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.
Mon, 04 Nov 2024
View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Eric Ravussin is a world-renowned expert on obesity, metabolism, and aging whose pioneering research has shaped much of what we understand today about energy balance and caloric restriction. In this episode, Eric shares insights from his cutting-edge work on energy expenditure—a critical factor in understanding how our bodies regulate weight and appetite. He discusses methods for measuring energy output, energy balance, food intake, and appetite regulation, and explores key studies on macronutrient manipulation. Eric then delves into the CALERIE study on caloric restriction, highlighting insights related to biomarkers of both primary and secondary aging. The conversation also covers the potential of GLP-1 agonists to replicate these effects and looks ahead to how AI and technology could transform metabolic research in the coming years. We discuss: Eric’s background and current work metabolism and measuring energy expenditure [3:00]; The science behind metabolic chambers for measuring energy expenditure, and the complexities of indirect and direct calorimetry [8:00]; The body's regulatory systems for maintaining energy balance and the primary influence of energy intake on body weight [18:30]; The epidemic of obesity and a discussion of resting metabolic rate [24:45]; The impact of exercise, appetite, gut hormones, and eating patterns on weight regulation [28:45]; Experiments looking at how macronutrient composition affects energy expenditure [38:45]; The challenges of studying diet in real-life settings, the potential of personalized nutrition, and how public health policy could play a role in guiding nutritional habits [51:00]; The importance of protein in the diet, the limitations of dietary data collection, and how AI could potentially transform nutrition science [1:08:15]; How Eric’s interest in caloric restriction (CR) began with Biosphere 2, metabolic efficiency's role in aging, and goals of the CALERIE study [1:15:15]; The CALERIE study: exploring the real-world impact of caloric restriction [1:28:00]; Notable findings from the CALERIE study after two years: sustained weight loss, participant retention, and more [1:40:00]; The effect of caloric restriction on the hallmarks of aging [1:47:00]; The challenge of applying CR to the general population, the potential of drugs and exercise to mimic the effects of CR [1:55:45]; Upcoming study comparing caloric restriction to time-restricting eating, and Peter’s takeaways from the discussion [2:02:45]; and More. Connect With Peter on Twitter, Instagram, Facebook and YouTube
Chapter 1: What is the main topic of this episode?
Hey everyone, welcome to The Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen.
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If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of a subscription. If you want to learn more about the benefits of our premium membership, head over to peteratiamd.com forward slash subscribe. My guest this week is Eric Ravison.
Eric is the director of the Nutrition Obesity Research Center at Louisiana State University's Pennington Biomedical Research Center, where he also serves as the Douglas L. Gordon Chair in Diabetes and Metabolism.
Having published over 600 peer-reviewed manuscripts, Eric is regarded as a world expert in obesity, metabolism, and aging, and has received numerous awards for his contributions to these fields.
As discussed at the beginning of this podcast, Eric and I worked together for about four years, roughly 15 years ago, and during that period of time, I just came to have such an admiration for Eric, his curiosity, and his intellect when it comes to this field.
We talk about Eric's background and his extensive experience in metabolic research, in particular when it comes to measuring energy expenditure, which turns out to be a very technically demanding problem. We go through the various methods that this has done, including what is today regarded as the gold standard.
This, of course, is necessary because if you want to understand energy balance, you must clearly be able to measure energy expenditure. We, of course, discuss energy balance, energy expenditure, and food intake,
how we regulate appetite, and the findings of a very important study that Eric did, which look at the impact of manipulating the ratio of macronutrients to see if it would indeed change energy expenditure. Disclosure, I was involved in the funding of that study.
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Chapter 2: How does caloric restriction influence aging?
But we kind of ignored the food intake that we were clamping. And this is not real life. If you do something and you talk about engaging on physical activity regimen or exercise and all that, I mean, you have to look at the impact on the other side. And this is the same question that I have. Now, I'm not helping you in designing the perfect study by saying that.
But on the other hand, again, we have good tools to measure energy expenditure. We have reasonably good tools to measure where do the calories come from. But we have no tools to measure energy intake. But it's going to come.
I bet you that within, I may not be here, but within a couple of decades, we'll have a caller here which is going to measure your calories coming from fat, carbohydrate, or protein.
I think it should be sooner than that, Eric. I mean, I really do think as image recognition gets better and better with AI, to me, I would actually hope that within a decade, if not less, we are at the point where if you can weigh something and take a photograph of it, We should have enough training data that you should be able to know exactly what is in it.
Now, that doesn't account for how much of that thing you eat, but assuming you have something that you weigh and you can photograph and you say, I ate all of it or I ate half of it, we should be able to do better than 10%. We should be able to do within 5%. What is the caloric density of that food and the macronutrient breakdown? I wouldn't have said that five years ago.
Like five years ago, I would say that's impossible. But given what I'm seeing with image recognition in AI, that to me has to be the future for nutrition research in a free living environment.
I think you put your finger on the exact point. And now I'm the PI of one of the six clinical sites for nutrition for precision health. This is basically an ancillary study of all of us. All of us is a million Americans who are basically providing biosamples access to the health electronic records and all that.
And then this sub-study is really to look at the intersection between their health and their nutrition. And there is three modules. One is on 10,000 people. And one of the way to measure is exactly this little camera sitting on your glasses and also a system which is measuring if you are chewing or not. It's not enough to see the food and going, but is it chewed? And I agree with you.
I mean, I was not thinking about that. I was thinking about something much more like a CGM. Who was dreaming of CGM 30 years ago? When I was working with the Pima Indians, we were not thinking about that. Now you have CGM, and you can measure probably your insulin from contact lenses and things like that. And I think this progress is going to help us
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Chapter 3: What are the challenges of measuring energy expenditure?
Yeah, mostly normal weight on the plus or minus side of normal weight.
Up to 27.9. We knew that they were going to lose at least 10%. And therefore, you cannot take somebody with a BMI of 20 to start with. You would have problems with bone mineral density. You may have problems with some safety concerns.
Men and women or just men?
Men and women.
Right, so the other thing, you're going to have problems with menstrual cycle and things like that. How long did they have to lose the 10% of body weight? Was they given six months to do this, or what were they forced into?
We didn't have that in the final protocol, but in our preliminary protocol, it was over three months. It was a low-calorie diet. It was like 800 and some calories per day. It was all liquid diet.
Provided by Pennington?
Yeah. But we could do muffins and things like that from these. It's called Health One Diet. And it's still on the market, by the way. The two-year study, then we decided, to my surprise, that they agreed to do the rate of living slash oxidative stress first endpoint. Let's go back to the subject. Age 21 to 47 for women and 55 for men. BMI 22 to 28.
And then going through a lot of screening to make sure that they were going to stick with us. And I can tell you, we randomized two to caloric restriction, 25%, for one to ad libitum. We had 95% completion in the ad libitum group and 85% in the calorie restriction. It's amazing for a two-year study. And the retention was spectacular. They were randomized 2 to 1 to caloric restriction.
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Chapter 4: How does macronutrient composition affect energy balance?
None of it makes sense. None of it makes sense.
If you tell me, I mean, are they true caloric restriction mimetics and do they decrease oxidative stress? Do they improve insulin sensitivity and all that? Among the one you cited, there's a lot of those. Now, the question is, how do you go about to test that?
Of course, there is all these failed drugs and things which have been tested for toxicity and safety and all that, that some people want to recycle in aging, and I'm not sure where it's going to be. To me, the secondary aging, which is the impact of your lifestyle and your environment, is what we should target first.
The primary aging, I like to hear David Clark talking about autophagy or the people on the East Coast and all that, but what do you do to have more autophagy or more mitophagy and all that? I don't know.
I mean, we know exercise does it. I mean, we know that autophagy is not just fueled by caloric restriction, but exercise is an incredibly potent driver of that for similar mechanisms, right? You could argue that it's basically a substrate utilization problem. It's the input, it's the output.
And when you transiently deprive the output, if you drive more output and you transiently create a deficit of energy, I don't think at the cellular level, the body is particularly concerned with, am I short on what's coming in or am I short because too much is going out? And again, this doesn't have to be an either or. That's the beauty of biology is we can look for accretive solutions.
So I think that those particular geroprotective agents, Eric, are probably not going to be as impressive on the secondary markers of aging with the exception of the GLP-1 agonist because of the obvious weight loss. I don't think metformin... Rapa, SGLT2s, Acarbose are going to result in weight loss. And even in the ITPs, they did not result in weight loss.
Remember the hypothesis of David Allison, who proposed Acarbose is, this is going to be a CR memetic that induces weight loss because of bad absorption. Well, guess what? Those mice weighed the exact same amount. They just lived a heck of a lot longer, suggesting it was actually the glucose metabolism that gave the benefit. But I don't know. I just think, Eric, what you've done is amazing.
And I know it just wasn't you. Of course it wasn't you. I mean, you had an incredible team. I've been to Pennington on many occasions. It's a wonderful place. I think it's dedication. It's the little stuff that matters, Eric. It's like, I know what your staff is like. I remember working with Courtney and the entire team of nutritionists there. I mean, that's the stuff.
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