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

00:00:00.000 Hey, everyone. Welcome to the Drive podcast. I'm your host, Peter Atiyah. This podcast,

00:00:16.540 my website, and my weekly newsletter all focus on the goal of translating the science of longevity

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00:00:53.200 of a subscription. If you want to learn more about the benefits of our premium membership,

00:00:58.000 head over to peteratiyahmd.com forward slash subscribe. My guest this week is Eric Ravison.

00:01:07.260 Eric is the director of the Nutrition Obesity Research Center at Louisiana State University's

00:01:12.560 Pennington Biomedical Research Center, where he also serves as the Douglas L. Gordon Chair in Diabetes

00:01:18.700 and Metabolism. Having published over 600 peer-reviewed manuscripts, Eric is regarded as a

00:01:24.560 world expert in obesity, metabolism, and aging, and has received numerous awards for his contributions

00:01:29.920 to these fields. As discussed at the beginning of this podcast, Eric and I worked together for about

00:01:34.280 four years, roughly 15 years ago, and during that period of time, I just came to have such an admiration

00:01:40.520 for Eric, his curiosity, and his intellect when it comes to this field. We talk about Eric's

00:01:46.520 background and his extensive experience in metabolic research, in particular when it comes

00:01:51.000 to measuring energy expenditure, which turns out to be a very technically demanding problem. We go

00:01:56.580 through the various methods that this has done, including what is today regarded as the gold

00:02:00.800 standard. This, of course, is necessary because if you want to understand energy balance, you must

00:02:05.860 clearly be able to measure energy expenditure. We, of course, discuss energy balance, energy expenditure,

00:02:10.880 and food intake, how we regulate appetite, and the findings of a very important study that Eric did,

00:02:17.620 which look at the impact of manipulating the ratio of macronutrients to see if it would indeed change

00:02:22.300 energy expenditure. Disclosure, I was involved in the funding of that study. We then delve into the

00:02:28.600 calorie study, which looked at caloric restriction and discuss its insights as it pertains to the biomarkers

00:02:35.220 of both primary and secondary aging. We speak about the implications of GLP-1 agonists and similar drugs

00:02:41.940 in replicating the benefits of caloric restriction, and look to the future of this research and see

00:02:47.420 how new technology advancements like AI might come into play. So, without further delay,

00:02:52.680 please enjoy my conversation with Dr. Eric Ravison.

00:02:55.440 Well, Eric, thank you so much for joining me. Sorry that we can't be in person, but given that

00:03:06.020 you're in the south of France and I'm over here in Texas, that would have made it pretty difficult

00:03:10.480 because normally we're quite a bit closer. You're obviously in Louisiana. But anyway,

00:03:14.620 it's wonderful to see you again. It has been close to 10 years, right?

00:03:18.920 I think so. I think so. But I have found memories of our interactions.

00:03:23.800 Yes, as do I. I guess by way of background, maybe we can even just give people a bit of a sense of

00:03:29.680 how closely we did work together for four years. At the time, I was part of an organization called

00:03:35.120 NUSI, and you were one of the six principal investigators for what was a very audacious

00:03:41.840 experiment and part of something called the Energy Balance Consortium, along with Kevin Hall,

00:03:47.600 Steve Smith, Rudy Leibel, Mike Rosenbaum, and God, who am I missing? Mark Reitman.

00:03:53.960 Nevertheless, this was a once-in-a-lifetime opportunity to do something that had never

00:03:57.680 been done before, which was a multi-center, indirect calorimetry, inpatient study that was

00:04:03.120 really aimed at trying to at least pilot what would be necessary to do the definitive experiment

00:04:09.560 to answer a question that I'm sure we're going to talk about a lot today, which has to do with

00:04:13.880 the nature of calories and weight gain. I will leave it at that only by way of background to say that

00:04:19.060 we had the incredible pleasure of working together and really getting into the weeds of how one

00:04:24.880 technically tries to measure these things and how difficult it is on all of the challenges and

00:04:29.500 potential pitfalls of this. But let's just take a step back and maybe give folks a sense of your

00:04:33.680 life's work and your life's passion. You've been the head of Pennington Biomedical Research for how

00:04:38.380 many years now? Is it 20 years?

00:04:39.060 I have been for 24 years at Pennington. I was Associate Executive Director for Clinical Science.

00:04:46.900 I'm not the head of the Pennington. I joined after spending two and a half years at Eli Lilly.

00:04:52.740 And before I was 15 years intramural NIH. And the reason I came to this country was to build the

00:05:00.500 first metabolic chamber or indirect calorimetry chamber to measure energy expenditure in people

00:05:07.940 over periods of hours and days. Tell folks a little bit about what it means to be intramural

00:05:13.180 versus extramural NIH. I think when people hear NIH, they sort of have a vague sense of what it is,

00:05:18.840 but maybe that distinction isn't clear to most people.

00:05:21.800 Yeah, the NIH budget is about $33 to $35 billion. But there is a group which is intramural,

00:05:30.580 but most of the money, 80 to 85 percent, goes to all the academic institutions

00:05:36.480 doing biomedical research in the country. I like to be intramural.

00:05:41.520 Just so folks understand what that means, that means you are an employee of the NIH. You work at the

00:05:46.220 NIH campus, and your funding comes from the organization that you work for, unlike someone

00:05:51.320 who's at Stanford or Harvard, who's receiving extramural NIH funds.

00:05:56.200 Correctly. And I was intramural, but based in Phoenix, Arizona, because I worked a lot with the

00:06:02.060 Pima Indians, who have, as you know, the highest prevalence of type 2 diabetes and the second highest

00:06:08.140 prevalence of obesity in the world. But intramural, what I like, you are judged after the facts.

00:06:14.440 You have a budget, and you can do whatever you want. But every three years, you are judged.

00:06:20.820 Whereas extramural, as you know, we chase these grants, and you have to basically provide preliminary

00:06:27.020 data, hypotheses, and you are judged before doing the study. And I think you can be much more creative

00:06:33.840 being intramural than extramural. I'm sure that my colleagues intramural are going to hate me that

00:06:40.120 I say that, but it's true. They should enjoy to be judged after the facts rather than before.

00:06:46.960 So tell us a little bit about Pennington. It's obviously a pretty unique institution. You've been

00:06:52.780 there, as you say, for 24 years. But yet, I suspect it's a place that most people listening to us won't

00:06:57.800 necessarily be familiar with.

00:06:59.160 It's becoming, I think, the largest institution for research in nutrition and obesity. We concentrate

00:07:07.880 mostly on nutrition and obesity. We have about 500 people working at Pennington, and everybody

00:07:14.500 is doing research. We have no teaching. I mean, yes, I have postdocs and things like that, but no formal

00:07:21.260 teaching. And we do research, and we chase. We have maybe a budget, a functional budget of $80 million

00:07:28.660 per year. 50% or 45% of that is NIH. Extramural money coming to Pennington. We do some sponsored

00:07:38.280 projects for pharma or biotech. We have grants from associations like the American Diabetes Association

00:07:46.180 or American Heart Association and so on. And we do basic science, clinical science, and population

00:07:54.280 science, basically, which is to reach the community and implement some of the discovery into the

00:08:01.840 community.

00:08:03.060 Yeah. So the other thing you mentioned a few minutes ago, Eric, was the words metabolic chamber

00:08:08.220 and indirect calorimetry. And I think at some point, because this is going to come up in our discussion

00:08:14.000 as we get into the weeds on metabolism, it's going to be necessary, I think, for the listener to kind

00:08:20.160 of understand how those techniques work. I know I've discussed this on previous podcasts. There's at

00:08:24.980 least probably half a dozen episodes where I've explained how one uses the ventilation of oxygen and

00:08:32.240 CO2 to quite accurately estimate energy expenditure and substrate utilization. But it can never be a bad

00:08:40.620 thing to explain it one more time. So why don't you explain how it works? And you can even use the

00:08:47.140 example of when I was in the chamber for a couple of days, 10 years ago, when I was out at Pennington as

00:08:52.760 a subject or pretend subject.

00:08:55.300 Yeah, there's two things, indirect calorimetry and direct calorimetry. You generate your energy metabolism or

00:09:03.880 ATP by oxidative process. And you oxidize carbohydrate, fat, and a little protein. You don't want to oxidize

00:09:12.680 too many proteins. And this basically build up these ATPs, which are used online for generation or

00:09:21.860 maintenance of the cells or activity and so on. Now, when you have this metabolism, you produce heat.

00:09:30.000 If you have no exercise, no external work, all the energy which is provided in generating this ATP is

00:09:39.560 lost as heat. And this is direct calorimetry. And I was fortunate when I did my PhD back in Lausanne,

00:09:47.660 Switzerland, to have access to both indirect and direct calorimetry. You can really do fantastic

00:09:55.520 studies. We did a study of measuring in vivo what we call the PO ratio. How many oxygen do you need

00:10:04.360 to generate one ATP and all these kind of things by the combination of these two techniques. Now,

00:10:10.860 going to indirect calorimetry, this is an easier one than direct.

00:10:15.700 And sorry, just to interrupt you for a second, Eric, when you're doing direct calorimetry,

00:10:20.300 obviously when it comes to something like food, if you want to know the energy content of food,

00:10:23.780 you can burn the food and measure the heat. When you're doing it otherwise on a living organism,

00:10:28.780 is it possible to do direct calorimetry on something as large as a human? Or is that something you're

00:10:33.900 typically doing on a mouse or something that is small enough that the chamber in which you can

00:10:39.120 measure changes in heat is much smaller and easier to manage?

00:10:42.780 No, we can do that in humans. I was fortunate to be at a place which had one of the two direct

00:10:50.380 calorimeter. At the time, there was one in Bethesda. It doesn't exist anymore. The one in Switzerland

00:10:56.760 doesn't exist anymore. I wish I had a picture to show you, but this is a basically, I would say,

00:11:03.140 1.2 meters by 1.2. It's a little bit bigger than a cubic meter box. And you recover all the heat,

00:11:13.440 and you have dry heat by convection, and you have a layer, a gradient light layer capturing the heat

00:11:21.840 production. You collect the evaporative heat losses from perspiration, expiration, and so on.

00:11:31.220 And you merge all that, and you have a complete heat balance of the person. And we measure these two

00:11:38.400 kinds of heat, and this is basically equal to your metabolic rate. You generate energy by oxidation of

00:11:47.700 substrate, and the byproduct is heat. And with that exercise or external work, energy in is equal energy

00:11:57.680 out. And this is what we measured, and I did a lot of these studies during my PhD. But then at that time,

00:12:05.220 we decided to build a metabolic chamber, which is like an hotel room in which you can live one day

00:12:13.020 or two days. And I think you stayed for two days in one of these rooms at Pennington in Baton Rouge.

00:12:19.520 And here, we measure oxygen consumption and CO2 production. Oxygen is used to oxidize the substrate.

00:12:27.660 It produces CO2 and water. And knowing oxygen consumption, CO2 production, you can calculate

00:12:36.720 the energy expenditure or the energy generated by this oxidative process. And you can also calculate

00:12:44.540 the substrate that you oxidize. If the ratio between the VCO2, the CO2 production, and the oxygen

00:12:53.220 consumption is one, you oxidize carbohydrate. If it's 0.7, you oxidize fat. And protein is something

00:13:02.240 in between, 0.82, depending on the protein.

00:13:06.280 Yeah. And so basically, by measuring just these two things, the actual concentration of oxygen that's

00:13:13.780 being consumed and the rate at which it's being consumed, and the same with production of CO2,

00:13:18.580 you can really infer two things. One, the total energy consumption, total calories consumed,

00:13:26.560 Kcals. And by looking at the ratio of the VCO2 and the VO2, you can calculate what fraction of that

00:13:34.380 is coming from oxidizing carbohydrate versus fat. Having spent probably a total of eight days of my

00:13:40.860 life inside metabolic chambers across a period of a couple of years, it never ceases to amaze me.

00:13:46.280 Never. Just how accurately these rooms work. Because I use an indirect calorimeter all the time

00:13:53.480 measuring VO2 max. It's basically the exact same technology, but it's easier because you're

00:13:58.760 strapping the mask to your face so you have perfect access to exactly the O2 consumption and the CO2

00:14:06.860 production. But it's doing the exact same calculation. It's going to tell you exactly how much energy you're

00:14:12.360 utilizing and where the substrate comes from. And of course, in that situation, you're interested in

00:14:17.080 knowing the maximum amount of VO2 or O2 consumption. So what would you estimate is the error on the hotel

00:14:25.040 room-sized indirect calorimeter where you don't have the luxury of just slapping a mask to the person's face

00:14:31.340 for a few days? Yeah. When I was at NIH, we did a lot of reliability testing in the same person,

00:14:40.140 or you can calibrate the system. You calibrate the system with standard gas that you know the exact

00:14:47.320 concentration to calibrate the analyzers. But you can also mimic someone by burning alcohol or propane,

00:14:55.440 and you can vary the rate of burning. And this is what we did when we did this study with four

00:15:02.280 different chambers. We validated the chambers once against the other one, and we accepted to have

00:15:10.500 3% deviation for CO2 or oxygen based on stoichiometry. You know exactly how much alcohol or propane you burn.

00:15:20.860 You know how much CO2 should be produced and how much oxygen has been consumed. And this is what we did.

00:15:27.440 And you are right. They are very, very precise. And you don't have the inconvenience of the mask. I mean,

00:15:33.100 you couldn't measure with a mask for 24 hours or two days. Right. Because when I was in that chamber for

00:15:38.920 a couple of days on separate occasions, we were trying to replicate as much as possible my life.

00:15:45.240 So I had three meals prepared. I had an exercise bike. I had weights in there, equipment to do everything.

00:15:53.360 And we were very interested in seeing how that would compare with, for example, what we knew I was

00:15:59.160 experiencing in the outside world based on when we could put a mask on me. And also, separately, if you may

00:16:05.380 recall, Eric, we also spent about 10 days using doubly labeled water, which I'm sure we'll talk about at some

00:16:10.880 point as well as a more real world example of this. So all of that is to say that scientists such as

00:16:18.940 yourself have some pretty high fidelity tools to measure energy expenditure. But it comes with a

00:16:27.900 caveat, which is it has to be done under this very controlled setting. These people need to be in the

00:16:33.120 hospital and not just in a hospital, but in a metabolic ward and inside a chamber, which is basically a

00:16:38.640 NASA grade gas chamber with how many sensors, by the way, just out of curiosity, how many O2 and CO2

00:16:45.280 sensors would be in a particular chamber? We don't need many because we need to homogenize the air in 0.96

00:16:52.240 the room. And what you sample in one corner of the room is the same as the other corners. That's why,

00:16:58.360 but we have to measure humidity. You have to measure temperature because you have to do this

00:17:04.240 correction, what we call STPD, which is standard pressure, et cetera, to calculate the energy

00:17:11.400 generated by this oxygen. But yeah, I mean, it's quite phenomenal, the accuracy of those. And to go

00:17:18.540 back to your question, the accuracy or the precision is about two and a half percent. Now, if you repeat

00:17:25.700 yourself five times or, and myself, there's a little bit more variability because we vary from one day to

00:17:32.580 another one and so on. But I mean, this is quite amazing that we can calculate so precisely your

00:17:40.240 energy expenditure during a day or two days and so on. I wish we had the same system to calculate the

00:17:46.880 energy that we put in. Yeah, that's a great point. Outside of having food prepared in a metabolic

00:17:53.820 kitchen, which of course was also done for this experience, I think at best we're probably plus or

00:17:59.380 minus 10%, right? I mean, it's very difficult to estimate energy intake.

00:18:04.980 When it's in free living, it's worse. When you do that under supervision and you provide all the

00:18:12.320 meals like Kevin Hall is doing, like we're doing, then you have a good estimate and you subtract what

00:18:18.920 is returned on the plate or this kind of things. But it's not normal life. As soon as you go to normal

00:18:25.140 life and free living conditions, things are falling apart. I think that is a really nice intro into

00:18:32.560 kind of a philosophical question that will take us towards some of the experimental work. So

00:18:37.540 I was actually going to launch into the explanation of the energy balance model and talk about the work

00:18:43.580 that you and the other folks that we just talked about did a decade ago. But let's pause for a moment

00:18:49.360 on the statement you just said, which was, look, in the free living environment, we cannot estimate

00:18:54.820 energy intake worth a damn, which is to say that 99% of people out there who aren't weighing every

00:19:02.780 single morsel of food they eat every single time they open their mouth, which again is virtually nobody,

00:19:09.240 are going to have enormous variability in what they're eating. And so I put myself in that category,

00:19:14.500 right? I pay no attention to how much I'm eating in terms of weight. I'm just sort of eating by

00:19:19.320 kind of my appetite. Sometimes I overeat too much. My appetite gets the best of me. I'm surrounded by

00:19:25.580 highly palatable foods that I overeat. And other times, you know, I'm just really busy. Like yesterday,

00:19:30.780 I just didn't get around to eating that much. But here's what's interesting, Eric. My weight lives

00:19:36.400 within about a two pound variation for years. And I don't think I'm unique in that. I would guess

00:19:43.580 that you're pretty similar as well. I think many of us find ourselves in kind of a couple of pounds

00:19:48.380 of variation, most of which is probably water weight varying over years. And yet we're not really

00:19:55.080 paying attention in excruciating detail to how much we eat. So first of all, do you agree with the

00:20:02.240 assessment that that's not an uncommon phenomenon? Yes. But on the other hand, if you take your lifetime

00:20:09.060 history, maybe you're an exception, but I have gained some weight. When I got married in 1975,

00:20:18.420 I weighed 69 kilos. Now I weigh close to 77. Now it's 50 years later, of course, but you have this

00:20:28.000 change. You have also a change in your body composition. And it's very rare that people

00:20:33.660 are staying the same constantly. I mean, you may be an exception. No, no, I would not suggest that

00:20:40.800 I'm an exception. I've had probably more variation in my weight than even what you're describing over

00:20:45.580 the period of time. But I guess the question I'm getting at, Eric, is how does the body regulate

00:20:53.360 energy storage, which is effectively what is determining our weight? It's how much are we storing

00:20:59.400 as fat? How much are we storing as lean tissue? That seems very, very regulated, despite very

00:21:07.540 little control over the input and the output. We're free living animals who live in an environment with

00:21:15.180 endless inputs. So we have to somehow regulate that. And frankly, very little reason to do deliberate

00:21:22.900 outputs, right? Obviously, the majority of our energy expenditure is based on essential function of

00:21:29.080 life, just the necessary ATP production, as you described it for cellular function. But it's not

00:21:35.120 like most of us are out there expending energy deliberately, i.e. exercising and moving necessarily

00:21:42.820 to expend energy. So as we enter this discussion of the energy balance model, let's just talk about

00:21:48.780 energy balance. Why are we so largely able to conserve mass despite very noisy inputs and output

00:21:59.040 into the black box? I think I had an answer. I hope that I had an answer, but I don't. You know,

00:22:05.820 when leptin was discovered, it was a ha-ha moment. We have a signal which comes from the energy storage,

00:22:13.720 and therefore, you know, it seems to regulate food intake, also energy expenditure and all that.

00:22:20.200 I was fortunate to have access to the three Turkish leptin-deficient people that we measured in these 1.00

00:22:27.960 chambers in Baton Rouge. We thought that we would have a clue, and it was not the case. We know that

00:22:35.440 leptin is very good to defend against the loss of weight when it becomes extreme, but it doesn't work

00:22:43.200 on the other side of the equation when you creep up with your weight because you become leptin-resistant

00:22:51.620 and your leptin is not telling you stop to eat. I think that we learn a lot about the biology of energy

00:22:59.820 balance thanks to leptin. But then we need to think that we have also signals coming from the fat-free mass.

00:23:09.020 Now, what is the fat-free mass? We measure it as everything but the fat, and we call that fat-free

00:23:16.380 mass, but it's liver, it's skeletal muscle, it's everything but the fat. And I think that there

00:23:22.820 are signals that we are still chasing. John Blundell showed that we eat according to our fat-free mass,

00:23:31.000 which is basically we eat according to our resting metabolic rate, because fat-free mass is the major

00:23:37.040 determinant of your resting metabolic rate. But what are the signals? I don't know. I still don't

00:23:44.020 know. We have to be modest here and say there are still things that we don't understand when it comes

00:23:50.060 to this energy balance. Now, I can understand that why you don't gain five kilograms over this coming

00:23:57.620 year, because in response to creeping up your weight, you burn more energy. If you do the same physical

00:24:05.160 activity, this extra five kilos or 10 pounds is going to cost you more energy. Your resting metabolic

00:24:13.140 rate is creeping up, and basically you offset that. But why are we so good at maintaining, like you said,

00:24:21.980 within a couple of pounds over a year or two years or three years or five years? And I think that we are

00:24:28.240 still missing some signals, but I think that there are signals coming from when FGF21, which is a signal

00:24:35.300 coming from the liver, was discovered. I said, oh, maybe that is. Or when you have some of the

00:24:41.120 myokines coming from the skeletal muscle, I said, maybe this is it. And it's not been it. And I think

00:24:48.100 that we have to be modest and say, hey, we still have things to discover when it comes to this regulation of

00:24:56.040 energy balance. But as a population, we have not been very good. I mean, from the 1980s to 2010,

00:25:03.500 the American population has gained 10 kilograms. It's 22 pounds in 30 years. It means that there is 0.97

00:25:13.300 still the major driver is this environment. And the change in the environment has been the trigger

00:25:20.320 of this weight gain. But of course, people, some people are successful, some are less. And this is

00:25:27.800 a problem. And of course, now we have an epidemic of obesity. It has replaced the contagious disease

00:25:34.340 of the past. And now we have all these constellation of conditions which are associated with obesity.

00:25:41.560 Eric, if you were to guess, which I think is the best we can do, although I think it's informed guessing,

00:25:47.260 I don't think we're just guessing in the dark. How much of the regulation do you think is occurring

00:25:54.920 on the appetite side, meaning feedback from whatever is happening in the system? And let's just

00:26:00.460 pause it, as you said, that it's coming from the lean part of the system. So the organs, the skeletal muscles,

00:26:06.560 all but the adipose tissue, and that that is working to feed into the appetitive system.

00:26:13.740 Or do you think the balance is more on the expenditure system, where those signals are

00:26:21.260 feeding to make us move a little bit more? Or simply, as you say, it's the extra weight you have

00:26:27.480 to move around. If you're going to carry, people should pick up what 10 kilos is. That's an awful lot

00:26:32.040 of weight. If you have to carry an extra 10 kilos up a flight of stairs, and every time you get up and

00:26:37.160 move around, you're going to expend more energy. So do you have a sense of the balance of that

00:26:42.820 regulatory pressure?

00:26:45.000 Yeah. Peter, when I first joined the NIH, I did a study in Pima Indians, who are very prone to weight 1.00

00:26:53.400 gain, as you know. And we measure in 150 people, the 24-hour energy expenditure, as well as the resting

00:27:02.440 metabolic rate. And we found that there was large variability between people after adjusting for

00:27:09.720 their body size, fat-free mass and fat mass. Now we do better because we have organ size, and we do MRI,

00:27:15.740 MRI, and all these kind of things. But there is variability, and this variability is associated

00:27:22.060 with family membership. In other words, we can say that there is a genetic background to that.

00:27:28.240 But what we found was that those people in the lower tertile of this metabolic rate adjusted for body

00:27:35.880 size were at much higher risk of gaining weight. But when we try to attribute the weight gain either to

00:27:43.720 energy expenditure being low or the other side of the equation, intake was 80%. It reminds me,

00:27:54.220 there are so many systems which are basically regulating energy expenditure and food intake.

00:28:01.540 Take nicotine. Nicotine is a stimulant of energy expenditure. Smokers have higher metabolic rate,

00:28:08.620 but they have less appetite. Take the activity of your sympathetic nervous system. It is also

00:28:15.620 thermogenic, but it cut appetite. And I think that we have to understand better these two systems.

00:28:23.700 But to answer your question, I would say 80% is on the side of the energy intake.

00:28:29.800 That's sort of been my intuition as well. But because I don't keep up with this literature

00:28:34.700 nearly as much as I used to, I wanted to make sure that that was still largely the view of the people

00:28:40.340 at the forefront of this field. And you know, for example, sorry to interrupt, but we know that

00:28:45.580 exercise is pretty bad for weight loss. If you just tell people, okay, go to the gym three times,

00:28:52.260 or you even do under supervision, people don't lose weight. And Donnelly at University of Kansas has done

00:28:59.040 a ton of study like that. And the physical activity for weight loss is a B minus at best in term of

00:29:07.680 evidence that it plays a role.

00:29:10.200 And let's talk about why, because again, it is counterintuitive. I know this, and I preach this

00:29:15.140 to my patients left, right, and center, which is, you probably heard me say, Eric, I will go to my

00:29:19.180 grave maintaining, I suspect, until new evidence emerges that exercise is the single most important

00:29:24.360 thing we need to do for health. But I'm always quick to follow that up if asked with, but it's

00:29:29.340 not the tool you're going to use to regulate body weight. Energy intake, nutrition is the more

00:29:35.720 important tool to regulate body weight. And so explain to people why perhaps, if you could provide

00:29:42.640 a teleologic explanation for why, because it is counterintuitive. If you just look at the human

00:29:48.100 body as a machine, you should have no preference for expenditure of energy versus input of energy,

00:29:55.500 you should say they're equally efficacious. But again, any clinician will tell you that's not true.

00:30:01.360 And any scientist will tell you that's not true. But do we have a reason for why it's not true?

00:30:07.080 I think, first of all, if you try to put calories on your exercise, it's easy on a bicycle,

00:30:14.500 you know, the efficiency, 25%, you know, the workload, and so on. And you can calculate or

00:30:21.900 you can use your mask and measure oxygen consumption. It's very easy like that. And I think

00:30:28.620 that there is a compensation. Now, exercise, very vigorous exercise is anorectic. You don't want to eat

00:30:36.400 after you finish a marathon, or at least I don't.

00:30:40.120 No. And by the way, just to interject, I interviewed George Brooks from Berkeley recently,

00:30:44.100 and he shared with me on the podcast something I didn't know before, which was that lactate

00:30:49.040 specifically is probably partially driving the anorexia we experience following intense exercise

00:30:56.020 that might not be present with low intensity exercise. So I thought that was an interesting

00:31:01.280 way to connect a fact that I think most people appreciate, which is go off and do interval

00:31:06.920 training. The last thing you want to do for the next hour or so is eat.

00:31:10.100 But light exercise has the opposite effect. I think it drives a little bit appetite. And I think

00:31:19.140 Tim Church, who was at Pennington, did a study called eMechanic. And basically, they measured every

00:31:27.300 calorie spent on exercise, on a treadmill, on a bicycle ergometer, and all that, and look at the weight

00:31:35.220 of the people with these different doses of exercise. And there was a compensation. Now,

00:31:41.140 what he didn't measure was to use doubly labeled water. Did they compensate by being less active out

00:31:48.660 of their periods of exercise? You have 90 minutes of exercise, but then, you know, you relax a little bit

00:31:56.100 more rather than fidgeting or moving and so on, or you sleep a little bit longer. This he didn't measure,

00:32:02.740 but there was this compensation with food intake. And I think, first of all, I didn't say that

00:32:09.660 exercise is not good for health. Right. I didn't suggest you were. I was just making sure people

00:32:14.600 knew the distinction. Because I want to make sure, because I'm an aficionado of exercise. I know you

00:32:19.480 are. I know how good it is for health. Yes, yes. But it's not as good for weight control

00:32:24.140 in general. And I think that you have to do the calculation of how many calories are burned

00:32:31.100 when you run a K or a mile and so on versus how quickly you can ingest the calories, the same amount

00:32:40.580 or much more. And I think that there is a difference here that people understand. But exercise and physical

00:32:47.140 activity is the key for weight loss maintenance. And you know, the weight registry from Rena Wing and

00:32:55.100 Jim Hill, they showed that those who were successful at maintaining the weight loss at five years after

00:33:03.240 the intervention were those who engaged in more physical activity. And I still believe that a

00:33:10.320 nutritional approach to weight loss without physical activity or exercise prescribed is not a good

00:33:18.620 strategy. We should implement both and try to have people enjoying the exercise. Most people,

00:33:27.560 I remember one of my colleagues, Richard Mergman, said, I would never exercise. I'd rather be sitting in a

00:33:34.020 cold bathtub to generate some heat rather than exercise. And there are some people who cannot

00:33:41.000 exercise. But I think, again, this is from childhood, that you take the taste of exercise, that you become

00:33:48.640 more physically active in the rest of your life. It's not at the age of 40 because you have too much

00:33:55.700 weight that they can tell you, oh, you have to do your 150 minutes per week of moderate to vigorous

00:34:02.340 activity and all that.

00:34:04.020 It doesn't work in general. But I think physical activity is a key point in metabolic health in

00:34:13.200 general. I agree with that completely. When I look at the data from Jim Hill that you've just cited,

00:34:19.540 I've always found it difficult to infer the direction of causality. And you're correct that

00:34:25.040 the people who are most successful in maintaining weight loss are going to be on balance far more likely

00:34:31.160 to be people who do a lot of exercise than those who don't. And so, of course, it could be that doing

00:34:36.100 a lot of exercise is a valuable tool to drive weight maintenance, i.e. maintenance of energy

00:34:41.900 balance. Alternatively, it could be the people who metabolically get fixed through weight loss are the

00:34:48.400 ones that have an easier time exercising. But I will say this, and I'm curious how robust the data are.

00:34:55.460 I do think one thing that exercise can do for you, and I feel this personally, and I know a lot of my

00:35:01.960 patients do as well, is yes, you could go ride your bike for an hour and you could burn 600 kilocalories

00:35:09.100 and you can eat 600 kilocalories in way less than an hour. But exercise seems to sharpen your appetite

00:35:16.560 to a point that makes you a more responsible eater, if that makes sense. In other words, I think it hones

00:35:23.440 your appetitive signals. And the one thing you as the individual have to do is just be mindful of the

00:35:29.560 speed at which you eat so that you give the brain a moment to recognize what is happening. So let me give

00:35:37.180 you an example of how that works tangibly. If I do a zone two bike ride for an hour, again, that's going

00:35:44.680 to be for me, I know because I measure it, I can measure it exactly. That's going to be about 750 to

00:35:49.760 800 kcal is how much energy I will expend. Above your resting? No, total. Total energy expenditure is

00:35:57.980 750 to 800 kcal in the hour. So call it 800 to make the math about easy. So if I wait an hour before I

00:36:08.320 eat, and I don't eat very quickly, I don't do the usual Peter Atiyah, there's someone who's going to

00:36:14.740 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

00:36:20.220 the day, I won't have a hyperbolic appetite. Conversely, if I go to eat within 20 minutes, 30 minutes, and I

00:36:28.160 pay no attention to the speed at which I eat, I can easily consume 1000 calories in that one sitting and

00:36:34.840 abrogate the entire energy effect of the exercise. Obviously, I'm still getting all the benefits of the

00:36:40.060 exercise. So first of all, curious if you have seen this, if you have any insight into the effect of exercise on

00:36:48.120 how we subsequently regulate appetite, and how we might sense the hunger hormones, everything from

00:36:55.520 leptin, ghrelin, and even GLP-1? I don't have an answer to that, because it's not my field energy

00:37:02.800 intake. But on the other hand, you just mentioned the GLP-1. I think these gut hormones, I mean, you take

00:37:11.320 GLP-1, GIP, CCK, PYY. Glucagon. Glucagon. If you put glucagon in insulin, I was talking about the gut,

00:37:21.100 the GI hormones. Anyway, I think that there is no question now we start to know more, because they are

00:37:28.040 such good targets for weight management. We start to know more about the physiology of these hormones.

00:37:36.160 And I think that there is no question in my mind that the speed at which you deliver this food in the stomach

00:37:44.940 and it leaves the stomach is very important for the kinetic of these gut hormones, which are important for

00:37:51.820 the regulation of your food intake in general. I think this is one of the things that these GLP-1 and

00:38:00.580 combination of peptides now has shed light on is that they are potent modulators of your intake.

00:38:10.300 Now, the interaction between the exercise that you do before and the meal that you have 20 minutes

00:38:16.660 after and the speed of the meal and all that, I don't know this triangle how it works, but I think

00:38:23.660 it would be a very good topic of research to know the interaction between your physical activity or

00:38:31.300 the bout of exercise, the speed at which you ingest the calories and the delivery of these gut hormones.

00:38:39.880 And again, to make it an even more interesting experiment, but now much more complicated,

00:38:45.400 you introduce a fourth variable, which would be the macronutrient composition of the meal itself at

00:38:53.400 isocaloric substitutions. And maybe that's something we'll talk about now as we go back to the idea of

00:38:59.460 energy balance. So going back to how you and I met and the kind of work that we were interested in,

00:39:05.940 we were interested in a question, a very specific question. And I like specific questions because

00:39:11.200 the more specific the question, the easier it is to design an experiment to test it. And the more

00:39:16.700 likely you are to get an answer that you can interpret as highly probable. Feel free to modify

00:39:21.460 this, Eric. But I think the question we were trying to ask was under isocaloric conditions,

00:39:27.700 does varying the macronutrient composition specifically between carbohydrate and fat while holding

00:39:35.200 protein constant have any bearing on non-deliberate energy expenditure? First of all, would you agree

00:39:42.800 with that statement? And then we can turn it into English, but just scientifically, would you agree

00:39:46.460 that that was the question we were trying to answer? Yes, it was the question. Isocaloric is the

00:39:52.240 important word. That's right. Because now can you do that in the everyday life under not isocaloric

00:40:00.140 condition, but what you want to eat? Which of course, we'll talk about that in spades.

00:40:05.200 But this was a very important question, although truthfully, I think most people felt the answer

00:40:09.740 was known. Well, I guess I should translate what I just said into English. Feel free to interject and

00:40:14.420 help me. What we basically said was, if you give people, a bunch of people, meals, let's just not

00:40:20.660 even use a bunch of people, one individual. You take one individual and you feed them meals on subsequent

00:40:27.560 days or weeks or whatever, where you don't change the total number of calories one iota. You don't even

00:40:34.100 change the amount of protein. You simply manipulate the ratio of carbohydrate and fat, such that

00:40:40.580 obviously when one goes up, the other has to go down, such that you can preserve the total number

00:40:44.760 of calories. And when you feed people meals under those conditions, the null hypothesis should be

00:40:51.300 that their energy expenditure doesn't change. Why would holding a fixed number of calories in

00:40:59.380 to this system change the number of calories that the system expends? Again, it's important that we

00:41:04.860 held protein constant because we know about the thermogenic effect of protein. So that can actually

00:41:10.300 sway things if you change protein a lot. But the alternative hypothesis that was being tested was,

00:41:15.720 no, actually, if you really swing fat and carbohydrate a lot, you could indeed change energy expenditure.

00:41:24.340 Would you add anything to the English version of the question?

00:41:28.060 No, I think it was a question. And we were a little bit skeptical. It was the start of the

00:41:34.420 carbohydrate insulin model. We're used to the energy balance model, but I think it was a good question.

00:41:43.180 And I like the way we debated that with the red team, the blue team, if I recall correctly,

00:41:49.280 and we were arguing about the best design. And at the end, now, if I had to redesign this study,

00:41:56.000 I would do it differently.

00:41:57.860 Tell people how it was done, and then tell people what you would do different. Because

00:42:02.660 this is probably an experiment that might be worth redoing under improved conditions. But I'm very

00:42:08.540 curious, because I haven't given this much thought, but I'm very curious as to what you would do

00:42:12.020 different. Explain to people how this experiment was done.

00:42:14.160 The experiment was done to do a isocaloric intake over four weeks, I think. We had the

00:42:22.620 baseline diet, which was the SED diet, the standard American diet. And we had after a low-carbohydrate

00:42:32.580 diet or ketogenic diet for four weeks. And the hypothesis was that, and this was led by

00:42:40.100 the people, we've been bringing up the carbohydrate insulin model, saying that you create a basically

00:42:48.760 uptake of these substrate from the blood into the storage, mostly the adipose tissue and maybe some

00:42:56.820 in the liver. And you deplete from a substrate or energy substrate your circulation, and it puts you

00:43:06.300 in a state of semi-starvation. What is happening when it goes to the brain when you have semi-starvation,

00:43:14.480 you shut down your energy expenditure and you increase your appetite. And this was playing with

00:43:21.480 that, saying that now if we switch to a diet which is going to be less conducive to storage,

00:43:30.500 i.e. less insulin secretion, because it was less than 10% carbohydrate, between 5% and 10%,

00:43:39.480 if I recall correctly, we would cause this, basically this semi-starvation condition in the

00:43:46.300 systemic circulation. And this would basically increase your energy expenditure. And I think

00:43:53.240 that David Ludwig at the time had some data already showing by doubly labeled water that there was an

00:43:59.780 increase. But we are arguing that doubly labeled water is not precise enough. It goes back to our

00:44:05.960 discussion about indirect calorimetry. And we said, why don't we do it in the confinement of a metabolic

00:44:13.440 chamber? And this is what we did. And to my surprise, there was an increase, at least early, because we

00:44:21.040 had couples of, I didn't go back to the papers, but we had measurements every week for two days, if I recall

00:44:28.320 correctly for the four weeks. And the first week and maybe the second week, there was an increase

00:44:34.780 which was significantly higher in sleeping metabolic rate, as well as 24-hour energy expenditure

00:44:41.400 under the ketogenic diet. And boom, yes, there is an increase. Now, was it a significant physiological

00:44:50.660 increase? I mean, we can argue about that. When we talk about metabolic adaptation, because people are

00:44:56.680 talking about that now, we always say we need at least 150 calories. In the study, we achieved

00:45:03.860 statistical significance, but it was just above 100 calories per day. And I was surprised myself of that.

00:45:12.380 Now, we didn't measure the appetite of the people. I mean, were they less hungry under the ketogenic diet?

00:45:19.500 Now, it brings us to all the weight loss studies which have been done either with a low-fat diet or

00:45:26.840 low-carbohydrate diet. If you do a meta-analysis, it seems that there is a slight advantage to the

00:45:33.500 ketogenic diet for the weight loss period. Basically, I was surprised, and I was, as a Swiss, I was kind of a

00:45:42.020 little bit more neutral sometime, rather than the two camps, the red and the blue. I was surprised that

00:45:48.540 there was this effect, but it disappeared at the fourth week or the third and the fourth week.

00:45:55.240 So again, just to make sure people understand that finding. So the finding, and I'm glad you

00:45:59.760 remembered. I forgot the numbers. I didn't think it was 100. For some reason, I thought it was 90. But

00:46:03.980 again, who cares at that point? We had sleeping metabolic rate or 24 hours.

00:46:09.340 That's right. That's right. What the study basically found, and the study was, again,

00:46:13.620 it was a very well-designed study in that there were maybe 16 subjects, which is obviously sounds

00:46:19.380 like a very small number, and it is. But given the complexity and cost of keeping 16 subjects

00:46:24.580 housed in a hospital for a month, and then also putting them in metabolic chambers every few days,

00:46:30.960 this isn't a study that you're going to do with 500 patients. But to increase the statistical power

00:46:36.660 of the study, it was a crossover study, which meant that every patient was their own control,

00:46:41.940 and that's what allows you to get away with having so few subjects. So interestingly, I think it's safe

00:46:47.840 to say that the effect size was large enough that it suggested a signal, but not so large that it

00:46:55.420 dispositively answered the question. And in many ways, it served as fodder for more questions,

00:47:01.980 which I guess is not uncommon in research. It's very rare that one experiment gives you the

00:47:07.520 definitive answer, and rather, it just points you in a slightly different direction and gives you

00:47:12.360 more questions, which then begs the question, which is, if resources were not a limit, what would be

00:47:18.500 the follow-up experiment to that? I wish I had an answer. I mean, I'm tortured between very well

00:47:26.080 controlled studies. We do, like Kevin Hall does, where you basically domicile the people, you feed

00:47:34.840 them whatever you want, you know exactly what you feed them, and you look at outcomes. I mean, I like

00:47:41.380 that, but then how do you transpose that in real life? And one of my mentors was JP Flatt, and JP Flatt

00:47:49.840 says, obesity scientists, they have a tendency to either look at the expenditure side of the equation

00:47:56.780 or the energy intake, but they never put the two together. And he was right, because a lot of studies,

00:48:04.780 you have an outcome which is on this side or on this side, and you maintain the other one.

00:48:09.760 And I think that, to me, designing a study would be, first of all, in free living condition, but it

00:48:16.800 would need a lot of people, because you know you can prescribe all what you want to people. They're

00:48:23.320 going to do whatever they want at the end of the day. Some of them, if you screen them very carefully,

00:48:29.040 are going to be much more compliant and adherent to the instruction. But this is what needs to be done.

00:48:35.960 And by changing here, we changed not the calories, just the composition of the two diets, 10%

00:48:44.680 carbohydrate versus 45% or 50% carbohydrate in the other diet. And that's all what we did. And I think

00:48:54.680 we concentrated only on the energy expenditure, but we even didn't ask very much. They had visual

00:49:02.060 analog scale if they were more hungry or all these kinds of things. But we kind of ignored the food intake

00:49:09.220 that we were clamping. And this is not real life. If you do something, and you know, you talk about

00:49:16.240 engaging on physical activity regimen or exercise and all that, I mean, you have to look at the impact on

00:49:24.620 the other side. And this is the same question that I have. Now, I'm not helping you in designing the perfect

00:49:31.660 study by saying that. But on the other hand, again, we have good tools to measure energy expenditure. We have

00:49:40.080 reasonably good tools to measure where do the calories come from. But we have no tools to measure energy intake. But it's

00:49:50.340 going to come. I bet you that within, I may not be here, but within a couple of decades, we'll have a

00:49:58.300 caller here, which is going to measure your calories coming from fat, carbohydrate, or protein.

00:50:04.500 I think it should be sooner than that, Eric. I mean, I really do think as image recognition gets better

00:50:10.480 and better with AI. To me, I would actually hope that within a decade, if not less, we are at the

00:50:17.700 point where if you can weigh something and take a photograph of it, we should have enough training

00:50:24.820 data that you should be able to know exactly what is in it. Now, that doesn't account for how much of

00:50:30.100 that thing you eat. But assuming you have something that you weigh and you can photograph and you say,

00:50:35.600 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

00:50:41.360 within 5%. What is the caloric density of that food and the macronutrient breakdown? I wouldn't

00:50:47.660 have said that five years ago. Like five years ago, I would say that's impossible. But given what I'm

00:50:52.140 seeing with image recognition in AI, that to me has to be the future for nutrition research and in a

00:50:59.900 free living environment. I think you put your finger on the exact point. And now I'm the PI of one of the

00:51:06.480 six clinical sites for nutrition for precision health. This is basically a ancillary study of all

00:51:15.200 of us. All of us is a million Americans who are basically providing biosamples, access to the health

00:51:24.240 electronic records and all that. And then this sub study is really to look at the intersection between

00:51:32.040 their health and their nutrition. And there is three modules. One is on 10,000 people. And one of the

00:51:41.380 way to measure is exactly this little camera sitting on your glasses, and also a system which is measuring

00:51:50.600 if you are chewing or not. It's not enough to see the food and going, but is it chewed? And I agree

00:51:58.880 with you. I mean, I was not thinking about that. I was thinking about something much more like a CGM.

00:52:06.020 Who was dreaming of CGM 30 years ago when I was working with the Pima Indians? We were not thinking 1.00

00:52:12.500 about that. Now you have CGM and you can measure your, probably your insulin from contact lenses and things

00:52:21.800 like that. And I think this progress are going to help us. Now, are we going to be smarter designing the

00:52:27.860 study? I'm not so sure, but we'll have the tools to be a little bit more real life rather than incarceration

00:52:36.520 in a metabolic ward. Yeah. I mean, I think that, and again, it's, you're so much more thoughtful on

00:52:43.740 this, Eric, because it is your world. It's not my world, but I occasionally will think about it.

00:52:48.440 But as I'm sitting here now reflecting on it with you, my intuition is that the questions are

00:52:53.480 complicated enough that the difference between efficacy and effectiveness have to be separated in

00:52:58.340 studies. And I think if this question of macronutrient composition, isocaloric macronutrient

00:53:06.540 manipulation impacting energy expenditure is to be put to rest, it can only answer that question. It

00:53:14.160 cannot attempt to answer the impact of appetite as a movable variable. It can do it as a swing variable,

00:53:21.640 meaning, as you said, you can force people to eat a clamped amount of food and then measure

00:53:27.640 subjectively or even using PPY and ghrelin and other hormones. So somewhat objectively,

00:53:34.820 somewhat subjectively measure a petitive response to that. I think the biggest mistake of that study

00:53:40.440 was actually not creating a big enough divide in the macronutrients. I think as an efficacy study

00:53:47.120 that was testing a theory, just a theory with, again, you start with a very theoretical response

00:53:54.520 and then you build from there to say, okay, is this theory applicable? In retrospect, I think it should

00:54:00.640 have been more extreme in the carbohydrate and fat differences. I think one should have been, if the

00:54:07.320 carbohydrate insulin model was being tested, one should have been a very, very, very high insulin diet and a

00:54:14.300 very, very low insulin diet that were isocaloric. And by the way, let's assume you do that experiment and

00:54:20.400 you get a difference of 250 kcal a day. Well, you still don't know if a ketogenic diet is a better

00:54:28.060 diet in a free living environment because you're probably not comparing it to somebody who's eating

00:54:33.900 80% carbohydrates. So then you still have to do the next experiment, which is maybe the one we did.

00:54:41.180 And then ultimately you have to be able to do the free living experiment where people make their own

00:54:48.720 choices based on appetite. That has to be sequenced, I think, to answer the questions. These are difficult

00:54:55.740 and costly experiments to do. Also, one thing that I still have in my mind, all the studies which came

00:55:04.500 from Europe about modulating the composition of the diet and look at the impact on the matching of

00:55:14.860 your RQ to the intake. Even Steve Smith that we're working with did this study called ADAPT. He was

00:55:24.100 isocaloric all across, but all of a sudden you continue with more fat. The FQ of the diet,

00:55:32.120 the food quotient, was decreased. And then it takes days to basically have a matching of your RQ to the

00:55:41.820 FQ, which means you oxidize what you eat. Whereas if you do the contrary, you increase carbohydrate,

00:55:50.560 it takes one day. And that's why I still believe. And back in Switzerland, we did this study where we

00:55:58.180 were giving extra fat as LCT, long chain triglyceride or MCT, because the MCTs are oxidized quicker.

00:56:09.460 And we found that against the culprit is always the fat. And we are very good at matching

00:56:18.480 carbohydrate oxidation to carbohydrate intake. Very good. It's very difficult. First of all,

00:56:24.920 you have what? 500 grams of glycogen stores, 100 in the liver, 300 to 500 in the muscle. That's all.

00:56:33.560 It means if you have a lot of carbohydrate, that's a huge signal. And protein, the same thing. You know

00:56:40.580 how difficult it is to build up your muscle mass or your protein mass in the body by just eating more

00:56:48.980 protein. You have to exercise or you have to take anabolic steroids or whatever. But the fat is the

00:56:57.040 one which is not regulated. That's why I still have this problem with the carbohydrate insulin model.

00:57:03.720 It works. Let's say there was a slight increase in energy expenditure. It seems to work for weight

00:57:10.540 loss. It's better with ketogenic diet than with a low fat diet. But in your entire life, I don't think

00:57:19.320 it works. And piling the fat. I mean, you have done some of that. I did it for three years. My intuition

00:57:27.680 is that this always sounds like a cop-out when you say it. And I hate when people say it. But I do think

00:57:34.200 it's kind of true when it comes to nutrition. There's so much heterogeneity between individuals,

00:57:40.740 both genetically and environmentally, that we have to release our agenda from this idea that there is

00:57:49.400 a perfect diet for everybody. Never mind health, even when it comes to weight maintenance. Let's pick

00:57:55.920 a simpler variable, which is nothing but a subset of health. Weight maintenance as one piece of the

00:58:02.740 health puzzle, it strikes me as impossible to suggest that there is a true diet that is good for

00:58:10.720 everybody. I think that, again, based on a person's genetics and their own living evolution, i.e. their

00:58:18.480 epigenetics and their environment and other factors, psychological factors, which of course can be quite

00:58:24.160 genetic, there are either several or few dietary options that are easiest for a person to adhere to

00:58:33.560 to maintain weight balance. I think that carbohydrate restriction, especially extreme

00:58:40.260 carbohydrate restriction, happens to be one of the more efficacious ways for individuals to restrict

00:58:49.620 something in the larger service of restricting calories. Because at the end of the day, whatever

00:58:56.740 you choose to restrict, whether it be certain macronutrients, alcohol, the time during which you allow

00:59:05.220 yourself to eat or just directly the number of calories, some form of restriction is necessary

00:59:13.700 for weight balance in an infinite food environment, which is the one that we have now found ourselves

00:59:21.340 living in for the past 0.01% of our genetic existence as a species. It's a very new problem that we have

00:59:28.660 to be so surrounded by infinite nutrition and therefore it requires some degree of restriction.

00:59:37.020 And you just have to pick your poison. Do you want to directly restrict calories? We're going to talk

00:59:41.420 about that. That's the calorie study. Do you want to restrict the timing in which you eat? We're going

00:59:45.680 to talk about that as well. That's time restriction. Make a smaller and smaller eating window. Or do you just

00:59:51.120 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.

00:59:56.680 I don't eat animal protein. I don't eat whatever. And if I do that enough, I'm going to also restrict

01:00:03.100 energy intake. That's not a very satisfying answer. I think people want to believe that there is one

01:00:09.080 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

01:00:18.080 era of precision medicine or personalized medicine. And I think that this is what the NIH is embarking

01:00:26.660 on when they do this nutrition for precision health, when they do this study that I'm also a PI of a

01:00:34.500 clinical site, which is molecular transducers of physical activity, to look at in lieu of your

01:00:42.700 genetic background, your environment, your socioeconomical status, one size does not fit all.

01:00:49.780 We have the dietary guidelines. They are applied for the entire nation. And they tell you, you know,

01:00:57.880 every time it's the Mediterranean diet or the DASH diet, which are the best and all these kind of

01:01:04.160 things, but not for all. And I think that this is where we are going to have a huge development. It's

01:01:11.620 to go, I don't think it's going to be individualized, but at least for groups of people

01:01:17.600 having the same, you know, different strategies and restriction has to be one of that. But now,

01:01:26.160 how do you restrict? Do you restrict by public policies, by taxing things?

01:01:32.880 I feel strongly against that. But of course, I would describe myself as a pretty staunch libertarian

01:01:37.760 when it comes to that kind of stuff, not an extremist. I do believe there's a role for

01:01:42.120 government, but I think long-term compliance and trust on the part of the public will not come

01:01:48.060 through that type of environment. So what I think is really the answer is one is better education.

01:01:54.820 And I don't mean education, like we're going to sit kids down in first grade and teach them this.

01:01:58.980 I just mean public education and better advocacy and education from the scientific and medical

01:02:04.040 community, which says kind of what I just said a few minutes ago, which is, hey, you're not broken,

01:02:08.960 you're not defective, but you might be one of the people for whom the average approach is not going

01:02:14.400 to work. But step one is every one of us needs to accept that in exchange for living in the greatest

01:02:22.660 period of civilization, which is where we all live, none of us would trade places with the king of France

01:02:30.680 or the king of England 500 years ago. You just wouldn't do it. I'd rather be the most average

01:02:36.180 human being in 2024 than the single most important person in 1400. So we just have to accept the fact

01:02:42.800 that we are all so shockingly privileged to be alive at this moment, but that privilege comes with a

01:02:49.460 couple of expenses, comes with some costs. And one of the costs is we live in an environment that has a

01:02:56.820 little bit of toxicity with respect to things like food. And we have to pay a price. We have to pay a

01:03:03.220 price. We're going to have to make a trade-off and a restriction. And I just think people knowing that

01:03:09.040 can take a breath and go, ah, okay, I'm not broken. Now, different people will have to do a greater

01:03:16.060 amount of restriction. That's just the way the cards crumble. Not everybody has the same IQ.

01:03:20.940 Not everybody has the same athleticism. Not everybody has the same emotional intelligence.

01:03:25.760 And not everybody has the same metabolism. So some people are going to have to be not very

01:03:30.980 restrictive. They just have to be somewhat mindful of what they eat and the cards fall into place.

01:03:35.040 That's my wife. Barely thinks about anything and it all works out. And you get people like me in the 0.70

01:03:40.460 middle. I have to be thinking about it every day. Not crazy. It doesn't have to occupy my every minute

01:03:46.600 of my life, but I can't eat on autopilot. And of course there are people even further where

01:03:52.480 unfortunately they're going to have to be very mindful and restrictive of what they eat in lieu

01:03:57.860 of potentially using drugs like GLP-1 agonist. So that's step one, Eric, in my view. And then step

01:04:02.900 two is, which goes to your point about personalized precision nutrition. Then what we need are the

01:04:08.400 technological breakthroughs that allow people to become their own laboratory animals and allow people

01:04:14.420 in the real world, in the free living environment to do the empirical stuff that you and I are talking

01:04:22.020 about and will talk about with respect to the experiments to test the hypotheses. How much fat

01:04:27.180 and protein and carbohydrates should I be eating to optimize my appetite, to optimize and regulate my

01:04:33.220 appetite and my energy expenditure? And again, we're sitting here now talking about the fact we can't

01:04:38.320 even give people that tool yet. We don't have the tool that allows the person to do that test

01:04:44.920 with any degree of accuracy. So I know that's not the most optimistic response, but that's kind of my

01:04:50.840 view is like that has to be the direction we go in as opposed to continuing to try to answer the what

01:04:57.860 is the best diet question, which obviously you're not trying to answer because you realize the futility of

01:05:03.480 that as well as I do. But I still think many people in the public view that as the question that's

01:05:08.920 trying to be answered.

01:05:10.400 Yeah, you're correct. And I see that with this new study that we are doing, people, when you say the

01:05:16.220 word diet, they think weight loss, they think something miracle is going to happen. And we tell them,

01:05:23.220 no, no, it's we want to know what you eat in relationship with your health and your genetic makeup and your

01:05:31.720 environment and all these kinds of things. I'm with you on that. Now, I'm a little bit more

01:05:38.040 pessimistic that I always say education is a major cornerstone of that. But we also are going to need

01:05:47.000 to have public health policies. I mean, it's been done with trans fat. It's being done now in South 0.56

01:05:54.080 America with black label on dangerous thing in ultra processed food and all this kind of thing.

01:06:00.840 I don't know that I'm opposed to labeling things. I guess I just, I do worry a little bit with excise

01:06:08.260 taxes on things. Although in fairness, if I'm going to be critical of my own point of view,

01:06:12.760 I do support excise taxes on tobacco. I do think alcohol and tobacco should be taxed to cover their

01:06:19.780 consequences on the back end. So maybe I need to revisit my thinking on this, but I do sort of bristle

01:06:25.460 at the idea a little bit of taxing certain foods more than others. Only I think, Eric, because I've

01:06:32.200 lost faith in the government to determine on the margin what's healthy and what's not healthy.

01:06:37.380 Is butter healthy or not healthy? Should butter be taxed disproportionately relative to bread? I mean,

01:06:43.720 that's an area where I simply don't want anybody at the FDA or the USDA or the ATF or anybody else

01:06:50.840 weighing in. But anyway, tell me more of what you think from a policy perspective would be helpful.

01:06:56.840 I think that the government should work very closely with the nutrition companies. And the nutrition

01:07:04.560 companies have been masters at doing two things, to produce very palatable and very cheap food. I

01:07:13.480 remember John Blandell saying, those are the two things that people don't compromise on. It has to be

01:07:20.200 tasty. They need to enjoy it. And it needs to be cheap. And this is what we have now. I mean,

01:07:27.780 a lot of added sugar, a lot of fat, and it's very delicious and all these kind of things. But we have

01:07:33.520 to reverse some of that. And I think that now we know enough about that. And I was at a conference

01:07:41.000 a month ago in Sao Paulo, the International Congress of Obesity, and they have been very, very active in

01:07:48.000 South America when it comes to ultra-processed food. And I was impressed to see even, you know,

01:07:54.340 the protein content of all the ultra-processed food is on the side of 12 to 13 percent. Whereas,

01:08:03.660 you know, we need something between 15 and 18 percent. And if you believe in the protein leverage

01:08:11.200 theory, this is an important factor. Tell folks what that is. I've talked about

01:08:16.920 it a little bit on the podcast, but let's remind people what that theory is. I don't think there's

01:08:21.160 any one theory. I think it's an amalgamation of theories, but I actually think there's some

01:08:25.260 validity to this theory. Tell folks how that works. I mean, in simple words, it's that we eat for a given

01:08:31.500 amount of protein, which is proportional to our body size and all that. And by the way, I remember when I

01:08:37.540 were studying, we were saying during a low-calorie diet, you need 1.2 gram of protein per kilogram

01:08:45.360 of body weight or this kind of things. But the experiment started with insects, and then they

01:08:51.640 went in rodents, and they manipulated the content of protein of the diet. And they found out that

01:09:00.420 basically the intake was all to gravitate around a protein content which was sufficient for the

01:09:10.000 weight of the animal and so on. And this is called the protein leverage theory. And now I'm a little

01:09:18.100 bit more skeptical when Simpson and the two guys in Australia are saying the pandemic of obesity has been

01:09:26.380 parallel by a decrease in the protein content of the diet. And this is what has triggered the

01:09:33.340 increased caloric intake to get the same amount of protein.

01:09:39.160 Yeah, it's basically they're arguing that it's not that total protein has gone down. It's that

01:09:42.860 protein density within food, especially processed food, has gone down. And so people are seeking

01:09:48.420 more calories to subconsciously get more protein. And the data, I mean, I reviewed these data in

01:09:54.640 huge detail for a previous podcast. The data in the rodents is staggeringly compelling. It's

01:10:01.380 unambiguous. A rodent will consume to its level of protein in the studies where this has been tested,

01:10:07.500 even if it means eating way more calories. I do think humans must be more complicated because I

01:10:12.340 don't think the human literature are quite as clear. Do you?

01:10:15.980 No. Once again, with rodents, you can feed them whatever you want. With people, you don't.

01:10:22.180 I remember Dr. George Bray saying, you know, these dietary recall are not worth the paper on which

01:10:28.900 you write the data. Yeah, I couldn't agree more with Dr. Bray on that.

01:10:32.900 This is where we lack tools to know exactly your glasses with the camera or whatever is going to be

01:10:39.600 useful. But I think we need better ways of measuring what people eat and what is the content of their meal

01:10:49.180 and all these kind of things. And that's why it's so easy to do that in rodents, because you feed them

01:10:55.760 with this or these three diets or five diets and you look at how much they eat. You weigh the food and

01:11:02.160 the calories. A little bit more pessimistic.

01:11:05.420 Yeah. You mentioned that George Bray made this funny comment offhand about the role of food frequency

01:11:11.900 questionnaires, which is they're not worth the paper they're written on. And of course,

01:11:15.160 John Ioannidis has famously said that the food frequency questionnaire belongs in the waste

01:11:20.180 basket. I mean, that's basically the only place it belongs. And yet the food frequency

01:11:25.180 questionnaire is the backbone, is the scaffolding of nutritional epidemiology. And so do you as an

01:11:35.220 empirical scientist, an experimental scientist, have concern at how much food policy is being driven

01:11:44.640 by nutritional epidemiology rather than experimental science? When we understand why, why there's an

01:11:52.280 effort around nutritional epidemiology, because these questions are otherwise difficult to answer.

01:11:56.600 But given the fidelity of the data, i.e. the thing you put in the system to calculate isn't worth the

01:12:05.120 paper it's written on, according to basically anybody who understands how it works. So how do we reconcile

01:12:10.580 this problem? Which is, I mean, even things that we're talking about now, which is the role of

01:12:14.900 ultra-processed food. Well, those are determinations from epidemiology. It's epidemiology that's at least

01:12:20.260 telling us or hinting to us that ultra-processed foods on balance are bad. That confirms what I think

01:12:25.840 most people would intuit. But where do we draw the line between what we are letting nutritional

01:12:33.000 epidemiology tell us from a health policy perspective to where maybe it's overstepping and getting things

01:12:39.820 wrong because of the data integrity problem? I think the problem is really jumping from basically

01:12:46.620 nutritional epidemiology to policies or labeling or dietary guidelines. And I think, to me, now we are at a

01:12:57.040 point that the epidemiology should basically provide us with hypotheses to be tested in better control

01:13:07.020 situation. And maybe in domicile with full feeding of people. These studies are expensive, but we are

01:13:15.740 missing a step. And I think, once again, these new studies from NIH, this consortia of nutrition for

01:13:23.740 precision health, are going towards this direction of basically, you are right, the food frequency

01:13:30.540 questionnaire is here every day for 10 days in this module one of the study. But then there are these

01:13:37.740 other ways. There is the remote photography system that you take a picture with your phone of the plates,

01:13:45.260 you have these cameras and all that. And I think that now I hope that we're not going to make policy

01:13:51.900 only or policy or guidelines only based on the nutritional epidemiology, but also on studies,

01:14:00.620 basically testing some hypotheses related to what the nutrition epidemiology has shown.

01:14:07.420 I think all roads, both from a personal health perspective and from a nutrition science perspective,

01:14:13.900 need to point towards AI. Such a cliche thing to say right now. Basically, everybody's saying AI is

01:14:19.420 everything. But when people ask me, how could AI change medicine? It's not by being a better doctor

01:14:26.700 and being better at diagnosing if you have syphilis or not. Sure, that's valuable. A lot of it's in the

01:14:32.700 very unsexy stuff. Image recognition and radiology, insurance, billing, reconciliation, and this. When you

01:14:40.220 want to talk about biomedical research, the thing that gets all the attention is protein folding. And that is

01:14:45.580 truly magnificent. The protein folding predictions from the amino acid sequence is mind-boggling.

01:14:51.260 And that will absolutely shave some time and money off drug discovery. But if AI could solve this

01:14:58.380 quote-unquote simple problem, I say simple in conceptual terms, not technical terms, you change

01:15:04.380 nutrition science. You really start to answer questions that have vexed us for hundreds of years.

01:15:10.620 So anyway, I hope somebody out there who's got serious AI chops is listening to this and thinking

01:15:16.060 this is an area to pursue. Let's pivot a little bit, Eric, to talk about one of the most important

01:15:20.860 parts of your career. I believe you are, if not one of the senior PIs, you might be the single most

01:15:26.860 senior PI on the calorie study. Is that correct? Yeah, I was one of the four PIs. But I was the one who

01:15:34.940 drove the write-up and the design of the study and all that. Calorie was an important study. It was

01:15:42.220 funded by the National Institute on Aging. And it was really the first attempt to look at the impact

01:15:50.940 of caloric restriction on biomarkers of aging. Now, don't ask me what are the biomarkers of aging,

01:15:59.260 because there's still a lot of discussion around that. If I tell you it's your fasting insulin going

01:16:06.060 up with life, it's your VO2 max going down, it's not your gray air or your lack of air or these kind

01:16:13.820 of things. But anyway, you have some more sophisticated protein glycation and production

01:16:20.540 of isoprostane and all that. I want to talk about the details of the study in a moment. But just before I

01:16:25.820 forget, how much banked serum do you still have that is available for analysis in five years or

01:16:33.580 10 years when better and better tools or biomarkers become available? Has it all been spoken for and has

01:16:40.340 it all been tested or are there still some banked samples? It's great that you asked the question

01:16:45.300 because now there is a calorie legacy study, which is to follow up these people. But also there is a

01:16:54.300 biorepository of all the plasma samples, muscle biopsies, fat biopsies at Duke, which was the

01:17:03.740 coordinating center. And these samples are available, of course, with a request. And the PI of that is

01:17:12.580 Bill Krauss. You may know the name. He's a cardiologist, but he's at Duke. And it's interesting that you ask that

01:17:20.580 because one of my colleagues just published a paper in science on a postdoc analysis of adipose tissue

01:17:30.340 in these people before and after caloric restriction. He found a gene of interest. He's an immunologist.

01:17:37.860 Deep Dixit is at Yale. And he really mined these transcriptomes from adipose tissue and found a gene

01:17:48.100 which is related to the immune function and found that if you knock out this gene in mice,

01:17:54.740 they are resistant to weight gain. This is like a calorie restriction mimetic and they improve the

01:18:01.300 immune function and all that. Yeah, your question is very appropriate. There are still

01:18:07.060 samples available. Of course, they become less and less available or more and more difficult. I'm just

01:18:14.980 digging in some of the samples that we had to send to somebody at UT Southwestern because he

01:18:21.620 has a new molecule that he would like to test before and after weight loss in non-obese people.

01:18:27.780 But the goldmine of these studies is really to be able to bank biosamples. We all bank the data

01:18:37.220 and the results, but the biosamples, it's very, very important.

01:18:40.740 That's the treasure trove. So tell folks about the study. So how many subjects? What was the

01:18:45.700 intervention? How were they monitored and tracked? How long were they followed? Let's just start with

01:18:50.980 the basics. First of all, I became interested in caloric restriction because of, I don't know if

01:18:58.100 you remember, Peter, Biosphere 2. I sure do. It was a glass and steel structure southeast of Phoenix,

01:19:07.540 in between Phoenix and Tucson. And eight people went into this biosphere. They had seven different

01:19:16.340 biomes. There was desert, marsh, ocean, agriculture. How big was it? Habitat. It was about three acres.

01:19:26.180 And this was a rich Texan donor who wanted to do that basically for the sake of NASA to know how people

01:19:35.220 can live in otasi. Anyway, eight people entered this Biosphere 2. It's called 2 because Biosphere 1

01:19:45.620 was the Earth. And they decided to call it 2. Among these eight people, there was a faculty from UCLA,

01:19:53.780 Roy Walford, who wrote the textbook with Rick Weindruck on caloric restriction. And while they were in the

01:20:02.580 biosphere and I was in Phoenix, Roy called me and said, we would like to do measurements of energy

01:20:09.700 expenditure. Can we sneak in a delta track or metabolic cart to measure our energy expenditure?

01:20:18.340 And I said, oh, absolutely. And we can also measure your free living energy expenditure using

01:20:24.180 W-label water. And we did that. Anyway.

01:20:27.620 Remind me how long they stayed in the Biosphere 2. Two years.

01:20:31.220 Two years. Yeah, God, Lord.

01:20:32.420 From 1991 to 1993. Roy Walford was a physician of the group, but he was very, very interested in

01:20:41.780 caloric restriction. What he didn't know, things went south. The agriculture, you know, they had pests,

01:20:49.620 they couldn't control some of the insects, they had goats dying, and very quickly they didn't have

01:20:57.300 enough food. And they lost on average 15% of their weight. None of them except one was maybe a BMI of

01:21:04.260 26 or 7. They were all between 20 and 25. And they became calorie restricted. And you had the guy who was

01:21:14.340 writing the textbook on calorie restriction, being the physician in the Biosphere 2. We started to

01:21:21.220 collaborate. And then when this RFA came out in the early 2000, a request for application grant from

01:21:29.940 the NIA, immediately I called Roy and I said, Roy, we have done this study of energy expenditure. And

01:21:37.860 they came and they stayed in the chamber, five of them for one day, right when they came out of the

01:21:44.740 Biosphere. And we need you as a consultant and we want to write a grant which is going to be

01:21:50.180 competitive. I'm not known in aging research. He accepted. By the way, what did you find of their

01:21:57.380 energy expenditure when they were in the chambers? It was low. I mean, very low because of their caloric

01:22:02.980 restriction. We had to compare to a group of 72 people. I mean, it's all published and I can send

01:22:10.020 you some of the papers. They were about 200 calories below what you would expect for their weight and

01:22:16.340 body composition. Interesting. Even correcting for their highly reduced weight and altered body

01:22:22.820 composition, they were still 200 below. Yeah. Three of them said, hey, we have been stuck for two years

01:22:28.980 now in this Biosphere. We don't want to go to the metabolic chamber in Phoenix, but the five who came,

01:22:36.180 they came back six months later and they would regain their weight. They were normal weight,

01:22:41.860 like at the entry. And we published this data. And was their energy expenditure normal as well?

01:22:47.220 Yeah. Normalized. Normalized. Yeah. There's this argument with metabolic adaptation,

01:22:51.780 how long does it last and this kind of things, but it was normal. Roy passed away kind of prematurely,

01:22:58.740 didn't he? Yeah. He blamed it on Biosphere a little bit because they were supposed to be

01:23:04.820 totally independent except for light from the rest of the world. But a few times they had to

01:23:10.980 purge CO2 and in flux O2, but he said there was probably gases, but it was his story. I don't know

01:23:19.300 how true it was, but he said that he was intoxicated by gas in the Biosphere.

01:23:26.100 Yeah. I didn't realize that story, Eric, that it was on the back of Biosphere 2 that your personal

01:23:32.260 interest in this hypothesis emerged and that that's the first thread that pulled towards the

01:23:38.980 calorie study. So I'm glad you shared that story with us. Yeah. Now move almost 10 years later,

01:23:45.620 Roy Walford and I don't remember the name of the investigator in San Antonio came,

01:23:52.020 we brainstorm, what should be the hypothesis. I was very serious. I wanted to have this grant.

01:23:57.940 And we said, what are we going to test? Because if you are Steve Austin, how many theories of

01:24:05.220 behind calorie restriction is going to tell you more than 50 or a hundred and so on.

01:24:10.500 And myself, I was pretty convinced by two things, the rate of living theory, the higher your metabolism,

01:24:19.220 the shorter your life. And the elephant is a very low metabolism per unit of tissue compared to a

01:24:27.140 shrew and all these kinds of things. And the oxidative stress theories.

01:24:31.940 Does that explain the difference between a human and a dog? Is that explained fully the 10x delta

01:24:37.860 in lifespan between a human and a dog or whatever it is? Okay.

01:24:41.140 You can look at the Kleiber book, you have the energy metabolism.

01:24:47.460 Yeah. Yeah. I need to go. And it's not 10x. I said 10x.

01:24:49.620 They are all on the same line. They are all on the same line.

01:24:52.820 Got it.

01:24:53.540 We brainstormed for three or four days. I have beautiful memories of this time.

01:24:59.220 And we said, okay, we're going to write a grant. It was a seven-year grant. The first two years,

01:25:05.220 which was you do a study, show us that you can recruit people and maintain them in calorie restriction,

01:25:12.180 and they have to be not obese. They can be overweight. And the second is from the three

01:25:20.180 chosen group. We're going to design one study, and it's going to be a two-year intervention.

01:25:26.420 And the first study we decided was basically to test if caloric restriction decrease your energy

01:25:35.620 metabolism more than what you would expect on the basis of the body weight. And in other words,

01:25:41.700 do you become more efficient? And the answer is yes. And we talk about metabolic adaptation.

01:25:48.020 Now, this is in non-obese people here, but they become more efficient. 0.99

01:25:52.500 Which, by the way, always sounds like a good thing, but it's not really a good thing when it

01:25:57.140 comes to weight maintenance, right? It's the exact opposite. Becoming efficient is not what you want.

01:26:02.740 You want to be the most inefficient consumer of calories in an ideal world.

01:26:07.060 You're right. And when I did studies of efficiency of athletes, or do they ever hire

01:26:13.780 a more efficient resting metabolic rate, and therefore can have more energy for the exercise

01:26:21.620 or the tasks that they are doing? You cannot win both sides. Like you said, you are better at

01:26:27.860 controlling your weight when you are a little bit more inefficient, but you are less performant and all

01:26:33.380 these kinds of things. Potentially, energy efficiency can be very good for longevity. And it has been

01:26:41.060 shown in some studies. The Baltimore Longitudinal Study showed that some people with lower metabolic

01:26:48.340 rate were living longer. On the other hand, energy efficiency is a liability for weight gain, for

01:26:56.020 example, because you are more efficient and you are more prone to weight gain. And I think it's a

01:27:01.940 balance between the two. But anyway, I think there is no right answer. But having a high metabolic rate

01:27:09.780 can be a liability because associated with the generation of ATP, you have some what we call

01:27:19.380 production of reactive oxygen species. In other words, the efficiency of the transfer of oxygen into ATP

01:27:30.180 is not perfect. And sometimes you have some reactive oxygen species being generated by the mitochondria,

01:27:39.380 and these reactive oxygen species can damage not only your DNA, but your protein, your lipids, and so on.

01:27:48.980 And this is one of the theory of aging. It is too many reactive oxygen species and therefore a higher degree of oxidative stress.

01:28:00.980 And when we designed the first part of our calorie study, it was a six-month intervention. We had four groups,

01:28:10.580 a ad libitum group, 25% caloric restriction, another group being 25% energy deficient, but half by

01:28:21.700 calorie restriction, 12.5% and half by increasing energy expenditure by exercise. And the last group was

01:28:31.300 weight loss, 10% with very low calorie diet and maintenance of this weight loss. It means you are

01:28:38.020 in calorie restriction compared to that baseline.

01:28:41.300 So just to be clear, the last group, the target was the weight reduction, whereas in the other groups,

01:28:48.340 the target was the energy intake and or energy expenditure.

01:28:51.780 Correct.

01:28:52.500 Now, how did you even do this, Eric? Because in theory, this sounds like a brilliant experiment,

01:28:57.380 right? I mean, those are big enough. Those are seismic changes, right? You take a hundred kilo person

01:29:03.060 down to 90 kilos. I mean, that's a big loss of weight. A 190 pound person is going to be 170 pounds

01:29:10.500 when that experiment is done. That's meaningful. The caloric restriction of 25% is enormous one way

01:29:16.580 or the other. But now the question is, you're doing this in the real world over, in one case,

01:29:22.100 I think months, ultimately over years. How did you think about tools for compliance to see that you

01:29:30.500 could hit even close to those targets? I think it was a lot of work with our psychology group who said,

01:29:38.500 we have to screen the people. We have to screen them for barriers to the intervention,

01:29:44.980 for adherence, and so on. And there was a lot, a lot of screening of our volunteers.

01:29:52.420 Do you remember what your rejection rate was? You know, for every 10 people you screened,

01:29:58.420 how many would pass the psychology test?

01:30:00.500 It is in the console diagram of the publication. I know, if I recall correctly, for the two-year study,

01:30:10.660 we screened more than 5,000 people to enroll 225.

01:30:17.620 Wow. So basically only 5% of people.

01:30:23.140 There was telephone, web screening, telephone screening, in-person screening visit. And there

01:30:29.220 were five screening visits to make sure that they show up. If they don't show up for the screening visit,

01:30:35.460 forget them. And the first study, we published that in JAMA, and we did find that there was metabolic

01:30:41.780 adaptation or you become more efficient. And we had also some indication of less oxidative stress.

01:30:50.580 We did what we call a comet essay. You look at damage of DNA in nucleated blood cells,

01:30:58.660 and we measure isoprostane and all that. After that, the three sites where Washington University with

01:31:06.260 John Holosey was Tufts in Boston with Susan Roberts and us in Baton Rouge. Our study was six months,

01:31:15.620 our preliminary study. Theirs were one year. But after two years, when we analyzed the data and all

01:31:22.900 that, we started to design the study, which was going to be the same for the three sites.

01:31:28.180 And was the only difference in the short study, Eric, the duration of the study and the sample size to

01:31:35.220 just confirm the technical doings of the study? No, they were all different. We insisted to have

01:31:43.140 these four groups ourselves in the preliminary study. Boston had only two groups, low glycemic index

01:31:50.980 versus higher glycemic index in the diet of the caloric restriction. And WashU, I don't remember the

01:31:58.180 details, but there was a component of physical activity in their study. He was John Holosey,

01:32:04.980 was a biochemist of exercise and all that. But after that, we compared our endpoints and our

01:32:14.020 basically intervention, and we designed this study. Now, the RFA was specifying that they have to be

01:32:21.220 non-obese. In our preliminary study, we didn't want to go because of this 10% weight loss. If you start

01:32:29.220 with a BMI of 26, you are 70 kilos and you have to lose seven kilos, you become thin. We decided about

01:32:39.140 the range of BMI and we decided for the study to go from 22 to 27.9 of BMI for admission means normal

01:32:51.540 weight. Yeah, mostly normal weight on the plus or minus side of normal weight. Up to 27.9. We knew that

01:32:59.620 they were going to lose at least 10%. And therefore, you cannot take somebody with a BMI of 20 to start

01:33:07.380 with. You would have problems with bone mineral density. You may have problems with some safety

01:33:15.180 concerns. Men and women or just men? Men and women. Right. So the other thing, you're going to have

01:33:20.440 problems with menstrual cycle and things like that. How long did they have to lose the 10% of body weight?

01:33:27.580 Was they given six months to do this or what were they forced into? We didn't have that in the final

01:33:32.460 protocol, but he now preliminary protocol. He was over three months. He was a low calorie diet. He was

01:33:40.640 like 800 and some calories per day. He was all liquid diet. Provided by Pennington? Yeah. But we could do

01:33:50.000 muffins and things like that from these. It's called a health one diet. And it's still on the market,

01:33:57.620 by the way. The two-year study, then we decided to my surprise that they agreed to do the rate of

01:34:05.980 living slash oxidative stress first endpoint. Let's go back to the subjects. Age 21 to 47 for women

01:34:16.320 and 55 for men. BMI 22 to 28. And then going through a lot of screening to make sure that they were going

01:34:26.700 to stick with us. And I can tell you, we randomized two, two-calorie restriction, 25% for one, two ad

01:34:36.240 libitum. We had 95% completion in the ad libitum group and 85% in the calorie restriction. It's amazing

01:34:47.220 for a two-year study. And the retention was spectacular. They were randomized two, two, one, two,

01:34:55.120 caloric restriction. Unlike the preliminary study we did in which we fed them entirely,

01:35:03.060 they came to Pennington to basically learn how to cook whatever diet they wanted. It could be a low

01:35:10.600 fat diet, a low carbohydrate diet, a med diet. And sorry, Eric, tell me again, it was 25% CR target in

01:35:19.180 the CR group. Yep. It was based on two measurements of doubly labeled water. The average, I just checked

01:35:26.320 that this morning, the average energy requirement was 2,400. It means on average, they were cut by

01:35:34.820 a little bit more than 500, 600 calories. And for two years and the first three months,

01:35:43.060 they could come whenever they wanted to learn to cook. And they were also provided some of the meal

01:35:50.500 if they needed to. I remember one is still our star of the volunteers. His daughter thought he was

01:35:58.080 working at Pennington because he was going every day to Pennington. And his daughter was five when they

01:36:04.120 asked her at the kindergarten, where does your dad work? Oh, he works at Pennington. And he was a

01:36:09.200 volunteer for our study. After that, we had a lot of measurements about resting metabolic rate,

01:36:16.940 about oxidative stress. And the endpoints were really the first RMR, the second Ross formation.

01:36:27.320 And after that, it was CVD markers. It was insulin sensitivity, immune function, neuroendocrine

01:36:34.460 parameters, quality of life, and cognitive function. What was the average percent weight

01:36:41.660 loss of the individuals in the treatment group? One year, the average was 12%. And at two years,

01:36:49.240 it was 10.4%. Now, the caloric restriction that we kind of estimated by doubly labeled water,

01:36:57.480 it's called the intake balance method. You measure energy expenditure, you measure change in body

01:37:04.440 composition. We had about almost 20% of caloric restriction for the first six months. And this

01:37:11.840 is where the weight loss. And after that, it started to decrease to close to 15% at one year. And then at

01:37:21.580 the end of the two years, the overall caloric restriction was 12.5%. Basically, we got half of what we were

01:37:30.460 asking for, which is not bad for, like you said, it's an important cut in your intake. And it was

01:37:38.160 square from day one. It was not a ramping up. And then we did this measurements at six months, 12 months,

01:37:45.940 18 and 24 months.

01:37:48.820 Just for the Pennington part of this, not including the other two sites, what was the budget for

01:37:53.260 everything? Meaning the preparation, planning, the study, the analysis for the first publications,

01:37:58.780 et cetera, not the ongoing, but just the bulk of what you would call that calorie study had a budget

01:38:03.400 of how much?

01:38:04.420 My original grant was 10.4 million and it was in 2003. And after that, because we were recruiting

01:38:13.220 so well, they asked us to boost up our recruitment and they gave us another million and a half.

01:38:20.480 Yeah. Close to 13 million.

01:38:22.240 That was the direct cost or direct plus indirect?

01:38:24.940 No, plus indirect total cost.

01:38:27.280 So let's just apply a little inflation to that and say that that's 20 million in today's dollars

01:38:32.760 conservatively.

01:38:34.400 Yeah. Yeah. Yeah.

01:38:36.020 Again, that sounds like a lot of money, but when you think about the fact that the NIH budget

01:38:41.980 is on the order of $35 billion for both intra and extramural and the extramural budget of which

01:38:50.180 this was part of is on the order of, oh, $28 billion. $20 million on a $28 billion budget

01:39:04.520 is a drop in the bucket. It's less than a tenth of a percent. And yet this is a very important

01:39:10.000 question. I think your success in this study, I think it's the single best study that's ever looked

01:39:15.740 at, even attempted to look at the effects of caloric restriction in a free living environment.

01:39:20.240 And in large part, I agree. I think your recruiting was exceptional and your hands-on ability to work

01:39:27.280 with the subjects longitudinally is what made the difference. People think that the study is like,

01:39:32.700 you design the study, you recruit the subjects, you go, and then you forget about them, but

01:39:36.180 you would have failed. You did all the unsexy stuff so well, and that's why you got something

01:39:42.780 so remarkable. And as we start to now talk about the results of the study, part of my frustration is

01:39:48.660 I worry that the NIH is funding some stuff that's not that interesting and not that relevant compared

01:39:54.260 to the jugular questions of human health. And this would be a great example of the kind of work that

01:39:58.600 should be getting much more funding in my view. But I'll get off my soapbox now. Let's talk about

01:40:04.140 the findings at the end of two years. What were the most notable findings aside from the obvious,

01:40:09.000 which is weight loss? One amazing was the retention rate. I thought that it was exceptional

01:40:15.220 that between the three sites, and it was much more difficult in Boston, to be honest,

01:40:20.560 than it was in Baton Rouge or even in St. Louis. But anyway, retention was exceptional.

01:40:26.880 Sorry to keep interrupting you, Eric, but what did the subjects tell you? You got to know these people

01:40:31.220 really well. Why did they stay in the study? I mean, it can't be pleasant to be that calorically 0.96

01:40:36.260 restricted for two years. Or did they say, actually, you know, guys, it really felt lousy for six

01:40:42.700 months, and then it didn't feel lousy at all. And I came to really enjoy this. I'm very curious as to

01:40:47.860 what their subjective experience was. It's interesting that you are asking, because we have been interested

01:40:53.680 in that. And we are even now following up these people. We're studied from 2005 to 2008. And they are

01:41:03.060 part of this legacy study, Calary legacy study. He was really building a team between the investigators

01:41:10.940 and the study coordinators and study managers and all that, and the people. He was also providing them

01:41:19.340 with some of the results. And we had to fight for that, because normally you don't want to have people

01:41:26.740 having their results. But we said, it's not going to change their behavior if we tell them about their

01:41:32.640 total cholesterol. Right. It's not blinded. Yeah. LDL. And it's not going to change anything or their

01:41:38.840 body composition. They love to see this DEXA. My percent body fat went from 15 to 12 in a guy and so on.

01:41:48.300 And he was kind of building a, we had Mardi Gras with the volunteers. We had every two months,

01:41:57.300 we had a reception and all that, sending postcards for birthdays and all these kinds of things

01:42:03.980 are part of the retention and building a team between the investigators and the study volunteers.

01:42:12.760 And I think we succeeded in that. But again, this was the screening, which was essential.

01:42:20.120 Because you are right. I remember the first person that we randomized, she ended up in the Adlib group.

01:42:28.400 She came to my office and said, I want to do this study because I have read about what it does to your 0.98

01:42:36.760 metabolic health, to your cholesterol, to your body composition. And I'm in the control group.

01:42:43.680 She was crying and said, but we're going to give you data. And after we're going to offer you maybe a

01:42:50.900 weight loss or help you for caloric restriction and all these kinds of things. Of course, two years later,

01:42:57.960 we still see them, but not on a regular basis like during the study. It's a lot of investment from the

01:43:05.020 investigative group and also for the study participants because they had so many visits.

01:43:12.740 So talk to me about the lipid changes, the markers of insulin sensitivity, the body composition changes.

01:43:18.600 Let's just kind of run through the list of what improved. I don't think it's a surprise that these

01:43:23.560 things improved, but the magnitude in some cases is interesting. And again, this question of,

01:43:28.580 I'm very curious as to subjective markers of satisfaction in that group, because most people

01:43:37.080 would say, look, if you told me I have to restrict my calories by 20 or 25%, there's no amount of benefit

01:43:44.340 to my health that could justify the unhappiness and unpleasantness of that experience. So where were

01:43:51.180 they psychologically as that trial progressed into its second year? I think, first of all, there was

01:43:57.320 quite a lot of press around the study at the time done at a national level as well as local levels.

01:44:04.720 And they like to know and to know that they are part of an important study. It's like this nutrition

01:44:09.680 for precision health now or motor pack are things which get some press and all that. Most of the people

01:44:17.400 like to be part of a key study. The second thing was really building this relationship between the

01:44:24.300 investigators and the study volunteers, and also the return of results and the sharing of experience

01:44:34.260 with other people. You were asking, you know, how long does it last to have this problem with hunger,

01:44:41.780 suffering, and all that? And it seems that for most people, after one month, he was totally

01:44:48.120 manageable. We taught them also to increase the volume and decrease the fat content to satisfy

01:44:56.400 on a volumetric basis how much food they were eating with less fat and less calorie density in the diet

01:45:04.620 against the ketogenic diet here. And do you have a sense of how their macronutrients shifted? So

01:45:11.620 did the ad lib people effectively mirror the standard American diet of 50 to 55 percent

01:45:19.020 carbohydrate? And did the CR group end up at a higher fraction of carbohydrates because of this

01:45:25.520 attempt to lower caloric density? We have published, I don't remember exactly if there was a clear cut

01:45:33.160 impact of being in the caloric restriction group versus the ad lib group. This I don't know,

01:45:40.420 but I know that quite a few people wanted to make a difference in their diet and they wanted to know

01:45:47.660 more about the med diet, the DASH diet, the low-fat diet and all that. And surprisingly, there are some

01:45:56.340 people, and like I said in this legacy study, and Dr. Redman is the PI now, people are still, a lot of them

01:46:06.200 did not regain all the weight. And now it's more than 15 years after. And they are still using what

01:46:15.260 they have learned during these two years because there was a lot of learning.

01:46:19.220 When was the last time you took blood, gathered any sort of data on those people besides weight?

01:46:23.940 In other words, is there any way to infer whether two years of caloric restriction 20 years ago

01:46:29.540 had any lasting difference relative to the controls?

01:46:33.660 Like I said, this legacy study is targeting all the people. Now, I don't know how many,

01:46:40.340 but I'm pretty sure we're going to get...

01:46:42.300 But we don't have the results yet.

01:46:43.720 No. No, it's ongoing now. But us, we did a six-month follow-up study at Pennington,

01:46:51.540 and here, they were continuing. That's not the thing they said, oh, heck with this study. I go back

01:46:59.500 to my normal life. It was a game changer for their lifestyle for these people.

01:47:05.960 So what do you think, from an anti-aging perspective, were the most important biomarkers

01:47:12.420 that changed? For example, did you do OGTTs or euglycemic clamps? I mean, how much did you

01:47:19.920 scrutinize glucose disposal and insulin sensitivity in these people?

01:47:24.600 We didn't do clamps. Let me tell you, there are two kinds of aging. There's primary aging,

01:47:31.120 which is more like senescence or mitochondrial dysfunction, leaky membrane. And there is secondary

01:47:39.040 aging, which is basically the impact of your environment and your lifestyle. When you ask about

01:47:46.160 insulin sensitivity or cardiovascular factor, it's more secondary aging. And here, we did a lot of

01:47:53.360 measures. Bill Krauss published a quite cited paper five years after the end of the study in JAMA

01:48:01.220 on all the cardiovascular, cardiometabolic risk factors. And everything was tremendously improved,

01:48:09.620 despite the fact that these people were healthy to begin with. BMI 22 to 27.9 and so on. And remarkable

01:48:19.520 improvement in all these markers of secondary aging. Now, when it comes to primary aging, that's a

01:48:27.840 different story because it's much more difficult to measure autophagy, to measure mitochondrial function,

01:48:34.820 to measure leakiness of a cell membrane in these people. And what we ended up to measure was really

01:48:43.160 some of these hallmarks of aging. You have probably seen these papers. There was one in 2012 and one 10

01:48:52.120 years later. We don't have as many data that we would like. But for example, we did measure mitochondrial

01:49:01.460 biogenesis by looking at the relationship between nuclear markers and mitochondrial DNA. And we observed

01:49:13.560 in humans that there was an increased mitochondrial biogenesis. Despite the fact that you use less energy,

01:49:23.040 you become more efficient. You increase your biogenesis of mitochondria, which is quite spectacular

01:49:31.160 because the ROS production of these reactive oxygen species are produced by older mitochondria. The new

01:49:40.260 mitochondria are much more efficient. They don't produce as many ROSs. So let me make sure I

01:49:46.420 understand that, Eric. Sorry. You're saying that the people in the CR group had a greater turnover of

01:49:53.020 their mitochondria. In the muscle, skeletal muscle, it was. It's interesting. And so we would expect

01:50:00.960 that people who are calorically restricted would have lower ROS generation, but we would expect that

01:50:08.860 the reason for that is lower substrate utilization. You're saying, yeah, they had lower ROS generation,

01:50:15.980 but it might actually be just as much from the fact that they had more mitochondrial biogenesis and

01:50:21.220 they were using newer machinery for the substrate utilization. So it could be both of those things

01:50:26.660 are reducing ROS. Is that what you're saying? Absolutely right. I think it's both. When it

01:50:32.180 comes to mitophagy, these old mitochondria, it's been shown in insect, in rodents, that this is improved

01:50:40.220 with caloric restriction. Autophagy, of course, all these organelles in the cells. Did you measure any of

01:50:46.900 the tubules or anything for autophagy? No. No, I'll see too. Okay. But we measured mitochondrial turnover

01:50:52.400 by this method and we found that it was increased with caloric restriction. And I think you are right

01:51:00.740 on the point here. There's both mechanism, less energy requirement, but also more efficient

01:51:08.040 mitochondria. Today, if you were to do this study, for example, I mean, I know the legacy study isn't

01:51:14.260 the same because not as many of the people are going to still be carrying out. But if you could

01:51:19.080 go back and look at the banked samples, are there any other biomarkers you would be able to look at

01:51:24.940 today vis-a-vis the hallmarks of aging? Is there anything we could be doing to better understand

01:51:29.160 senescence? What would you look at in terms of inflammatory markers? I would certainly put that

01:51:33.400 down as primary aging. How much of a suite of the interleukins, TNF, and things of that nature did you

01:51:39.240 look at? Yeah, I mean, we did. We did at 6, 12, 24 months. We didn't do 18 months for that.

01:51:47.200 But we had the whole panel of inflammation and high sensitivities, CRP, and then all the

01:51:54.460 interleukin, TNF-alpha, and all that. Everything improved or just some things?

01:52:00.400 No, everything improved. One thing which was spectacular when it comes to immune function,

01:52:06.660 we did some imaging of the thymus and there was loss of fat.

01:52:13.560 Oh, oh, involution. Okay, fat reduction.

01:52:15.620 There was a reduction of fat in the thymus and our friend Deep Dixit was all excited by that and

01:52:24.360 this is why he pursued all the immune responses from transcriptomics in different tissues and all

01:52:32.700 that. But chronic inflammation, first of all, it was not abnormal to begin with, but there was

01:52:40.000 tremendous improvement. And I think that Bill Krauss in the discussion of his paper, if I recall,

01:52:47.500 he used the Framingham index of cardiometabolic health and there was an improvement in the age.

01:52:57.520 I don't know exactly the index.

01:52:59.220 Yeah, using the Framingham risk calculator, of course, everything would have got better

01:53:03.620 based on the biomarkers. And he was quite spectacular. It was like they were gaining 10

01:53:09.700 years in two years.

01:53:11.500 I mean, again, Eric, I think it's very interesting. And I think it is hands down the best experimental

01:53:18.500 evidence we have that caloric restriction for those who can do it may indeed be a great tool.

01:53:24.740 Of course, there are other questions that I think can't be answered by this study based on its duration

01:53:31.640 and the age of the subjects. And that is, would those benefits extend into the eighth decade of

01:53:39.260 life, a period of time when sarcopenia becomes a significant driver of not just mortality, but truly

01:53:47.640 morbidity? And would we indeed see a trade-off in lean muscle? Again, the answer is not necessarily

01:53:55.060 that you would. I do think that one could indeed consume fewer calories without any restriction of

01:54:02.160 protein and while doing all of the necessary strength training. So in other words, I think

01:54:06.800 there's a deliberate way to do this. But if one were just to restrict calories and lose lean mass,

01:54:14.000 I mean, I don't remember, Eric, but obviously the subjects got lighter and obviously their body

01:54:18.820 composition improved, meaning they disproportionately lost fat to muscle. But do you recall,

01:54:25.060 if there was also a meaningful reduction in lean tissue independent of the improvement in body

01:54:31.080 composition? I would have to go back to the publication exactly. It was less than a quarter.

01:54:38.200 Less than a quarter. Yep. We like to hold on to that as the gold standard of limit lean body mass to a 1.00

01:54:44.180 quarter of total weight loss. We didn't restrict physical activity, but to be enrolled, they had to be

01:54:50.540 screened for not being regular exercises, for example. Do you know the cronies, the calorie

01:54:57.900 restriction optimal nutrition society? I've never interacted with them, but I'm familiar.

01:55:03.780 There is about 200 self-imposed calorie restricted people. They are afraid of exercise. They don't

01:55:11.840 exercise at all because they are afraid that exercise is going to increase...

01:55:16.540 Increase their appetite.

01:55:17.780 Their appetite and their food intake. And they are religious with that. And that's why,

01:55:24.020 I mean, your question about sarcopenia, when you start with people with a BMI of 24 and you

01:55:30.520 lose your 10, 12% and you keep this 12% off and you go in your 70s and 80s, what is happening to

01:55:40.280 your muscle mass and this kind of things? And I don't think we have an answer.

01:55:44.700 I mean, to me, Eric, the experiment that I want to see done is not even an experiment at this point.

01:55:50.520 Frankly, it's literally, it's a much easier experiment, which is your tissue and serum

01:55:55.680 samples provide a very compelling case of you can take healthy people, CR them for a couple of years

01:56:03.780 and make them better across the board by every objective measure of both primary and secondary

01:56:09.440 aging. The secondary stuff's so obvious, it's not even worth talking about. So people that are

01:56:14.500 interested in that can go back and look at the papers and see the lipid profiles and see the

01:56:18.380 insulin sensitivity. But it's really these primary markers of aging. I had forgotten or didn't know

01:56:23.540 about the thymic fat reduction. That's very interesting to me. So now the question is this,

01:56:28.600 well, you were dealing with a very narrow population. You started with 2,500 people and

01:56:33.540 through intensive psychological profiling, you winnowed it down to the 5% of people who were going

01:56:40.340 to be able to most adhere to this. And then on top of that, you provided arguably the most robust

01:56:47.040 support for those people during this journey, the kind of support they couldn't buy outside.

01:56:54.340 Those people as regular people on the outside world couldn't have purchased the level of care and

01:57:01.280 support and encouragement they got for that two-year study. So all of that is not to be a critic of the

01:57:06.380 study. It's to simply say those were the necessary steps to get such exceptional compliance, which is

01:57:11.980 what was necessary to get such a meaningful answer. But if we want to ask the question, how would you

01:57:19.280 help the 99% of people who on their own could not adhere to that? The answer, of course, becomes

01:57:26.140 CR mimetic drugs. This is the question that is on everybody's mind, which is, Eric, you've convinced me

01:57:34.620 that CR to this extent will absolutely help me live a longer, better life, but I just can't do it.

01:57:42.820 I'm not in that percent of the population. But will a GLP-1 agonist give me the same benefit?

01:57:49.920 Will rapamycin give me the same benefit? Will acarbose give me the same benefit? Will an SGLT2 inhibitor

01:57:57.820 give me the same benefit? Will metformin give me the same benefit? And those studies are much easier

01:58:05.340 to do. We can easily put people on those drugs for two years and do the exact same analysis.

01:58:13.140 You've given us the gold standard. You've given us the template. Now we just need to compare

01:58:18.660 every single marker you've measured, plus some you haven't. I really want to see the epigenome

01:58:24.080 in these subjects pre and post. And so is it just me that feels this way, or is that also

01:58:29.340 screaming out to you as the most interesting question to come out of this?

01:58:34.100 It's been a little bit of a roller coaster, the CR mimetics. You remember all the Sirtuin stories. 0.69

01:58:42.900 Yes, but notice I picked something very carefully. I only picked drugs, with the exception of GLP-1

01:58:48.880 agonists. I only picked winners of the ITP. And Sirtuins are garbage. Everybody knows they're 1.00

01:58:56.140 garbage. I'm sorry to offend people who work on them now, although I don't think anybody's still 0.96

01:59:00.380 working on them. But the Sirtuins were a scam story that never materialized. And it never, 0.79

01:59:06.860 ever, ever was the mechanism by which CR worked, ever. I've gone back. I have talked to Matt

01:59:13.240 Kaberlin, who did the first study. I have gone through every experiment that was done in that lab.

01:59:18.700 There is zero evidence that Sirtuins' supposed efficacy, which I think is true in yeast, by the

01:59:26.120 way, was mediated through CR. And of course, Sirtuins have had no efficacy post-yeast. So anyway,

01:59:33.740 I'm just being a little pointed in my language to make the point that I'm being particular about

01:59:38.460 which CR mimetics I discuss. Yeah, okay. And you pick metformin, and of course, I'm sure you

01:59:44.120 know neobasili. Of course. My hypothesis, by the way, is that metformin is not a CR mimetic,

01:59:50.440 but I just think we should include it. There's a reasonable enough probability that all of those

01:59:55.180 molecules I suggested, I think should be tested. I mean, the GLP-1 are so potent when it comes to

02:00:03.580 weight loss, metabolic health, and all that. I mean, there's not a week without a new paper on GLP-1.

02:00:09.600 I know. I just read a blood pressure one today on trisepatide.

02:00:13.760 Why would that be? Because when you calorie restrict yourself, you eat less,

02:00:19.560 and therefore you stimulate less these GI peptides.

02:00:24.720 None of it makes sense. None of it makes sense.

02:00:28.040 If you tell me, I mean, are they true caloric restriction mimetics, and do they decrease oxidative

02:00:36.760 stress? Do they improve insulin sensitivity and all that? Among the one you cited, there's a lot of

02:00:43.840 those. Now, the question is, how do you go about to test that? Of course, there is all these failed

02:00:51.940 drugs and things which have been tested for toxicity and safety and all that, that some people want to

02:01:00.320 recycle in aging, and I'm not sure where it's going to be. To me, the secondary aging, which is the impact

02:01:08.980 of your lifestyle and your environment, is what we should target first. The primary aging, 0.73

02:01:16.420 I like to hear David Clark talking about autophagy or the people on the East Coast and all that,

02:01:24.100 but what do you do to have more autophagy or more mitophagy and all that? I don't know.

02:01:32.720 I mean, we know exercise does it. I mean, we know that autophagy is not just fueled by caloric

02:01:37.980 restriction, but exercise is an incredibly potent driver of that for similar mechanisms, right? You could

02:01:44.220 argue that it's basically a substrate utilization problem. It's the input, it's the output. And when

02:01:49.420 you transiently deprive the output, if you drive more output and you transiently create a deficit

02:01:55.740 of energy, I don't think at the cellular level, the body is particularly concerned with, am I short on

02:02:01.740 what's coming in or am I short because too much is going out? And again, this doesn't have to be an

02:02:07.000 either or. That's the beauty of biology is we can look for accretive solutions. So I think that

02:02:13.160 those particular gyroprotective agents, Eric, are probably not going to be as impressive

02:02:18.080 on the secondary markers of aging with the exception of the GLP-1 agonist because of the obvious weight

02:02:24.320 loss. I don't think metformin, RAPA, SGLT2s, acarbose are going to result in weight loss. And

02:02:29.640 even in the ITPs, they did not result in weight loss. Remember the hypothesis of David Allison who

02:02:35.160 proposed acarbose is this is going to be a CR memetic that induces weight loss because of bad

02:02:41.380 absorption. Well, guess what? Those mice weighed the exact same amount. They just lived a heck of

02:02:46.380 a lot longer, suggesting it was actually the glucose metabolism that gave the benefit. But

02:02:51.720 I don't know. I just think, Eric, what you've done is amazing. And I know it just wasn't you.

02:02:56.240 Of course it wasn't you. I mean, you had an incredible team. I've been to Pennington on many

02:03:01.140 occasions. It's a wonderful place. I think it's dedication. It's the little stuff that matters,

02:03:06.580 Eric. It's like, I know what your staff is like. I remember working with Courtney and the entire team

02:03:11.960 of nutritionists there. I mean, that's the stuff that's not sexy, but that's what's necessary to do

02:03:17.920 this kind of work. I hope that through this podcast, we're giving people an appreciation for

02:03:22.400 how hard it is to do nutrition science. If you're an experimentalist, anybody can do epidemiology.

02:03:29.180 And I kind of share the view of George and John and the people who think that it is a very,

02:03:36.480 very limited use, not of no use. There is a case, but we over-index on that stuff when what we really,

02:03:44.420 in my mind, need to be doing is doubling down on the kind of work you do, because that's the only

02:03:49.700 place I think we're going to get causal information and information that we could make people's lives

02:03:55.900 better with. So thank you for what you're doing. My pleasure. Stay tuned, because you mentioned

02:04:01.960 time-restricted eating, and now there is a study which is going to be implemented in a year or two,

02:04:09.480 a five-year intervention, calorie restriction versus time-restricted eating. What's the time

02:04:15.740 window of restriction going to be? I don't know the details. The protocol is not finalized. It's one of

02:04:21.660 these exercise where we were part of one of the study, and now you put all your brain together,

02:04:27.940 but it's going to be probably eight hours a day. My vote, if you give me a vote, Eric, make it more

02:04:33.880 restrictive. The first study we did was six hours. Yeah. If you really want to see if there's a signal

02:04:40.060 independent of calorie restriction, because I think the goal has to be, you're going to have to match

02:04:44.840 their calories. This is the isocaloric difference between CR and time-restricted feeding. In my experience,

02:04:51.220 eight hours will give you a null answer. I bet a million dollars you'll get a null answer if you

02:04:56.500 compare eight hours, but four to six is interesting, and I'd be very curious. Yep. Interesting you bring

02:05:03.840 that up, but our study was the first in humans, and this was Courtney Peterson who did that,

02:05:11.480 and we had six hours, and people said it would be easier with eight hours and all that, but

02:05:17.960 after, if I recall correctly, after two weeks anyway, they were perfectly fine with six hours.

02:05:24.220 Even if at the end, the exit interview, they said it would be easier for eight hours, but I think it

02:05:29.660 was at the start, and you can maybe ramp it down from eight to six hours. Yeah, yeah. Well, Eric,

02:05:38.560 great to spend time with you today. Thank you. I know you're in Europe, so that obviously you've had

02:05:42.620 to stay up a little bit later, but hopefully the next time we do this, we're talking about this study

02:05:46.640 and maybe the follow-up studies that I'd like to see done on some of these CR memetics, and we're

02:05:50.800 doing it in person. All right. Thank you very much, Peter. My pleasure. Thanks, Eric.

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The Peter Attia Drive - November 04, 2024

#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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