Hey everyone, welcome to the drive podcast. I'm your host Peter Atia, this podcast, my website and My Weekly Newsletter, all focus on the goal of translating, the science of longevity into something, accessible for everyone. Our goal is to provide the best content in health and wellness. And we've assembled a great team of analysts to make this happen. If you enjoyed
this podcast, we've created a membership program that brings you far more in-depth content if you want to take your knowledge of the 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 Peter attea, m.com forward, slash subscribe. Now without further delay, here's today's episode, my guest this week is Matt K Berlin, who, of course, is a returning guest. He's been a previous podcast guess that number of times. Most recently joining me on am a 35
In May of 2022. Matt is not only one of our most recurring guest, 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 going to 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 focus the conversation around nutrition as it relates to aging and Longevity. This really came out of a paper that Matt wrote is a
View 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 talked pretty deeply about the literature on caloric restriction. We talked about epigenetic clocks.
Aging and its effect on DNA and sell 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 mtor, you've obviously heard me talk a lot about mtor. We understand that a drug that inhibits mtor namely rapamycin, seems to produce a whole bunch of wonderful effects and yet protein particularly an amino acid called
You seen seem 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
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 podcast, let me just give you a really brief reminder. Matt is a globally recognized leader in a basic biology of Aging. He's a professor of laboratory medicine in pathology and Adjunct professor of genomic sciences and an adjunct, professor of oral Health Sciences at the University of Washington in Seattle, his research interests are focused on the basic mechanisms of Aging in order to facilitate translational interventions that
Promote Health band and provide a healthy way of life. So without further delay, please enjoy my conversation with Matt cable, that'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 talked about so much over email which is to say I don't think a week ago.
By that, we are exchanging an email about some aspect of the relationship or the Inner Space Between nutrition and Longevity. Does that speak to our ignorance? Does that speak to the ubiquity of such content? I don't what does that say about?
It's an area that a lot of people are really interested in and 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
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 will 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 rapamycin, but all sorts of them, right? We recently talked about nmn and our NAD talked about metformin and it's easier almost to ask the questions in the from the standpoint of jira protective 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 rapamycin 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 fake? 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,
Edge and trying to ask that question of your
food, you know, will 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.
Ages 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 the challenging question to address to
Buddy, satisfaction
honestly. Yeah that's actually 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 we're 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, you know, as a 15-year study, right? So it's a great study well by definition.
Initially 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're right 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 slow slowly, the people who are in there,
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.
There's a bit of a Mia culpa 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've you 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
Patient. I'm asking a question. Are you over nourished or undernourished? Are you under muscled or adequately muscled? So that's a 2 by 2 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 dexa, scan 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 and the hardest of those to treat by far is over nutrition under muscled and unfortunately 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 isn't? 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 nutrition.
Rationally 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. I think I'm doing okay for my age with
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 help 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 I 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 know, 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 sir.
On The Fad diet side the diet gurus what they're saying today? How do we know ten 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 Sciences across-the-board, low, quality 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 scientist. 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, 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. Sorry, 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 a 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. 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. And so, I think starting from that big picture perspective, allows you to get most people 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 ten, twenty thirty percent, 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 Ferriss. 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 could be 80 percent proficient in a language in a month. I'm the opposite, I'm the guy who loves the tail, I love the asymptotes, 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
Roi on the exercise front, then eking out incremental value on the nutrition front. I've joked about this before, other guest, 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. Not allowed to be out to a finer points of
nutrition. Yeah, we can talk to Ilan 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 wants 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 two 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 are 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.
Friction 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 all hundred years. Yeah, the first experiments were published in the early to mid 1930s, 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 by-product, 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 percent longer.
So, we're talking really significant increases in lifespan and then the other thing that was appreciated, pretty quickly was not only are their 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 lifespan, but also extending Health span that led to a large body of literature. Since then studying the effect of caloric restriction,
Not just rodents rats and mice, but also all sorts of simpler organisms, invertebrates like fruit flies and c, 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 the 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 messages 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 gonna say before we get to ni a 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.
Or 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 causes atherosclerosis. Now that's true in the United States. It's true across the globe. When you mix in develop an undeveloped it doesn't matter. Vibratory mice aren't that way. They died of
One thing and one thing alone and that is actually at 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 end points where I want a mouse. Reaches that in point, they had 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 atherosclerosis, right? 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 there are. This is maybe getting in the weeds a little bit, but there are certainly Mouse strains that have been designed either transgenic Ali, or through selection to develop other pathologies, that will shorten their life span 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.
It's about 75 80 percent. We
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 caloric, the interpretation of the caloric restriction literature that is. Could it be the case that really, what caloric restriction is doing is preventing cancer and that's why you see these big increases in life span. And I think that's really difficult to definitively answer. One way or the other, what I would say is, my student velop, functional declines in every tissue,
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 my show all of those same declines in function with age and caloric restriction, seems to delay or prevent those declines as well. So yeah, maybe the lifespan effect is primarily due to cancer but caloric restriction is having an effect.
Currently 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, epigenetic 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.
Yeah. It's 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. And 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 aging clock, what they really mean, or 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
Changes in the epigenome with age. And 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 will 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 in owner.
Might want to know their age. So I think that is a real used 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 get, 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 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 in a mouse. Could be in 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
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 measured the epigenetic profiles of those people 10 20, 30 years ago and asked how well does that correlate with mortality outcomes? For example, in the future and they do work.
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 son, Claire. 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 talked, as if changing the epigenome is going to change, everything about aging, we have no data to support that. It just have to say that 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.
You know, eight or nine or ten, 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 an exaggeration at worst an 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 yamanaka factors 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 and an animal in tissues and you can
These reprogramming factors into the cells and turn them on. There are four yamanaka factors for 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,
Actually you get virgin new cells that could differentiate into any cell type in the body. So it's been known for many years. What is relatively more recent over the last eight or nine years? Our people are trying to express these reprogramming factors in an animal do 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 my. So it's called a purge air roid model where they're very short-lived. They're very sick. But these
Programming factors can extend lifespan by remember what the exact numbers are? But a significant amount. Maybe 40, 50 percent well, which seems like a lot except you have recognized 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 Davidson Claire's lab where they use this optic to generation models. So the generation of the I showed that they could reverse that with these reprogramming factors and then tried 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 argue
Generate the optic nerve in an old mouse, so that 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. There are two things so I would be convinced that this is useful potentially therapeutic.
We an important I'm actually already convinced it could be useful therapeutically, and I would become really excited if somebody could do as good as rapamycin in a mouse. So I'm not asking for much in my view. We know. Rapamycin can extend lifespan 25%, at least again. I do 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.
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 her 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 process.
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 this 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 get turned into protein 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 affect expression of the
the jeans. 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. So 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 a
Aging, if you're healthy, your body is generally in homeostasis and what happens as we get older as 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. So you get covid. For example, your immune system works, you're out of a 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 and 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 could 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, it 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.
5, 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?
Well I'm asking. 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
protein. Certainly functions better, I guess what I was
He's getting at though, is that 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 the island, 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 absolute like what else
explains why his collagen so much better than mine? What are the other well factors that
I
rented. 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 be that I have more senescence.
Cells and more senescence. L 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 still complicated. But I think the Crux of the question we started from is if you only fix the epigenome,
do you feel after you fix all these that do you fix
everything? And nobody knows? I think is the fairy answer? I would be shocked if that was the case, that epigenetic changes drive, all of Aging, but it's
Possibly, 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 epigenome. 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 answer
for sure, but let's now talk about something else which is near and dear to
Your heart, no pun 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 slapped off, when you get sick, when you think about your fingernails in your hair, but 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.
Lat. 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 called partial
This should be pretty
dangerous. Well, as I 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 going to 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.
One way to think about it as you restore the homeostatic mechanisms to a more youthful stay where then the homeostatic mechanisms that all of our cells have can basically clean up the rest of the mess 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
he stay 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 aged 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 things true with rapamycin.
Right, I would not argue. We see that short-term treatment with rapamycin. 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 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. And 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 in 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
Just think that's going to be a really hard problem to overcome but, you know, 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 things, problem from the perspective of the scientific, community's 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 is going to get worked out. I can sort of do what I want, because in 10 years, they're going to 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? You know, 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 know, you're the CEO of Matco, I'm the CEO of peat. Co, I can't think of a more important asset within my company, to manage than my own life. Do I have enough money yet? You know, 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, you know, they're overweight or whatever. Like they don't
look healthy. Yeah, and I'm like, guys, you can do both. You can
believe that in 10 years were going to fix this problem, but you could still
We 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. I 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. So, I don't have to worry about this. This is going to 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 reprogrammed, 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, 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 side effects. So I think it's a long road before we have reprogramming strategies that 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 easy.
Your path. But for now I think it's going to take awhile. 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 is still going to be a long road
and I wonder if the first winds are going to be things like what David Sinclair is 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.
Able, but again, I agree with you. I think this stuff takes four times as long and cost 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 rapamycin 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 Senna lytx 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,
Are 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 I. 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 as 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
Odds that you're trying to win a 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 in, 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 will get you most of the way there. So, yeah, I
totally the exercise correctly.
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 Mets times. One hour would be one way to get there, but in reality, no one who's that unfit? Going to do 15 minutes but that would be like three hours a week of five.
Mets to put that in perspective and five Mets 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 Matt hours, but the point is that you can get depending on the study 30 to 50 percent of the benefit. Going from being completely sedentary 215 met hours per week is pretty amazed
which is a big benefit, right? And again, it's sort of remarkable that that information.
Nation isn't out there and 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 per 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 Sea.
Our stuff. So what do we know about? The effect of c are in the laboratory animals on the immune
system? So it's a little bit complicated, first of all laboratory animals and then it laboratory are kept in what's called a specific pathogen free environments. 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, see our animals and they respond better. At least the old animals respond better than age-matched ad libitum fed control. So ad libitum just means it's eat as much as you want. But then for certain types of challenges caloric, restriction, clearly causes a
deficit. Yeah. The sepsis experiments are pretty clear with the CR animals compared to controls. When you induce sepsis in the movie are 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 you'll see this cron cro and right caloric restriction, with optimal nutrition or crayon caloric 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 micro nutrients 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 see are 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
Value, or the specific micro nutrients 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.
Like based on solely on Mouse studies, I get really concerned because of this environmental complexity that humans live in and we haven't 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 see our 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 calorically restricted animals, including measures of Frailty and measures of sarcopenia. The same thing again is true with rapamycin. 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 him tour with rapamycin or caloric restriction, which is a potent inhibitor of mtor, that you would actually see accelerated sarcopenia. And that just isn't the observation in
Tori 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, weight, and the calorically restricted my sway, substantially less than the ad libitum fed mice. Usually, I think it's on the order of 30, 35 percent less,
it's usually grip strength normalized to wait.
Right. So, what you're actually seeing is that the caloric Lee 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 percent 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?
Thing or a bad thing if they lost thirty percent 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 percent of their body weight, presumably their body composition is in 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 thirty percent of your body weight, but it would disproportionately be adipose tissue and you
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 see our 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 intermittent fasting studies where the question sometimes in these studies.
Is, are they isochoric or are they calorically restricted when they're put on intermittent fasting and people will claim their ISO caloric? But the mice lose weight. And what they really are, is, aiso caloric, when normalized body weight, right? So they're really calorically 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.
The weight loss, one driven by a caloric 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 see our group did. Yeah. So you know, 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 is invaluable, but it begs. The question is CR the right tool for longevity. Once you've achieved optimal.
Wait 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 see our impact, longevity positively. We know if you go on CR, you're going to lose weight. So if the answer to that is yes, then by definition optimal weight is lower than what we think, right? Well, I mean humans though, I would say we still don't really know what optimal weight is. So again, this I think just reflects the challenges and coming to definitive answers and the way I think.
About it more. 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 downsize 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
Ugh, 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 NIH, I've read this study a thousand times if I can get the details right one, so 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.
Hurt it. Ran for a couple of decades. Given the lifespan of rhesus monkeys, the Wisconsin animals were fed the controls and the treatment. See, our animals were fed 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 and a half percent of total calories, so, high quality diet.
Facetiously the CR animals. The calorically restrict animals were fed 25% of what the control animals were fed and in that experiment we found a benefit to caloric restriction, the see our animals outlived, the control
animals, and they had fewer age-related diseases. So I think you go back to that original 2009 paper. You know the lifespan effect is compelling and it looks real. But what again is really indicative of that, it might be having an effect on
Beijing, is that they saw reduced rates of cancer. Again, not surprisingly as we talked about in mice but also heart disease and metabolic diseases. 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've 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 diet's 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, you know, sugar in it really. I think it was like about three percent sucrose. It was almost kind of like a vegetarian pescatarian sort of diet. Fish was the dominant source of protein, you know, is a high quality diet relative to the
Content and quality 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 see our animals did not outlive and so while the Wisconsin study was first published in 2009 and it said, CR works, the 2012. Publication for Niña said, CR doesn't work, at least that's the lay press.
Love it. So how do you kind of reconcile? These findings.
One thing to add to that is the niaaa study at Bethesda in their paper. At least, they did show some evidence for improvements in, at least some health spend metrics. So, if you read that paper closely, I think what they're really saying is CR, didn't extend lifespan, but it did have what appear to be, some beneficial effects on health spend metrics. So it wasn't a complete failure in that sense. I mean, I think it's interesting because since then, the remember when the 2011 paper came out
Constant, 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 age, you know, you could make an argument that the Dez de monkeys were somewhat slightly.
Lika largely restricted controls the controls? Yes,
Ari. Yes. The controls at Bethesda 8, less than the controls and 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
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 the came in at older ages started CR at older ages. Maybe got a 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 or experiment. We're never going to find out but 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 rhesus 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
Is that the Wisconsin study to some extent? Probably does mirror. What is closer to a typical American situation? At least these days? I do not believe that they started with that intention, but where we're at today? It probably is relatively close as you can get for a controlled laboratory study. The question though, in my mind is between these two studies. Do they suggest the caloric restriction slows aging when let's just start relative to the typical.
In 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 Rose Anderson who still at Wisconsin has really I think been a leader in this is you can study the molecular signatures of caloric restriction in the monkeys.
Ask does it look similar to the molecular signatures of caloric, restriction, in rodents and you might ask? Well, why would you do, that? 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, rhesus macaques are much closer evolutionarily to people than mice are. So if you see the same molecular changes, it's suggestive that caloric. 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 and mtor 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
Is 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 NIH 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.
NG right? What the Niña 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 and 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 Niña monkeys, which were eating, you know what, we'll call a superior diet to the Wisconsin. Monkeys also a
Last on the Wisconsin monkeys in total. Yep. 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 bodyweight 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 really have a great understanding of even how we
Differ from the rhesus monkeys. So you know I recently read Herman panzers book. I don't have you read it by the way. Now 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 difference is our incredible capacity to store excess energy. So our metabolic rates, you know you documents this through. Lots of Assessments of doubly, labeled water on not just ourselves but
Also hunter-gatherers 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. Yeah. So there's kind of a reason we're at the top of the food chain which is we have 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 Perry pancreatic space into the perinephric space and pericardial space. It's that fat that escapes the normal Depot of Sub-Q 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
Lex as a rhesus 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 change.
Jizz insulin resistance, for example, that you see in
people and do you see it absent? The adiposity, can you see
it - 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 crap. You're 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, develop diabetes.
Yes. I want to say, like a quarter of the controls were pre-diabetic by the end of the study.
Again, which probably speaks to even though they weren't overweight, when you get twenty eight and a half percent of your calories from sugar, it's probably going to impair your
metabolism. The other point that's may be 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 ate
Hundred thousand years 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, and 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 we're not going
to when they should be. Yeah. And 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 overnutrition, it gave us even more flexibility with what we could
eat. Is that maybe part of the reason why human
It seemed to be fairly robust towards eating really really crappy diet. 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
flexibility is going to make a totally different point. That's almost orthogonal to that which is you can make a case that people can survive.
I've in really Remarkable Health with diets that look nothing like one another. And there is, 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 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. 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 that preservatives is dramatically different than it was 50 years ago. Both in caloric content and nutritional content and taste it tastes 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
I think, and that makes it really again, complicated to try to get into the minutiae of what is optimal, maybe we should be thinking about, what's good enough, the first, right? Because I think it's gonna 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 from most people today than it was returned. Another
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, there are 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, we're going to kill themselves, eating ramen, noodles, and crackers, and cookies all day. So you can be vegan and eat pure garbage. You could be keto and eat pure garbage. The second thing I would say is if you're eating those diets. Well, and 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 a 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. Think this is what you're getting. 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.
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 I thought was a great paper and we should discuss it in.
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 him tour. I've been thinking a lot about caloric, restriction, and particularly other nutritional strategies that people have been studying in the
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 of 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 and in vertebrates and C elegans, but we never really have done a lot of dietary interventions in mice before I go into the literature. I had this impression that all of these.
Diets were similar in some ways and had may be 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 caloric restriction, other dietary interventions are very one-sided. They
Really have phrases like fasting is known to have all of these, fantastic benefits, slows aging and every place where it's been looked at, and you can see that for all these different dietary strategies. So I proposed to the editor that, you know, 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? And to the extent possible? Can we gain any insights into whether or not these nutritional strategies? The, whether there's evidence that they have an
On the aging process and 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 appreciate it. Exactly how challenging that was going to, because it's a huge area of literature. And turns out maybe not shockingly, that there are many more questions than 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 do really great early career.
Scientist who really helped me with this and did a lot of the legwork I just want to mention them by name. Please do so Alessandro Beto 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 scientist. So, we started by asking ourselves, okay. What are the different popular dietary interventions that people have?
Named 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 in 65%
of cow or 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,
Flies and worms and 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 I've 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,
And
how did you differentiate those two? I have a definition but I want to make sure yours is
clear. So in mice. Well, so first of all, the first differentiator, we need to put across all of these things, is it isochoric? 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 our flavors of caloric restriction. And what I mean by that is the experimental group, eat less calories than the
sewer, stroheim restricted feeding, but it's really caloric restriction in
Narrower window, intermittent,
caloric, restriction, may be 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, an 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 eats. And there are obviously, you're aware of this. There are flavors of time, restricted feeding and people were 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 needs intermittent fasting. I would put in a 24 hour or more fast, that's a reasonable doubt is
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 it 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 we're 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
Our connection between how much we eat. And when we eat the ties into circadian rhythms and that circadian biology. Even since this review came out, there have been papers that have come out, that re-emphasize 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 going to be significant in terms of the consequences of the long-term health
of our time. Hoping I'm going to remember to come back to that, but let's keep
going. So then there's what people call fasting.
King 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 isochoric, protein
restriction. Also again you really have to look you have to take each paper one by one and figure out is it I see.
Lori core, 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 and ad-lib. Ketogenic diet might end up restricting energy but none
deliberately it'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, and I, so 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
An 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 different.
Is in the window of time. Restricted, feeding for Inhumans, 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%, caloric restriction. That 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 calorically restricted Mouse its 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.
In 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? I don't know,
I really don't feel comfortable even speculating. So the first simplistic approach would be to say, well, I 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?
So that's why I was going to go next. I think that length of life span is not the approach you take when it comes to metabolism. So I
Would say that 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 45-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 done. Yeah,
exactly. It's not a perfect equivalency, but maybe 1245. I hope. I'm not saying something totally stupid here, but I think that's probably pretty close. So, again, it's very different, but
Actually, these kinds of studies in mice. The other thing that I think most people don't appreciate, unless they've actually done these colors. Restriction experiments is that if you go back to the classic experiments of Rick, wind rook and right Walford, those mice are fed. A calorically restricted diet. They're also fed three times a week. So they are in
fact since saying that, it's like 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 nicer being fed three times a week, they're going
Going through this reduction in Oregon size and then this
huge rabbit
hypertrophy. And you can see that decrease in Oregon size and then rapid increase even on some of the fasting mimicking diet work that valter Longo, has done, because 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 see our group are given
80% of that but they're fed at the same time intervals constantly throughout the day. 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 and in my mind I think this is really important because this is one of the points that we made in our review as if you look at the vast majority of
of the literature around, intermittent fasting and time restricted, feeding and fasting mimicking diets, their calorically restricted. So there's a fasting period and a caloric restriction component and none of the prior studies really, really tease 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 fast at that? Still I think is an open question.
What else can we?
Say about early feeding versus late feeding
you mean early in life.
Like no early and day versus later today.
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 going to 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 to spike. The doing that right before you go to bed, probably suboptimal, right? So I think that maybe that can explain most of that observation that has been made that you're going to do a Time restricted feeding might be better earlier in somewhere 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 looking at Sleep Quality, maybe it's going to be different, or maybe it's gonna be different in different people. If you're looking at other biomarkers again, it could be different. So my mind at least baby 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
Whoo. Whoo. We're 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 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
More cortisol. You get a little more hepatic, glucose output, I don't really know if that makes sense. I mean I've heard people argue that but the same time you see a radically 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 have 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 minutiae of 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.
Get up. Let me get 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 their whole variety of reasons for that, but that's
Of where I ended up think they're super useful for understanding the biology. I'm really not sure that they're going to work the same way
in. What did you learn about the protein restriction? In the ketogenic diet mechanistically in the mice,
the ketogenic diet studies. I've really only been to that. I'm aware of that. Looked at life span 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 different
France from people, one of the studies that fed a ketogenic diet, lifelong Saint no effect on life span 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 I've regular diet. Oh interesting. Wow. Yeah.
So that was just back and forth between the control diet. The ketogenic diet
and that didn't result in caloric restriction.
So thing, the mice were calorically restrict is so, it's in some ways. It's a
Permit and caloric 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
Clark 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 percent increase in lifespan. So these are big. Big, wow sizes.
I wasn't aware of that. Yeah, that's this wind reckon Walford paper and when did they start that? And how long did that restriction? Last
second question. I don't remember. It was probably six or nine months, I think most of their studies were early onset. Caloric, restriction. This.
Was it really interesting because they did a graded response from 90% 80% 60% 50% 40% of ad-lib. You get essentially a graded response in lifespan and it's roughly linear.
So 90% animals no
but they didn't go that far. Okay, they didn't go beyond 60 or 65, okay, okay. 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 to. Yeah, this gets back to an element that we don't think about enough.
Which is what are those mice, feel like, like think about how angry those mice would have been on a third of their normal caloric
intake and I haven't done these kind of mouse. Caloric restriction 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 and that's one of the remarkable things about caloric restriction in mice is that they are more active throughout life than ad-lib 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 I'll just run and run and run and run. Yeah, there are behavioral changes. For sure in mice, that are calorically restricted and this is actually one of my real concerns about caloric, restriction and people. First of all, we should be realistic and recognize you're never going to get a significant fraction of the population to calorically restrict. It's hard enough to get people to calorically restrict down to a healthy weight to get.
Them to go thirty percent 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 caloric restriction has real psychological consequences and I really would be concerned. My have been concerned for some of the people I know who've done this if we started trying to do this and the General Public,
There's social isolation that you get when you're calorically 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, my sites hard to know what their psychological consequences are. What do we
know about caloric? Restriction, later in life in the mice versus earlier? This 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 Niña 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 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 passed, 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 sometime
Pre-development the early rat studies were pre development, and then sometimes, you know, 69 months of age, when I first started in the field, that's kind of what I was told. Like this is a settled question, more recent studies that have been done in some ways more carefully different diets. Certainly, if you do a graded on set of caloric restriction, in other words, don't go right from ad-lib to 40% of restriction. The next day you do sort of a graded on set, 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 answer's. No, you 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 mad on this topic of crn, my
Again, the Dogma is generally been, and I've been victim of this just blindly assuming it to be the case that CR in mice, only works early in life. How applicable is that to humans? I don't know, but I listened to the podcast actually pointed out that in fact, there are some data that try to get at this question. They're just Hans study 2019, which will 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 a ad libitum diet. And then
At three months, they were split. Randomized to believe a 40%. Yeah, calorie restriction versus ad-lib. They ran that out, until 24 months. And then each of those groups was further split ad-lib versus continued on. So you had one group that was everybody's the same two or 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 you're looking at the figure earlier today, 1200 days. Roughly maximum lifespan. Yeah, maximum lifespan. That's right. Median. Lifespan would have been looking at the graph about 900 days which is pretty good. Yeah, it was going to say, how does that stack up with what we talked about in the last podcast about length of like a
reasonable life span for control? I think, if I remember correctly, this was also done, not in c57 Black 6, but in a little bit longer lived, hybrid stress right now, F1 hybrid, so it's reasonable
life.
Spin. Okay. Looking at the all CR, all day mice, looks like they had a maximum life span of just below colored 1400 and change with a median that I'm going to say was about 1150. Good life span extender. Okay. So now what's interesting is the middle groups which is really try. So, I'm going to give you my little iPad. So you can look at that table which will link to this guy right here. You got it right
here. Remember the
take-home you do. Okay. Yeah. So what happened to the two middle
groups? One thing I would say is I think this is a pretty early onset of.
And this 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 caloric restriction, late in life or what this study did and I'm not really aware of anybody doing previously is kind of the flips, almost like a crossover. Just, 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.
Starting late in life that seems to be the consensus. The thing that's really interesting here is, you know, what happens if your CR to for an earlier period in life and then back on a l, 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 CR late in life. You could ask some questions about. Is it about the total amount of your life that you're restricted is 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 ones that were on CR and then switch to ad libitum. Yes. That's right. They lived a little bit longer
but the bigger difference was the median life expectancy was higher then the
flip. Yes. Although I think we have a little bit difference in definitions. I tend to think first about median. You seem 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. The muesli
difference. The maximum is very
trivial, that's right. The real question here is well, aside from what is 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 MTAR and rapamycin. So with rapamycin, the data are pretty clear that you can start rapamycin certainly well into middle age and maybe even at a very old age and get most of the benefits. So, if you compare the curve here, where they started the mice on CR, 22, or 24 months, whatever it is, the effect is pretty small compared to see our with rapamycin. You get almost exactly the same benefit starting at
20 22, 24 months, as you do, starting early in life. So that might tell us that there's a difference right there, clearly is a different
mechanism potentially, as well. It could be the rationale you in 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, my favorite story, and he study one of my
Berries inside. Yeah, yeah, tell people that story.
So, take a step back, the Niña started. This program called the interventions testing program must have been the early 90s and the idea here was made was early 2000s. Sorry, dating myself again, losing my decade 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 intervention is selected, then the intervention testing program sites. Start the cohorts of mice on that intervention, you know, and whatever your it was selected for. So sometime, back in the early 2000s, Dave Sharpe nominated rapamycin, some ways he was ahead of his time because I think, when he nominated rapamycin, it was even before.
The first invertebrate studies on mtor and rapamycin is 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 rapamycin, 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 rapamycin was one of them, Randy strong, who's one of the
The pi is on the height. EP was 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 because this is relevant for people as well so and it gets broken down in the pH of the guy. 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 recognize that right when they were supposed to start the experiment and you know of course they were like crap, what do we do? We could just not test rapamycin.
And I don't know if those Randy or who somebody said, well, I think I can figure out a way to stabilize the rapamycin, put it in the food so that we can give it to the mice 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 e-wrap an encapsulated rapamycin, it's basically designed so that it won't break down and the gastric pH once they develop that they were now 18 months into this life span experiment before this, I think everybody myself included.
The field thought 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 rapamycin 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
Come obviously. Because first of all, nobody thought it was gonna work except maybe Rich Miller. I'll get rich credit, maybe he thought it was gonna work and it was really the first time. Anybody had convincingly shown that you could start a intervention
prevention and not even
drunk middle-aged in a mouse and get robust lifespan 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 geroscience because you might be able to intervene late in the age.
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're going to make a point about the bioavailability
around this
Is something that's only recently come across my radar but I've heard several results now that convinced me that it's true. So you know I mentioned the reason why they had to make this e-wrap as because rapamycin isn't stable at the gastric pH of mice. The same thing seems to be true and people. So there are people who are getting their rapamycin from the rap immune, which is the brand name, generic or the brand name. Sarah, Limas 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 then in the actual rape of a
triangle, the white and yellow
triangle. 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 we honest with you? We've never had it compounded. So, we've only prescribed Sorella must or wrapping me. And, you know, it's not a cheap drug. So, I can understand why there's a desire to compound it, because it's, it's got to be like five, six bucks, a milligram. Yeah, I think that's about, right. That's very interesting, you know?
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 back 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 my wife. That's the only part of nutrition that is kind of, I don't know. 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, their 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
Consumed 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, there's 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 though it's sort of
normalized to it. They and the reason why I bring this up as 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 may be a lot of areas, so I think that's just worth expanding on.
Just I sort of jokingly think of the RDA for protein as what you need to not waste away and with
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 is 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 that the mouse studies. I think there it's pretty clear that you can extend lifespan through protein restriction and there are actually a couple of flavors
urza protein restriction, you can restrict all protein down to some percentage, some low percentage, or you can restrict specific amino acids, particularly Ranch contains tryptophan methionine or branched 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
None of em tour. 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 branched-chain amino acids can directly activate mtor, through sestra ins. And that's sort of all worked out.
Out. And so it seems intuitive the protein. Restriction would be beneficial by turning down mtor. It seems counterintuitive that what you were just talking about. Would be beneficial because you might be hyper activating a so we can dive into that. That's the simplest possible mechanism. I can think of for why protein restriction, especially branched-chain amino acid, restriction would be having an impact on the Life, Span 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 mtor reduction of igf-1. So that seems to be required for the lifespan extension, that is seen from protein, restriction in mice, potentially partially Upstream of them tour and and liver metabolism. The interesting thing there is fgf21 overexpression by itself.
Elf has also been reported to be sufficient, to extend lifespan in 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. Be less eat the same amount and eat more. And it's interesting because you can actually find examples of all of those can 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 tryptophan 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.
A branched chain amino acid and with Ian, Ian restriction studies are pretty clear that those animals are consuming more calories than certainly, if you match to wait, then the ad libitum mice and they're living longer.
And what do we think is the router mechanism through, which Matheny and exerts this
effect that's still really being worked out. There are lots of mechanisms 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, they're
Back to the epigenome that we talked about with Ian, Ian 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 of
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 the literature in the invertebrate in division of protein synthesis in some cases,
Is 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. Is 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 mtor is being activated in response to that set of
You know 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, branch chain amino acids during a workout because you want as much anabolic signal as possible. And this 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 from getting his name. Right? Was it? Bobby Sutton was guy who did that science paper that looked at the leucine sensor right 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 mtor that. Unless you had an intravenous drip of this stuff, it was going to be very difficult so much. So that the idea of using BCAA analogues, to treat sarcopenia was going to require drug
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 acids are metabolites, right there involved in many different, metabolic reactions within certain levels, and there are all sorts of mechanisms to ensure that if and metabolites gets outside of that range that we
I soaked 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 branched-chain, amino acids far, outside the normal range. What I would say though, is that slightly elevated branched chain? Amino acids? Chronically can have big effects on the downstream processes and there are some in borne diseases of childhood. Where you have elevated levels of branched chain amino acids. We know that there are consequences to even having somewhat modest
Increases in mtor. So hyper activation of mtor signaling chronically. So again, I think the context really matters, but yes, it's my intuition, that that is probably hard to get very large persistent increases in mtor. Simply from taking Anna Branch chain amino acid supplement. 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.
If I mean, the total anabolic data suggests, it's not necessary it
Just getting muscle protein synthesis. Window is open long enough that simply delivering a great source of whey 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 am targets turned on or how low it gets turned down. It's also about where that happens people for a long.
I am 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 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 were maybe more to do with where mtor is being affected. Then how much were inhibiting M4 when were inhibiting mtor? And so I think the same things 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, m4m for signaling in the context of rapamycin.
It's a very technically challenging problem,
well, and this is why I 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 eight has, if anything as big maybe, bigger effect on mtor signaling than rapid mice.
They're 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
gets 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 rapamycin?
It 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 wrap em tour 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
Three work where they basically looked at different compositions of carbohydrates, fats and
proteins Australia? Yeah, exactly.
And you know looked at, I don't remember how many diets 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 ask 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 diet's were the mice live, the longest word.
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 restrict it.
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 interrelationships of these macro nutrients in the diet with enough sophistication to get Beyond sort of 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, know, that that's true, but
it's my intuition, well, as well, because clinically what we see in what I call the
Sparse the deaf 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 under muscled are insane and it ranges from the metabolic consequences of being under muscled, 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 homeostasis 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
To consider the entire population that they know over the age of 75 and I would ask you to take every person that is alive today. There'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 percent of people. Over the age of 75 are experiencing this and if you look at the activity just
At 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 ones 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
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. Just like, that's my view. I mean, I think that's
absolutely correct. I guess the question, 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 going to 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
Has the double RDA standard, and it's a significant difference. Yeah, 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 just I'm going to say something that's going to be wrong and 20 people are going to still 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
Back to the point I kind of started with which is the you can find the answer you want for almost any question in this area that intersects it nutrition and aging there will be a study that will fit your belief. So I think you really have to be careful or I try at least to take a global view and try to understand what is the totality of the data say, 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, the valter longo
I
think the senior author on and 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 and I think they add 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 for you. Want to be alive? Yeah, 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 cause mortality and above 65. You saw that reverse that's
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 nonlinearly. 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, 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
Aim impact on mortality early in life. I think the question here is what are the relative effect? They did model this a little bit and it is in their model. I couldn't get the data. 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 in order of magnitude greater than the relative impact of
the. So I'm sorry to say what they're finding was again at the age of
6. 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 50s. 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.
To find low, what you define High
you know there and you're trying to ask the question. When should you switch the
diet or maybe more formally at what age does the risk equal
out? What's the crossover? Yeah. And what did you find? So mine was closer to like 50. Yep. 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 serving God to me, because whether it's 50 or 60, Matt, it's a benefit on mortality, which is really weird.
Are 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 related. Why, why can't there be a better late in life? I'm saying why not?
Well, I'm saying, like if your protein restricted,
late-in-life a low protein has no benefit on house band. 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
tourist. 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
Rapamycin experiments where everybody who knew anything about muscle said that if you gave a mouse rapamycin 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. Would 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.
Our Nuance here that could complicate things but I think in general you're probably I think the
other area where this gets very complicated is the I want to say by necessity, but just by convention, we use igf-1 as a biomarker for protein intake. It certainly associate with the protein intake but you want to tell people, what igf-1 is, where it comes from and what it's a proxy for so.
Igf-1 insulin-like growth factor-1 a hormone that's in the growth hormone pathway so you can take 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 igf-1 levels and high mtor, this is a part of the mtor pathway as well, Upstream of mtor. 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. And so the most famous and one of the first genes that was shown to clearly from
A mechanistic perspective affect aging is it comes from work, Cynthia, Kenyon, and even Tom Johnson a little bit before her, which is the insulin-like receptor in C, elegans called deaf too. And Cynthia, published a classic paper showing that if you make a mutation in daf-2, 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 little bit more complicated and worms because it's called the insulin igf-1 like signaling pathway so it's not
A nickel, 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 there are
so this means g h does not activate the production of more igf-1. That's right.
So, you have through a variety of
equity. GH, low igf-1
animal. Well, low GHC
Signaling but they probably are hidin times.
It's the receptor that's mutated. That's right. So those animals tend to be very long-lived, a rival caloric restriction, in terms of the magnitude of lifespan extension and there are several different mutations in that pathway the mutations. In igf-1, 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 igf-1 itself and the effects on lifespan.
I'm not going to wade into that because I think it still hasn't been resolved, but there's no question that mutations that reduce growth hormone signaling in mice. Extend 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 constitutive lie, 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 barzillai and hasi Cohen, 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 percent median lifespan.
That was an antibody. That did not penetrate the CNS. If I recall, think 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, but without the hotel,
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 must be fundamentally different than high igf-1 in the periphery. So, that study I think is the best evidence in mice that you can get some benefit specifically from reducing igf-1 signaling in middle age. 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
I'm not comfortable with 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 a weird thing with growth hormone. Like 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
Back 35. Maybe 40 years probably to the early 80s
where are the bodies. Yeah,
there need to be more body. 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 gyro protection and then all of the mechanistic stuff that is
Stanley 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. 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 g h and anabolic steroids to help with recovery and it could have been true, true an unrelated but I felt the worst I've ever felt after a week of growth hormone and nandrolone and I was like I'm done now again, I think it was a happened.
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 that growth hormone therapy,
should it be very most toxic therapy? You could give a
human. Yeah.
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. 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 it is surprising. And I do have a couple of patients who have taken it. Usually other doctors were prescribing it or you know,
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, but 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
it's of data. In fact, we have a paucity of data, suggesting its 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 igf-1, particularly is probably not that informative in people. Particularly, you know, once you get past 50 years, 50 years at arbitrary but that's kind of where I would put the number.
Obviously, again, igf-1 itself is complicated because you don't really know what that means in terms of igf-1 signaling and downstream activity. But important, I guess
for people to understand that just like testosterone is mostly bound to sex hormone-binding globulin. There's only a small amount of testosterone that's free. It's the same with igf-1, it has these. I gfb PS or binding proteins that bind most of it. And therefore total igf is not really completely informative as to what's happening. Even
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 I GF B p-- ratio, the bigger that number is in theory, the more igf signaling you would have but you know, this gets to now when you look at sort of the epidemiologic curves which on the x-axis would show in, you know, deciles or quartiles or whatever buckets by GF levels rising and then on the y-axis would show you mortality. I've never seen
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 dean 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 igf-1. In that context might be very different than somebody who
is free on radiative
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 for protein. Consumption particular 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 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.
CERN, if you've got somebody who's overweight, obese diabetic sedentary, so high calorie plus high. Protein could be
problematic, but we 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 Caliber
exactly. The other thing that I think is also potentially interesting to think about inhuman 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.
On signaling, you know, from development, even in utero, potentially they go through their entire lives, a couple of studies again, valter Longo, obviously prolific in this area had a study and little people of Ecuador. Right there have been several studies but the
most more on dwarfs.
Oh, yeah. That's right. The LaRon 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 environment. Yeah,
it's a really fascinating study. The interesting things are, there's no difference in life span, but the people with low levels of growth hormone. Signaling, the reduction in cancer risk is or found, I don't remember the exact numbers, but I think it was Zero. There was one person in their cohort, who developed a Cancer and remember what it was and she was treated. And then she left the rest of her life, but none of them died from cancer and the rate of diabetes was low or in the little people, but Ecuador, at least that part of
That time had a very low diabetes rate to begin with something 5%. So it 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
Like 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 anyway, 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 constitutive lie low in growth hormone through your entire life. You know, what would happen if you did that in bursts, you know?
Post developmentally just after puberty say, in your 20s and 30s, who knows, right? We don't have any there are no naturally occurring examples of that I do are very few that we could look at and actually evaluate. By the way, do we have
examples? But there are enough data to look at people with acromegaly during different periods of their life to see if that's had the exact top. We seen a 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 imagined somebody's looked at that the incidence of cancer in people with adult-onset acromegaly 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 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
Are a mixture of normal, people typically. And so the lifestyles, most people are living are, what gets waited in those types of analyses, and that may be very different as we talked about, if you are normal way high, protein may be 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 at this is going to be some pure speculation on my part.
And there's no question. I don't think that high growth hormone signaling and high igf-1 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, but if we just look at that one variable signaling through that pathway higher signaling higher risk of cancer. So then if it's the case, which we could make an argument that that doesn't seem to be the case,
Least in certain populations of people that high growth hormone signaling or treating with growth hormone dramatically increases the cancer. Incidence, so why is that orange 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, we're not having it creates a deficiency of cancer. So going from sort of a hundred 230 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, and
could the word you use? There is interesting, as you said removes, it know, 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 to metastasis to you know, somebody dying from it. There's steps that have to happen there and there are different defense mechanisms that acted 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 detect and clear. Those cancers declines. There's obviously other stuff going on accumulation of snow
Essence 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 a appropriate diet biologically, you're 40 years old. At least your immune system is functioning like a forty-year-old. You might have a little bit higher. Igf-1, you might have a little bit higher of that early cancerous, 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. Now 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 caloric restriction. 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 caloric, restriction, on life's.
Man, so maybe we can't answer the big detailed questions. 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
I still in ketosis. I got to do my breath monitor. Every you know, 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 that's been flavored 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.
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