The Peter Attia Drive - #222 ‒ How nutrition impacts longevity | Matt Kaeberlein, Ph.D

Episode Date: September 12, 2022

View the Show Notes Page for This Episode Become a Member to Receive Exclusive Content Sign Up to Receive Peter’s Weekly Newsletter Dr. Matt Kaeberlein is a globally recognized expert on the biology of aging and recurring on The Drive. In this episode, Matt explains his research findings on nutrition as it relates to aging and longevity, including the results from his recent review article in Science. From there, he and Peter dive deep into the literature on calorie restriction (CR), explaining the nuance, benefits for lifespan and healthspan, and potential downsides of CR. He discusses the epigenetic changes that occur with age and potential benefits and downsides of epigenetic reprogramming, often viewed as a panacea for reversing aging. Matt also explains the impact of dietary protein on aging, including the interesting dichotomy around how protein, a critical macronutrient, and rapamycin, a geroprotective molecule, have opposite effects on mTOR. Additionally, he talks about low-protein vs. high-protein diets and their effects on muscle mass and mortality, as well as the impact of IGF-1 signaling and growth hormone on lifespan. We discuss: Challenges with understanding the effects of nutrition and studying interventions for aging [3:30]; How Peter’s and Matt’s convictions on nutrition and thoughts optimal health have evolved [8:15]; Calorie restriction for improving lifespan in animal models [16:15]; Utility of epigenetic clocks and possibility of epigenetic reprogramming [22:00]; Mutations and changes to the epigenome with aging [31:45]; Epigenetic reprogramming: potential benefits and downsides and whether it can work in every organ/tissue [35:15]; First potential applications of anti-aging therapies and tips for aging well [43:00]; Impact of calorie restriction on the immune system, muscle mass, and strength [47:00]; Insights from famous calorie restriction studies in rhesus macaques [55:00]; An evolutionary perspective of the human diet [1:03:45]; Antiaging diets: Separating fact from fiction—Matt’s 2021 review in Science [1:12:30]; Mouse models of time-restricted feeding in the context of calorie restriction [1:19:30]; Nutritional interventions that consistently impact lifespan in mice, and concerns around efficacy in humans [1:27:00]; Differing impact of calorie restriction when started later in life [1:31:00]; Lifespan extension with rapamycin in older mice [1:37:15]; Relationship between protein intake and aging, and mouse studies showing protein restriction can extend lifespan [1:43:30]; Impact of protein intake on mTOR, and why inhibition of mTOR doesn’t cause muscle loss [1:50:45]; Low-protein vs. high-protein diets and their effects on muscle mass, mortality, and more [1:55:30]; The impact of IGF-1 signaling and growth hormone on lifespan [2:06:30]; Parting thoughts on the contribution of nutrition to healthspan and lifespan [2:19:45]; More. Connect With Peter on Twitter, Instagram, Facebook and YouTube

Hey everyone, welcome to the Drive Podcast. I'm your host, Peter Atia. This podcast, my website, and my weekly newsletter, I'll focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content and health and wellness. Full stop, and we've assembled a great team of analysts to make this happen. If you enjoy this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of this space to the next level. At the end of this episode, I'll explain what those benefits are, or if you want to learn more now, head over to peteratia MD dot com forward slash subscribe.

Now without further delay, here's today's episode. My guest this week is Matt Kiberlin, who of course is a returning guest. He's been a previous podcast guest a number of times most recently joining me on AMA 35 back in May of 2022. Matt is not only one of our most recurring guests, but he's also one of the people I will consistently share emails with discussing various topics, probably not a week goes by that we're not sending each other a paper or something like that. And so when I found out when Matt was gonna be in Texas

for a project, I figured let's sit down together in person and do one of these things instead of remotely, which we normally do. In this episode, we really focused the conversation around nutrition as it relates to aging and longevity. This really came out of a paper that Matt wrote as a review article about a year ago, which I remember reading in draft, really appreciating it and loved reading the final version of it. So even though nutrition science is not the topic I'm most interested in talking about, given the things I've mentioned in the past, which is sort of diets and fads and the religion around that stuff.

We tried to really make this as biochemical a discussion as possible. So we obviously discuss Matt's recent review article, and we talk pretty deeply about the literature on chloric restriction. We talk about epigenetic clocks, aging, and its effect on DNA and cell reprogramming. We then focus around protein and aging. So this is the one macronutrient that stands out, right? Carbohydrates and fats are really there for energy use. Protein is not.

We then get into this seeming dichotomy around protein and emtore. You've obviously heard me talk a lot about emtore. We understand that a drug that inhibits emtore, namely rapamycin, seems to produce a whole bunch of wonderful effects, and yet protein, particularly an amino acid called lucine, seems to really trigger mTOR. So how can those two things simultaneously be true if having muscle is good, but taking rapamycin is probably good? We get into the importance of muscle mass,

the RDA on protein itself, IGF, growth hormone, and a lot more. I want to point something out here. This is a topic for which we just don't have easy answers. And it's possible you're going to walk away from this entire conversation with more questions than answers. My goal is that you come away from this realizing that, yeah, there's quite a bit of uncertainty here, but I have a better way that I can think about it, and I have a better sense of what questions to ask. Now, for those of you who may not remember who Matt is or maybe even didn't listen to any of our previous podcasts, let me just give you a really brief reminder. Matt is a globally recognized leader in the basic biology of aging. He's a professor of laboratory medicine

and pathology and adjunct professor of genomic sciences and an adjunct professor of oral health sciences at the University of Washington, Seattle Seattle His research interests are focused on the basic mechanisms of aging in order to facilitate translational interventions that promote health ban and Provo to healthquay life So without further delay, please enjoy my conversation with Matt Cable Matt it's great to finally be able to do one of these in person with you We've done a lot of these remotely. We're taking advantage of the fact that you're in Texas filming a documentary about aging, which is pretty awesome.

So when we knew that this was going to happen, we said, well, let's take advantage of you being here and let's come up with something that we both talk about so much over email, which is to say, I don't think a week goes by that we are in exchanging an email about some aspect of the relationship or the interspace between nutrition and longevity. Does that speak to our ignorance? Does that speak to the ubiquity of such content? What does that say about us?

It's an area that a lot of people are really interested in, and it certainly intersects with popular culture. So having been in the aging field for a long time, I certainly recognize how complicated that biology is. And I think the biology of nutrition is equally complicated. And when you get at the interface of those two, it's really hard, I think, sometimes to draw a definitive conclusion.

So a new paper will come out, and you usually read the papers before I do, and you're like, hey, what do you think about this? And then, you know, we throw it back and forth. It's hard sometimes to get to concrete answers. So certainly we'll try to do that today. But I also think this will be a little bit of a theme that there are many things we don't understand yet about optimal nutrition and how that intersects with optimal health span. You and I have spent so much time on the podcast speaking about the molecules. Of course, our favorite being Rapa Mice and but all sorts of them, right? We recently talked about NMN and R and AD. We've talked about metformin. And it's easier

almost to ask the questions in the, from the standpoint of geroprotective molecules, because the intervention is much cleaner. Yeah, absolutely. Like, are you taking this drug, yes or no? And of course, what's interesting about that, and I think it speaks to what we're going to talk about today, think about the one drug among those that stands out, which is Rapa Mison, even within that, just I think yesterday or two days ago you and me and David Sabatini had a back and forth about timing of the dose, frequency within the dosing schedule, the dose itself, I mean, even with a drug, it's still very complicated to say, well, what about during this fate?

Because at the study, I think we were talking about was looking at mice, and it was asking the question of early exposure of rapamycin later in life, constant dosing, intermittent dosing. That's for a drug, and we're still struggling to piece it together. Now imagine trying to ask that question of your food. You know, we'll obviously talk a lot as well about the animal models and what they can tell us about what might affect human aging, but the big piece that gets lost with the animal models on top of all that complexity is the environment.

You know, we keep these mice in a well controlled environment, usually relatively pathogen free, and they live in that same environment their entire life. Now you think about the human experience where our environment is extremely complicated. We're constantly getting bombarded with all sorts of challenges and infectious agents and our environment changes dramatically throughout our lives. In fact, maybe this is something we want to touch on. A lot of the epidemiological studies on optimal nutrition are from 20, 30, 40 years

ago. The average human environment is very different today than it was when those studies were done. And how does that potentially change the interaction between nutrition and health outcomes? I think it's a really interesting but challenging question to address to anybody's satisfaction, honestly. Yeah, that's actually a great point.

And I made a similar point on a totally different topic, which was all of the studies that use, that talk about cancer screening are very backwards looking by definition, right? You have to look at controlled trials that were done in the past. But the technology of radiology is changing so much. Radiology is a very, you know, physics-based field of medicine. And so when you read a study that talked about mammography for screening, it was a 15-year study, right? So it's a great study. Well, by definition, it was done based on 30 to 20-year-old

technology that by the time the study has been completed, you have the follow-up data, you write up the paper, it doesn't necessarily represent what's happening today. And that's a huge challenge of evaluating that type of data. And in people, because we age so slowly, there's really not a lot you can do about that if you want to try to do correlative longitudinal studies of aging.

Because people age so slowly, the people who are in their 70s today were in their 30s 40 years ago. And so the environment that they were in is probably quite different than the environment that 30 year olds are in today. So there's not a great way around that. I think the key is to recognize that limitation and be potentially even more careful

about assuming causation from correlation over many decades. As a bit of a meoculpa on the topic of nutrition, which is really my least favorite topic, despite the fact that it keeps coming up on this podcast and it's unavoidable. As I reflect back on my own understanding of this topic, the strength with which I held convictions over the past more than decade.

I would say, I've gone in reverse, right? I have looser and looser convictions as time goes on, and I view fewer and fewer things with certainty as time goes on. When I think about this problem clinically, I have what I would consider to be an incredibly simple framework, which is if I'm looking at a patient,

I'm asking a question, are you overnourished or undernourished? Are you undermuscled or adequately muscled? So that's a two by two. And then are you metabolically healthy or not? That's sort of my first order question. Now, one of those spaces doesn't really have too many people in it.

The adequately muscled, undernourished, metabolically unhealthy bucket doesn't really exist. So these aren't people aren't uniformly distributed in those buckets, but it's a pretty good way to sort people. And you can't sort someone by looking at them into that bucket, but by looking at them, doing some functional testing, looking at their biomarkers,

and that might include also doing things like a dexascan where you can actually get some objective data, you can pretty quickly figure that out. And the reason we think that's important is it helps us understand, do you need an energy deficit? Do you need an energy surplus? What's your protein intake need to be to achieve that in combination with your calorie needs? with your calorie needs. And the hardest of those to treat by far is over nutrition under muscle.

And unfortunately, that's a very common phenotype. That's a lot of people these days, yeah. I think as a general approach, first order approach, that makes a ton of sense. You know, one of the things that that allows you to recognize, right, is that the optimal strategy is, there's no one size fits all, I guess would be the way I'd say it.

Different people are going to have different needs nutritionally and what works really well for one person may not work at all for another person. And so I think looking at it at that level allows you to not have to try to say everybody should be doing X. That is pretty similar to the way I think about it. Obviously I don't practice medicine and I try not to make recommendations for what people should do, but in my own life, that's generally the way that I try to approach it as well. And I hope I'm doing okay. You

haven't tested me yet, so you can't tell me which bucket I'm in. But I think I'm doing okay for my age with my nutritional strategies. And the other thing that I sort of have realized similar to what you were saying before is that, you know, it's an ongoing learning process. And so I think it's really important that we be willing to change our beliefs about nutrition and other aspects of health as more data comes in. So I think if you take that strategy then you can be open to the possibility that what you believed 10 years ago might not have been exactly right. And maybe we need to tweak it a little bit. I'll be honest, I have real trust problems with nutritionists. You know, in part, it stems from I remember very vividly when I was, I think it was probably in my early 20s. I read one of these diet guru books.

This was, I'm going to date myself, but this was, you know, early 90s, I guess. The theme back then was, you could eat anything you wanted as long as you cut out the fat. You could have this really high simple carbohydrate diet, just keep it low fat and you'll be fine. And we now know that's exactly wrong. I can't help but look at a lot of what people, what I would put sort of on the fat diet side,

the diet gurus, what they're saying today, how do we know 10 years from now, we're not going to look back on that. And again, be like, that just makes no sense. I think some of us today can look at some of what's out there and say, that just makes no sense. But again, this gets back to what I was saying before. It's not that I would say nutrition science is across the board low quality. I think they're actually really good scientists doing really good work in this area. It's just a really hard problem. And I do think, to some extent, the biology of aging and the biology of nutrition do

share that. These are extremely complicated biological systems. We're trying to understand in the context of this changing environment over time. So I don't blame the scientists. I just think we have to be really careful to recognize what the limitations are and not draw really strong conclusions. Like everybody should eat, you know, a low protein diet. That's kind of one of the fads that are out there today. That's a mistake to recommend across the board nutritional strategies for everyone.

I guess the last thing, I'm talking a long time here, but I guess the last thing that what you said makes me think of as well, and I think this is really important because people lose sight of this is exactly what you said. If you can be somewhere close to optimal nutritional intake, just like total calories, regardless of composition, body composition is somewhere close to where it should be. That's a big chunk of what you need to give yourself the best chance of being healthy going forward. You don't have to optimize every single thing. Now, I know you're all into optimization, and I respect that about you. I think if you can do that, that's great.

But you don't have to to get most of the benefits. So I think starting from that big picture perspective allows you to get most people most of the way there. Then when they're most of the way there. And then when they're most of the way there, you can focus on how do we get that last 10, 20, 30% whatever it is. I couldn't agree with you more Matt, and I would argue, and I do argue now in a very different way from where I used to be a few years ago. There are most things in my life where I don't like the 80-20 principle. My good friend Tim Ferris, he's the king of this, he's the king of how can I get 80% of the learning with 20% of the time.

And I've never seen anybody who can do it like Tim, like the guy can learn a language in a month. He can be 80% proficient in a language in a month. I'm the opposite. I'm the guy who loves the tale. I love the asymptote. I'm the opposite. I'm the guy who loves the tail. I love the asymptote. I love the perfection of something. I would say in nutrition that is exactly not where my interest lies. I agree that you can just get 80% of this right by focusing on exactly what we've

talked about. And the details, the complete optimization are not worth it, and it's instead better to put that effort into exercise. That's where I think. If you're going to really go down the rabbit hole and put more of your mental energy, more of your time and more of your focus into something, you have far more of an ROI on the exercise front than eking out incremental value on the nutrition front. I've joked about this before other guests on the podcast, Lane Norton, and I have had riffs on this back and forth.

The people who sit there on Twitter, which I realize is not a representative sampling of the world. It's simply an annoying vocal group of people who will waste endless hours debating the finer points of their dietary pet peeves who can't do 10 pull-ups is amazing. There should be a rule that says, if you can't deadlift twice your body weight and do 15 pull-ups, you shouldn't be allowed

to pontificate endlessly. You're not allowed to be on Twitter. I'm not the finer points of nutrition. We can talk to Elon about that. Maybe that can be a new rule. I think we've established nutrition matters here, but I think at the same time David Allison said it once to me, it's amazing how little we know about this subject matter. Kind of rehashing what we said. We know

that too much and too little are bad. And for most of our existence, we were worried about the too little problem. The too much problem has become a relatively recent phenomenon. And they're bad in different ways, acutely, chronically. They have different limitations. We know that certain things are toxic acutely or chronically. Not a lot. We know, I mean, with definitive clarity, there's not a lot we know beyond those things. One thing that seems to be true is,

at least from the animal literature, caloric restriction seems to reproducibly improve lifespan. Let's kind of talk about how that came to be as an understanding. This area of research is actually quite a hundred years. Yeah, the first experiments were published in the early to mid 19301930s, which means they were probably started in the 1920s. So almost a hundred years ago, people were going down this line

of thinking of asking, you know, what is the effect of significant restriction of calories on the aging process in mammals? So the early studies were all done in rats. If I remember correctly, these studies were originally designed from a developmental perspective. So they were really thinking about malnutrition and its effects on development. And as a byproduct made the observation that yes, when you restrict calories in a rat early on in life, they have a smaller body size. But then if you let them live out their entire lives, this is in the laboratory, and I think that's really important to keep in mind, they live 40, 50% longer. So we're talking really significant increases in lifespan. And then the other thing that was appreciated pretty quickly was not only are they living longer, but they seem to be

healthier as they're living longer. So this concept of health span in the period of life that is spent in good health free from disease and disability It seemed as if caloric restriction was not only increasing life span but also extending health span that led to a large body of literature since then Studying the effect of caloric restriction in not just Rodents rats and mice but also all sorts of simpler organisms in vertebrates like fruit flies and sea elegans and yeast. And the common theme seems to be that, again, starting from laboratory conditions, if you restrict nutrients by a whole variety of different methods, you can increase lifespan and apparently

increase health span proportionally, at least proportionally. So there's a lot of nuance there, a lot that we can dive into and to unpack. But I think that's generally the take home, is that over and over and over again across the evolutionary distance we're talking about is much, much greater than the evolutionary distance between rodents and humans. So over a very wide evolutionary distance in pretty much every organism where it's ever been studied, you can find evidence that caloric restriction slows aging. Again, there are cases where that didn't happen, where lifespan wasn't extended, where

lifespan was shortened. Maybe we want to talk about this at some point. The interaction between genetics and environment and caloric restriction. But in general, the take home message is caloric restriction can slow aging in laboratory animals pretty much everywhere where it's been studied. The one question that some people have is whether that's true in non-human primates. I was going to say before we get to NIA Wisconsin, which is perhaps the single greatest experiment that's ever been done to test this hypothesis, both in terms of its duration, level of control, and proximity

to our genome. Let's spend a moment on that. Before we do, any things that come up from the rodent studies that are worth talking about, so for example, one of the things that I think is always important to point out is there's a very particular death that tends to fall on laboratory mice. If you look at the death bars for humans, there's much more heterogeneity, but the leading cause is atherosclerosis. Now, that's true in the United States. It's true across the globe. When you mix in, develop, and undevelop, it doesn't matter. Laboratory mice aren't that way. They die of pretty much one thing and one thing alone, and that is... Actually, it's euthanasia, but I know where you're going.

and one thing alone. That is. Actually, it's euthanasia, but I know where you're going. Cancer, right? So certainly, every old mouse at time of death will have cancer. And again, because of the way animal studies are done, usually you have defined endpoints where when a mouse reaches that endpoint, they have to be euthanized. But the expectation is, if they hadn't been euthanized, they would have died from the cancer. So I think you're absolutely right. They're not dying from atherosclerotic. That's right. But when you look at their arteries, they're not littered with plaques the way ours are. At least the commonly used inbred mouse strains, that is definitely true for it. There are, this is maybe getting in the weeds a little bit, but there are certainly mouse

strains that have been designed either transgenically or through selection to develop other pathologies that will shorten their lifespan. But if you let a typical mouse strain in the lab live out its natural life, it will have a very high tumor burden at the end of life. And most likely, I guess I should know this, I don't know exactly, I'm guessing 80% of the animal would die from cancer. So it's different from humans in that way. And I actually think this is a legitimate criticism,

to some extent of the color, the interpretation of the coloric restriction literature that is, could it be the case that really what coloric restriction is doing is preventing cancer? And that's why you see these big increases in lifespan. And I think that's really difficult to definitively answer one way or the other.

What I would say is, mice do develop functional declines in every tissue and organ as they age very much like people do. So a person may die from cardiovascular disease, but at the same time, if they're in their 80s, their kidney isn't functioning as well, their heart isn't functioning as well, their brain probably isn't functioning as well. So mice show all of those same declines in function with age, and caloric restriction seems to delay the outbreak. Prevent those declines as well.

So yeah, maybe the lifespan effect is primarily due to cancer, but caloric restriction is having an effect apparently on the underlying biological aging process in all sorts of different ways. And I really like the functional measures. A lot of people in the field these days are really enamored with the aging clocks, the apigenetic clocks, biochemical markers. I think those are all useful and important.

But from my perspective, what really gets my attention is if somebody shows that the heart is still functioning like a young heart or the immune system is still functioning. Yeah, I wasn't planning to go down that rabbit hole, but since you brought it up, can you convince me of the utility of the clocks absent the type of data that would actually demonstrate longitudinally their benefit, which to my knowledge, we really don't have yet?

I would say a couple things on that. I think we need to be precise in what we mean when we talk about the clocks, because there's lots of flavors of clocks. Most people these days, if you just say age and clock, what they really mean are the epigenetic clocks that are showing the characteristic changes in the epigenome, epigenetic marks that are seen with age. Again, in every organism where it's really been studied, you do see these characteristic changes in the epigenome with age.

So I would say one place where their utility is clear, at least to me, is as a chronological measure. Now you might ask, okay, why would I ever want to use an epigenetic clock to tell my chronological age? I know how old I am, but forensics, for example, might be a place where that's useful. Their crime has been committed. They want to know with some level of precision

how old the perpetrator is. You could use an epigenetic clock for that reason. In my world, as part of the dog aging project, there are many dogs that are rescued and owner might want to know their age. So I think that is a real use, and clearly the clocks will work for that. I think really what you're asking, though, is, can I convince you that the epigenetic clocks and potentially other types of clocks are actually measuring biological aging? And that's a harder, in my mind, that's a harder thing to prove.

And personally, I have no interest in convincing you of that, because I'm not convinced. So I think this is an area where the field is influx a little bit. And there are certainly scientists who I respect a lot in the field, who believe at their core that these epigenetic clocks tell us about biological aging, or can beetic clocks tell us about biological aging or can be used to tell us about biological aging. Then there are people like me who want to see the proof. And I think the proof

is really being able to show at an individual level. That could be an amounts, could be a person, could be in a dog, at an individual level, you can predict someone's biological age at some point in their life, and with some level of precision predict what's going to happen in the future. What are their future health outcomes? How long are they going to live? Nobody has done that yet. What they've done comes close, I guess. So what has been done is to look at longitudinal studies in people where we have samples from people 10, 20, 30 years ago,

measure the epigenetic profiles of those people 10, 20, 30 years ago and ask how well does that correlate with mortality outcomes, for example, in the future? And they do work to some extent. I think people will debate how well they work. Are they any better than other markers you could look at in predicting mortality? I think that's unclear, but there is some correlation there. So it really depends to some extent maybe on how skeptical you are.

I'm a skeptic by nature, and I want to actually see the proof. I guess the last thing I would say about this, I'm talking mostly about the epigenetic clocks. Maybe it's worth talking about other types of clocks that people can make. The other thing I want to caution people, the on though, is assuming that the epigenetic clocks are the only important thing about aging. There is, again, a small number of very vocal and popular people in the field who talk as if changing the epigenome is going to change everything about aging. We have no data to support that. It just have to say it, that is not true at this point.

We have no data to support it. What we know about the biology of aging is that epigenetic changes are one of, depending on how you categorize things, eight or nine or 10 molecular processes that seem to contribute, that the field has reached consensus on. It's only one of those things. Is it possible? It is sort of in a hierarchy the most important

and drives a lot of those other changes? Yes, that's possible. We don't have any data to support it. So this idea that reversing the epigenome is reversing aging is at best in exaggeration, at worst, and outright lie. I mean, it's just not true. is reversing aging is at best in exaggeration, at worst, and outright lie. I mean, it's just not true. What a set of experiments, technology-wise, would you need to be able to do to even test that hypothesis, say, in a mouse?

We're close, well, maybe close. I guess I should qualify that a little bit. Conceptually, we're close. So there have been these factors called the Yom Anaka factors that can reprogram the epigenome. So this has been these factors called the Yom and Ockofactors that can reprogram the epigenome. So this has been done in cells. So if you take cells in culture, in a laboratory, and you passage them many, many times, you can

see changes in the epigenome, just like you might see changes in the epigenome in an animal in tissues. And you can put these reprogramming factors into the cells and turn them on. Are there four Yom and Ockofactors? There are four Yamanaka factors? There are four Yamanaka factors and people are trying different cocktails, adding some other stuff in, taking some stuff out,

but yes, there are the four classic Yamanaka factors. And what those factors do is they basically wipe clean the epigenetic changes that have happened over time. And also what's amazing is that they restore those cells back to a, if you take it far enough, back to a pluripotent state. So essentially, you get virgin new cells that could differentiate into any cell type in the body.

So this has been known for many years. What is relatively more recent over the last eight or nine years, are people are trying to express these reprogramming factors in an animal. So instead of doing it in cells in the laboratory, do it in an animal. And I think the most compelling work is work in a premature aging model of mice, so it's called a progeroid model, where they're very short-lived, they're very sick. But these reprogramming factors can stand lifespan by, I don't remember what the exact numbers are, but a significant amount, maybe 40, 50%, which seems like a lot, except you have to recognize these mice

live maybe 25% of the length of a normal mouse, right? So they're very sick. But there are impressive changes that happen that are consistent with the idea that you fixed or made something better. So the experiment to do would be to express these reprogramming factors in an old mouse and make that mouse young again. And this is where I think the exaggeration, I'll use the nice word, has gotten ahead of the actual data.

So what has been done is showing that in one or two, maybe three tissues, you can see an improvement in function. The most impressive, I think, is work from David St. Clair's lab where they use this optic degeneration models. So degeneration of the eye show that they could reverse that with these reprogramming factors and then try to do the same thing in an old mouse. You know, the data was mixed,

but I think pretty compelling that you could, to some extent, regenerate the optic nerve in an old mouse. So that's certainly impressive, exciting, but nobody has ever taken an old mouse and turned it into a young mouse. So when people start talking about reversing aging, that implies that you have taken an old animal or person and to some extent biologically made them young again. That hasn't happened. So what I would say needs to happen to really convince me they're two things. So I would be convinced that this is useful, potentially therapeutically and important.

I'm actually already convinced it could be useful therapeutically, but I would become really excited if somebody could do as good as rapper Myson in a mouse. So I'm not asking for much in my view. We know rapper Myson can extend lifespan 25%, at least, again, dose hasn't been optimized, but 25% let's stick with that. And you can reverse functional declines in many tissues. So show me you can do that with reprogramming

and I'll be excited. Nobody's done even that yet. Show me you can take a two and a half year old mouse, make it look like a one year old mouse, and then it lives to be five years old. I'll be really excited. Look, I'll be all on board. I might even come on your show and apologize for saying that people were exaggerating, although they are exaggerating now. But I think the enthusiasm has just gotten so far ahead of where the science is. Let's maybe help folks understand what the Yamanaka factors are doing and how one can be sure that even if you fix the aging problem, you don't create a new problem.

So if the objective is I want to take the DNA as I had it when I was young. So when I was 20, this is what my DNA looked like. Now that I'm 50, it looks different. It has literally these methyl groups that are sitting directly on the cysteine residues, like literally on my DNA. Okay.

We want to take those off. Maybe. First of all, it's important to understand why that's even a problem. Why is my 50 year old crappy DNA not as good as my 20 year old DNA? So again, this is taking a step back to sort of basic biology. So, the DNA is where all the information is,

but then that DNA has to get turned into RNA, that's called transcription, or gene expression, which is called gene expression, and then that RNA has to get turned into protein, and in general, it's the protein that does the work. So, what these epigenetic changes, the methyl groups that you were talking about, do, primarily, we think, is effect that does the work. So what these epigenetic changes, the methyl groups that you were talking about do, primarily we think, is affect expression of the genes.

So basically what you're seeing with aging, we think, is a shift in the epigenome that leads to certain genes being expressed that shouldn't be, and certain genes not being expressed that should be. And I think there's a little bit of a debate about which is more important right now, but it probably doesn't really matter, right?

So the idea is you're getting things turned on and turned off inappropriately as we get older. There's a loss of regulation, which probably contributes to a loss of homeostasis. And homeostasis is, I think, a really useful way to think about aging. If you're healthy, your body is generally in homeostasis. And what happens as we get older is it becomes harder and harder for our body to maintain homeostasis. When you get out of homeostasis, if your defense mechanisms are working right, you can get

back in. You get COVID, for example, your immune system works. You're out of homeostasis, but you come back in and then you're okay again. I think as we get older, it gets harder to come back into homeostasis. That's why we start to see pathology and mortality. So let me differentiate two states of pathology. My five-year-old son was on his scooter two weeks ago going down the steepest hill in the world, which I had no idea how I didn't see that he was about to do that. Like, face planted, and when he came up, all I could think is, how quickly can we get to the hospital? I mean, he was a bloodbath.

I'm not making this up, Matt. Six days later, there was one little tiny scar, eight or nine days later, you would have had no idea this kid ripped his face off on pavement. He's five. I get a cut. It's like nine months until the scar is gone. So there's a very clear distinction between a five year olds DNA and a 50 year olds DNA in terms of how he can literally make new proteins that are better than my proteins.

Let me stop you there just for a second. I think this is actually the crux of the question. You said it's a difference in your DNA. I think what I'm trying to get at is that's a clear case of the protein that he makes is better than my protein. He's making much better proteins. Certainly functions better. I guess what I was getting at though is the one question I think that's really important here is there can be changes to the DNA to the sequence, right? So the sequence of the DNA is the information. Those are called mutations and those accumulate as we age and that's honestly what drives a lot of cancer. So we've known this for a long time. The epigenetic changes are sort of on top of each other. Yeah, and while it more regulates expression, I'm wondering how much that factors into the example I just gave.

It's a good question. I'm sure it does, to some extent, absolutely. Like what else explains why his college ends so much better than mine? What are the other factors that go into that? I mean, I think there are probably many reasons why healing, our ability to heal declines with age. I actually,

again, we've talked about this before, I think inflammation is a huge driver of our loss of ability to recover as we get older. So, you know, all sorts of things go wrong if you have a high level of sterile inflammation in your body, including the ability of stem cells to function. And a lot of injuries require stem cells to function to build back what's been broken. So it's complicated, I guess I would say, but the question is, that I have more senescent cells and more senescent cells factors

that are impairing the ability of cells to heal. Just to throw a wrench in that, there's actually a body of thought that senescent cells actually promote wound healing. Again, this is where the biology is so complicated. But I think the crux of the question we started from is, if you only fix the epigenome, do you fix everything? I know you fix all these things. Yeah, do you fix everything.

And nobody knows, I think, is the fair answer. I would be shocked if that was the case that epigenetic changes drive all of aging. But it's possible. I think we have to be open to that idea that epigenetic changes sit on top of or upstream of the other hallmarks of aging. First of all, let me say one thing, it won't fix everything. You will not fix mutations by fixing the epigenum. The question is, do mutations, do they happen with enough frequency to be a major contributor to functional declines that go along with aging?

Certainly cancer, you can point to that. Cancer for sure, but let's now talk about something else, which is near and dear to your heart and open intended, but ejection fraction. Again, because you study dogs, not only is cancer a big problem, but so is heart failure. So now we're dealing with a muscle, a set of cells that really aren't being turned over the way skin is. So when we think about the example of my son, when you think about your gut epithelium being sloughed off when you get sick, when you think about your fingernails in your hair,

boy, it's really easy to think about those things as rapidly being turned over. But neurons, cardiac myocytes, these things don't get turned over a whole heck of a lot. So what is it about reprogramming that we think is going to fix an aging neuron or an aging cardiac myocyte? This is an area where the biology of what's really happening, at least to my knowledge, is so poorly understood that I think the real answer is we don't completely know. I'm going to give a very simplistic answer, which is that what people are trying to do is not reprogram all the way back to the pluripotent state

So this is called partial reprogram. It should be pretty dangerous Well, that's what I was going to say if you're a single-celled organism No problem going back to the pluripotent state you can then start over in a complicated animal if we reprogram you back to the pluripotent state that's not gonna end well No, right? So I think the idea is to go back far enough that you restore the epigenome to its pristine state, young state, and then hope that when you do that, you restore gene expression to where it's supposed to be. Maybe one way to think about it is you restore the homeostatic mechanisms to a more youthful

state where then the homeostatic mechanisms to a more youthful state, where then the homeostatic mechanisms that all of ourselves have can basically clean up the rest of the mass. Because we know, as we get older, for example, we all accumulate damaged mitochondria. Changing the epigenome, which is the nuclear genome isn't going to fix anything that's wrong with your mitochondria directly. But maybe by fixing the epigenome, you restore the homeostatic mechanisms that then maintain mitochondria in a healthy state, and you can fix the damage to the mitochondria. So that's the concept.

And again, I would say the evidence is suggestive that if you do it just right, you can improve function in at least some age to tissues organs by partial reprogramming. I've yet to see anything that convinces me that anybody has made an old heart into a young heart in an old animal with partial reprogramming in the heart. But you can't improve function.

I would also say the same thing is true with rapamysin, right? I would not argue, we see that short-term treatment with rapamysin in mice makes an old heart function functionally to some extent more like a young heart. I would never argue that we have taken that heart and now it's young, it's just in an old body. We don't know that and that's hard to prove. You can see some evidence that it should be possible with partial reprogramming to do

that. You know, the question is, will it work everywhere? Will it work in some tissues and organs and not in others? We don't really know. So let's just say 10, 20 years from now people have figured out a lot of the complexity starting to move these things into the clinic. Maybe we will see really large effects on lifespan and health, span and mice. What I've yet to hear anybody give a convincing explanation of is how you do that in the brain. Because so much of who we are and what we are comes from our experiences and our memories.

And so how do you ensure that you can reprogram somebody's brain in a way that isn't going to change that? And I just think that's going to be a really hard problem to overcome. But maybe somebody will figure it out. There are tons of really smart people working in this area. Lots of resources going into this area. So I think it's exciting. Again, my big concern is that we don't mislead people

into thinking that we're close to reversing aging. And I think it's a problem from the perspective of the general public. I think it's a problem from the perspective of the scientific communities. Other scientists look at that and they're like, this is snake oil. This is just not true. My concern with it is from the perspective of the scientific communities. Other scientists look at that and they're like, this is snake oil. This is just not true.

My concern with it is actually in terms of the impact it has on people, which are, hey, this is awesome. This thing's gonna get worked out. I can sort of do what I want because in 10 years they're gonna reprogram me. And my view on that is even if that is true, or even if you have a high degree of confidence that that is true,

how would you not hedge? Again, hedging is such an important part of how companies manage risk. So, the difference between good companies and bad companies when it comes to risk management is everything. That's why some companies do really well in economic downturns and others don't. It's basically about risk management. And a very important part of risk management is indeed hedging.

So if we think of ourselves each as little companies, you're the CEO of Matt Coe, I'm the CEO of Pete Coe, I can't think of a more important asset within my company to manage than my own life. Do I have enough money? Yeah, do I have enough fun? Yeah, those are all important assets, but existing would be the number one asset and to not take a risk management approach of hedging to that is insane. And yet what I see is so many grand promises of this stuff

and nobody's sort of paying attention to what they eat or how much exercise they do because I don't need to. This is going to be worked out. So the thing that I always find amazing is some of the most vocal advocates for this stuff. Don't have an ounce of muscle on them. They're overweight or whatever. They don't look healthy. Yeah. And I'm like, guys, you can do both. You can believe that in 10 years, we're going to fix this problem, but you could still actually care about your health. Now, I think that's a really important point. And having, again, been in this field for a long time now, I think you can just look back over the last 20, 30 years and look at predictions people made on how fast these things

were going to come along and get into the clinic. And none of that has happened. So I totally agree with you. Also, being in the center of it, I take a view of, again, pretty strong skepticism when people say, this is going to happen in 10, 15 years. I honestly have not appreciated that there are maybe a lot of people out there looking at what they read

in the New York Times or on CNN and thinking to themselves, oh, I don't have to worry about this, this is gonna get worked out. So my advice would be don't expect major changes in treatments to improve lifespan and health span in the next 20 years. And that doesn't mean I'm not optimistic. I think there are opportunities there. It would not surprise me if we do see some of these things get into the clinic, but I certainly wouldn't expect it. Because there are so many barriers that we don't yet appreciate. There are lots of barriers just

in moving something through the clinical trial process. I think the reprogramming stuff is a perfect example. So you actually alluded to this earlier, are there potential side effects? Absolutely. You push it too far, you reprogram too far, you're gone. We know that certain types of cancers are a side effect of this partial reprogramming in mice.

Again, doesn't mean it can't be worked out, but there are really reasons I think to be concerned this is going to be hard to implement therapeutically. The other thing I would say, even if those things can be worked out, the FDA is going to be extremely skeptical of this kind of approach. So as people move these through the clinical trial process, they are going to have to show with really rock solid compelling data that reprogramming strategies are not going to cause significant show with really rock solid compelling data that reprogramming strategies are not going to cause significant side effects. So I think it's a long road before we have reprogramming strategies to get into the clinic.

Maybe somebody will identify a small molecule that can do some of this and I know people are working on that. Maybe that'll be an easier path. But for now, I think it's going to take a while. That's the best case scenario. That's if we really can partially, I'm going to say partially reverse aging, reverse aspects of aging.

It's still going to be a long road. And I wonder if the first wins are going to be things like what David Sinclair has done where you've got one very niche application. I think another one that would be amazing would be osteoarthritis. If you could figure out a way to regenerate human cartilage without joint replacements, those are huge wins that seem at least a little more feasible.

But again, I agree with you. I think this stuff takes four times as long and costs four times as much as we think. You and I are, I mean, honestly, we're pretty lucky because we know about a lot of this stuff. We actually can start practicing some of this stuff like rapamycin before it gets out there, right? Again, I'm not recommending anybody take rapimicin necessarily without talking to your physician first, but we know this stuff and we have at least a pretty good idea of the relative risk reward. But before it gets out to where it hits the mainstream from a clinical perspective, it's a really long path. I totally agree with what you said though about specific

indications where you can target it very precisely, hopefully, and where there's no other solution currently. I think those are opportunities. That's exactly the strategy that people have tried to take with senolytics, that these molecules that will clear senescent cells. And even that's been hard. I mean, Unity is the sort of largest company in this space,

and their first clinical trial for osteoarthritis failed. So now they're looking at the eye, because it's a nice indication where, for some of these eye diseases, there isn't any solution, and you can, in principle, target it quite precisely to the eye. So yeah, I think that is exactly the strategy that people will be taking, and hopefully it'll be successful. I want this stuff to work. I just try to be a realist at the same time. The way I would kind of describe this to people is if you want to bring it back to a financial analogy, it's a lottery ticket.

And so if your entire financial planning system is based on winning the lottery, the odds that you're trying to win are pretty low. Instead, if you're going to play the lottery, play it in the context of an otherwise great saving and investing strategy. I guess the other thing I would add to that is, and this is what we talked about before,

you don't have to do everything right. Get 80% of the way there, which nutritionally, I don't think is, I mean, for some people it's very challenging, but I think most people could do that. Exercise, you don't have to optimize your physical activity. Do something, and that'll get you most of the way there. So yeah, I totally... Yeah, the exercise curve, which we've covered a lot in previous podcasts, you get most of the

benefit. I would say literally 50% of the benefit based on at least the the so-so epidemiologic data, about 50% of the full benefit of exercise is captured going from nothing to about 15 met hours per week. You know, that would be 15 met times one hour would be one way to get there, but in reality, no one who's that unfit can do 15 met. But that would be like three hours a week of five met's to put that in perspective.

And five met's is like a very, very brisk walk or a slow jog, something to that effect. So you get a sense of like 15 MET hours per week. By extension, I do about 100 MET hours per week of exercise. I think of everything in terms of MET hours. But the point is that you can get, depending on the study, 30 to 50% of the benefit going from being completely sedentary to 15 met hours per week is pretty amazing.

Which is a big benefit, right? And again, it's sort of remarkable that that information isn't out there for the gent, most people in the general public don't know that. I don't know what the solution is. I think you're obviously doing a great public service by trying to get that information out there, but it's unfortunate because I think again,

most people understood how much benefit they could get from just getting out and moving a little bit. Maybe a lot, maybe three hours a week is a lot for some people, but the magnitude of the benefit compared to the effort that you put in, I think most people just don't know that and it's unfortunate. Let's go back to the CR stuff. What do we know about the effective CR in the laboratory animals on the immune system? So it's a little bit complicated. First of all, laboratory animals in the laboratory are kept in what's called a specific pathogen-free

environment. So that doesn't mean there's no pathogens, but it's a relatively low pathogen environment where they are not obligated to really use their immune systems against all the challenges that we would face in the real world. So, one question has come up, are animals that are on calorie restriction immune compromised? And again, I think the data is a little bit mixed. There have been studies where people have done pathogen challenges on CR animals, and they

respond better, at least the old animals respond better than age matched ad-libitum fed control. So ad-libitum just each as much as you want. But then for certain types of challenges, colarch restriction clearly causes a deficit. Yeah, the sepsis experiments are pretty clear with the CR animals compared to controls when you induce sepsis in them, the CR animals die much more quickly.

And so of course, the obvious implication of that is that maybe CR would impair immune function in people and lead to higher risk of all sorts of infectious diseases. And this gets additionally complicated, though, by the question of optimal CR with optimal nutrition. So you might sometimes just see this cron, CRON, right? Chaloric restriction with optimal nutrition or crayon, Chaloric restriction with adequate nutrition. That can be done in a mouse.

We can control all of that, so we make sure that they get all the micronutrients and vitamins that they need when they're on this CR diet. When you move into the real world and people start practicing caloric restriction, that all goes out the window. If I wanted to do caloric restriction off the top of my head, I wouldn't even know what to do to make sure that I'm getting optimal nutrition. And so in that state where you are CR without optimal nutrition, I think that's where I really

become worried about the side effects, particularly as you raised immune deficits, because you may not be getting the nutrient value or the specific micronutrients and vitamins that you need to maintain a functioning immune system. Sure, you may affect some aspects of the biology of aging in a way that you're aging biologically more slowly. That doesn't matter if you get influenza and die. So again, I think that's an additional complication that comes into play.

When we start talking about, we haven't talked about all the other anti-aging nutritional strategies. When we start talking about recommending those nutritional strategies to the general public, based on solely on mouse studies, I get really concerned because of this environmental complexity that humans live in. And we haven't even talked about the genetic complexity, right? So there's all sorts of things that are just different about laboratory animals compared to people living in the real world.

And then what can we say about frailty, sarcopenia, as it changes in an animal in a CR environment and can that be extrapolated also? It's pretty clear, I think, that much like rapamycin, most functional measures of aging seem to be preserved in colorically restricted animals, including measures of frailty and measures of sarcopenia. The same thing again is true with Rapa Mice. And this actually surprised a lot of people when the first studies were done because the expectation was because mTOR plays such a big role in muscle synthesis that if you inhibit mTOR with Rapa Mice, or coloric restriction, which is a potent inhibitor of mTOR,

that you would actually see accelerated sarcopenia. And that just isn't the observation in laboratory animals. Again, we have to be careful not to extrapolate to people, but it doesn't seem to be the case that you lose muscle, mass, and function in the way that people would define sarcopenia. I think the important complication here is that all of the caloric restriction studies

that I'm aware of when they look at muscle function normalize the body. The caloricly restricted mice weigh substantially less than the adlibitum fed mice. Usually I think it's on the order of 30-35% less. It's usually grip strength normalized to weight. What you're actually seeing is that the caloricly restricted mice have maintained muscle function proportionate to their body weight. And I don't know the answer to this, but it's something that I thought of when we were talking about this show, let's just say you did that in a person.

You would be able to answer this. I'm sure you've got a 60 year old person who needs to lose 30% of their body weight. But of course, you want to maintain their muscle mass, their muscle function. Would you view it as a good thing or a bad thing if they lost 30% of their body weight and 30% of their strength? I don't think we would and I don't think we would view it as a good thing. If you're telling me that someone needs to lose 30% of their body weight, presumably their body composition isn't great to begin with. So, no, I think you would view that as maybe a better thing than where they started, but not optimal either. Optimal might be you would lose 30% of your body weight, but it would disproportionately

be adipose tissue and you might only lose 10% of your strength or none at all, depending on the change in lean body mass. This is just a complication of the CR studies. It's hard for me sometimes. It takes me 20, 30 minutes of trying to dig through the paper to really figure out what normalization did they do to look at metabolic rate or muscle mass or lean mass or fat mass or muscle function. But usually these studies will be normalized to body weight.

This actually comes up also in some of the the intermittent fasting studies where the question sometimes in these studies is, are they isocaloric or are they colloquially restricted when they're put on intermittent fasting? And people will claim they're isocaloric, but the mice lose weight and what they really are is isocaloric when normalized body weight, right? So they're really colorically restricted, but you have to kind of dig to get how the normalizations were done to really understand. When we think about what we know in humans, you know, there was a study that looked at the difference in bone mineral density in people who underwent

equal amounts of weight loss, one driven by a chloric restriction strategy, one driven by an exercise driven strategy, and the exercise driven weight loss group did not experience a reduction in BMD, but the CR group did. So that's interesting. That's yet another thing that makes you think there's a little more nuance to this, which is not to say CR from a weight loss perspective isn't valuable, but it begs the question, is CR the right tool for longevity? Once you've achieved optimal weight,

is additional CR beneficial? That makes the assumption we know what optimal weight is. I mean, I think that's kind of the crux of the question, right? We're asking, does CR impact longevity positively? We know if you go on CR, you're gonna lose weight. So if the answer to that is yes, then by definition, optimal weight is lower than what we think.

In humans, though. I would say we still don't really know what optimal weight is. So again, this I think just reflects the challenges in coming to definitive answers. And the way I think about it, more so is what are the downsides potentially to colaric restriction. or so is what are the downsides potentially to caloric restriction? And if we don't know the caloric restriction has big benefits in terms of health span and perhaps lifespan, what are the downsides and do those downsides outweigh the uncertainty we have about whether caloric restriction is beneficial? And unfortunately, I think this is something that not very many people in this field pay

attention to. We all expect if you do a clinical trial of a drug, you're going to report adverse events, and you're going to look at side effects. Very rarely do people think about that before they write a book recommending that people should do diet X. Even in the clinical trials, some of the nutritional clinical trials, they don't really carefully monitor adverse events. It's a bias in the way we think about interventions. We feel like nutritional interventions

are by their very nature safe. And certainly for extreme nutritional interventions, that's clearly not true. So I think we should be thinking about what are the risks associated with significant caloric restriction in people as a therapeutic strategy. So let's talk about the experiment and all experiments with respect to caloric restriction, which is the very famous one we alluded to earlier at the University of Wisconsin and the NIA. I've read this study a thousand times if I can get the details right once I'll be happy.

But between the two of us, I hope we can do this. You had two groups of animals, one at the University of Wisconsin and one directly in Bethesda, Maryland. This was obviously a huge NIH funded effort. It ran for a couple of decades, given the lifespan of Reese's monkeys. The Wisconsin animals were fed, the controls and the treatment CR animals were fed, a very processed diet. At least after the fact, the investigators there suggested they wanted to more mimic a very processed diet. At least after the fact the investigators there suggested

they wanted to more mimic a standard American diet. Of note, I recall the amount of sugar, pure sucrose in their diet was 28.5% of total calories. So a high-quality diet, facetiously. The CR animals, the colorically restricted animals, were fed 25% of what the control animals were fed. And in that experiment, we found a benefit to coloric restriction. The CR animals outlived the control animals. And they had fewer age-related diseases. So I think if you go back to that original 2009 paper, the lifespan effect is compelling

and it looks real. But what again is really indicative of that it might be having an effect on biological aging is that they saw reduced rates of cancer, again, not surprisingly, as we talked about in mice, but also heart disease and metabolic disease. So it's consistent with the idea that in that cohort of monkeys, again, given what you mentioned about the dietary composition, caloric restriction was in fact having a beneficial impact on the aging process. And those animals all came in at about the same age. Right.

So that was sort of an apples to apples comparison. Now we go down the road to Bethesda. We have a totally different experiment in a way. I don't know how much of this was deliberate and how much of it was not. The diets were different, so that's maybe a good contrast. These animals were actually fed the closest diet that could mimic their real diet. It didn't have any sugar in it really. I think it was like about 3% sucrose. It was almost kind of like a vegetarian pescatarian sort of diet. Fish was the dominant source of protein. You know, it was a high quality diet relative to the Wisconsin animal.

For sure. The complicating factor here was the animals didn't come in at all the same age. So you had some animals that came in young, some animals that came in old. The net results of the study was there was no difference. The CR animals did not outlive. And so while the Wisconsin study was first published in 2009 and it said CR works, the 2012 publication for NIA said CR doesn't work, at least that's the lay press interpretation of it.

So how do you kind of reconcile these findings? One thing to add to that is the NIA study at Bethesda, in their paper at least, they did show some evidence for improvements in at least some health-span metrics. So if you read that paper closely, I think what they're really saying is, see our didn't extend lifespan, but it did have what appeared to be some beneficial effects on health-span metrics. So it wasn't a complete failure in that sense. I mean, I think it's interesting because since then, I remember when the 2011 paper came out, the Wisconsin people were pretty upset understandably. So I think since then they've had sort of a reconciliation

paper and where they try to figure out what does it mean that we got these different results. And I think their conclusion, which certainly is plausible, is that a lot of it comes down to the difference in diets. And if you look at the actual body weights of the animals and how much food they ate, not just the composition, but actually how much they ate, you know, you could make an argument that the Thesda monkeys were somewhat slightly colorically restricted. Controls.

The controls. Yes, the controls at Bethesda ate less than the controls in Wisconsin, and that would have narrowed the gap between them and the treatment. And so then I think, as you also alluded to, the fact that the Bethesda study was a little bit less controlled for age of onset, I don't remember the details exactly. There were also some genetic differences in there. So there's a combination of factors that make it a little bit difficult to conclude that it all is about the diet. The monkeys in the Bethesda study came in at different ages.

There was at least a hint, I think that the monkeys that came in at older ages started CR at older ages, maybe got somewhat of a benefit, whereas the ones that started early didn't get any benefit. So it's complicated to interpret, and it's interesting because we see this a lot of times in the basic biology of aging, basic science studies,

where different labs will get different results in what seems to be the same exact experiment, and then you start to dig into it. And yeah, there's all these differences in the way it was done. It's really hard to know which of those differences contributed to the different outcomes. In this particular case, because it was a 30, 40 year experiment,

we're never gonna find out. If it can't be done again. Yeah, I just won't be repeated, both because of how long it takes and also because the view on primate research, these are racist macaques. The view on primate research publicly has changed. I just don't think we'll ever see that

experiment done again. My gut feeling is that the Wisconsin study, to some extent, probably does mirror what is closer to a typical American situation at least at these days. I do not believe that they started with that intention, but where we're at today, it probably is relatively as close as you can get for a controlled laboratory study. The question, though, in my mind, is between these two studies, do they suggest that caloric restriction slows aging? And let's just start relative to the typical American diet. Somebody is moderately obese, and they're eating terrible. Is it caloric restriction or is it just returning to what you would call like an optimal body weight, optimal body mass?

And I don't think we know the answer. From these studies, you can't draw many conclusions. I think the one thing you can do, and Roz Anderson, who's still at Wisconsin, is really I think been a leader in this, is you can study the molecular signatures of caloric restriction in the monkeys and ask, does it look similar to the molecular signatures of caloric restriction in rodents? And you might ask, well, why would you do that? It seems obvious. But again, a lot of the questions

that people have around caloric restriction studies in mice is, will it work the same way in people? And obviously, recessed macaques are much closer evolutionarily to people than mice are. So if you see the same molecular changes, it's suggestive that colark restriction is having the same molecular changes in people, certainly in primates. And in fact, that seems to be the case. A lot of what we see in terms of changes in amtore signaling and mitochondrial function and other metabolic pathways is in fact shared between mice and monkeys. That is one important outcome from these studies

that we can definitely say is rock solid. I tend to believe that the pretty dramatic declines and age-related disease seen in the Wisconsin studies are telling us something, but again, is it just telling us that not being obese reduces your risk for a lot of these diseases? We kind of already know that from the human literature. Exactly. The other thing that isn't entirely clear given that the NIA study didn't find a difference is we don't know how much of this was the CR versus the DR, the dietary restriction. In other words, what the Wisconsin experiment suggests is if you have an awful diet, reducing the amount of awful food you eat is a good thing.

Right. What the NIA experiment doesn't tell us is the contrapositive. It doesn't suggest that if you have a good diet, eating less of that will help you live longer. It might, but it isn't definitive. So we don't know if the Wisconsin animals live longer simply because they lost weight or because they lost weight and they were eating less processed food. Right, and I think the other thing to add to that is the NIA

monkeys, which were eating, you know, what we'll call a superior diet to the Wisconsin monkeys, also ate less than the Wisconsin monkeys. So, yeah. So in other words, if you ate more of a good diet, would that be detrimental? We also don't know that. It's an interesting question actually, and it's too bad. We don't know the answer to that, but I think if they had been body weight matched or caloric consumption matched, that would have been an interesting comparison to be able to see are there differences there. And the other thing that just kind of gets off into weeds that we don't need to necessarily go into is, I don't really have a great understanding of even how we differ from the Reese's monkeys.

So I recently read Herman Ponser's book. I don't have you read it by the way No, so he kind of goes into the ecology and evolution of humans as a species and how different we are even from our closest evolutionary cousins and one of the fundamental differences are incredible capacity to store excess energy. So our metabolic rates, you know, he documents this through lots of assessments of doubly labeled water on not just ourselves, but also undergatherers that are still around today. And then of course, all the primates is we're really kind of unique in our energy expenditure. Our energy needs are far greater than anything else. And people like that would argue, hey, that was kind of an advantage that we took

to allow our development, including our brain development. So there's kind of a reason we're at the top of the food chain, which is we have a much greater brain. And the price we pay for that is higher energy expenditure. And the price we pay for that is we better be able to store energy because we will have a much harder time tolerating a low energy environment and so he talks about how even when you put these animals in captivity and you overfeed them They're not getting that much fatter. They're actually putting on lean mass You know, I think what you could argue and he doesn't talk about this But knowing what we know about human biology you might argue that they're still getting metabolically sick.

Just as humans, when you're overfed, the real metabolic sickness comes not with the inflation of your subcutaneous fat. It's when that spills out into the viscera, into the liver, into the peripancreatic space, into the perinephoric space, into the pericardial space. It's that fat that escapes the normal depot of subcute fat that is truly inflammatory and truly metabolically disturbing. So, I throw all that in there just to say, like it's just one more confounding variable that makes it difficult to compare us even to an organism as complex as a racist monkey.

People certainly have made that criticism of the caloric restriction literature writ large, not even taking into account the monkey studies, but the mouse studies, right, that there are all sorts of differences between people and mice and the metabolic state that people have evolved to fill is just completely different. Having said that, you're absolutely right that even mice in the laboratory, as they get older, will show metabolic syndrome, right? You will see many of the same changes in insulin resistance, for example, that you see in people. And do you see it absent the adiposity? Can you see it? Mice gain adiposity with HD. They do, in fact, become obese with age. Again, on a pretty crappy diet, right? I stand, well, I don't know if it's crappy or not, the standard mouse diet. I don't remember what the number is you may, but in the Wisconsin

study, right, a significant fraction of the control fed monkeys developed diabetes. Yes. I want to say like a quarter of the controls were prediabetic by the end of the study, again, which probably speaks to even though they weren't overweight, when you get 28 and a half percent of your calories from sugar, it's probably going to impair your metabolism. The other point that's maybe worth at least just mentioning here, because I hear people talk about how certain diets are better for humans because it more mimics what we evolved to eat. I don't know whether that's true or not, you could argue both sides of that. I don't see any particularly compelling reason to think that that was the optimal longevity diet that, you know, humans

800,000 years ago. I think that argument is illogical on several fronts. The first is, and I don't know who coined this phrase, but it's so ubiquitous that it's obvious. Like, by necessity, we had to be opportunistic omnivores, to even suggest that our hunter gatherer, forefathers, were sitting around pontificating about what they were and were not going to eat on me. It's just the dumbest thing I've ever heard. I mean, I don't think people are actually arguing that, but my point is the argument becomes so nonsensical when you realize our evolution necessitated the most flexibility from a nutritional standpoint. Yes.

And therefore, we ate anything and everything. And I think because we never probably existed in an environment where food abundance was so great that we could reach the level of over-nutrition, it gave us even more flexibility with what we could eat. Is that maybe part of the reason why humans seem to be fairly robust towards eating really, really crappy diets? Obviously we have an obesity epidemic and all of that stuff happening, but people seem to be able to tolerate

a wide variety of different diets, some of which are pretty darn bad for them for many, many years before you start to really see the significant consequences. And it may be that metabolic flexibular. I was going to make a totally different point that's almost orthogonal to that, which is you can make a case that people can survive in really remarkable health with diets that look nothing like one another. In other words, you can look at somebody eating a really well-formulated strict vegan diet where they're not getting any animal protein, which clearly

our ancestors all had animal protein whenever they could. They're often a little protein malnourished, but they're very healthy. And similarly, look at the opposite end of that spectrum. You can look at somebody on a ketogenic diet. The only thing they would have in common between that other person is probably a lot of leafy vegetables. But other than that, it's a much higher fat, higher protein diet. They can be very healthy. That, to me, speaks to the resilience of our genome in terms of its interaction with nutrition. And that's sort of where I started, which is that there's no reason to think that the

ancestral diet is best. There's no reason to think that the ancestral diet is best. There's no reason to think that. But the other thing that I was thinking about when I started down this path is that, like many other things, our, as a species, our dietary options and the typical diet is evolving rapidly now. The quality of the food, the stuff that's in it, the preservatives, is dramatically different than it was 50 years ago, both in caloric content and nutritional content and taste. And taste, right, absolutely, which contributes to why a lot of people want to eat more.

So high calorie, really good tasting food that's often cheap. But the environment that we evolved into, obviously, is completely different than it is today. But our environment is changing at an accelerating pace, I think. And that makes it really, again, complicated to try to get into the minutia of what is optimal. Maybe we should be thinking about what's good enough first, right? Because I think it's going to be really hard. And again, this is where I struggle with the data that comes from epidemiological studies

of people 20 years ago. The environment, the food quality is just very different for most people today. This is where the grandmother test comes in. And this is where when I watch like the extremists on both sides argue, I say two things. The first is, look, they're a really good and really bad ways to do your respective diet. I don't want to hear somebody tell me that everybody on a vegan diet is doing well because I watched a lot of those kids in college and they literally were going to kill themselves eating ramen noodles and crackers and cookies all day. So you can be vegan and eat pure garbage. You can be keto and eat pure garbage. The second thing I would say

is if you're eating those diets well and I I'm being a little subjective when I say well, you're all shopping on the outer part of the perimeter of the grocery store. It doesn't matter if you're carnivore, vegan, keto, low carb, paleo, whatever. If you're doing those diets in the way that they were at least thought to exist, you aren't going down any aisles of the grocery store. And that's kind of this grandmother test. Like if your great grandmother didn't recognize what you're eating, it doesn't mean it's not good. I don't want to say that a protein bar is not a good thing to eat. You just have to acknowledge there's a little more risk there.

Eating a carrot is inherently less risky than eating a protein bar with 14 ingredients in it. That's just a fact. I think this is what you're getting at. Just a little bit of a humility around what is known, what is not known, and as we push the envelope of convenience, of nutrient density, of economics, price, shareability, portability, right? The ability to preserve things. We're going to take some risk. I think that's exactly right. Let's talk about more broadly a paper you wrote. How long has it been two years? We probably wrote it longer than two years ago. I think it came out at the end of 2021. Okay, okay. So it's fairly recent. So talk about the impetus for that paper, which

was, I thought it was a great paper and we should discuss it in the next video. Yeah, so I was asked by one of the editors at Science to write a review, I think on MTOR, actually. And like, well, lots of people have written reviews on MTOR. I've been thinking a lot about colar restriction and particularly other nutritional strategies that people have been studying in the field like ketogenic diet, protein restriction,

time restricted feeding, intermittent fasting. And what do we actually know about those diets and their effects on aging? Because I was up the, before I started to really dive into it. And this isn't something that my lab research is directly. So we've previously done work on caloric restriction in invertebrates and sealagons, but we never really have done a lot of dietary interventions in mice. You know, before I dove into the literature, I had this impression that all of these diets were similar in some ways and had maybe comparable effects on lifespan. At least that's the way it gets portrayed.

If you read some of these reviews, and I don't even like to call them reviews because I don't think honestly much of what gets into the literature as review articles are actually reviews. It's more one person's opinion piece on their specific thing that they study, which is unfortunate. But if you read most of the reviews on Cholaric Restriction and other dietary interventions, they're very one-sided. They usually have phrases like fasting is known to have all of these fantastic benefits, flows aging in every place where it's been looked at. You can see that for all these different dietary strategies. I proposed to the editor that maybe we should do

a critical review of this space and think about what do we know, what do we don't know, are they equivalent? To the extent possible, can we gain any insights into whether or not these nutritional strategies, whether there's evidence that they have an impact on the aging process in people. So that's kind of where we started. And I knew it was an ambitious thing to tackle when I said it, and I'm not sure I really

appreciated exactly how challenging that was going to be, because it's a huge area of literature. And it turns out, maybe not shockingly, that there are many more questions than there are challenging that was going to be because it's a huge area of literature and Turns out maybe not shockingly that there are many more questions and there are answers when you really dive into it So what was your process? The first step was and I should say I had a fantastic set of co-authors all you know really great early career Scientists who really helped me with this and did a lot of the legwork. I just want to mention them by name Please too. So Alessandro Bito, who was a postdoc with me, Mitchell Lee, who was a former graduate student with me, and Crystal Hill, who's at the Pennington

Biomedical Research Institute, and she works on FGF21 and protein restriction. So those three were co-authors on this paper with me, all just really fantastic early career scientists. So we started by asking ourselves, okay, what are the different popular dietary interventions that people have claimed have an effect on aging? And we came up with, I don't know, six or seven. The ones I've already mentioned. So there's true caloric restriction,

which is pretty straightforward. That really just means limiting the overall caloric intake that an animal gets by somewhere between 20 towards the low end and the most I've ever seen is 65% of Can you were doing this in animals and humans? We were mostly focusing on mice. We narrowed it pretty quickly when we realized the scope of what we had undertaken. So we could have tried to do it and you know fruit flies and worms and all that stuff. We said let's start with mice, see what's known and then all that stuff. We said, let's start with mice, see what's known, and then try to look into humans and ask, are there parallels? So, caloric restriction, pretty straightforward. We actually don't go very deep into caloric restriction because that literature is huge, and other people, I think, have done a pretty good job of reviewing true caloric restriction. But there are some points there that we probably want to touch on that are important.

And then there are variants of caloric restriction, which include intermittent fasting, time restricted feeding. How did you differentiate those two? I have a definition, but I want to make sure yours is clear. Right. So in mice, well, so first of all, the first differentiator we need to put across all of these things, is it isocaloric or is it a flavor of caloric restriction? Because it turns out, I would say the vast majority of studies

in mice of all of the things that we're going to talk about are flavors of caloric restriction. And what I mean by that is the experimental group ate less calories than the time-restricted feeding, but it's really caloric restriction in a narrower window. Intermittent caloric restriction, maybe so you want to think of it. And there's actually some nuance there that we can get to. So how am I differentiating between time restricted feeding and intermittent fasting? I would say, to my view, the easiest differentiator is time restricted feeding is limiting the number of hours in any 24 hour period that the animal or person needs. And there are obviously you're aware of this. There are flavors of time restricted feeding and people where the window can be anywhere from 12 to 6, sometimes even more extreme than that.

But you limit the hours per day that the animal or the person eats. Intermittent fasting I would put in a 24 hour or more fast. That's a reasonable deficit. That's actually the definition I use. An intermittent fast is a fast that occurs at a frequency of greater than once a day. Right. Exactly. The other thing I would say though, is that a time restricted feeding

gets even more complicated than that, because there's evidence that it's not only about how big the window is, but where in the day of the window is. And that's actually one of the things that came out of our review of the literature is there is this clear connection between how much we eat and when we eat

that ties into circadian rhythms. And that circadian biology, even since this review came out, there have been papers that have come out that reemphasize the importance of when we eat and what we eat. I don't think it's either. I think it's both.

That suggests that that's probably gonna be significant in terms of the consequences of the long-term health effect. I'm hoping I'm gonna remember to come back to that, but let's keep going. So then there's what people call fasting mimicking diets, which are diets that I've been engineered to some extent to induce the same metabolic changes as caloric restriction, usually very low sugar, relatively low protein, high fat, but also very low calorie. So that clearly goes in the bucket of a flavor of caloric restriction. There's ketogenic diets is another one,

and then there's protein restriction. So isocoloric protein restriction? Well, both. So again, you really have to look, you have to take each paper one by one and figure out, is it isocoloric or isn't it? And that's in some cases simply not possible because the data is just not there,

but you have to look closely. So there are examples of both. I guess one way to think about it is, is it ad-lib or not? In other words, an ad-lib ketogenic diet might end up restricting energy, but non-deliberately. That's one way to think about it, but I don't know that that answers the question of whether the benefit comes from caloric restriction or not. That's the complication. But I agree with you, that is, it's different. We don't think about this much in mice, but certainly in people, it's true. If you are not ad lib, there are psychological consequences to not eating when you want, to being hungry all the time.

Good, bad, indifferent, but those have biological consequences as well. So they are different, absolutely. Let's go back to the circadian one. I want to kind of get the insights there. So first of all, let's talk about what you know in mice. And then let's figure out if there's any extrapolation. So when we wrote the paper, there wasn't much on this. I mean, people were thinking about it, particularly in the context of time restricted feeding, that

there might be differences in the window of time restricted feeding for in humans right early in the day, late in the day. There's been a couple of papers that have come out since we wrote the review in mice that I think make a pretty compelling case that the lifespan benefit from, say, a 30% caloric restriction diet is a combination of when the animals are eating and how much they're eating. Most of the benefit seems to come from the calories. So, you know, let's just say this may not be exactly right, but I think it's close. Let's just say

that you get a 30% lifespan extension from 30% Chloric Restriction. The two-thirds of that benefit comes from the calories. But one-third of the benefit actually comes from the fact that those mice eat all their food in a short window and are fasted, essentially, the rest of that 24 hour period. And if you force them, and I say, force, because if you give a colorically restricted mouse, it's food, it's going to eat it right away. So if you force them to eat little bits throughout the day, you lose a portion of that lifespan benefit, which is really interesting.

Now, a mouse eating in an hour and then going 23 hours without food, what would we even compare that to a human? I don't know. I really don't feel comfortable even speculating. So the first simplistic approach would be to say, well, a mouse lives about three years, a human lives about. I was thinking more of like, how long does a mouse take before it dies from starvation?

Yeah, so that's where I was going to go next. I think that length of lifespan is not the approach you take when it comes to metabolism. So I would say that, and this is total back of the envelope calculation, maybe it's like a one to four ratio. So one day mouse fast might be a four or five day fast in people, but that's not even perfectly true because a mouse will go into ketosis relatively quickly within 24 hours. And a human can go into ketosis that quickly. Depending on their incoming diet.

Yeah, exactly. It's not a perfect equivalency, but maybe one to four or five. I hope I'm not saying something totally stupid here, but I think that's probably pretty close. So again, it's very different, potentially, these kinds of studies and mice. The other thing that I think most people don't appreciate unless they've actually done these colaric restriction experiments is that if you go back to the classic experiments of Rick Windrick and Roy Wallford, those mice are fed a colarically restricted diet. They're also fed three times a week. So they are,

in fact, fasting. They're basically doing a two-week fast between their meals. Yeah. And so what you see, even in 24 hours in a fasted mouse, is you see pretty dramatic reductions in organ size. The mice are being fed three times a week. They're going through this reduction in organ size and then this huge rapid hypertrophy. And you can see that decrease in organ size and then rapid increase even on some of the fasting mimicking diet work that Walter Longo has done. Has anybody done their reverse experiment where you try to actually mimic the way humans eat and you take two groups of mice and the controls are fed whatever 100% of the nutrient, but they're fed every two hours over the course of the day and the CR group are given 70% of that, but they're fed at the same time intervals constantly throughout the day. In other words, you make it purely a calorie

thing and you really take out the fasting except when they're sleeping. At least one of these two studies that I was referring to did that. Oh, so that's how they were able to identify that two thirds of the benefit came from the reduction in calories and a third of it came from the additional fast. Right. Exactly. So in my mind, I think this is really important because this is one of the points that we made in our review is if you look at the vast majority of the literature around intermittent, really teased that out in a way that allowed us to have an understanding of how much is calories and how much is fasting. And maybe how much is when you're fasting. That's still, I think, as an open question. What else can we say about early

feeding versus late feeding? You mean early in life, like? No, early in day versus late in day. Yeah, I mean, this is an area I'll admit. I'm not an expert in. So I don't honestly have an opinion about which is better. And again, this is where I think mice are not gonna be a good model for human. Those studies need to be done in people. Some have suggested that an early feeding window versus a late feeding window produces

better pairing of our insulin sensitivity to our nutrient arrival, right? I think that makes sense. Most people would agree that, particularly if you're eating something that causes your blood sugar despite that doing that right before you go to bed, probably suboptimal. So I think that maybe that can explain most of that observation that has been made. If you're going to do a time restricted feeding, it might be better early or at least not right before bedtime. I guess I would say. These kinds of questions are really complicated in humans because you could ask what benefit

are we looking at? So if you're looking at overnight blood glucose levels, it makes perfect sense. If you're looking at sleep quality, maybe it's going to be different. Or maybe it's going to be different in different people. If you're looking at other biomarkers, again, it could be different. So my mind at least, maybe you have a different opinion on this. And my mind at least, it's not even really clear how we evaluate what is better and what is suboptimal. It may depend on what your endpoint is, what you're actually interested in optimizing. Clinically, we see in people who wear CGM that early feeding produces an overall lower average glucose for sure,

because even if you get the same spike, like if you're doing the same meal early in the day versus late in the day, there's something about how long it takes to come down at night versus in the morning. Now, that could be your more insulin sensitive in the morning, and therefore it comes down quicker. It could be something to do with pairing sleep with the nutrition that is tweaking this and that there's a feedback loop where the excess glucose creates a little more cortisol. You get a little more hepatic glucose up, but I don't really know if that makes sense. I mean, I've heard people argue that, but at the same time, you theoretically should have the lowest cortisol at night anyway,

so that really shouldn't be an issue. I don't really know what it is, other than just to say I've observed it empirically, you know, it generally doesn't produce a great quality of sleep, but to me, this starts to get into, which I want to hear more about, but this gets into the minutia. At some point, you just got to focus more on other things,

but I want to go down this rabbit hole just for the sake of completeness. Yeah, sure. To some extent, that's almost where we ended up. Let me give the big picture answer for why I think this is important. So I think these nutritional intervention studies in mice are very powerful for dissecting the biological mechanisms

that underlie the effects that they have. And some of these diets clearly have effects on aging. I'm very, very hesitant to suggest that people should adopt any of these diets based on the rodent literature where it's at today. And I think there are a whole variety of reasons for that. But that's kind of where I ended up. I think they're super useful for understanding the biology.

I'm really not sure that they're going to work the same way. What did you learn about the protein restriction in the ketogenic diet mechanistically in the mice? The ketogenic diet studies, there have really only been two that I'm aware of that looked at lifespan and health span in mice. They were slightly different, but in mice,

you have to go to really, really low sugar to actually get the mice to go into ketosis. Essentially, 1% or less carbohydrate diets. So again, that's a difference from people. One of the studies that fed a ketogenic diet lifelong, so no effect on lifespan, but they did an intermittent ketogenic diet. I don't remember the exact protocol, but it was something like every other day or maybe once every three days or something. And there there was about a, I think, a 15% increase in lifespan. And I'm sorry, what did they do on the other days? The animals.

Regular diet. Oh, interesting. Wow. Yeah. So it was just back and forth between the control diet and the ketogenic diet. And that didn't result in chloric restriction. Uh, it's a thing. The mice were colorically restricted. So it's in some ways, it's a intermittent coloric restriction. And this is what I would say is also interesting because the fasting mimicking diet papers are intermittent ketogenic diets. Maybe that's one thing to agree on is that intermittent ketogenic diets in mice can increase lifespan and seem to have benefits for health span. The effects aren't huge.

That's the other take home I would say from our study. There are two nutritional interventions that relatively consistently give big effects on lifespan. One is caloric restriction and one is protein restriction. Caloric restriction, the most extreme study that I've seen is 65% restriction and that gave about a 65% increase in lifespan. So these are big, big, small sizes. I wasn't aware of that. Yeah, that's this

windrick and walford paper. And when did they start that and how long did that restriction last? That's a good question. I don't remember. It was probably six or nine months. I think most of their studies were early onset caloric restriction. This study was really interesting because they did a graded response from 90%, 80%, 60%, 50%, 40% of Adlib. You get essentially a graded response in lifespan, and it's roughly linear. So 90% animals? No, but they didn't go that far.

They didn't go beyond 60 or 65. OK, OK. And I also think this is an interesting study because I don't think you could do that study today because the animal care wouldn't allow you. Yeah, this gets back to an element that we don't think you could do that study today because the animal care wouldn't allow you. Yeah, this gets back to an element that we don't think about enough, which is what does mice feel like? Like, think about how angry those mice would have been on a third of their normal caloric intake. You know, again, I haven't done these kind of mouse caloric restrictions studies

myself. I've obviously talked to a lot of people who did. I think to really appreciate that, you've got to probably be in the animal room seeing them. Certainly activity goes up quite dramatically. That's one of the remarkable things about colar restriction in mice is that they are more active throughout life than adlib fed mice are. And maybe it's a sort of foraging response, evolutionarily selected foraging response, but they are definitely, you give them a running wheel and they'll just run and run and run and run and run. Yeah, there are behavioral changes for sure in mice that are colloquially restricted. And this is actually one of my real concerns about colloquial restriction in people. First of all, we should be realistic and recognize you're never going to get a significant fraction of the population to caloricly restrict. It's hard enough to get people to caloricly restrict down to a healthy weight.

To get them to go 30% beyond that, it's just not going to happen. But of the people I know, I mean, being in this field, I know people who have done every possible anti-aging intervention you could imagine. And of the people I know, and I know a lot of people who dabbled in various forms of caloric restriction, certainly true coloric restriction has real psychological consequences. And I really would be concerned, might have been concerned for some of the people I know who've done this, if we started trying to do this in the general public, there's social isolation that you get when

you're colarically restricting, but then there's the biological changes in the brain and you're hungry all the time. We often don't appreciate those aspects of some of these nutritional interventions. But in the mice, I'd hard to know what their psychological consequences are. And what do we know about coloric restriction later in life in the mice versus earlier? The sort of traditional thinking is,

you have a window in which you can do it early and beyond that it's not as effective. I think we're going to talk about some data that counter that. And then, of course, you have the NIA experiment we talked about earlier. In the monkeys. In the monkeys where the early fast didn't improve longevity, the late fast appears to have, although that was sort of a subgroup analysis. Hard to draw a causation there. What I would say about the mice is that for a long time, the dogma was the

caloric restriction didn't work if you started it past, I don't know, 15 months of age, which is maybe the mouse equivalent of a 40-50-year-old person. So most of the early caloric restriction studies were done, like I said, starting sometimes pre-development. The early rat studies were pre-development, and then sometimes, you know, six, nine months of age. When I first started in the field, that's kind of what I was told, like this is a saddled question. More recent studies that have been done in some ways more carefully, different diets, certainly, if you do a graded onset of caloric restriction, in other words, don't go right from ad lib to 40% restriction the next day.

If you do sort of a grad at onset, you can get lifespan benefits from caloric restriction 20, 22 months of age. So whether it's as good as starting early, I think the consensus is still that the answers know you're never going to get the same magnitude of benefit from caloric restriction starting late as you do starting early. But that could be wrong. So I would say that's the consensus, but I don't think we know for sure whether it's possible if you did it just right, that you could get most or all of the benefits

from starting late in life. So Matt, on this topic of CR and mice, again, the dogma has generally been, and I've been victim of this just blindly assuming it to be the case, that CR and mice only works early in life. How applicable is that to humans, I don't know. But I listen to the podcast, actually pointed out that, in fact, there are some data that try to get at this question.

So there's just a Han study 2019, which we'll link to, that looked at 800 female mice. Now, this is a pretty elegant experiment. So for the first three months, they ran these mice out on an adlib at a bit of diet. And then at three months, they were split randomised to believe a 40%. Yeah, calorie restriction versus adlib. They ran that out until 24 months. And then each of those groups was further split adlib versus continued on. So you had one group that was everybody's the same till three months, one group that spent the rest of their life on dietary restriction, one group that spent the rest of their life ad lib, and then you had the middle groups. 21 months calorie restricted then to ad lib 21 months ad lib to then calorie restricted. Okay, so the ends of this were not interesting. Meaning the ad lib group lived the shortest. We were looking at the figure earlier today, 1200 days, roughly maximum life span. Yeah, maximum life span. That's right.

Media and life span would have been looking at the graph about 900 days, which is pretty good. Yeah. So it's going to say, how does that stack up with what we talked about on the last podcast about length of life as a reasonable life span for control? I think if I remember correctly, this was also done not in C 57 black six, but in a little bit longer lived hybrid. That's right. F1 hybrid. So it's reasonable lifespan. Okay. Looking at the all CR all day, mice, looks like they had a maximum lifespan of just below, call it 1400 in change with a median that I'm going to say was about 1150. Good lifespan extension.

Okay. So now what's interesting is the middle groups, which is really try. So I'm going to just give you my little iPads. You can look at that table, which will link to this. Yeah, I got it right here. You got it right here. Remember the take-home message. You do. Okay. Yeah. Yeah. So what happened to the two middle groups? One thing I would say is I think this is a pretty early onset of CR. It really is three months. Yeah, this gets back to what I was talking about before that it seems likely from the early studies that were done in rats where they got some of these really, really large effects that some of the benefits of CR come from actually being restricted during development itself. I think that's useful

to put into context. So then the big question here is what happens if you start color restriction latent life or what this study did, then I'm not really aware of anybody doing previously is kind of the flip. It's almost like a crossover. That's right. Yeah, totally is. So in this case, when they started CR late in life, there is a significant but not huge effect. Like the magnitude of the lifespan extension is much less than in the mice that were on CR

from three months of age. That makes sense. That fits with what else is in the literature. There were earlier studies. I think Steve Spindler did one, not too many years, maybe four or five years before this one that did sort of a similar sort of approach starting around 15 months of age. And they saw a significant but not as large benefit from starting late in life. That seems to be the consensus. The thing that's really interesting here is, you know, what happens if your CRD for an earlier period in life and then back on AL, do you lose the benefit? And it seems like the answer is no. Those animals actually were longer lived than the mice that went on CRD in life. You could ask some questions about, is it about the total amount of your

life that you're restricted? Is it about when you go on and when you come off? And I think in mice, this is still an open question. We don't really know what the mechanisms are. Although the early life mice had a longer median, the median life expectancy was the ones that were on CR and then switched to ad libidum. Yes, that's right. They lived a little bit longer, but the bigger difference was the median life expectancy was higher than they flipped. Yes, although I think we have a little bit difference in definitions. I tend to think first about median, you seem to think first about maximum, but yeah, I mean,

I think what you're saying is right, the median lifespan is quite different between those two groups. It is the difference. The maximum is very trivial. That's right. The real question here is, well, aside from what does this mean for humans, which I would say we can't draw too many conclusions from humans from this, but what is the underlying mechanism?

And is it really just about the total amount of time that you've been on CR, or is it an interaction with how old you are, the developmental process, and then what happens at the end of life, which is mostly the degenerative process and when you go on CR. One thing that's worth adding to this too, is it's an interesting comparison to what we know about M-Tor and RAPA-MISIN. So with RAPA-MISIN, the data are pretty clear

that you can start RAPA-MISIN, certainly well into middle age and maybe even into very old age and get most of the benefit. So if you compare the curve here where they started the mice on CR at 22 or 24 months, whatever it is, the effect is pretty small compared to CR. With Rapa Mison, you get almost exactly the same benefit starting at 22, 24 months as you do starting early in life.

So that might tell us that there's a difference, right? There's a different mechanism potentially as well. It could be that rappers do something different, or it's a different dose effect relative to exactly. So that's an open question exactly why it's different, but it seems to be different. I'm really glad you brought that up because we talked about that with Rich Miller on his podcast, which was a fortuitous accident, basically because they couldn't get the formulation of rapamycin for a study. My favorite story in society. One of my favorite stories in society.

Yeah. Yeah, tell people that story. So take a step back. The NIA started this program called the Interventions Testing Program. It must have been in the early 90s. And the idea here was, maybe it was early 2000, sorry,

dating myself again, losing my decades. So early 2000s. And the idea here was I think really smart. The idea was that we could create a tool where the scientific community could nominate interventions for lifespan testing in mice. And it was set up so that it would be done in triplicate three sites. There still are three sites for the ITP. So anybody in the community can nominate any intervention. There's a selection

committee that selects them every year. And if an intervention is selected, then the intervention testing program sites start the cohorts of mice on that intervention, you know, in whatever year it was selected for. So sometime back in the early 2000s, Dave Sharp nominated Rapa Mison. Some ways he was ahead of his time because I think when he nominated Rapa Myson. In some ways, he was ahead of his time, because I think when he nominated Rapa Myson, it was even before the first invertebrate studies on M-Torin Rapa Myson, right around the same time they were being published. So he, I think, was thinking about it

from a cancer perspective, primarily. In any case, he nominated Rapa Myson, it got selected. It went into the cohort, and they typically test five or six interventions or drugs each year. So they have a huge number of animals at each of these three sites that are destined for these interventions to be tested in and Rappamysen was one of them. Randy Strong, who's one of the PIs on the high T.P., who's also got a strong biochemistry

background, I think recognized pretty quickly that the rapamycin wasn't stable in the food. We could actually come back to this if you want to, because this is relevant for people as well. And it gets broken down in the pH of the gut. So basically if they just put the powder in the food, there's no bioavailability. It doesn't get taken up by the mice. And so they recognized that,

right when they were supposed to start the experiment. And of course they were like crap. What do we do? We could just not test Rapa Mison. And I don't know if it was Randy or who. Somebody said, well, I think I can figure out a way to stabilize the Rapa Mison, put it in the food so that we can give it to the Mison,

and we can do the lifespan experiment. I think what they didn't recognize was that it was going to take 18 months or so to figure this out. So once they finally developed what they call eRaparap, a encapsulated wrap of mysin, it's basically designed so that it won't break down in the gastric pH. Once they developed that, they were now 18 months into this lifespan experiment. Before this, I think everybody, myself included in the field, but you had to start early in life or you weren't going to get much of a benefit. There was really almost no chance a drug was going to increase lifespan starting that late in life. But fortunately, they went ahead

with the experiment starting at 20 months of age. And what they found was that they got this robust lifespan extension from starting with rapid mice and treatment at 20 months of age. And just to give some context, that's about the mouse equivalent of a 60 or 65 year old person. And I love the experiment. I love the outcome, obviously, because first of all, nobody thought it was going to work, except maybe Rich Miller. I'll give Rich credit. Maybe he thought it was going to work.

And it was really the first time anybody had convincingly shown that you could start a intervention in middle age in a mouse and get robust life-span extension. And for me, honestly, I reviewed that paper. And when I first time I saw that result, I'm like, this changes everything. We actually have a chance for translational neuroscience because you might be able to intervene late in the aging process and have significant impact. That was 2009 when that paper came out.

So in the 13 years since then, the whole paradigm in the field has changed. Most people who are studying interventions today are studying things that they test for efficacy, late in life, because that's what we need to do in people. So it was a super important result for the field for that reason. And it all came about by an accident. Nobody would have designed that study that way beforehand. Now you were going to make a point about the bioavailability of rap. So this is something that's only recently come across my radar, but I've heard several

results now that convince me that it's true. So, you know, I mentioned the reason why they had to make this e-rappa is because rapamycin isn't stable at the gastric pH of mice. The same thing seems to be true in people. So So there are people who are getting their rapamycin from the rapamine, which is the brand name generic or the brand name Sarah Lymas comes in these triangle-shaped bills. There are also people who are getting it from compounding pharmacies. And I've heard of several cases now where the bioavailability is much lower in the compounded rapamycin in a capsule than in the actual rapamine. The triangle, the white and yellow triangle. Exactly.

So it's just something for people to be aware of. And I don't think most physicians are aware of it. I don't think most compounding pharmacies are aware of it. I have a... We've never had it compounded. So we've only prescribed serolumas or rapamine. You know, it's not a cheap drug. So I can understand why there's a desire to compound it because it's, I don't know, it's

got to be like five, six bucks a milligram. Yeah, I think that's about right. That's, that's very interesting. Yeah. So Matt, obviously one of the other things that came out of that review article in the animal stuff was, as you said, the protein restriction. And I think of all the topics in nutrition. This is the one I'm most interested in. I really don't care that much about fat and carbs.

Don't tell anybody, but I care an awful lot about protein. You know, in fact, when you came over today, you probably saw me chasing down what was left of a protein shake. And I think I was mentioning to you or for my wife, that's the only part of nutrition that is kind of, I don't want to say a chore, but it's a very deliberate part of how I go about the day, which is I really have to think about it. And the reason is, I'm trying to eat a gram of protein per pound of body weight spread out into four buckets. There's reasonable evidence to suggest that if you consume too much protein in one sitting and it's typically more than about 0.25 grams per pound is the general thinking, you're

going to end up oxidizing some of that protein. So it's not that it's harmful. It's just that you're not getting the amino acids you need for muscle protein synthesis, which is, of course, our objective. So that means I'm kind of walking around trying to get 40 grams here, 40 grams there, 40 grams here, 40 grams there. And truthfully, that's not trivial if you're not willing to consume a whole bunch of crap with it. If you're really just trying to focus on the protein quality. So, look, the RDA says I'm crazy. The recommended daily allowance of protein is 0.8 grams per kilogram, which is less than half of what I would consume.

And by the way, it's not just that I'm making up the amount that I'm consuming. I'm doing it on the basis of other data that suggests that this is the amount of protein consumption you need for optimal muscle protein synthesis. So where does this disconnect? First of all, we can talk about the rodent studies, which is in the biology of aging. I think the RDA question, that's a different question. It's my understanding that that actually was developed to be protein balance for 95% of the population when sedentary. What that means,

first of all, that's a minimum amount, not necessarily the optimal amount, and it probably very much depends on lifestyle. And lean body mass to begin with, even that sort of normalize to it. And the reason why I bring this up is I think there's a lot, again, a lot of confusion among the general public about what the RDA means. And it's not necessarily a bad thing to be above the RDA in some areas, maybe a lot of areas. So I think that's just worth expanding on just a little bit. I sort of jokingly think of the RDA for protein as what you need to not waste away and wither up and die.

Right. So you're not losing muscle mass. So then the question of what is the relationship between protein and aging? I think it's a really important one, and it's gotten a lot of attention in the field. And like I think a lot of other things, there's a lack of clarity about what we actually know and what we should be recommending to people. So let's take a step back and start with the animal studies, the mouse studies. I think they're it's pretty clear that you can extend lifespan through protein restriction.

And there are actually a couple of flavors of protein restriction. You can restrict all protein down to some percentage, some low percentage, or you can restrict specific amino acids, particularly- Branch change. Triptophan, methionine, or branch chain amino acids are the ones that have been studied. And again, I make that distinction because it's not really clear that the mechanisms are the same across these different flavors of protein restriction. The common mechanism that does seem to potentially underlie all of these forms of protein restriction is inhibition of amator. And again, that's partly why this

becomes complicated, especially when we start talking about extrapolation to human, you and I both recognize that inhibition of mTOR can have beneficial effects in the context of aging and health span, certainly in mice, almost certainly in people, I would say. And protein is an activator of mTOR, and we know a fair amount about the biochemistry of that, that particularly branch chain amino acids can directly activate emtore through cestrens and that's sort of all worked out. And so it seems intuitive that protein restriction would be beneficial by turning down emtore. It seems counterintuitive that what you were just talking about would be beneficial because you might be hyperactivating emtore. So we can dive into that. That's the simplest possible mechanism I can think of for why protein restriction, especially

branch chain amino acid restriction would be having an impact on lifespan and health span in mice. The other player that seems to be important, particularly in total protein restriction, is a protein called FGF21, fibroblast growth factor 21, that is secreted in response to a low protein diet and then has effects on liver metabolism and also inhibition of emittor reduction of IGF1. So that seems to be required for the lifespan extension that is seen from protein restriction in mice, potentially partially upstream of femtor and liver metabolism. The interesting thing there is FGF21 over expression by itself has also been reported to be sufficient to extend lifespan and mice. So it kind of fits that that could be part of the story.

So the question one question is, is protein restriction always beneficial in mice and can we separate it from caloric restriction? This is where you really have to look closely at the studies and determine did the mice on protein restriction eat less, eat the same amount, and eat more, and it's interesting because you can actually find examples of all of those. And honestly, I don't really understand why that's the case except it's something about the different compositions of the diet. What does seem to be the case is that when you restrict for certain amino acids, if you're deficient for methionine, for example, or triptophan,

the mice absolutely will eat more and they don't gain weight and they do seem to live a little bit longer. So that could be a somewhat distinct mechanism there that we don't really understand. What was the most compelling evidence you saw when you tried to tease apart the relationship between protein and total intake? I think the branch chain amino acid and methionine restriction studies are pretty clear that those animals are consuming more calories than

certainly if you matched a weight than the adlibitum mice and they're living longer. And what do we think is the route or mechanism through which methionine exerts this effect? That's still really being worked out. There are lots of mechanisms that have been proposed. I suspect mTOR plays a role. Methylation, methyl donors are important for a bunch of different epigenetic modifications. So there may be a role there going back to the epigenum that we talked about. Methionine is the first amino acid in every protein, so there could be effects on protein synthesis. There's evidence linking methionine restriction to sulfur amino acid biology, which has been implicated in aging. So it's hard to know, and maybe it's not one thing.

And those all sound like potentially just a substrate reduction problem, right? Like less sulfur cross bridging, less protein synthesis. You know, if you look back in the literature in the invertebrate, an inhibition of protein synthesis, in some cases, is enough to extend lifespan. And of course, MTOR is a primary regulator of protein synthesis. So when you inhibit MTOR, you can also inhibit protein synthesis.

That's part of the challenge here. This network is so interconnected that when you tweak one part of it, you have effects throughout the network, and it's really hard to know which of those effects are causal. So let's talk about time course. When you consume a protein-rich meal, do we have a sense of how long M-tours being activated in response to that set of amino acids? I'm sure somebody does.

I don't know the answer to that. I almost certainly it's going to depend on what you eat in combination with the protein, when you eat, how active you are. I remember talking to David Sabatini about this through the lens of BCAA drinks. If you're going to pound branching amino acids during a workout because you want as much anabolic signal as possible, and this is a couple of years ago. So maybe things have changed. But based on that work, I think Bobby Sutton had done the work in his lab. I'm getting his name right.

Was it Bobby Sutton? Was a guy who did that science paper that looked at the Lucine sensor on MTOR. The answer was it didn't stay on long at all. Free amino acids were so short in their ability to turn on M-Tore that unless you had an intravenous drip of this stuff, it was gonna be very difficult so much so

that the idea of using BCAA analogs to treat sarcopenia was going to require drugs that could stay on much longer. Is that kind of within your frame of thinking? I think so and I think it also makes sense in a biological context. I mean, cells and tissues, you know, again, this gets back to the whole homeostasis concept. Cells and tissues have evolved to maintain metabolites and amino acid are metabolites, right? They're involved in many different metabolic reactions within certain levels. And there are all sorts of mechanisms to ensure that if a metabolite gets outside of that range range that we soak it up, we do something else

with it. So I think it makes sense that you're probably not going to have a persistent increase in branch chain amino acids far outside the normal range. What I would say though is that slightly elevated branch chain amino acids chronically can have big effects on the downstream processes. And there are some inborn diseases of childhood where you have elevated levels of branch chain amino acids. We know that there are consequences to even having somewhat modest increases in hematosis,

hyperactivation of hematosis signaling chronically. So again, I think the context really matters. But yes, it's my intuition that it is probably hard to get very large persistent increases in amator simply from taking an branch chain amino acid supplement. It doesn't mean it couldn't have some effect on muscle building right after a workout. But I suspect it's hard to have long-term persistent effect. I mean, the anabolic data suggests it's not necessary.

It's just, again, muscle protein synthesis window is open long enough that simply delivering a great source of way protein in the hours after a workout seems sufficient to not restrict muscle potential growth. I think the other thing, though, that is also important to appreciate. And this is true with rapamycin as well. I think a lot of people get confused about this, is it's not only about how high M. Torgets turned on or how low it gets turned down. It's also about where that happens. People for a long time thought that rapamycin would cause muscle loss. We don't see that. We just don't see it in mice and we don't see it in people.

And I think it's probably because- I'm guessing you're not seeing in dogs. We have not seen anything to suggest that in dogs. Yeah. I'm guessing that has as much to do with how much work maybe more to do with where amtore is being affected than how much we're inhibiting M for when we're inhibiting M. And so I think the same thing to drop you. And do we know where the selectivity of rapamycin is?

I mean, is it more selective in hepatocytes? Is it more selective in adipose tissue? I mean, I don't know of any good studies that have really carefully looked at this. There have been a few studies in mice that tried to look at tissue emitter signaling in the context of rapamycin. It's a very technically challenging problem.

Well, and this is what I was just going to say. It gets even more complicated because even in a mouse where you can essentially control almost everything, what the mice are eating and when they last ate, has, if anything, as big, maybe bigger effect on amtore signaling than rap and mice, there have been, like I said, a couple studies that looked at this and I'm not sure,

and they got different answers, and I'm not sure who to believe because I don't think either was wrong. The only way I could imagine doing this is you have to be able to do subtractive studies where you have to be able to do it in the context of a whole bunch of different diets first, get kind of a baseline that you then pull out

of potentially what you're seeing, but I mean, it's complicated. And again, that's why I often will gravitate back towards what are the functional consequences we can actually measure? Sure, I get it. You think that treating a mouse with rapid mice is going to cause sarcopenia? Let's do the experiment and find out. The answer is no. It doesn't. Right, so that tells us it's at least not as simple as we thought it was going to be.

Now, what about the flip side of that is more protein versus less protein activating M-tor in a way that is counterproductive? I think it can. I think there are probably certainly cases where it can. I don't know that anybody has really carefully done that study in mice. There was a study, it's a really interesting study by Steve Simpson and colleagues

where they did this nutritional geometry work where they basically looked at different compositions of carbohydrates, fats, and proteins. Is it an Australia? Yeah, exactly. And you know, looked at, I don't remember how many diets, it was a whole range of carbohydrates, fats, and proteins. Is it an Australian? Yeah, exactly. And, you know, looked at, I don't remember how many diets, it was a whole range of diets,

different compositions of the three macronutrients, tried to control for caloric intake, which is hard, as you can imagine, but I think they did a pretty good job. And then asked, what does it look like in terms of metabolism, energy expenditure, lifespan? So the lifespan studies, I think, are pretty clear that most of the

diets where the mice live the longest were towards the low-end in protein. But there were some things that I think called into question exactly what was going on there because it wasn't the case that the mice that were energetic, the diets that were energetically lowest, gave the longest lifespan as you might expect from caloric restriction. And the diet that actually gave the absolute longest lifespan had like, I don't know, like a 40% protein in it. So the way I interpret that is that there are many ways to get to- And how calorie restricted was that?

They were not calorically restricted at all. So you're saying that a diet that was ad-lib with 40% protein had the best outcome? The best absolute lifespan, yes. How do we even reconcile this body of literature? My view is there are probably multiple paths to longevity. And we really don't understand the inner relationships of these macronutrients in the diet with enough sophistication to get beyond broad general predictions.

And again, this is an area where I believe, sophistication to get beyond broad general predictions. And again, this is an area where I believe, like I can't prove it, but my intuition from the data that I've seen and just my observations of people is that in humans, this relationship between protein and health during aging is probably very different than it is in mice. I think mice are able to tolerate a very low protein diet without some of the consequences

that we see in people. That's my intuition. I don't know that that's true, but that's my intuition. My intuition well, as well, because clinically what we see in what I call the death bars, the death bars is our internal nomenclature for how people die. We just constantly look at death bars and we double click and double click and double click all the way to try to tease out everything that is reducing lifespan and health span. And the problems that occur in humans when they are undermuscled are insane.

And it ranges from the metabolic consequences of being undermuscled. Our muscles are a sink for glucose. They are the single most important sink we have for glucose. And our ability to tolerate glucose and maintain glucose homie estasis in the presence of larger more metabolically healthy muscles is the difference between having diabetes and not having diabetes. Furthermore, when you think about sarcopenia and when you think about osteoporosis, which, again, I just don't think we're talking

about how these things impact animals. Like we don't study any animal, including primates in a setting where sarcopenia and osteoporosis are problematic. And yet I would ask anyone to consider the entire population that they know over the age of 75. And I would ask you, take every person that is alive today that's over 75 and tell me how many of them are not suffering at least

some consequence of one or both of those phenomenon. And if somebody did that analysis, I would be shocked if we didn't find at least 80% of people over the age of 75 are experiencing this. And if you look at the activity, just monitor the activity level, once they hit 75, they fall off a cliff. So muscle mass dramatically plummets activity levels dramatically plummet, difficult to say which one's feeding which, but there's no question that something is happening to our species at about the age of 75, that is a structural problem. And none of this other stuff matters if that sucks.

I don't care if I live to 100 and don't have cancer if I'm an invalid for the last 25 years and I can't play with my grandkids and throw a ball. For me personally, I'm not saying that's a, that's not a view that everyone should take in the world. There's something that's my view. I mean, I think that's absolutely correct I guess the question and I think this is still where some of the confusion comes from is How important is dietary protein in that maintenance of muscle or loss of muscle and people who are gonna go the wrong direction?

I think the data is that it is quite important There are lots of studies that have compared the RDA versus the double RDA standard, and it's a significant difference. Protein makes a very big difference following obviously the training that is necessary to stimulate muscle protein synthesis. So I think those have to be coupled to some extent. Absolutely. I believe there are data, and I hate when I have to say this, because I'm going to say

something and it's going to be wrong, and 20 people are going to respond. It's okay, I do it all the time, don't worry about it. And anticipation of the fact that there are data that I've read, and I don't have the memory I once had, I believe there are data that show just the protein difference alone can make some difference, but it's not nearly the difference you get when you pair it with hypertrophy training. That's my recollection as well, which brings us to the interesting question then, why is it that there is a camp? And in my field, it's a pretty vocal camp in the aging field that would argue that low protein is the best nutritional strategy for aging and health span in people. And this gets back to the point I

kind of started with, which is that you can find the answer you want for almost any question in this area that intersects with nutrition and aging. There will be a study that will fit your belief. So I think you really have to be careful. I try at least to take a global view and try to understand what is the totality of the data. But there are epidemiological studies. And one, in the field, most people will point to when they go to humans and they talk about low protein. The study that Walter Longo was, I think, the senior author on in Morgan Levine was the

first author on where they looked at protein consumption and all-cause mortality as a function of age. In people, there were some studies in, I think they had some yeast studies in there as well, maybe some cell culture studies. The take home message was that low protein is beneficial up to about 65 years of age. And then once you get above 65 years of age, kind of flips and people who ate a higher protein diet have lower all-cause mortality. I should be clear, when I say beneficial, we're talking specifically about all-cause mortality. Which at the end of the day is a very important metric. Sure, you want to be alive.

Yeah, but it's not the most important metric. Necessarily, you could argue it's equally important to the health span metrics. Okay, so let's make sure people understand what that means. That means below the age of 65, the epidemiologic data in this study suggested people eating less protein had lower mortality and all caused mortality. And above 65, you saw that reverse. That's right. Now, did that paper make any attempt to quantify the net impact on mortality?

Because the very misleading thing about an assessment like that is when you look at mortality adjusted by population, before the age of 65, it's relatively low. Above the age of 65, it goes up very non-linearly. So when we do our death bar analysis, So when we do our death bar analysis, it's like, this is the death per 100,000 people. If you're 40, 50, 60, 70, 80, night, like, you know what I mean, it just becomes insane. So you could argue through that analysis, you're much better off with a high protein strategy, even if it's throughout life, because the absolute reduction in mortality would unquestionably be lower as a result of the benefit you would have later in life.

I absolutely agree conceptually with what you said. The impact of a change in mortality, late in life is going to usually swamp the impact, certainly swamp the same impact on mortality early in life. I think the question here is, what are the relative effects? They did model this a little bit. And it is, in their model, I couldn't get the date if I can't evaluate exactly what they did.

But in their model, the relative risk crossed somewhere in the 60s, right? In other words, your total mortality benefit was lower eating a high protein diet. I think it was starting somewhere in the 60s, and that actually surprised me because for exactly the reason you said, the relative impact of the high protein diet early in life would have to be an order of magnitude greater than the relative impact of the... So I'm sorry, say what their finding was again at the age of 60s. I don't remember the exact number. It's in the paper. You can see the curves cross. It was much later than I thought it would be, given that 65 was the point that they kind of pick

So I would have thought maybe in your 50 so I actually tried to do my own modeling of this off of the data that I could find on Relative risk for low and high protein again, but you define low what you define high You know there and you're trying to ask the question when should you switch diet? Or maybe more formally at what age does the risk equal out? Yeah, what's the crossover? And what did you find? So mine was closer to like 50. That's the point where once you get past 50, the benefit of a high protein diet on mortality

seems to outweigh any detriment that you would get from starting. So that's odd to me because whether it's 50 or 60, it's a benefit on mortality, which is really where more of the argument is, there's can't be any benefit on health span. From low protein, you mean? No, from high protein. Early in life, or late, why can't there be a benefit of it?

Late in life, I'm saying. Why not? Well, I'm saying like, if your protein restricted late in life, low protein has no benefit on health span. Yeah, yeah, yeah. So I would agree with you intuitively. I'll exclude special cases. So I'm not talking about people who have renal insufficiency for whom they have to

restrict. I agree with you conceptually. The only thing that makes me hesitate a little bit is I've just seen like I was talking about the mouse wrap a mice and experiments where everybody who knew anything about muscle said that if you gave a mouse wrap a mice and throughout life, it was going to get sarcopenia. That just didn't happen. But I'm saying we have clinical data that suggests that when people over the age of 65 are protein deficient versus protein significant, there's a huge difference in muscle mass.

Which we know is going to be associated with frailty and poor outcome. We'll totally agree with that. I don't know. Do we have controlled studies where people were eating low protein and doing resistance training late in life? There are nuance here that could complicate things. But I think in general, you're probably wrong. I think the other area where this gets very complicated is the, I don't want to say by necessity, but just by convention, we use IGF1 as a biomarker for protein intake. It's certainly associated with protein intake, but you want to tell people what IGF1 is, where it comes from and what it's a proxy for. So IGF1 is insulin-like growth factor one,

hormone that's in the growth hormone pathway. So you can think of as a growth promoting hormones. Part of this central pathway that promotes growth in many, many different tissues. So if you have high growth hormone levels, you'll have high IGF1 levels, and high M-tore. This is a part of the M-TOR pathway as well, upstream of M-TOR. The reason why people have been really interested in IGF-1 in the field of aging biology, it comes from studies again in the very simple laboratory model systems. So

the most famous and one of the first genes that was shown to clearly from a mechanistic perspective of fat aging is it comes from, we're Cynthia Canyon and even Tom Johnson a little bit before her, which is the insulin-like receptor in Cialigans called DAF2. And Cynthia published a classic paper showing that if you make a mutation in DAF2, you could double the lifespan of worms and they seem to be healthier about twice as long. And what that mutation does is it turns down signaling through this pathway. Now, a little bit more complicated in worms because it's called the insulin IGF-1 like signaling pathway. So it's not identical. There's one path in worms that kind of takes the place of both IGF-1 signaling and insulin signaling, but you kind of think of them as equivalent. And then there are a whole bunch of studies in mice for mostly mutations in the growth

hormone upstream signaling, upstream of IGF-1 that lead to increased lifespan. So this means GH does not activate the production of more IGF-1. That's right. So you have through a variety of mechanisms. You have high GH, low IGF1 animals. Well, low GH signaling. But they probably are high in that. Oftentimes it's the receptor that's mutated. That's right. So those animals tend to be very long live. They rival chaloric restriction

in terms of the magnitude of lifespan extension. And there are several different mutations in that pathway. The mutations in IGF1, I guess I should know the current state of that literature a little bit better. It's complicated and there have been some controversies in the field about the different mutations that directly affect IGF1 itself and the effects on lifespan. So I'm not going to wait into that because I think it still hasn't been resolved. But there's no question that mutations that reduce growth hormone signaling in my

extended lifespan. Now, it's important to understand, though, that with one exception, those studies are all cases where the animals are growth hormone signaling deficient through development. So they are very, very small animals, and then they have constitutively low levels of signaling through that pathway for the rest of their life. There's one study that I think it used a monoclonal antibody to the IGF-1 receptor in mice. This is from near Barzoli and the Hasekoan, where they treated mice with this antibody late in life,

and they got, you know, a reasonably sized lifespan extension. I think it was, I don't know, 14, 15% median lifespan. That was an antibody that did not penetrate the CNS, if I recall. I remember near talking about this and saying, you would get all the benefits of IGF in the brain without the benefits of IGF in the, without the potential harm of IGF in the periphery. Another complication, right, where the effects of IGF in the brain might be fundamental on, for health span and cognitive function

might be fundamentally different than high IGF1 in the periphery. So that study I think is the best evidence in mice that you can get some benefit specifically from reducing IGF1 signaling in middle age. And this is such an important question I get asked all the time. I have a lot of patients that are asking to be put on growth hormone.

We just don't do it. The reason is, I just am not comfortable with, I don't see enough data in humans to suggest that it's necessarily safe. Conversely, I don't really see evidence to suggest it's not. This is sort of the weird thing with growth hormone. If you buy hook line and sinker, the argument that more growth hormone equals more IGF equals more mortality, and you look at how much growth hormone is being used. I mean, it is hands down, the most abused drug in sports.

It's first, second, third, nobody's even within the zip code. And this is going back 35, maybe 40 years, probably to the early 80s. Where are the bodies? Yeah. There need to be more bodies. So I'm stuck with, like, I don't see where the bodies are, but at the same time, it's still a bit of a leap for me and I don't have the luxury of rapamycin' data

where I can at least point to all of the humans who have taken rapamycin' for 23 years and we know what that looks like. And then, even though it's not for zero protection, and then all of the mechanistic stuff that is consistently pointing the right way. So there's going to be some patient of mine listening to this saying, Peter, you almost talked me into taking growth hormone based on your discussion. And it's no, I can't. It's funny. I even took it for a week after my

shoulder surgery. I had sort of looked at some literature using GH and anabolic steroids to help with recovery. And it could have been true to you and unrelated, but I felt the worst I've ever felt after a week of growth hormone and andralone, and I was like, yeah, I'm done. Now again, I think it was, I happened to be sick as well, but my blood pressure went up, my blood sugar went up, I felt like crap, I couldn't sleep. Again, a lot of confounding factors, shoulder surgery and a nasty virus. So it could all be irrelevant. So first of all, obviously I've never given growth hormone to anyone, I've never taken

growth hormone, not an expert in the human application of growth hormone, but I've certainly tried to follow that literature because based on the mouse studies, you would have predicted right, the growth hormone therapy should be the most toxic therapy you could give a human. Yeah, certainly should cause increased risk for a bunch of different diseases, including cancer. Mostly cancer.

And my understanding of the literature here is that, like you said, it's not clear that there are significant benefits, particularly for strength. I think there's some evidence that muscle mass may increase, but strength doesn't. But it's also not clear that there's any real detriment, that there's any significant risk, which is a little bit surprising. Yeah, it is surprising.

And I do have a couple of patients who have taken it. Usually other doctors were prescribing it, or they came in under the care of somebody else. And they all seem to claim they feel infinitely better on it. There may be something to that. It might be that in 20 years, we have enough data to say, you know what, by the time you're 60, you should just be on a slow amount of growth hormone for all of these reasons.

I'd love to see somebody do this study because it's a very important question to be asked. And I also think we have enough data to suggest that such a study is not unethical. In other words, we don't have an abundance of data, in fact we have a POSITY of data suggesting it's harm, that it would justify ethically doing a study like this. That's sort of a hope I would have, because I really find this to be one of the most confusing questions in this space.

I agree, and again, this is sort of why I personally have settled around the idea for now at least that IGF1 particularly is probably not that informative in people particularly, you know, once you get past 50 years 50 years as arbitrary, but that's kind of where I would put the number. Obviously, again, IGF1 itself is complicated because you don't really know what that means in terms of IGF1 signaling and downstream activity. Yeah, I'm important, I guess, for people to understand that just like testosterone is mostly bound to sex and combining globulin, there's only a small amount of testosterone that's free. It's the same with IGF1. It has these IGFBPs or binding proteins that bind most of it. And therefore, total IGF is not really completely informative as to what's happening, even in terms of the quantity that's there for signaling, because it's not the unbound

portion of it. So some people look at things like IGF2, IGFBP ratio. The bigger that number is in theory, the more IGF signaling you would have. But this gets to now when you look at the epidemiologic curves, which on the X-axis would show in desiles or quartiles or whatever buckets IGF levels rising, and then on the Y-axis would show you mortality. I've never seen one of those curves that just goes up. Sometimes they're U-shaped, sometimes they're down-sloped, sometimes they're flat, and it depends on the indication, but the story seems much more complicated than IGF is bad.

You know, going back to the bean paper that we were talking about. Again, it's an important paper, it's a well-done paper. You really have to recognize that population you're looking in might make a big difference as well. If you're talking about a population of people where 30% of them are obese, some high percentage have metabolic disease or diabetes, having high IGF1 in that context might be very different than somebody who is

pro-reun sensitive exercising, eating a high protein diet, right? And again, those kinds of things don't typically come out in these epidemiological studies. The other thing I'll say is today, I went and tried to look through the literature and see what other studies have shown that same relationship. And they're all over the place. You can find studies that really don't show protein consumption, particularly. You can find studies epidemiological that really don't show any downside to eating a high protein diet in people. It's hard for me to draw too much confidence

that high protein is significantly detrimental when you're younger than 50. And I feel pretty confident that a higher, at least certainly higher than the RDA, level of dietary protein intake when you're above 50 is beneficial, particularly if you're exercising. I mean, that's where I would be a little bit concerned.

If you've got somebody who's overweight, obese, diabetic, sedentary, so high calorie plus high protein, could be problem at. Totally agree. And by the way, I frankly think a lot of the epidemiology is tainted by that. It's high protein in the context of high calorie. Exactly.

The other thing that I think is also potentially interesting to think about in human are these people who have mutations in the growth hormone pathway. So this is now maybe more akin to these mouse models where they have low growth hormone signaling, you know, from development, even in utero, potentially, they go through their entire lives. Couple of studies. Again, Walter Longo, obviously prolific in this area had a study in a little people of Ecuador, right?

There have been several studies, but the most lorond orbs of... Yeah, that's right, the lorons syndrome. Yeah, the most famous study is one that was published in science where they looked at lifespan and age-related health outcomes in the people with low growth hormone signaling versus controls in their same environment. Yeah, it's a really fascinating study. The interesting things are there's no difference in lifespan, but the people with low levels of growth hormone signaling, the reduction in cancer risk is profound. I don't remember the exact numbers, but I think it was zero. There was one person in their cohort

who developed a cancer. I don't remember what it was, and she was one person in their cohort who developed a cancer, I don't remember what it was, and she was treated, and then she lived the rest of her life. But none of them died from cancer. And the rate of diabetes was lower in the little people, but Ecuador, at least that part of Ecuador at that time, had a very low diabetes rate to begin with,

something 5%. So it's a little bit harder to say, but certainly cancer, dramatic reduction in risk of cancer. So why didn't they live longer? And it's a little bit harder to say, but certainly cancer, dramatic reduction in risk of cancer. So why didn't they live longer? And it's a little bit ambiguous. They don't really say, but you know, they say that there is a higher, much higher rate of alcoholism, liver failure, and accidents. This gets back to the social and psychological consequences in humans that are just different

than we have in mice. The growth hormone deficient mice aren't going to be subject, well, it might be probably not subject to the same social pressures that somebody, you know, has very low growth hormone signaling in people is subjected to, which may contribute to other things later on like alcoholism. So, anyways, fascinating though, biology, which is consistent with the idea, I think, that you can impact, at least a subset of age-related biology by being constitutively low in growth hormone through your entire life. You know, what would happen if you did that in bursts, you know, like post-developmentally

just after puberty, say from your 20s and 30s, who knows, right? We don't have any, there are no naturally occurring examples of that. I don't, or very few that we could look at and actually evaluate. By the way, do we have examples? Is there enough data to look at people with acromegaly during different periods of their life to see if that's had the exact, do we see an higher incidence of cancer? I don't know the answer to that. Those populations would be relatively small, but yeah, maybe.

Maybe it's possible. Yeah, it seems like I'm adding somebody's looked at that, the incidence of cancer and people with adult onset acromagoleal or something to that effect. The other thing I would say on the IGF thing before we leave that is the interplay with insulin. And so high insulin, high IGF, low insulin, low IGF, low low insulin high IGF. I mean, these are very different physiologic states. It's very difficult to think that we're teasing those out when we look at broad swaths.

I think this just comes back to the fact that these, especially these epidemiological studies are a mixture of normal people typically. And so the lifestyles, most people are living are what gets weighted in those types of analyses. And that the lifestyles, most people are living are what gets weighted in those types of analyses. And that may be very different, as we talked about, if you are normal way high protein, maybe high calorie, because you're extremely active, then if you're overweight, sedentary, and eating a calorie diet, I really think that's underappreciated and probably really important. And thinking about the cancer, this is going to be some pure speculation on my part. There's no question, I don't

think that high growth hormone signaling and high IGF1 signaling, everything else being equal in a person leads to a higher risk of developing cancer. You don't. I don't. I think that's true. Oh, you do think that's true. Okay. I believe that that's true. Everything else being equal, of course, everything isn't going to be equal. If we just look at that one variable, signaling through that pathway, higher signaling, higher risk of cancer. If it's the case, which we could make an argument that that doesn't seem to be the case, at least in certain populations of people, that high growth hormone signaling or treating with growth

hormone dramatically increases the cancer incidence. Why is that? Or in people who are... And by the way, we should also differentiate between high causes it versus low removes it. Just because we have a genetic example of where not having it creates a deficiency of cancer. So going from sort of 100 to 30 decreases cancer doesn't mean going from 100 to 30 increases cancer. 100 to 130 increases cancer. That's right. I mean, we don't know.

We could. The word you use there is interesting because you said removes it. No, this isn't what you meant, but this is, I think, something that is also important to appreciate. So to go from pre-initiation of cancer to cancer toastasis, to somebody dying from it. There's steps that have to happen there. And there are different defense mechanisms that act at each of those steps. My guess is growth hormone and IGF-1 is primarily acting at the very early steps where we know

that if you promote cell division, that that is a sort of a permissive early environment for mutations to happen and cancers to get a foothold. In most cases, it seems to be the case that those early cancers are detected and wiped out by our immune system. One of the reasons why I think a lot of cancers become more prevalent as we get older is because the function of the immune system to detecting clear those cancers declines. There's obviously other stuff going on,

accumulation of senescent cells, which contributes to this process. But if you are, say, I shouldn't even say this, because I bother people about the biological clocks, let's just say though, theoretically, you're a 60 year old person, but biologically, because you are exercising, eating an appropriate diet, biologically, you're 40 years old, at least your immune

system is functioning like a 40-year-old. You might have a little bit higher IGF1, you might have a little bit higher of that early cancer risk, but you have a much lower total risk of developing cancer because your immune system has a much better chance of catching it and getting rid of it. And those are things we don't even think about. Well, Matt, I don't know that we settled anything today. Pretty safe to say, we've probably, for the listener, created more questions than answers. No, I'm sure we've done some good. It's a complicated question. And you know, we actually did not dive into the genetic interaction with color restrictions. So I mean, I think the take home there is that even in mice, where we

can control everything else, if you look across genotypes, you get different results from the same diet and the effect of color restriction on lifespan. So maybe we can't answer the big detailed questions. I guess the take homes I would have are we've learned a ton from these nutritional studies in laboratory animals about the biological mechanisms. We've learned a lot about which proteins and pathways are important. And that has led us to things like rapamycin, which might be a more effective intervention in humans. So they have value for that. The other take home that we've talked about is, you don't have to worry about every little

detail. Most people can get a big chunk of the way there by eating a relatively healthy diet. Don't worry so much about how much protein, how much carbs, how much fat, eat good foods. Don't overeat and be active. Exercise. I do worry a little bit that society does this, but scientists do it sometimes too, when we start really getting into the weeds and making recommendations to people that we overthink things a little bit.

Give people anxiety about my eating alone of protein diet or am I on, am I still in ketosis? I got to do my breath monitor every day. Yeah, what should my fasting window be? The questions are out there to what extent do any of these things have big benefits? I think you can get most of the benefits without worrying about a lot of that. Yeah, I agree. Well, Matt, glad we finally got to do one of these in person. Yeah, it's been a pleasure.

Maybe the next one should be in-person as well. Absolutely. Thank you for listening to this week's episode of The Drive. If you're interested in diving deeper into any topics we discuss, we've created a membership program that allows us to bring you more in-depth, exclusive content without relying on paid ads. It's our goal to ensure members get back much more than the price of the subscription. Now, to that end, membership benefits include a bunch of things.

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