the other side of intake being high intake was 80%. It reminds me there are so many system which are basically regulating energy expenditure and food intake. Take nicotine. Nicotine is a stimulant of energy expenditure. Smokers have higher metabolic rate, but they have less appetite. Take the activity of your sympathetic nervous system. It is also thermogenic, but it cut appetite. And I think that we have to understand better these two system. But to answer your question, I would say 80% is on the side of the energy intake.

That's sort of been my intuition as well. But because I don't keep up with this literature nearly as much as I used to, I wanted to make sure that that was still Largely the view of the people at the forefront of this field.

And you know, for example, sorry to interrupt, but we know that exercise is pretty bad for weight loss. If you just tell people, okay, go to the gym three times, or you even do under supervision, people don't lose weight. And Donnelly at University of Kansas has done ton of study like that. And the physical activity for weight loss is a B minus at best in term of evidence that it plays a role.

And let's talk about why, because again, it is counterintuitive. I know this and I preach this to my patients left, right and center, which is, you've probably heard me say, eric, I will go to my grave maintaining, I suspect, until new evidence emerges that exercise is the single most important thing we need to do for health. But I'm always quick to follow that up if asked with, but it's not the tool you're going to use to regulate body weight. Energy intake, nutrition is the more important tool to regulate body weight. And so explain to people why. Perhaps if you could provide a teleologic explanation for why, because it is counterintuitive. If you just look at the human body as a machine, you should have no preference for expenditure of energy versus input of energy. You should say they're equally efficacious. But again, any clinician will tell you that's not true and any scientist will tell you that's not true. But do we have a reason for why it's not true?

I think, first of all, if you try to put calories on your exercise, it's easy on a bicycle. You know the efficiency 25%, you know the workload and so on. And you can calculate, or you can use your mask and measure oxygen consumption. It's very easy like that. And I think that there is a compensation. Now, exercise, very vigorous exercise, is anorectic. You don't want to eat after you finish a marathon, or at least I don't, no.

And by the way, just to interject, I interviewed George Brooks from Berkeley recently and he shared with me on the podcast something I didn't know before, which was that lactate specifically is probably partially driving the anorexia we experience following intense exercise that might not be present with low intensity exercise. So I thought that was an interesting way to connect a fact that I think most people appreciate, which is go off and do interval training. The last thing you want to do for the next hour or so is eat.

But light exercise has the opposite effect. I think it drives a little bit appetite. And I think Tim Church was At Pennington did a study called E Mechanic. And basically they measured every calorie spent on exercise on a treadmill, on a bicycle ergometer and all that. And look at the weight of the people with these different doses of exercise. And there was a compensation. Now, what it didn't measure was to use doubly labeled water. Did they compensate by being less active out of their periods of exercise? You have 90 minutes of exercise, but then, you know, you relax a little bit more rather than fidgeting or moving and so on, or you sleep a little bit longer. This he didn't measure, but there was this compensation with food intake. And I think, first of all, I didn't say that exercise is not good for health.

Right. I didn't suggest you were. I was just making sure people knew the distinction between.

I want to make sure because I'm an aficionado of exercise.

I know you are.

I know how good it is for health.

Yes, yes.

But it's not as good for weight control in general. And I think that you have to do the calculation of how many calories are burned when you run a K or a mile and so on versus how quickly you can ingest the calories, the same amount or much more. And I think that there is a difference here that people understand. But exercise and physical activity is the key for weight loss maintenance. And you know, the weight registry from Rena Wing and Jim Hill, they showed that those who were successful at maintaining the weight loss at five years after the intervention were those who engaged in more physical activity. And I still believe that a nutritional approach to weight loss without physical activity or exercise prescribed is not a good strategy. We should implement both and try to have people enjoying the exercise. Most people, I remember one of my colleague, Richard Bergman, said, I would never exercise. I'd rather be sitting in a cold bathtub to generate some heat rather than exercise. And there are some people who cannot exercise. But I think, again, this is from childhood that you take the taste of exercise, that you become more physically active in the rest of your life. It's not at the age of 40 because you have too much weight that they can tell you, oh, you have to do your 150 minutes per week of moderate to vigorous activity and all that. It doesn't work in general, but I think physical activity is a key point in metabolic health in general.

I agree with that completely. When I look at the data from Jim Hill that you've just cited, I've always found it difficult to infer the direction of causality. And you're correct that the people who are most successful in maintaining weight loss are going to be, on balance, far more likely to be people who do a lot of exercise than those who don't. And so, of course, it could be that doing a lot of exercise is a valuable tool to drive weight maintenance, I. E. Maintenance of energy balance. Alternatively, it could be the people who metabolically get fixed through weight loss are the ones that have an easier time exercising. But I will say this, and I'm curious how robust the data are. I do think one thing that exercise can do for you, and I feel this personally, and I know a lot of my patients do as well, is yes, you could go ride your bike for an hour and you could burn 600 kilocalories and you can eat 600 kilocalories in way less than an hour. But exercise seems to sharpen your appetite to a point that makes you a more responsible eater, if that makes sense. In other words, I think it hones your appetitive signals. And the one thing you as the individual have to do is just be mindful of the speed at which you eat so that you give the brain a moment to recognize what is happening. So let me give you an example of how that works tangibly. If I do a zone 2 bike ride for an hour, again, that's going to be for me. I know because I measure it. I can measure it exactly. That's going to be about 750 to 800kcal is how much energy I will.

Expend above your resting.

No, total total energy expenditure is 750-800kcal in the hour. So call it 800 to make the math about easy. So if I wait an hour before I eat and I don't eat very quickly, I don't do the usual Peter Attia. There's someone who's going to take the plate from me if I don't finish this right away. I won't overeat and I'll be fine for the rest of the day. I won't have a hyperbolic appetite. Conversely, if I go to eat within 20 minutes, 30 minutes, and I pay no attention to the speed at which I eat, I can easily consume a thousand calories in that one sitting and abrogate the entire energy effect of the exercise. Obviously, I'm still getting all the benefits of the exercise. So first of all, curious if you have seen this, if you have any insight into the effect of exercise on how we subsequently regulate appetite and how we might sense the Hunger hormones, everything from leptin, ghrelin and even GLP1.

I don't have an answer to that because it's not my field energy intake. But on the other hand, you just mentioned the GLP1. I think these gut hormones, I mean you take GLP1, GIP, CCK, PY1, glucagon. Glucagon, if you put glucagon in insulin. I was talking about the gut, the GI hormones. Anyway, I think that there is no question, now we start to know more because they are such good targets for weight management, we start to know more about the physiology of these hormones. And I think that there is no question in my mind that the speed at which you deliver this food in the stomach and it leaves the stomach is very important for the kinetic of these gut hormones which are important for the regulation of your food intake in general. I think this is one of the things that these GLP1 and combination of peptides now has shed light on is that they are potent modulators of your intake. Now the interaction between the exercise that you do before and the meal that you have 20 minutes after and the speed of the meal and all that, I don't know this triangle, how it works, but I think it would be a very good topic of research to know the interaction between your physical activity or the bout of exercise, the speed at which you ingest the calories and the delivery of these gut hormones.

And again, to make it an even more interesting experiment, but now much more complicated, you introduce a fourth variable which would be the macronutrient composition of the meal itself at isocaloric substitutions. And maybe that's something we'll talk about now as we go back to the idea of energy balance. So going back to how you and I met and the kind of work that we were interested in, we were interested in a question, very specific question. And I like specific questions because the more specific the question, the easier it is to design an experiment to test it and the more likely you are to get an answer that you can interpret as highly probable. Feel free to modify this, Eric, but I think the question we were trying to ask was under isocaloric conditions, does varying the macronutrient composition, specifically between carbohydrate and fat, while holding protein constant, have any bearing on non deliberate energy expenditure? First of all, would you agree with that statement? And then we can turn it into English. But just scientifically, would you agree that that was the question we were trying to answer?

Yes, it was the question isocaloric is the important word.

That's right.

Because now can you do that in the everyday life under not isocaloric condition, but what you want to eat?

Which, of course, we'll talk about that in spades. But this was a very important question, although truthfully, I think most people felt the answer was known. Well, I guess I should translate what I just said into English and feel free to interject and help me. What we basically said was if you give people a bunch of people meals, let's just not even use a bunch of people. One individual. You take one individual and you feed them meals on subsequent days or weeks or whatever where you don't change the total number of calories one iota, you don't even change the amount of protein, you simply manipulate the ratio of carbohydrate and fat such that obviously when one goes up, the other has to go down, such that you can preserve the total number of calories. And when you feed people meals under those conditions, the null hypothesis should be that their energy expenditure doesn't change. Why would holding a fixed number of calories in to this system change the number of calories that the system expends? Again, it's important that we held protein constant because we know about the thermogenic effect of protein. So that can actually sway things if you change protein a lot. But the alternative hypothesis that was being tested was no, actually, if you really swing fat and carbohydrate a lot, you could indeed change energy expenditure. Would you add anything to the English version of the question?

No, I think it was a question and we were a little bit skeptical. It was the start of the carbohydrate insulin model. We're used to the energy balance model, but I think it was a good question. And I like the way we debated that with the red team, the blue team, if I recall correctly, and we were arguing about the best design and at the end. Now, if I had to redesign this study, I would do it differently.

Tell people how it was done and then tell people what you would do different. Because this is probably an experiment that might be worth redoing under improved conditions. But I'm very curious because I haven't given this much thought, but I'm very curious as to what you would do different. Explain to people how this experiment was done.

The experiment was done to do a isocaloric intake over four weeks. I think we had the baseline diet, which was the SAD diet, the standard American diet, and we had after a low carbohydrate diet or ketogenic diet for Four weeks. And the hypothesis was that, and this was led by the people who have been bringing up the carbohydrate insulin model, saying that you create a basically uptake of these substrate from the blood into the storage, mostly the adipose tissue and maybe some in the liver, and you deplete from substrate or energy substrate your circulation and it puts you in a state of semi starvation. What is happening when it goes to the brain, when you have semi starvation, you shut down your energy expenditure and you increase your appetite. And this was playing with that, saying that now if we switch to a diet which is going to be less conducive to storage, I. E. Less insulin secretion because it was less than 10% carbohydrate, between 5 and 10% if I recall correctly, we would cause this basically this semi starvation condition in the systemic circulation and this would basically increase your energy expenditure. And I think that David Ludwig at the time had some data already showing by doubly labeled water that there was an increase. But we are arguing that doubly labeled water is not precise enough. It goes back to our discussion about indirect calorimetry and we said why don't we do it in the confinement of a metabolic chamber? And this is what we did. And to my surprise, there was an increase at least early because we had couples of. I didn't go back to the papers, but we had measurements every week for two days, if I recall correctly, for the four weeks and the first week and maybe the second week there was an increase which was significantly higher in sleeping metabolic rate as well as 24 hour energy expenditure under the ketogenic diet. And boom, yes, there is an increase. Now was that a significant physiological increase? I mean we can argue about that when we talk about metabolic adaptation because people are talking about that now. We always say we need at least 150 calories. In the study we achieved statistical significance, but it was just above 100 calories per day. And I was surprised myself of that. Now we didn't measure the appetite of the people. I mean, were they less hungry under the ketogenic diet? Now it brings us to all the weight loss studies which have been done either with a low fat diet or low carbohydrate diet. If you do a meta analysis, it seems that there is a slight advantage to the ketogenic diet for the weight loss period. Basically I was surprised and I was, as a Swiss, I was kind of a little bit more neutral sometime rather than the two camps, the red and the blue. I was surprised that there was this effect. But it disappeared at the fourth week or the third and the fourth week.

So again, just to make sure people understand that finding. So the finding, and I'm glad you remembered, I forgot the numbers. I didn't think it was 100 for some reason, I thought it was 90, but again, who cares at that point.

We had sleeping metabolic rate or 24 hours.

That's right, that's right. What the study basically found. And the study was again, it was a very well designed study in that there were maybe 16 subjects, which is obviously sounds like a very small number, and it is. But given the complexity and cost of keeping 16 subjects housed in a hospital for a month and then also putting them in metabolic chambers every few days, this isn't a study you're going to do with 500 patients. But to increase the statistical power of the study, it was a crossover study which meant that every patient was their own control. And that's what allows you to get away with having so few subjects. So interestingly, I think it's safe to say that the effect size was large enough that it suggested a signal, but not so large that it dispositively answered the question. And in many ways it served as fodder for more questions, which I guess is not uncommon in research. It's very rare that one experiment gives you the definitive answer and rather it just points you in a slightly different direction and gives you more questions, which then begs the question, which is if resources were not a limit, what would be the follow up experiment to that?

I wish I had an answer. I mean, I'm tortured between very well controlled studies we do, like Kevin hall does, where you basically domicile the people, you feed them whatever you want, you know exactly what you feed them and you look at outcomes. I mean, I like that, but then how do you transpose that in real life? And one of my mentor was JP Flatt, and JP Flatt says obesity scientists, they have a tendency to either look at the expenditure side of the equation or the energy intake, but they never put the two together. And he was right. Because a lot of studies you have an outcome which is on this side or on this side and you maintain the other one. And I think that to me, designing a study would be first of all in free living condition, but it would need a lot of people because, you know, you can prescribe all what you want to people, they're going to do whatever they want. At the end of the day, some of them, if you screen them very carefully, are going to be much More compliant and adherent to the instruction. But this is what needs to be done. And by changing here, we change not the calories, just the composition of the two diet. 10% carbohydrate versus 45% or 50% carbohydrate in the other diet. And that's all what we did. And I think we concentrated only on the energy expenditure, but we even didn't ask very much their visual analog scale if they were more hungry or all these kind of things. But we kind of ignored the food intake that we were clamping. And this is not real life. If you do something and you know, you talk about engaging on physical activity, regimen or exercise and all that, I mean, you have to look at the impact on the other side. And this is the same question that I have now, I'm not helping you in designing the perfect study by saying that. But on the other hand, again, we have good tools to measure energy expenditure. We have reasonably good tools to measure where do the calories come from. But we have no tools to measure energy intake. But it's going to come. I bet you that within, I may not be here, but within a couple of decades we'll have a color here which is going to measure your calories coming from fat, carbohydrate or protein.

I think it should be sooner than that, Eric. I mean, I really do think as image recognition gets better and better with AI, to me, I would actually hope that within a decade, if not less, we are at the point where if you can weigh something and take a photograph of it, we should have enough training data that you should be able to know exactly what is in it. Now, that doesn't account for how much of that thing you eat. But assuming you have something that you weigh and you can photograph and you say I ate all of it or I ate half of it, we should be able to do better than 10%. We should be able to do within 5% what is the caloric density of that food and the macronutrient breakdown. I wouldn't have said that five years ago. Like five years ago, I would say that's impossible. But given what I'm seeing with image recognition in AI, that to me has to be the future for nutrition research and in a free living environment.

I think you put your finger on the exact point. And now I'm the PI of one of the six clinical sites for nutrition, for precision health. This is basically a ancillary study of all of us. All of us is a million Americans who are basically providing Biosamples, access to the health electronic records and all that. And then this sub study is really to look at the intersection between their health and their nutrition. And there is three modules, one is on 10,000 people and one of the way to measure is exactly this little camera sitting on your glasses. And also a system which is measuring if you are chewing or not. It's not enough to see the food and going, but is a chewed. And I agree with you. I mean I was not thinking about that. I was thinking about something much more like a CGM. Who was dreaming of CGM 30 years ago when I was working with the Pima Indians? We were not thinking about that. Now you have CGM and you can measure your probably your insulin from contact lenses and things like that. And I think these progress are going to help us. Now are we going to be smarter at designing the study? I'm not so sure. But we'll have the tools to be a little bit more real life rather than incarceration in metabolic world.

Yeah, I mean, I think that. And again, you're so much more thoughtful on this Eric, because it is your world. It's not my world, but I occasionally will think about it. But as I'm sitting here now reflecting on it with you, my intuition is that the questions are complicated enough that the difference between efficacy and effectiveness have to be separated in studies. And I think if this question of macronutrient composition, isocaloric macronutrient manipulation impacting energy expenditure is to be put to rest, it can only answer that question. It cannot attempt to answer the impact of appetite as a movable variable. It can do it as a swing variable. Meaning as you said, you can force people to eat a clamped amount of food and then measure subjectively or even using PPY and ghrelin and other hormones. So somewhat objectively, somewhat subjectively measure appetitive response to that. I think the biggest mistake of that study was actually not creating a big enough divide in the macronutrients. I think as an efficacy study that was testing a theory, just a theory with again you start with a very theoretical response and then you build from there to say, okay, is this theory applicable in retrospect? I think it should have been more extreme in the carbohydrate and fat differences. I think one should have been, if the carbohydrate insulin model was being tested, one should have been a very, very, very high insulin diet and a very very low insulin diet that were isocaloric. And by the way, let's assume you do that. Experiment and you get a difference of 250kcal a day. Well, you still don't know if a ketogenic diet is a better diet in a free living environment because you're probably not comparing it to somebody who's eating 80% carbohydrates. So then you still have to do the next experiment, which is maybe the one we did. And then ultimately you have to be able to do the free living experiment where people make their own choices based on appetite. That has to be sequenced. I think to answer the questions. These are difficult and costly experiments to do.

Also one thing that I still have in my mind, all the studies which came from Europe about modulating the composition of the diet and look at the impact on the matching of oxidation to the intake. Even Steve Smith that we are working with did this study called adapt. He was isocaloric all across. But all of a sudden you continue with more fat. The FQ of the diet, the food quotient goes down, decrease and then it takes days to basically have a matching of your RQ to the fq, which means you oxidize what you eat, whereas if you do the contrary, you increase carbohydrate. It takes one day. And that's why I still believe. And back in Switzerland we did this study where we were giving extra fat as LCT, long chain triglyceride or MCT, because the MCTs are oxidized quicker. And we found that against the culprit is always the fat. And we are very good at matching carbohydrate oxidation to carbohydrate intake. Very good. It's very difficult. First of all, you have what, 500 grams of glycogen, glycogen 100 in the liver, three to 500 in the muscle. That's all it means. If you have a lot of carbohydrate, that's a huge signal. And protein, the same thing. You know how difficult it is to build up your muscle mass or your protein mass in the body by just eating more protein. You have to exercise or you have to take anabolic steroids or whatever, but the fat is the one which is not regulated. That's why I still have this problem with the carbohydrate insulin model. It works. Let's say there was a slight increase in energy expenditure. It seems to work for weight loss. It's better with ketogenic diet than with a low fat diet. But in your entire life, I don't think it works. And piling the fat, I mean you have done some of That I did.

It for three years. My intuition is that this always sounds like a cop out when you say it, and I hate when people say it. But I do think it's kind of true when it comes to nutrition, is there's so much heterogeneity between individuals, both genetically and environmentally, that we have to release our agenda from this idea that there is a perfect diet for everybody. Never mind health, even when it comes to weight maintenance, let's pick a simpler variable which is nothing but a subset of health. Weight maintenance. As one piece of the health puzzle, it strikes me as impossible to suggest that there is a true diet that is good for everybody. I think that again, based on a person's genetics and their own living evolution, that is their epigenetics and their environment and other factors, psychological factors, which of course can be quite genetic, there are either several or few dietary options that are easiest for a person to adhere to to maintain weight balance. I think that carbohydrate restriction, especially extreme carbohydrate restriction, happens to be one of the more efficacious ways for individuals to restrict something in the larger service of restricting calories. Because at the end of the day, whatever you choose to restrict, whether it be certain macronutrients, alcohol, the time during which you allow yourself to eat, or just directly the number of calories, some form of restriction is necessary for weight balance. In an infinite food environment, which is the one that we have now found ourselves living in for the past 0.01% of our genetic existence as a species. It's a very new problem that we have to be so surrounded by infinite nutrition, and therefore it requires some degree of restriction and you just have to pick your poison. Do you want to directly restrict calories? We're going to talk about that. That's the calorie study. Do you want to restrict the timing in which you eat? We're going to talk about that as well. That's time restriction. Make a smaller and smaller eating window. Or do you just want to pick some boogeymen within the diet and say they're the bad guys, I don't eat fat, I don't eat carbs, I don't eat animal protein, I don't eat whatever. And if I do that enough, I'm going to also restrict energy intake. That's not a very satisfying answer. I think people want to believe that there is one perfect diet, one perfect way, but I just don't buy it.

I'm with you. And I think that we are now in the era of precision medicine or personalized medicine. And I think that this is what the NIH is embarking on when they do this. Nutrition for precision health. When they do this study that I'm also a PI of a clinical site, which is molecular transducers of physical activity to look at in lieu of your genetic background, your environment, your socioeconomical status. One size does not fit all. We have the dietary guidelines. They are applied for the entire nation and they tell you, you know, every time it's Mediterranean diet or the DASH diet, which are the best and all these kind of things, but not for all. And I think that this is where we are going to have a huge development. It's to go. I don't think it's going to be individualized, but at least for groups of people having the same, you know, different strategies and restriction has to be one of that. But now how do you restrict, do you restrict by public policies, by taxing things?

I feel strongly against that, but of course I would describe myself as a pretty staunch libertarian when it comes to that kind of stuff, not an extremist. I do believe there's a role for government, but I think long term compliance and trust on the part of the public will not come through that type of environment. So what I think is really the answer is one is better education. And I don't mean education like we're going to sit kids down in first grade and teach them this. I just mean public education and better advocacy and education from the scientific and medical community which says kind of what I just said a few minutes ago, which is, hey, you're not broken, you're not defective, but you might be one of the people for whom the average approach is not going to work. But step one is every one of us needs to accept that in exchange for living in the greatest period of civilization, which is where we all live, none of us would trade places with the King of France or the king of England 500 years ago. You just wouldn't do it. I'd rather be the most average human being in 2024 than the single most important person in 1400. So we just have to accept the fact that we are all so shockingly privileged to be alive at this moment. But that privilege comes with a couple of expenses, comes with some costs. And one of the costs is we live in an environment that has a little bit of toxicity with respect to things like food. And we have to pay a price. We have to pay a price. We're going to have to make a trade off And a restriction. And I just think people knowing that can take a breath and go, ah, okay, I'm not broken. Now different people will have to do a greater amount of restriction. That's just the way the cards crumble. Not everybody has the same iq, not everybody is the same athleticism, not everybody has the same emotional intelligence, and not everybody has the same metabolism. So some people are going to have to be not very restrictive. They just have to be somewhat mindful of what they eat and the cards fall into place. That's my wife. Barely thinks about anything and it all works out. Then you get people like me in the middle. I have to be thinking about it every day. Not crazy. It doesn't have to occupy my every minute of my life. But I can't eat on autopilot. And of course, there are people even further where unfortunately they're gonna have to be very mindful and restrictive of what they eat in lieu of potentially using drugs like GLP1 agonist. So that's step one, Eric, in my view. And then step two is, which goes to your point about personalized precision nutrition, then what we need are the technological breakthroughs that allow people to become their own laboratory animals and allow people in the real world, in the free living environment to do the empirical stuff that you and I are talking about and will talk about with respect to the experiments to test the hypotheses. How much fat and protein and carbohydrates should I be eating to optimize my appetite, to optimize and regulate my appetite and my energy expenditure. And again, we're sitting here now talking about the fact we can't even give people that tool yet we don't have the tool that allows the person to do that test with any degree of accuracy. So I know that's not the most optimistic response, but that's kind of, my view is like that has to be the direction we go in as opposed to continuing to try to answer the what is the best diet question, which obviously you're not trying to answer because you realize the futility of that as well as I do. But, but I still think many people in the public view that as the question that's trying to be answered.

Yeah, you're correct. And I see that with this new study that we are doing, people when you say the word diet, they think weight loss, they think something miracle is going to happen. And we tell them, no, no, it's, we want to know what you eat in relationship with your health and your genetic makeup and your environment and all These kind of things. I'm with you on that. Now I'm a little bit more pessimistic that I always say education is a major cornerstone of that. But we also are going to need to have public health policies. I mean, it's been done with trans fat. It's being done now in South America with black label on dangerous thing in ultra processed food and all this kind of thing.

I don't know that I'm opposed to labeling things. I guess I just, I do worry a little bit with excise taxes on things. Although in fairness, if I'm going to be critical of my own point of view, I do support excise taxes on tobacco. I do think alcohol and tobacco should be taxed to cover their consequences on the back end. So maybe I need to revisit my thinking on this. But I do sort of bristle at the idea a little bit of taxing certain foods more than others. Only I think, Eric, because I've lost faith in the government to determine on the margin what's healthy and what's not healthy. Is butter healthy or not healthy? Should butter be taxed disproportionately relative to bread? I mean, that's an area where I simply don't want anybody at the FDA or the USDA or the ATF or anybody else weighing in. But anyway, tell me more of what you think from a policy perspective would be helpful.

I think that the government should work very closely with the nutrition companies. And the nutrition companies have been masters at doing two things to produce very palatable and very cheap food. I remember John Blundell saying, those are the two things that people don't compromise on. It is to be tasty, they need to enjoy it and it needs to be cheap. And this is what we have now. I mean, a lot of added sugar, a lot of fat, and it's very delicious and all these kind of things. But we have to reverse some of that. And I think that now we know enough about that. And I was at a conference a month ago in Sao Paulo, the International Congress of Obesity, and they have been very, very active in South America when it comes to ultra processed food. And I was impressed to see even, you know, the protein content of all the ultra processed food is on the side of 12 to 13%, whereas, you know, we need something between 15 and 18%. And if you believe in the protein leverage theory, this is an important factor.

Tell folks what that is. I've talked about it a little bit on the podcast, but let's remind people what that theory Is I don't think there's any one theory. I think it's an amalgamation of theories. But I actually think there's some validity to this theory. Tell folks how that works.

I mean, in simple words is that we eat for a given amount of protein, which is proportional to our body size and all that. And by the way, I remember when I was studying, we were saying during a low calorie Diet, you need 1.2 gram of protein per kilogram of body weight, or these kind of things. But the experiment started with insects, and then they went in rodents and they manipulated the content of protein of the diet and they found out that basically the intake was all to gravitate around a protein content which was sufficient for the weight of the animal and so on. And this is called the protein leverage theory. And now I'm a little bit more skeptical when Simpson and the two guys in Australia are saying the pandemic of obesity has been paralleled by a decrease in the protein content of the diet and this is what has triggered the increased caloric intake to get the same amount of protein.

Yeah, it's basically they're arguing that it's not that total protein has gone down, it's that protein density within food, especially processed food, has gone down. And so people are seeking more calories to subconsciously get more protein. And the data, I mean, I reviewed these data in huge detail for a previous podcast. The data in the rodents is staggeringly compelling. It's unambiguous. A rodent will consume to its level of protein in the studies where this has been tested, even if it means eating way more calories. I do think humans must be more complicated because I don't think the human literature are quite as clear, do you?

No. Once again, with rodents, you can feed them whatever you want. With people you don't. I remember Dr. George Bray saying, you know, these dietary recall are not worth the paper on which you write the data.

Yeah, I couldn't agree more with Dr. Bray on that.

This is where we lack tools to know exactly. Your glasses with the camera or whatever is going to be useful. But I think we need better ways of measuring what people eat and what is the content of their meal and all these kind of things. And that's why it's so easy to do that in rodents, because you feed them with this or these three diets or five diets, and you look at how much they eat, you weigh the food and the calories a little bit more pessimistic.

Yeah, you mentioned that George Bray made this funny comment offhand about the role of food frequency questionnaires, which is they're not worth the paper they're written on. And of course, John Ioannidis has famously said that the food frequency questionnaire belongs in the wastebasket. I mean, that's basically the only place it belongs. And yet the food frequency questionnaire is the backbone, is the scaffolding of nutritional epidemiology. And so do you, as an empirical scientist, an experimental scientist, have concern at how much food policy is being driven by nutritional epidemiology rather than experimental science? When we understand why, why there's an effort around nutritional epidemiology? Because these questions are otherwise difficult to answer. But given the fidelity of the data, that is the thing you put in the system to calculate isn't worth the paper it's written on, according to basically anybody who understands how it works. So how do we reconcile this problem, which is, I mean, even things that we're talking about now, which is the role of ultra processed food? Well, those are determinations from epidemiology. It's epidemiology that's at least telling us or hinting to us that ultra processed foods on balance are bad. That confirms what I think most people would intuit. But where do we draw the line between what we are letting nutritional epidemiology tell us from a health policy perspective to where maybe it's overstepping and getting things wrong because of the data integrity problem?

I think the problem is really jumping from basically nutritional epidemiology to policies or labeling or dietary guidelines. And I think to me now we are at a point that the epidemiology should basically provide us with hypothesis to be tested in better controlled situation and maybe in domiciled with full feeding of people. These studies are expensive, but we're missing a step. And I think once again these new studies from nih, this consortia of nutrition for Precision Health, are going towards this direction of basically you are right, the food frequency questionnaire is here every day for 10 days in this module one of the study. But then there are these other ways. There is the remote photography system that you take a picture with your phone of the plates, you have these cameras and all that. And I think that now I hope that we're not going to make policy only, or policy or guidelines only based on the nutritional epidemiology, but also on studies basically testing some hypothesis related to what the nutrition epidemiology has shown.

I think all roads, both from a personal health perspective and from a nutrition science perspective. Need to point towards AI. Such a cliche thing to say. Right now, basically everybody's saying AI is everything. But when people ask me, how could AI change medicine? It's not by being a better doctor and being better at diagnosing. If you have syphilis or not, sure that's valuable, but a lot of it's in the very unsexy stuff. Image recognition and radiology, insurance, billing, reconciliation and this. When you want to talk about biomedical research, the thing that gets all the attention is protein folding. And that is truly magnificent. The protein folding predictions from the amino acid sequence is mind boggling. And that will absolutely shave some time and money off drug discovery. But if AI could solve this simple problem. I say simple in conceptual terms, not technical terms. You change nutrition science, you really start to answer questions that have vexed us for hundreds of years. So anyway, I hope somebody out there who's got serious AI chops is listening to this and thinking this is an area to pursue. Let's pivot a little bit, Eric, to talk about one of the most important parts of your career. I believe you are, if not one of the senior PIs, you might be the single most senior PI on the calorie study. Is that correct?

Yeah, I was one of the four PIs, but I was the one who drove the write up and the design of the study and all that calorie was an important study. It was funded by the National Institute on Aging and it was really the first attempt to look at the impact of caloric restriction on biomarkers of aging. Now don't ask me what are the biomarkers of aging, because there's still a lot of discussion around that. If I tell you it's your fasting insulin going up with Life, it's your VO2 max going down, it's not your gray air or your lack of air, all these kind of things. But anyway, you have some more sophisticated protein glycation and production of isoprostane and all that.

I want to talk about the details of the study in a moment, but just before I forget, how much banked serum do you still have that is available for analysis in five years or 10 years when better and better tools or biomarkers become available? Has it all been spoken for and has it all been tested or are there still some banked samples?

It's great that you asked the question because now there is a calorie legacy study which is to follow up these people, but also there is a biorepository of all the plasma samples, muscle Biopsies, fat biopsies at Duke, which was the coordinating center. And these samples are available of course, with a request. And the PI of that is Bill Krause, you may know the name, he's a cardiologist, but he's at Duke. And it's interesting that you ask that because one of my colleague just published a paper in Science on a postdoc analysis of adipose tissue in these people before and after caloric restriction. He found a gene of interest. He's an immunologist, Deep dig cities at Yale. And he really mined these transcriptomes from adipose tissue and found a gene which is related to the immune function and found that if you knock out this gene in mice, they are resistant to weight gain. This is like a calorie restriction mimetic. And they improve the immune function and all that. Yeah, your question is very appropriate. There are still samples available, of course, they become less and less available or more and more difficult. I'm just digging in some of the samples that we had to send to somebody at UT Southwestern because he has a new molecule that he would like to test before and after weight loss in non obese people. But the gold mine of these studies is really to be able to bank biosamples. We all bank the data and the results, but the biosamples, it's very.

Yeah, that's, that's the treasure trove.

Yep.

So tell folks about the study. So how many subjects? What was the intervention? How were they monitored and tracked? How long were they followed? Let's just start with the basics.

First of all, I became interested in caloric restriction because of. I don't know if you remember, Peter, Biosphere 2.

I sure do.

It was a glass and steel structure southeast of Phoenix, in between Phoenix and Tucson. And eight people went into this biosphere. They had seven different biomes. There was desert, marsh, ocean, agriculture.

How big was it?

Habitat? It was about three acres. And this was a rich Texan donor who wanted to do that basically for the sake of NASA to know how people can live in Otasi. Anyway, eight people entered this Biosphere 2. And it's called 2 because Biosphere 1 was the Earth. And they decided to call it 2. Among these eight people there was a faculty from UCLA, Roy Walford, who wrote the textbook with Rick Weindruck on caloric restriction. And while they were in the biosphere and I was in Phoenix, Roy called me and said we would like to do measurements of energy expenditure. Can we sneak in a delta track or metabolic card to measure our energy expenditure? And I said, oh, absolutely. And we can also measure your free living energy expenditure using doubly labeled water. And we did that anyway.

Remind me how long they stayed in the biosphere too.

From 1991 to 1993. Roy Walford was a physician of the group, but he was very, very interested in caloric restriction. What he didn't know, things went south. The agriculture, you know, they had pests they couldn't control some of the insect. They had goats dying, and very quickly they didn't have enough food. And they lost on average 15% of their weight. None of them, except one, was maybe a BMI of 26 or 7. They were all between 20 and 25. And they became calorie restricted. And you had the guy who was writing the textbook on calorie restriction being the physician in the biosphere 2. We started to collaborate. And then when this RFA came out in the early 2000, a request for application grant from the NIA, immediately I called Roy and I said, roy, we have done this study of energy expenditure. And they came and they stayed in the chamber, five of them for one day. Right. When they came out of the biosphere, and we need you as a consultant and we want to write a grant which is going to be competitive. I'm not known in aging research. He accepted.

By the way, what did you find of their energy expenditure when they were in the chambers?

It was low. I mean, very low, because of their caloric restriction. We had to compare to a group of 72 people. I mean, it's all published and I can send you some of the papers. They were about 200 calories below what you would expect for their weight and body composition.

Interesting. Even correcting for their highly reduced weight and altered body composition, they were still 200 below.

Yeah. Three of them said, hey, we have been stuck for two years now in this biosphere. We don't want to go to a metabolic chamber in Phoenix. But the five who came, they came back six months later and they regained their weight. They were normal weight, like at the entry. And we published this data.

And was their energy expenditure normal as.

Well, or did they normalized? Normalized, yeah. There's this argument with metabolic adaptation. How long does it last? And these kind of things. But it was normal.

Roy passed away kind of prematurely, didn't he?

Yeah, he blamed it on biosphere a little bit because they were supposed to be totally independent, except for light from the rest of the world. But a few times they had to purge CO2 and influx O2. But he said there was probably gases, but it was his story. I don't know how true it was, but he said that he was intoxicated by gas in the biosphere.

I didn't realize that story, Eric, that it was on the back of Biosphere 2 that your personal interest in this hypothesis emerged and that that's the first thread that pulled towards the calorie study. So I'm glad you shared that story with us.

Yeah. Now move. Almost 10 years later, Roy Walford and I don't remember the name of the investigator in San Antonio came. We brainstormed what should be the hypothesis. I was very serious. I wanted to have this grant. And we said what are we going to test? Because if you ask Steve Osted how many theories behind calorie restriction, he's going to tell you more than 50 or 100 and so on. Myself, I was pretty convinced by two things. The rate of living theory, the higher your metabolism, the shorter your life. And the elephant has a very low metabolism per unit of tissue containing compared to a shrew and all these kind of things. And the oxidative stress theories, does that.

Explain the difference between a human and a dog? Is that explained fully? The 10x delta in lifespan between a human and a dog or whatever it is?

Okay, you can look at Kleiber book. You have the energy metabolism.

Yeah, yeah, I need to go. And it's not 10x. I said 10x.

They are all on 7 or 8x. They are all on the same line.

Got it.

We brainstormed for three or four days. I have beautiful memories of this time. And we said okay, we're going to write a grant. It was a seven year grant, a first two years which was you do a study, show us that you can recruit people and maintain them in calorie restriction. And they have to be not obese, they can be overweight. And the second is from the three chosen group, we're going to design one study and it's going to be a two year intervention. And the first study we decided was basically to test if caloric restriction decrease your energy metabolism more than what you would expect on the basis of the body weight. And in other words, do you become more efficient? And the answer is yes. And we talk about metabolic adaptation. Now this is in non obese people here. But they become more efficient, which by.

The way always sounds like a good thing. But it's not really a good thing when it comes to weight maintenance. Right. It's the exact opposite. Becoming efficient is not what you want. You want to be the most Inefficient consumer of calories. In an ideal world, you're right.

And when I did studies of efficiency of athletes, or do they have a higher, a more efficient resting metabolic rate and therefore can have more energy for the exercise or the task that they are doing. You cannot win both sides. Like you said, you are better at controlling your weight when you are a little bit more inefficient, but you are less performant and all these kind of things. Potentially, energy efficiency can be very good for longevity. And it has been shown in some studies. The Baltimore Longitudinal Study showed that some people with lower metabolic rate were living longer. On the other hand, energy efficiency is a liability for weight gain, for example, because you are more efficient and you are more prone to weight gain. And I think it's a balance between the two. But anyway, I think there is no right answer. But having a high metabolic rate can be a liability because associated with the generation of ATP you have some, what we call production of reactive oxygen species. In other words, the efficiency of the transfer of oxygen into ATP is not perfect. And sometime you have some reactive oxygen species being generated by the mitochondria. And these reactive oxygen species can damage not only your DNA, but your protein, your lipids and so on. And this is one of the theory of aging. It is too many reactive oxygen species and therefore a higher degree of oxidative stress. And when we designed the first part of our calorie study, it was a six month intervention. We had four groups. A ad libitum group, 25% caloric restriction, another group being 25% energy deficient, but half by caloric restriction, 12 and a half percent and half by increasing energy expenditure by exercise. And the last group was weight loss, 10% with very low calorie diet and maintenance of this weight loss. It means you are in calorie restriction compared to that baseline.

So just to be clear, the last group, the target was the weight reduction, whereas in the other groups the target was the energy intake and or energy expenditure.

Correct.

Now how did you even do this, Eric? Because in theory this sounds like a brilliant experiment, right? I mean those are big enough. Those are some seismic changes, right? You take a 100 kilo person down to 90 kilos. I mean that's a big loss of weight. A 190 pound person is going to be 170 pounds when that experiment is done. That's meaningful. The caloric restriction of 25% is enormous one way or the other. But now the question is, you're doing this in the real world. Over in one case, I think months, ultimately over years. How did you think about tools for compliance to see that you could hit even close to those targets?

I think it was a lot of work with our psychology group who said we have to screen the people, we have to screen them for barriers to the intervention, for adherence and so on. And there was a lot, a lot of screening of our volunteers.

Do you remember what your rejection rate was? You know, for every 10 people you screened, how many would pass the psychology test?

It is in the console diagram of the publication. I know if I recall correctly, for the two year study we screened more than 5,000 people doing enroll 225. Wow.

So basically only 5% of people.

Telephone web screening, telephone screening, in person screening visit. And there were five screening visits to make sure that they show up. If they don't show up for the screening visit, forget them. And the first study we published that in JAMA and we did find that there was metabolic adaptation or you become more efficient. And we had also some indication of less oxidative stress. We did what we call a comet assay. You look at damage of DNA in nucleated blood cells and we measure isoprostane and all that. After that, the three sites were Washington University with John Halsey was Tufts in Boston with Susan Roberts and us in Baton Rouge. Our study was six months. Our preliminary study theirs with one year. But after two years, when we analyzed the data and all that, we started to design the study which was going to be the same for the three.

Sites and was the only difference in the short study. Eric, the duration of the study and the sample size to just confirm the technical doings of the study.

No, they were all different. We insisted to have these four groups ourselves. In the preliminary study, Boston had only two groups. Low glycemic index versus higher glycemic index in the diet of the caloric restriction and washu. I don't remember the details, but there was a component of physical activity in their study. He was John Hollis, he was a biochemist of exercise and all that. But after that we compared our endpoints and our basically intervention and we designed this study. Now the RFA was specifying that they have to be non obese. In our preliminary study we didn't want to go because of this 10% weight loss. If you start with a BMI of 26, you are 70 kilos and you have to lose 7 kilos, you become thin. We decided about the range of BMI and we decided for the study to go from 22 to 27.9 of BMI for admission means normal weight.

Yeah, mostly normal weight. On the plus or minus side of.

Normal weight up to 27.9. We knew that they were going to lose at least 10% and therefore you cannot take somebody with a BMI of 20 to start with. You would have problems with bone mineral density. You may have problems with some safety concerns.

Men and women or just men?

Men and women.

Right.

So the other thing you're going to have problems with menstrual cycle and things like that. How long did they have to lose the 10% of body weight? Was they given six months to do this or what were they forced into?

We didn't have that in the final protocol, but he now preliminary protocol, it was over three months. It was a low calorie diet. It was like 800 and some calories per day. It was all liquid diet provided by Pennington. Yeah, but we could do muffins and things like that from these. It's called Health One diet and it's still on the market by the way. The two year study. Then we decided to my surprise that they agreed to do the rate of living oxidative stress. First endpoint, let's go back to the subjects, age 21 to 47 for women and 55 for men. BMI 22 to 28. And then going through a lot of screening to make sure that they were going to stick with us. And I can tell you, we randomized two to caloric restriction, 25% for one, two ad libitum. We had 95% completion in the ad libitum group and 85% in the calorie restriction. It's amazing for a two year study. And the retention was spectacular. They were randomized 2 to 1 to caloric restriction. Unlike the preliminary study we did in which we fed them entirely. They came to Pennington to basically learn how to cook whatever diet they wanted. It could be a low fat diet, a low carbohydrate diet, a med diet.

And Sorry, Eric, tell me again. It was 25% CR target in the CR group.

Yep. It was based on two measurements of doubly labeled water. The average. I just checked that this morning. The average energy requirement was 2,400. It means on average they were cut by a little bit more than 500600 calories. And for two years and the first three months they could come whenever they wanted to learn to cook. And they were also provided some of the meal if they needed to. I remember one, he's still our star of the Volunteers. His daughter thought he was working at Pennington because he was going every day to Pennington. And his daughter was five when they asked her at the kindergarten. Where does your dad work? Oh, he works at Pennington. And he was a volunteer for our study. After that, we had a lot of measurements about resting metabolic rate, about oxidative stress. And the endpoints were really the first rmr, the second ROS formation. And after that it was CVD markers. It was insulin sensitivity, immune function, neuroendocrine parameters, quality of life and cognitive function.

What Was the average percent weight loss of the individuals in the treatment group?

One year, the average was 12%. And at two years it was 10.4%. Now, the caloric restriction that we kind of estimated by doubly labeled water, it's called the intake balance method. You measure energy expenditure, you measure change in body composition. We had about almost 20% of caloric restriction for the first six months. And this is where the weight loss. And after that, it started to decrease to close to 15% at one year. And then at the end of the two years, the overall caloric restriction was 12.5%. Basically, we got half of what we were asking for, which is not bad for, like you said, it's an important cut in your intake. And he was square from day one. It was not a ramping up. And then we did this measurement at 6 months, 12 months, 18 and 24.

Months, just for the Pennington part of this, not including the other two sites. What was the budget for? Everything. Meaning the preparation, planning, the study, the analysis for the first publications, et cetera. Not the ongoing, but just the bulk of what you would call that calorie study had a budget of how much?

My original grant was 10.4 million, and it was in 2003. And after that, because we were recruiting so well, they asked us to boost up our recruitment and they gave us another million and a half. Yeah, close to 13 million.

That was the direct cost, or direct plus indirect.

No, plus indirect total cost.

So let's just apply a little inflation to that and say that that's 20 million in today's dollars. Conservatively.

Yeah. Yeah, yeah.

Again, that sounds like a lot of money. But when you think about the fact that the NIH budget is on the order of $35 billion for both intra and extramural, and the extramural budget of which this was part of is on the order of, oh, $28 billion. $20 million on a $28 billion, $28 billion budget is a drop in the Bucket. It's less than a tenth of a percent. And yet this is a very important question. I think your success in this study, I think it's the single best study that's ever looked at, even attempted to look at the effects of caloric restriction in a free living environment. In large part, I agree. I think you're recruiting was exceptional and your hands on ability to work with the subjects longitudinally is what made the difference. People think that the study is like you design the study, you recruit the subjects, you go and then you forget about them. But you would have failed. You did all the unsexy stuff so well and that's why you got something so remarkable. And as we start to now talk about the results of this study, part of my frustration is I worry that the NIH is funding some stuff that's not that interesting and not that relevant compared to the jugular questions of human health. And this would be a great example of the kind of work that should be getting much more funding in my view. But I'll get off my soapbox now. Let's talk about the findings at the end of two years. What were the most notable findings? Aside from the obvious, which is weight loss?

One amazing was the retention rate. I thought that it was exceptional that between the three sides and it was much more difficult in Boston to be honest, than it was in Baton Rouge or even in St. Louis. But anyway, retention was exceptional.

Sorry to keep interrupting you, Eric, but what did the subjects tell you? You got to know these people really well. Why did they stay in this study? I mean it can't be pleasant to be that calorically restricted for two years. Or did they say actually, you know guys, it really felt lousy for six months and then it didn't feel lousy at all. And I, I came to really enjoy this. I'm very curious as to what their subjective experience was.

It's interesting that you are asking because we have been interested in that and we are even now following up. These people were studied from 2005 to 2008 and they are part of this legacy study, callery legacy study. He was really building a team between the investigators and the study coordinators and study managers and all that and the people. He was also providing them with some of the results and we had to fight for that because normally you don't want to have people having their results. But we said it's not going to change their behavior if we tell them about their total cholesterol.

Right. It's not blinded.

Yeah, ldl and it's not going to change anything or their body composition. They love to see this. Dexa My percent body fat went from 15 to 12 in a guy and so on. And he was kind of building a. We had Mardi Gras with the volunteers. We had every two months we had a reception and all that, sending postcards for birthdays and all these kind of things are part of the retention and building a team between the investigators and the study volunteers. And I think we succeeded in that. But again, this was the screening which was essential because you are right. I remember the first person that we randomized, she ended up in the ad lib group. She came to my office and said, I want to do this study because I have read about what it does to your metabolic health, to your cholesterol, to your body compos. And I'm in the control group. She was crying and said, but we're going to give you data and after we're going to offer you maybe a weight loss or help you for caloric restriction and all these kind of things. Of course, two years later we still see them, but not on a regular basis like during the study. It's a lot of investment from the investigative group and also for the study participants because they had so many visits.

So talk to me about the lipid changes, the markers of insulin sensitivity, the body composition changes. Let's just kind of run through the list of what improved. I don't think it's a surprise that these things improved, but the magnitude in some cases is interesting. And again, this question of. I'm very curious as to subjective markers of satisfaction in that group because most people would say, look, if you told me I have to restrict my calories by 20 or 25%, there's no amount of benefit to my health that could justify the unhappiness and unpleasantness of that experience. So where were they psychologically as that trial progressed into its second year?

I think first of all, there was quite a lot of press around the study at the time done at a national level as well as local levels. And they like to know and to know that they are part of an important study. It's like this Nutrition for Precision Health now or modapak are things which get some press and all that. Most of the people like to be part of a key study. The second thing was really building this relationship between the investigators and the study volunteers and also the return of results and the sharing of experience with other people. You were asking, you know, how long does it last to have this problem with hunger Suffering and all that. And it seems that for most people after one month it was totally manageable. We taught them also to increase the volume and decrease the fat content to satisfy on a volumetric basis how much food they were eating with less fat and less calorie density in the diet against the ketogenic diet here.

And do you have a sense of how their macronutrients shifted? So did the ad lib people effectively mirror the standard American diet of 50 to 55% carbohydrate? And did the CR group end up at a higher fraction of carbohydrates because of this attempt to lower caloric density?

We have published, I don't remember exactly if there was a clear cut impact of being in the caloric restriction group versus the adlib group. This I don't know. But I know that quite a few people wanted to make a difference in their diet and they wanted to know more about the med diet, the DASH diet, the low fat diet and all that. And surprisingly there are some people and like I said in this legacy study and Dr. Redman is the PI now people are still a lot of them did not regain all the weight and now it's more than 15 years after and they are still using what they have learned during these two years because there was a lot of learning.

When was the last time you took blood, gathered any sort of data on those people besides weight? In other words, is there any way to infer whether two years of caloric restriction 20 years ago had any lasting difference relative to the controls?

Like I said, this legacy study is targeting all the people. Now I don't know how many but I'm pretty sure we're going to get.

But we don't have the results yet.

No, no, it's ongoing now. But us, we did a six month follow up study at Pennington and here they were continuing. That's not the thing they said oh heck with this study I go back to my normal life. It was a game changer for their lifestyle for these people.

So what do you think from an anti aging perspective where the most important biomarkers that changed, for example, did you do OGTTS or euglycemic clamps? I mean how much did you scrutinize glucose disposal and insulin sensitivity in these people?

We didn't do clamps. Let me tell you there are two kind of aging. There's primary aging which is more like senescence or mitochondrial dysfunction, leaky membrane. And there is secondary aging which is basically the impact of your environment and your lifestyle. When you ask about insulin sensitivity or cardiovascular factor, it's more secondary aging. And here we did a lot of measures. Bill Kraus published a quite cited paper five years after the end of the study in JAMA on all the cardiovascular cardiometabolic risk factors. And everything was tremendously improved, despite the fact that these people were healthy to begin with. BMI 22 to 27.9 and so on, and remarkable improvement in all these markers of secondary aging. Now, when it comes to primary aging, that's a different story because it's much more difficult to measure autophagy, to measure mitochondrial function, to measure leakiness of a cell membrane in these people. And what we ended up to measure was really some of these hallmarks of aging. You have probably seen these papers. There was one in 2012 and one ten years later. We don't have as many data that we would like, but for example, we did measure mitochondrial biogenesis by looking at the relationship between nucle clear markers and mitochondrial DNA. And we observed in humans that there was an increased mitochondrial biogenesis. Despite the fact that you use less energy, you become more efficient, you increase your biogenesis of mitochondria, which is quite spectacular because the Ross production of these reactive oxygen species are produced by older mitochondria. The new mitochondria are much more efficient. They don't produce as many ros.

So let me make sure I understand that, Eric. Sorry, you're saying that the people in the CR group had a greater turnover of their mitochondria in the muscle, skeletal muscle.

He was.

It's interesting. And so we would expect that people who are calorically restricted would have lower Ross generation, but we would expect that the reason for that is lower substrate utilization. You're saying? Yeah, they had lower Ross generation, but it might actually be just as much from the fact that they had more mitochondrial biogenesis and they were using newer machinery for the substrate utilization. So it could be both of those things are reducing Ross, is that what you're saying?

Absolutely right. I think it's both. When it comes to mitophagy, these all mitochondria, it's been shown in insect, in rodents, that this is improved with caloric restriction. Autophagy, of course, all these organelles in the cells.

Did you measure any of the tubules or anything for autophagy? No, no lct.

Okay.

But we measured mitochondrial turnover by this method, and we found that it was increased with caloric restriction. And I think you are right on the point here. There's both mechanisms. Less energy requirement, but also More efficient mitochondria today.

If you were to do this study, for example, I mean, I know the legacy study isn't the same because not as many of the people are going to still be carrying out, but if you could go back and look at the banked samples, are there any other biomarkers you would be able to look at today vis a vis the hallmarks of aging? Is there anything we could be doing to better understand senescence? What would you look at in terms of inflammatory markers? I would certainly put that down as primary aging. How much of a suite of the interleukins TNF and things of that nature did you look at?

Yeah, I mean, we did. We did at 6, 12 and 24 months. We didn't do 18 months for that, but we had the whole panel of inflammation and high sensitivity CRP and then all the interleukin TNF alpha and all that.

Everything improved or just some things?

No, everything improved. One thing which was spectacular when it comes to immune function. We did some imaging of the thymus and there was loss of fat.

Oh, oh, involution. Okay. Fat reduction.

There was a reduction of fat in the thymus. And our friend Deep Dixit was all excited and this is why he pursue all the immune responses from transcriptomics in different tissues and all that. But chronic inflammation, first of all, it was not abnormal to begin with, but there was tremendous improvement. And I think that Bill Krauss, in the discussion of his paper, if I recall, he used the Framingham index of cardiometabolic health and there was an improvement in the age. I don't know exactly the index.

Yeah. Using the Framingham risk calculator. Of course, everything would have got better based on the biomarkers.

And it was quite spectacular. It was like they were gaining 10 years in two years.

I mean, again, Eric, I think it's very interesting and I think it is hands down the best experimental evidence we have that caloric restriction, for those who can do it, may indeed be a great tool. Of course, there are other questions that I think can't be answered by this study based on its duration and the age of the subjects. And that is, would those benefits extend into the eighth decade of life, a period of time when sarcopenia becomes a significant driver of not just mortality, but truly morbidity? And would we indeed see a trade off in lean muscle? Again, the answer is not necessarily that you would. I do think that one could indeed consume fewer calories without any restriction of protein and while doing all of the necessary strength training so in other words, I think there's a deliberate way to do this. But if one were just to restrict calories and lose lean mass, I mean, I don't remember, Eric, but obviously the subjects got lighter and obviously their body composition improved, meaning they disproportionately lost fat to muscle. But do you recall if there was also a meaningful reduction in lean tissue independent of the improvement in body composition?

I would have to go back to the publication. Exactly. It was less than a quarter.

Less than a quarter, Yep. We like to hold onto that as the gold standard of limit lean body mass to a quarter of total weight loss.

We didn't restrict physical activity, but to be enrolled they had to be screened for not being regular exercisers. For example, do you know the cronies, the calorie restriction Optimal Nutrition Society?

I've never interacted with them, but I'm familiar.

There is about 200 self imposed calorie restricted people. They are afraid of exercise. They don't exercise at all because they are afraid that exercise is going to increase their appetite, their appetite and their food intake. And they are religious with that. And that's why, I mean, your question about sarcopenia, when you start with people with a BMI of 24 and you lose your 10, 12% and you keep this 12% off and you go in your 70s and 80s, what is happening to your muscle mass and these kind of things? And I don't think we have an answer.

I mean, to me, Eric, the experiment that I want to see done is not even an experiment at this point, frankly. It's literally. It's a much easier experiment, which is your tissue and serum samples provide a very compelling case of you can take healthy people, CR them for a couple of years and make them better across the board by every objective measure of both primary and secondary aging. The secondary stuff's so obvious it's not even worth talking about. So people that are interested in that can go back and look at the papers and see the lipid profiles and see the insulin sensitivity, but it's really these primary markers of aging. I had forgotten or didn't know about the thymic fat reduction. That's very interesting to me. So now the question is this. Well, you were dealing with a very narrow population. You started with 2,500 people and through intensive psychological profiling, you winnowed it down to the 5% of people who were going to be able to most adhere to this. And then on top of that, you provided arguably the most robust support for those people during this journey, the kind of support they couldn't buy outside. Those people, as regular people on the outside world couldn't have purchased the level of care and support and encouragement they got for that two year study. So all of that is not to be a critic of the study. It's to simply say those were the necessary steps to get such exceptional compliance, which is what was necessary to get such a meaningful answer. But if we want to ask the question, how would you help the 99% of people who on their own could not adhere to that? The answer, of course, becomes CR mimetic drugs. This is the question that is on everybody's mind, which is, Eric, you've convinced me that CR to this extent will absolutely help me live a longer, better life. But I just can't do it. I'm not in that percent of the population. But will a GLP1 agonist give me the same benefit? Will rapamycin give me the same benefit? Will acarbose give me the same benefit? Will an SGLT2 inhibitor give me the same benefit? Will metformin give me the same benefit? And those studies are much easier to do. We can easily put people on those drugs for two years and do the exact same analysis. You've given us the gold standard, you've given us the template. Now we just need to compare every single marker you've measured plus some you haven't. I really want to see the epigenome in these subjects pre and post. And so is it just me that feels this way, or is that also screaming out to you as the most interesting question to come out of this?

It's been a little bit of a roller coaster. The CR mimetics. You remember all the sirtuin stories?

Yes, but notice I picked something very carefully. I only picked drugs. With the exception of GLP1 agonists, I only picked winners of the ITP. Yeah, and Sirtuins are garbage. Everybody knows they're garbage. I'm sorry to offend people who work on them now, although I don't think anybody's still working on them. But the sirtuins were a scam story that never materialized. And it never, ever, ever was the mechanism by which CR worked, ever. I've gone back, I have talked to Matt Kaeberlin, who did the first study. I have gone through every experiment that was done in that lab. There is zero evidence that sirtuins supposed efficacy, which I think is true in yeast, by the way, was mediated through cr. And of course, sirtuins have had no efficacy post yeast. So anyway, I'M just being a little pointed in my language to make the point that I'm being particular about which CR memetics I discuss.

Yeah, okay. And you pick metformin. And of course, I'm sure you, you know, neo baselai.

And of course, my hypothesis, by the way, is that metformin is not a CR memetic, but I just think we should include it. There's a reasonable enough probability that all of those molecules I suggested, I think should be tested.

I mean, the GLP1 are so potent when it comes to weight loss, metabolic health and all that. I mean, there's not a week without a new paper on GLP1.

I know. I just read a blood pressure one today on tirzepatide.

Why would that be? Because when you calorie, restrict yourself, you eat less and therefore you stimulate less. These GI peptides, none of it makes sense.

None of it makes sense if you.

Tell me, I mean, are they true caloric restriction mimetics, and do they decrease oxidative stress? Do they improve insulin sensitivity and all that? Among the one you cited, there's a lot of those. Now, the question is, how do you go about to test that? Of course, there is all these failed drugs and things which have been tested for toxicity and safety and all that, that some people want to recycle in aging. And I'm not sure where it's going to be. To me, the secondary aging, which is the impact of your lifestyle and your environment, is what we should target first, the primary aging. I like to hear David Clark talking about autophagy or the people on the east coast and all that. But. But what do you do to have more autophagy or more mitophagy and all that? I don't know.

I mean, we know exercise does it. I mean, we know that autophagy is not just fueled by caloric restriction, but exercise is an incredibly potent driver of that for similar mechanisms. Right. You could argue that it's basically a substrate utilization problem. It's the input. It's the output. And when you transiently deprive the output, if you drive more output and you transiently create a deficit of energy, I don't think at the cellular level, the body is particularly concerned with am I short on what's coming in, or am I short because too much is going out? And again, this doesn't have to be an either or. That's the beauty of biology, is we can look for accretive solutions. So I think that those particular geoprotective agents, Eric, are probably not going to be as impressive on the secondary markers of aging, with the exception of the GLP1 agonist. Because of the obvious weight loss. I don't think metformin, Rapa, SGLT2's a carbose are gonna result in weight loss. And even in the, in the itps, they did not result in weight loss. Remember the hypothesis of David Allison who proposed acarbose is this is gonna be a CR mimetic that induces weight loss because of bad absorption. Well, guess what? Those mice weighed the exact same amount. They just lived a heck of a lot longer, suggesting it was actually the glucose metabolism that gave the benefit. But I don't know. I just think, Eric, what you've done is amazing and I know it just wasn't you. Of course it wasn't you. I mean, you had an incredible team. I've been to Pennington on many occasions. It's a wonderful place. I think it's dedication. It's the little stuff that matters. Eric, it's like I know what your staff is like. I remember working with Courtney and the entire team of nutritionists there. I mean, that's the stuff that's not sexy, but that's what's necessary to do this kind of work. I hope that through this podcast we're giving people an appreciation for how hard it is to do nutrition science. If you're an experimentalist, anybody can do epidemiology. And I kind of share the view of George and John and the people who think that it is a very, very limited use. Not of no use. There is a case, but we over index on that stuff when what we really in my mind need to be doing is doubling down on the kind of work you do. Because that's the only place I think we're going to get causal information and information that we could make people's lives better with. So thank you for what you're doing.

My pleasure. Stay tuned. Because you mentioned time restricted eating and now there is a study which is going to be implemented in a year or two, a five year intervention, calorie restriction versus time restricted eating.

What's the time window of restriction going to be?

I don't know the details. The protocol is not finalized. It's one of these exercises where we were part of one of the study and now you put all your brain together, but it's going to be probably eight hours a day.

My vote. If you give me a vote, Eric, make it more restrictive.

The first study we did was six hours.

Yeah. If you really want to see if there's a signal independent of calorie restriction. Because I think the goal has to be you're going to have to match their calories. This is the isocaloric difference between CR and time restricted feeding. In my experience, 8 hours will give you a null answer. I bet a million dollars you'll get a null answer if you compare eight hours. But four to six is interesting and I'd be very curious.

Yep, interesting you bring that up. But our study was the first in humans and this was Courtney Peterson who did that. And we had six hours and people said it would be easier with eight hours and all that. But after, if I recall correctly, after two weeks anyway, they were perfectly fine with six hours. Even if at the end, the exit interview they said it would be easier for eight hours. But I think it was at the start and you can maybe ramp it down from eight to six hours.

Yeah. Yeah. Well, Eric, great to spend time with you today. Thank you. I know you're in Europe so that obviously you've had to stay up a little bit later, but hopefully the next time we do this, we're talking about this study and maybe the follow up studies that I'd like to see done on some of these CR memetics. And we're doing it in person.

All right, thank you very much, Peters. My pleasure.

Thanks Eric.

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Sam.